[Senate Report 105-43]
[From the U.S. Government Publishing Office]
Calendar No. 105
105th Congress Report
SENATE
1st Session 105-43
_______________________________________________________________________
FOOD AND DRUG ADMINISTRATION MODERNIZATION AND ACCOUNTABILITY ACT OF
1997
_______
July 1, 1997.--Ordered to be printed
Filed, under authority of the order of the Senate of June 27, 1997
_______________________________________________________________________
Mr. Jeffords, from the Committee on Labor and Human Resources,
submitted the following
R E P O R T
together with
ADDITIONAL AND MINORITY VIEWS
[To accompany S. 830]
The Committee on Labor and Human Resources, to which was
referred the bill (S. 830) to amend the Federal Food, Drug, and
Cosmetic Act and the Public Health Service Act to improve the
regulation of food, drugs, and biological products, and for
other purposes, having considered the same, reports favorably
thereon with an amendment in the nature of a substitute and
recommends that the bill (as amended) do pass.
CONTENTS
Page
I. Purpose and summary..............................................2
II. Background and need for the legislation..........................6
III. Legislative history and votes in committee......................11
IV. Explanation of the legislation and committee views..............15
V. Cost estimate...................................................69
VI. Regulatory impact statement.....................................74
VII. Section-by-section analysis.....................................75
VIII.Additional views...............................................101
IX. Minority views.................................................107
X. Changes in existing law........................................113
I. Purpose and Summary
Under the Federal Food, Drug, and Cosmetic Act (FFDCA), the
Food and Drug Administration (FDA) has two important functions:
(1) the review and approval of important new products that can
improve the public health, such as lifesaving drugs, biological
products, and medical devices; and (2) the prevention of harm
to the public from marketed products that are unsafe or
ineffective. Since 1938, the Federal Food, Drug, and Cosmetic
Act has been amended numerous times to strengthen the FDA's
function of ensuring that unsafe or ineffective products are
not marketed but has been changed only once, by the
Prescription Drug User Fee Act of 1992 (PDUFA), to strengthen
the FDA's function of reviewing and approving important new
products that can improve the public health.
The Food and Drug Administration Modernization and
Accountability Act of 1997, S. 830, is designed to ensure the
timely availability of safe and effective new products that
will benefit the public and to ensure that our Nation continues
to lead the world in new product innovation and development.
The legislation accomplishes three major objectives: it builds
upon recent administrative reforms that both streamline FDA's
procedures and strengthen the agency's ability to accomplish
its mandate in an era of limited Federal resources; it requires
a greater degree of accountability from the agency in how it
pursues its mandate; and it provides for the reauthorization of
PDUFA.
The FDA acknowledges that its mandate requires it to
regulate over one-third of our Nation's products. Within its
purview the FDA regulates nearly all of the food and all of the
cosmetics, medical devices and drugs made available to our
citizens. This legislation identifies areas where improvements
can be made that will strengthen the agency's ability to
approve safe and effective products more expeditiously. It
builds upon the numerous investigations by Congress, the FDA,
the General Accounting Office (GAO), and other organizations
that have identified problems with the current FDA product
approval system and have recommended reasonable reforms to
streamline and strengthen that system. It includes the
following major provisions:
1. the legislation establishes a clearly defined, balanced mission for
the fda
Congress has never established a mission statement for the
FDA. The FDA in March of 1993 adopted a formal statement
declaring that the agency ``is a team of dedicated
professionals working to protect and promote the health of the
American people.'' Although this statement defines the agency's
mission in terms of ensuring that the products it regulates
comply with the law, there is no reference to the importance of
approving new products that benefit the public. The legislation
amends the Food Drug and Cosmetic Act by adding an agency
mission statement focused on: (1) protecting the public health
by ensuring that the products it regulates meet the appropriate
FDA regulatory standards, (2) promptly and efficiently
reviewing clinical research and taking appropriate action on
the marketing of regulated products in a manner which does not
unduly impede innovation or product availability, and, (3)
participating with other countries to reduce regulatory
burdens, harmonize regulatory requirements, and achieve
appropriate reciprocal arrangements with other countries.
2. the legislation improves patient access to needed therapies and
provides expedited humanitarian access to medical devices
The FDA has no crosscutting program that ensures access by
patients with serious or life-threatening diseases to drugs or
devices in clinical trials--even when that unapproved therapy
may be the only way to save the patient's life. The legislation
would create new law whereby manufacturers may provide, under
strictly controlled circumstances and in response to a patients
request, an investigational product for those patients needing
treatment for a serious or life-threatening disease. The
legislation also improves the existing program for the
humanitarian use of medical devices for patient populations of
fewer than 4,000.
3. the legislation creates new incentives for determining better
pharmaceuticals for children
Children have for years been wrongly considered ``small
adults'' when estimating the effect of prescription drugs on
their overall health. Currently there is no systematic means
for testing the safety and efficacy of drugs on the pediatric
population. The legislation gives the Secretary authority to
request pediatric clinical trials for new drug applications and
provides 6 extra months of market exclusivity to drugs when the
manufacturer voluntarily meet certain conditions under the
program. The Secretary must determine in writing that
information relating to the use of a drug in the pediatric
population is needed. In addition, the FDA may establish time
frames for completing such pediatric studies before additional
exclusivity is granted.
4. the legislation gives patients access to new therapies more quickly
through a new ``fast-track'' drug approval process
For several years the FDA has allowed the expedited review
and approval of drugs but such review has been largely confined
to treatments for HIV/AIDS or cancer. This provision
facilitates development and expedites approval of new drugs for
the treatment of any serious or life-threatening diseases.
5. the legislation increases access to information by health
professionals and patients
For years, sophisticated users of health related economic
information, like health maintenance organizations, have been
constrained from access to important information that could
help them reduce health-care costs. The legislation would apply
the Federal Trade Commission's ``competent and reliable
scientific evidence'' standard for FDA review of health care
economic statements distributed by manufacturers to
sophisticated purchasers. In the past, only a few patient
groups have had access to information about ongoing clinical
trials for lifesaving therapies. The legislation expands
patient access to information by requiring the creation of
databases on ongoing research related to the treatment,
detection, and prevention of serious or life-threatening
diseases.
6. the legislation increases agency access to expertise and resources
Current law contains no provisions to assure that the FDA
can access expertise housed at the National Institutes of
Health (NIH) and other science-based Federal agencies to
enhance the scientific and technical expertise available to
FDA's product reviewers. The legislation requires FDA to
develop programs and policies to foster such collaboration. The
legislation also authorizes the agency to contract with outside
experts to review all or parts of applications when it will add
to the timeliness or quality of a product review, and provides
for the use of accredited outside organizations for the review
of medical devices.
7. the legislation improves the certainty and clarity of rules
The legislation makes a series of changes related to the
classification, review and approval of FDA regulated products
designed to ensure that sponsors of new products face
consistent and equitable regulatory requirements. In addition,
the legislation gives FDA 2 years to evaluate the success of
its recently issued ``Good Guidance Practices'' guidance after
which FDA is required to implement this policy as a regulation,
making any modifications necessary to reflect experience during
the 2-year trial period.
The legislation provides medical device manufacturers with
the ability to make recommendations to the FDA respecting
initial product classifications. It facilitates the
reclassification and/or approval of device applications by
allowing FDA to consider historical data in making its
determinations, and the legislation more clearly states the
relationship of labeling claims to approval and clearance of
medical devices. It increases the certainty of review time
frames by providing a definition of a day with respect to the
agency's ``review time clock'' and by requiring the agency to
approve or disapprove a device application within 180 days.
The legislation also prohibits FDA from withholding the
initial classification of a device because of a failure to
comply with any provision of the unrelated to making a
determination of substantial equivalence, and it clarifies that
FDA has discretion in determining the number of clinical trials
required for the approval of a drug or device. FDA would retain
total discretion to require a sufficient number of trials to
show safety and efficacy. The provision introduces the concept
that two trials are not always necessary, establishes the
primacy of quality data over quantity of data, and requires the
FDA to consider the number and type of trials on a product-by-
product basis.
8. the legislation improves agency accountability and provides for
better resource allocation by setting priorities
Except as required under PDUFA, the FFDCA provides no form
of public accountability by the FDA for its performance of its
statutory obligations. The legislation requires FDA to develop
a plan designed to: (1) minimize deaths and injuries suffered
by persons who may use products regulated by the FDA; (2)
maximize the clarity and availability of information about the
product review process; (3) implement all inspection and post-
market monitoring provisions of the Act by 1999; (4) ensure
access to the scientific and technical expertise necessary to
properly review products; (5) establish a schedule to bring the
FDA into compliance by 1999 with the product review times in
the Act for products submitted after the date of enactment of
this section; and (6) eliminate the backlog of products
awaiting final action by the year 2000. The legislation also
requires FDA to submit an annual report to assist Congress in
assessing the agency's performance in accomplishing the
objectives laid out in the agency plan.
The legislation streamlines several FDA functions with
respect to certain review and inspection processes thus
allowing the agency to focus its limited resources on areas of
greatest need. The legislation provides FDA with the discretion
to approve drugs and biologics on the basis of products
manufactured in pilot and small-scale facilities. FDA is also
directed to establish policies to facilitate the approval of
supplemental applications for new uses for an approved product.
Further, the legislation establishes procedures and policies to
foster a collaborative review process between the agency and
the sponsors of medical device applications. Finally, the
legislation streamlines the review of minor modifications to
medical devices.
9. the legislation simplifies the approval process for indirect food
contact substances and provides a more reasonable standard for some
health claims
Current law requires the agency to preapprove food contact
substances, most of which pose little if any risk to human
health. The legislation replaces the preapproval process for
these substances (primarily packaging materials) with a simple
notification requirement. The legislation also provides for
health claims for foods, with premarket notification, when the
claims are based on authoritative recommendations by an
authoritative scientific body of the U.S. Government such as
the National Institutes of Health, the Centers for Disease
Control and Prevention, or the National Academy of Sciences.
10. the legislation reauthorizes the pdufa program thus ensuring
additional resource availability for the agency
PDUFA is reauthorized for 5 years. Performance goals beyond
those set for the 1992 Act will be identified in side letters
between the FDA and the Senate Committee on Labor and Human
Resources. The bill assumes that FDA will receive for fiscal
year 1998 the 1997 level of appropriated funds for the agency.
For fiscal years 1999 through 2002, the bill assumes an annual
inflation adjustment.
II. Background and Need for the Legislation
a. background
Over the years, Congress has dramatically expanded the
reach and responsibilities of the FDA. The Federal Food and
Drugs Act of 1906, the first national statute enacted by
Congress to regulate the American food and drug supply, gave
the Agency the authority to police the market and remove
adulterated or misbranded foods and drugs.
In 1938, Congress passed the Federal Food, Drug, and
Cosmetic Act, which expanded the agency's reach to the
regulation of cosmetics and medical devices and, for the first
time, provided the agency with the authority to review and
assure the safety of a product--new drugs--prior to the
marketing of that product. The 1938 statute required sponsors
of new drugs to file a new drug application notifying the FDA
prior to marketing a new human or animal drug. The new drug
application became effective after 60 days (which could be
extended to 180 days), unless the Agency found that it had
insufficient information to determine whether the drug was safe
for its intended use.
In the ensuing years, Congress enacted a series of statutes
further expanding the FDA's regulatory reach. These included
the 1944 Pitts Act, which gave the FDA the authority to
regulate biological products, and the Miller Pesticide
Amendments of 1954, which required FDA premarket approval for
pesticides in or on raw or processed foods. The Food Additive
Amendment of 1958 required premarket approval of food
additives, and the Color Additive Amendments of 1960 required
premarket approval of color additives in food, drugs, and
cosmetics. The Drug Amendments of 1968 consolidated the
premarket approval requirements for new animal drugs and feed
additives. The Medical Device Amendments of 1976 created a
device ranging from the most simple to the most complex and
premarket approval for new medical devices, and the Safe
Medical Devices Act of 1990 codified FDA's premarket
notification program and increased the agency's postmarket
enforcement capabilities.
From 1906 to the present, then, the FDA's role has expanded
from one of removing adulterated or misbranded products from
the market to one of preapproving the testing and marketing of
products.
b. need for the legislation
Over the years, and particularly with the enactment of
requirements that the FDA determine that drugs and devices are
effective as well as safe, the FDA's requirements for clinical
testing and its premarket reviews of new products have grown
increasingly complex, time-consuming, and costly. From the
1960's to the 1990's, for example, the time required to
complete clinical trials for new drugs has grown from 2.5 to
nearly 6 years. Applications for the approval of new drugs
typically run to hundreds of thousands of pages in length.
According to a recently published study, from the beginning of
the process to the end, it takes an average of 15 years and
costs in the range of $500 million dollars to bring a new drug
to market. [DiMasi, Trends in Drug Development, Costs, Times,
and Risks, 29 Drug Information Journal 375, 382, April-June
1995.]
By law, the FDA is required to review and act on
applications for the approval of new drugs and devices within
180 days. According to the FDA's own budget justification for
fiscal year 1998, it takes the agency an average of 12 months
longer than the statute allows for the agency to review new
drugs and three and one-half months longer than the statute
allows for premarket approval (PMA) devices. And the agency in
its budget submission to Congress for FY 1998 projects that the
backlog for devices is projected to increase by 17 percent from
this year to next.
These increases in the time, complexity, and cost of
bringing new products to market are borne directly by the
public, in delayed access to important new products--including
life-saving medical therapies--and in higher costs. They are a
growing disincentive to continued investment in the development
of innovative new products and a growing incentive for American
companies to move research, development, and production abroad,
threatening our Nation's continued world leadership in new
product development, costing American jobs, and further
delaying the public's access to important new products.
Over the past 20 years, a bipartisan consensus has emerged
on the need for reforms of the FDA premarket approval process
to strike a better balance between the need to ensure that
products are safe and effective, on the one hand, and to
facilitate the timely availability of new products, on the
other.
During 1978 and 1979, Congress considered a wholesale
revision of the new drug approval process. This committee led
that effort, reporting legislation introduced by Senator
Kennedy, the Drug Regulation Reform Act of 1979. That
legislation was subsequently approved by the Senate but was not
considered by the House of Representatives. A number of the
provisions in that legislation are reflected in S. 830,
including provisions to permit new drug sponsors to obtain
advice from the agency regarding their investigational plans;
to require the FDA to issue written guidelines regarding
protocols and methods for conducting drug investigations; and
to require the FDA to take measures to ensure that reviews are
conducted efficiently and expeditiously.
Many of these same changes were recommended by the
Commission on the Federal Drug Approval Process, convened at
the request of then-Representative Albert Gore, Jr., chairman
of the House Subcommittee on Investigations and Oversight and
then-Representative James Scheuer, chairman of the House
Subcommittee on Natural Resources, Agricultural Research and
Environment. The Commission's 1982 report recommended such
changes as simplification of the investigational new drug
requirements; recognition that drug effectiveness could be
demonstrated by one study in appropriate cases; greater
utilization of outside expert advice; improving interactions
with industry; tracking the review process to ensure
timeliness; simplified procedures for the use of
investigational drugs for therapeutic purposes; greater
reliance upon expert judgment in determining the safety and
effectiveness of drugs; concurrent review of portions of new
drug applications by FDA; and greater reliance on foreign
studies. Some of the Commission's recommendations are
incorporated in S. 830.
In 1988, concern about the slow process for the development
and approval of AIDS and cancer drugs led to the establishment,
under the auspices of the President's Cancer Panel, of a
National Committee to Review Current Procedures for Approval of
New Drugs for Cancer and AIDS. The committee's final report,
issued in 1990, recommended a national policy to foster the
development of new drugs for AIDS and cancer; expediting
approval of important new drugs; greater use of scientific
judgment of qualified experts in determining the effectiveness
of new drugs; the use of surrogate end points to establish drug
effectiveness; a more open relationship between the FDA and the
regulated industry in order to foster a spirit of mutual
cooperation; responsiveness to the needs of patient advocacy
groups; a fundamental restructuring of the FDA advisory
committee system; more flexible use of investigational drugs
for treatment; the right of patients to obtain investigational
drugs under expanded access conditions; greater use by the FDA
of outside review of new drug applications; and automatic
approval of supplemental new drug applications for minor
technical changes such as manufacturing modifications. Again,
many of these recommendations are incorporated in S. 830.
In 1989, in response to serious questions that were being
raised about the ability of the FDA to perform its job,
Secretary of Health and Human Services, Dr. Louis Sullivan,
chartered the Advisory Committee on the Food and Drug
Administration. The committee was chaired by Dr. Charles
Edwards, a former FDA commissioner. Dr. David Kessler served on
the committee until his appointment as FDA commissioner. The
charter directed the committee to examine the mission,
responsibilities, and structure of the FDA and to make
recommendations for improving the agency's operations.
One of the major findings of the committee was the need for
the FDA to set forth a clear statement of its mission and goals
and a plan for achieving the goals. In formulating a statement
of purpose and program goals, the committee found that--
* * * the agency should be guided by the principle
that expeditious approval of useful and safe new
products enhances the health of the American people.
Approving such products can be as important as
preventing the marketing of harmful or ineffective
products. This is especially true for people with life-
threatening illnesses and for diseases for which
alternative therapies have not been approved.
This key recommendation underlies the legislation's Mission
Statement and many of the provisions found in S. 830.
In 1991, The Council on Competitiveness, chaired by Vice
President Dan Quayle, announced an important administration
initiative to improve the FDA's drug approval process. The
initiative was designed to achieve three overarching goals by
1994--a substantial reduction in the average development and
approval time for all new drugs; a reduction in FDA approval
time for important new drugs to 6 months; and a reduction in
FDA approval time to 12 months for all other drugs.
The Council on Competitiveness also recommended a number of
specific reforms, including expanded use of outside reviews;
expanded use of advisory committees; flexible interpretation of
the efficacy standard; accelerated approval through a reduction
in the number of clinical studies required prior to approval
and the amount of time FDA requires to grant approval,
including reliance on surrogate endpoints; enhanced
computerization to track applications and expedite review; and
enhanced internal management, including the measurement of
progress in application review against statutory deadlines.
Many of these recommendations are incorporated in S. 830.
Most recently, Vice President Gore has pressed for reform
of the FDA product approval system as part of President
Clinton's Reinventing Government initiative. The President and
Vice President have issued six reports, covering drugs and
medical devices, drugs made from biotechnology, food, and
cancer drugs, animal drugs, and human tissue. The
administrative reforms and recommendations in these reports are
designed to improve the product approval system, eliminate
outmoded regulations, and update the Federal Food, Drug, and
Cosmetic Act to reflect advances in the science of new product
development and testing. Many of the recommendations in these
reports are incorporated in S. 830.
During the 104th Congress, the committee held four hearings
on reforming the FDA. The witnesses--several of whom had served
on these advisory panels--testified about the same problems
that have been described in the reports summarized above and
recommended many of the same solutions. As a result of those
hearings the committee last year reported legislation with
strong bipartisan support, S. 1477, that would have
incorporated many of the recommendations discussed above. In
addition, during the 104th Congress, action was taken to better
acknowledge the global marketplace and facilitate United States
manufacturer's ability to get medical products to doctors and
patients overseas through passage of the Food and Drug Export
Reforms contained in P.L. 104-134.
Most recently, this committee has continued the effort to
modernize and bring greater accountability to the FDA. The
committee held two hearings in early 1997. During the first the
committee received testimony from the lead FDA Deputy
Commissioner, Dr. Michael Friedman, and all of the FDA Center
Directors. The second hearing included representatives from
patient and consumer coalitions and from the food, drug, and
medical device sectors regulated by the FDA.
The committee learned from the administrative reforms and
the progress it has already undertaken, areas that remain a
challenge, and those areas that require legislative authority
to change.
The committee listened to consumers' concerns about
provisions that were considered last year that they felt would
weaken the FDA's ability to protect the public health. Finally,
the committee learned of the ongoing and needless delays and
frustrations facing the health care and consumer product
sectors of our economy in working with the FDA. The committee
learned of the frustrated attempts to work through the
bureaucratic maze of needless regulatory delays--delays that
prohibited people from getting access to vitally needed, life
saving medical treatments, drugs and devices.
Every administration in the past 20 years has recognized
the need for modernizing the FDA's product approval system to
bring into better balance the need to ensure the safety and
effectiveness of products and the need to facilitate the
development, testing, and timely approval of safe and effective
products that benefit the public. Until recently, the FDA has
been very slow to respond, or has not responded at all, to
recommendations for reform made by the distinguished advisory
panels that have been convened over the years.
America's pharmaceutical, biotech, medical device, and food
industries are among our most innovative, dynamic, and
productive. They contribute significantly to our Nation's high
standard of health care and to our unparalleled supply of
wholesome, abundant, and affordable food. They hold the promise
of further breakthroughs in life-saving and enhancing therapies
to combat the diseases and disabling conditions afflicting us
today and those which may emerge in the future. They hold the
promise of new food technologies that will enhance diets and
improve health, provide natural resistance to pests, droughts,
and other plagues, and help meet the nutritional needs of a
growing world population. They are job-creating industries that
contribute positively to our balance of trade.
Formidable challenges must be met, however, if these
opportunities are to be realized and America is to continue to
lead the world in product innovation. Domestically, our health
care system is rapidly reorganizing, consolidating, and moving
into managed care, with potentially profound effects on the
market for products and the revenues necessary for continued
research and product development. International markets are
becoming increasingly competitive, particularly as the European
Union moves to adopt a uniform drug and device approval system.
If we are to confront these challenges and realized the
opportunities on today's and tomorrow's horizons, we cannot
afford an overly complex, bureaucratic, time-consuming, and
expensive regulatory system. Nor can we afford an adversarial
relationship between the FDA and the industries it regulates or
an agency pursuing so many agendas that it lacks a clear-cut
mission and sphere of responsibility. We must update our food
and drug laws and our regulatory practices to reflect the
scientific and technological advances that have occurred in the
development and testing of new products and to ensure that the
FDA is an agency committed to fostering innovation and ensuring
timely public access to beneficial new products.
It is no easy task that Americans ask FDA to perform.
Americans want it to hold the gate to the market tightly shut
against unsafe or ineffective products while opening it wide
for the next generation of innovation--with all of its
potential promise, but not without its risks. Clear statutory
guidance is needed to assist the Agency to find this delicate
balance and to bring our food and drug laws and regulatory
systems into the next century. The FDA Modernization and
Accountability Act of 1997, S. 830, embodies many of the
bipartisan conclusions and recommendations reached by the
expert panels for accomplishing this difficult task of
balancing risk and promise.
III. Legislative History and Votes in Committee
``The Food and Drug Administration Modernization and
Accountability Act of 1997,'' S. 830, was introduced by Senator
Jeffords on June 5, 1997. Prior to the drafting of the
legislation, the committee held 2 days of hearings: on March 19
and April 11, 1997, entitled ``Addressing the FDA's
Performance, Efficiency, and Use of Resources.'' These hearings
examined the challenges and opportunities facing our Nation's
pharmaceutical, biotech, medical device, and food industries
and ways that the FDA's regulation of these industries might
need to be reformed to ensure that these challenges are met and
opportunities realized.
On June 11 and 18, 1997, the committee held executive
sessions to consider S. 830. Senator Jeffords offered an
amendment in the nature of a substitute that was considered as
original text for purposes of further amendment. Thirteen
additional amendments were considered in the executive sessions
and the substitute as amended was adopted on a roll call vote
of 14 yeas to 4 nays. S. 830, as amended, was approved by voice
vote.
A. Amendments and Motions Adopted by Voice Vote During Executive
Sessions
Six amendments were adopted in the executive sessions by
voice vote and one amendment was adopted by unanimous consent.
1. Senator Kennedy offered an amendment to section 609 to
clarify key definitions of radiopharmaceuticals. The bill
provided that the Secretary shall, within 18 months after
enactment of this Act, promulgate regulations that shall
provide that the determination of the safety and effectiveness
of a radiopharmaceutical shall include, but not be limited to,
consideration of the proposed use of the radiopharmaceutical in
the practice of medicine, the pharmacological and toxicological
activity of the pharmaceutical (including any carrier or ligand
component of the radiopharmaceutical), and the estimated
absorbed radiation dose of the radiopharmaceutical. These
standards were further clarified by Senator Kennedy's
amendment.
2. Senator Kennedy offered an amendment to section 613
which provides for the expedited approval of certain drugs
intended for the treatment of serious or life-threatening
conditions. The amendment provides that approval of drugs under
this ``fast track'' process may be subject to a requirement
that the sponsor submit copies of all promotional materials
related to the fast track drug during the preapproval review
period and, following approval, at least 30 days prior to
dissemination of the materials for such period of time as the
Secretary deems appropriate. In addition, the amendment
clarifies the conditions under which incomplete applications
may be accepted for filing review, establishes expedited
procedures for the withdrawal of approval of a fast track drug,
and, provides that within 1 year after enactment of this Act
the Secretary shall issue guidance describing the policies and
procedures related to fast track drugs.
3. Senator Dodd offered an amendment to the Public Health
Service Act that would establish, under a new section 807, a
one-stop shopping information service for individuals with
serious or life-threatening diseases.
4. Senator Jeffords offered an amendment to modify a series
of amendments that had been filed June 11 for which further
agreement had been reached.
5. Senator Kennedy offered an amendment to strike section
611 of S. 830 relating to supplemental applications for the
approval of new uses of approved drugs and devices and replace
that section with alternative provisions to improve the FDA's
supplemental application review process.
6. Senator Hutchinson offered an amendment to authorize and
clarify provisions related to the pharmacy compounding of
drugs.
7. Senator Gregg offered an amendment related to health
claims for food products that was accepted by unanimous consent
as a modification of the health claims language included in S.
830. The provision extends from 90 to 120 the number of days a
person would be required to submit to the Secretary a notice of
the health claim prior to first introduction of the health
claim into interstate commerce. The amendment also clarifies
that false and misleading claims are prohibited under section
403(a) of the Act, and that ``significant scientific
agreement'' is required as the basis for a health claim, as
required by section 403(r)(3)(B) of the Act. In addition, the
amendment clarifies that the Secretary may undertake rulemaking
to stop the use of a claim, or go to court in an enforcement
proceeding, at any point in time.
B. RollCall Votes Taken During The Executive Sessions
Six rollcall votes on amendments were taken during the
executive session:
1. Senator Kennedy offered an amendment to strike the
provisions related to health claims for food products. The
amendment was defeated by a rollcall vote of 5 yeas to 13 nays.
Yeas Nays
Kennedy
Bingaman
Wellstone
Murray
Reed Jeffords
Coats
Gregg
Frist
DeWine
Enzi
Hutchinson
Collins
Warner
McConnell
Dodd
Harkin
Mikulski
2. Senator Gregg offered an amendment to prohibit State and
local governments from establishing or continuing any
requirement relating to the regulation of nonprescription drugs
or cosmetics which is different from, or in addition to, or
otherwise not identical with Federal requirements. The
amendment permits States to apply to the Secretary for an
exemption from the prohibition and propose a requirement which
is justified by protecting an important public interest that
would otherwise be unprotected, that would not cause the
nonprescription drug or cosmetic to be in violation of any
applicable requirement or prohibition under Federal law, and
that would not unduly burden interstate commerce. The amendment
was adopted on a rollcall vote of 15 yeas to 3 nays.
Yeas Nays
Jeffords
Coats
Gregg
Frist
Enzi
Hutchinson
Collins
Warner
McConnell
Dodd
Harkin
Mikulski
Bingaman
Wellstone
Reed DeWine
Kennedy
Murray
3. Senator Kennedy offered an amendment to provide the FDA
with authority to level civil monetary penalties for failure of
a company to perform post-approval research. The amendment was
defeated by a rollcall vote of 6 yeas to 12 nays.
Yeas Nays
Kennedy
Wellstone
Bingaman
Murray
Reed Jeffords
Coats
Gregg
Frist
DeWine
Enzi
Hutchinson
Collins
Warner
McConnell
Dodd
Harkin
Mikulski
4. Senator Harkin offered an amendment to the provision
pertaining to the review of medical device applications by
organizations accredited by the FDA. Senator Harkin's amendment
would have required the Secretary to check for conflicts of
interest and review the terms of compensation between the
accredited party reviewer and the manufacturer of the product
to be reviewed. Prior to the roll call vote, Senator Harkin
modified his amendment by clarifying that the Secretary would
have the authority to review the terms of the compensation, but
not be required to do so. The amendment was defeated on a
rollcall vote of 8 yeas to 10 nays.
Yeas Nays
Kennedy
Dodd
Harkin
Mikulski
Bingaman
Wellstone
Murray
Reed Jeffords
Coats
Gregg
Frist
DeWine
Enzi
Hutchinson
Collins
Warner
McConnell
5. Senator Harkin offered an amendment to: (1) limit scope
of reviews of medical devices by organizations accredited by
the FDA to devices for which the agency has not required
clinical data, (2) limit the scope to devices for which the
agency has prepared vertical standards or guidance documents,
and (3) reduce by half the number of devices required to be
eligible for the pilot. The amendment was defeated by a
rollcall vote of 6 yeas to 12 nays.
Yeas Nays
Kennedy
Harkin
Bingaman
Wellstone
Murray
Reed Jeffords
Coats
Gregg
Frist
DeWine
Enzi
Hutchinson
Collins
Warner
McConnell
Dodd
Mikulski
6. Senator Jeffords offered the substitute as amended by
the committee and it was passed on a rollcall vote of 14 yeas
to 4 nays.
Yeas Nays
Jeffords
Coats
Gregg
Frist
DeWine
Enzi
Hutchinson
Collins
Warner
McConnell
Dodd
Mikulski
Wellstone
Murray Kennedy
Harkin
Bingaman
Reed
C. FOUR AMENDMENTS OFFERED AND SUBSEQUENTLY WITHDRAWN
1. Senator McConnell offered and then withdrew two
amendments related to food labeling.
2. Senator Gregg offered and then withdrew an amendment to
modify the drug fees provision.
3. Senator Harkin offered and then withdrew an amendment to
permit an individual to be treated by a health care
practitioner with any method of medical treatment such an
individual requests.
IV. Explanation of the Legislation and Committee Views
TITLE I--IMPROVING PATIENT ACCESS
Mission
The first title of S. 830 establishes in statute that the
mission of the FDA is to protect the public health by ensuring
that foods are safe, wholesome, and sanitary; human and
veterinary drugs are safe and effective; there is a reasonable
assurance of safety and effectiveness of devices intended for
human use; cosmetics are safe and properly labeled; and the
public health and safety are protected from electronic product
radiation. In addition, the FDA shall promptly and efficiently
review clinical research and take appropriate action on the
marketing of regulated products in a manner that does not
unduly impede innovation or product availability. The FDA shall
participate with other countries to reduce the burden of
regulation, to harmonize regulatory requirements, and to
achieve appropriate reciprocal arrangements.
The committee concurs with the view of the Advisory
Committee on Food and Drug Administration (discussed above)
that ``the agency should be guided by the principle that
expeditious approval of useful and safe new products enhances
the health of the American people. Approving such products can
be as important as preventing the marketing of harmful or
ineffective products.''
From the 1906 Food and Drugs Act through the 1990 Safe
Medical Devices Act, food and drug law has emphasized that the
duty of the FDA is to protect the public against unsafe or
ineffective products. The purpose of this legislation, as
reflected in the mission statement, is to continue protection
of the public against unsafe or ineffective products while
providing a better balance in the law by ensuring timely access
to safe and effective products.
Expanded access to investigational therapies
For many years, the need for patients to have access to
unapproved therapies went unrecognized under the Federal Food,
Drug and Cosmetic Act. The FDA established informal policies
relating to compassionate use of investigational products
shortly affer enactment of the 1938 Act, but these policies
remained informal and outside FDA regulations.
Recently the FDA has established programs some of which are
embodied in regulation, to make investigational drugs and
devices available to patient with serious and life-threatening
conditions and to patients in emergency situations. Most (but
not all) such programs have resulted in access to promising new
investigational and experimental therapies for HIV/AIDS and
cancer. The committee commends the FDA for adopting these
needed programs but the committee wishes to provide statutory
direction to expanded access programs and emphasize that
opportunities to participate in expanded access programs are
available to every individual with a life-threatening or
seriously debilitating illness for which there is not an
effective, approved therapy.
The legislation establishes in statute that any person,
acting through a licensed physician, may request access to an
unapproved investigational drug or device, and that any
manufacturer or distributor may provide that unapproved
product, if it is for the diagnosis, monitoring, or treatment
of a serious disease or condition, an immediately life-
threatening or seriously debilitating disease or condition, or
any other disease or condition designated by the FDA as
appropriate for expanded access. The Secretary is given
oversight over key aspects of this process to ensure that there
is sufficient evidence of safety and efficacy to support the
use of the investigational drug or device outside of a clinical
trial. Further, the Secretary must determine that expanded
access will not interfere with the adequate enrollment of
patients into clinical trials for the testing of the drug or
device.
The physician must determine that a patient has no
comparable or satisfactory alternative and that the risk from
the investigational product is not greater than the risk from
the disease. An exemption for the investigational drug or
device must be in effect under the FFDCA. The manufacturer must
be pursuing marketing approval with due diligence. A
manufacturer or distributor may decline to make an
investigational product available under such a program.
Consistent with the desire of the committee to help ensure
that patients with serious conditions and no realistic
alternative treatment shave available to them investigational
products that may offer some promise of help, the legislation
requires the Commissioner to inform the medical profession and
such groups as voluntary health associations about the
availability of investigational products for expanded access
use. Too often, patients and their physicians are unaware that
new drugs and devices are under investigation and are available
for expanded use pending review by the FDA. This provision will
help to ensure that all patients will have equal knowledge of
and access to investigational products.
The committee emphasizes that it has purposely used broad
language in this section relating to ``serious'' conditions,
without attempting to define them, in order to permit wide
flexibility in implementation. Illnesses that do not cause
death can nonetheless destroy the lives of both patients and
their families. The committee therefore intends that the
seriousness of an illness be given broad consideration, to take
into account all of the circumstances involved.
Expanded humanitarian use of devices
The Safe Medical Devices Act of 1990 included a new
provision authorizing the use of devices for humanitarian
purposes for small populations of targeted patients for whom
products are not generally available to treat or cure a
condition or disease. This provision permits device approval
based on specified safety criteria and exempts effectiveness
showings from approval requirements. The provision required the
Secretary to issue implementing regulations within 1 year.
However, final regulations were not promulgated until June of
1996 and only became effective in October of that year--almost
7 years after the provision became law.
The regulations currently provide for a 45-day designation
period and a 180-day review period to show safety (compared
with the 30-day period now required to show safety under an
investigational device exemption (IDE) and the 180-day period
required under a PMA to show safety and effectiveness). The
legislation would provide for a 60-day period to review the
safety showing. This period is greater than that required for a
response to an investigational device exemption application,
which requires a finding that a device is sufficiently safe for
use in humans, but less than the 180-day period required for a
showing of safety and effectiveness under a premarket approval
application.
The statute currently requires an institutional review
board (IRB) to approve use of the product before the product
may be used. However, because some IRB's typically meet
infrequently a patient is at risk of harm or death if the IRB
is unable to consider a physician's request. This proposal
would permit a physician to approve use of the product where
the patient would suffer harm or death waiting for the approval
if the physician in good faith is unable to secure IRB
consideration but later notifies the IRB.
Finally, current law requires the company to reprove its
exemption every 18 months even if there is no basis for
doubting the status of the exemption. Further, the program
automatically expires after 5 years. This proposal would
require the company to reprove its exemption when the Secretary
has cause for requiring such showing; and no longer requires a
sunset of the program.
Title II--Increasing Access to Expertise and Resources
Interagency collaboration and FDA facility consolidation
The legislation requires the Secretary to implement
programs and policies that will foster collaboration between
the FDA, the National Institutes of Health, and other science-
based Federal agencies to enhance the scientific expertise
available to the Commissioner for the evaluation of emerging
medical therapies, including complementary therapies, and
advances in nutrition and food science.
The committee includes this provision to help ensure that
the FDA has available to it the expertise and assistance it may
need to enhance its own capacity for the efficient evaluation
of applications for the approval of products that pose
substantial new scientific or technical issues.
The committee strongly supports the consolidation of FDA
facilities at White Oak, MD, as proposed by the FDA in
consultation with the General Services Administration (GSA).
The consolidation of FDA's facilities into state-of-the-art
laboratory space and supporting office space has great
significance not only to the FDA, but to the Nation as a whole.
FDA laboratories and facilities are now scattered among 50
buildings at 20 locations in the Washington, DC, metropolitan
area. Many of these facilities are old, poorly maintained, and
do not meet accepted standards for laboratory research. These
antiquated facilities and fragmentation of agency programs have
proven burdensome in many ways. The cost of leasing space for
FDA and the difficulty in managing programs that are so widely
scattered in the Washington area is a tremendous burden for the
FDA. The FDA cannot do its job if it does not have the tools it
needs to accomplish its mission. The committee believes that
providing the FDA with consolidated, modern, state-of-the-art
facilities will enable the FDA to do its job faster and more
efficiently, benefiting the taxpayer and the consumer.
Sense of the committee regarding mutual recognition agreements and
global harmonization efforts
The U.S. Government has long been involved in negotiation--
an effort being spearheaded by the U.S. Trade Representative
(USTR)--with representatives of the European Union (EU)
Commission to achieve a mutual recognition agreement (MRA). The
overall MRA, being directed by Under Secretary for
International Trade Stuart Eizenstat and USTR Deputy Trade
Representative Jeffrey Lang, has been estimated by the
Department of Commerce as a possible savings to United States
businesses of $100 million annually. The Commerce Department
has also stated that this MRA will expedite $40 billion in
transatlantic trade each year between the United States and the
15-nation EU by eliminating trade barriers. The Department of
Commerce and the USTR expect this agreement to provide
especially strong benefits to the U.S. telecommunications
industry, the U.S. medical device industry, and the U.S.
pharmaceutical industry.
Only recently have we gotten good news that an important
portion of the MRA which involves the mutual recognition of
inspection reports for good manufacturing practices (GMP) for
medical device and pharmaceutical products, and medical device
review standards may be close to an agreement. It is important
to recognize these efforts for what they are: these agreements
would not make GMP inspection or product review necessarily
uniform but would allow equivalent regulatory bodies to conduct
a single review or inspection that would satisfy all of the
criteria for all of the countries concerned, instead of
conducting multiple inspections, often at great costs. The
committee intends and specifically instructs the FDA to promote
and protect the health of the American public in implementing
the MRA. The MRA should not place U.S. consumers of drugs and
devices at risk, nor adversely affect the quality, quantity, or
variety of drugs available to the American public.
This MRA also will lay a flagstone in the path being built
toward harmonization activities on things like increased
reliance on international standards, an effort the Food and
Drug Administration and professional groups are already engaged
in with their foreign counterparts. This is an especially
important effort in light of the extent to which our
marketplace has become globalized.
There was agreement by President Clinton and his European
counterparts at last December's U.S.-EU Summit meeting that
this MRA represents a critical point that has taken a number of
yearsto reach. The United States was recently urged by
President Santer of the European Commission to achieve a successful
conclusion of these negotiations, and the committee is pleased to see
that the excellent effort coordinated by USTR is close to having
positive results.
The committee looks forward to seeing more global
partnership in the form of a quality mutual recognition
agreement that compliments both our high public health and
safety standards in the United States and appropriate
international regulatory controls. As noted by Commerce
Secretary Richard Daley, ``Under this landmark agreement U.S.
regulatory agencies for the first time have entered into a
cooperative international agreement that strives to reduce
regulatory costs while at the same time seeks to expand market
access and protect the health and safety of consumers on both
sides of the Atlantic.''
Contracts for expert review
For many years, the FDA has contracted with outside
individuals and organizations to review part or all of product
applications or Agency decisions respecting the safety and
effectiveness of marketed products. The FDA contracted with the
National Academy of Sciences (NAS) to review the effectiveness
of all new drugs for which new drug applications were made
effective during 1938-62 and with the Federation of American
Societies for Experimental Biology (FASEB) to review the safety
of all food substances that the Agency had earlier determined
to be generally recognized as safe for their intended use in
food. The FDA has contracted with individual experts to review
aspects of new drug applications and recently contracted with
the Mitre Corporation (now incorporated as Mitretek
Corporation) to review supplements to new drug applications.
Finally, the FDA has developed a pilot program for third-party
review of class I and class II medical device submissions, a
step beyond traditional Agency contracting out activities.
There are sound reasons for using outside individuals and
organizations to review, evaluate, and make conclusions and
recommendations to the FDA with respect to applications
submitted to the FDA. In some instances, individuals outside
the FDA have unique expertise not available to the agency. In
other instances, the FDA's internal resources are inadequate to
handle surges in the workload. In still other instances,
internal FDA resources must be focused on priority matters and
cannot be diverted to more routine matters that become
backlogged. The FDA has in the past used outside individuals
and organizations for these reasons.
The legislation explicitly authorizes the FDA to contract
with outside individuals and organizations with expertise in
relevant disciplines to review, evaluate, and make conclusions
and recommendations to the FDA on any form of submission made
to the agency. Under this legislation, the FDA retains full
authority to make any determinations with respect to the
classification, approval, or disapproval of any product. Thus,
although outside experts will assist and advise the FDA, they
cannot commit or make any final decision for the agency. Final
action must be a function solely within the power of the FDA.
However, the FDA is advised not to arbitrarily or
systematically disregard the recommendations of the reviewers
it has accredited and qualified or to redo without cause the
work completed by such reviewers.
The legislation requires the FDA to use its authority to
use outside experts under contract (on a basis other than a
``pilot'' or ``demonstration'' basis) whenever the Secretary
determines that doing so will improve the timeliness or quality
of the review of an application or submission. It is the intent
of the committee that improvements to application or submission
review may include providing the Secretary with increased
scientific or technical expertise necessary to review or
evaluate new therapies or technologies. It is not the intent of
the committee that the FDA be compelled to use an outside
expert when the timeliness of a review would be improved yet
the quality of that review would unduly suffer or vice versa.
Rater, the FDA should wisely and rationally use this authority
as a tool to manage an increasing workload in an era of flat or
declining resources available to the Federal government, and
bring to bear outside expertise when it is helpful.
Accredited party reviews
In recent years, the FDA has consumed substantially more
and more time for the review of medical devices than in past
years. For example, FDA's average review time for premarket
notificationclassifications has increased in the years 1990 to
1996 by well over 100 percent (from 82 days to 178 days for a total
review time; from 66 days to 137 days for time in the FDA's hands)
while the number of applications has generally held steady. In
addition, premarket approval times have increased (from 348 to 773
total days, 247 to 606 days in FDA's hands) on average, while
submissions in the same 6 year period dropped from 84 to 43 (almost in
half). By statute, premarket notification classifications are expected
within 90 days and premarket approvals must be granted or denied within
180 days.
Although the agency represents that review times for
devices have dropped recently, the agency's current budget
justification confirms continued cause for concern. Even given
a net resource increase of almost 4 percent, the agency
anticipates a 17 percent increase in the backlog of pending PMA
applications and a decline in timeliness of final actions on
510(k) premarket notification submissions--from 59 percent
within 90 days to only 40 percent. Again, this is in the
context of declining numbers of 510(k) submissions and
virtually steady PMA applications.
This delay is in part a consequence of the agency's
difficulty in maintaining the technological expertise and
capability necessary to review applications within the
statutory timeframe. Also contributing to this delay is the
FDA's management of its resources. The FDA has regularly made
this committee and others aware of its desire to have more
resources in order to address its inability to review products
within the statutory time frame. In past years, Congress has
responded with increasing appropriations. However, as resources
available to the Federal Government have tightened, the agency
and Congress have been pressed to find alternative sources of
revenue.
In August 1996, the agency responded by establishing a
``third party'' pilot program to review a very limited number
of device submissions. For reasons discussed below, that pilot
has not been useful in providing alternative revenue sources or
in gauging the effectiveness of ``third party'' review. As a
result, the committee decided to expand the agency's pilot
program to better supplement FDA resources with fees paid by a
product sponsor directly to FDA-accredited reviewers and to
supplement FDA expertise with that of other public and private
parties. Ultimately, the committee believes that this expansion
will reduce delays in medical device reviews and improve the
technical sophistication of those reviews.
The legislation provides that accredited individuals and
organizations with relevant expertise will, at the option of a
product sponsor, be used to provide recommendations to the FDA
regarding premarket notifications and premarket approval
applications. The FDA will then review those recommendations
and make a final decision with respect to classification or
approval or disapproval of the premarket approval application.
The provision maintains a strong, continued role for the
FDA in the device approval process. For example, the FDA alone
accredits the pool of qualified private parties to conduct the
reviews and selects from that pool two or more accredited
parties from whom the product sponsor may select. Although a
product sponsor has the option to select an accredited party,
it does so only from a list pre-selected and accredited by the
FDA, thus limiting if not eliminating potential ``forum
shopping'' as it does in its current pilot. The FDA also
establishes rules protecting the confidentiality and the
proprietary nature of information contained in the review. The
FDA promulgates the rules to prevent conflict of interest. The
FDA has authority to ensure compliance by the accrediting party
and has the ability to withdraw or suspend accreditation of
parties not in compliance. In short, the FDA will have all
necessary control over the individuals and organizations
eligible for selection.
The FDA's role is not limited to accredited-party
selection. In addition, the Agency retains all of the authority
it has under current law to make final product review
decisions. This legislation does not authorize any other person
or organization outside the agency to make such a final
decision. The FDA will have no less than 30 days (of the 90
days allotted under the statute) to review a submission under
section 510(k) and 60 days (of 180 days under statute) to
review a premarket approval application. Again, the agency is
not bound by an accredited party's determination--there is no
presumption given to the accredited party's recommendation of
approvability or classification of a product.
The provision expands the types of device submissions that
may be considered under the current agency pilot program.
Thecurrent program is open to nonexempt class I devices and a limited
number (approximately 30 at this time) of class II devices. However,
because of the limited scope of the pilot fewer than 10 submissions
have been considered under the pilot in the initial 10 months of its
planned 24-month existence. S. 830 would permit any 510(k) device into
the program with several exceptions: specifically, devices that are
life-supporting, life-sustaining, or intended for implantation for a
period of over 1 year. However, the agency retains discretion to allow
these devices to be reviewed by a third party.
As a supplement to the resources available to the FDA, the
product sponsor will directly contract with and pay the
accredited party at the sponsor's own expense. This mechanism
is similar to that proposed by the FDA in its own pilot project
at the Center for Devices and Radiological Health. As with the
current pilot, the agency retains the ability to review
invoices and fee schedules, and, if the agency has cause to
believe that a party is engaged in forum shopping or if the
submission presents some form of conflict of interest, the
agency may review the terms of compensation prior to a
particular review. The committee is aware that the Agency does
not consider it a worthwhile or reasonable use of resources
generally to preapprove or prereview compensation agreements.
The agency's current pilot is clearly not sufficient to
permit meaningfully evaluation of a program incorporating
accredited-party reviewers. In large part, this is a result of
the agency's insistence that no product be reviewed without a
vertical standard or guidance document. While for some reviews
this may be useful, for most reviews the committee believes
that the agency has unwisely consumed resources in developing
documents that its own employees have not been required to use
for their own product reviews. In addition, the agency has
accredited parties that it has certified as capable of
preforming reviews, yet only allows them to do little more than
follow a cookbook recipe for approval; and again, the agency
does not subject its own reviewers to these constraints.
Ultimately, through this policy, the agency has unreasonably
constrained the scope of the pilot and rendered the pilot
virtually without utility. Accordingly, the committee directs
the agency, under the expanded pilot program, not to continue
this practice except in the limited cases where it is essential
to protect the public health. The expansion established under
this provision will be subject to independent study within 5
years of the agency's establishing an expanded pilot program
with sufficient eligible products or within 4 years of the
agency's expanding the program so that 35 percent of products
are actually reviewed under the program. A full analysis of the
strengths and weaknesses of the program will be conducted and
provided to Congress and the public, enabling Congress to
extend, modify, or discontinue the program at that time.
Device performance standards
Long before the enactment of the Medical Device Amendments
of 1976, voluntary standards-setting organization in the United
States and abroad have established performance standards for
categories and characteristics related to medical device
products. These organizations include the American National
Standards Institute (ANSI), the International Standards
Organization (ISO), and the International Electrotechnical
Commission (IEC), as well as others. Although standards from
these organizations are recognized as authoritative, and are
therefore followed throughout the world, the FDA has failed to
establish any policy regarding their recognition and use under
the Federal Food, Drug, and Cosmetic Act in this country. This
legislation remedies that problem
The legislation gives the FDA authority to recognize all or
portions of appropriate medical device performance standards
developed by organizations such as ANSI, ISO, IEC, and any
other standards-setting organization. It is the intent of the
committee that FDA can reduce the amount of effort required on
its part to assess product applications and submissions which
show conformity with a standard, recognized by FDA, as the
basis for all or part of a product application or submission.
The legislation establishes procedures for recognition by
the agency of these standards, grants express authority to FDA
to subsequently withdraw a recognized standard, and clearly
establishes the FDA's authority to assure that devices that
purport or are represented to be in conformance with a standard
in fact meet the requirements of the standard identified with
the device.
It is important that all medical device performance
standards recognized by the FDA under this new procedure be
publicly listed, so that any interested person will know the
regulatory status of the standard. Accordingly, the legislation
requires FDA to public in the Federal Register the name of all
standards to which recognition has been given. Any standard not
on the published list would not be accepted as recognized by
the FDA under this provision.
Other provisions in the Federal Food, Drug, and Cosmetic
Act authorize FDA to promulgate performance standards for
medical devices using the procedures set forth in the law. This
legislation does not in any way change the authority of FDA to
promulgate such standards, which may differ from the standards
established by certified organizations and recognized under
this new provision.
The FDA may not require conformity with any recognized
standard as a condition for approving or classifying any type
of medical device premarket submission if the submitter
demonstrates with information other than that required by a
recognized standard that the device is substantially equivalent
to a legally marketed predicate device or otherwise provides
reasonable assurance of safety and effectiveness.
Importantly, reliance on a recognized standard in a
premarket notification, a section 604 classification, or a
premarket approval application, will not create a continuing
compliance requirement such that legal modifications to devices
may not be made. For example, a device classified into class II
under section 604, subject to a special control performance
standard, may be legally modified without maintaining
compliance with the recognized standard, and without filing a
510(k) submission, if the modification insignificantly affects
safety or effectiveness. On the other hand, if the 510(k) were
required, the person submitting the premarket notification
could choose to rely on the standard or demonstrate substantial
equivalence in another way.
The committee notes that the amendment to section 501(e) is
intended to ensure that statements or actions directed to the
consuming public indicating conformance to a recognized
standard must be correct. If they are not, the device will be
considered adulterated. Additionally, section 301 is amended to
create as prohibited acts false declarations of conformity to a
recognized standard or the withholding of information required
to be provided to the Secretary under this provision.
Although most national and international standards
development organizations use a consensus based approach that
allows interested parties to participate in the development of
performance standards, the committee recognizes the importance
of public participation in agency decision making. Therefore,
the committee is recommending that the FDA provide the public
an opportunity to comment on agency decisions to recognize
standards on a case-by-case basis when a particular standard
may warrant or benefit from further public comment. The
committee is not recommending that the Agency use notice and
comment rulemaking to recognize these standards because their
use by industry is voluntary. Instead, the committee is
recommending that the agency, as appropriate, provide the
public a reasonable opportunity to comment in a way that is
consistent with the agency's recently issued Good Guidance
Practices.
Title III--Improving Collaboration and Communications
Collaborative determinations of device data requirements
The committee is aware that persons who submit premarket
approval applications and the FDA not infrequently disagree on
what constitutes an appropriate showing of device
effectiveness. Significantly, and unfortunately, this conflict
at times emerges well into the review process, when it may be
too late to remedy. Although the agency has been willing to
meet with persons who intend to submit investigational device
exemption applications, the committee believes that a special
meeting to determine the scientific showing for device
effectiveness is necessary and will prove to be an investment
against the significant costs to companies and the FDA related
to review process conflicts over device effectiveness showings.
The vehicle for obtaining a meeting to determine the type of
valid scientific evidence necessary to demonstrate
effectiveness will be a written request which sets forth a full
device description, a detailed description of the conditions of
use and, when available, information about the device's
expected performance. Within 30 days of the meeting, FDA will
provide its written response identifying the types of evidence
that will demonstrate effectiveness for a specified device for
a particular use.
The committee intends that FDA will be found by its
determination of device effectiveness requirements, unless
holding the agency to its determination is contrary to the
public health or, based on new information, the determination
is scientifically inappropriate. Importantly, ``new
information'' may not include a re-examination of the
information before the FDA when the agency made its
determination of types of scientific evidence needed to show
effectiveness. In other words, when public health protection
requires a change in direction, the committee intends that such
change will occur. However, this provision is intended to
establish an institutional commitment within the FDA to stand
by its advice regarding appropriate scientific showings and to
thoroughly consider the implications of such advice, when
given.
The intent of this provision is to be a starting point for
designing an investigational plan; it should only result in a
specification of the types of valid scientific evidence that
will demonstrate effectiveness. The provision is not intended
to address the development of a complete device investigational
plan.
This amendment of section 513(a)(3) is also intended to
carry through the philosophy of the ``Medical Device Amendments
of 1976.'' Those amendments were committed to avoiding
overregulation of devices. Section 301 achieves this laudable
goal by requiring that the FDA's specification of the types of
evidence to demonstrate a reasonable assurance of effectiveness
``result [from] a determination by the [Agency] that such data
are necessary to establish device effectiveness and that no
other less burdensome means of evaluation device effectiveness
is available which would have a reasonable likelihood of
resulting in an approval.'' Simply put, the FDA may not ask for
the ultimate study to prove effectiveness. It must ask for the
least burdensome type of valid scientific evidence that will
meet Congress' criteria for effectiveness. It is Congress'
formulation for proving effectiveness that counts. FDA has
never had freedom to require evidentiary showings that exceed
what is required under the law for an approval. This provision
reinforces that fact.
Collaborative review process
Consistent with a purpose behind section 310, the committee
intends that section 302 facilitate communications between FDA
and persons who submit premarket approval applications to
improve the efficiency of the device review process. Because
the committee is aware that the FDA has failed to timely review
PMA's, this bill includes a provision requiring a 180-day
review that cannot be extended or modified by the agency's
request for an amendment of the PMA. Instead, when the agency
desires additional information, the regulatory review clock
will stop until the applicant responds to the agency's request,
including a response that the applicant will rest on its
application as is. The committee intends that the 100 day
meeting required by section 302 will occur a bit after the
midpoint in the 180-day review process and will reinforce the
180 day review deadline by requiring the FDA to identify the
deficiencies that would preclude an approval of the PMA.
This requirement will force the agency to critically
consider the PMA up front in the review circle and not wait
until late in the review process, which has all too often been
the agency's pattern. Additionally, the section will require
FDA to describe the information necessary to bring the PMA into
an approval form, a form in which the FDA would be prepared to
approve the pending PMA if certain tasks, excluding clinical
investigations, were outstanding and reasonably capable of
being accomplished within a reasonably short period of time.
Both the statement of deficiencies and advice to improve the
PMA are to be in writing and made available to the applicant
prior to the meeting. Importantly, any deficiency discovered by
the agency after the 100-day meeting, must be reduced to
writing by the Agency and immediately provided to the
applicant. For purposes of this provision ``immediately'' shall
mean within 48 hours of an agency employee becoming aware of
the deficiency.
Title IV--Improving Certainty and Clarity of Rules
Policy statements
In the past decade, the FDA has relied less on developing
its policies and procedures through formal, public, or binding
mechanisms such as promulgating regulations and more on the use
of informal policy statements, including guidelines, points to
consider, and memoranda, generally without the benefit of
public comment. This has had the advantage of consuming fewer
agency resources than the cumbersome process of promulgating
substantive regulations and permits the agency to respond more
quickly and efficiently to requests for policy guidance.
However, the FDA's increasing reliance on policy statements
has also produced several problems. First, until recently, the
FDA has maintained no compilation of these documents. The
regulated industries and the public were often not aware that
they existed or did not know how they could be found. Second,
until recently, there was no systematic process for their
adoption or amendment. There may or may not have been an
opportunity for interested outside individuals and
organizations to have any input into their formulation or
amendment. Third, there was inconsistency among FDA personnel
in the use of these documents. Some FDA employees insisted that
industry strictly follow them, and others did not.
In February 1997, FDA published in the Federal Register (62
Fed. Reg. 8961) the Good Guidance Practices document
identifying policies for the development, issuance, and use of
guidance documents. The committee recognizes that this new
policy on guidance has only been effective for a short time and
that it is premature for the Congress to require FDA to
promulgate this new policy as a regulation without adequate
time to assess the success of this policy and consider
modifications, if any, that should be made to the policy.
However, it is the committee's intent that ultimately, the
policies governing guidance documents and informal policies be
in regulation. Therefore, the legislation requires that FDA
promulgate a regulation specifying the policies and procedures
of the FDA for the development, issuance, and use of guidance
documents by February 27, 1999.
Product classification
It is often difficult for an applicant to determine the
proper classification of a product as a drug, biological
product, or device. Even where the classification of the
product is known, the proper organizational center in the FDA
where the application will be handled can be uncertain. The
legislation therefore provides that, within 60 days of receipt
of a written request, the FDA must provide an applicant with a
written determination regarding the classification of the
product or the component of FDA within which it will be
handled, or both. This determination is binding. If the FDA
fails to meet this requirement, the applicant's designation
shall be final and binding. However, the FDA is given authority
to modify these otherwise binding determinations and
designations for public health reasons.
Use of data relating to premarket approval
The committee recognizes that in some instances minor
differences between separate versions of the same device can
result in significant divergent performance characteristics and
clinical results. Therefore, the FDA may find under Section 403
of S. 830 that on occasion it may not be scientifically
appropriate to utilize data from a single (or even a multiple)
application to approve another device, determine whether a
product development protocol has been completed for another
device, or establish a performance standard or special control
for another device.
Labeling claims for medical devices
With the ``Medical Device Amendments of 1976,'' Congress
intended that device classification and approval decisions be
made based on the intended use of devices as described in
labeling. Over the years, FDA has made premarket regulatory
decisions based on uses for devices that are unrelated to the
intended uses set forth in labeling. This section includes two
provisions that express the committee's specific intention to
limit FDA's review of premarket submissions to the proposed
labeling before the agency. Considerations like cost
effectiveness, relative effectiveness, or whether the product
effects some improvement in a patient's ``quality of life,''
are irrelevant to a premarket review unless such claims are
includedin proposed labeling. Simply put, the committee does
not want FDA to exceed its jurisdictional responsibilities by
incorporating into the review process claims not before the agency for
review consideration.
For premarket notification submissions, the labeling
proposed in the submission will be controlling of a device's
intended use. If the intended use is the same or sufficiently
similar to the intended use of a predicate device, then the
device may be found to be substantially equivalent to the
predicate. No considerations outside of the proposed labeling
for the 510(k) device should bear on the question of whether or
not the proposed labeling of the newer device is compatible
with the labeling of the predicate device.
For premarket approval applications, the determination of
whether or not there is a reasonable assurance of device safety
and effectiveness must be based on claims in proposed labeling
if such labeling is neither false nor misleading. The FDA may
fairly consider all facts which are pertinent to proposed
labeling in PMS's in determining whether or not the labeling is
false or misleading. Facts which are ``pertinent'' to proposed
labeling are those which directly relate to claims in such
labeling. For example, proposed labeling stating that a device
is for use in treating atherosclerosis cannot be false or
misleading because another device is more effective for that
purpose. Nor can the proposed labeling be false or misleading
because another device provides the same treatment benefits but
is less expensive to purchase and operate. However, the failure
to state a material fact about the device itself will make
labeling in a pending PMA false or misleading.
Definition of a day
The committee has included in this legislation the
codification of FDA's method of calculating a day, as that term
is used in various places in the Act in which specified times
for the FDA to complete statutory product review requirements
are identified. The committee believes it is important to have
a consistent understanding of a day both as a means for persons
who make submissions to FDA to determine where in the review
cycle their submission resides and to make FDA more accountable
for the timeliness of its reviews. Concern has been expressed
that FDA performance data are difficult to review because often
it is difficult to determine what is being presented by the FDA
for analysis. The committee hopes defining a day for product
reviews will help lessen the difficulty experienced in
evaluating FDA performance data.
For purposes of determining the length of review of various
specified product submissions, a ``day'' will be a calendar day
in which the agency has responsibility to review a submission.
The regulatory clock will not commence until the date a
complete submission is received by the FDA. When the agency
reviews a submission and requests additional information, the
regulatory clock will stop on the date that such a request by
FDA is made. The clock will re-commence when the additional
information is received by the FDA or when the regulated person
requests that the review continue.
Certainty of review timeframes
In section 406, the committee set a timeframe for reviewing
premarket notifications required under section 510(k). Also, a
strict limit was placed on the 180 day requirement for PMA
reviews.
Historically, FDA has operated as if premarket notification
classification determinations were required to be made in 90
days. Indeed, the internal yardstick for success in reviewing
these submission was the 90-day timeframe. The committee
believes that to ensure accountability, and avoid the long
review times seen from 1993 through 1996 for a majority of
devices, it is important to codify this informal agency
yardstick. This change in the Act should not create any
disadvantage or hardship for the FDA because it does no more
than put into law FDA's longstanding practice. Finally, with
regard to the review time for PMA's, the legislation clearly
states the committee's intent that FDA should approve or
disapprove a PMA application within the 180-day timeframe set
in the Act. The committee recognizes that this may result in
the disapproval of PMA's that FDA today might continue to work
on beyond the 180-day period in the well-intentioned effort of
ultimately approving the PMA.
Limitations on initial classification determinations
The committee included section 407 in S. 830 because of a
concern that FDA was inappropriately using the device premarket
notification process for compliance purposes and not solely for
its intended purpose of classifying devices intended for
introduction into interstate commerce after May 28, 1976, the
enactment date of the ``Medical Device Amendments of 1976.''
Over the past five years, the FDA has withheld device
classification determinations of substantial equivalence
because of its belief that firms were not in compliance with
good manufacturing practices. Such firms were placed on a
``reference list'' and were not removed from the list until FDA
was satisfied that such firms' facilities complied with GMPs.
Once a reference list form satisfied FDA with its GMP program,
the agency would complete a pending premarket notification
review and device classifications would then occur.
This process was unfair and denied device manufacturers an
opportunity to dispute effectively FDA's allegations that firms
were not in GMP compliance. FDA set itself up as judge and jury
and, in essence, administratively enjoined the classification
of devices until manufacturers satisfied the agency's view,
notwithstanding a regulated person's disagreement with FDA.
Clearly, FDA has substantial authority to enforce the Act
against illegal devices and the persons who market them. It is
unacceptable that the agency misuse premarket notification to
avoid enforcing the Act. FDA can find a device substantially
equivalent to a predicate device and still inform the device
manufacturer that although the device is substantially
equivalent it should not be marketed because of the agency's
view that the device does not comply with the law in some
specified respect. Then, if a person markets the device after
such notice, FDA can enforce the Act. This approach was used by
FDA for years before the advent of the reference list.
Although the FDA announced some time ago that it had
discontinued its reference list program, the committee is aware
that the agency still has withheld premarket notification
determinations for devices because of the agency's unilateral
determination of a lack of GMP compliance. Accordingly, the
committee believes this provision is essential to once and for
all eliminate all reference-list-like programs. Simply put,
initial classification determinations may not be withheld for
any compliance-related reason under the Act, including any
purported violation of GMPs.
Clarification with respect to a general use and specific use of a
device
Section 408 of the bill represents the committee's interest
in clarifying when devices with general intended use labeling
may be predicates for substantially equivalence determinations
for newer devices with more specific intended use statements.
This clarification is important because FDA has not established
a consistent pattern upon which persons who submit premarket
notification may rely.
To be substantially equivalent to a legally marketed
device, a person intending to market a device must show, among
other things, that a newer device has the same, or nearly the
same, intended use as a legally marketed device. Some legally
marketed devices, which are labeled for general uses, have been
used as predicate devices for substantial equivalence
determinations regarding newer devices with more specific
claims, e.g., condoms labeled for prevention of sexually
transmitted diseases were predicates for condoms labeled for
HIV prevention. Here, FDA found that the condom labeled for a
general use could be a predicate for a condom labeled for
prevention of a specific sexually transmitted virus, HIV.
This determination made perfect public health sense,
despite the fact that the general use labeling pre-dated the
``Medical Device Amendments of 1976'' and HIV was unknown at
that time. Consequently, the specific use for HIV prevention
could not have been included within the general use labeling
for condoms. The committee's concern is that although the
agency can make good determinations like the one just
discussed, no policy exists regarding the availability of
general use predicates for regulated persons to rely upon.
The committee believes that FDA should state its policy
regarding reliance on general use predicates in the context of
a regulation. The regulation should state when reliance on a
general use predicate is appropriate. FDA should permit
premarket notification submitters to provide information
showing that specific uses for a device are reasonably included
within apredicate's general use. For example, if the medical
literature shows that a newer device is used for several specific uses
within a predicate's general use, then FDA should permit the general
use predicate to be the basis for a substantial equivalence finding for
the newer device. The FDA's regulation should seek to describe rules
that the agency and industry can follow.
Clarification of the number of required clinical investigations for
approval
The drug amendments of 1962 added to the Federal Food, Drug
and Cosmetic Act the requirement that the effectiveness of a
drug be established by ``substantial evidence,'' which is
defined as adequate and well-controlled investigations,
including clinical investigations, by qualified experts on the
basis of which such experts could fairly and responsibly
conclude that the drug will have the labeled effect.
The committee believes that the science and practice of
drug development and clinical evaluation have evolved
significantly in the past 35 years, and this evolution has
implications for the amount and type of data needed to support
effectiveness in certain cases. Modern clinical trial design
often utilizes multiple investigators, multiple study sites,
randomization, large enrollment numbers, statistical power,
controls, clinical endpoints and other mechanisms that can
demonstrate the reproducibility underlying FDA's request for
two or more separate studies for each new drug and/or
indication. Therefore, it is the committee's understanding that
independent substantiation is the scientific basis underlying
FDA's substantial evidence requirements.
The FDA usually interprets the requirement to demonstrate
substantial evidence of effectiveness to require two adequate
and well-controlled clinical studies, but has shown flexibility
and approved some drugs on the basis of one adequate and well-
controlled clinical study. Given scientific advancement in the
past 35 years and the promise of further advancement, it is the
committee's belief that the structure of a particular clinical
protocol and the quality of the data underlying a new drug
application should guide FDA's substantiation requirements.
Therefore, the legislation confirms the current FDA
interpretation that substantial evidence may, as appropriate,
when the Secretary determines, based on relevant science,
consist of data from one adequate and well-controlled clinical
investigation and confirmatory evidence (obtained either before
or after the investigation).
The statutory standard for proof of effectiveness of a
medical device was purposely chosen in the Medical Device
Amendments of 1976 to be different from that for new drugs.
Different language was used for the express purpose of
emphasizing this difference. As the Cooper Committee emphasized
in its 1969 report, drugs and devices are different in nature
and present different issues when considering safety and
effectiveness. For medical devices, for example, the skill of
the person using the device is often of paramount importance,
in contrast with the use of new drugs.
The committee amended section 513(a)(3)(A) of the Act to
permit effectiveness to be demonstrated with ``one or more
well-controlled clinical investigations.'' This requirement
replaces the one in current law which literally requires more
than one well-controlled clinical investigation to demonstrate
a reasonable assurance of device effectiveness. The committee
changed the law because FDA has typically required only one
well-controlled clinical investigation to demonstrate device
effectiveness and it makes little sense to continue a law in a
manner inconsistent with its interpretation by an expert,
scientific agency.
Title V--Improving Accountability
The committee recognizes the ongoing effort at FDA to
improve its performance in meeting the statutory deadlines and
other responsibilities imposed upon the FDA under the Federal
Food, Drug and Cosmetic Act. The Prescription Drug User Fee Act
has assisted the FDA in coming closer to meeting the statutory
review times established in the Act. The recent efforts by the
Center for Devices and Radiological Health to reduce the 510(k)
backlog, more prompt review of Investigational Device
Exemptions, and the pending Center for Devices and Radiological
Health (CDRH) re-engineering effort are all promising signs of
a new attitude and responsiveness at the FDA. Nonetheless, the
committee remains concerned that there are no effective
measures available to ensure FDA compliance with statutorily
required performance goals.
The legislation requires FDA to develop an agency plan to
come into compliance with the Act and provide an annual report
providing detailed information regarding implementation of the
agency plan, including statistical information which will
assist the committee in fulfilling its oversight
responsibilities.
Notwithstanding the efforts by the agency noted above, the
committee remains concerned that review times for many products
are substantially in excess of those required in the FFDCA.
Further, the agency is in many cases behind in its reporting
requirements and is incompletely implementing other
requirements. An example of the latter are the regulations
promulgated by the Health Care Financing Administration
following enactment of the Clinical Laboratory Improvement
Amendments of 1988 (CLIA).
Under CLIA, the FDA was provided the responsibility to
categorize the complexity of new in vitro diagnostic (IVD)
devices. However, the FDA failed to undertake this task and the
responsibility for regulating the complexity of these IVD
products was assumed by the Centers for Disease Control and
Prevention (CDC). At the same time, FDA continues to conduct
extensive evaluations of these IVD devices before clearing them
for market under the FDCA, including reviewing their
instructions for use.
The committee is concerned that this dual responsibility
has resulted in a process that causes confusion and unnecessary
conflict for IVD device manufacturers. In many cases, this
overlap has delayed the delivery of potentially lifesaving
devices to market. Additionally, CDC's focus on the same safety
and effectiveness issues as FDA highlights the wastefulness of
this duplicative review. Therefore, the committee believes that
FDA should reassert its exclusive role in the implementation of
the complexity evaluations under the CLIA regulations.
Title VI--Better Allocation of Resources Setting Priorities
Minor modifications
In section 601, the committee addressed changes made in
investigational devices and modifications of approved PMA
devices. First, the committee requires the FDA to promulgate a
regulation modifying its current investigational device
exemption regulation by including a provision that permits
developmental changes to investigational devices that are based
on information learned during an investigation without
submitting a supplement to an approved investigational device
exemption application. Specifically, if a study sponsor
determines, based on credible information, that the change does
not affect the scientific soundness of the investigational plan
or patient rights, and the change does not constitute a
significant design change or a change in basic operating
principles, then no supplement of original IDE application will
be necessary. For purposes of this provision, ``credible
information'' shall mean information upon which a reasonable
person in a manufacturer's position would rely upon in making a
decision to change or modify an investigational device.
The committee also altered section 515 of the Act to
accommodate this amendment of the FDA's investigational device
exemption regulations. In addition to permitting the use in
PMA's of data from devices altered during an investigation, the
agency will be required to consider data from approved device
investigations for devices already subject to PMA approvals,
when the data are relevant to the design and intended use of
the device subject to the pending PMA. In other words, if PMA
data for a device are available for use by an applicant, that
data could be used to approve a newer version of an already
approved device if other data address any differences between
the approved device and the one pending before the agency.
The committee looked at two forms of change to an approved
PMA device: Manufacturing changes and incremental device design
changes. In lieu of a supplement for a manufacturing change,
the bill requires that manufacturers proposing such a change
provide the FDA a 14-day notice prior to commercial
distribution of a device manufactured under the changed
conditions. The notice must provide a detailed description of
the change, data or information supporting the change, and an
assertion that the change was made under Good Manufacturing
Practices (GMP's). The committee believes that the agency's new
GMP regulation, including its design validation provisions
which address all changes that could affect device performance,
provides adequate protection for the public health in lieu of
supplements to the approved application. This is particularly
true in light of the fact that the agency approves
manufacturing facilities as part of PMA product approvals.
Avoiding delays in implementing manufacturing changes cuts
costs and typically results in improved products. Importantly,
with the notice required under this section, FDA could dispatch
inspectors to review the changes that require attention.
Moreover, if a change appeared suspect based on the notice,
administratively FDA could stop shipments of devices made under
the changed conditions. All in all the purpose of this
provision is to avoid delay and reduce the use of FDA resources
on issues that should not merit the agency's attention.
The committee addressed incremental design changes to
approved PMA devices that affect safety or effectiveness by
requiring the FDA to approve a supplement if bench data
demonstrate that the design modification achieved its purpose
and clinical data from the approved application and supplements
thereto demonstrate a reasonable assurance of safety and
effectiveness for the modified device. However, if the
Secretary believes that additional clinical data are necessary,
the Secretary may require such data but only insofar as the
data relate to the design modification.
This change reflects the committee's understanding that
devices develop incrementally, often through very small
modifications. To avoid over regulation and wasteful
expenditure of agency review resources, the committee wants the
Agency to determine when new clinical data are necessary as
opposed to presuming such data are always necessary.
Environmental impact review
The National Environmental Policy Act requires that all
Federal action be subject to environmental consideration. Some
State laws also require a similar analysis. In only one
instance, however, has the FDA ever determined that action on
anew drug application might potentially have a significant
environmental impact. Even in that instance, the importance of the drug
involved to human health outweighed the environmental impact and the
drug was therefore approved. In the meantime, new product sponsors are
generally required to file environmental assessments with new product
approval applications, adding substantially to the cost of new product
development, adding time to the development and approval process, and
consuming valuable FDA review resources.
The legislation ends the automatic requirement for filing
environmental assessments, environmental impact statements, or
other environmental considerations. New product sponsors would
be required to conduct such assessments only if the FDA in
writing and specifying the basis therefore, determines that
there is a reasonable probability that the environmental impact
of the action is sufficiently substantial and within the
factors that the FDA is authorized to consider under the
Federal Food, Drug, and Cosmetic Act and that consideration of
that impact will directly affect the decision on the matter.
This assures that, whenever environmental considerations are in
fact significant, they will be fully analyzed and taken into
account and that industry and agency resources will be focused
on considering issues related to the safety and effectiveness
of products.
Exemption of certain class devices from premarket notification
requirements
Under the medical device provisions of the law that were
enacted as part of the Medical Device Amendments of 1976 and
amended under the Safe Medical Devices Act of 1990,
approximately 97 percent of all devices were cleared for
marketing through FDA's premarket notification program. When a
device is found to be substantially equivalent to a legally
marketed device, it may be marketed after the FDA issues an
order making that finding.
After the enactment of the Safe Medical Devices Act of
1990, severe backlogs of premarket notifications and premarket
approval applications developed at the FDA. Recognizing that
part of the problem was the sheer number of notifications the
agency was receiving for class I or II products that posed
little risk, President Clinton announced a reinventing
government initiative to eliminate the notification requirement
for some devices posing a minimal risk, and the FDA has now
acted to exempt a substantial number of such devices. By
eliminating premarket notification reviews for some low-risk
devices, agency resources could instead be used on more
critical devices, including those subject to premarket approval
applications.
Building on the President's initiative, the legislation
exempts all class I devices from premarket notification
requirements, except those the intended use of which is of
substantial importance in preventing impairment of human
health, or presents a potential unreasonable risk of illness or
injury. In addition, the FDA is required to review all class II
products to determine those that should and should not be
exempt from the section 510(k) process. The FDA is provided 30
days to complete the class II exemption process.
Because the agency on its own initiative has already had
this matter under review for several years, and because the
committee put the agency on notice through multiple requests
over the last year for a list of any such devices which do not
require premarket notification to protect the public health,
this is a reasonable time within which to complete the job.
Further, at any time, on the Secretary's own initiative or
in response to the petition of an interested person, the FDA
may exempt a type of class II device from the section 510(k)
process. By eliminating low-risk devices from the FDA's
premarket review responsibility, FDA personnel will be better
able to handle within statutory deadlines the remaining section
510(k) notifications and premarket approval applications for
devices that may pose a risk to public health and safety or
provide health benefits to patients.
Evaluation of automatic class III designation
Section 604 includes a process that permits the Secretary
to classify devices based on the Act's risk-based
classification criteria when a device is found to be not
substantially equivalent to a predicate device. Specifically,
thirty days after receipt of a not substantially equivalent
determination, the person receiving the Secretary's
classification order may request that the Secretary make a risk
based classification determination for the person's device, if
the type of device hadnot been previously classified. The
manufacturer should provide information to assist the Secretary in
making the risk-based classification. The Secretary will then determine
the device's classification based on the classification definitions in
section 513(a)(1). These definitions have been used by the Secretary to
classify or reclassify over a thousand types of devices.
Within 60 days of the above request, the Secretary must
make a classification determination, placing the device into
one of three statutory device classes. If the device is placed
into classes I or II, it may be commercially distributed
immediately. Of course, like any device, devices classified
into class I or II under section 604 will be subject to all
provisions of the Act. However, if the device is placed in
class III, its status will remain unchanged from its not
substantially equivalent designation; that is, the device will
be classified into class III and will require an approved
premarket application under section 515 before marketing.
A device may be placed into class II conditioned upon
complying with ``special controls.'' Devices placed into class
II under section 604 must comply with those controls to
maintain a class II status. A failure to comply with special
controls will result in the device reverting to its not
substantially equivalent, class III designation. Marketing of a
class III device under these circumstances will result in the
device being adulterated within the meaning of 501(f)(1)(B),
assuming it has not been distributed under an investigational
device exemption, because the device will be an unapproved
class III device classified under section 513(f)(1).
Once a device is classified into class I or II under
section 604, it becomes a predicate for future premarket
notification submissions. Persons who file reports under
section 510(k) may demonstrate the substantial equivalence of
newer devices to these predicates. Substantial equivalence may
be demonstrated by complying with the specified special
controls used to establish the classification of the predicate
device and other information, when necessary, or it may be
demonstrated in another manner. As with current law, the person
making a premarket notification submission will have the option
of determining how to demonstrate the substantial equivalence
of a device to a predicate device, and the agency will have the
responsibility to make substantial equivalence determinations.
The committee realizes that ``special controls'' can be
controls or a variety of controls that will assist in providing
a reasonable assurance of device safety and effectiveness. When
conducting a classification review under this section, the
Secretary may classify a device into class II even when special
controls to not yet exist. Under these circumstances, the
Secretary should inform the person seeking a risk based
classification of the Secretary's intention to rely on a
special control in the future and specify the nature of the
special control.
Importantly, the fact that a device is subject to a special
control under this section does not mean that enforcement
authority over in other parts of the Act become ineffective.
For example, postmarket surveillance and labeling can be
special controls. Nonetheless, postmarket surveillance is still
enforceable as a misbranding under section 502(t) and specified
labeling instructions remain enforceable under either section
502(a) or 502(f)(1) as misbrandings, depending on the labeling
control at issue.
The committee included section 604 to avoid the needless
expenditure of the Secretary's resources that would occur if
lower risk devices were subjected to premarket approval reviews
under section 515 because such devices were unique and found to
be not substantially equivalent to a predicate device. The
Committee also believes that section 604 may permit the
Secretary to avoid time and resources consuming substantial
equivalence determinations that rely on remote predicates. The
Committee did not include this section in its bill to increase
significantly the number of not substantially equivalent
determinations, and specifically it did not intend that section
604 would otherwise alter the Act's substantial equivalence
provisions or the Secretary's longstanding approach to the
510(k) classification process.
Concern has been expressed that the Secretary will attempt
to use this provision as a means of creating mandatory [. . .
requirements] out of voluntary ones, thus subjecting regulated
persons to enforcement consequences without process. That is
not the Committee's intent. For example, once a deviceis
classified into class II under a risk based assessment, compliance with
applicable special controls will be unnecessary to demonstrate
substantial equivalence between a newer device and the section 604
predicate device, unless the special control is a part of the device's
intended use. The Committee's intent behind section 604 is simple:
Section 604 will permit the Secretary to avoid over-regulation of
devices that should not be subject to premarket approval requirements.
In other words, the Committee does not intend section 604 to supplant
or otherwise change the ``510(k) classification process.''
Tracking
The Safe Medical Devices Act of 1990 added a new provision
to require device tracking for every device the failure of
which would be reasonably likely to have serious adverse health
consequences and which is a permanently implanted device or a
life-sustaining device that is used outside a device user
facility, as well as any other device designated by the FDA.
This statutory mandate has proven to be uncertain with
regard to which devices require mandatory tracking. The FDA's
regulation for tracking identifies an illustrative list of
devices subject to mandatory tracking, suggesting that the list
is comprehensive, yet not complete.
To address these problems, the legislation requires FDA to
affirmatively list those devices which it intends to be subject
to tracking. Devices not so listed are presumed exempt from
tracking requirements until such time as FDA chooses to
affirmatively require tracking. The legislation does not modify
the existing mandatory or discretionary tracking authority. The
Committee notes the intent of the tracking provisions in the
Safe Medical Devices Act of 1990 was to track medical devices
to facilitate recalls.
Postmarket surveillance
The Safe Medical Devices Act of 1990 also included a
provision requiring a manufacturer to conduct postmarket
surveillance for any device first marketed after January 1,
1991, that is a permanent implant the failure of which may
cause serious adverse health consequences or death, is intended
for use in supporting or sustaining human life, or potentially
presents a serious risk to human health. In addition to this
mandatory surveillance, FDA was authorized to require
postmarket surveillance for any device when the agency
determined that surveillance is necessary to protect the public
health or to provide safety or effectiveness data. All
manufacturers subject to mandatory postmarket surveillance were
required to submit protocols for FDA approval within 30 days of
first marketing the device. The FDA was required to determine
the adequacy of the principal investigator and the protocol and
to approve the protocol after review by an appropriately
qualified advisory committee.
In practice, the provision for mandatory surveillance, like
the one for mandatory tracking, is so broadly worded that it is
causing a good deal of uncertainty about those devices which
are subject to this requirement. Further, the committee is
concerned that FDA not interpret the postmarket surveillance
authority as power to require longitudinal studies for FDA
approved products. The committee legislation repeals mandatory
surveillance and provides the Secretary with broad discretion
to implement postmarket surveillance. Under current law,
required surveillance is limited to devices first introduced
into commerce after January 1, 1991. Under the legislation,
subject to the Secretary's discretion, any device may be
subject to surveillance.
The legislation sets the initial period of surveillance at
24 months. After an informal hearing to consider the need for
further surveillance, FDA may require that the surveillance
continue for such time as is necessary.
Since 1976, and reinforced in 1990, the Federal Food, Drug,
and Cosmetic Act has required medical device reporting by
distributors as well as manufacturers. The Safe Medical Devices
Act of 1990 added this requirement for device user facilities.
As a result, there has been a substantial increase in reporting
for medical devices, including, as documented by the GAO, much
duplication and some inaccurate filings. Further, the FDA,
after request by the committee, has been unable to confirm that
it either tracks distributor reports or acts on the basis of
suchreports. To avoid duplication and the costs associated with
it, the legislation continues to require manufacturers and user
facilities to report adverse events to the FDA but eliminates
distributor reporting. Because user facilities and manufacturers submit
medical device reports to the FDA, there is no need for additional
reporting by distributors. Further, the registration requirement for
distributors is deleted. Finally, the record keeping requirements for
distributors are retained. Because the agency has represented it is
aggressively pursuing reforms to address the concerns raised in the GAO
report with respect to user reporting, namely, letting a contract to
explore a sentinel, statistically significant user reporting system,
the committee has not proposed a statutory remedy in that area at this
time.
Pilot and small-scale manufacture
An important part of applications for new drugs and
biological products consists of the information on chemistry,
manufacturing, and controls (CMC). During the investigation of
a new product, only a relatively small amount of the drug is
needed to support the preclinical and clinical trials. It is
only after marketing approval is obtained from the FDA that
large-scale manufacturing is justified.
For some drugs, where the evidence of effectiveness is
overwhelming, companies are prepared to scale up to large
manufacturing facilities even before FDA approval is obtained.
For small companies with modest capitalization, however, it is
common practice to wait for FDA approval of the premarket
approval application before scaling up to larger processes.
This is particularly characteristic of startup biotechnology
companies.
In the past, the FDA has for some drugs required CMC data
relating to large-scale manufacture before approval will be
granted. This penalizes small companies and especially the
biotechnology industry. The legislation therefore states the
general rule that the FDA review and approve new drugs and
biological products on the basis of pilot and small-scale
manufacturing, and permit the company to scale up to a larger
facility after the product has been approved. Scaling up can
readily be undertaken on the basis of process validation,
without additional clinical trials. Only in the very rare case
where full-scale production is necessary to ensure the safety
or effectiveness of the new drug or biological product prior to
approval is the FDA given the authority to require such
manufacture as a condition of approval. This is the approach
that has been announced in the Reinventing Government
initiative relating to drug and medical device regulations. The
need for supplemental approval of the manufacturing changes
needed to scale up to larger facilities is subject to the new
requirements in section 614 of the legislation.
Requirements for radiopharmaceuticals
The purpose of section 610 is to acknowledge the special
characteristics of radiopharmaceuticals used for diagnostic and
monitoring purposes that should be taken into account in
evaluating their safety and efficacy. Radiopharmaceutical
diagnostic and imaging agents are not normally used
chronically. They are administered on an occasional and
intermittent basis. Because of the contribution of the
radioactive isotope, only small quantities of the carrier or
ligand drug are needed to produce the desired effect. Section
609 recognizes that the determination of the safety and
effectiveness of such a radiopharmaceutical diagnostic or
monitoring agent should include consideration of these unique
characteristics and directs the FDA to develop regulations
governing the approval of radiopharmaceuticals used for
diagnostic and monitoring purposes. The provision states that
the determination of safety and effectiveness should include
consideration of the proposed use of the radiopharmaceutical in
the practice of medicine, the pharmacological and toxicological
activity of the radiopharmaceutical (including any carrier or
ligand component), and the estimated absorbed radiation dose of
the radiopharmaceutical. However, this provision is not
intended to change the standards, or limit the data
requirements, under section 505 of the Federal Food, Drug and
Cosmetic Act or section 351 of the Public Health Service Act,
by which the safety and effectiveness of such
radiopharmaceuticals are determined.
In addition, section 610 acknowledges that the indications
for which radiopharmaceuticals are used may, in appropriate
cases, refer to manifestations of disease (such as biochemical,
physiological, anatomic, or pathological processes) common to
or present in 1 or more disease states. This refers to the
factthat radiopharmaceutical diagnostic and monitoring agents may,
under appropriate circumstances, be approved for use on the basis of
their effectiveness in showing how a disease or process has developed,
is developing, or is progressing.
This section is limited to radiopharmaceuticals used for
diagnosis and monitoring and does not address
radiopharmaceuticals used for therapeutic purposes. Thus,
radiopharmaceutical is defined for purposes of this section
only as (1) an article (A) that is intended for use in the
diagnosis or monitoring of a disease or a manifestation of a
disease in humans; and (B) which exhibits spontaneous
disintegration of unstable nuclei with the emission of nuclear
particles or photons; or (2) any nonradioactive reagent kit or
nuclide generator which is intended to be used in the
preparation of any such article.
Modernization of regulation of biological products
The provisions of section 351 of the Public Health Service
Act that govern the FDA regulation of biological products were
initially enacted by Congress in 1902 and were recodified in
1944. Responsibility for implementing these provisions was
initially in other parts of the Public Health Service until it
was transferred to the FDA in 1972. The basic concept of the
statutory requirements has not been revised in more than 90
years.
When FDA assumed responsibility for regulating biological
products in 1972, it made two important policy decisions.
First, it retained a separate organizational structure and
regulatory focus for biological products, rather than combining
these products with new drugs. (Even when the two
organizational structures were temporarily combined in the
1980's, a separate regulatory focus was maintained). Second,
because biological products are also drugs, more recent
regulatory concepts that were applied to new drugs, (e.g.,
compliance with drug GMP regulations) were incorporated into
the older system for biological products. In the past 25 years,
the two regulatory systems have become similar, although each
retains its separate identify.
The legislation takes this logical progression one step
further. It substantially revises section 351 of the Public
Health Service Act to make it much closer to the current
approach for approval of new drugs. The most important revision
repeals existing requirements for a facilities license. Since
1902, the law has been interpreted to require that the
applicant for a new biological product ordinarily obtain both a
product license and an establishment license. In contrast, the
applicant for approval of anew drug is required to submit only
a single application, which covers both the product and the
manufacturing processes in the establishment. The legislation
adopts the same approach for pioneer biological products as for
new drugs. Thus, the current statutory requirement for licenses
for biological products is clarified to require only one
license--covering both the product and the facility in which
the product is manufactured.
To ensure consistency in regulation of new drugs and
biological products, the bill requires the FDA to take measures
to minimize the differences in review and approval of products
required to have biologics license applications under the
revised section 351 of the Public Health Service Act and full
new drug applications under section 505(b)(1) of the FFDCA.
This requirement for harmonization does not apply in the case
of generic products, however, since the authority for
abbreviated new drug applications under section 505(j) is not
applicable to biological products.
The FDA is required to establish, by regulations, the
requirements that an applicant must meet in order to obtain
approval of a biological product license application. The
biological product must be demonstrated to be ``safe, pure and
potent''. Potent is intended to mean ``effectiveness'' as FDA
has historically interpreted the term. The applicant must also
demonstrate compliance with GMP requirements. Preapproval
inspection for compliance with GMP is included.
Among the most important biological products subject to FDA
regulation are blood and products derived from blood. There are
two basic categories of these products: (1) blood and blood
components, and (2) products that are derived from blood and
blood components. For currently licensed blood and its
components, the FDA has established appropriate standards
designed to assure safety, purity, and potency. The
legislationis not intended to change FDA's ability to approve blood and
its components that meet these standards. Blood and its components must
also be obtained, held, processed, and utilized in accordance with GMP
regulations. The safety determination for blood, blood components, and
blood derivative products, as for other biological products, includes
assessment of benefits and risks. There is always some degree of risk
associated with blood and products made from blood.
Establishments that collect, process, and use blood and its
components are uniquely located at the local community level.
There are more than a thousand of these blood establishments,
located throughout the country, in contrast with the usual
situation with other pharmaceutical establishments. The
committee intends that regulatory requirements be streamlined
and made efficient. For example, a single license application
could cover all facilities under one management to utilize
particular types of products or methods of processing when the
application makes clear that all facilities and products meet
applicable requirements and standards for their use. Requiring
separate license applications for each separate facility and
product can be wasteful of both industry and government
resources and achieves no useful public health purpose.
It is important that, when a problem is found at a
particular facility, the FDA has adequate power to revoke
whatever licenses are applicable with respect to that specific
location. If ten facilities are under one management and the
FDA discovers that two fail to meet GMP requirements, or two
are not properly using products or processes for which all of
the facilities are licensed, FDA may suspend and revoke the
applicable license with respect to those two facilities and
their products.
Even before the FDA was delegated responsibility for the
regulation of biological products, the FDA regulations
governing investigational new drugs were used as the applicable
requirements for the investigation of biological products as
well. This practice is not changed under the legislation.
To simplify the statutory language, the legislation
incorporates a definition of ``biological product'' to
encompass all of the products that are presently included
within the Public Health Service Act provisions governing this
category of products. That defined term is then used throughout
the new provision as well as in sections of the Food, Drug, and
Cosmetic Act that apply to both biological products and non-
biological new drugs.
Supplemental new drug applications
A new use of an approved drug can be added to the product
label if the sponsor files a supplemental new drug application
with FDA and FDA approves that application. Although the review
times for these supplemental applications have improved over
the past few years (in part due to the Prescription Drug User
Fee Act of 1992), there are still many drug labels that do not
reflect up-to-date information on new uses for approved
products. Without adequate information about new uses on the
drug label, there are risks of unsafe or inappropriate uses.
In an ideal world, common medical practice should be
reflected on the FDA approved label for the product. In
addition, the process for updating the label for an approved
product should be sufficiently expeditious to justify the time
and expense associated with the conduct of new clinical trials
and submission of a supplemental approval application. In fact,
however, there are many reasons why supplemental applications
are not submitted, including:
Excessively high costs of a supplemental NDA
(including the necessary clinical work) relative to the
market for the new use, indication, or dosage;
Delays in the approval of supplements, which are
currently running at one year from submission (as a
median and a mean); and,
Patent or market exclusivity may expire.
In many cases products are prescribed for use, indications,
or in doses that are not within the label approved by the FDA.
In fact, many older, off-patent drugs are prescribed in this
manner. According to the US General Accounting Office, one-
third of all cancer drugs are used for uses other than that for
which they were approved, 44 of 46 approved cancer drugs are
used forat least one additional, non-approved use, and 56% of
all cancer patients use at least one drug prescribed for a use other
than that for which they were approved. This type of prescribing is
also common with AIDS drugs--78% of all AIDS patients receive a drug in
this manner. Overall, 80% of all prescription drugs are prescribed in a
manner which differs in some respect from the approved labeling.
The legislation takes steps toward addressing this problem
in several ways. First, it directs FDA to establish performance
standards for the review of supplemental applications for
approved products.
Second, FDA must issue final guidance documents that
clarify the requirements for, and facilitate the submission of,
data to support approval of such supplemental requirements. The
guidance will clarify the circumstance in which published
studies may be the basis for approval, specify data
requirements that will avoid duplication of previously
submitted data, and define supplemental applications that are
eligible for priority review. FDA has already issued draft
guidance documents that address most of these issues.
Third, the legislation requires FDA to designate an
individual in each center (except the Center for Food Safety
and Applied Nutrition) who will have responsibility for
encouraging prompt review of supplemental applications and
working with sponsors to facilitate the development and
submission of data to support such supplemental applications.
Finally, FDA is directed to implement programs and policies
to foster collaboration between FDA, the National Institutes of
Health and others to identify published and unpublished studies
to support supplemental applications and to encourage sponsors
to make applications or conduct further research in support of
an application based on such studies.
Health care economic information
The committee believes that the FDA should allow companies
to share health economic information about approved ``on
label'' uses for products under the same standard applied to
over-the-counter drugs and other products. The agency currently
requires these claims--which differ from efficacy claims--to be
subjected to two clinical trials. The agency on several
occasions conceded that this standard is inappropriate for such
claims and agreed that it should be modified to a more
appropriate standard.
Health economic information about approved ``on label''
uses is needed by managed care experts and other health care
providers responsible for evaluating the benefits, other
consequences, and costs of competing therapies. Health care
providers also rely on companies to conduct studies in the
providers' own or comparable representative populations to help
the providers predict the specific benefits and costs of FDA-
approved products for their particular organizations. Companies
typically have the best and most comprehensive information
about the cost, effectiveness, and safety of their products.
The FDA should not unduly impede the flow of that information
to experts who need it for patient and health plan decisions.
Undue restrictions on the ability of companies to make
competent and reliable claims on the basis of cost,
effectiveness, or safety of approved uses of products interfere
with the public health by encouraging the sale and use of
needlessly expensive products.
This provision differentiates between clinical claims and
economic claims. Clinical claims would continue to be governed
by the evidence standard in the Act. Economic claims would be
governed by the ``competent and reliable scientific evidence
standard used by the Federal Trade Commission, drawing from
available evidence in the relevant economic fields of science.
Economic claims could only be distributed to drug formulary
committees, managed care entities, or similar entities with
responsibility for drug selection decisions. Economic claims
are defined as those that identify, measure, or compare the
costs (direct, indirect, or intangible) and health care
consequences of a drug to another drug or to another health
care intervention for the same indication, or to no
intervention, where the primary endpoint is an economic outcome
of the research or analysis on which the statement is based.
Expediting approval and of fast-track drugs
The FDA currently has a number of mechanisms aimed
atstreamlining the development and approval process for new therapies
for serious and life-threatening conditions. The committee believes
that a formal statutory mechanism for identifying breakthrough drugs
early in product development that provides sponsors of such drugs a
reasonable opportunity for early interaction with the agency may help
to further streamline the development and approval processes for such
drugs.
This legislation is intended to clarify and coordinate some
of FDA's mechanisms for new drugs and biological products that
are intended for the treatment of serious and life threatening
conditions and that demonstrate the potential to address unmet
medical needs for such conditions. It defines and clarifies the
processes pursuant to which sponsors of these drugs may
interact with the FDA and includes provisions that will ensure
that these processes are well known and well understood.
Pursuant to the legislation, drugs for serious and life
threatening conditions that demonstrate the potential to
address unmet medical needs will be eligible for a ``fast
track'' designation. Sponsors may seek fast track designation
concurrently with (or after) the submission of an application
for the investigation of the drug. If the FDA determines that
the drug should be designated as fast track, it will take
appropriate action to expedite the development and review of
the drug. For example, if preliminary evaluation of clinical
efficacy data show evidence of effectiveness, FDA will evaluate
for filing incomplete portions of the application and if the
portion is filed, FDA may commence review of that portion. A
sponsor will be eligible for this ``rolling review,'' however,
only if it has provided a schedule for submission of
information necessary to make the application complete and any
fee required under the Prescription Drug User Free Act.
The FDA may approve an application for approval of a fast
track drug under section 505(b) or under section 351(a) of the
Public Health Service Act upon a determination that the drug
has an effect on a surrogate endpoint that is reasonably likely
to predict clinical benefit. This provision is not intended to
change the standards under section 505 or section 351 of the
Public Health Service Act, pursuant to which the safety and
effectiveness of such drugs are determined. All fast track
drugs must meet the evidentiary standards in section 505(d) or
section 351(a) of the Public Health Service Act. Moreover, the
Secretary may require the sponsor to conduct a post-approval
study to validate the surrogate endpoint or otherwise confirm
the clinical benefit of the drug. The Secretary also may
require the sponsor to submit promotional materials during the
pre-approval review period and following approval. The
Secretary may withdraw approval of a fast track drug using
expedited procedures if the sponsor fails to conduct required
postmarketing studies, the post-approval study fails to verify
clinical benefit, other evidence demonstrates that the drug is
not safe or effective, or the sponsor disseminates promotional
materials that are false or misleading. These expedite
procedures include an opportunity for an informal hearing, as
currently provided in FDA's accelerated approval regulation,
rather than for a formal evidentiary hearing as provided in
certain other circumstances.
In cases where there exists a surrogate endpoint which can
be measured more rapidly than clinical endpoints and where a
drug's effect on that surrogate endpoint is reasonably likely
to predict clinical benefit, the acceptance of effects on
surrogate endpoints as evidence of efficacy can lead to more
rapid availability of safe and effective drugs for Americans
with serious or life threatening illnesses. In order to reap
that benefit, it is essential that potentially useful surrogate
endpoints be identified and evaluated for their likelihood of
predicting clinical benefit. To that end, it is the intent of
Congress that the FDA participate with other public health
agencies, patient groups, industry, academic, and medical
groups and other interested parties in efforts to improve the
utilization of surrogate endpoints. The committee is not
directing the FDA to develop such surrogate endpoints, but
rather is directing the agency to support the efforts of others
to develop and validate surrogate endpoints.
This provision is not intended to modify any agreement
reached under the Prescription Drug User Fee Act. The review
periods agreed to under PDUFA will not begin to run until a
complete application for a fast-track drug has been submitted
to the agency.
To ensure that the processes and policies set forth in the
fast-track provision are well known and well understood, this
provision directs the Secretary to provide physicians,
patientorganizations, industry, and other appropriate persons a
comprehensive description of the fast track provisions established
under this legislation and within 1 year to issue guidance that
describes the policies and procedures pertaining to fast-track drugs.
Finally, the committee recognizes that his opportunity for
drugs to be approved on an urgent basis with what may be fewer
data than are customary may require increasing reliance on
post-approval studies to gather confirmatory or additional
information. The committee urges the industry to cooperate
fully in the gathering of such post-approval studies in order
to assure that drugs approved on a fast track are, indeed, safe
and effective and to assure that patients and their providers
are given information about the appropriate use of these drugs.
Manufacturing changes
The manufacturing processes and facilities used to produce
a new drug or biological product undergo changes throughout the
investigation of the product and after marketing approval is
obtained from the FDA. Innovations are sought to reduce
impurities, increase yield, reduce the complexity and time
required for manufacture, eliminate equipment, automate
procedures, increase stability, and otherwise to improve the
drug and reduce its cost. The benefits of these innovations are
passed on to the consumer in the form of improved products and
lower prices.
In the past, the FDA has imposed very stringent limitations
on the ability of the pharmaceutical and biotechnology
industries to adopt new manufacturing procedures. For most
manufacturing changes, FDA approval of the supplemental
application is required. For only a few has the FDA permitted
the change to be made immediately and simply reported to the
FDA by a simultaneous supplement or in the annual report
submitted to the FDA for the drug. For biological products, FDA
has been even more stringent, requiring clinical trials to
support new manufacturing processes in many situations.
Supplemental applications for manufacturing changes have,
moreover, traditionally been given a very low priority within
the FDA. As a result, it can be years before a new
manufacturing process can be used, even if it results in a
substantial improvement in the drug.
The impact of past FDA policy in this area on the
pharmaceutical and biotechnology industries has been
substantial. First, many companies have established
manufacturing facilities abroad, where they can use a modern
process to supply a drug to the rest of the world long before
they can use the same process to supply the United States.
Second, some companies do not make important drug manufacturing
improvements because of the cost and lengthy process required
for approval. The development of new technology, the public
health and pocketbook have all suffered.
To address these problems, the legislation considered by
the committee included a new approach to manufacturing changes
for new drugs and biological products. Current law governing
manufacturing changes shall remain in effect until 24 months of
the date of enactment of this legislation or the effective date
of regulations promulgated by the FDA implementing the new
policy, whichever is sooner. The policy focuses on the
specifications of the drug or biological product found in the
license application and sorts manufacturing changes into three
categories. Major manufacturing changes, which are of a type
determined by the FDA to have a substantial potential to
adversely affect the identity, strength, quality, purity, and
potency of a drug, as those characteristics relate to safety
and efficacy, shall require prior approval of a supplemental
application. The FDA will identify other types of manufacturing
changes which can be made at will with only a requirement to
note the change in an annual report to the FDA. Other changes
may be made, if FDA has not notified the company within 30 days
after the submission of a supplement that a prior approval is
required. FDA shall also designate changes for which
distribution of the products may begin at the time the
supplement is submitted. All supplements will continue to be
approved or disapproved. If FDA later determines that the
supplemental NDA is not immediately approvable, the agency will
work with the applicant to resolve all issues and to assure the
continued availability of the drug.
Food contact substances
This provisions adds to the FFDCA a premarket notification
system that is intended to be the primary method by which FDA
regulates food contact substances. The food additive petition
process in its present form will continue to exist in the law,
but will be invoked for food contact substances only in
thosecases where FDA determines that a petition is necessary to provide
adequate assurance of safety or where a company and FDA agree that a
petition may be submitted.
In creating the PMN system, this bill leaves in full force
and effect the current food additive regulations covering food
contact substances. It is not the intent of this legislation to
require PMNs for materials that FDA already has received and
found to be safe for their intended use.
This legislation also maintains the existing definition of
``food additive'' in Section 201(s) of the FFDCA (21 U.S.C.
321(s)). Therefore, a PMN will be required only for a food
contact substance that is a ``food additive'' within the
meaning of section 201(s). Similarly, a food contact substances
that is a food additive but is not the subject of either a food
additive regulation or an effective notification would be in
violation of the food adulteration provision in section
401(a)(2)(C) of the FFDCA. Although the notification is
effective for the purchaser of the substance manufactured by
the notifier, the notification is not effective for other
manufacturers of the same substance.
The legislation creates a premarket notification (PMN)
system for clearance by the FDA of substances to be used in
contact with food (i.e., food contact substances). Food contact
substances include a variety of materials (e.g., plastics and
paper), and their components, that are used to package,
transport, hold, and manufacture food, which substances come in
contact with food but are not intended to affect the food.
Under the PMN system, any manufacturer or supplier may file
with FDA a notification providing complete information
supporting the safe use of a food contact substance. The
notifying party may lawfully market and use the food contact
substance 120 days after the date such a filing is received,
unless FDA determines that the notifier has not provided
information showing that the substance is safe, and informs the
notifier of this determination and the basis for such
determination.
The legislation provides an alternate system for the
clearance of food contact substances that, in most cases, will
replace for such substances the current food additive petition
process established under the Food Additives Amendment of 1958.
The legislation expressly provides that the petition process
will remain available for certain food contact substances.
Section 617 will encourage and expedite the development and
introduction of new food contact substances and new uses of
existing substances without sacrificing the protection afforded
consumers against unsafe substances in the food supply.
The need for this legislation arises from the fact that the
Food Additives Amendment of 1958 requires FDA to regulate two
different types of products in the same way, without due regard
for their different public health and safety implications.
These two categories of products are ``direct food additives,''
which are intended to have a specific technical effect in the
food and are intended to be ingested as part of the food
supply, and ``food contact substances'' (often described as
``indirect food additives'' under the current regulatory
system), which are intended to contact food but are not
intended to have a technical effect in the food and whose
ingestion is incidental to their use.
Under the Food Additives Amendment of 1958, both categories
of substances are subject to the same regulatory procedures and
requirements in that both must go through the full food
additive petition process. Furthermore, (with the exception of
substances regulated under 21 CFR Sec. 170.39), lawful use of
either a direct food additive or a food contact substance
requires, following FDA safety review, publication of a
regulation in the Federal Register specifying the conditions
under which the substance can be safely used.
FDA regulation of these two different classes of products
in the same way results in a significant expenditure of
resources by the agency and by the industry on the premarket
clearance of food contact substances that in many cases is out
of proportion to any resulting increase in public health
protection. Petitions for regulation of food contact substances
outnumber those for direct additives by a substantial margin.
At present, FDA does not have the resources to complete the
review of all food additive petitions for food contact
substances within the current statutory time frame of 180 days
and also carry out its other important public health
responsibilities, including review of direct additives.
The committee is aware that reports indicate that the many
companies in the United States which now market globally are
experiencing even more severe delays in securing product
clearances in those parts of the world that are adopted
regulatory approaches for food contact materials similar to
that used here since 1958. Adoption of the PMN concept may
provide a useful model for changes in the rest of the world and
could, thereby, advance the goal of international harmonization
of regulatory systems.
Most food contact substances pose relatively little
potential risk to consumers because their use results in only
very low potential exposure to the substances in the diet.
Indeed, the Agency in recent years has implemented initiatives
to expedite and review of low-risk food contact substances.
These initiatives include implementation of a Threshold of
Regulation (TOR) rule, under which FDA has exempted from the
need for a food additive regulation food additives that are
used at a level that results in a dietary concentration below
the threshold set in the rule. The TOR approach to regulating
food additives is a thoroughly developed public policy, which
has been widely and publicly debated.
The premarket notification program builds upon FDA's almost
40 years of experience in reviewing and regulating food contact
substances, and upon its more recent experience with the TOR
approach to the review of low-risk additives. Such a program
will continue to ensure the safe use of these additives,
without requiring agency premarket review of food additive
petitions and publication of orders in the Federal Register.
Because of considerations such as level of consumption or
potential toxicity, the committee recognizes that some uses of
food contact substances may require premarket review and
approval under Sec. 409 in order to ensure their safe use. The
legislation is thus drafted to permit the agency to exclude
those uses of food contact substances from eligibility for
premarket notification, based on its experience with the safety
review of these food additives. A premarket notification system
for food contact substances would improve allocation of scarce
agency resources by allowing the agency to reduce the resources
spent on reviewing low-risk food additives, including most food
contact substances. This more efficient use of resources will
allow the Agency to focus on premaket review of those additives
with the greatest potential for risk to consumers.
A PMN is intended to be specific to the manufacturer or
supplier that files it and the particular product that is the
subject of the notification. This approach differs from food
additive regulations, which are generic regulations that permit
anyone, not just the petitioner, to manufacture the food
additive (subject to any patent restrictions). For the
regulated industry, there will still be costs associated with
preparing and filing a PMN that provides much of the same
information currently required for a food additive petition.
However, because of the shorter turnaround time, increased
predictability, and proprietary nature of the PMN, these costs
will be recouped much more quickly.
FDA also will benefit from the PMN system. The demands on
the agency's resources to address food contact substances will
be brought into line with the low potential risk associated
with most of these products. As a result, the PMN system for
food contact substances should free resources for dedication to
more pressing issues.
FDA also is likely to receive more information on the use
of all food contact substances in the American food supply
since more manufacturers and suppliers are likely to submit
PMN's than currently submit food additive petitions. In
addition, the increased predictability will increase the
incentive for companies to make FDA aware of new uses of food
contact substances. As a result, the agency should have an
improved data base to assess total exposure to food contact
materials. These additional data will ultimately benefit the
public health by providing FDA with more information on the
identity and levels of food contact substances in use. FDA will
then be able to more effectively monitor these substances and
respond to any public health problems that may arise.
Health claims of food products
This legislation makes amendments to section 403(r) of the
Federal Food, Drug, and Cosmetic Act to authorize truthful,
nonmisleading health claims that are based on the published
authoritative statements of scientific bodies of the U.S.
Government with official responsibility for public health
protection or research directly relating to human nutrition.
It has been the concern of the Congress from the start of
the nutrition labeling reform process begun nearly a decade ago
that health claims be authorized when they are supported by
appropriate scientific evidence and are stated in a truthful,
nonmisleading manner. Such claims serve the public health by
helping to disseminate important health information to the
public promptly, and at the point of purchase where they can
help shape healthful consumer food choices.
Under existing section 403(r)(3), health claims can be made
for food only after FDA issues a regulation authorizing the
specific claim. This same preclearance requirement applies to
all health claims--from the novel claim, to the claim that
would be supported by the authoritative statement of an
official public health agency of the Federal Government. This
procedure is inefficient and fails adequately to benefit from
the deliberative processes in which authoritative scientific
bodies engage in issuing statements on matters of public
health. Important Federal public health organizations, as part
of their official responsibilities, routinely review the
scientific evidence pertinent to diet and disease
relationships, and publish statements developed through such
reviews. The Surgeon General and National Academy of Sciences
have published authoritative reports on such relationships. The
National Cancer Institute has issued pamphlets recommending
food choices to reduce the risk of cancer. The National Heart,
Lung, and Blood Institute has issued a range of authoritative
publications aimed at reducing the risk of hypertension and
heart disease in the United States population.
The failure of the current system to give adequate weight
to the statements of such authoritative bodies, coupled with
the prohibitive economic burden that permits only the largest
food companies and trade organizations to file a health claim
petition to gain approval of a new health claim, has deprived
the public of the full disease prevention benefits health
claims were intended to provide.
This legislation maintains the rigorous scientific standard
health claims must meet under existing law but streamlines the
procedure for making health claims when the scientific basis
fora claim has been developed by an authoritative scientific
body outside FDA. This procedure targets regulatory resources more
effectively, and promises to benefit public health substantially more
than the current system.
The history of the folic acid and neural tube defects
health claim dramatizes the critical need for this legislation.
In 1992, the Centers for Disease Control and Prevention (CDC)
issued the following recommendation to women of childbearing
age, aimed at reducing the risk of pregnancies affected by
neural tube birth defects:
All women of childbearing age in the United States
who are capable of becoming pregnant should consume 0.4
mg of folic acid per day for the purpose of reducing
their risk of having a pregnancy affected with spina
bifida or [other neural tube defects].
Centers for Disease Control, 41 Morbidity and Mortality Weekly
Report (September 11, 1992). The CDC estimated that this
recommendation could reduce the number of cases of spina bifida
and other neural tube defects in the United States by 50
percent.
Despite the significant scientific agreement among
qualified experts concerning the evidence supporting the
recommendation, manufacturers of foods containing folic acid
were prohibited from making claims about the benefit of folic
acid in reducing the risk of neural tube defects until FDA
approved the claim through a notice and comment rulemaking
procedure.
Without appropriately accounting for the CDC
recommendation, FDA promulgated a rule in January 1993,
prohibiting claims concerning the relationship. In the wake of
controversy concerning FDA's action, and despite the absence of
any change in the scientific evidence, the Agency reversed
course, proposing to authorize such claims in October, 1993.
Final regulations authorizing the claim were promulgated in
March 1996. Undoubtedly, many children suffered from
preventable neural tube defects as a result of FDA's delay in
authorizing health claims based on the 1992 CDC recommendation.
The amendments this legislation makes to section 403(r)(3)
of the Federal Food Drug and Cosmetic Act would prevent a
recurrence of the kind of problem presented by the folic acid/
neural tube defect claim. While the legislation makes no change
to the existing standards governing the health claim approval
process, it establishes an alternative procedure by which
health claims supported by an authoritative statement of an
appropriate scientific body of the U.S. Government are
authorized. Such claims could be made after premarket
notification to FDA, without the delay that accompanies the
rulemaking process. The legislation would require manufacturers
intending to make such a health claim to submit a premarket
notice to FDA concisely describing the claim and the
authoritative statement relied upon. The notice would be
submitted at least 120 days before the first introduction of a
food bearing the claim into interstate commerce.
Although the legislation would eliminate the requirement
for FDA approval of such claims, it would continue to require
foods to conform to the ``disqualifying nutrient levels''
established by FDA under section 403(r)(3)(A)(ii) and require
all health claims to be presented in a truthful, nonmisleading
manner in conformance with sections 403(a) and 201(n) of the
Federal Food Drug and Cosmetic Act. For example, a food bearing
a truthful health claim based on an authoritative statement
would need to make a material dietary contribution of the
substance to which the claim refers to meet the requirements of
sections 403(a) and 201(n). The legislation specifically
mandates that a health claim accurately represent the
authoritative statement on which it is based, and be presented
in a manner enabling the public to comprehend the significance
of the claim in the context of a total diet.
The agency retains full authority to take enforcement
action against a health claim that mischaracterizes the
authoritative statement upon which it is based, or that is
otherwise misleading. The 120 day premarket notice requirement
would enable FDA to identify misleading claims and take action
to prevent their use before products bearing such claims are
introduced to the market. In response to notifications filed by
dietary supplement manufacturers concerning claims made under
section 403(r)(6) of the Act, a provision adopted as part of
the Dietary Supplement Health and Education Act of 1994, FDA
issues ``courtesy letters'' promptly alerting manufacturers
when claims submitted in their notification present a risk of
enforcementaction. Such an approach is an efficient and
effective means of deterring manufacturers from making violative
claims.
Under this legislation, the agency retains the full range
of enforcement powers it has possessed historically to remedy
misleading claims, including the powers of product seizure,
injunction, and criminal penalties. In addition, new section
403(r)(3)(D) assures that FDA retains full authority to
regulate health claims based on the statements of authoritative
bodies through rulemaking. Once FDA regulations governing
health claims concerning a particular diet/disease relationship
(e.g., calcium and osteoporosis) have become effective, no
claim concerning that diet/disease relationship based on the
statement of an authoritative scientific body could be made
unless it is consistent with the FDA regulation. The
legislation specifically provides that FDA may prohibit or
modify such health claims through rulemaking. In any such
proceeding, the standards and criteria for health claims
prescribed in section 403(r)(3) and implementing regulations,
including the significance scientific agreement standard, would
be fully applicable.
Pediatric studies of drugs
When it comes to pharmaceuticals, our Nation's children are
``therapeutic orphans.'' Currently, less than 20 percent of the
prescription medications on the United States market are
approved for use in the pediatric population and labeled for
pediatric use. Pediatricians using drugs developed with adults
in mind but which may also be effective or be the only option
for treating the same illnesses and diseases in children must
estimate dosages from dosages found to be safe and effective in
adults. Such estimates are uncertain because children, and
particularly those under 2 years of age, often metabolize drugs
differently than do adults. Further, some drugs have different
side effects and/or toxicities in children than in adults even
when appropriate doses are used.
For these reasons, pediatricians have long had an active
interest in promoting clinical studies of drugs in pediatric
populations so that the drugs may be labeled for pediatric use.
However, there is little incentive for drug sponsors to perform
studies for medications which they intend to market primarily
for adults and whose use in children is expected to generate
little additional revenue. Pediatric studies pose ethical and
moral issues relating to using new unapproved drugs in young
patients. Second, there are substantial product liability and
medical malpractice issues. Third, pediatric patients are more
difficult to attract into studies. Fourth, for some drugs,
pediatric use represents more difficult issues of drug
administration and patient compliance than adult use.
The FDA has sought to address this problem by using its
authority to approve labeling based upon the known
pharmacokinetics of the drug, as opposed to requiring pediatric
clinical trials for efficacy. The FDA has also issued
regulations that embody this policy in an attempt to encourage
pediatric labeling. These are clearly steps in the right
direction, and the committee commends the FDA's initiatives in
this area.
The legislation takes a modest further step toward a better
resolution of this problem by providing an additional 6 months
of market exclusivity when a drug manufacturer, at the request
of the FDA, conducts pediatric studies to support pediatric
labeling for a drug, either before the new drug approval
application is submitted or later.
Positron emission tomography
The committee intends in section 619 to provide a new
framework for the regulation of radiotracers used in positron
emission tomography (PET) scans based on standards set by the
United States Pharmacopoeia (USP) and enforced by the FDA and
state boards of pharmacy and medicine.
The committee intends to require that PET radiotracers meet
the standards set by the USP for safety, efficacy and
compounding, and that the FDA or state agencies will enforce
the standards set by the USP. The Committee does not intend
that the FDA set its own standards for compounding of PET
drugs. Makers and users of PET radiotracers will continue to be
subject to the requirements of the various state boards of
medicine and pharmacy which they are currently required to
meet.
USP standards are recognized in the FFDCA in the
adulteration and misbranding sections of the Act (Secs.
501(b)and 502 respectively). USP establishes standards for all marketed
drugs in the U.S. It first provided standards for PET pharmaceuticals
in 1988. During these years, USP standards have served to standardize
and help assure the quality of these items and protect the public
health. USP establishes standards for drugs through a rigorous peer
reviewed process, and the FDA provides input and comment to USP as part
of this process.
Section 619(a) amends the FFDCA to add a definition of a
``compounded positron emission tomography drug'' to mean a PET
drug (and associated software and hardware) which has been
compounded in accordance with State law by or on the order of a
practitioner licensed in that State or in a Federal facility in
accordance with the law of the State in which it is located.
Section 619(b) amends the FFDCA to provide that a
compounded PET drug is adulterated, and thus subject to
regulatory and/or legal action by FDA, if it is compounded,
processed, packed, or held other than in accordance with the
PET compounding standards and the official monographs of the
USP.
Section 619(c) amends the FFDCA to provide that neither a
New Drug Application (NDA) nor an Abbreviated New Drug
Application (ANDA) is required by a licensed practitioner to
produce a compounded PET drug produced in accordance with USP
standards.
Section 619(d) requires the revocation of certain Federal
Register notices which announced a rule inconsistent with this
legislation.
PET is an imaging technique that produces a computerized
image (scan) using small quantities of a radioactive tracer to
measure biochemical activity in the body. It has been
demonstrated to be an extremely effective method of separating
benign from malignant lesions, staging the degree of
metastasis, determining therapeutic effectiveness and
identifying early recurrence of disease in several types of
cancer, including lung, breast, colorectal, head and neck. In
addition, PET has a high degree of accuracy in identifying
early signs of coronary artery disease and in assessing whether
cardiac tissue is alive following a heart attack. In more than
one million uses of PET tracers in Europe and one million in
the United States, the Committee is unaware of any reported
instance of an adverse reaction to PET radiotracers. PET
radiopharmaceuticals have been used in patients in the United
States for over 30 years. Recent research and advances in
imaging technology have enhanced the clinical importance of
PET.
PET radiotracers are unique among radiopharmaceuticals
because of their short half-lives, ranging from 30 seconds to
110 minutes. Therefore, most PET radiotracers are made using a
cyclotron which is at or near the PET site, and most are made
up on an individual dose basis upon the prescription of a
licensed physician. At present, there are 70 PET centers in the
United States, almost all of which are part of academic medical
centers. PET technology and its applications were developed in
large part with almost $2 billion in federal research funds.
Yet, while PET is widely used in Europe, its benefits have not
been widely available to American patients, mainly because of
lack of reimbursement and inappropriate and costly regulations
promulgated by FDA.
Under current FDA regulations, PET centers which compound
PET radiopharmaceuticals on an individual dose basis would be
required to meet FDA's CGMP and to file NDA's and ANDA's for
each type of PET tracer and for each indication for which the
tracer might be used. This is the same type of regulation which
the FDA applies to large pharmaceutical manufacturers.
Academic medical centers are facing unprecedented cost
pressures. Without regulatory relief and expanded
reimbursement, particularly from the Medicare program, many PET
centers are likely to close, and the benefits of PET will be
unavailable to the taxpayers who funded their development. For
example, the University of California at Los Angeles estimated
that FDA's new PET regulations would cost the University at
least $300,000 for a single application for a single use of a
PET radiotracer.
The committee intends that adoption of this section will
establish a regulatory framework for PET drugs that will enable
PET centers to continue to make this valuable technology
available to patients at reasonable cost and assure that the
public health will be protected.
Title VII--Fees Relating to Drugs
The legislation reauthorizes the Prescription Drug User Fee
Act of 1992 (PDUFA I) to allow the continued collection of user
fees from prescription drug manufacturers for five additional
years. PDUFA I represented a consensus among the FDA, the
prescription drug industry, and Congress that the industry
would pay user fees to augment the resources of the FDA devoted
to the review of human drug applications. PDUFA I has succeeded
in substantially reducing review times for human drug
applications.
The PDUFA I legislation was accompanied by side letters
signed by the Commissioner of Food and Drugs and the Chairs and
Ranking Minority Members of the House Energy and Commerce
Committee and the Senate Labor and Human Resources Committee.
The side letters committed FDA to achieving certain performance
measures including:
Review and act on priority new drug and biologic
applications within 6 months:
Review and act on standard new drug and biologic
applications with 12 months;
Review and act on priority supplements and amendments
within 6 months;
Review and act on standard supplements and amendments
that do not require clinical data within 6 months;
Review and act on standard supplements and amendments
with clinical data within 12 months; and
Review and act on resubmitted applications within 6
months.
Title VII of S. 830 (PDUFA II) would build on PDUFA I by
including new commitments from FDA to implement more ambitious
and comprehensive improvements in its regulatory process. PDUFA
I focused on reducing the length of time taken by FDA in
reviewing an application. The committee commends FDA for
successfully meeting and at times exceeding the performance
goals established in PDUFA I. However, while review times for
submitted applications have improved, the period of time taken
to get a drug through the drug development phase has increased
from 2 years to seven years. Appropriately, PDUFA II will focus
on shortening overall development time and streamlining
interaction with FDA required of a drug innovator during the
highly regulated drug development phase and establish new
performance measures and procedures for FDA designed to reduce
the amount of time needed to take a drug from clinical testing
phase to the point where an application may be submitted for
review.
The legislation provides that the FDA's fiscal year 1997
appropriations will become the new PDUFA baseline
appropriation, adjusted for inflation after fiscal year 1998,
over the next five years. The bill assumes that for Fiscal year
1998, FDA will receive at least the Fiscal year 1997 level of
appropriated funds for salaries and expenses. It specifies
exactly what the application and supplemental fees will be per
product for the next five years, subject to adjustment for
inflation. In addition, it defines small businesses as those
with fewer than 500 employees, and allows a waiver for such
businesses fee payments on their first human drug applications.
FDA would continue to be required to send Congress annually a
financial report on how it spent PDUFA fees and report on
whether and how FDA met the new performance goals which focus
on expediting the drug development process and the review of
human drug applications.
The differences between PDUFA I and PDUFA II can be divided
into two categories. The first category of changes pertains to
financial provisions and performance goals. Among other things,
these changes include the increase in fees from PDUFA I to
accommodate enhanced performance by FDA and the adjustment of
total fees each year to reflect a changing FDA workload. As
with PDUFA I, revised performance goals will be set forth in
letters from the Secretary of the Department of Health and
Human Services official to the Chairman and Ranking Minority
Members of the House Commerce Committee and Senate Committee on
Labor and Human Resources. This letter is incorporated by
reference in the Findings section of Title VII of the bill. The
committee intends that the provisions be fully binding on the
agency and should be considered as minimum not maximum
commitments.
The second category of changes includes technical changes
and other improvements which primarily relate to fee collection
and exemptions from fees, including language providing the
Secretary flexibility to take into account special
circumstances associated with user fee waiver applications.
These special circumstances may include the ability to
stimulate innovation inbiomedical research by providing special
waivers or discounts to applicants participating in innovative research
development projects located in Federal empowerment and enterprise
zones. A detailed review of the performance goals and other measures
covered by PDUFA II, referenced in Section 702 of the bill, are
reflected in the exchange of letters that follow below.
These performance measures, agreed to by FDA officials and
the boards of the Biotechnology Industry Organization and the
Pharmaceutical Research and Manufacturers of America, are
contingent upon the level of appropriated funds for the FDA set
forth in the legislation. The committee observes that PDUFA I
was successful in large part because the underlying assumption
regarding steadily increasing appropriations levels available
to FDA was in fact borne out. The committee cautions that this
key assumption can not be taken for granted over the next five
years in light of the overriding imperative to reduce the
Federal budget deficit and the complicating factors contributed
by the President's proposed budget cut for the FDA in fiscal
year 1998.
Finally, the committee notes that the Food, Drug, and
Cosmetic Act gives the Secretary of HHS discretion to grant a
waiver from, or a reduction of 1 or more user fees where the
Secretary finds ``the assessment of the fee would present a
significant barrier to innovation because of limited resources
available to such person or other circumstances.'' This
language is intended to provide the Secretary flexibility to
take into account special circumstances associated with user
fee waiver applications including the ability to stimulate
innovation in biomedical research by providing special waivers
or discounts to applicants participating in innovative research
development projects in federal empowerment and enterprise
zones.
proposed pdufa ii performance goals and procedures
The proposed performance goals and procedures of the FDA
Center for Drug Evaluation and Research (CDER) and the Center
for Biologics Evaluation and Research (CBER), contingent upon
resolution of Agency and program budget issues, are summarized
as follows:
a. five-year review performance goals
Fiscal year 1998
1. Review and act on 90 percent of standard original New
Drug Application (NDA's) and Product License Applications
(PLA's)/Biologic License Applications (BLA's) filed during
fiscal year 1998 within 12 months of receipt.
2. Review and act on 90 percent of priority original NDA
and PLA/BLA submissions filed during fiscal year 1998 within 6
months of receipt.
3. Review and act on 90 percent of standard efficacy
supplements filed during fiscal year 1998 within 12 months of
receipt.
4. Review and act on 90 percent of priority efficacy
supplements filed during fiscal year 1998 within 6 months of
receipt.
5. Review and act on 90 percent of manufacturing
supplements filed during fiscal year 1998 within 6 months of
receipt.
6. Review and act on 90 percent of all resubmitted original
applications filed during fiscal year 1998 within 6 months of
receipt, and review and act on 30 percent of class 1
resubmitted original applications within 2 months of receipt.
Fiscal year 1999
1. Review and act on 90 percent of standard original NDA
and PLA/BLA submissions filed during fiscal year 1999 within 12
months of receipt and review and act on 30 percent within 10
months of receipt.
2. Review and act on 90 percent of priority original NDA
and PLA/BLA submissions filed during fiscal year 1999 within 6
months of receipt.
3. Review and act on 90 percent of standard efficacy
supplements filed during fiscal year 1999 within 12 months of
receipt and review and act on 30 percent within 10 months of
receipt.
4. Review and act on 90 percent of priority efficacy
supplements filed during fiscal year 1999 within 6 months of
receipt.
5. Review and act on 90 percent of manufacturing
supplements filed during fiscal year 1999 within 6 months of
receipt and review and act on 30 percent of manufacturing
supplements requiring prior approval within 4 months of
receipt.
6. Review and act on 90 percent of class 1 resubmitted
original applications filed during fiscal year 1999 within 4
months of receipt and review and act on 50 percent within 2
months of receipt.
7. Review and act on 90 percent of class 2 resubmitted
original applications filed during fiscal year 1999 within 6
months of receipt.
Fiscal year 2000
1. Review and act on 90 percent of standard original NDA
and PLA/BLA submissions filed during fiscal year 2000 within 12
months of receipt and review and act on 50 percent within 10
months of receipt.
2. Review and act on 90 percent of priority original NDA
and PLA/BLA submissions filed during fiscal year 2000 within 6
months of receipt.
3. Review and act on 90 percent of standard efficacy
supplements filed during fiscal year 2000 within 12 months of
receipt and review and act on 50 percent within 10 months of
receipt.
4. Review and act on 90 percent of priority efficacy
supplements filed during fiscal year 2000 within 6 months of
receipt.
5. Review and act on 90 percent of manufacturing
supplements filed during fiscal year 2000 within 6 months of
receipt and review and act on 50 percent of manufacturing
supplements requiring prior approval within 4 months of
receipt.
6. Review and act on 90 percent of class 1 resubmitted
original applications filed during fiscal year 2000 within 4
months and review and act on 50 percent within 2 months of
receipt.
7. Review and act on 90 percent of class 2 resubmitted
original applications filed during fiscal year 2000 within 6
months of receipt.
Fiscal year 2001
1. Review and act on 90 percent of standard original NDA
and PLA/BLA submissions filed during fiscal year 2001 within 12
months of receipt and review and act on 70 percent within 10
months of receipt.
2. Review and act on 90 percent of priority original NDA
and PLA/BLA submissions filed during fiscal year 2001 within 6
months of receipt.
3. Review and act on 90 percent of standard efficacy
supplements filed during fiscal year 2001 within 12 months of
receipt and review and act on 50 percent within 10 months of
receipt.
4. Review and act on 90 percent of priority efficacy
supplements filed during fiscal year 2001 within 6 months of
receipt.
5. Review and act on 90 percent of manufacturing
supplements filed during fiscal year 2001 within 6 months of
receipt and review and act on 70 percent of manufacturing
supplements requiring prior approval within 4 months of
receipt.
6. Review and act on 90 percent of class 1 resubmitted
original applications filed during fiscal year 2001 within 4
months and review and act on 70 percent within 2 months of
receipt.
7. Review and act on 90 percent of class 2 resubmitted
original applications within 6 months of receipt.
Fiscal year 2002
1. Review and act on 90 percent of standard original NDA
and PLA/BLA submissions filed during fiscal year 2001 within 12
months of receipt.
2. Review and act on 90 percent of priority original NDA
and PLA/BLA submissions filed during fiscal year 2001 within 6
months of receipt.
3. Review and act on 90 percent of standard efficacy
supplements filed during fiscal year 2001 within 10 months of
receipt.
4. Review and act on 90 percent of priority efficacy
supplements filed during fiscal year 2001 within 6 months of
receipt.
5. Review and act on 90 percent of manufacturing
supplements filed during fiscal year 2001 within 6 months of
receipt and review and act on 90 percent of manufacturing
supplements requiring prior approval within 4 months of
receipt.
6. Review and act on 90 percent of class 1 resubmitted
original applications within 6 months of receipt.
7. Review and act on 90 percent of class 2 resubmitted
original applications within 6 months of receipt.
These review goals are summarized in the following tables:
Original NDA's/BLA's/PLA's and Efficacy Supplements:
------------------------------------------------------------------------
Submission cohort Standard Priority
------------------------------------------------------------------------
Fiscal year 1998............... 90 percent in 12 90 percent in 6 mo.
mo.
Fiscal year 1999............... 30 percent in 10 90 percent in 6 mo.
mo.
90 percent in 12
mo
Fiscal year 2000............... 50 percent in 10 90 percent in 6 mo.
mo.
90 percent in 12
mo
Fiscal year 2001............... 70 percent in 10 90 percent in 6 mo.
mo.
90 percent in 12
mo
Fiscal year 2002............... 90 percent in 10 90 percent in 6 mo.
mo.
------------------------------------------------------------------------
Manufacturing supplements:
------------------------------------------------------------------------
Manufacturing
supplements that
do not require Manufacturing
prior approval supplements that do
Submission cohort (``changes being require prior
effected'' or approval
``30-day
supplements''
------------------------------------------------------------------------
Fiscal year 1998............... 90 percent in 6 90 percent in 6 mo.
mo.
Fiscal year 1999............... 90 percent in 6 30 percent in 4 mo.
mo. 90 percent in 6 mo.
Fiscal year 2000............... 90 percent in 6 50 percent in 4 mo.
mo. 90 percent in 6 mo.
Fiscal year 2001............... 90 percent in 6 70 percent in 4 mo.
mo. 90 percent in 6 mo.
Fiscal year 2002............... 90 percent in 6 90 percent in 4 mo.
mo.
------------------------------------------------------------------------
Resubmission of original NDA's/BLA's/PLA's:
------------------------------------------------------------------------
Submission cohort Class 1 Class 2
------------------------------------------------------------------------
Fiscal year 1998............... 90 percent in 6 90 percent in 6 mo.
mo.
30 percent in 2
mo
Fiscal year 1999............... 90 percent in 4 90 percent in 6 mo.
mo.
50 percent in 2
mo
Fiscal year 2000............... 90 percent in 4 90 percent in 6 mo.
mo.
70 percent in 2
mo
Fiscal year 2001............... 90 percent in 2 90 percent in 6 mo.
mo.
Fiscal year 2002............... 90 percent in 2 90 percent in 6 mo.
mo.
------------------------------------------------------------------------
b. new molecular entity (nme) performance goals
The performance goals for standard and priority original
NME's in each submission cohort will be the same as for all of
the original NDA's (including NME's) in each submission cohort
but shall be reported separately.
For biological products, for purposes of this performance
goal, all original BLAs/PLAs will be considered to be NMEs.
c. meeting management goals
1. Responses to meeting requests
a. Procedure: Within 14 calendar days of the agency's
receipt of a request from industry for a formal meeting (i.e.,
a scheduled face-to-face, teleconference, or videoconference)
CBER and CDER should notify the requester in writing (letter or
fax) of the date, time, and place for the meeting, as well as
expected Center participants.
b. Performance Goal: FDA will provide this notification
within 14 days for 70 percent of requests (based on request
receipt cohort year) starting in FY99; 80 percent in FY00; and
90 percent in subsequent fiscal years.
2. Scheduling meetings
a. Procedure: The meeting date should reflect the next
available date on which all applicable Center personnel are
available to attend, consistent with the component's other
business; however, the meeting should be scheduled consistent
with the type of meeting requested. If the requested date for
any of these types of meetings is greater than 30, 60, or 75
calendar days (as appropriate) from the date the request is
received by the agency, the meeting date should be within 14
calendar days of the date requested.
Type A meetings should occur within 30 calendar days of the
agency receipt of the meeting request.
Type B meetings should occur within 60 calendar days of the
agency receipt of the meeting request.
Type C meetings should occur within 75 calendar days of the
agency receipt of the meeting request.
b. Performance goal: 70 percent of meetings are held within
the timeframe (based on cohort year of request) starting in
FY99; 80 percent in FY00; and 90 percent in subsequent fiscal
years.
3. Meeting minutes
a. Procedure: The agency will prepare minutes which will be
available to the sponsor 30 calendar days after the meeting.
The minutes will clearly outline the important agreements,
disagreements, issues for further discussions, and action items
from the meeting in bulleted form and need not be in great
detail.
b. Performance goal: 70 percent of minutes are issued
within 30 calendar days of date of meeting (based on cohort
year of meeting) starting in FY99; 80 percent in FY00; and 90
percent in subsequent fiscal years.
4. Conditions
For a meeting to qualify for these performance goals:
a. A written request (letter or fax) should be
submitted to the review division; and
b. The letter should provide:
i. A brief statement of the purpose of the
meeting;
ii. A listing of the specific objectives/
outcomes the requester expects from the
meeting;
iii. A proposed agenda, including estimated
times needed for each agenda item;
iv. A listing of planned external attendees;
v. A listing of requested participants/
disciplines representative(s) from the Center;
vi. The approximate time that supporting
documentation (i.e., the ``backgrounder'') for
the meeting will be sent to the Center (i.e.,
``x'' weeks prior to the meeting, but should be
received by the Center at least 2 weeks in
advance of the scheduled meeting for Type or C
meetings and at least 1 month in advance of the
scheduled meeting for Type B meetings; and
c. The agency concurs that the meeting will serve a
useful purpose (i.e., it is not premature or clearly
unnecessary). However, requests for a ``Type B''
meeting will be honored except in the most unusual
circumstances.
D. CLINICAL HOLDS
1. Procedure: The Center should respond to a sponsor's
complete response to a clinical hold within 30 days of the
agency's receipt of the submission of such sponsor response.
2. Performance goal: 75 percent of such responses are
provided within 30 calendar days of the Agency's receipt of the
sponsor's response starting in FY98 (cohort of date of receipt)
and 90 percent in subsequent fiscal years.
E. Major dispute resolution
1. Procedure: For procedural or scientific matters
involving the review of human drug products (as defined in
PDUFA) that cannot be resolved at the divisional level
(including a request for reconsideration by the Division after
reviewing any materials that are planned to be forwarded with
an appeal to the next level), the response to appeals of
decisions will occur within 30 calendar days of the Center's
receipt of the written appeal.
2. Performance goal: 70 percent of such answers are
provided within 30 calendar days of the Center's receipt of the
written appeal starting in FY99; 80 percent in FY00; and 90
percent in subsequent fiscal years.
3. Conditions.
a. Sponsors should first try to resolve the procedural or
scientific issue at the Division level. If it cannot be
resolved at that level, it should be appealed to the Office
Director level (with a copy to the Division Director) and then,
if necessary, to the Deputy Center Director or Center Director
(with a copy to the Office Director).
b. Responses should be either verbal (followed by a written
confirmation within 14 calendar days of the verbal
notification) or written and should ordinarily be to either
deny or grant the appeal.
c. If the decision is to deny the appeal, the response
should include reasons for the denial and any actions the
sponsor might take in order to persuade the agency to reveres
its decision.
d. In some cases, further data or further input from others
might be needed to reach a decision on the appeal. In these
cases, the ``response'' should be the plan for obtaining that
information (e.g., requesting further information from the
sponsor, scheduling a meeting with the sponsor, scheduling the
issue for discussion at the next scheduled available advisory
committee).
e. In these cases, once the required information is
received by the agency (including any advice from an advisory
committee), the person to whom the appeal was made, again has
30 calendar days from the receipt of the required information
in which to either deny or grant the appeal.
f. Again, if the decision is to deny the appeal, the
response should include the reasons for the denial and any
actions the sponsor might take in order to persuade the agency
to reverse its decision.
g. N.B.: If the agency decides to present the issue to an
advisory committee and there are not 30 days before the next
scheduled advisory committee, the issue will be presented at
the following scheduled committee meeting in order to allow
conformance with advisory committee administrative procedures.
F. SPECIAL PROTOCOL QUESTION ASSESSMENT AND AGREEMENT
1. Procedure: Upon specific request by a sponsor (including
specific questions that the sponsor desiresto be answered), the
agency will evaluate certain protocols and issues to assess whether the
design is adequate to meet scientific and regulatory requirements
identified by the sponsor.
a. The sponsor should submit a limited number of specific
questions about the protocol design and scientific and
regulatory requirements for which the sponsor seeks agreement
(e.g., is the dose range in the carcinogenicity study adequate,
considering the intended clinical dosage; are the clinical
endpoints adequate to support a specific such an.
b. Within 45 days of agency receipt of the protocol and
specific questions, the agency will provide a written response
to the sponsor that includes a succinct assessment of the
protocol and answers to the questions posed by the sponsor. If
the agency does not agree that the protocol design, execution
plans, and data analyses are adequate to achieve the goals of
the sponsor, the reasons for the disagreement will be explained
in the response.
c. Protocols that qualify for this program include:
carcinogenicity protocols, stability protocols, and Phase 3
protocols for clinical trials that will form the primary basis
of an efficacy claim. (For such Phase 3 protocols to qualify
for this comprehensive protocol assessment, the sponsor must
have had an end of Phase 2/pre-Phase 3 meeting with the review
division so that the division is aware of the developmental
context in which the protocol is being reviewed and the
questions being answered.)
d. N.B.: For products that will be using Subpart E or
Subpart H development schemes, the Phase 3 protocols mentioned
in this paragraph should be construed to mean those protocols
for trials that will form the primary basis of an efficacy
claim no matter what phase of drug development in which they
happen to be conducted.
e. If a protocol is reviewed under the process outlined
above and agreement with the agency is reached on design,
execution, and analyses and if the results of the trial
conducted under the protocol substantiate the hypothesis of the
protocol, the agency agrees that the data from the protocol can
be used as part of the primary basis for approval of the
product. The fundamental agreement here is that having agreed
to the design, execution, and analyses proposed in protocols
reviewed under this process, the agency will not later alter
its perspective on the issues of design, execution, or analyses
unless public health concerns unrecognized at the time of
protocol assessment under this process are evident.
2. Performance goal: 60 percent of special protocols
assessments and agreement requests completed and returned to
sponsor within timeframes (based on cohort year of request)
starting in FY 99; 70 percent in FY00; 80 percent in Fiscal
year 01; and 90 percent in FY02.
g. electronic applications and submissions
The agency shall develop and update its information
management infrastructure to allow, by fiscal year 2002, the
paperless receipt and processing of INDs and human drug
applications, as defined in PDUFA, and related submissions.
h. additional procedures
1. Simplification of Action Letters.
To simplify regulatory procedures, the CBER and the CDER
intend to amend their regulations and processes to provide for
the issuance of either an ``approval'' (AP) or a ``complete
response'' (CR) action letter at the completion of a review
cycle for a marketing application.
2. Timing of Sponsor Notification of Deficiencies in
Applications.
To help expedite the development of drug and biologic
products, CBER and CDER intend to submit deficiencies to
sponsors in the form of an ``information request'' (IR) letter
when each discipline has finished its initial review of its
section of the pending application.
i. definitions and explanation of terms
1. The term ``review and act on'' is understood to mean the
issuance of a complete action letter after the complete review
of a filed complete application. The action letter, if it is
not an approval, will set forth in detail the specific
deficiencies and, where appropriate, the actions necessary to
place the application in condition for approval.
2. A major amendment to an original application submitted
within 3 months of the goal date extends the goal date by 3
months.
3. A resubmitted original application is a complete
response to an action letter addressing all identified
deficiencies.
4. Class 1 resubmitted applications are applications
resubmitted after a complete response letter (or a not
approvable or approvable letter) that include the following
items only (or combinations of these items):
a. Final printed labeling.
b. Draft labeling.
c. Safety updates submitted in the same format, including
tabulations, as the original safety submission with new data
and changes highlighted (except when large amounts of new
information including important new adverse experiences not
previously reported with the product are presented in the
resubmission).
d. Stability updates to support provisional or final dating
periods.
e. Commitments to perform Phase 4 studies, including
proposals for such studies.
f. Assay validation data.
g. Final release testing on the last 1-2 lots used to
support approval.
h. A minor reanalysis of data previously submitted to the
application (determined by the agency as fitting the class 1
category).
i. Other minor clarifying information (determined by the
agency as fitting the class 1 category).
j. Other specific items may be added later as the Agency
gains experience with the scheme and will be communicated via
guidance documents to industry.
5. Class 2 resubmissions are resubmissions that include any
other items, including any item that would require presentation
to an advisory committee.
6. A Type A meeting is a meeting which is necessary for an
otherwise stalled drug development program to proceed (a
``critical path'' meeting).
7. A Type B meeting is a (1) pre-IND, (2) end of Phase 1
(for Subpart E or Subpart H or similar products) or end of
Phase 2/pre-Phase 3, or (3) a pre-NDA/PLA/BLA meeting. Each
requestor should usually only request 1 each of these Type B
meetings for each potential application (NDA/PLA/BLA) (or
combination of closely related products, i.e., same active
ingredient but different dosage forms being developed
concurrently).
8. A Type C meeting is any other type of meeting.
Title VIII--Miscellaneous
Clarification of seizure authority
There are two situations under which FDA-regulated products
are imported into the United States and enter domestic
commerce. The first occurs when the product passes FDA and
Customs scrutiny at the border and is permitted entry into the
country. The second is under section 801(d)(3), as added by the
FDA Export Reform and Enhancement Act of 1996, which permits
products to be imported into the United States solely for
processing with the requirement that the finished product
subsequently be exported. Section 803 amends the seizure
provisions in section 304(d)(1) of the act to clarify that any
person who seeks to export an article that has been imported
under either of these conditions, pursuant to the export
provisions in section 801(e) of the Act, must demonstrate that
the article was intended for export at the time that it entered
commerce. The clarification of section 304(d) applies only to
seized and condemned imported articles and does not affect
articles proffered for import that are refused entry under
section 801(a) and properly exported within 90 days of refusal.
National uniformity for nonprescription drugs and cosmetics
The economic strength and vitality for consumer products in
the United States rests upon the tradition of one vast
nationwide marketplace, regulated by strong Federal and State
agencies committed to protecting the public health. An
essential element of a nationwide marketplace is a national
uniform system of regulation. It is intended that the FDA
provide national leadership in assuring the safety,
effectiveness, and proper labeling and packaging for
nonprescription drugs and cosmetics marketed throughout the
country, under the Federal Food, Drug, and Cosmetic Act, the
Poison Prevention Packaging Act, and the Fair Packaging and
Labeling Act.
Under our Federal system, it is important that State and
local officials enforce the same regulatory requirements for
products as do our Federal officials. Different or additional
requirements as the State or local level can work against our
national marketplace, confuse consumers, raise prices,
undermine public confidence in our regulatory system and in
products important to the public health, and result in
divergent public health protection throughout the country.
Federal law currently provides strong public health
protection for nonprescription drugs and cosmetics and their
constituents. Nonprescription drugs are subject to careful and
comprehensive regulation by the FDA. The conditions under which
nonprescription drugs are considered safe and effective, for
use by the lay consumer, are specified by FDA in
nonprescription drug monographs or by new drug and antibiotic
drug applications. FDA also ensures that the labeling of
nonprescription drugs provides adequate directions for use, and
adequate warnings against unsafe use, through these monographs
and drug marketing applications, as well as through a number of
general and specific labeling regulations. The FDA also has
strong legal authority to regulate cosmetics. A cosmetic is
considered adulterated if it contains a substance that may be
injurious to users. The FDA has required that every cosmetic
ingredient and every finished cosmetic product be substantiated
for safety before it can be marketed. A cosmetic is misbranded
if the safety of the product or an ingredient has not been
established prior to marketing and that fact is not disclosed
in a label warning. FDA also requires all ingredients to be
declared on the label of cosmetics. For both nonprescription
drugs and cosmetics, the FDA has clear statutory authority to
require warnings or to ban unsafe ingredients. Use of any
unsafe ingredient, or any false or misleading labeling, for a
nonprescription drug or a cosmetic is unlawful and subject to
regulatory action. The FDA authority in this area extends from
manufacture through retail sale of these products.
Section 808 of the legislation therefore established a new
section 761 of the Federal Food, Drug, and Cosmetic Act that
adopts, as a general rule, the requirement of national
uniformity in the regulation of nonprescription drugs and
cosmetics and their constituents. No State or local government
is permitted to impose different or additional requirements
that relate to the subject matter covered by the three Federal
laws as they apply to nonprescription drugs and cosmetics.
These include requirements imposed on product manufacture or
composition, labeling, advertising, or any other form of public
notification or communication.
Under the legislation, all States may vigorously enforce
requirements for nonprescription drugs and cosmetics that are
identical to the Federal requirements, including the Federal
prohibition against the adulteration or misbranding of these
products. Most States have enacted laws regulating
nonprescription drugs and cosmetics, based on the Federal laws,
that prohibit the adulteration or misbranding of these products
in the same terms as the Federal laws. These identical State
requirements may be enforced by State officials, without first
notifying the FDA or obtaining any Federal approval, using
compliance powers that are different from or in addition to the
Federal compliance mechanisms, e.g., the power of a State to
order an embargo or recall of a violative product or to impose
civil penalties. States may also continue to use such
traditional revenue measures as registration fees. Accordingly,
one consistent national regulatory system will be implemented,
relying upon both Federal and State enforcement, providing
strengthened public health protection throughout the country.
There may occasionally be situations where a local problem
could justify a different or additional regulatory requirement
for nonprescription drugs or cosmetics in a particular State.
The legislation therefore specifically authorizes States to
petition for an exemption from the general rule of national
uniformity under these circumstances. The FDA may grant an
exemption if the State demonstrates that its proposed local
requirement protects an important public interest that is not
protected under the Federal laws, the local requirement would
not cause any nonprescription drug or cosmetic to be in
violation of any Federal law, and the local requirement would
not unduly burden interstate commerce. State exemption
petitions should be given a high priority by the FDA, and
should be handled promptly upon receipt. Where the problem
identified by a State could represent a national problem, on
the other hand, the proper way for a State to proceed would be
by petitioning the FDA to change the national requirements,
using established agency procedures.
The legislation allows State officials to place a
nonprescription drug on prescription only, to solve a local
problem such as a localized outbreak of abuse of a product.
Once the problem has abated, the drug can then be switched back
to nonprescription status. Similarly, State laws will continue
to apply to the practice of pharmacy, i.e., to the licensing,
discipline, and professional duties of pharmacists.
Accordingly, the legislation clearly recognizes and reflects
the paramount need to protect the public health, both locally
and nationally.
A State, locality, or person may continue to take advantage
of their right to petition the FDA, where it has not issued a
regulation, to make a certain requirement a national
requirement, under the right supplied to them in 21 CFR 10.30,
the citizen petition provision of the Code of Federal
Regulations.
The FDA jurisdiction relating to dissemination of
information about nonprescription drugs and cosmetics and their
constituents applies to the label and labeling for these
products. It is important that any State or local requirements
imposed on industry relating to the advertising of
nonprescription drugs or cosmetics, or to any other form of
public notification or communication relating to these products
and their constituents, be identical with the FDA requirements
for the label and labeling of these products. Accordingly, the
legislation extends national uniformity to the requirements for
all forms of public information and public communication, not
just to the label and labeling. The legislation, however, would
not preclude State officials from issuing their own State
warnings in accordance with local law. Similarly, voluntary
programs such as the ``Mr. Yuk'' initiative sponsored by local
Poison Control Centers will not be affected.
Under the legislation, national uniformity is provided for
all of the types of requirements for nonprescription drugs and
cosmetics and their constituents under State laws that are
related to requirements included in the Federal laws, e.g.,
requirements to prevent adulteration or misbranding or other
illegal marketing or to issue public notice about the safety of
constituents. All forms of State requirements that affect these
products are included within the general rule of national
uniformity, whether they are specifically denominated as
applying to nonprescription drugs and cosmetics or more broadly
apply to unfair competition or to all chemicals, ingredients,
orcontaminants to which consumers and other members of the
public are exposed. To the extent that any type of State law imposes a
requirement for a warning or other type of public notification with
respect to nonprescription drugs or cosmetics or any constituent, that
requirement is prohibited unless such a requirement is prescribed under
one of the three identified Federal laws and the State requirement is
identical to the Federal requirement.
Finally, the legislation explicitly provides that it shall
not be construed to modify or otherwise affect the traditional
product liability law of any State. Tort liability rules and
requirements would remain unchanged and unaffected.
The committee further notes the importance of
nonprescription drugs in the nation's health care system. While
consumers spend less than 2 cents of their health care dollar
on nonprescription drugs, such drugs produce substantial
savings to the individual and the health care system in
reductions in physician visits, prescription drug costs,
insurance costs, lost time from work, and travel. The committee
notes that products switched from prescription to
nonprescription status contribute significantly to these
savings. For example, according to a study conducted by Kline &
Company, consumer health care savings attributable to self-care
with nonprescription medicines reached $20.6 billion in 1996.
Kline calculated that medicines transferred from prescription
to nonprescription status were responsible for $12.9 billion of
the $20.6 billion savings. The savings are determined by
calculating what consumers would be likely to spend if, instead
of using nonprescription medicines, they were to see a doctor,
purchase a prescription medicine and lose time from work.
The committee therefore expects that the FDA, as part of
its mission set forth in section 101 of this legislation (i.e.,
``shall promptly and efficiently review clinical research and
take appropriate action on the marketing of regulated products
in a manner that does not unduly impede innovation or product
availability'') will establish appropriate procedures and
policies, including performance standards, to expedite the
review of applications to switch prescription drugs to
nonprescription status. The committee encourages the FDA to
give strong consideration to establishing a separate office for
nonprescription drugs and conferring on that office primary
review and sign-off authority for applications to switch drugs
from prescription to nonprescription status. At a minimum, the
committee recommends that an individual or individuals within
the Center for Drug Evaluation and Research be designated to
ensure timely and efficient agency review and action on such
applications and that the agency consider using the explicit
authority granted to it to contract for outside expert review
when such contracts would achieve more timely and efficient
reviews.''
Information program on clinical trials for serious or life-threatening
diseases
Sec. 808 amends section 402 of the Public Health Services
Act to establish a registry of clinical trials, both publicly
or privately funded, of experimental drugs and biologicals for
serious or life-threatening medical conditions. Registry
information must be understandable to the general public and
include the purpose of the experimental protocol, trial
eligibility criteria, and sites and contact points for people
wishing to enroll in a trial. Patients, health care providers,
researchers and the public would access the registry through
toll-free telephone communications and other information
systems. Sec. 808 also requires the Secretary of HHS, within 2
years after enactment, to investigate and report on whether it
is necessary or feasible to include medical device trials in
the registry. The purpose of the registry is to simplify the
process through which individuals with serious or life-
threatening medical conditions obtain information about
opportunities to participate in clinical trials of experimental
therapies.
Pharmacy compounding
Section 809 of S. 830 is intended to clarify the
application of the Federal Food, Drug and Cosmetic Act to the
professional practice of pharmacist compounding of drug
products. States currently have the authority to license
pharmacists and regulate pharmacies, including the scope of
pharmacy practice. All Statesinclude compounding as a core
component of the profession of pharmacy. While the Food, Drug and
Cosmetic Act specifically exempts pharmacies from inspection and
registration provisions of the Act, it has been the contention of the
Food and Drug Administration that compounded products are not exempt
from the Act's new drug provisions. The committee has found that
clarification is necessary to address current concerns and uncertainty
about the Food and Drug Administration's regulatory authority over
pharmacy compounding.
The committee has worked extensively with the Food and Drug
Administration and other interested parties to reach consensus
on how to ensure continued availability of compounded drug
products as a component of individualized therapy, while
limiting the scope of compounding so as to prevent small-scale
manufacturing under the guise of compounding. Section 809
establishes parameters under which compounding is appropriate
and lawful. This section is not intended to subvert the
requirements that apply to investigational new drugs or to
result in experimentation without appropriate human subject
protections, including proper informed consent.
The views of the Committee with respect to certain
subsections of Section 809 are outlined below:
The exemptions in section (h)(1) are limited to
compounding for an individual patient based on the
medical need of such patient for the particular drug
compounded. To qualify for the exemptions, the
pharmacist or physician must be able to cite a
legitimate medical need for the compounded product that
would explain why a commercially available drug product
would not be appropriate. Although recording the
medical need directly on each prescription order would
not be required, this technique would be one of many
acceptable ways of documenting the medical need for
each compounded drug product. This medical need would
not include compounding drugs that are essentially
copies of commercially available drug products for
largely economic reasons. The pharmacist may rely on
appropriately documented input from the physician as to
whether a commercially available drug product is not
appropriate for the identified individual patient.
Implementation of subsection (h)(1)(B)(I)(I)(bb),
regarding bulk drug substances, is expected to coincide
with the implementation of subsection (h)(3), except
that compliance with the standards of an applicable
United States Pharmacopeia monograph is not dependent
on any further implementation under subsection (h)(3).
Among other requirements, a bulk drug substance used
for compounding must have been manufactured in an
establishment that has registered under section 510 of
the Act. In addition to applying to domestic
manufacturing establishments, this requirement shall
also apply to foreign establishments, once the
requirement in section 801 of this Act, which requires
foreign establishments to register and list under
section 510 of the Act, becomes effective.
In compliance with subsection (h)(1)(B)(I)(III),
pharmacists may retain each certificate of analysis
until the supply of such bulk drug substance has been
exhausted, and must record in the compounding record
the manufacturer, repackager (if any), and the lot
number of the bulk drug substance.
The list published pursuant to subsection
(h)(1)(B)(iv) includes drug products that have been
withdrawn or removed from the market because the
finished drug product and/or a component thereof has
been found to be unsafe or not effective. The Federal
Register document that includes the list should briefly
describe the basis for the withdrawal or removal and
provide interested parties with an opportunity to
comment. The list should not include products that have
been withdrawn or removed solely because of
manufacturing issues.
Interested parties should be allowed to petition,
under 21 CFR Sec. 10.30, to change the listing of a
particular drug product under subsection (h)(1)(B)(v)
should research and technology yield advances which
correct the compounding difficulties.
Regarding subsection (h)(2)(B), until the State
agency of jurisdiction in which the pharmacy is located
enters into a memorandum of understanding (MOU) with
the Secretary or 180 days after the development of the
standard MOU, whichever comes first, the exemption
shall not apply if inordinate quantities of compounded
products are distributed outside of the State in which
the compounding pharmacy or physician is located.
``Inordinate'' quantities means amounts typically
associated with ordinary commercial drug manufacturing.
As required under subsection (h)(3), the Secretary
will be required to promulgate regulations limiting
compounding to drug substances that are components of
drug products approved by the Secretary and to other
drug substances as the Secretary may identify. It is
expected that the Secretary's regulations would allow
compounding with drug products, or the components of
drug products, that are lawfully distributed, including
drug products that are not new drugs under 21 U.S.C.
Sec. 321(p) and drug substances that authorized for use
under an effective Investigational New Drug application
(IND) protocol under 21 U.S.C. Sec. 355(I) and 21 CFR
Part 312. The FDA may, in development of the list for
other substances approved for compounding, consult with
pharmacy organizations and other interested parties,
beyond the United States Pharmacopeia.
V. Cost Estimate
U.S. Congress,
Congressional Budget Office,
Washington, DC, June 27, 1997.
Hon. James M. Jeffords,
Chairman, Committee on Labor and Human Resources, United States Senate,
Washington, DC.
Dear Mr. Chairman: The Congressional Budget Office has
prepared the enclosed cost estimate for S. 830, the Food and
Drug Administration Modernization and Accountability Act of
1997.
If you wish further details on this estimate, we will be
pleased to provide them. The CBO staff contact is Anne Hunt.
Sincerely,
June E. O'Neill, Director.
S. 830--Food and Drug Administration Modernization and Accountability
Act of 1997
Summary: S. 830 would reauthorize the Prescription Drug
User Fee Act (PDUFA) of 1992, which empowers the Food and Drug
Administration (FDA) to collect user fees from the
pharmaceutical industry. The user fee program would be
reauthorized, with some modifications, for an additional five
years. The bill would also amend the Food, Drug and Cosmetic
Act (FD&CA) and the Public Health Service Act to reform the
FDA's regulatory and approval processes for drugs, biological
products, devices, foods and animal drugs. One provision would
grant a six-month extension of market exclusivity for
pharmaceutical manufacturers who conduct pediatric studies on
select prescription drugs.
CBO estimates that enacting S. 830 would result in net
additional discretionary spending of $63 million in 1998 and
$445 million over the 1998-2002 period, assuming appropriation
of the authorized amounts. Reauthorizing the user fee program
would yield $601 million in offsetting collections over five
years; these amounts would also be authorized to be spent,
subject to appropriation. Extending market exclusivity for
certain drugs would increase direct spending by $65 million
over the 1998-2002 period.
By preempting state and local laws that regulate
nonprescription drugs differently than federal law, S. 830
would impose an intergovernmental mandate as defined in the
Unfunded Mandates Reform Act (UMRA). CBO estimates that
compliance with this mandate would result in no significant
costs for state and local governments.
Estimated cost to the Federal Government: The estimated
budgetary impact of S. 830 is shown in the following table. For
the purposes of this estimate, CBO assumes that all amounts
authorized in the bill would be appropriated by the start of
each fiscal year and that outlays would follow the historical
spending patterns for the FDA. The costs of this legislation
fall within budget function 550 (Health).
[By fiscal year, in millions of dollars]
----------------------------------------------------------------------------------------------------------------
1997 1998 1999 2000 2001 2002
----------------------------------------------------------------------------------------------------------------
SPENDING SUBJECT TO APPROPRIATION
Spending Under Current Law
Estimated Authorizations:
Authorization Level................................... 887 919 949 982 1,016 1,050
Estimated Outlays..................................... 895 914 937 971 1,005 1,038
Collection of User Fees:
Authorization Level................................... -101 0 0 0 0 0
Estimated Outlays..................................... -101 0 0 0 0 0
Spending of User Fees:
Authorization Level................................... 101 0 0 0 0 0
Estimated Outlays..................................... 100 26 5 0 0 0
Proposed Changes
Estimated Authorizations:
Authorization Level................................... 0 63 93 102 90 97
Estimated Outlays..................................... 0 38 61 80 83 93
Collection of User Fees:
Authorization Level................................... 0 -110 -116 -119 -128 -128
Estimated Outlays..................................... 0 -110 -116 -119 -128 -128
Spending of User Fees:
Authorization Level................................... 0 110 116 119 128 128
Estimated Outlays..................................... 0 104 114 118 126 128
SPENDING SUBJECT TO APPROPRIATION
Spending Under S. 830
Estimated Authorizations:
Authorization Level \1\............................... 887 982 1,042 1,084 1,106 1,147
Estimated Outlays..................................... 895 952 998 1,051 1,088 1,131
Collection of User Fees:
Authorization Level \1\............................... -101 -110 -116 -119 -128 -128
Estimated Outlays..................................... -101 -110 -116 -119 -128 -128
Spending of User Fees:
Authorization Level \1\............................... 101 110 116 119 128 128
Estimated Outlays..................................... 100 130 119 118 126 128
DIRECT SPENDING
Direct Spending:
Estimated Budget Authority............................ 0 0 7 18 28 11
Estimated Outlays..................................... 0 0 7 18 28 11
----------------------------------------------------------------------------------------------------------------
\1\ The 1997 level is the amount appropriated for that year.
BASIS OF ESTIMATE
Estimated authorizations: In addition to reauthorizing the
user fee program, the bill would reform the FDA's approval and
regulatory processes with the intent of accelerating product
approvals and alleviating regulatory requirements. It would
require the FDA to comply with statutory deadlines for
reviewing new products. S. 830 would require the FDA, in
coordination with the National Institutes of Health (NIH) and
the Centers for Disease Control (CDC), to establish a program
to provide information on treatment, detection, and prevention
of serious diseases and onclinical trials currently studying
these conditions. Other provisions would result in small budgetary
savings.
Enforced Deadlines for FDA Action on Submissions. The bill
would require the Secretary to develop and publish in the
Federal Register a plan bringing the FDA into compliance with
the obligations and deadlines contained in the FD&CA and other
relevant statutes. Among other objectives, the plan must bring
the FDA into full compliance with the statutory review
deadlines in the FD&CA by July 1, 1999. The plan must also
ensure that the FDA eliminate any backlog of submissions by
January 1, 2000. The agency would also be required to implement
the FD&CA inspection and postmarket monitoring requirements by
July 1, 1999.
Assuming that the volume and quality standards for reviews
were to remain constant, the FDA would require additional staff
and resources to reduce review times significantly and
eliminate the backlog of product submissions. Because S. 830
would somewhat relax current FDA regulations, the number of
product applications could increase, placing further demands on
the agency's resources. CBO estimates that the additional
personnel and resources necessary to meet the proposed
deadlines would exceed any savings realized through regulatory
relief offered by S. 830. This provision would cost the federal
government an estimated $50 million in 1998 and $267 million
over five years.
Information Program on Clinical Trials. S. 830 would
require the Director of the National Institutes of Health in
coordination with the FDA and the Centers for Disease Control
to establish a program to provide information on treatment,
detection, and prevention of serious diseases and on clinical
trials currently studying these conditions. This program would
include establishing a database of all federally and privately
funded clinical trials and a toll-free telephone information
line available to health care providers, researchers,
individuals with serious diseases, and all other members of the
public.
The NIH already has such a program for clinical trials that
it funds for cancer, AIDS, and rare diseases. Privately funded
clinical trials are also included in these databases on a
voluntary basis. The FDA would be able to disclose information
on clinical trials, and NIH would be required to expand its
current database significantly to accommodate the increase in
volume of trials and information. After the system was set up,
additional maintenance costs would be incurred to keep up with
the status and results of clinical trials, and with new
protocols on treatment and prevention of serious diseases and
conditions. Costs would also arise to operate a telephone
information line staffed by health professionals.
CBO based its estimate on the cost of maintaining the
current data banks and information networks, the estimated
portion of clinical trials currently contained in NIH's
databases, and conversations with professionals experienced in
this area. CBO assumes that it would take two years to create a
system that would meet the minimum requirements specified in
the bill, at a cost of $20 million in 1998 and $45 million in
1999. For each year thereafter, CBO estimated a cost of $50
million for maintenance and quality improvement. Costs would
total $215 million over the 1998-2002 period.
Third-Party Review of Applications. The FDA would be
required to accredit independent entities and individuals to
review and make initial classification recommendations on
section 510(k) device submissions. Devices that are life-
sustaining or supporting, intended for implantation for more
than one year, or designated as class III devices under section
515 would be exempted from this provision, except at the
agency's discretion. The FDA would also have the discretion to
allow accredited entities and individuals review premarket
approval (PMA) applications for class III devices. Compensation
arrangements for these reviews would be made between the
sponsor and the reviewer. CBO estimates that this proposal
would save approximately $1 million over five years.
Reclassification of Class III Devices. S. 830 would amend
the FDA's current practice of automatically designating as
class III products new devices that are not substantially
equivalent to a legally marketed predicate device. Sponsors of
devices designated as class III could request the FDA to
classify their device as a class I or II device, and could make
a recommendation about the classification. The FDA would have
60 days to make a final determination on a sponsor's
recommendation. This provision would reduce the number of
premarket applications reviewed by the FDA, saving $1 million
in 1998 and $12 million over five years.
Reporting Product Changes to the FDA. The bill would waive
the requirement that manufacturers file an additional
application for an investigational device exemption for minor
changes in the intended use or design of an investigational
device. Minor changes are those that would not affect the
efficacy or safety of the device. CBO estimates that this
provision would save approximately $11 million over five years.
User fees
The bill would reauthorize current prescription drug user
fees through September 30, 2002. The current authorization
expires at the end of fiscal year 1997. The bill would also
authorize new fees to be levied on manufacturers and suppliers
of food contact substances. Proceeds from these fees would be
available for spending, subject to appropriation.
Reauthorization of the Prescription Drug User Fee Act of
1992. As with current law, the reauthorized program would levy
three types of user fees on pharmaceutical manufacturers:
application and supplement fees, establishment fees, and
product fees. Aggregate amountsof such fees are specified in
the bill for each of fiscal years 1998-2002; these amounts would be
adjusted to reflect cumulative inflation since 1997. CBO's estimate
assumes that the inflation adjustment would apply to the specified
authorization, not to the prior year's actual authorization. Under the
proposal, the FDA would make annual adjustments so that the total
revenues collected for establishment and product fees would equal those
for application and supplement fees. The amounts collected are
authorized to be spent, subject to appropriation. CBO estimates that
the FDA would collect $110 million in 1998 and $601 million over five
years.
Any fees collected in excess of the amount specified in the
appropriations act for a given year would be credited to the
FDA appropriations account and subtracted from the amount of
fees authorized for the following year. The FDA could not
assess the user fees unless appropriations for FDA salaries and
expenses, excluding any user fees, were at least equal to
appropriations for 1997, adjusted for inflation.
Fees for Food Contact Substances. The bill would include
food contact substances among the items regulated under the
FD&CA. Food contact substance could be used only if the FDA
issued, and the food contact substance met, standards for the
use of such additives. Alternatively, manufacturers or
suppliers could give the FDA advance notification that the
intended use of their food contact substance was safe according
to agency regulations. Unless the FDA determined that the food
contact substance was unsafe within 120 days of this notice,
the notification would become effective.
The Secretary could authorize a fee, based on the resources
needed to process these notifications, to be collected from
individuals submitting notifications. The fee would be
available to the FDA until expended, without fiscal year
limitation. Although CBO cannot determine the amount of such
fees, the provision would have no net budgetary impact, because
the fees would be set to cover the agency's costs for reviewing
and processing food contact substance notifications.
Direct spending
The bill would grant an additional six months of market
exclusivity to pharmaceutical manufacturers that conduct
pediatric studies on select drugs. This provision would affect
direct spending because it would increase costs for the
Medicaid rebate program and the Federal Employees Health
Benefit Program (FEHBP). This provision would apply to
pediatric studies commenced before January 1, 2004.
The Secretary of Health and Human Services, through the
Commissioner of the FDA, would issue a list of drugs for which
additional pediatric information might yield a health benefit.
If manufacturers of targeted drugs submitted pediatric
studies to the FDA, their product would receive an additional
six months of market exclusivity. This benefit would accrue to
both approved drugs and those awaiting approval. Manufacturers
of an approved drug that received an extension under this
provision could, if eligible, receive an additional six months
of exclusivity for a supplemental application.
By extending the market exclusivity of certain drugs, this
proposal would increase prescription drug costs for Medicaid,
FEHBP, Veterans Affairs (VA) facilities, the Department of
Defense, and the Public Health Service for the six months of
the extension. In the absence of this provision, these programs
may have had access to less expensive generic products. In the
case of Medicaid and FEHBP, the additional costs of this
provision would represent direct spending. At this time, the
costs to FEHBP, the VA, the Department of Defense, and the
Public Health Service cannot be determined. CBO estimates that
this provision would have no net budgetary effect in 1998 but
would increase federal outlays for Medicaid by $65 million over
the 1998-2002 period.
Pay-as-you-go considerations: The Balanced Budget and
Emergency Deficit Control Act of 1985 set up pay-as-you-go
procedures for legislation affecting direct spending or
receipts through 1998. CBO estimates that enactment of S. 830
would have no significant effect on direct spending or receipts
in 1998.
VI. Regulatory Impact Statement
Estimated impact on State, local, and tribal governments:
By preempting state and local laws that regulate
nonprescription drugs differently than federal law, S. 830
would impose an intergovernmental mandate as defined in UMRA.
CBO estimates that compliance with this mandate would result in
no significant costs for state and local governments.
Consequently, the threshold established in UMRA ($50 million in
1996, adjusted annually for inflation) would not be exceeded.
This mandate would not affect tribal governments.
By granting certain drug manufacturers a six-month
extension of market exclusivity for their products, the bill
would make prescription drugs provided under Medicaid more
expensive. CBO estimates that states' share of these costs
would total about $28 million over the next five years. This
provision would not constitute a mandate under UMRA because
prescription drugs under Medicaid are provided at a state's
option.
Estimated impact on the private sector: S. 830 would impose
some new private-sector mandates and would replace some
existing mandates with new, less burdensome requirements. In
addition, the bill would reauthorize application fees and
certain other fees paid by pharmaceutical companies. However,
since these fees do not become effective until Congress
appropriates them, they do not constitute a private-sector
mandate. Thus, the direct cost of all private-sector mandates
in this bill are minimal, and the total effect could be a net
reduction in mandated costs imposed on the private sector.
Sections 803 and 808 would impose new mandates on the
private sector. Section 803 would change the definition of when
a food, drug, device, or cosmetic intended for export is not
deemed to be adulterated or misbranded in situations in which
exportation is made to the original foreign supplier. This
section also would impose a new mandate on persons seeking to
export a condemned imported article by imposing a new
certification requirement. Section 808 would direct the
Secretary to establish ``a data bank of information on clinical
trials for drugs, and biologicals, for serious or life-
threatening diseases and conditions.'' This provision would
impose a new mandate on sponsors of such clinical trials by
requiring them to forward to the data bank information about
eligibility criteria for participation in the trial, the
location of the trial, and a point of contact within 21 days
after the clinical trial is approved by FDA. CBO estimates that
the costs of these mandates would be minimal.
Several new mandates would cost no more and perhaps less
than the current regulatory requirements that they would
replace. Section 601 would require manufacturers of medical
devices to submit a written notice, rather than a supplemental
application as currently required, for certain types of
manufacturing changes. Section 619 would set new quality
standards specifically for positron emission tomography drugs,
but relieve them of the new drug application process (required
under section 505 of the Food Drug and Cosmetic Act) and
certain other regulations. Section 610 would establish a single
licensing requirement for biological products that would
replace current licensing requirements.
Estimate prepared by: Federal cost: Anne Hunt (FDA) and
Cyndi Dudzinski (NIH); impact on State, local, and tribal
governments: John Patterson; and impact on the private sector:
Anna Cook.
Estimate approved by: Paul N. Van de Water, Assistant
Director for Budget Analysis.
VII. Section-by-Section Analysis
Sec. 1. Short Title.
Section 1 provides that the act be cited as the ``Food and
Drug Administration Modernization and Accountability Act of
1997.''
Sec. 2. Table of Contents.
Section 2 contains the table of contents.
Sec. 3. References.
Section 3 states that whenever this Act provides for
amendment to, or repeal of, a section or other provision, the
referenced section or provision is of the Federal Food, Drug,
and Cosmetic Act (FFDCA; 21 U.S.C. 321 et seq.)
title i--improving patient access
Sec. 101. Mission of the Food and Drug Administration.
Section 101 amends FFDCA section 903 (21 U.S.C. 393) by
redesignating subsections (b) and (c) as subsections (c) and
(d) and adding IN GENERAL that the Administration shall protect
the public health by ensuring that foods are safe, wholesome,
and sanitary; human and veterinary drugs are safe and
effective; there is a reasonable assurance of safety and
effectiveness of devices intended for human use; cosmetics are
safe and properly labeled; and the public health and safety are
protected from electronic product radiation, and (2) SPECIAL
RULES that require the Administration promptly and efficiently
review clinical research and take appropriate action on the
marketing of regulated products in a manner that does not
unduly impede innovation or product availability. Further, the
Administration shall participate with other countries to reduce
the burden of regulation, to harmonize regulatory requirements,
and to achieve appropriate reciprocal arrangements.
Sec. 102. Expedited Access to Investigative Therapies.
Section 102 amends Chapter V (21 U.S.C. 351 et seq.) to add
a new subchapter.
subchapter d--unapproved therapies and diagnostics
Sec. 551. Expanded Access to Unapproved Therapies and Diagnostics.
Section 102 of this Act creates a new section 551 of the
FFDCA. Section 551(a) allows any person, acting through a state
licensed physician, to request from manufacturers a product
that is under investigation for the Food and Drug
Administration's (FDA) approval for the diagnosis, monitoring,
or treatment of a serious disease or condition or any other
disease or condition designated by the Secretary as appropriate
for access to such products. Expanded access is conditional on
whether (1) a licensed physician determines that the person has
no comparable or satisfactory alternative therapy; (2) the
licensed physician determines that the risk to the patient from
the investigational product is not greater than that of the
risk from the disease or condition; (3) the Secretary
determines that an investigational drug (IND) or
investigational device (IDE) application complies with
regulations governing these applications; (4) the Secretary
determines that the manufacturer is diligently pursuing an
approval; and (5) the Secretary decides that expanded access to
an investigational product will not prevent adequate patient
enrollment for ongoing clinical trials for the unapproved
product. There is also to be a determination by FDA that there
is sufficient evidence of safety and effectiveness such that
the investigational product can be used in his manner.
Section 551(b) allows a sponsor to submit one or more
protocols for expanded access for an investigational product.
The protocols may include any use of the drug or device outside
a clinical investigation prior to approval for marketing,
including treatment use, single patient use, emergency use, and
uncontrolled trials. The Secretary may waive certain
requirements for expanded access to investigational new
products for use by a single patient only in an emergency when
times does not permit an application to be filed for an
exemption. The Secretary can authorize shipment and use of the
product in advance of any submission.
Section 551(c) allows the Secretary to inform national,
state, and local medical associations and societies, and other
appropriate organizations and persons about the availability of
the investigational drugs or devices under expanded access
protocols. However, this does not apply to protocols for single
patient use. Sec. 551(d) allows the Secretary at any time to
stop expanded access if the drugsor devices do not meet the
requirements set forth in this section.
Sec. 103. Expanded Humanitarian Use of Devices.
Section 103 amends section 520(m) (21 U.S.C 360j(m))
(Humanitarian Device Exemption section) formalizing requests
for exemption from device efficacy studies intended for patient
populations of less than 4,000. Requests would now be in the
form of an application that the Secretary must approve or deny
within 60 days. This section amends section 520(m)(4)(B) to
allow a physician, if he had not received a timely response
from a hospital institutional review committee (IRC) to which
the physician had applied for an exemption, to use the device
if the patient would suffer harm or death waiting for IRC
approval. The physician will then be required to inform the
chairperson of the IRC of such a use on a particular patient,
the date used, and why it was necessary. New section 520(m)(5)
allows the Secretary to require a recipient of an exemption to
demonstrate continued compliance with requirements if the
Secretary deems this necessary to protect the public health or
believes that the criteria for the exemption are no longer met.
title ii--increasing access to expertise and resources
Sec. 201. Interagency Collaboration.
Section 201 amends section 903(b) (21 U.S.C 393(b)) of the
FFDCA to require that the Secretary create programs to foster
collaboration among science-based federal agencies such as the
National Institutes of Health (NIH) and others to enhance the
scientific and technical expertise available to product
reviewers. This expertise will be available for review
activities for medical therapies such as the development,
clinical investigation, evaluation, and postmarket monitoring
of emerging therapies. It will also cover complementary
therapies and advances in nutrition and food science.
Sec. 202. Sense of the Committee Regarding Mutual Recognition
Agreements and Global Harmonization Efforts.
Section 202 gives the sense of the Senate Committee on
Labor and Human Resources that the Secretary should consult
with the Secretary of Commerce and support the Office of the
U.S. Trade Representative in moving toward acceptance of mutual
recognition agreements (MRAs) with the European Union. These
MRAs will cover the regulation of drugs, biological products,
devices, foods, food additives, and color additives as well as
good manufacturing practices. The Secretary should regularly
participate in meetings with other foreign governments to
harmonize regulatory requirements. The Committee also would
like to ensure that the Department of Health and Human
Services, Office of International Relations (established in
section 803 of the FFDCA) continuously works towards
harmonizing international regulatory requirements.
Sec. 203. Contracts for Expert Review.
Section 203 amends Chapter IX (21 U.S.C 391 et seq.) by
adding a new section on contracts for expert review. Under new
section 906, the Secretary will be authorized to enter into
contracts with qualified nongovernmental individuals or
organizations to make recommendations to the Secretary on any
applications or submissions for approval or classification
under FFDCA or under section 351(a) of the Public Health
Service Act (42 U.S.C 262(a)) for biological products. All such
contracts will be subject to requirements under section 708 of
the FFDCA relating to confidentiality of information.
The Secretary shall use this authority to enter into
contracts with individuals or organizations to review
applications or submissions whenever the Secretary determines
that such reviews will improve the timeliness or quality of the
application under review. The official at the FDA who is
responsible for the matter that the contractor is reviewing
must make final decisions on the contractors' recommendations
within 60 days. The Secretary shall retain authority to approve
or disapprove submissions for a product, or to classify an
article as a device under section 513(f)(1).
Sec. 204. Accredited-Party Participation.
Section 204 amends Subchapter A of Chapter V (21 U.S.C. 351
et seq.) of the FFDCA to establish new section 523--Accredited-
Party Participation. This section requires the Secretary to
accredit nongovernmental individuals or entities to make
recommendations for initial classification of and to review
premarket notification for medical devices. Devices that are
long-term implantable, life-sustaining, or life-supporting will
be excluded from accredited-party review.
Under subsection 523 of the new law, the Secretary will
have discretion to accredit nongovernmental groups or parties
to (a) review premarket notification reports for devices (under
section 510(k)) and make recommendations for their initial
classification, or (b) to review premarket approval
applications (under section 515) and make recommendations for
their approval or disapproval.
Within 180 days of enactment, the Secretary must establish
the accreditation process for third-party medical device
review. The accreditation process must be published in the
Federal Register. If an accredited party fails to comply with
duties published by the Secretary, such as avoidance of
conflicts of interest or protection of confidential
information, the Secretary may, after giving notice and
opportunity for a hearing, suspend or withdraw program
accreditation from that party.
Device sponsors who are considering filing a premarket
notification or a premarket approval application, as described
in subsection (2), will be given the option of selecting an
accredited entity. Upon request, the Secretary must provide the
device sponsor with a minimum of two accredited parties from
which to choose. Compensation must be arranged between the
sponsor and the accredited party.
The Secretary must require accredited parties to submit
their recommendations and supporting rationale in writing. For
initial classification of a device, the Secretary must make a
final decision within 30 days of receiving the recommendation.
For premarket approval applications, the Secretary will have
authority to change recommendations that an accredited party
proposes, and must provide the party submitting the application
or report with a written explanation of the reasons for the
change.
The program for third-party accreditation is authorized to
operate for a period of either five years following the date on
which at least two accredited parties are available to review
devices ``in each of at least 70 percent of generic types of
devices required for review under subsection (a)''; or, four
years after the date on which the Secretary notifies Congress
that the Secretary has acted upon at least 35 percent of the
devices under subsection (a) for classification or review,
whichever occurs first.
Within one year of enactment, the Secretary must contract
with an independent research organization to prepare and submit
a written report examining the use of accredited-parties to
review notifications of and applications for medical devices.
The Secretary must submit the report to Congress no later than
six months from the date when the accredited program concludes.
The report must contain a description of the benefits or
detriments to public health of using accredited parties to
conduct those reviews. The report must contain a summary of all
relevant data, including review times, compensation, and
recommendations made by the accredited party and the Secretary.
Sec. 205. Device Performance Standards.
Section 205 amends section 514 (21 U.S.C. 360(d)) of the
FFDCA by adding a new section for ``Recognition of a
Standard.'' Section 205 authorizes the Secretary to recognize
in the Federal Register nationally or internationally
recognized standards. Such standards may be used to meet
requirements for premarket submissions or other requirements of
the Act. If a regulated person uses a recognized standard then
that person must provide the Secretary with a declaration of
conformity certifying that the device conforms with the
recognized standard. When the recognized standard is no longer
appropriate for satisfying requirements under the Act, the
Secretary may withdraw recognition of that standard.
The Secretary must accept self-declarations from sponsors
that a device conforms with a recognized standard unless the
Secretary finds that (a) the data submitted to support
conformity is not consistent with the standard identified in
the self-declaration of conformity, or (b) the standard
identified in the declaration of conformity does not apply to
the device under review. The Secretary may request a device
sponsor to submit the data that was relied on to make a self-
declaration of conformity. Device sponsors who make self-
declarations of conformity for a recognized standard must
maintain data and information that supports conformity of the
device to the standard for a period of two years after the date
of classification or approval of the device, or for a period
equal to the life expectancy of the device, whichever is
longer.
Section 301 (21 U.S.C. 331) will be amended to prohibit the
falsification of a declaration of conformity or the failure or
refusal to provide data or information that the Secretary may
request under new section 514(c)(3).
Section 501 (21 U.S.C. 351(c)) will be amended to reflect a
new condition under which a device is adulterated. A device
would be adulterated if it is falsely declared to be in
conformity with recognized performance standards under section
514(c).
title iii--improving collaboration and communications
Sec. 301. Collaborative Determination of Device Data Requirements.
Section 301 amends section 513(a)(3) (21 U.S.C. 360c(a)(3))
of the FFDCA. Upon written request from a device sponsor, the
Secretary will be required to meet to determine the type of
scientific evidence that is necessary to demonstrate the
effectiveness of a device. It is proposed that such meetings
between the Secretary and device sponsors take place before
clinical trials begin or before an investigation device
exemption is filed. Within 30 days after the meeting, the
Secretary must specify the type of scientific evidence the
sponsor will need to support the proposed use of the device.
For any clinical data that the Secretary may require, the
Secretary must provide a written specification to the device
sponsor that reflects the Secretary's view that such data are
necessary to establish the effectiveness of the device, and
that a less burdensome means is not available. The Secretary's
specification for scientific evidence will be binding upon the
Secretary, unless he finds that (a) it is not in the interest
of the public health to modify the specification, or (b)
scientific evidence obtained during consideration of an
investigational device exemption makes the specification
inappropriate.
Sec. 302. Collaborative Review Process.
Section 302 amends section 515(d) (21 U.S.C. 360e(d)) of
the FFDCA. Within 100 days of receiving a complete premarket
approval application (PMA), the Secretary will be required to
meet the device sponsor to discuss the status of review, if so
requested in writing. If the PMA does not appear in a form that
will require an approval, the Secretary must indicate in
writing before the meeting any deficiencies that the device
sponsor must correct and information the device sponsor must
provide to bring the application to an approvable form. The
Secretary and the device sponsor may mutually agree on a
different meeting schedule.
title iv--improving certainty and clarity of rules
Sec. 401. Policy Statements.
Section 401 amends current section 701 (General Authority)
(21 U.S.C. 371(a)). After a two year evaluation period, the
Secretary, by February 27, 1999, a recently issued guidance
document for ``Good Guidance Practices'' (62 Federal Register
8961) into a regulation.
Sec. 402. Product Classification.
Section 402 amends chapter VII (21 U.S.C. 371 et seq.) of
the Act to add a new ``Subchapter D--Review of Applications and
Environmental Impact Reviews.'' Under new section 741, a
product sponsor for a drug, biological product, or device may
submit certain recommendations to the Secretary along with an
application for premarket review. Those recommendations may
call for a classification determination as well as a center-
specific review. The Secretary will have a total of 60 days to
(a) classify the product, or (b) assign it to a center for
review, and (c) inform the sponsor of the reasons for the
Secretary's decisions. The Secretary will be bound by these
decisions except for public health reasons or with the written
consent of the sponsor. If the Secretary does not make a
decision within 60 days, the sponsor's recommendations for
classification or assignment will be final.
Sec. 403. Use of Data Relating to Premarket Approval.
Section 403 amends current section 520(h)(4) (21 U.S.C.
360j(h)(4)). The Secretary is authorized to use data from a
premarket approval application six years after an application
is approved for the purpose of facilitating reclassification
and/or approval of applications submitted by other device
sponsors for the same kind of device. The publicly available
detailed safety and effectiveness summaries required to be
submitted for premarket approval shall be available for use by
the Secretary as the evidentiary basis for any action based on
the data.
Sec. 404. Consideration of Labeling Claims for Product Review.
Section 404 amends section 515(d)(1)(a) (21 U.S.C.
360e(d)(1)(A)) and section 513(i)(1) for labeling claims for
premarket approval applications under premarket notifications.
In making determinations to approve or deny an application, the
Secretary will be required to limit the evaluation of safety
and effectiveness to those uses proposed in the product label
if it is determined that the labeling is neither false nor
misleading. For products claiming substantial equivalence with
others having different technological characteristics, the
Secretary will be required to request only that information
that is necessary and corresponds to the least burdensome means
of demonstration. The Secretary must also base this finding
only on the intended uses in the proposed labeling in a report
submitted under section 510(k).
Sec. 405. Definition of a Day for Purposes of Product Review.
Section 405 amends section 201 (21 U.S.C. 321). A calendar
day is described as one in which the Secretary has
responsibility to review a new product. Any day during which a
product sponsor for a drug, device, biological product, new
animal drug, color additive, or food additive is responding to
Secretary requests for information from the Secretary will be
excluded. A reference to a date relating to the receipt of
filing of such an application means the date when the Secretary
receives or files, as appropriate, a complete application.
Sec. 406. Certainty of Review Timeframes.
Section 406 amends section 510(k) (21 U.S.C. 360) to state
that the Secretary must review premarket notifications within
90 days. This new requirement will conform with current
practice in reporting on review timeframes for 510(k)
submissions. This section will also amend section 515(d) (21
U.S.C. 360e(d)) to ensure that the Secretary must review
applications within 180 days even if the application is
amended.
Sec. 407. Limitations on Initial Classification Determinations.
Section 407 amends section 510 (21 U.S.C. 360). The
Secretary will be prohibited from the current practice of
withholding the initial classification of a device because of a
failure of a manufacturer to comply with any provision of the
FFDCA unrelated to making a determination of substantial
equivalence, including good manufacturing practice regulations.
Sec. 408. Clarification of General and Specific Uses of A Device For
Purposes of Substantial Equivalence.
Section 408 will require issuance of a new regulation.
Within 270 days of enactment, the Secretary must promulgate
final regulations establishing criteria that will be considered
when evaluating claims for substantial equivalence under
section 513(f)(1) (21 U.S.C. 360(f)(1)). The Secretary must
develop criteria to determine when the specific intended use of
a device is not reasonably included within its general use.
Sec. 409. Clarification of the Number of Required Clinical
Investigations.
Section 409 amends current sections 505(d) (21 U.S.C.
355(d)) and 513(a)(3)(A) (21 U.S.C. 360c(a)(3)(A)) adding a new
sentence to 505(d) giving the Secretary discretion to approve
drugs under certain conditions on the basis of one adequate and
well-controlled investigation with confirmatory evidence, and
by changing ``clinical investigations'' in 513(3)(a) to ``1 or
more clinical investigations.''
Sec. 410. Prohibited Acts.
Section 410 will repeal section 310(1) (21 U.S.C. 331(l))
of current law. The section of the FFDCA that prohibits
manufacturers from making truthful statement of facts about
Secretary-approved products will be repealed.
title v--improving accountability
Sec. 501. Agency Plan for Statutory Compliance and Annual Report.
Section 501 amends Section 903(b) (21 U.S.C. 393(b)) of the
FFDCA to create two new subsections 903(b)(4) Agency Plan for
Statutory Compliance and 903(b)(5) Annual Report. The Committee
does not intend to duplicate any requirement of current law
that applies under the Government Performance and Results Act
(GPRA) [P.L. 103-62].
New section 903(b)(4) will require that the Secretary, not
later than 180 days after enactment, develop a plan to bring
the Secretary into compliance with each of the FFDCA's
obligations. The plan will be developed after consultation with
experts, health care professionals, representatives of patients
and consumer advocacy groups, and regulated industries. The
plan must be published in the Federal Register and will be
reviewed biannually by the Secretary for revisions as
necessary. The plan's objectives will be to (i) minimize deaths
and injuries suffered by persons who may use products regulated
under the FFDCA; (ii) maximize the clarity and availability of
information about the product review process and new products
for potential consumers and patients; (iii) implement all
inspection and post-market monitoring provisions of the Act by
July 1, 1999; (iv) ensure access to the scientific and
technical expertise necessary to properly review products; (v)
establish a schedule to bring the ``Administration'' into
compliance by July 1, 1999 with the product review times in the
Act for products submitted after the date of enactment of this
section; and (vi) eliminate the backlog of products awaiting
final action by January 1, 2000.
New section 930(b)(5)(A) will require that the Secretary
solicit public comment by publishing in the Federal Register an
annual report that would: (i) contain statistical information
on the performance of the Secretary to assist Congress in
assessing his performance; (ii) compare the Secretary's
performance in that year to the plan and Secretary's statutory
obligations; (iii) analyze any failure to achieve any element
of the agency plan; (iv) identify any regulatory policy that
has a significant impact on compliance with any objective of
the agency plan or any statutory obligation; and (v) set forth
any proposed revision to any such regulatory policy, or
objective of the plan, that has not been met.
New section 903(b)(5)(B) will require that the information
given annually will include statistics on all applications and
submissions made under the FFDCA and approved or subject to
final action by the Secretary during that year. The statistical
information will consider the date of: (1) the submission of
any investigational application; (ii) the application of any
clinical hold; (iii) the number of applications submitted for
approval or clearance; (iv) the acceptance for filing of any
application; (v) the occurrence of any unapprovable action;
(vi) the occurrence of any approvable action; and (vii) the
approval or clearance of any application or submission
described in (iii).
title vi--better allocation of resources by setting priorities
Sec. 601. Minor Modifications.
Section 601 amends Section 520(g) (21 U.S.C. 360j(g)) of
the FFDCA to require the Secretary, within 120 days of
enactment, to issue new regulations modifying parts 812 and 813
of Title 21, Code of Federal Regulations, updating procedures
and conditions for granting exemptions, and governing, when the
manufacturer of a device, which is the subject of an approved
investigational device exemption, may make minor modifications
to that device without restarting the clinical trial or
submitting a supplement to the investigational device exemption
in effect for the clinical trial.
The new regulations must permit developmental changes in
devices (including manufacturing changes) in response to
information collected during the investigation, without
requiring an additional investigational device exemption
approval or the approval of a supplement, as long as the
sponsor determines, prior to making the changes, that they will
not affect the soundness of the investigational plan or the
rights, safety, or welfare of the human subjects involved.
Also, the changes must not constitute a significant change in
the design or basic operational principles of the device. In
reviewing an application, FDA is required to accept and review
data or information to determine whether there is a reasonable
assurance of safety and effectiveness of the device if: (I) the
data or information are derived from investigations of a
previously approved device, the device has been modified during
or after the investigations, and the modification does not
constitute a significant change in the device's design or basic
operational principles; or(II) the data or information relating
to the device are available for use under the Act, and are relevant to
the design and intended use of the device subject to the pending
application.
Supplemental applications will be required for any changes
to a marketed device that affect safety and efficacy. This will
not be required if the change is a modification in a
manufacturing method or procedure and the holder of the
application submits a written notice describing the change in
detail, summarizing the data or information supporting the
change, and informing the Secretary that, despite the change,
the manufacturer is still in compliance with the FDA's good
manufacturing practices (GMP) regulations. Holders of approved
applications who submit manufacturing change notifications may
not distribute their products until 14 days after the Secretary
has been notified.
When reviewing a supplement to an approved application for
an incremental change to the design of a device that affects
safety or effectiveness, the Secretary must approve the
supplement if non-clinical data show that the modification
creates the intended additional capacity, function, or
performance of the device, and the clinical data from the
approved application, and any of its supplements, provide a
reasonable assurance of safety and efficacy.
Sec. 602. Environmental Impact Review.
Section 602 amends Chapter VII (21 U.S.C. 371) of the
FFDCA, adding new section 742 dealing with environmental impact
reviews. The section establishes that no action taken by the
Secretary under this law shall be subject to an environmental
impact assessment, an environmental impact statement, or other
environmental consideration unless the Secretary demonstrates,
in writing, that (1) there is a reasonable probability that the
environmental impact of the action is substantial and within
the factors the Secretary is authorized to consider, and (2)
that consideration of the impact will directly affect the
decision on the action.
Sec. 603. Exemption of Certain Class Devices From Premarket
Notification Requirement.
Section 603 amends Section 510(k) (21 U.S.C. 360(k)) of the
FFDCA, establishing that all Class I devices, except those that
are intended for a use that is of substantial importance in
preventing impairment of human health, or present a potential
unreasonable risk of illness or injury, are exempted from pre-
market review. The FDA's enforcement powers and good
manufacturing practices will still apply to these devices. In
addition, the Secretary must, no later than 30 days after
enactment, publish a list of each type of Class II device that
does not require pre-market review. One day after the list is
published, a class II device, based on the Secretary's
initiative or upon the petition of an interested person, may be
exempted from the pre-market notification requirement. The
petition, or the Secretary's intent to exempt such a device,
must be published in the Federal Register and allow for a 30
day public comment period. Within 120 days of the Federal
Register notice, an order must be published setting forth the
Secretary's final determination about the device's exemption.
Sec. 604. Evaluation of Automatic Class III Designation.
Section 604 amends Section 513(f) (21 U.S.C. 360c(f)) of
the FFDCA to establish that any device manufacturer who submits
a report under section 510(k) for review of a type of device
that has not been previously classified under the Act, and
which is classified into Class III, may request, within 30 days
of receiving the notification, that the Secretary classify the
device into either Class I or II. In the request, the
manufacturer may recommend to the Secretary the device's
classification. The request must include a description of the
device, and detailed information and reasons for its
reclassification.
Not later than 60 days after a classification request, the
Secretary, by written order, must classify the device. This
classification will be the initial classification of the
device, and any device classified into Class I or II shall be a
predicate device for determining substantial equivalence. Any
device that remains in class III will be deemed adulterated
until it is either approved under section 515 or exempted from
such approval under section 520(g). Once an order classifying a
device is issued, the Secretary must, within 30 days, publish
its announcement in the Federal Register.
Sec. 605. Discretion To Track Devices.
Section 605 amends Section 519(e) (21 U.S.C. 360i(c)) of
the FFDCA, establishing that any patient who receives a device,
subject to tracking under this section, may refuse to release,
or refuse permission to release, their name, address, social
security number, or other identifying information used for
tracking purposes. Within 180 days of enactment, the Secretary
must develop and publish in theFederal Register a list
identifying devices that require tracking under the Act. Devices not
identified by the Secretary will be considered exempt from mandatory
tracking. The Secretary will have the authority to modify the list of
devices exempt from the mandatory tracking.
Sec. 606. Secretary's Discretion To Require Postmarket Surveillance.
Section 606 amends Section 522 (21 U.S.C. 3601) of the
FFDCA, establishing certain limitations on FDA's post-market
surveillance authority for devices. This section stipulates
that each device manufacturer, required to conduct post-market
surveillance must, within 30 days of receiving a notice that
surveillance is required, submit a surveillance plan for the
Secretary's approval. Within 60 days of receipt of the plan,
the Secretary must determine if the person who is to conduct
the surveillance is qualified and experienced and whether the
plan will result in the collection of useful data that can
reveal unforeseen adverse events necessary to protect the
public health and provide additional safety and effectiveness
information.
The Secretary may not approve the plan until it has been
reviewed by a scientifically qualified review committee, which
the Secretary is authorized to select. Manufacturers will be
required to conduct surveillance for no more than 24 months.
However, if the Secretary determines that additional
surveillance is necessary to further explore unforeseen adverse
events documented during the initial surveillance, the time
period may be extended, and the person conducting the
surveillance will be given an opportunity for an informal
hearing to determine whether the additional surveillance time
is appropriate.
Sec. 607. Reporting.
Section 607 amends Section 519 (21 U.S.C. 360i) of the
FFDCA, repealing certain reporting requirements for device
distributors. However, it establishes that regulations shall
require distributors, including importers, to keep records and
make them available to the Secretary upon request. In addition,
the provision adds new language to section 510 of the FFDCA
(Registration of producers of Drugs and Devices) that will
exempt wholesale distributors of devices, who do not
manufacturer, repackage, process, or relabel, from the Act's
registration requirements.
Sec. 608. Pilot and Small-Scale Manufacture.
Section 608 amends Section 505(c) (21 U.S.C. 355(c)) of the
FFDCA to establish that a new drug manufactured in a pilot or
small facility may be used to demonstrate the drug's safety and
effectiveness and to obtain its approval prior to scaling up to
a larger facility. The Secretary retains the authority to
determine whether a full scale production facility is necessary
to ensure the drug's safety and effectiveness.
Sec. 609. Requirements For Radiopharmaceuticals.
Section 609 requires the Secretary, within 180 days of
enactment, and after consultation with patient advocacy groups,
associations, physicians licensed to use radiopharmaceuticals,
and the regulated industry, to issue proposed regulations
governing the approval of radiopharmaceuticals designed for
diagnosis and monitoring of diseases and conditions. The
regulations must provide that the product's safety and
effectiveness, governed under section 505 of the FFDCA and
section 351 of the Public Health Service Act, must include (but
not be limited to) consideration of the product's proposed use
in the practice of medicine, the product's pharmacological and
toxicological activity (including any carrier or ligand of the
radiopharmaceutical), and the product's estimated absorbed
radiation dose.
Within 18 months of enactment, the Secretary must issue
final regulations governing the approval of
radiopharmaceuticals. This section establishes a ``SPECIAL
RULE'' stating that in the case of a radiopharmaceutical
intended to be used for diagnostic or monitoring purposes, its
approved marketing indications may, in appropriate situations,
refer to manifestations of disease (such as biochemical,
physiological, anatomic, or pathological processes) common to
or present in one or more disease states. The term
``radiopharmaceutical'' is defined to mean an article: (A)
intended for use in the diagnosis or monitoring of a disease or
a manifestation of a disease in humans; and (B) which exhibits
spontaneous disintegration of unstable nuclei with the emission
of nuclear particles or photons; or any nonradioactive reagent
kit or nuclide generator which is intended to be used in its
preparation.
Sec. 610. Modernization of Regulation of Biological Products.
Section 610 amends section 351(a) of the Public Health
Service Act (PHSA) (42 U.S.C. 262(a)), to codify the regulation
of biological products. It states that a biological product may
not be introduced into interstate commerce unless (A) the
product has a biologics license; and (B) the package is marked
with the product's name, the manufacturer's name, address, and
license number, and the product's expiration date. By
regulation, the Secretary must establish requirements for the
approval, suspension, and revocation of biologics licenses. A
license will be approved based on a demonstration that the
biological product is safe, pure, and potent, and that the
facility where the product is manufactured, processed, packed,
or held meets standards to assure its continued safety, purity,
and potency. Also, the application will be approved only on the
condition that the licensee agrees to permit inspection of its
production facility. The Secretary must prescribe certain
licensing and labeling exemptions for products undergoing
investigation.
The section amends section 351 of the PHSA eliminating the
requirement that biologics manufacturers obtain establishment
licenses, and redefines biological product to mean: ``a virus,
therapeutic serum, toxin, antitoxin, vaccine, blood, blood
component or derivative, allergenic product, analogous product,
or arsphenamine or its derivatives (or any other trivalent
organic arsenic compound) applicable to the prevention,
treatment, or cure of diseases or conditions of human beings.''
In addition, the section establishes a ``SPECIAL RULE''
directing the Secretary to take steps necessary to minimize
differences in the review and approval of products required to
have both a biologic license application under section 351 of
the PHSA and a new drug application (NDA) under section
505(b)(1) of the FFDCA.
Sec. 611. Approval of Supplemental Applications for Approved Products.
This section states that within 180 days of enactment, the
Secretary must publish in the Federal Register performance
standards for the prompt review of supplemental applications
for drugs previously approved under the Act. Within this same
timeframe, the Secretary must also issue final guidance to
clarify the requirements and facilitate the submission of data
to support the approval of the supplemental application. The
guidance must: (1) clarify the circumstances that will permit
published material to qualify as the basis for approval; (2)
specify data requirements that will avoid duplication by
recognizing the availability of data previously submitted; and
(3) define supplemental applications that are eligible for
priority review.
The Secretary must designate someone in each FDA Center
(except the Center for Food Safety and Applied Nutrition) who
will be responsible for encouraging prompt review of
supplemental applications, and who will work with sponsors to
facilitate the development of and data to support supplemental
applications. In addition, the Secretary must implement
programs and policies that will foster collaboration between
FDA, NIH, professional medical and scientific societies, and
others to identify published and unpublished studies that could
support a supplemental application. Moreover, the Secretary
must encourage sponsors to submit supplemental applications or
conduct further research based on these studies.
Sec. 612. Health Care Economic Information.
Section 612 amends Section 502 (21 U.S.C. 352) of the
FFDCA, which specifies the circumstances whereby drugs and
devices may be deemed ``misbranded,'' by adding language to
deal with pharmacoeconomic health care claims. It establishes
that a drug or device, about which a health care economic
statement may be included in its labeling or advertising
submitted to a formulary committee, managed care organization,
or similar entity with drug selection responsibilities, will be
considered misbranded if the economic statement is not based on
``competent and reliable'' scientific evidence.
The bill states that any such economic statements will be
subject to section 502 only, and defines ``health care economic
statement'' as ``any statement that identifies, measures, or
compares the costs (direct, indirect, or intangible) and health
care consequences of a drug to another drug or to another
health care intervention for the same indication, or to no
intervention, where the primary endpoint is an economic
outcome.''
Sec. 613. Expediting Study and Approval of Fast Track Drugs.
Section 613 amends Chapter V (21 U.S.C. 351) of the FFDCA,
establishing a new Section 561 under new Subchapter E--Fast
Track Drugs. The bill states that the Secretary will facilitate
development and expedite approval of new drugs and biological
products, to be known as ``fast track drugs,'' that are
intended for treating serious and life-threatening conditions
and show potential to address unmet medical needs. Drug
sponsors may request that the Secretary designate drugs for
fast track consideration, and the designation may be made
concurrently with, or at any time after, the submission of the
investigation application. Within 30 days of the request, the
Secretary will determine if the drug meets the fast track
criteria, and if so, will designate the drug and take action to
expedite its development and review.
The Secretary may approve a fast track drug based on a
determination that the drug has an effect on a surrogate
endpoint that is reasonably likely to predict clinical benefit.
Such an approval may obligate the manufacturer to (i) conduct
post-approval studies to validate the surrogate endpoint and
confirm its clinical benefit; and (ii) submit copies of all
promotional materials related to the fast tack drug during the
preapproval review period and, following approval, at least 30
days prior to the dissemination of the materials for such a
time as the Secretary finds appropriate.
The approval of a fast track drug may be withdrawn using
expedited procedures, including an opportunity for informal
hearing, if the sponsor fails to diligently conduct the post-
approval studies; a post-approval study fails to verify a
clinical benefit; other evidence demonstrates that the drug is
not safe or effective under its conditions of use; or the
manufacturer disseminates false for misleading promotional
materials.
This provision also provides for the review of incomplete
applications for the approval of fast track drugs. If early
evaluation of clinical data for a fast track drug shows
evidence of effectiveness, the Secretary will evaluate for
filing and may commence review of portions of an application if
the sponsor provides a schedule for submitting the information
necessary for a complete application and any required user fee.
In situations where the fast track drug's application is
incomplete, the time periods for review of human drug
applications agreed to in section 736 [drug user fee authority]
will not apply until a completed application is submitted.
The Secretary must develop and widely distribute to
physicians, patient organizations, pharmaceutical and
biotechnology companies, a comprehensive description of the
provisions applicable to fast track drugs, and establish an
ongoing program to encourage the development of surrogate
endpoints that are reasonably likely to predict clinical
benefit. Within 1 year of enactment the Secretary must issue
guidance that describes the EPA's policies and procedures
required to implement this provision.
Sec. 614. Manufacturing Changes For Drugs and Biologics.
Section 614 amends Chapter VII (21 U.S.C. 371) of the
FFDCA, establishing new Section 751 under new Subchapter E--
Manufacturing Changes. It describes the types of manufacturing
changes the manufacturer of a new drug or biologic may make
under the Act.
Before distributing a new drug or biologic made after a
change in the manufacturing process established in its original
application, the sponsor must validate the effect of the change
on the product's identity, strength, quality, purity, and
potency--as they may relate to its safety and effectiveness.
Changes needing validation must be reported to the Secretary,
and the manufacturer may distribute the drug after a change is
made as follows: (A) Major manufacturing changes, determined by
the Secretary to have a substantial potential to adversely
affect identity, strength, quality, purity, and potency as they
may relate to safety and effectiveness, must be submitted in a
supplemental application. Drugs made after these changes may
not be distributed until the Secretary approves the supplement.
Major manufacturing changes means: (1) changes in the
qualificative or quantitive formulation or specifications; (2)
changes the Secretary determines require an appropriate human
study; and (3) changes which the Secretary determines have a
substantial potential to have an adverse effect on the drug's
safety or effectiveness; (B) As determined by the Secretary,
manufacturing changes other than major changes, can be made at
any time and must be reported annually with supporting data, or
be reported in a supplemental application. Drugs having
undergone a minor manufacturing change may be distributed 30
days after the Secretary receives a supplemental application,
unless the applicant is notified that prior approval of the
supplement is required. After notification to the applicant,
the Secretary must approve or disapprove each supplement. The
bill proposes a ``SPECIAL RULE'' that allows the Secretary to
determine the types of manufacturing changes after which
distribution of the drug may begin whenthe supplement is
submitted. A period for transition from prior requirements is defined.
Sec. 615. Data Requirements for Drugs and Biologics.
Section 615 requires the Secretary through the Commissioner
of FDA, within 1 year of enactment, to issue guidance that
describes when manufacturers will be permitted to submit
certain abbreviated study reports instead of traditional full
reports with their new drug applications (NDAs). The guidance
must describe when abbreviated reports are appropriate and what
their format should be.
Sec. 616. Food Contact Substances.
Section 617(a) amends Section 409(a) of the FFDCA (21
U.S.C. 348(a)) by providing that a food additive that is a food
contact substance is unsafe unless it is used in conformity
with an applicable food additive regulation or an effective
premarket notification. This section further amends Section
409(a) to state that a food is not adulterated by virtue of
containing or bearing a food additive that is a food contact
substance used in accordance with an applicable regulation or
effective notification. Section 617(a) establishes a new
process, premarket notification, by which food contact
substances can lawfully enter the marketplace.
Section 617(b) creates a new Section 409(h) of the FFDCA. A
new Section (h)(1) establishes the process, terms, and
conditions of the PMN approach for food contact substances.
Receipt by FDA of the PMN is required at least 120 days prior
to introduction of the substance into interstate commerce or
its delivery for such introduction. The notification must
provide notice of the identity and intended use of the
substance and other information that forms the basis of the
notifier's determination that the intended use of the food
contact substance is safe. The standard for safety for food
contact substances incorporates the standard under current law,
specifically Section 409(c)(3)(A) of the FFDCA (21 U.S.C.
348(c)(3)(A)). Section (h)(1) also authorizes FDA to issue
regulations specifying the information required in a PMN. The
types and amount of information required will be comparable to
that currently required for food additive petitions for
``indirect additives.''
A new Section (h)(2) created by Section 617(b) of this bill
specifies that a PMN becomes effective automatically 120 days
after receipt by FDA, unless FDA objects. FDA is not required
to publish a notice of filing in the Federal Register as it
currently does in response to food additive petitions. Thus,
the time period for consideration of a PMN runs from the fier
has not demonstrated in the PMN that the food contact substance
is safe. FDA is required to notify the submitter of this
determination, and it is expected that this notice will specify
the basis for the determination insufficient detail to
establish that the Agency has not been arbitrary or capricious.
Section (h)(2) also establishes that FDA's decision to object
to a PMN is final agency action subject to immediate judicial
review. Finally, the Section specifies that a notification is
only effective with respect to the specific substance listed in
the notification, and does not extend to similar or identical
substances manufactured by a person other than the manufacturer
listed in the notification.
Section (h)(3) created by Section 617(b) of the bill
mandates that the PMN process be utilized for authorizing the
marketing of a food contact substance unless FDA determines
that a food additive petition is necessary to provide adequate
assurance of safety, or unless FDA and a company agree that a
petition may be submitted. FDA is authorized to issue
regulations to identify the circumstances under which petitions
will be required, and the Committee fully expects that such
regulations will be based on sound scientific considerations
reasonably related to public health and safety, such as
probable consumption levels and potential toxicity. It is
intended that the PMN process will be the primary method for
authorizing the marketing of food contact substances.
Section (h)(4) created by Section 617(b) requires FDA to
keep all information in the PMN confidential for the duration
of the 120 day review period. Following this period, the
contents of the PMN would be available for disclosure to the
public as are safety and functionality data filed in a food
additive petition, consistent with the Freedom of Information
Act (FOIA) and other related disclosure statutes.
Section reasonable fees from those who file a PMN in order
to assure that FDA has the resources needed to review thePMN
within 120 days. These fees must be based on the resources necessary to
process the PMNs, including reasonable administrative costs. FDA is
directed by the bill to conduct a study of the costs of administering
the PMN program, and, on the basis of this study, issue regulations
within 18 months of enactment establishing the amount of the fee for a
PMN. The fees must only reflect the actual costs of processing the
PMNs, and must be set at a level that is not unduly burdensome on
industry. These fees will be credited to the FDA, and will be used by
the Agency solely to defray the costs of administering the PMN program.
Section (h)(6) provides the new definition of ``food
contact substance'' to be added to the FFDCA. The definition of
food contact substance includes any substance intended for use
as a material or a component of materials used in
manufacturing, packing, packaging, transporting, or holding
food if such use is not intended to have any technical effect
in such food. This definition includes some substances that do
not meet the definition of a food additive because, for
example, such substances are generally recognized as safe or
prior sanctioned for their uses, or they are not reasonably
expected to become a component of food. ``Not reasonably
expected to become a component of food'' has been interpreted
by FDA to include food contact substances separated from food
by a barrier to migration and those processing aids (e.g.,
solvents and catalysts) that by virtue of the conditions of
manufacture are removed from the final food contact substance.
A premarket notification is permitted for food contact
substances that are not food additives, but is required only
for those food contact substances that also meet the definition
of a food additive.
Section 617(b)(3) of this bill adds authorization for FDA
to issue regulations establision demonstrates that just as
Congress recognized the need for a process for revoking a
regulation for a food additive, the situation is no different
for food contact substances being marketed subject to a PMN.
Section 617(c) specifies that this legislation shall be
effective following 18 months from the date of its enactment.
PMNs may be filed after this period (and become effective 120
days after their receipt by FDA) without regard to whether FDA
has issued regulations implementing this legislation.
Sec. 617. Health Claims for Food Products.
Section 617 amends section 403(r)(3) (21 U.S.C. 343(r)(3))
of the FFDCA. It provides an alternative to the current
standard and review process by allowing health claims to be
made based on information published by authoritative U.S.
government scientific bodies. The new provision will allow a
health claim in food labeling without FDA authorization, if it
consists of or will otherwise summarize or reflect information
contained in a publication of a Federal Government scientific
organization or some component of the National Academy of
Sciences. If any such health claim is made, it must be
submitted to FDA, along with the published information on which
it is based, at least 120 days prior to its appearance in the
marketplace. A claim meeting the requirements may be made until
a final regulation, prohibiting or modifying the claim, becomes
effective, or a U.S. District Court determines that the
nutritional claims requirements have not been met.
Sec. 618. Pediatric Studies Marketing Exclusivity.
Section 618 amends Chapter V (21 U.S.C. 351 et seq.) of the
FFDCA by creating new section 515A--Pediatric Studies of Drugs.
If, prior to the approval of a new drug, the Secretary
determines that information about the drug will produce health
benefits in a pediatric population, and makes a written request
for pediatric studies, and the studies are completed and
accepted, then the sponsor or manufacturer can qualify for up
to 6 months of extra market exclusivity. If the Secretary makes
a written request for pediatric studies of an already marketed
drug, and those studies are completed, then the manufacturer
can be granted up to 6 months of increased market exclusivity
as well.
Within 180 days of enactment, the Secretary, after
consultation with experts, must develop and publish an initial
list of approved drugs for which additional pediatric
information may produce health benefits. When the Secretary has
formally requested pediatric studies those studies must be
conducted by a written protocol agreed to by the sponsor,
patent holder, and the Secretary. Less than 60 days after the
pediatric studies have been submitted, the Secretary must
determine whether the studies were done properly and notify the
sponsor or holder. In addition, theprovision contains a section
describing other means by which the study protocol requirements can be
met.
This section contains a sunset provision that states that
no market exclusivity will be granted based on pediatric
studies begun after January 1, 2004. In addition, the Secretary
must complete a study and report to Congress no later than
January 1, 2003, the agency's experience under the program. The
report must address the program's effectiveness, the adequacy
of its incentives, the program's economic impact, and any
suggestions for the program's modification.
Sec. 619. Positron Emission Tomography
Section 619 amends the FFDCA to include the regulation of
compounded positron emission tomography (PET) drugs. The
provision defines compounded PET drugs to mean drugs that
exhibit spontaneous disintegration of unstable nuclei; includes
nonradioactive reagents, nuclide generators, accelerators,
electronic synthesizers, or associated software used to prepare
any such drug; and, which have been compounded in accordance
with State law by or on the order of a practitioner licensed in
that State or in a federal facility in accordance with the laws
of the State in which it is located. The Act is amended to
stipulate that a compounded PET drug is adulterated, and thus
subject to regulatory and/or legal action by FDA if it is not
compounded, processed, packed, or held in accordance with the
PET compounding standards and official monographs of the United
States Pharmacopoeia (USP).
The act is further amended to provide that neither a New
Drug Application (NDA) nor an Abbreviated New Drug Application
(ANDA) is required by a licensed practitioner to produce a
compounded PET product in accordance with USP standards. Within
30 days of enactment, the Secretary must publish in the Federal
Register a notice revoking all previously published efforts by
FDA to provide industry guidance and regulatory standards for
PET products.
TITLE VII--FEES RELATING TO DRUGS
Sec. 701. Short Title.
Section 701 provides that this title be cited as the
``Prescription Drug Users Fee Reauthorization Act of 1997.''
Sec. 702. Findings.
Section 702 sets forth four congressional findings: (1) the
prompt approval of safe and effective new drugs and other
therapies is critical to improve public health; (2) additional
resources augmenting the Food and Drug Administration's (FDA)
review of human drug applications serve the public health; (3)
the successful Prescription Drug User Fee Act of 1992 (PDUFA)
program reduced drug review times; therefore it should be
reauthorized for an additional 5 years and should be carried
out by FDA with more ambitious and comprehensive regulatory
goals; (4) fees authorized by amendments will be used to
expedite the drug development and application review process
through goals identified in letters [date unspecified] from the
Secretary to the Chairman of the House Committee on Commerce
and Chairman of the Senate Committee on Labor and Human
Resources, as set forth in the Congressional Record [date
unspecified].
Sec. 703. Definitions.
Section 703 augments several definitions in section 735 (21
U.S.C. 379(g)). New section 735 will not allow PDUFA funds to
pay for review or processing of biological license applications
for further manufacturing only nor cover a product that is not
sod commercially and whose application or supplement is
submitted by a State or Federal government entity. PDUFA would
cover review of licenses for large volume biological products
used for single dose intravenous injection or infusion. Section
703(3) amends section 735(4) to ensure that the term ``final
dosage form'' of a prescription drug does not need any further
``substantial'' modification. Section 735(7) is amended to
allow expenses of contractors of FDA to be paid with PDUFA
funds. The ``adjustment factor'' would now be the lower of
either the Consumer Price Index for all urban consumers (with
August 1992 replaced with April 1997) or one plus the total
percentage increase for a fiscal year since 1997 in the general
schedule of base pay for federal employees after adjustments
have been made for employees stationed in the District of
Columbia. The term ``business affiliate'' means a business
relationship in which one business, directly or indirectly,
controls or has the power to control, the other businesses, or
a third party controls, or has the power to control both
businesses.
Sec. 704. Authority to Assess and Use Drug Fees.
Section 704(a) amends Section 736(a) (21 U.S.C. 379h(a))
establishing types of fees. PDUFA re-authorization will begin
in fiscal year (FY) 1998. It will require payment offees
whenever an application or supplement is submitted to the agency.
Section 736(a)(1)(D) is amended to allow 75 percent of the fee to be
refunded if FDA refuses to file an application.
Section 704(2) also adds three exceptions to the payment of
fees. Section 736(a)(1) exempts in new subsection (E) an
application or supplement for designated orphan drugs or
indications submitted under section 526 to treat a rare disease
or condition. To get an exemption, the application or
supplement cannot include any uses other than for rare diseases
or conditions. Section 736(a)(1) is amended to add a new
subsection (F) wherein a person submitting an application for a
pediatric drug will be assessed a fee only if the application
is for the initial approval for use in a pediatric population
or for use by pediatric and non-pediatric populations. Section
736(a)(1) is amended to add subsection (G) to refund a fee if
the application is withdrawn. It allows the Secretary sole
discretion to waive and refund a fee if no substantial work was
performed on the application or supplement before it was
withdrawn.
Section 704(3) also amends section 736(a)(2), the
prescription drug establishment fee, to ensure that generic
drug manufacturing establishments, whether they produce drugs
that were approved before or after 1984 will not pay a fee nor
will establishments that manufacture generic antibiotics.
Section 704(4) amends section 736(a)(3), the prescription
drug product fee, to expand the definition of those who must
pay the fee. It will require all applicants be included whose
product has been submitted for listing with the Secretary. It
also amends the schedule for payment so that a fee will be paid
for the fiscal year in which the product is first submitted for
listing under section 510 of the FFDCA (Registration of
Producers of Drugs and Devices) or for relisting if the product
had been withdrawn. After the fee is paid for the fiscal year,
the fee must be paid on or before January 31 of each year
thereafter. Innovator antibiotic drug products (antibiotic
drugs whose initial certification or approval was under section
507) are subject to product fees; however, generic antibiotic
drug products with approval granted prior to the Drug Price
Competition and Patent Term Restoration Act of 1984.
Section 704(b) amends section 736(b) relating to fee
amounts (21 U.S.C. 379h(b)) to eliminate the word ``schedule''
and set the fee to be assessed as follows: (1)(A) FULL FEES.
The application fee shall be $250,704 in FY 1998, $256,338 in
FY 1999 and 2000, $267,606 in FY 2001, and $258,451 in FY 2002.
(1)(B) PARTIAL FEES. The supplement fee shall be $125,352 in FY
1998, $128,169 in FY 1999 and 2000, $133,803 in FY 2001, and
$129,226 in FY 2002.
Section 736(b)(2) will also amend fee revenue amounts to be
collected from establishment fees. Total fee revenues collected
as establishment fees shall be $35.6 million in FY 1998, $36.4
million in FY 1999 and 2000, $38 million in FY 2001, and $36.7
million in FY 2002.
Section 736(b)(3) will also amend fee revenue amounts to be
collected from product fees. Total revenues collected from
product fees for a fiscal year shall equal total establishment
fees each year.
Section 736(c) is amended to create a section entitled
``Adjustments,'' with a new subsection title ``(1) Inflation
Adjustment.'' The Secretary could change the adjustment made
each fiscal year to the fees collected by adding, on a
compounded basis, the sum of all adjustments made each fiscal
year after FY 1997. The annual fee adjustment should begin on
September 30, 1997, and the establishment and product fees
should be adjusted so that their revenue shall be set to equal
the revenues collected from application and supplement fees.
Section 736(d) on fee waiver and reduction (21 U.S.C.
379h(d)) restructures the paragraphs and adds to the assessment
provision that if the applicant is a small business and submits
its first new drug application to the Secretary for review, it
can receive a waiver or reduction in fees. Section
736g(d)(3)(A) defines the term ``small business'' to mean an
entity that has fewer than 500 employees, including employees
of affiliates. Section 736g(d)(3)(B) allows the Secretary to
waive the fee if the small business or affiliate is submitting
for the first time an application for approval of a human drug.
After this first time waiver is granted, the small business or
affiliate must pay fees on all subsequent applications or
supplements. The Secretary may also use ``standard costs'' in
making the finding that the waiver or fee reduction is
necessary to protect the public health.
Section 704(e) amends section 736(f)(1) (21 U.S.C.
379g(f)(1)) to update to FY 1997. Section 704(f) amends section
736(g) (21 USC 379g(g)) to allow the transfer of appropriated
funds from the account for salaries and expenses of one fiscal
year to another fiscal year accountif the funds are available
solely for reviewing human drug applications. It also amends the
statute to allow funds to be collected in each fiscal year in an amount
specified in appropriation Acts or otherwise be made available for
obligation. It also specifies that fees shall only be collected and be
available to defray increases in the costs of the resources allocated
for the review process for human drugs over such costs, excluding costs
paid for fees collected under this section, for FY 1997; and multiplied
by the adjustment factor.
Section 704(f) amends section 736(g)(3) and authorizes to
be appropriated for fees: (A) $106,800,000 for FY 1998; (B) and
(C) $109,200,000 for FY 1999 and 2000; (D) $114,000,000 for FY
2001; and (E) $110,100,000 for FY 2002. These amounts reflect
adjustments in the total fee revenues made under this section
and changes in the total funds collected by the four fees:
application, supplement, establishment, and product fees.
Section 704(f)(3) amends section 736(g) to add a new
section: (f)(4) OFFSET. This subsection allows any collected
fees over the authorized amount to be credited to an
appropriation account of the FDA and be subtracted from the
subsequent fiscal year authorization to collect fees.
Section 704(g) amends section 736 (21 U.S.C. 379h) to
create a subsection (i) and provides that, to qualify for
consideration of a waiver or fee reduction or refund, a person
must submit a written request to the Secretary for this action
within 180 days after the fee is due.
Section 704(h) amends section 736 (21 U.S.C. 379h) to
create a subsection (h) providing for a special rule for
waiver, refunds, and exceptions. It allows that any requests
for waivers, refunds, or exceptions for fees paid prior to the
date of enactment could be submitted in writing to the
Secretary within one year after enactment of this Act.
Sec. 705. Annual Report.
Section 705 requires two reports to be prepared by the
Secretary of Health and Human Resources and submitted to the
House Committee on Commerce and the Senate Committee on Labor
and Human Resources. The first will report, within 60 days
after the end of the fiscal year, on the progress FDA achieved
in meeting the performance goals identified in the letters
described in section 702(4). The second will report within 120
days on the implementation of the authority for such fees
during the fiscal year and FDA's use of the fees.
title viii. miscellaneous
Sec. 801. Registration of Foreign Establishments.
Section 801 amends section 510(i) of the FFDCA to require
that any establishment within any foreign country engaged in
the manufacture, preparation, propagation, compounding, or
processing of a drug or a device that is imported or offered
for import into the United States must register with the
Secretary the name and place of business of the establishment
and its United States' agent. The establishment must provide
the information required under section 510(j) of the FFDCA.
Section 801 authorizes the Secretary to enter into cooperative
agreements with foreign countries to ensure that adequate and
effective means are available to determine whether drugs or
devices manufactured, prepared, propagated, compounded, or
processed by a foreign establishment, if imported or offered
for import into the U.S., should be refused admission on
grounds set forth in section 801(a) of the FFDCA, i.e., imports
and exports.
Sec. 802. Elimination of Certain Labeling Requirements.
Section 802 amends section 503(b)(4) of the FFDCA and
provides that a drug subject to section 503(b)(1) is misbranded
if at any time prior to dispensing the label of the drug does
not bear, at a minimum, the symbol ``Rx only.'' A drug that
does not fall under (b)(1) is deemed to be misbranded if at any
time prior to dispensing the label of the drug bears the symbol
``Rx only.'' Also, section 502(d) of the FFDCA is repealed,
i.e., labeling on habit forming narcotic or hypnotic drugs.
Sec. 803. Clarification of Seizure Authority.
Section 803 amends section 304(d)(1) of the FFDCA by
removing the reference to paragraphs (1) and (2) of section
801(e)(1) of the FFDCA and inserting a reference to only
subparagraphs (A) and (B) of section 801(e)(1) of the FFDCA.
While the current provision appears to make inapplicable all of
paragraphs (1) and (2) to the situation where a condemned
article is exported to the original foreign supplier, the
amending language makes inapplicable only two requirements
found in subparagraphs (A) and (B). Additionally, this section
adds the new sentence which provides that any person seeking to
export an imported article under section 304(d) of theFFDCA
must establish that the article was intended for export at the time the
article entered commerce.
Sec. 804. Intramural Research Training Award Program.
Section 804 amends Chapter IX of the FFDCA [Miscellaneous],
by adding the new section 907 [sic] which establishes the
``Research Training Award Program.'' New subsection (a)
authorizes the Secretary, acting through the Commissioner,
directly or through grants, contracts, or cooperative
agreements, to conduct and support research training in
regulatory scientific programs by pre- and postdoctoral
scientists and physicians. This may include support through the
use of fellowships. New subsection (b) provides that the
recipient of a fellowship may not be an employee of the Federal
government. And, under new subsection (c), the Secretary is
authorized, acting through the Commissioner, to support the
provision of assistance for fellowships through a Cooperative
Research and Development Agreement.
Sec. 805. Device Samples.
Section 805(a)(1) amends section 518(e)(2) of the FFDCA
[Recall authority for devices] adding the new subsection
(e)(2)(C) which provides that if the Secretary issues an
amended order under subparagraph (A), he may require the person
subject to the order to submit such samples of the device and
its components as the Secretary may reasonably require. If the
submission of the samples is impracticable or unduly
burdensome, this requirement may be met by submitting complete
information concerning the location of one or more such devices
readily available for examination and testing. Section
805(a)(2) of the bill amends section 518(e)(2)(A) of the FFDCA
by providing a technical amendment which strikes an apparently
erroneous reference to subparagraph (C) in (e)(2)(A).
Section 805(b) [Records and reports on devices] amends
section 519(a) of the FFDCA, as amended by section 607(a) of
the bill, and adds new paragraph (a)(9) which provides that
regulations issued under the first sentence of subsection (a)
may reasonably require a manufacturer, importer, or distributor
to submit samples of a device or its components that may have
caused or contributed to a death or serious injury. This
submission is not required if it is impracticable or unduly
burdensome. The requirement may be met by the submission of
complete information concerning the location of one or more
such devices readily available for examination and testing.
Sec. 806. Interstate Commerce.
Section 806 amends section 709 of the FEDCA by providing
that in any action to enforce the FFDCA respecting a device,
food, drug, or cosmetic, the connection with interstate
commerce required for jurisdiction shall be presumed to exist.
Sec. 807. National Uniformity for Nonprescription Drugs and Cosmetics.
(Amendment offered by Senator Gregg.) (This section was
number 808 in amendments to the bill.)
Section 807 amends Chapter VII [General Authority] of the
FFDCA, as amended by section 615 of the bill, by adding a new
subchapter F entitled ``National Uniformity for Nonprescription
Drugs for Human Use and Cosmetics.'' New section 761(a)
provides that, except in certain subsections, no State or
political subdivision of a State may establish or continue to
effect any requirement (1) that relates to the regulation of a
drug intended for human use that is not subject to the
requirements of section 503(b)(1) or a cosmetic and (2) that is
different from or in addition to a requirement of this Act, the
Poison Prevention Packaging Act, or the Fair Packaging and
Labeling Act.
However, upon application by the State, the Secretary may,
by regulation, after notice and opportunity for written and
oral views, exempt a State requirement that protects an
important public interest that will otherwise be unprotected;
will not cause any drug or cosmetic to be in violation of any
applicable requirement or prohibition under Federal law; and,
will not unduly burden interstate commerce. This provision
shall not include any requirement that relates to the practice
of pharmacy or any requirement that a drug be dispensed only
upon the prescription of a practitioner licensed by law to
administer the drug. Furthermore, with regard to scope, this
provision shall include any requirement relating to public
information or any public communication relating to the safety
and effectiveness of a drug or cosmetic. Any, nothing in this
section shall be construed to modify or otherwise affect any
action or the liability of any person under the product
liability law of any State.
Sec. 808. Information Program on Clinical Trials for Serious or Life-
Threatening Diseases.
(Amendment offered by Senator Dodd) (This section was
number 808 in amendments.)
Section 808 amends section 402 of the Public Health Service
Act (42 U.S.C. Sec. 282; Director of National Institutes of
Health) by inserting a new subsection 282(j), after
redesignating subsection (j) as (k) and subsection (k) as (l).
The new subsection provides that the Secretary, acting through
the Director of NIH and subject to available appropriations,
shall establish, maintain, and operate a program with respect
to information on research relating to the treatment,
detection, and prevention of serious or life-threatening
diseases and conditions. The program shall, with respect to the
agencies of HHS, be integrated and coordinated and, to the
extent practicable, coordinated with other information banks.
After consulting with the Commissioner, the directors of
the institutes of NIH, including the National Library of
Medicine, and the Director of the CDC, the Secretary shall
establish a data bank of information on clinical trials for
drugs, and biologicals, for serious or life-threatening
diseases and conditions. The Secretary shall collect, catalog,
store and disseminate this information through information
systems, which must include toll-free telephone communications
and be available to persons with serious or life-threatening
diseases and conditions, the public, health care providers an
researchers.
The Data Bank must include: (A) a registry of clinical
trials of experimental treatments for serious or life-
threatening diseases or condition that describes the purpose of
each experimental drug or biological protocol, either with the
consent of the sponsor or when a trial to test efficacy begins.
The information shall consist of eligibility criteria, location
of trial sites, point of contact, in a form readily understood
by the public, and must be forwarded to the data bank by the
sponsor of the trail not later than 21 days after the approval
by the FDA; (B) information pertaining to treatments that may
be available under a treatment investigational new drug
application that has been submitted to the FDA under pertinent
regulations or as a Group C cancer drug. The Bank may include
information relating to the results of clinical trials, with
the consent of the sponsor, including potential toxicities or
adverse effects. It shall not include information relating to
an investigation if the sponsor has certified to the Secretary
that disclosure will substantially interfere with the timely
enrollment ofsubjects in the investigation. To carry out the
program, the bill authorizes to be appropriated such sums as may be
necessary, and fees collected under section 736 of the Act shall not be
used or appropriated for this.
Section 808(b) provides that the Secretary, the Director of
NIH, and the Commissioner shall collaborate to determine the
feasibility of including device investigations within the
registry. Within two years of enactment, the Secretary must
prepare and submit to the Senate Committee on Labor and Human
Resources and the House Committee on Commerce a report that
considers, among other things, the public health need for
including devices and the adverse impact, if any, on device
innovation and research if information on devices is publicly
disclosed.
Sec. 809. Application of Federal Law to the Practice of Pharmacy
Compounding.
Section 809 amends section 503 of the FFDCA by adding the
new subsection (h). New subsection (h)(1) provides that
sections 501(a)(2)(B) [Adulterated drug], 502(f)(1) [Misbranded
drug], 502(1) [Antibiotic drug], 505 [New drugs], and 507
[Certification of antibiotics] shall not apply to a drug
product that is compounded for an identified patient based on a
medical need for a compounded product (1) by a licensed
pharmacist in a State licensed pharmacy or Federal facility or
licensed physician on the prescription order of a physician or
other licensed practitioner authorized by State law to
prescribe drugs; (2) by a licensed pharmacist or licensed
physician in limited quantities, before receiving a valid
prescription order for an identified individual if the
compounding of the drug is based on a history of receiving
valid orders that have been generated solely within an
established relationship between the pharmacist and the
individual patient or the physician or other licensed
practitioner who will write the prescription order.
The above noted sections of the FFDCE shall not apply to a
drug product if the pharmacist or physician (1) compounds a
drug product using bulk drug substances that meet the
requirements of this section; (2) compounds a drug product
using ingredients other than bulk drug substances that comply
with an applicable U.S. Pharmacopeia monograph and the U.S.
Pharmacopeia chapter on pharmacy compounding; (3) does no more
than advertise or promote the compounding service and does not
advertise or promote the compounding of a particular drug,
class of drug or type of drug; (4) does not compound a drug
product that appears on a list published by the Secretary of
drug products that have been withdrawn or removed from market
because it is unsafe or not effective; (5) does not compound a
particular drug product that is identified by the Secretary in
regulation as having demonstrable difficulties in being
compounded that reasonably demonstrate an adverse affect on the
safety and effectiveness of that drug product; and (6) does not
distribute compounded drugs outside the State in which the
pharmacy is located, unless the State agency of jurisdiction
has entered into a memorandum of understanding (MOU) with the
Secretary based on adequate regulation of compounding performed
in the State, which provides for appropriate investigation of
complaints by the State agency relating to compounded products
distributed outside the State.
In cooperation with the National Association of Boards of
Pharmacy, the Secretary is required to develop a standard MOU
for use by States in complying with the subsection relating to
distribution outside the State. Until 180 days after the
standard MOU is developed or the date entered in the MOU,
whichever is first, the subsection relating to distribution
outside the State [new section 503(h)(2)(vi)] does not apply to
a pharmacist or physician who does not distribute inordinate
amounts of compounded drugs out of State.
Section 809(b) requires the Secretary, after consultation
with the U.S. Pharmacopeia, to develop regulations limiting
compounding to drug substances that are components of drug
products approved by the Secretary and other substances
identified by the Secretary. Sections 809 (c) and (d) state
that new section 503(h)(1) shall not apply to compounded
positron emission tomography drugs, as defined in section
202(jj), or radiopharmaceuticals.
VIII. Additional Views
----------
ADDITIONAL VIEWS OF SENATORS GREGG AND McCONNELL
During the course of the Committee's consideration of S.
830, Senator Gregg offered, and subsequently withdrew, an
amendment to modify the PDUFA ``maintenance of effort''
requirement as proposed for authorization by this legislation.
This amendment would have created critical protections for the
FDA budget while instituting a realistic budgetary foundation
for the PDUFA reauthorization provisions contained in S. 830.
The goal of the amendment was to ensure that the FDA budget
may not take a reduction in the Agency's base appropriation
level at a percentage greater than the percentage by which the
602(b) allocation of the Agriculture Subcommittee of
Appropriations was reduced in order for the ``trigger''--FDA's
ability to collect and spend industry-paid user fees--to be
activated. The mutual agreement of the FDA and the
pharmaceutical industry holds promising benefits for the health
and welfare of American patients. We are concerned, however,
that the absence of thorough discussions on the relationship
between the reauthorization of PDUFA and Congress' efforts to
attain a balanced budget may undermine these objectives.
During the course of the Committee consideration, the
Members of the Committee were never provided with information
to clarify the level of total agency appropriations necessary
in each of the next five fiscal years to ``trigger'' the
collection of user fees for new human drugs. According to the
FDA, in written response to questions asked by Members of the
Senate, the base year funding required in FY 1997--the last
year of the current PDUFA program--the FDA must dedicate
$125.794 million in appropriated funds to human prescription
drugs reviews. In FY 1998, under current law requirements, the
FDA would have to dedicate over $128.833 million to these
activities. However, it is apparent that the FDA does not even
have a clearly defined system of checks and balances agency-
wide; while they are able to produce accounting reports
associated with PDUFA, they are unable to provide Congress with
reports of equivalent quality for the total agency
appropriation. In addition, it is unclear as to whether the FDA
is dedicating a disproportionate amount of funds to these
activities at the expense of other accounts, such as those
funds that are intended to be expended on the review of medical
devices, foods, or generic drugs, which are not covered by user
fee agreements.
Further, the Administration requested 8% reduction, $68
million, for the FDA's FY 1998 appropriations. To ``replace''
these funds, the OMB assumed $131 million in unauthorized user
fees with no indication of the likelihood for industry or
Congressional approval and little information on the validity
of OMB's assumption regarding these requested funds. This,
coupled with the assumption that FDA will not see any changes
in its mandated mission--for example, a transfer of a
regulatory and fiscal obligation such as ensuring seafood
safety from FDA to USDA--puts Congress in the uncomfortable
position of trying to maintain funding for activities that may
or may not remain relevant during the five year period of this
reauthorization.
Clearly, PDUFA's continued role as a source of
supplemental, not replacement, fund is important to the
prescription drug industry and the consumers it serves. We feel
that the direction of this amendment provides a reasonable
middle ground between the mutual objectives of industry and the
FDA and the Administration's balanced budget mode. This
amendment recognizes the importance of the FDA as a national
public health agency and that it should not be a site for
``found money'' within the Agricultural account, while it
acknowledges that 602(b) allocations conceivably may experience
reduction in future years.
We believe that the Secretary of Health and Human Services
sent the Committee a clear signal of concurrence in a letter
addressed to the Chairman, dated June 11, 1997, when she wrote:
We would support a user fee proposal that is
consistent with our FY 1998 Budget proposal, but we are
concerned that the proposal to collect user fees in
this legislation imposes additional pressure on the
fixed level of discretionary resources agreed to under
the Bipartisan Budget Agreement.
While we believe that cooperative discussions with the
Appropriations Committee and the Administration can best
address this issue, it is of utmost importance that the Members
of this Committee recognize the seriousness of this matter to
PDUFA's future. We are confident that this Committee does not
intend to reauthorize PDUFA in a manner that could potentially
prohibit the Agency's ability to collect the agreed upon fees,
nor to force the Appropriations Committee to act independently
of the reauthorization provisions in order to make PDUFA work.
We hope that the broader involvement of Members of the
Appropriations Committee and the Administration will provide
the fiscal framework necessary to the successful resolution of
this important matter for American patients and pharmaceutical
providers.
Judd Gregg.
Mitch McConnell.
ADDITIONAL VIEWS OF SENATOR HARKIN
While I strongly support meaningful reform of the Food Drug
and Cosmetics Act, I voted against S. 830 because I believe
that critical improvements must be made to the provision
relating to accredited review of medical devices. In addition,
I do not believe the bill goes far enough to improve the post-
market surveillance of high risk, potentially life-threatening
devices.
The provision relating to accredited party review is
described as a ``pilot'' to test whether the use of third party
reviewers would reduce delays in medical device approvals. But
the provision is overly broad in scope and it is my hope that
the ``pilot'' can be altered to address the concerns outlined
below.
The ``pilot'' in S. 830 does not limit in any way the
number and types of products that may go through a third party
reviewer. I believe a test of third party review should be
limited to less complex devices that pose a smaller potential
risk to patients should this new review process prove
ineffective. This is simply common sense. If we plan to test an
unproven process, let's do so in a manner that regardless of
outcome, poses the least amount of risk to public health and
safety.
There are provisions in S. 830 giving FDA final product
review authority, but I am concerned that a 30 or 60 day time
limit for FDA action will be extremely difficult, or
impossible, for the Agency to meet.
In addition, under S. 830 the manufacturer of the device
selects the reviewer and also directly pays the reviewer.
Direct payment by the manufacturer of the reviewer, without
approval or even review by FDA, creates obvious conflicts of
interest. Under FDA's current third party review regulations,
the Agency has the authority to review compensation agreements
between the manufacturer and the reviewer. However, the bill
does not provide FDA full and clear authority in this area. I
believe the FDA should have the authority in the statue to
review payment agreements and check for conflict of interest.
I am also concerned that this bill fails to provide
adequate performance criteria for the post market surveillance
of sophisticated, potentially life-threatening medical devices.
If this bill requires the Agency to be more efficient during
the approval process, I believe we need to make extra sure the
FDA strengthens its efforts to track and monitor products that
would present a danger to the public health should they be
found to be unsafe or ineffective.
Tom Harkin.
ADDITIONAL VIEWS OF SENATOR MURRAY
I strongly endorse FDA modernization and reform which is
why I voted to report S. 830 out of committee. But, I believe
that several points need to be made to clarify my position on
this legislation. First, I would like to make a few comments on
the process and express my concerns regarding this pending
bill. First, I do want to recognize the work that you and your
staff have done in developing this measure. I appreciate your
efforts to work to correct some of my concerns and your
willingness to craft acceptable language when appropriate.
Having said that, I do need to express some concerns with
this process. As a new member of this committee I did not have
the benefit of being here for last year's mark-up where many of
these issues were discussed and debated at length. I realize
that we did have two hearings on FDA reform, but one primarily
focused on PDUFA. As we all know, these issues are far from
simple and in most cases are extremely complicated. In
addition, the implications of what we do or don't do are
significant.
There has been limited time to review your draft and the
many amendments under consideration. In light of the important
public health issues involved I believe that the prudent course
would have been to schedule a hearing on your draft in order to
hear testimony from expert witnesses as to the ramifications of
each section.
My objective all along has been to reform FDA, to
revitalize a public health agency that faces life or death
decisions every day. One of the reasons I worked to secure a
position on this committee is because I wanted to play a direct
role in health care policy--FDA is one of the most critical
health care policy issues this committee will consider in the
105th Congress. We have an opportunity to improve access to
health care products for million of Americans. Effective reform
of the FDA can be a life saver.
I do want to make it clear that there are some real reform
proposals included in the bill that will serve to improve the
overall performance of the FDA. I want to thank the Chairman
for including some of these items.
I am here today because I made the decision several years
ago, to be an advocate for children. I got directly involved in
the political process because I was concerned that the voices
of children were not being heard. I have always considered
children's issues my top priorities. Because of this, I am
pleased that included in the legislation is the Dodd/Dewine
Pediatric Studies Marketing Exclusivity title. I believe that
the FDA has not done enough to encourage greater pediatric
clinical trials. For too long children have simply been
ignored. Providing patent exclusivity incentivesto companies to
include children in clinical trails may be the push that the industry
needs. I realize that there are some questions and concerns about this
approach, but unfortunately, this is the only solution I have seen that
will work. I am hopeful that we can address some of the concerns of the
generic drug manufacturers. No one wants to increase the cost of health
care, but if children are denied life saving treatments or are unable
to benefit from break through drugs that can reduce the severity of
their illness, we have saved in the long run. I am willing to work on
some type of transitional language or criteria for the Secretary's
selection process, but honestly believe we have an obligation to expand
clinical trial to include children.
I would also like to point out that the improvements made
in the expansion of the humanitarian use of devices will
provide life saving alternatives to physicians and patients.
I am also pleased that the Chairman has worked to improve
collaboration and communication between the FDA and industry.
The language in the bill does require more collaboration
between the FDA and industry throughout the approval process,
but this should be seen as a positive step, not a burden on the
agency. Success is much easier to obtain if the FDA and the
industry work more as a team with clear expectations and open
lines of communications.
It is unfortunate that due to many of the more
controversial issues, we have not talked much about Title VII--
PDUFA reauthorization. This is one of the most positive aspects
of the bill and illustrates the success we can achieve when we
all share the same objectives and priorities. Title VII
establishes new performance standards for the FDA that will
only improve the process. I want to commend the FDA for putting
forth this reauthorization language and working with, not
against industry and the patients.
Despite the many positive improvements, the current draft
of the pending legislation has some serious flaws and I am
concerned that in an effort to reform and revitalize the FDA,
we weaken their role as a public health agency. Despite
modifications, I am still concerned about some of the proposed
changes on substantial evidenc--we simply cannot and should not
act to limit the ability of the FDA to require comprehensive
clinical trials. I believe that the current Guidance Document
that governs FDA practices does offer each investigator the
``guidance'' necessary to determine the number of clinical
trails necessary--I am still not convinced that the proposal
before use today will actually clarify, but rather limit the
ability of FDA to require two trials in order to replicate
science.
One of the most significant problems facing FDA is
theapproval, tracking and surveillance of medical devices. Because of a
lack of targeted resources, the FDA has been unable to ensure timely
approval for many, life saving devices. I would acknowledge that the
agency has made some improvements in this process, but I still believe
that we need some reform and innovative solutions. There are several
proposed solutions to the device approval delays. One approach that I
do believe has some merit is a third party review process. But, if the
objective to by-pass the FDA, privitize the FDA, as opposed to
enhancing the activities of the FDA, than I would recommend we seek
other solutions. From the language in the Chairman's current bill, it
appears that the structure of the third party review, the types of
devices that could be approved by a third party and the inherent
conflict of interest questions could jeopardize the public health. I
have still not seen any assurance that the public's health and safety
would not be jeopardized and that the current language would truly
enhance the FDA's role as the lead agency for device approval. I am
still not convinced that adding another layer of ``bureaucracy'' will
improve the approval process--beyond the improvements already achieved
by FDA. I have several other concerns regarding the device tracking and
surveillance provisions in the bill and am some what disappointed that
so much controversy has surrounded one of the most pressing FDA reform
issues--that is improving and streamlining the device approval,
surveillance and tracking processes.
I also believe it is essential that the Gregg amendment
which preempts a State's ability to enact labeling restriction
or requirements on over the counter drugs needs to be revised.
This amendment could effectively prohibit a State from
requiring warning labels on harmful medications unless they
first petitioned the FDA for this ability. A State should not
have to petition FDA in order to require warning labels, such
as Mr. Yuk, which is an important tool in protecting children.
While Mr. Yuk may be a voluntary, education campaign, States
should have the ability to require this kind of labeling.
Seeking FDA approval is clearly an unfunded mandate on the
States. While uniformity may be the objective of the Gregg
amendment, I am concerned that the unintended consequence could
be harmful for children.
There are several other areas that I believe need greater
clarification and do not want to delay this process any
further, except to say that I am concerned that many of these
provisions could jeopardize FDA reform and revitalization
efforts. In addition, the timely reauthorization of PDUFA is
threatened by much of what we do here today. This in itself
deeply troubles me.
I am planning on voting to report this measure out of the
committee because of the urgency in moving this legislation to
the floor. I do so with some hesitation, but I sincerely
believe that moving this process along is a positive step and
essential for meeting my goal of a public debate on the issues.
However, the current bill still has many flaws that must be
adequately addressed before this bill can be sent to the
President. I am hopeful that I can continue to work with the
Chairman to improve the legislation without threatening the
many positive provisions. Without substantial changes and
revisions I would have a difficult time supporting this
legislation on the floor. I hope that we can all work to
achieve real reform that improves the regulatory process, but
does not weaken an agency that many of us simply take for
granted. What may have been lost in all of this is the fact
that the FDA's number one priority is and should always be,
guarding the public's health and safety.
Thank you, Mr. Chairman.
Patty Murray.
IX. MINORITY VIEWS OF SENATORS KENNEDY, BINGAMAN, AND REED
As stated in S. 830 the mission of the Food and Drug
Administration is to protect public health including ensuring
that drugs and devices are safe and effective and that food is
wholesome. S. 830 presents a sweeping package of changes that
will impact every family that fills a prescription, depends
upon a medical device, or relies on food labels to choose the
healthiest products for their dinner table.
Many of the provisions included in this bill are consensus
items with broad, bipartisan support. If we were to report
legislation today that includes only the items on which
consensus has been achieved, we would have crafted the broadest
FDA reform legislation in decades--reforms that could pass the
Senate unanimously.
Unfortunately, despite the progress that has been made,
this legislation also includes controversial provisions that
threaten public health. These provisions do not improve the
FDA--they weaken it. Given these concerns, we oppose the bill
as currently drafted. If controversial provisions are not
modified or eliminated from the bill, it will be difficult to
achieve timely reauthorization of the Prescription Drug User
Fee Act. We believe Senator Jeffords is committed to trying to
work out a consensus on these issues before the legislation
goes to the floor--and we are committed to working with him.
prescription drug user fee act (pdufa) reauthorization
The most important of the consensus items in this bill is
the reauthorization of the Prescription Drug User Fee Act. This
committee authored the Prescription Drug User Fee Act in 1992.
This legislation is one of the most effective regulatory reform
programs ever enacted. The bill established a new partnership
between the industry and the agency. The industry agreed to
provide additional, resources; the agency agreed to measurable
performance standards to speed the review of products. Every
goal set by that legislation for the FDA has not only been met,
it has been exceeded.
Today, the FDA is unequalled in the world in its record of
getting new drugs quickly to market without sacrificing patient
protection. In fact, last year, average review times in the
United States were twice as fast as in Europe. Fifteen new
drugs were approved in both the European Union and the United
States--and in 80 percent of the cases, the United States
approved the new drugs either first or at the same time as the
European Union. More companies chose the United States for the
introduction of breakthrough drugs than any other country.
The Prescription Drug User Fee Act reauthorization, as
negotiated between the FDA and industry and contained in this
bill, will maintain and enhance the progress that has been
achieved. Especially important is the promotion of early
cooperation between the FDA and industry in order to reduce
total drug development time, not just FDA review time. This
legislation is vital, and speedy action is essential. If this
legislation is not passed by August 1, the FDA will have to
begin sending lay-off notices to the 600 employees who are
supported through user fees and who are vital to the timely
review of drugs and biologics. We are committed to ensuring the
timely passage of PDUFA in combination with consensus reforms.
drug provisions
Other important consensus provisions in this bill clarify
that FDA may approve drugs and biologics on the basis of
products manufactured in pilot and small scale facilities;
direct FDA to propose regulations governing the approval of
diagnostic and monitoring radiopharmaceuticals; codify agency
policies regarding modernization of biologics approvals;
establish a mechanism for the FDA to review manufacturing
changes for drugs; require the Agency to issue guidance
streamlining data submissions for drugs and biologics; and
provide incentives to encourage drug manufacturers to conduct
studies on pediatric uses of specified drugs. The bill also
establishes a ``fast track'' mechanism to facilitate the
development and expedited approval of new drugs intended for
the treatment of serious and life-threatening conditions.
These provisions address a number of industry concerns and
improve the predictability and efficiency of drug approval and
manufacturing. In recent years, in partnership with Congress
and the Administration, the FDA has responded to criticism and
alleged delays in approving newproducts by taking impressive
steps to improve its performance. Provisions in this bill will codify
some of the important practices that the FDA has established to reduce
unnecessary regulatory burdens on industry and to modernize its
regulatory processes. These steps have added up to a quiet revolution
in the way the FDA fulfills its critical missions.
concerns related to drugs and biologics
Included in this bill is a provision to allow distribution
of health economic claims to formularly committees and managed
care organizations. Health economics is a developing area with
standards and guidelines that even the experts do not agree
upon. While this is an important area that should eventually be
addressed, there has not been time to adequately reflect on the
complex questions presented. The language included in the bill
has not been considered in public hearings nor have patient
groups had an opportunity to provide input on this issue.
The FDA is developing a policy on regulation of
pharmacoeconomic data which deals with the fundamental
questions related to data to support claims of cost-
effectiveness. These fundamental questions should be dealt with
before enactment of any statutory changes. A more reasonable
provision would require the agency to develop a policy on
regulation of pharmacoeconomics. Such a policy would lay the
groundwork for consideration of distribution of
pharmacoeconomic claims to formularies and managed care
organizations. Without this groundwork, there is a danger that
policies related to dissemination of health economic
information will become an avenue for off-label promotion of
unsubstantiated clinical efficacy claims. It is not clear why a
controversial provision related to health economics that has
not had adequate public consideration should be attached to
this bill.
Issues not included in the current bill must also be
addressed before a balanced reform package for drugs and
biologics can be achieved. This is particularly important in
the area of enforcement. The citizens of this country expect
the FDA to protect them from unsafe or ineffective drugs and
biologics. We must provide FDA with the tools needed to carry
out this mission.
This is particularly important under circumstances where
FDA has been given the authority to approve drugs and biologics
in an accelerated mode. In the early 1990's, new regulations
made it possible for the FDA to grant marketing approval under
accelerated reviews to drugs used to treat serious and life-
threatening illnesses. Under these programs, and under the
proposed fast track program, surrogate endpoints may be used to
provide early indications of potential clinical benefit. While
these endpoints are useful for getting drugs to patients
faster, it is essential that adequate phase IV, post-marketing
studies be performed to determine the ultimate safety and
efficacy of the drug.
A 1996 report by the Department of Health and Human
Services Inspector General on postmarketing studies of new
molecular entities indicated that 77 percent of phase IV
studies requested between 1987 and 1993 were in progress or
have been submitted to the agency. Of the 23 percent that were
not in progress or submitted, approximately 6 percent of these
studies will not be conducted because the FDA released the
company from their commitment. Of the remaining studies that
were not in progress or submitted, 11 percent or over 40
studies had not been completed for reasons that were unknown or
because the company had simply failed to fulfill its
responsibility. In some of these cases, over 6 years have
elapsed and the companies still insist that their studies will
begin sometime in the future.
The FDA should have the authority to enforce a request for
post-market or confirmatory clinical trials especially when
this data is pursuant to an accelerated approval of a new drug.
If a company fails to complete a requested trial, currently the
only remedy available to the Secretary is to remove the drug
from the market. Even if the process of withdrawal is
expedited, this remains a cumbersome process which punishes
patients who depend upon the drug in question. The Patient
Coalition regards enforcement procedures for phase IV studies
as a high priority. If we are truly trying to enhance patient
access to important medicines by providing accelerated
approvals, we should be prepared to assure that these drugs are
truly safe and effective.
The FDA should be given the authority to impose
intermediate sanctions of civil money penalties for failure to
perform post-approval research. When phase IV studies are
needed, theyprovide critically important data to assure safety
and effectiveness of new drugs. Failure to enforce these requirements
is unfair to those companies who do fulfill their obligations. We must
devise fair procedures that will assure that all companies complete
required studies in a timely manner.
device provisions
We have worked hard to balance the need for changes to
device approval processes with protection of public health.
Although a number of consensus device reform provisions have
been agreed upon, we are concerned that, on balance, this bill
weakens patient protections from unsafe medical devices. It is
important to note that the Safe Medical Devices Act of 1990 was
enacted because medical device oversight in this country was
deemed inadequate and placed patients at risk. It is also
important to note that the FDA has made significant
improvements in the area of device approval.
Even without additional resources in the device area, the
FDA's recent achievements have been impressive. So-called
510(k) applications--devices which are reviewed by the FDA to
determine their substantial equivalence to a device already on
the market--account for 98 percent of all device submissions.
The FDA has now essentially eliminated its backlog. Last year,
it reviewed 94 percent of these devices within the statutory
time frame--compared to only 40 percent just 4 years ago.
In the area of Class III devices, where most problems
remain, the FDA has improved its performance substantially.
According to a study by the General Accounting Office, median
review times dropped 60 percent between 1991 and 1996. A recent
survey of device industry executives reported that the business
climate for the industry is the best in the 5 year history of
the survey. The sponsor of the survey attributes this favorable
response, in large measure, to improvements at FDA, and
concludes, ``The agency has not only reduced the produce
approval delays that slowed new product introductions, but,
perhaps more importantly, has also greatly reduced both
executives' and investors' uncertainty about the timeliness of
future product introductions.''
We support many of the device reform provisions included in
the bill. We agree that FDA should be granted the authority to
recognize performance standards established by nationally or
internationally recognized standard setting entities. We
encourage implementation of a system that will provide for
appropriate industry and public input concerning which
standards should be accepted.
We also support provisions that would require FDA to exempt
certain class devices from premarket notification requirements;
allow use of data from a premarket approval 6 years after
approval of the first device of a type; require the FDA to
issue a regulation establishing criteria to be used in
determining when a specific intended use of a device is not
included in a general use; and provide mechanisms for
preventing inappropriate classification of low or moderate risk
devices into Class III.
concerns related to devices
We remain very concerned with provisions in the bill that
turn over reviews of critical medical devices to private
companies selected and paid by the very industry they are
supposed to regulate. The FDA currently has a pilot project to
explore this concept with low risk devices. Some expansion of
this pilot is warranted. But to test this concept by turning
over the regulation of the most sensitive and potentially
dangerous devices to private companies chosen and paid by the
manufacturer is an unacceptable experiment with the public's
health. No manufacturer will choose a reviewing company that it
thinks is going to be too rigorous. Every reviewing company
knows that its prospects for future business--and even the
generosity of its fees--are likely to depend on decisions that
are favorable to the manufacturer.
Americans today have a high degree of protection against
unsafe and ineffective devices, because these devices have been
reviewed by the professional, capable, objective public
officials at the FDA, who owe allegiance to no interest except
the public interest.
The American people deserve protection from unsafe heart
valves and pacemakers, inaccurate imaging machines used to
detect breast cancer or brain tumors, faulty drug infusion
pumps, and other unsafe and ineffective medical technologies.
They should not have to rely for that protection on untested
private companies hired and paid by the very firms producing
thepotentially faulty products.
In addition the bill also allows device manufacturers to
manipulate the product label to avoid careful FDA scrutiny and
to make basic changes in the manufacturing process without
effective FDA oversight, even if those changes threaten the
sterility, the safety, or the effectiveness of the product. The
bill establishes a mechanism for automatic reclassification of
class III devices without a clear standard for subsequent
review of the product. Post-market surveillance is arbitrarily
limited to an initial 24-month period even on products where
longer surveillance will clearly be required. The cumulative
effect of these and several other provisions, is to weaken the
FDA's ability to assure safety and effectiveness of medical
devices.
Food Provisions
We support the inclusion of a consensus provision on food
contact substances that has been endorsed by both the FDA and
the food industry.
We cannot support the inclusion of a provision that would
weaken the FDA's oversight of food health claims. The Nutrition
Labelling and Education Act of 1990 established landmark
requirements for food labelling that give consumers the right
to the information they need in order to choose healthy
products for the family dinner table. This legislation would
undermine that important right by allowing manufacturers to
make health claims that could be misleading and even
inaccurate. This faulty provision in the bill is strongly
opposed by 20 leading health and consumer organizations,
including the American Cancer Society, the American Heart
Association, the National Council on the Aging, and the
Consumer Federation of America.
Weakening FDA oversight of health claims would allow food
companies to use scientific statements about nutrition and
health made by other government agencies as a basis for health
claims--even if such statements are not supported by
``significant scientific agreement''. For example, in 1980 the
Food and Nutrition Board, an arm of the National Academy of
Sciences, published a report stating that Americans need not
cut back on cholesterol in order to reduce their risk of heart
disease. The report's findings were disputed by the American
Medical Association, the American Heart Association, and many
other public health and medical organizations. This and other
cases underscore the need to assign the job of pre-clearing
health claims to a single regulatory agency that can sort
through the data and determine if a claim is supported by
``significant scientific agreement''.
Cumulative Agency Burdens Without New Resources
At a time when agency resources are scarce and demands for
rapid product review are increasing, this bill will impose a
number of new bureaucratic burdens. Eighteen new statutory
deadlines are mandated and twenty Federal Register documents
must be produced, including 12 regulations by February 1999.
Excluding new statutory deadlines and required Federal Register
documents, an additional 28 new statutory tasks will be
required. A disproportionate share of new bureaucratic
requirements fall on the Center for Devices and Radiological
Health (CDRH).
There are few more important agencies of the federal
government than the Food an Drug Administration. The FDA is
responsible for assuring the Nation's food supply is pure and
health. The FDA provides a guarantee that the drugs and devices
we rely on to cure or treat diseases are safe and effective. If
it does its job well, the FDA can speed medical miracles from
the laboratory bench to the patient's bedside. If the agency
does its job poorly, it can expose millions of Americans to
unsafe or ineffective medical products and jeopardize the
safety of our food.
Given the importance of the FDA to the American public, any
reform of this agency should have the broadcast bipartisan
support. We must work together to reach agreement on provisions
in this bill that will allow the FDA to do its job well and
build on the successes of the Prescription Drug User Fee Act.
Edward M. Kennedy.
Jeff Bingaman.
Jack Reed.
X. Changes in Existing Law
In compliance with rule XXVI paragraph 12 of the Standing
Rules of the Senate, the following provides a print of the
statute or the part or section thereof to be amended or
replaced (existing law proposed to be omitted is enclosed in
black brackets, new matter is printed in italic, existing law
in which no change is proposed is shown in roman):
federal food, drug, and cosmetic act
* * * * * * *
chapter ii--definitions
Sec. 201. [321] for the purposes of this Act--(a)(1) * * *
* * * * * * *
(hh) * * *
* * * * * * *
(ii) In any provision relating to a review of any
application or submission (including a petition, notification,
and any other similar form of request), made under this Act
with respect to an article that is a new drug, device,
biological product, new animal drug, and animal feed bearing or
containing a new animal drug, color additive, or food additive,
that is submitted to the Secretary to obtain marketing
approval, to obtain classification of a device under section
513(f)(1), or to establish or clarify the regulatory status of
the article--
(1) the term ``day'' means a calendar day in which
the Secretary has responsibility to review such an
application or submission; and
(2) a reference to a date relating to receipt of such
an application or submission by the Secretary shall be
deemed to be a reference to the date on which the
Secretary receives a complete application or submission
within the meaning of this Act and the regulations
promulgated under this Act.
(jj) The term ``compounded position emission tomography
drug'' means a drug that--
(1) exhibits spontaneous disintegration of unstable
nuclei, including the emission of positrons;
(2) includes any nonradioactive reagent, reagent kit,
ingredient, nuclide generator, accelerator, target
material, electronic synthesizer, or other apparatus or
computer program to be used in the preparation of any
such drug; and
(3)(A) has been compounded in a State in accordance
with State law for a patient or for research, teaching,
or quality control by or on the order of a practitioner
licensed by that State to compound or order such a
drug; or
(B) has been compounded in a Federal facility in a
State in accordance with the law of the State in which
the facility is located.
* * * * * * *
Chapter III--Prohibited Acts and Penalties
prohibited acts
Sec. 301. * * *
* * * * * * *
seizure
Sec. 304. [334] (a)(1) * * *
* * * * * * *
(d)(1) Any food, drug, device, or cosmetic condemned under
this section shall, after entry of the decree, be disposed of
by destruction or sale as the court may, in accordance with the
provisions of this section, direct and the proceeds thereof, if
sold, less the legal costs and charges, shall be paid into the
Treasury of the United States; but such article shall not be
sold under such decree contrary to the provisions of this Act
or the laws of the jurisdiction in which sold. After entry of
the decree and upon the payment of the costs of such
proceedings and the execution of a good and sufficient bond
conditioned that such article shall not be sold or disposed of
contrary to the provisions of this Act or the laws of any State
or Territory in which sold, the court may by order direct that
such article be delivered to the owner thereof to be destroyed
or brought into compliance with the provisions of this Act
under the supervision of an officer or employee duly designated
by the Secretary, and the expenses of such supervision shall be
paid by the person obtaining release of the article under bond.
If the article was imported into the United States and the
person seeking its release establishes (A) that the
adulteration, misbranding, or violation did not occur after the
article was imported, and (B) that he had no cause for
believing that it was adulterated, misbranded, or in violation
before it was released from customs custody, the court may
permit the article to be delivered to the owner for exportation
in lieu of destruction upon a showing by the owner that all of
the conditions of section 801(e) can and will be met. The
provisions of this sentence shall not apply where condemnation
is based upon violation of section 402(a) (1), (2), or (6),
section 501(a)(3), section 502(j), or section 601 (a) or (d).
Where such exportation is made to the original foreign
supplier, then [paragraphs (1) and (2) of section 801(e)]
subparagraphs (A) and (B) of section 801(e)(1) and the
preceding sentence shall not be applicable; and in all cases of
exportation the bond shall be conditioned that the article
shall not be sold or disposed of until the applicable
conditions of section 801(e) have been met. Any person seeking
to export an imported article pursuant to any of the provisions
of this subsection shall establish that the article was
intended for export at the time the article entered commerce.
Any article condemned by reason of its being an article which
may not, under section 404 or 505, be introduced into
interstate commerce, shall be disposed of by destruction.
* * * * * * *
(l) The using, on the labeling of any drug or device or in
any advertising relating to such drug or device, of any
representation or suggestion that approval of an application
with respect to such drug or device is in effect under section
505, 515, or 520(g), as the case may be, or that such drug or
device complies with the provisions of such section.
* * * * * * *
(w) * * *
* * * * * * *
(x) The falsification of a declaration of conformity
submitted under subsection (c) of section 514 or the failure or
refusal to provide data or information requested by the
Secretary under section 514(c)(3).
* * * * * * *
MISBRANDED FOOD
Sec. 403. * * *
* * * * * * *
(r)(1) * * *
* * * * * * *
(3)(A) * * *
* * * * * * *
(C) Notwithstanding the provisions of clauses (A)(i) and
(B), a claim of the type described in subparagraph (1)(B) that
is not authorized by the Secretary in a regulation promulgated
in accordance with clause (B) shall be authorized and may be
made if--
(i) an authoritative scientific body of the Federal
Government with official responsibility for public
health protection or research directly relating to
human nutrition (such as the National Institutes of
Health or the Centers for Disease Control and
Prevention), the National Academy of Sciences, or a
subdivision of the scientific body or the National
Academy of Sciences, has published an authoritative
statement, which is currently in effect, about the
relationship betweena nutrient and a disease or health-
related condition to which the claim refers;
(ii) a person has submitted to the Secretary at least
90 days before the first introduction of a food into
interstate commerce a notice of the claim, including a
concise description of the basis upon which such person
relied for determining that the requirements of
subclause (i) have been satisfied;
(iii) the claim and the food for which the claim is
made are in compliance with clause (A)(ii), and are
otherwise in compliance with paragraph (a) and section
201(n); and
(iv) the claim is stated in a manner so that the
claim is an accurate representation of the
authoritative statement referred to in subclause (i)
and so that the claim enables the public to comprehend
the information provided in the claim and to understand
the relative significance of such information in the
context of a total daily diet.
For purposes of this paragraph, a statement shall be regarded
as an authoritative statement of such a scientific body
described in subclause (i) only if the statement is published
by the scientific body and shall not include a statement of an
employee of the scientific body made in the individual capacity
of the employee.
(D) A claim meeting the requirements of clause (C) may be
made until--
(i) such time as the Secretary issues a final
regulation under clause (B) prohibiting or modifying
the claim, and the regulations has become effective; or
(ii) a district court of the United States in an
enforcement proceeding under chapter III has determined
that the requirements of clause (C) have not been met.
* * * * * * *
food additives
Unsafe Food Additives
Sec. 409. (a) A food additive shall, with respect to any
particular use or intended use of such additives, be deemed to
be unsafe for the purposes of the application of clause (2)(C)
of section 402(a), unless--
(1) it and its use or intended use conform to the
terms of an exemption which is in effect pursuant to
[subsection (i)] of this section; [or]
(2) there is in effect, and it and its use or
intended use are in conformity with, a regulation
issued under this section prescribing the conditions
under which such additive may be safely used[.]; or
(3) in the case of a food additive as defined in this
Act that is a food contact substance, there is--
(A) in effect, and such substance and the use
of such substance are in conformity with, a
regulation issued under this section
prescribing the conditions under which such
additive may be safely used; or
(B) a notification submitted under subsection
(h) that is effective.
[While such a regulation relating to a food additive is in
effect, a food shall not, reason of bearing or containing such
an additive in accordance with the regulation, be considered
adulterated within the meaning of clause (1) of section
402(a).]
While such a regulation relating to a food additive, or such a
notification under subsection (h) relating to a food additive
that is a food contact substance, is in effect, and has not
been revoked pursuant to subsection (i), a food shall not, by
reason of bearing or containing such a food additive in
accordance with the regulation or notification, be considered
adulterated under section 402(a)(1).
Notification Relating to a Food Contact Substance
(h)(1) Subject to such regulations as may be promulgated
under paragraph (3), a manufacturer or supplier of a food
contact substance may, at least 120 days prior to the
introduction or delivery for introduction into interstate
commerce of the food contact substance, notify the Secretary of
the identity and intended use of the food contact substance,
and of the determination of the manufacturer or supplier that
the intended use of such food contact substance is safe under
the standard described in subsection (c)(3)(A). The
notification shall contain the information that forms the basis
of the determination, the fee required under paragraph (5), and
all information required to be submitted by regulations
promulgated by the Secretary.
(2)(A) A notification submitted under paragraph (1) shall
become effective 120 days after the date of receipt by the
Secretary and the food contact substance may be introduced or
delivered for introduction into interstate commerce, unless the
Secretary makes a determination within the 120-day period that,
based on the data and information before the Secretary, such
use of the food contact substance has not been shown to be safe
under the standard described in subsection (c)(3)(A), and
informs the manufacturer or supplier of such determination.
(B) A decision by the Secretary to object to a notification
shall constitute final agency action subject to judicial
review.
(C) In this paragraph, the term ``food contact substance''
means the substance that is the subject of a notification
submitted under paragraph (1), and does not include a similar
or identical substance manufactured or prepared by a person
other than the manufacturer identified in the notification.
(3)(A) The process in this subsection shall be utilized for
authorizing the marketing of a food contact substance except
where the Secretary determines that submission and review of a
petition under subsection (b) is necessary to provide adequate
assurance of safety, or where the Secretary and any
manufacturer or supplier agree that such manufacturer or
supplier may submit a petition under subsection (b).
(B) The Secretary is authorized to promulgate regulations
to identify the circumstances in which a petition shall be
filed under subsection (b), and shall consider criteria such as
the probable consumption of such food contact substance and
potential toxicity of the food contact substance in determining
the circumstances in which a petition shall be filed under
subsection (b).
(4) The Secretary shall keep confidential any information
provided in a notification under paragraph (1) for 120 days
after receipt by the Secretary of the notification. After the
expiration of such 120 days, the information shall be available
to any interested party except for any matter in the
notification that is a trade secret or confidential commercial
information.
(5)(A) Each person that submits a notification regarding a
food contact substance under this section shall be subject to
the payment of a reasonable fee. The fee shall be based on the
resources required to process the notification including
reasonable administrative costs for such processing.
(B) The Secretary shall conduct a study of the costs of
administering the notification program established under this
section and, on the basis of the results of such study, shall,
within 18 months after the date of enactment of the Food ad
Drug Administration Modernization and Accountability Act of
1997, promulgate regulations establishing the fee required by
subparagraph (A).
(C) A notification submitted without the appropriate fee is
not complete and shall not become effective for the purposes of
subsection (a)(3) until the appropriate fee is paid.
(D) Fees collected pursuant to this subsection--
(i) shall not be deposited as an offsetting
collection to the appropriations for the Department of
Health and Human Services;
(ii) shall be credited to the appropriate account of
the Food and Drug Administration; and
(iii) shall be available in accordance with
appropriation Acts until expended, without fiscal year
limitation.
(6) In this section, the term ``food contact substance''
means any substance intended for use as a component of
materials used in manufacturing, packing, packaging,
transporting, or holding food if such use is not intended to
have any technical effect in such food.
Amendment or Repeal of Regulations
[h] (i) The Secretary shall by regulation prescribe the
procedure by which regulations under the foregoing provisions
of this section may be amended or repealed, and such procedure
shall conform to the procedure provided in this section for the
promulgation of such regulations.
Exemptions for Investigational Use
[i] (j) Without regard to [subsections (b) to (h)]
subsections (b) to (i), inclusive, of this section, the
Secretary shall be regulation provide for exempting from the
requirements of this section any food additive, and any food
bearing or containing such additive, intended solely for
investigational use by qualified experts when in his opinion
such exemption is consistent with the public health.
* * * * * * *
CHAPTER V--DRUGS AND DEVICES
Subchapter A--Drugs and Devices
adulterated drugs and devices
Sec. 501. A drug or device shall be deemed to be
adulterated--
(a)(1) If it consists in whole or in part of any filthy,
putrid, or decomposed substance; or (2)(A) if it has been
prepared, packed, or held under insanitary conditions whereby
it may have been contaminated with filth, or whereby it may
have been rendered injurious to health; or (B) if it is a drug
and the methods used in, or the facilities or controls used
for, its manufacture, processing, packing, or holding do not
conform to or are not operated or administered in conformity
with current good manufacturing practice to assure that such
drug meets the requirements of this Act as to safety and has
the identity and strength, and meets the quality and purity
characteristics, which it purports or is represented to
possess[; or (3)]; or (C) if it is a compounded positron
emission tomography drug and the methods used in, or the
facilities and controls used for, its compounding, processing,
packing, or holding do not conform to or are not operated or
administered in conformity with the positron emission
tomography compounding standards and the official monographs of
the United States Pharmacopoeia to assure that such drug meets
the requirements of this Act as to safety and has the identity
and strength, and meets the quality and purity characteristics,
which it purports or is represented to possess; or (3) if its
container is composed, in whole or in part, of any poisonous or
deleterious substance which may render the contents injurious
to health; or (4) if (A) it bears or contains, for purposes of
coloring only, a color additive which is unsafe within the
meaning of section 721(a), or (B) it is a color additive the
intended use of which in or on drugs or devices is for purposes
of coloring only and is unsafe within the meaning of section
721(a); or (5) if it is a new animal drug which is unsafe
within the meaning of section 512; or (6) if it is an animal
feed bearing or containing a new animal drug, and such animal
feed is unsafe within the meaning of section 512.
* * * * * * *
[(e)] (e)(1) If it is, or purports to be or is represented
as, a device which is subject to a performance standard
established under section 514, unless such device is in all
respects in conformity with such standard.
(2) If it is, declared to be, purports to be, or is
represented as, a device that is in conformity with any
performance standard recognized under section 514(c) unless
such device is in all respects in conformity with such
standard.
* * * * * * *
misbranded drugs and devices
Sec. 502. * * *
* * * * * * *
(u) In the case of a health care economic statement that is
included in labeling or advertising provided to formulary
committee, managed care organization, or similar entity with
responsibility for drug selection decisions (other than the
label or approved physician package insert) relating to an
indication approved under section 505 or 351 of the Public
Health Service Act (42 U.S.C. 262), if the health care economic
statement is not based on competent and reliable scientific
evidence. The only requirement applicable to any such statement
under this Act shall be the requirements of this paragraph. In
this paragraph, the term ``health care economic statement''
means any statement that identifies, measures, or compares the
costs (direct, indirect, and intangible) and health care
consequences of a drug to another drug, to another health care
intervention for the same indication, or to no intervention,
where the primary endpoint is an economic outcome.
exemptions and considerations for certain drugs, devices, and
biological products
Sec 503. * * *
* * * * * * *
(b)(1) A drug intended for use by man which--
* * * * * * *
[(A) is a habit-forming drug to which section 502(d)
applies; or]
[(B)] (A) because of its toxicity or other
potentiality for harmful effect, or the method of its
use, or the collateral measures necessary to its use,
is not safe for use except under the supervision of a
practitioner licensed by law to administer such drug;
or
[(C)] (B) is limited by an approved application under
section 505 to use under the professional supervision
of a practitioner licensed by law to administer such
drug;
* * * * * * *
(3) The Secretary may by regulation remove drugs subject to
[section 502(d) and] section 505 from the requirements of
paragraph (1) of this subsection when such requirements are not
necessary for the protection of the public health.
[(4) A drug which is subject to paragraph (1) of this
subsection shall be deemed to be misbranded if at any time
prior to dispensing its label fails to bear the statement
``Caution: Federal law prohibits dispensing without
prescription.'' A drug to which paragraph (1) of this
subsection does not apply shall be deemed to be misbranded if
at any time prior to dispensing its label bears the caution
statement quoted in the preceding sentence.]
(4)(A) A drug that is subject to paragraph (1) shall be
deemed to be misbranded if at any time prior to dispensing the
label of the drug fails to bear, at a minimum, the symbol ``Rx
only''.
(B) A drug to which paragraph (1) does not apply shall be
deemed to be misbranded if at any time prior to dispensing the
label of the drug bears the symbol described in subparagraph
(A).
* * * * * * *
(g)(1) * * *
* * * * * * *
(4) As used in this subection:
(A) The term ``biological product'' has the meaning
given the term in [section 351(a)] section 351(i) [of
the Public Health Service Act (42 U.S.C. [262(a)]
262(i)).
(B) The term ``market clearance'' includes--
(i) approval of an application under section
505, 507, 515, or 520(g),
(ii) a finding of substantial equivalence
under this subchapter, and
(iii) approval of a [product or establishment
license under subsection (a) or (d)] biologics
license application under subsection (a) of
section 351 of the Public Health Service Act
(42 U.S.C. 262).
* * * * * * *
(h)(1) Sections 502(a)(2)(B), 502(f)(1), 502(l), 505, and
507 shall not apply to a drug product if--
(A) the drug produce is compounded for an identified
individual patient based on a medical need for
compounded product--
(i) by a licensed pharmacist in a State
licensed pharmacy or a Federal facility, or a
licensed physician on the prescription order of
a licensed physician or other licensed
practitioner authorized by State law to
prescribe drugs; or
(ii) by a licensed pharmacist or licensed
physician in limited quantities, prior to the
receipt of a valid prescription order for the
identified individual patient, and is
compounded based on a history of the licensed
pharmacist or licensed physician receiving
valid prescription orders for the compounding
of the drug product that have been generated
solely within an established relationship
between the licensed pharmacist, or licensed
physician, and--
(I) the individual patient for whom
the prescription order will be
provided; or
(II) the physician or other licensed
practitioner who will write such
prescription order; and
(B) the licensed pharmacist or licensed physician--
(i) compounds the drug product using bulk
drug substances--
(I) that--
(aa) comply with the
standards of an applicable
United States Pharmacopeia
monograph; or
(bb) in a case in which such
a monograph does not exist, or
drug substances that are
covered by regulations issued
by the Secretary under
paragraph (3);
(II) that are manufactured by an
establishment that is registered under
section 510 (including a foreign
establishment that is registered under
section 510(i)); and
(III) that are accompanied by valid
certificates of analysis for each bulk
drug substance;
(ii) compounds the drug product using
ingredients (other than bulk drug substances)
that comply with the standards of an applicable
United States Pharmacopeia monograph and the
United States Pharmacopeia chapter on pharmacy
compounding;
(iii) only advertises or promotes the
compounding service provided by the licensed
pharmacist or licensed physician and does not
advertise or promote the compounding of any
particular drug, class of drug, or type of
drug;
(iv) does not compound a drug product that
appears on a list published by the Secretary in
the Federal Register of drug products that have
been withdrawn or removed from the market
because such drug products or components of
such drug products have been found to be unsafe
or not effective;
(v) does not compound a drug product that is
identified by the Secretary in regulation as
presenting demonstrable difficulties for
compounding that reasonably demonstrate an
adverse effect on the safety or effectiveness
of that drug product; and
(vi) does not distribute compounded drugs
outside of the State in which the drugs are
compounded, unless the principal State agency
of jurisdiction that regulates the practice of
pharmacy in such State has entered into a
memorandum of understanding with the Secretary
(based on the adequate regulation of
compounding performed in the State) that
provides for appropriate investigation by the
State agency of complaints relating to
compounded products distributed outside of the
State.
(2)(A) The Secretary shall, after consultation with the
National Association of Boards of Pharmacy, develop a standard
memorandum of understanding for use by States in complying with
paragraph (1)(B)(vi).
(B) Paragraph (1)(B)(vi) shall not apply to a licensed
pharmacist or licensed physician, who does not distribute
inordinate amounts of compounded products outside of the State,
until--
(i) the date that is 180 days after the development
of the standard memorandum of understanding; or
(ii) the date on which the State agency enters into a
memorandum of understanding under paragraph (1)(B)(vi),
whichever occurs first.
(3) The Secretary, after consultation with the United
States pharmacopeia Convention Incorporated, shall promulgate
regulations limiting compounding under paragraph
(1)(B)(i)(I)(bb) to drug substances that are components of drug
products approved by the Secretary and to other drug substances
as the Secretary may identify.
(4) The provisions of paragraph (1) shall not apply--
(A) to compounded positron emission tomography drugs
as defined in section 202(jj); or
(B) to radiopharmaceuticals.
* * * * * * *
new drugs
Sec. 505. [355] (a) * * *
* * * * * * *
(4) A new drug manufactured in a pilot or other small
facility may be used to demonstrate the safety and
effectiveness of the new drug and to obtain approval of the new
drug prior to scaling up to a larger facility, unless the
Secretary determines that a full scale production facility is
necessary to ensure the safety or effectiveness of the new
drug.
* * * * * * *
(d) If the Secretary finds, after due notice to the
applicant in accordance with subsection (c) and giving him an
opportunity for a hearing, in accordance with said subsection,
that (1) the investigations, reports of which are required to
be submitted to the Secretary pursuant to subsection (b), do
not include adequate tests by all methods reasonably applicable
to show whether or not such drug is safe for use under the
conditions prescribed, recommended or suggested in the proposed
labeling thereof; (2) the results of such tests show that such
drug is unsafe for use under such conditions or do not show
that such drug is safe for use under such conditions; (3) the
methods used in, and the facilities and controls used for, the
manufacture, processing, and packing of such drug are
inadequate to preserve its identity, strength, quality, and
purity; (4) upon the basis of the information submitted to him
as part of the application, or upon the basis of any other
information before him with respect to such drug, he has
insufficient information to determine whether such drug is safe
for use under such conditions; or (5) evaluated on the basis of
the information submitted to him as part of the application and
any other information before him with respect to such drug,
there is a lack of substantial evidence that the drug will have
the effect it purports or is represented to have under the
conditions of use prescribed, recommended, or suggested in the
proposed labeling thereof; or (6) the application failed to
contain the patent information prescribed by subsection (b); or
(7) bad on a fair evaluation of all material facts, such
labeling is false or misleading in any particular; he shall
issue an order refusing to approve he application. If, after
such notice and opportunity for hearing, the Secretary finds
that clauses (1) through (6) do not apply, he shall issue an
order approving the application. As used in this subsection and
subsection (e), the term ``substantial evidence'' means
evidence consisting of adequate and well-controlled
investigations, including clinical investigations, by experts
qualified by scientific training and experience to evaluate the
effectiveness of the drug involved, on the basis of which it
could fairly and responsibly be concluded by such experts that
the drug will have the effect it purports or is represented to
have under the conditions of used prescribed, recommended, or
suggested in the labeling or proposed labeling thereof.
Substantial evidence may, as appropriate, consist of data from
1 adequate and well-controlled clinical investigation and
confirmatory evidence (obtained prior to or after such
investigation), if the Secretary determines, based on relevant
science, that such data and evidence are sufficient to
establish effectiveness.
* * * * * * *
(n) The provisions of subsections (a) and (j) shall not
apply to the preparation of a compounded positron emission
tomography drug.
SEC. 505A. PEDIATRIC STUDIES OF DRUGS.
(a) Market Exclusivity for New Drugs.--If, prior to
approval of an application that is submitted under section
505(b)(1) the Secretary determines that information relating to
the use of a drug in the pediatric population may produce
health benefits in that population, the Secretary makes a
written request for pediatric studies (which may include a
timeframe for completing such studies), and such studies are
completed within any such timeframe and the reports thereof
submitted in accordance with subsection (d)(2) or completed
within any such timeframe and the reports thereof are accepted
in accordance with subsection (d)(3)--
(1)(A) the period during which an application may not
be submitted under subsections (c)(3)(D)(ii) and
(i)(4)(D)(ii) of section 505 shall be five years and
six months rather than five years, and the references
in subsections (c)(3)(D)(ii) and (j)(4)(D)(ii) of
section 505 to four years, to forty-eight months, and
to seven and one-half years shall be deemed to be four
and one-half years, fifty-four months, and eight years,
respectively; or
(B) the period of market exclusivity under
subsections (c)(3)(D) (iii) and (iv) and (j)(4)(D)
(iii) and (iv) of section 505 shall be three years and
six months rather than three years; and
(2)(A) if the drug is the subject of--
(i) a listed patent for which a certification
has been submitted under section
505(b)(2)(A)(ii) or section (j)(2)(A)(vii)(II)
and for which pediatric studies were submitted
prior to the expiration of the patent
(including any patent extensions); or
(ii) a listed patent for which a
certification has been submitted undersection
505(b)(2)(A(iii) or section 505(j)(2)(A)(vii)(III),
the period during which an application may not be
approved under section 505(c)(3) or section
505(j)(4)(B) shall be extended by a period of six
months after the date the patent expires (including any
patent extensions); or
(B) if the drug is the subject of a listed patent for
which a certification has been submitted under section
505(b)(2)(A)(iv) or section 505(j)(2)(A)(vii)(IV), and
in the patent infringement litigation resulting from
the certification the court determines that the patent
is valid and would be infringed, the period during
which an application may not be approved under section
505(c)(3) or section 505(j)(4)(B) shall be extended by
a period of six months after the date the patent
expires (including any patent extensions).
(b) Secretary To Develop List of Drugs for Which Additional
Pediatric Information May Be Beneficial.--Not later than 180
days after the date of enactment of this section, the
Secretary, after consultation with experts in pediatric
research (such as the American Academy of Pediatrics, the
Pediatric Pharmacology Research Unit Network, and the United
States Pharmacopoeia) shall develop, prioritize, and publish an
initial list of approved drugs for which additional pediatric
information may produce health benefits in the pediatric
population. The Secretary shall annually update the list.
(c) Market Exclusivity for Already-Marketed Drugs.--If the
Secretary makes a written request for pediatric studies (which
may include a timeframe for completing such studies) concerning
a drug identified in the list described in subsection (b) to
the holder of an approved application under section 505(b)(1)
for the drug, the holder agrees to the request, and the studies
are completed within any such timeframe and the reports thereof
submitted in accordance with subsection (d)(2) or completed
within any such timeframe and the reports thereof accepted in
accordance with subsection with subsection (d)(3)--
(1)(A) the period during which an application may not
be submitted under subsections (c)(3)(D)(ii) and
(j)(4)(D)(ii) of section 505 shall be five years and
six months rather than five years, and the references
in subsections (c)(3)(D)(ii) and (j)(4)(D)(ii) of
section 505 to four years, to forty-eight months, and
to seven and one-half years shall be deemed to be four
and one-half years, fifty-four months, and eight years,
respectively; or
(B) the period of market exclusively under
subsections (c)(3)(D) (iii) and (iv) and (j)(4)(D)
(iii) and (iv) of section 505 shall be three years and
six months rather than three years; and
(2)(A) if the drug is the subject of--
(i) listed patent for which a certification
has been submitted under section
505(b)(2)(A)(ii) or (j)(2)(A)(vii)(II) and for
which pediatric studies were submitted prior to
the expiration of the patent (including any
patent extensions); or
(ii) a listed patent for which a
certification has been submitted under section
505(b)(2)(A)(iii) or section
505(j)(2)(A)(vii)(III),
the period during which an application may not be
approved under section 505(c)(3) or section
505(j)(4)(B) shall be extended by a period of six
months after the date the patent expires (including any
patent extensions); or
(B) if the drug is the subject of a listed patent for
which a certification has been submitted under section
505(b)(2)(A)(iv) or section 505(j)(2)(A)(vii)(IV), and
in the patent infringement litigation resulting from
the certification the court determines that the patent
is valid and would be infringed, the period during
which an application may not be approved under section
505(c)(3) or section 505(j)(4)(B) shall be extended by
a period of six months after the date the patent
expires (including any patent extensions).
(d) Conduct of Pediatric Studies.--
(1) Agreement for studies.--The Secretary may,
pursuant to a written request for studies, after
consultation with--
(A) the sponsor of an application for an
investigational new drug under section 505(i);
(B) the sponsor of an application for a drug
under section 505(b)(1); or
(C) the holder of an approved application for
a drug under section 505(b)(1),
agree with the sponsor or holder for the conduct of
pediatric studies for such drug.
(2) Written protocols to meet the studies
requirement.--If the sponsor or holder and the
Secretary agree upon written protocols for the studies,
the studies requirement of subsection (a) or (c) is
satisfied upon the completion of the studies and
submission of the reports thereof in accordance with
the original written request and the written agreement
referred to in paragraph (1). Not later than 60 days
after the submission of the report of the studies, the
Secretary shall determine if such studies were or were
not conducted in accordance with the original written
request and the written agreement and reported in
accordance with the requirements of the Secretary for
filing and so notify the sponsor or holder.
(3) Other methods to meet the studies requirement.--
If the sponsor or holder and the Secretary have not
agreed in writing on the protocols for the studies, the
studies requirement of subsection (a) or (c) is
satisfied when such studies have been completed and the
reports accepted by the Secretary. Not later than 90
days after the submission of the reports of the
studies, the Secretary shall accept or reject such
reports and so notify the sponsor or holder. The
Secretary's only responsibility in accepting or
rejecting the reports shall be to determine, within the
90 days, whether the studies fairly respond to the
written request, whether such studies have been
conducted in accordance with commonly accepted
scientific principles and protocols, and whether such
studies have been reported in accordance with the
requirements of the Secretary for filing.
(e) Delay of Effective Date for Certain Applications;
Period of Market Exclusivity.--If the Secretary determines that
the acceptance or approval of an application under section
505(b)(2) or 505(j) for a drug may occur after submission of
reports of pediatric studies under this section, which were
submitted prior to the expiration of the patent (including any
patent extension) or market exclusivity protection, but before
the Secretary has determined whether the requirements of
subsection (d) have been satisfied, the Secretary shall delay
the acceptance or approval under section 505(b)(2) or 505(j),
respectively, until the determination under subsection (d) is
made, but such delay shall not exceed 90 days. In the event
that requirements of this section are satisfied, the applicable
period of market exclusivity referred to in subsection (a) or
(c) shall be deemed to have been running during the period of
delay.
(f) Notice of Determination on Studies Requirements.--The
Secretary shall publish a notice of any determination that the
requirements of subsection (d) have been met and that
submissions and approvals under section 505(b)(2) or (j) for a
drug will be subject to the provisions of this section.
(g) Definitions.--As used in this section, the term
``pediatric studies'' or ``studies'' means at least 1 clinical
investigation (that, at the Secretary's discretion, may include
pharmacokinetic studies) in pediatric age-groups in which a
drug is anticipated to be used.
(h) Limitation.--The holder of an approved application for
a new drug that has already received six months of market
exclusivity under subsection (a) or (c) may, if otherwise
eligible, obtain six months of market exclusivity under
subsection (c)(1)(B) for a supplemental application, except
that the holder is not eligible for exclusivity under
subsection(c)(2).
(i) Sunset.--No period of market exclusivity shall be
granted under this section based on studies commenced after
January 1, 2004. The Secretary shall conduct at study and
report to Congress not later than January 1, 2003 based on the
experience under the program. The study and report shall
examine all relevant issues, including--
(1) the effectiveness of the program in improving
information about important pediatric uses for approved
drugs;
(2) the adequacy of the incentive provided under this
section;
(3) the economic impact of the program; and
(4) any suggestions for modification that the
Secretary deems appropriate.
* * * * * * *
registration of producers of drugs and devices
Sec. 510. [360] (a) As used in this section--
* * * * * * *
(4) any distributor who acts as a wholesale
distributor of devices, and who does not manufacture,
repackage, process, or relabel a device; or
[4)] (5) such other classes of persons as the
Secretary may be regulation exempt from the application
of this section upon a finding that registration by
such classes of persons in accordance with this section
is not necessary for the protection of the public
health.
In this subsection, the term ``wholesale distributor'' means
any person who distributes a device from the original place of
manufacture to the person who makes the final delivery or sale
of the device to the ultimate consumer or user.
* * * * * * *
[(i) Any establishment within any foreign country engaged
in the manufacture, preparation, propagation, compounding, or
processing of a drug or drugs or a device or devices, shall be
permitted to register under this section pursuant to
regulations promulgated by the Secretary. Such regulations
shall require such establishment to provide the information
required by section (j) and shall require such establishment to
provide information required by subsection (j) in the case of a
device or devices and shall include provisions for registration
of any such establishment upon condition that adequate and
effective means are available, by arrangement with the
government of such foreign country or otherwise, to enable the
Secretary to determine from time to time whether drugs or
devices manufactured, prepared, propagated, compounded, or
processed in such establishment, if imported or offered for
import into the United States, shall be refused admission on
any of the grounds set forth in section 801(a) of this Act.]
(i)(1) Any establishment within any foreign country engaged
in the manufacture, preparation, propagation, compounding, or
processing of a drug or a device that is imported or offered
for import into the United States shall register with the
Secretary the name and place of business of the establishment
and the name of the United States agent for the establishment.
(2) The establishment shall also provide the information
required by subsection (j).
(3) The Secretary is authorized to enter into cooperative
arrangements with foreign countries to ensure that adequate and
effective means are available for purposes of determining, from
time to time, whether drugs or devices manufactured, prepared,
propagated, compounded, or processed by an establishment
described in paragraph (1), if imported or offered for import
into the United States, shall be refused admission on any of
the grounds set forth in section 801(a).
* * * * * * *
(k) Each person who is required to register under this
section and who proposes to begin the introduction or delivery
for introduction into interstate commerce for commercial
distribution of a device [intended for human use] intended for
human use (except a device that is classified into class I
under section 513 or 520 unless the Secretary determines such
device is intended for a use which is of substantial importance
in preventing impairment of human health, or presents a
potential unreasonable risk of illness or injury, or a device
that is classified into class II under section 513 or 520 and
is exempt from the requirements of this subsection under
subsection (l)) shall, at least ninety days before making such
introduction or delivery, report to the Secretary (in such form
and manner as the Secretary shall by regulation prescribe--
* * * * * * *
The Secretary shall review the notification required by this
subsection and make a determination under section 513(f)(1) not
later than 90 days after receiving the notification.
(l)(1) Not later than 30 days after the date of enactment
of this subsection, the Secretary shall publish in the Federal
Register a list of each type of class II device that does not
require a notification under subsection (k) to provide
reasonable assurance of safety and effectiveness. Each type of
class II device identified by the Secretary not to require the
notification shall be exempt from the requirement to provide
notification under subsection (k) as of the date of the
publication of the list in the Federal Register.
(2) Beginning on the date that is 1 day after the date of
the publication of a list under this subsection, the Secretary
may exempt a class II device from the notification requirement
subsection (k), upon the Secretary's own initiative or a
petition of an interested person, if the Secretary determines
that such notification is not necessary to assure the safety
and effectiveness of the device. The Secretary shall publish in
the Federal Register notice of the intent of the Secretary to
exempt the device, or of the petition, and provide a 30-day
comment period for public comment. Within 120 days after the
issuance of the notice in the Federal Register, the Secretary
shall publish an order in the Federal Register that sets forth
the final determination of the Secretary regarding the
exemption of the device that was the subject of the notice.
(m)(l) The Secretary may not withhold a determination of
the initial classification of a device under section 513(f)(1)
because of a failure to comply with any provision of this Act
that is unrelated to a substantial equivalence decision,
including a failure to comply with the requirements relating to
good manufacturing practices under section 520(f).
* * * * * * *
classification of devices intended for human use
Device Classes
Sec. 513 [360c] (a)(1) * * *
* * * * * * *
(3)(A) Except as authorized by subparagraph (B), the
effectiveness of a device is, for purposes of this section and
sections 514 and 515, to be determined, in accordance with
regulations promulgated by the Secretary, on the basis of well-
controlled investigations, including [clinical investigations]
1 or more clinical investigations where appropriate, by experts
qualified by training and experience to evaluate the
effectiveness of the device, from which investigations it can
fairly and responsibly be concluded by qualified experts that
the device will have the effect it purports or is represented
to have under the conditions of use prescribed, recommended, or
suggested in the labeling of the device.
* * * * * * *
(C)(i)(I) The Secretary, upon the written request of any
person intending to submit an application under section 515,
shall meet with such person to determine the type of valid
scientific evidence (within the meaning of subparagraphs (A)
and (B)) that will be necessary to demonstrate the
effectiveness of a device for the conditions of use proposed by
such person, to support an approval of an application. The
written request shall include a detailed description of the
device, a detail description of the proposed conditions of use
of the device, and, if available, information regarding the
expected performance from the device. Within 30 days after such
meeting, the Secretary shall specify in writing the type of
valid scientific evidence that will provide a reasonable
assurance that a device is effective under the conditions of
use proposed by such person.
(II) Any clinical data, including 1 or more well-controlled
investigations, specified in writing by the Secretary for
demonstrating a reasonable assurance of device effectiveness
shall be specified as a result of a determination by the
Secretary--
(aa) that such data are necessary to establish device
effectiveness; and
(bb) that no other less burdensome means of
evaluating device effectiveness is available that would
have a reasonable likelihood of resulting in an
approval.
(ii) The determination of the Secretary with respect to the
specification of valid scientific evidence under clause (i)
shall be binding upon the Secretary, unless--
(I) such determination by the Secretary would be
contrary to the public health; or
(II) based on new information (other than the
information reviewed by the Secretary in making such
determination) obtained by the Secretary prior to the
approval of an application for an investigational
device exemption under section 520(g), the Secretary
finds that such determination is scientifically
inappropriate.
* * * * * * *
(f)(1) * * *
* * * * * * *
(B) the Secretary in response to a petition submitted
under [paragraph (2)] paragraph (3) has classified such
device in class I or II.
A device classified in class III under this paragraph shall be
classified in that class until the effective date of an order
of the Secretary under [paragraph (2)] paragraph (2) or (3)
classifying the device in class I or II.
(2)(A) Any person who submits a report under section 510(k)
for a type of device that has not been previously classified
under this Act, and that is classified into class III under
paragraph (1), may request, within 30 days after receiving
written notice of such a classification, the Secretary to
classify the device into class I or II under the criteria set
forth in subparagraphs (A) through (C) subsection (a)(1). The
person may, in the request, recommend to the Secretary a
classification for the device. The request shall describe the
device and provide detailed information and reasons for the
recommended classification.
(B)(i) Not later than 60 days after the date of the
submission of the request under subparagraph (A) for
classification of a device under the criteria set forth in
subparagraphs (A) through (C) of subsection (a)(1), the
Secretary shall by written order classify the device. Such
classification shall be the initial classification of the
device for purposes of paragraph (1) and any device classified
under this paragraph into class I or II shall be a predicate
device for determining substantial equivalence under paragraph
(1).
(ii) A device that remains in class III under this
subparagraph shall be deemed to be adulterated with the meaning
of section 501(f)(B) until approved under section 515 or
exempted from such approval under section 520(g).
(C) Within 30 days after the issuance of an order
classifying a device under this paragraph, the Secretary shall
publish a notice in the Federal Register announcing such
classification.
[(2)] (3)(A) The Secretary may initiate the
reclassification of a device classified into class III under
paragraph (1) of this subsection or the manufacturer or
importer of a device classified under paragraph (1) may
petition the Secretary (in such form and manner as he shall
prescribe) for the issuance of an order classifying the device
in class I or class II. Within thirty days of the filing of
such a petition, the Secretary shall notify the petitioner for
any deficiencies in the petition which prevent the Secretary
from making a decision on the petition.
* * * * * * *
[(3)] (4) If a manufacturer reports to the Secretary under
section 510(k) that a device is substantially equivalent to
another device--
* * * * * * *
(C) Whenever the Secretary requests information to
demonstrate that the devices with differing
technological characteristics are substantially
equivalent, the Secretary shall only request
information that is necessary to make a substantial
equivalence determination. In making such a request,
the Secretary shall consider the least burdensome means
of demonstrating substantial equivalence and shall
request information accordingly.
(D) The determinations of the Secretary under this
section and section 513(f)(1) with respect to the
intended use of a device shall be based on the intended
use included in proposed labeling of the device
submitted in a report under section 510(k).
* * * * * * *
performance standards
Provisions of Standards
Sec. 514. [360d] (a)(1) * * *
* * * * * * *
Recognition of a Standard
(c)(1)(A) In addition to establishing performance standards
under this section, the Secretary may, by publication in the
Federal Register recognize all or part of a performance
standard established by a nationally or internationally
recognized standard development organization for which a person
may submit a declaration of conformity in order to meet
premarket submission requirements or other requirements under
this Act to which such standards are applicable.
(B) If a person elects to use a performance standard
recognized by the Secretary under subparagraph (A) to meet the
requirements described in subparagraph (A), the person shall
provide a declaration of conformity to the Secretary that
certifies that the device is in conformity with such standard.
A person may elect to use data, or information, other than data
required by a standard recognized under subparagraph (A) to
fulfill or satisfy any requirement under this Act.
(2) The Secretary may withdraw such recognition of a
performance standard through publication of a notice in the
Federal Register that the Secretary will no longer recognize
the standard, if the Secretary determines that the standard is
no longer appropriate for meeting the requirements under this
Act.
(3)(A) Subject to subparagraph (B), the Secretary shall
accept a declaration of conformity that a device is in
conformity with a standard recognized under paragraph (1)
unless the Secretary finds--
(i) that the data or information submitted to support
such declaration does not demonstrate that the device
is in conformity with the standard identified in the
declaration of conformity; or
(ii) that the standard identified in the declaration
of conformity is not applicable to the particular
device under review.
(B) The Secretary may request, at any time, the data or
information relied on by the person to make a declaration of
conformity with respect to a standard recognized under
paragraph (1).
(C) A person relying on a declaration of conformity with
respect to a standard recognized under paragraph (1) shall
maintain the data and information demonstrating conformity of
the device to the standard for a period of 2 years after the
date of the classification or approval of the device by the
Secretary or a period equal to the expected design life of the
device, whichever is longer.
* * * * * * *
premarket approval
General Requirement
Sec. 515. [360e] (a) A class III device--
* * * * * * *
Action on an Application for Premarket Approval
(d)(1)(A) * * *
* * * * * * *
(i) issue an order approving the application if he
finds that none of the grounds for denying approval
specified in [paragraph (2) of this subsection ]
paragraph 4 applies; or
(ii) deny approval of the application if he finds
(and sets forth the basis for such finding as part of
or accompanying such denial) that one or more grounds
for denial specified in [paragraph (2) of this
subsection ] paragraph 4 apply.
In making the determination whether to approve or deny an
application, the Secretary shall rely on the conditions of use
proposed in the labeling of a device as the basis for
determining whether or not there is a reasonable assurance of
safety and effectiveness. If, based on a fair evaluation of all
material facts, the proposed labeling is neither false nor
misleading in any particular, the Secretary, in making the
determination, shall not consider conditions of use not
included in the proposed labeling.
(2)(A)(i) The Secretary shall, upon the written request of
the applicant involved, meet with the applicant not later than
100 days after the receipt of an application, from the
applicant, that has been filed as complete under subsection
(c), to discuss the review status of the application.
(ii) If the application does not appear in a form that
would require an approval under this subsection, the Secretary
shall in writing, and prior to the meeting, provide to the
applicant a description of any deficiencies in the application
identified by the Secretary and identify the information (other
than information the Secretary needs to make a finding under
paragraph (4)(C)) that is required to bring the application
into an approvable form.
(iii) The Secretary and the applicant may, by mutual
consent, establish a different schedule for a meeting required
under this paragraph.
(B) The Secretary shall notify the applicant immediately of
any deficiency identified in the application that was not
described as a deficiency in the written description provided
by the Secretary under subparagraph (A).
(3) Except as provided in paragraph (1), the period for the
review of an application by the Secretary under this subsection
shall be not more than 180 days. Such period may not be
restarted or extended even if the application is amended.
[(2)] (4) The Secretary shall deny approval of an
application for a device if, upon the basis of the information
submitted to the Secretary as part of the application and any
other information before him with respect to such device, the
Secretary finds that--
* * * * * * *
[(3)] (5) An applicant whose application has been denied
approval may, by petition filed on or before the thirtieth day
after the date upon which he receives notice of such denial,
obtain review thereof in accordance with either paragraph (1)
or (2) of subsection (g), and any interested person may obtain
review, in accordance with paragraph (1) or (2) of subsection
(g), of an order of the Secretary approving an application.
* * * * * * *
(iii) The Secretary shall accept and review data and any
other information from investigations conducted under the
authority of regulations required by section 520(g), to make a
determination of whether there is a reasonable assurance of
safety and effectiveness of a device subject to a pending
application under this section if--
(I) the data or information is derived from
investigations of an earlier version of the device, the
device has been modified during or after the
investigations (but prior to submission of an
application under subsection (c)) and such a
modification of the device does not constitute a
significant change in the design or in the basic
principles of operation of the device that would
invalidate the data or information; or
(II) the data or information relates to a device
approved under this section, is available for use under
this Act, and is relevant to the design and intended
use of the device for which the application is pending.
* * * * * * *
(6)(A)(i) A supplemental application shall be required for
any change to a device subject to an approved application under
this subsection that affects safety or effectiveness, unless
such change is a modification in a manufacturing procedure or
method of manufacturing and the holder of the approved
application submits a written notice to the Secretary that
describes in detail the change, summarizes the data or
information supporting the change, and informs the Secretary
that the change has been made under the requirements of section
520(f).
(ii) The holder of an approved application who submits a
notice under clause (i) with respect to a manufacturing change
of a device shall not distribute the device for a period of 14
days after the date on which the Secretary receives the notice.
(B)(i) Subject to clause (ii), in reviewing a supplement to
an approved application, for an incremental change to the
design of a device that affects safety or effectiveness, the
Secretary shall approve such supplement if--
(I) nonclinical data demonstrate that the design
modification creates the intended additional capacity,
function, or performance of the device; and
(II) clinical data from the approved application and
any supplement to the approval application provide a
reasonable assurance of safety and effectiveness for
the changed device.
(ii) The Secretary may require, when necessary, additional
clinical data to evaluate the design modification to provide a
reasonable assurance of safety and effectiveness.
* * * * * * *
judicial review
Application of Section
Sec. 517. [360g] (a) Not later than thirty days after--
* * * * * * *
(8) an order pursuant to section 513(i), or
(9) a regulation under section 515(i)(2) or
520(l)(5)(B)[, or],
[(10) an order under section 520(h)(4)(B),]
* * * * * * *
notfication and other remedies
Notification
Sec. 518. (a) If the Secretary determines that--
* * * * * * *
Recall Authority
(e)(1) * * *
* * * * * * *
(2)(A) If, after providing an opportunity for an informal
hearing under paragraph (1), the Secretary determines that the
order should be amended to include a recall of the device with
respect to which the order was issued, the Secretary shall,
except as provided in [subparagraphs (B) and (C)] subparagraph
(B), amend the order to require a recall. The Secretary shall
specify a timetable in which the device recall will occur and
shall require periodic reports to the Secretary describing the
progress of the recall.
* * * * * * *
(C) If the Secretary issues an amended order under
subparagraph (A), the Secretary may require the person subject
to the order to submit such samples of the device and of
components of the device as the Secretary may reasonably
require. If the submission of such samples is impracticable or
unduly burdensome, the requirement of this subparagraph may be
met by the submission of complete information concerning the
location of 1 or more such devices readily available for
examination and testing.
* * * * * * *
records and reports on devices
General Rule
Sec. 519. [360i] (a) Every person who is a manufacturer,
importer, or distributor of a device intended for human use
shall establish and maintain such records, [make such reports,
and provide such information,] and submit such samples and
components of devices (as required by paragraph (10)), as the
Secretary may by regulation reasonably require to assure that
such device is not adulterated or misbranded and to otherwise
assure its safety and effectiveness. Every person who is a
manufacturer or importer of a device intended for human use
shall make reports, and provide such information, as the
Secretary may by regulation reasonably require to assure that
such device is not adulterated or misbranded and to assure the
safety and effectiveness of such device. Regulations prescribed
under the preceding [sentence] sentences--
* * * * * * *
(8) may not require a manufacturer, importer, or
distributor of a class I device to--
(A) maintain for such device records
respecting information not in the possession of
the manufacturer, importer, or distributor, or
(B) to submit for such a device to the
Secretary any report or information--
(i) not in the possession of the
manufacturer, importer, or distributor,
or
(ii) on a periodic basis,
unless such report or information is necessary to
determine if the device should be reclassified or if
the device is adulterated or misbranded[; and];
[(9) shall require distributors who submit such
reports to submit copies of the reports to the
manufacturer of the device for which the report was
made.]
(9) shall require distributors to keep records and
make such records available to the Secretary upon
request; and
(10) may reasonably require a manufacturer, importer,
or distributor to submit samples of a device and of
components of the device that may have caused or
contributed to a death or serious injury, except that
if the submission of such samples is impracticable or
unduly burdensome, the requirement of this paragraph
may be met by the submission of complete information
concerning the location of 1 or more such devices
readily available for examination and testing.
[Certification
[(d) Each manufacturer, importer, and distributor required
to make reports under subsection (a) shall submit to the
Secretary annually a statement certifying that--
[(1) the manufacturer, importer, or distributor did
file a certain number of such reports, or
[(2) the manufacturer, importer, or distributor did
not file any report under subsection (a).]
* * * * * * *
Reports of Removals and Corrections
(f)(1) Except as provided in paragraph (2), the Secretary
shall by regulation require a manufacturer[, importer, or
distributor] or importer of a device to report promptly to the
Secretary any correction or removal of a device undertaken by
such manufacturer, importer, or distributor if the removal or
correction was undertaken--
(A) to reduce the risk to health posed by the device,
or
(B) to remedy a violation of this Act caused by the
device which may present a risk to health.
A manfacturer[, importer, or distributor] or importer of a
device who undertakes a correction or removal of a device which
is not required to be reported under this paragraph shall keep
a record of such correction or removal.
* * * * * * *
(e) * * *
* * * * * * *
Any patient receiving a device subject to tracking under this
section may refuse to release, or refuse permission to release,
the patient's name, address, social security number, or other
identifying information for the purpose of tracking.
* * * * * * *
general provisions respecting control of devices intended for human use
General Rule
Sec. 520. [360j] (a) * * *
* * * * * * *
(6)(A) The Secretary shall, not later than 120 days
after the date of enactment of this paragraph, by
regulation modify parts 812 and 813 of title 21, Code
of Federal Regulations to update the procedures and
conditions under which a device intended for human use
may, upon application by the sponsor of the device, be
granted an exemption from the requirements of this Act.
(B) The regulation shall permit developmental changes
in a device (including manufacturing changes) in
response to information collected during an
investigation without requiring an additional approval
of an application for an investigational device
exemption or the approval of a supplemental to such
application, if the sponsor of the investigation
determines, based on credible information, prior to
making any such changes, that the changes--
(i) do not affect the scientific soundness of
an investigational plan submitted under
paragraph (3)(A) or the rights, safety, or
welfare of the human subjects involved in the
investigation; and
(i) do not constitute a significant change in
design, or a significant change in basis
principles of operation, of the device.
[(4)(A) Any information contained in an application
for premarket approval filed with the Secretary
pursuant to section 515(c), including clinical and
preclinical tests or studies, but excluding
descriptions of methods of manufacture and product
composition, that demonstrates the safety and
effectiveness of a device shall be available 1 year
after the original application for the fourth device of
a kind has been approved by the Secretary, for use by
the Secretary in approving devices, or determining
whether a product development protocol has been
completed, under section 515, establishing a
performance standard under section 514, and
reclassifying devices under subsections (e) and (f) of
section 513, and subsection (l)(2). The Secretary shall
deem devices that incorporate the same technologies,
have the same principles of operation, and are intended
for the same use or uses to be within a kind of
device.]
(4)(A) Any information contained in an application
for premarket approval filed with the Secretary
pursuant to section 515(c) (including information from
clinical and preclinical tests or studies that
demonstrate the safety and effectiveness of a device,
but excluding descriptions of methods of manufacture
and product composition) shall be available, 6 years
after the application has been approved by the
Secretary, for use by the Secretary in--
(i) approving another device;
(ii) determining whether a product
development protocol has been completed, under
section 515 for another device;
(iii) establishing a performance standard or
special control under section 514 for another
device; and
(iv) classifying or reclassifying another
device under section 513 and subsection (l)(2).
(B) The publicly available detailed summaries of
information respecting the safety and effectiveness of
devices required by paragraph (l)(A) shall be available
for use by the Secretary as the evidentiary basis for
the agency action described in subparagraph (A).
* * * * * * *
general provisions respecting control of devices intended for human use
General Rule
Sec. 520. [360j] (a) * * *
* * * * * * *
(m)(1) * * *
* * * * * * *
The request shall be in the form of an application
submitted to the Secretary. Not later than 60 days after the
date of the receipt of the application, the Secretary shall
issue an order approving or denying the application.
* * * * * * *
(4) Devices granted an exemption under paragraph (2)
may only be used--
* * * * * * *
(B) if, before the use of a device, an institutional
review committee approves the use in the treatment or
diagnosis of a disease or condition referred to in
paragraph (2)(A), unless a physician determines that
waiting for such an approval from an institutional
review committee will cause harm or death to a patient,
and makes a good faith effort to obtain the approval,
and does not receive a timely response from an
institutional review committee on the request of the
physician for approval to use the device for such
treatment or diagnosis.
In a case in which a physician described in
subparagraph (B) uses a device without an approval from
an institutional review committee, the physician shall,
after the use of the device, notify the chairperson of
the institutional review committee of such use. Such
notification shall include the identification of the
patient involved, the date on which the device was
used, and the reason for the use.
* * * * * * *
[(5) An exemption under paragraph (2) shall be for a
term of 18 months and may only be initially granted in
the 5-year period beginning on the date regulations
under paragraph (6) take effect. The Secretary may
extend such an exemption for a period of 18 months if
the Secretary is able to make the findings set forth in
paragraph (2) and if the applicant supplies information
demonstrating compliance with paragraph (3). An
exemption may be extended more than once and may be
extended after the expiration of such 5-year period.]
(5) The Secretary may require a person granted an
exemption under paragraph (2) to demonstrate continued
compliance with the requirements of this subsection if
the Secretary believes such demonstration to be
necessary to protect the public health or if the
Secretary has reason to believe that the criteria for
the exemption are no longer met.
* * * * * * *
postmarket surveillance
[Sec. 522. [3601] (a) In General.--
(1) Required surveillance.--The Secretary shall
require a manufacturee to conduct postmarket
surveillance for any device of the manufacturer first
introduced or delivered for introduction into
interstate commerce after January 1, 1991, that--
(A) is a permanent implant the failure of
which may cause serious, adverse health
consequences or death,
(B) is intended for a use in supporting or
sustaining human life, or
(C) potentially presents a serious risk to
human health.
(2) Discretionary surveillance.--The] Sec. 522. (a)
Discretionary Surveillance._The Secretary may require a
manufacturer to conduct postmarket surveillance for a
device of the manufacturer if the Secretary determines
that postmarket surveillance of the device is necessary
to protect the public health or to provide safety or
effectiveness data for the device.
[(b) Surveillance Approval.--Each manufacturer required to
conduct a surveillance of a device under subsection (a)(1)
shall, within 30 days of the first introduction or delivery for
introduction of such device into interstate commerce, submit,
for the approval of the Secretary, a protocol for the required
surveillance. Each manufacturer required to conduct a
surveillance of a device under subsection (a)(2) shall within
30 days after receiving notice that the manufacturer is
required to conduct such surveillance, submit, for the approval
of the Secretary, a protocol for the required surveillance. The
Secretary, within 60 days of the receipt of such protocol,
shall determine if the principal investigator proposed to be
used in the surveillance has sufficient qualifications and
experience to conduct such surveillance and if such protocol
will result in collection of useful data or other information
necessary to protect the public health and to provide safety
and effectiveness information for the device. The Secretary may
not approve such a protocol until it has been reviewed by an
appropriately qualified scientific and technical review
committee established by the Secretary.]
(b) Surveillance Approval.--
(1) In general.--Each manufacturer that receives
notice from the Secretary that the manufacturer is
required to conduct surveillance of a device under
subsection (a) shall, not later than 30 days after
receiving the notice, submit for the approval of the
Secretary, a plan for the required surveillance.
(2) Determination.--Not later than 60 days after the
receipt of the plan, the Secretary shall determine if a
person proposed in the plan to conduct the surveillance
has sufficient qualifications and experience to conduct
the surveillance and if the plan will result in the
collection of useful data that can reveal unforeseen
adverse events or other information necessary to
protect the public health and to provide safety and
effectiveness information for the device.
(3) Limitation on plan approval.--The Secretary may
not approve the plan until the plan has been reviewed
by a qualified scientific and technical review
committee established by the Secretary.
(c) Duration of Surveillance.--
(1) In general.--Each manufacturer required to
conduct surveillance of a device under subsection (a)
shall be required to conduct such surveillance for not
longer than 24 months.
(2) Extension of the period of surveillance.--If the
Secretary determines that additional surveillance is
needed to identify the incidence of adverse events
documented during the initial period of surveillance
that were not foreseen at the time of approval or
classification of the device, the Secretary may extend
the period of surveillance for such time as may be
necessary after providing the person required to
conduct such surveillance an opportunity for an
informal hearing to determine whether or not additional
surveillance is appropriate and to determine the
appropriate period, if any, for such surveillance.
* * * * * * *
SEC. 523. ACCREDITED-PARTY PARTICIPATION.
(a) Accreditation.--
(1) In general.--Not later than 1 year after the date
of enactment of this section, the Secretary shall
accredit entities or individuals who are not employees
of the Federal Government, to review reports made to
the Secretary under section 510(k) for devices and make
recommendations to the Secretary regarding the initial
classification of such devices under section 513(f)(1),
except that this paragraph shall not apply to reports
made to the Secretary under section 510(k) for devices
that are--
(A) life-supporting;
(B) life sustaining; or
(C) intended for implantation in the human
body for a period of over 1 year.
(2) Special rule.--The Secretary shall have the
discretion to accredit entities or individuals who are
not employees of the Federal Government--
(A) to review reports made to the Secretary
under section 510(k) for devices described in
subparagraphs (A) through (C) of paragraph (1),
and make recommendations of initial
classification of such devices; or
(B) to review applications for premarket
approval for class III devices under section
515 and make recommendations with respect to
the approval or disapproval of such
applications.
(b) Accreditation.--Within 180 days after the date of
enactment of this section, the Secretary shall adopt methods of
accreditation that ensure that entities or individuals who
conduct reviews and make recommendations under this section are
qualified, properly trained, knowledgeable about handling
confidential documents and information, and free of conflicts
of interest. The Secretary shall publish the methods of
accreditation in the Federal Register on the adoption of the
methods.
(c) Withdrawal of Accreditation.--The Secretary may suspend
or withdraw the accreditation of any entity or individual
accredited under this section, after providing notice and an
opportunity for an informal hearing, if such entity or
individual acts in a manner that is substantially not in
compliance with the requirements established by the Secretary
under subsection (b), including the failure to avoid conflicts
of interest, the failure to protect confidentiality of
information, or the failure to competently review premarket
submissions for devices.
(d) Selection and Compensation.--Subject to subsection
(a)(2), a person who intends to make a report described in
subsection (a), or to submit an application described in
subsection (a), to the Secretary shall have the option to
select an accredited entity or individual to review such report
or application. Upon the request by a person to have a report
or application reviewed by an accredited entity or individual,
the Secretary shall identify for the person no less than 2
accredited entities or individuals from whom the selection may
be made. Compensation for an accredited entity or individual
shall be determined by agreement between the accredited entity
or individual and the person who engages the services of the
accredited entity or individual and shall be paid by the person
who engages such services.
(e) Review by Secretary.--
(1) In general.--The Secretary shall require an
accredited entity or individual, upon making a
recommendation under this section with respect to an
initial classification of a device or approval or
disapproval of an application for premarket approval,
to notify the Secretary in writing of the reasons for
such recommendation.
(2) Time period for review.--
(A) Initial classification.--Not later than
30 days after the date on which the Secretary
is notified under paragraph (1) by an
accredited entity or individual with respect to
a recommendation of an initial classification
of a device, the Secretary shall make a
determination with respect to the initial
classification.
(B) Premarket approval.--Not later than 60
days after the date on which the Secretary is
notified under paragraph (1) by an accredited
entity or individual with respect to a
recommendation of an approval or disapproval of
an application for a device, the Secretary
shall make a determination with respect to the
approval or disapproval.
(3) Special rule.--The Secretary may change the
initial classification under section 513(f)(1), or the
approval or disapproval of the application under
section 515(d), that is recommended by the accredited
entity or individual under this section, and in such
case shall notify in writing the person making the
report or application described in subsection (a) of
the detailed reasons for the change.
(f) Duration.--The authority provided by this section
terminates--
(1) 5 years after the date on which the Secretary
notifies Congress that at least 2 persons accredited
under subsection (b) are available to review devices
for each of at least 70 percent of the generic types of
devices subject to review under subsection (a); or
(2) 4 years after the date on which the Secretary
notifies Congress that at least 35 percent of the
devices that are subject to review under subsection
(a), and that were the subject of final action by the
Secretary in the fiscal year preceding the date of such
notification, were reviewed by the Secretary under
subsection (e),
whichever occurs first.
(g) Report.--
(1) In general.--Not later than 1 year after the date
of enactment of this section, the Secretary shall
contract with an independent research organization to
prepare and submit to the Secretary a written report
examining the use of accredited entities and
individuals to conduct reviews under this section. The
Secretary shall submit the report to Congress not later
than 6 months prior to the conclusion of the applicable
period described in subsection (f).
(2) Contents.--The report by the independent research
organization described in paragraph (1) shall identify
the benefits or detriments to public and patient health
of using accredited entities and individuals to conduct
such reviews, and shall summarize all relevant data,
including data on the review of accredited entities and
individuals (including data on the review times,
recommendations, and compensation of the entities and
individuals), and data on the review of the Secretary
(including data on the review times, changes, and
reasons for changes of the Secretary).
* * * * * * *
Subchapter D--Unapproved Therapies and Diagnostics
SEC. 551. EXPANDED ACCESS TO UNAPPROVED THERAPIES AND DIAGNOSTICS.
(a) In General.--Any person, acting through a physician
licensed in accordance with State law, may requestfrom a
manufacturer or distributor, and any manufacturer or distributor may
provide to a person after compliance with the provisions of this
section, an investigational drug (including a biological product) or
investigational device for the diagnosis, monitoring, or treatment of a
serious disease or condition, or any other disease or condition
designated by the Secretary as appropriate for expanded access under
this section if--
(1) the licensed physician determines that the person
has no comparable or satisfactory alternative therapy
available to diagnose, monitor, or treat the disease or
condition involved;
(2) the licensed physician determines that the risk
to the person from the investigational drug or
investigational device is not greater than the risk
from the disease or condition;
(3) the Secretary determines that an exemption for
the investigational drug or investigational device is
in effect under a regulation promulgated pursuant to
section 505(i) or 520(g) and the sponsor of the drug or
device and investigators comply with such regulation;
(4) the Secretary determines that the manufacturer of
the investigational drug or investigational device is
actively pursuing marketing approval with due
diligence; and
(5) the Secretary determines that expanded access to
the investigational drug or investigational device will
not interfere with adequate enrollment of patients by
the investigator in the ongoing clinical investigation
of the investigational drug or investigational device
authorized under section 505(i) or 520(g); and
(6) the Secretary determines that there is sufficient
evidence of safety and effectiveness to support the
expanded use of the investigational drug or
investigational device in accordance with this section.
(b) Protocols.--A manufacturer or distributor may submit to
the Secretary 1 or more expanded access protocols covering
expanded access use of a drug or device described in subsection
(a). The protocols shall be subject to the provisions of
section 505(i) or 520(g) and may include any form of use of the
drug or device outside a clinical investigation, prior to
approval of the drug or device for marketing including
protocols for treatment use, emergency use, or uncontrolled
trials, and single patient protocols. If the request for
expanded access to an investigational drug or investigational
device is intended for a single patient only, the Secretary may
waive the requirements of paragraphs (3) and (4) of subsection
(a) and accept a submission under sections 505(i) and 520(g)
for an exemption for the investigational drug or
investigational device for the single patient use. In the case
of an emergency that does not allow sufficient time for a
submission under section 505(i) or (520)(g), the Secretary may,
prior to the submission, authorize the shipment of the
investigational drug or investigational device for a single
patient use.
(c) Notification of Availability.--The Secretary shall
inform national, State, and local medical associations and
societies, voluntary health associations, and other appropriate
persons about the availability of an investigational drug or
investigational device under expanded access protocols
submitted under this section, except that this subsection shall
not apply to expanded access protocols for single patient use.
(d) Termination.--The Secretary may at anytime terminate
expanded access provided under subsection (a) for an
investigational drug or investigational device if the
requirements under this section are no longer met.
* * * * * * *
Subchapter E--Fast Track Drugs
SEC. 561. FAST TRACK DRUGS.
(a) Designation of Drug as a Fast Track Drug.--
(1) In general.--The Secretary shall facilitate
development, and expedite review and approval of new
drugs and biological products that are intended for the
treatment of serious or life-threatening conditions and
that demonstrate the potential to address unmet medical
needs for such conditions. In this Act, such products
shall be known as ``Fast track drugs.''
(2) Request for designation.--The sponsor of a drug
(including a biological product) may request the
Secretary to designate the drug as a fast track drug. A
request for the designation may be made concurrently
with, or at any time after, submission of an
application for the investigation of the drug under
section 505(i) or section 351(a)(4) of the Public
Health Service Act.
(3) Designation.--Within 30 calendar days after the
receipt of a request under paragraph (2), the Secretary
shall determine whether the drug that is the subject of
the request meets the criteria described in paragraph
(1). If the Secretary finds that the drug meets the
criteria, the Secretary shall designate the drug as a
fast track drug and shall take such actions as are
appropriate to expedite the development and review of
the drug.
(b) Approval of Application for a Fast Track Drug.--
(1) In general.--The Secretary may approve an
application for approval of a fast track drug under
section 505(b) or section 351 of the Public Health
Service Act (21 U.S.C. 262) upon a determination that
the drug has an effect on a surrogate endpoint that is
reasonably likely to predict clinical benefit.
(2) Limitation.--Approval of a fast track drug under
this subsection may be subject to the requirements--
(A) that the sponsor conduct appropriate
post-approval studies to validate the surrogate
endpoint or otherwise confirm the clinical
benefit of the drug; and
(B) that the sponsor submit copies of all
promotional materials related to the fast track
drug during the preapproval review period and
following approval, at least 30 days prior to
dissemination of the materials for such period
of time as the Secretary deems appropriate.
(3) Expedited withdrawal of approval.--The Secretary
may withdraw approval of a fast track drug using
expedited procedures (as prescribed by the Secretary in
regulations) including a procedure that provides an
opportunity for an informal hearing, if--
(A) the sponsor fails to conduct any required
post-approval study of the fast track drug with
due diligence;
(B) a post-approval study of the fast track
drug fails to verify clinical benefit of the
fast track drug;
(C) other evidence demonstrates that the fast
track drug is not safe or effective under
conditions of use of the drug; or
(D) the sponsor disseminates false or
misleading promotional materials with respect
to the fast track drug.
(c) Review of Incomplete Applications for Approval of a
Fast Track Drug.--
(1) In general.--If preliminary evaluation by the
Secretary of clinical efficacy data for a fast track
drug under investigation shows evidence of
effectiveness, the Secretary shall evaluate for filing,
and may commence review of portions, of an application
for the approval of the drug if the applicant provides
a schedule for submission of information necessary to
make the application complete and any fee that may be
required under section 736.
(2) Exception.--Any time period for review of human
drug applications that has been agreed to by the
Secretary and that has been set forth in goals
identified in letters of the Secretary (relating to the
use of fees collected under section 736 to expedite the
drug development process and the review of human drug
applications) shall not apply to an application
submitted under paragraph (1) until the date on which
the application is complete.
(d) Awareness Efforts.--The Secretary shall--
(1) develop and widely disseminate to physicians,
patient organizations, pharmaceutical and biotechnology
companies, and other appropriate persons a
comprehensive description of the provisions applicable
to fast track drugs established under this section; and
(2) establish an ongoing program to encourage the
development of surrogate endpoints that are reasonably
likely to predict clinical benefit for serious or life-
threatening conditions for which there exist
significant unmet medical needs.
* * * * * * *
CHAPTER VII--GENERAL AUTHORITY
Subchapter A--General Administrative Provisions
regulations and hearings
Sec. 701 [371] [(a) The] (a)(1) The authority to promulgate
regulations for the efficient enforcement of this Act, except
as otherwise provided in this section, is hereby vested in the
Secretary.
(2) Not later than February 27, 1999, the Secretary, after
evaluating the effectiveness of the Good Guidance Practices
document published in the Federal Register at 62 Fed. Reg.
8961, shall promulgate a regulation specifying the policies and
procedures of the Food and Drug Administration for the
development, issuance, and use of guidance documents.
* * * * * * *
PRESUMPTION
Sec. 709. In any action to enforce the requirements of this
Act respecting [a device] a device, food, drug, or cosmetic.
The connection with interstate commerce required for
jurisdiction in such action shall be presumed to exist.
PART 2--FEES RELATING TO DRUGS
SEC. 735. DEFINITIONS.
For purposes of this subchapter:
(1) The term ``human drug application'' means an
application for--
* * * * * * *
Such term does not include a supplement to such an
application, does not include an application with
respect to whole blood or a blood component for
transfusion, does not include an application with
respect to a bovine blood product for topical
application licensed before September 1, 1992, an
allergenic extract product, or an in vitro diagnostic
biologic product licensed under section 351 of the
Public Health [Service Act, and] Service Act, does not
include an application with respect to a large volume
parenteral drug product approved before [September 1,
1992.] September 1, 1992, does not include an
application for a licensure of a biological product for
further manufacturing use only, and does not include an
application or supplement submitted by a State or
Federal Government entity for a drug or biological
product that is not distributed commercially. Such term
does include an application for licensure, as described
in subparagraph (D), of a large volume biological
product intended for single dose injection for
intravenous use or infusion.
* * * * * * *
Such term does not include whole blood or a blood
component for transfusion, does not include a bovine
blood product for topical application licensed before
September 1, 1992, an allergenic extract product, or an
in vitro diagnostic biologic product licensed under
section 351 of the Public Health [Service Act, and]
Service Act, does not include a large volume parenteral
drug product approved before [September 1, 1992.]
September 1, 1992, does not include biological product
that is licensed for further manufacturing use only,
and does not include a drug or biological product that
is not distributed commercially and is the subject of
an application or supplement submitted by a State or
Federal Government entity. Such term does include a
large volume biological product intended for single
dose injection for intravenous use or infusion.
(4) The term ``final dosage form'' means, with
respect to a prescription drug product, a finished
dosage form which is approved for administration to a
patient [without] without substantial further
manufacturing.
* * * * * * *
(7) The term ``costs of resources allocated for the
process for the review of human drug applications''
means the expenses incurred in connection with the
process for the review of human drug applications for--
(A) officers and employees of the Food and
Drug Administration, [employees under contract
with the Food and Drug Administration who work
in facilities owned or leased for the Food and
Drug Administration,] Contractors of the Food
and Drug Administration advisory committees,
and costs related to such officers, employees,
[and committees,] and committees and to
contracts with such contractors,
* * * * * * *
(8) The term ``adjustment factor'' applicable to a
fiscal year is the lower of--
(A) the Consumer Price Index for all urban
consumers (all items; United States city
average) for [August of] April of the preceding
fiscal year divided by such Index for [August
1992] April 1997, or
[(B) the total of discretionary budget
authority provided for programs in the domestic
category for the immediately preceding fiscal
year (as reported in the Office of Management
and Budget sequestration preview report, if
available, required under section 254(d) of the
Balanced Budget and Emergency Deficit Control
Act of 1985) divided by such budget authority
for fiscal year 1992 (as reported in the Office
of Management and Budget final sequentration
report submitted after the end of the 102d
Congress, 2d Session).]
(B) 1 plus the total percentage increase for
such fiscal year since fiscal year 1997 in
basic pay under the General Schedule in
accordance with section 5332 of title 5, United
States Code, as adjusted by any locality-based
comparability payment pursuant to section 5304
of such title for Federal employees stationed
in the District of Columbia.
[The terms ``budget authority'' and ``category'' in
subparagraph (B) are as defined the Balanced Budget and
Emergency Deficit Control Act of 1985, as in effect as
of September 1, 1992.]
(9) The term affiliate means a business entity that
has a relationship with a second business entity if,
directly or indirectly--
(A) 1 business entity controls, or has the
power to control, the other business entity; or
(B) a third party controls, or has power to
control both of the business entities.
* * * * * * *
SEC. 736. AUTHORITY TO ASSESS AND USE DRUG FEES.
(a) Type of Fees.--[Beginning in fiscal year 1993]
Beginning in fiscal year 1988, the Secretary shall assess and
collect fees in accordance with this section as follows:
* * * * * * *
(B) Payment schedule.--
[(i) First payment.--50 percent of
the fee required by subparagraph (A)
shall be due upon submission of the
application or supplement.
[(ii) Final payment.--The remaining
50 percent of the fee required by
subparagraph (A) will be due upon--
[(I) the expiration of 30
days from the date the
Secretary sends to the
applicant a letter designated
by the Secretary as an action
letter described in section
735(6)(B), or
[ (II) the withdrawal of the
application or supplement after
it is filed unless the
Secretary waives the fee or a
portion of the fee because no
substantial work was performed
on such application or
supplement after it was filed.
The designation under subclause (I) or
the waiver under subclause (II) shall
be solely in the discretion of the
Secretary and shall not be reviewable.]
(B) Payment.--The fee required by
subparagraph (A) shall be due upon submission
of the application or supplement.
* * * * * * *
(D) Refund of fee if application [not
accepted] refused for filing.--The Secretary
shall refund [50 percent] 75 percent of the fee
paid under [subparagraph (B)(i)] subparagraph
(B) for any application or supplement which is
[not accepted] refused for filing.
(E) Exception for designated orphan drug or
indication.--A person that submits a human drug
application for a prescription drug product
that has been designated as a drug for a rare
disease or condition pursuant to section 526,
or a supplement proposing to include a new
indication for a rare disease or condition
pursuant to section 526, shall not be assessed
a fee under subparagraph (A), unless the human
drug application includes indications for other
than rare diseases or conditions.
(F) Exception for applications and
supplements for pediatric indications.--A
person that submits a human drug application or
supplement that includes an indication for use
in pediatric populations shall be assessed a
fee under subparagraph (A) only if--
(i) the application is for initial
approval for use in a pediatric
population; or
(ii) the application or supplement is
for approval for use in pediatric and
nonpediatric populations.
(G) Refund of fee if application withdrawn.--
If an application or supplement is withdrawn
after the application or supplement is filed,
the Secretary may waive and refund the fee or a
portion of the fee if no substantial work was
performed on the application or supplement
after the application or supplement was filed.
The Secretary shall have the sole discretion to
waive and refund a fee or a portion of the fee
under this subparagraph. A determination by the
Secretary concerning a waiver or refund under
this paragraph shall not be reviewable.
(2) Prescription drug establishment fee.--Each person
that--
(A) owns a prescription drug establishment,
at which is manufactured at least 1
prescription drug product which is not the, or
not the same as a, product approved under an
application filed under section 505(b)(2) or
[505(j), and] 505(j) or under an abbreviated
new drug application pursuant to regulations in
effect prior to the implementation of the Drug
Price Competition and Patent Term Restoration
Act of 1984, or a product approved under an
application filed under section 507 that is
abbreviated, and
* * * * * * *
(3) Prescription drug product fee.--
(A) In general.--Except as provided in
subparagraph (B), each person--
(i) who is named as the applicant in
a human drug application for a
prescription drug product which [is
listed] has been submitted for listing
under section 510, and
(ii) who, after September 1, 1992,
had pending before the Secretary a
human drug application or supplement,
shall pay for each such prescription drug
product the annual fee established in
subsection (b). [Such fee shall be payable at
the time of the first such listing of such
product in each calendar year. Such fee shall
be paid only once each year for each listed
prescription drug product irrespective of the
number of times such product is listed under
section 510.] Such fee shall be payable for the
fiscal year in which the product is first
submitted for listing under section 510, or for
relisting under section 510 if the product has
been withdrawn from listing and relisted. After
such fee is paid for that fiscal year, such fee
shall be payable on or before January 31 of
each year. Such fee shall be paid only once for
each product for a fiscal year in which the fee
is payable.
(B) Exception.--The listing of a prescription
drug product under section 510 shall not
require the person who listed such product to
pay the fee prescribed by subparagraph (A) if
such product is the same product as a product
approved under an application filed under
section 505(b)(2) or [505(j).] 505(j), or under
an abbreviated new drug application pursuant to
regulations in effect prior to the
implementation of the Drug Price Competition
and Patent Term Restoration Act of 1984, or is
a product approved under an application filed
under section 507 that is abbreviated.
[(b) Fee Amounts.--]
(b) Fee Amounts.--Except as provided in subsections (c),
(d), (f), and (g), the fees required under subsection (a) shall
be determined and assessed as follows:
(1) Application and supplement fees.--
(A) Full fees.--The application fee under
subsection (a)(1)(A)(i) shall be $250,704 in
fiscal year 1998, $256,338 in each of fiscal
years 1999 and 2000, $267,606 in fiscal year
2001, and $258,451 in fiscal year 2002.
(B) Other fees.--The fee under subsection
(a)(1)(A)(ii) shall be $125,352 in fiscal year
1998, $128,169 in each of fiscal years 1999 and
2000, $133,803 in fiscal year 2001 and $129,226
in fiscal year 2002.
(2) Fee revenues for establishment fees.--The total
fee revenues to be collected in establishment fees
under subsection (a)(2) shall be $35,600,000 in fiscal
year 1998, $36,400,000 in each of fiscal years 1999 and
2000, $38,000,000 in fiscal year 2001, and $36,700,000
in fiscal year 2002.
(3) Total fee revenues for product fees.--The total
fee revenues to be collected in product fees under
subsection (a)(3) in a fiscal year shall be equal to
the total fee revenues collected in establishment fees
under subsection (a)(2) in that fiscal year.
* * * * * * *
(c) [Increases and] Adjustments.--
[(1) Revenue increase.--The total fee revenues
established by the schedule in subsection (b)(1) shall
be increased by the Secretary] (1) Inflation
adjustment.--The fees and total fee revenues
established in subsection (b) shall be adjusted by the
Secretary by notice, published in the Federal Register,
for a fiscal year to reflect the greater of--
(A) the total percentage [increase] change
that occurred during the preceding fiscal year
in the Consumer Price Index for all urban
consumers (all items; U.S. city average), or
(B) the total percentage [increase] change
for such fiscal year in basic pay under the
General Schedule in accordance with section
5332 of title 5, United States Code, as
adjusted by any locality-based comparability
payment pursuant to section 5304 of such title
for Federal employees stationed in the District
of Columbia.
The adjustment made each fiscal year by this subsection
will be added on a compounded basis to the sum of all
adjustments made each fiscal year after fiscal year
1997 under this subsection.
(2) Annual fee adjustment.--Subject to the amount
appropriated for a fiscal year under subsection (g),
the Secretary shall, within 60 days after the end of
each fiscal year beginning after [October 1, 1992,
adjust the fees established by the schedule in
subsection (b)(1) for the following fiscal year to
achieve the total fee revenues, as may be increased
under paragraph (1). Such fees shall be adjusted under
this paragraph to maintain the proportions established
in such schedule.] September 30, 1997, adjust the
establishment and product fees described in subsection
(b) for the fiscal year in which the adjustment occurs
so that the revenues collected from each of the
categories of fees described in paragraphs (2) and (3)
of subsection (b) shall be set to be equal to the
revenues collected during the past fiscal year from the
category of application and supplement fees described
in paragraph (1) of subsection (b).
(3) Limit.--The total amount of fees charged, as
adjusted under [paragraph (2)] this subsection, for a
fiscal year may not exceed the total costs for such
fiscal year for the resources allocated for the process
for review of human drug applications.
(d) Fee Waiver or Reduction.--[The Secretary shall grant a
waiver from or a reduction of 1 or more fees under subsection
(a) where the Secretary finds that--] (1) In general._The
Secretary shall grant a waiver from or a reduction of 1 or more
fees assessed under subsection (a) where the Secretary finds
that--
[(1)] (A) such waiver or reduction is necessary to
protect the public health,
[(2)] (B) the assessment of the fee would present a
significant barrier to innovation because of limited
resources available to such person or other
circumstances,
[(3)] (C) the fees to be paid by such person will
exceed the anticipated present and future costs
incurred by the Secretary in conducting the process for
the review of human drug applications for such person[,
or],
[(4)] (D) assessment of the fee for an application or
a supplement filed under section 505(b)(1) pertaining
to a drug containing an active ingredient would be
inequitable because an application for a product
containing the same active ingredient filed by another
person under section 505(b)(2) could not be assessed
fees under subsection (a)(1)[.], or;
(E) the applicant is a small business submitting its
first human drug applicaiton to the Secretary for
review.
[In making the finding in paragraph (3), the Secretary may use
standard costs.]
(2) Use of standard costs.--In making the finding in
paragraph (1)(C), the Secretary may use standard costs.
(3) Rules relating to small businesses.--
(A) Definition.--In paragraph (1)(E), the term
``small business'' means an entity that has fewer than
500 employees, including employees of affiliates.
(B) Waiver of application fee.--The Secretary shall
waive under paragraph (1)(E) the application fee for
the first human drug application that a small business
or its affiliate submits to the Secretary for review.
After a small business or its affiliate is granted such
a waiver, the small business or its affiliate shall
pay--
(i) application fees for all subsequent human
drug applications submitted to the Secretary
for review in the same manner as an entity that
does not qualify as a small business; and
(ii) all supplement fees for all supplements
to human drug applications submitted to the
Secretary for review in the same manner as an
entity that does not qualify as a small
business.
* * * * * * *
(f) Assessment of Fees.--
(1) Limitation.--Fees may not be assessed under
subsection (a) for a fiscal year beginning after
[fiscal year 1993] fiscal year 1997 unless
appropriations for salaries and expenses of the Food
and Drug Administration for such fiscal year (excluding
the amount of fees appropriated for such fiscal year)
are equal to or greater than the amount of
appropriations for the salaries and expenses of the
Food and Drug Administration for the [fiscal year 1992]
fiscal year 1997 (excluding the amount of fees
appropriated for such fiscal year) multiplied by the
adjustment factor applicable to the fiscal year
involved.
* * * * * * *
(g) Crediting and Availability of Fees.--
(1) In general.--Fees collected for a fiscal year
pursuant to subsection (a) shall be credited to the
appropriation account for salaries and expenses of the
Food and Drug Administration and shall be available in
accordance with appropriation Acts until expended
without fiscal year limitation. Such sums as may be
necessary may be transferred from the Food and Drug
Administration salaries and expenses appropriation
account without fiscal year limitation to such
appropriation account for salaries and expenses with
such fiscal year limitation. The sums transferred shall
be available solely for the process for the review of
human drug applications within the meaning of section
735(6).
(2) Collections and appropriation acts.--The fees
authorized by this section--
(A) shall be collected in each fiscal year in
an amount equal to the amount specified in
appropriation [Acts] Acts, or otherwise made
available for obligation for such fiscal year,
and
(B) shall only be collected and available to
defray increases in the costs of the resources
allocated for the process for the review of
human drug applications (including increases in
such costs for an additional number of full-
time equivalent positions in the Department of
Health and Human Services to be engaged in such
process) [over such costs for fiscal year 1992]
over such costs, excluding costs paid from fees
collected under this section, for fiscal year
1997 multiplied by the adjustment factor.
[(3) Authorization of appropriations.--There are
authorized to be appropriated for fees under this
section--
[(A) $36,000,000 for fiscal year 1993,
[(B) $54,000,000 for fiscal year 1994,
[(C) $75,000,000 for fiscal year 1995,
[(D) $78,000,000 for fiscal year 1996, and
[(E) $84,000,000 for fiscal year 1997, as
adjusted to reflect increases in the total fee
revenues made under subsection (c)(1).]
(3) Authorization of appropriations.--There is
authorized to be appropriated for fees under this
section--
(A) $106,800,000 for fiscal year 1998;
(B) $109,200,000 for fiscal year 1999;
(C) $109,200,000 for fiscal year 2000;
(D) $114,000,000 for fiscal year 2001; and
(E) $110,100,000 for fiscal year 2002,
as adjusted to reflect adjustments in the total fee
revenues made under this section and changes in the
total amounts collected by application, supplement,
establishment, and product fees.
(4) Offset.--Any amount of fees collected for a
fiscal year which exceeds the amount of fees specified
in appropriation Acts for such fiscal year, shall be
credited to the appropriation account of the Food and
Drug Administration as provided in paragraph (1), and
shall be subtracted from the amount of fees that would
otherwise be authorized to be collected under
appropriation Acts for a subsequent fiscal year.
* * * * * * *
(i) Written Requests for Waivers, Reductions, and
Refunds.--To qualify for consideration for a waiver or
reduction under subsection (d), or for a refund, of any fee
collected in accordance with subsection (a), a person shall
submit to the Secretary a written request for such waiver,
reduction, or refund not later than 180 days after such fee is
due.
[(i)] (j) Construction.--This section may not be construed
to require that the number of full-time equivalent position in
the Department of Health and Human Services, for officers,
employers, and advisory committees not engaged in the process
of the review of human drug applications, be reduced to offset
the number of officers, employees, and advisory committees so
engaged.
* * * * * * *
Subchapter D--Classification of Product and Environmental Impact
Reviews
SEC. 741. CLASSIFICATION OF PRODUCTS.
(a) Request.--A person who submits an application or
submission (including a petition, notification, and any other
similar form of request) under this Act, may submit a request
to the Secretary respecting the classification of an article
(including an article that is a combination product subject to
section 503(g)) as a drug, biological product, or device, or
respecting the component of the Food and Drug Administration
that will regulate the article. In submitting the request, the
person shall recommend a classification for the article, or a
component to regulate the article, as appropriate.
(b) Statement.--Not later than 60 days after the receipt of
the request described in subsection (a), the Secretary shall
determine the classification of the article or the component of
the Food and Drug Administration that will regulate the article
and shall provide to the person a written statement that
identifies the classification of the article or the component
of the Food and Drug Administration that will regulate the
article and the reasons for such determination. The Secretary
may not modify such statement except with the written consent
of the person or for public health reasons.
(c) Inaction of Secretary.--If the Secretary does not
provide the statement within the 60-day period described in
subsection (b), the recommendation made by the person under
subsection (a) shall be considered to be a final determination
by the Secretary of the classification of the article or the
component of the Food and Drug Administration that will
regulate the article and may not be modified by the Secretary
except with the written consent of the person or for public
health reasons.
* * * * * * *
SEC. 742. ENVIRONMENTAL IMPACT REVIEW.
Nothwithstanding any other provision of law, no action by
the Secretary pursuant to this Act shall be subject to an
environmental assessment, an environmental impact statement, or
other environmental consideration unless the Secretary
demonstrates, in writing--
(1) that there is a reasonable probability that the
environmental impact of the action is sufficiently
substantial and within the factors that the Secretary
is authorized to consider under this Act; and
(2) that consideration of the environmental impact
will directly affect the decision on the action.
* * * * * * *
Subchapter E--Manufacturing Changes
SEC. 751. MANUFACTURING CHANGES.
(a) In General.--A change in the manufacture of a new drug,
including a biological product, may be made in accordance with
this section.
(b) Changes.--
(1) Validation.--Before distributing a drug made
after a change in the manufacture of the drug from the
manufacturing process established in the approved new
drug application under section 505, or license
application under section 351 of the Public Health
Service Act, the applicant shall validate the effect of
the change on the identity, strength, quality, purity,
and potency of the drug as the identity, strength,
quality, purity, and potency may relate to the safety
or effectiveness of the drug.
(2) Reports.--The applicant shall report the change
described in paragraph (1) to the Secretary and may
distribute a drug made after the change as follows:
(A) Major manufacturing changes.
(i) In general.--Major manufacturing
changes, which are of a type determined
by the Secretary to have substantial
potential to adversely affect the
identity, strength, quality, purity, or
potency of the drug as the identity,
strength, quality, purity, and potency
may relate to the safety or
effectiveness of a drug, shall be
submitted to the Secretary in a
supplemental application and drugs made
after such changes may not be
distributed until the Secretary
approves the supplemental application.
(ii) Definition.--In this
subparagraph, the term ``major
manufacturing changes'' means--
(I) changes in the
qualitative or quantitative
formulation of a drug or the
specifications in the approved
marketing application for the
drug (unless exempted by the
Secretary from the requirements
of this subparagraph);
(II) changes that the
Secretary determines by
regulation or issuance of
guidance require completion of
an appropriate human study
demonstrating equivalence of
the drug to the drug
manufactured before such
changes; and
(III) other changes that the
Secretary determines by
regulation or issuance of
guidance have a substantial
potential to adversely affect
the safety or effectiveness of
the drug.
(B) Other manufacturing changes.--
(i) In general.--As determined by the
Secretary, manufacturing changes other
than major manufacturing changes
shall--
(I) be made at any time and
reported annually to the
Secretary, with supporting
data; or
(II) be reported to the
Secretary in a supplemental
application.
(ii) Distriction of the drug.--In the
case of changes reported in accordance
with clause (i)(II)--
(I) the applicant may
distribute the drug 30 days
after the Secretary receives
the supplemental application
unless the Secretary notifies
the applicant within such 30-
day period that prior approval
of such supplemental
application is required; and
(II) the Secretary shall,
after making the notification
to the applicant under
subclause (I), approve or
disapprove each such
supplemental application.
(iii) Special rule.--The Secretary
may determine types of manufacturing
changes after which distribution of a
drug may commence at the time of
submission of supplemental application.
* * * * * * *
Subchapter F--National Uniformity for Nonprescription Drugs for Human
Use and Cosmetics
SEC. 761. NATIONAL UNIFORMITY FOR NONPRESCRIPTION DRUGS AND COSMETICS.
(a) In General.--Except as provided in subsection (b),
(c)(1), or (d), no State or political subdivision of a State
may establish or continue in effect any requirement--
(1) that relates to the regulation of a drug intended
for human use that is not subject to the requirements
of section 503(b)(1) or a cosmetic; and
(2) that is different from or in addition to, or that
is otherwise not identical with, a requirement of this
Act, the Poison Prevention Packaging Act of 1970 (15
U.S.C. 1471 et seq.), or the Fair Packaging and
Labeling Act (15 U.S.C. 1451 et seq.).
(b) Exemption.--Upon application of a State, the Secretary
may by regulation, after notice and opportunity for written and
oral presentation of views, exempt from subsection (a), under
such condition as may be prescribed in such regulation a State
requirement that---
(1) protects an important public interest that would
otherwise be unprotected.
(2) would not cause any drug or cosmetic to be in
violation of any applicable requirement or prohibition
under Federal law; and
(3) would not unduly burden interstate commerce.
(c) Scope.--For purposes of subsection (a), a requirement
that relates to the regulation of a drug or cometic--
(1) shall not include any requirement that relates to
the practice of pharmacy or any requirement that a drug
be dispensed only upon the prescription of a
practitioner licensed by law to administer such drug;
and
(2) shall be deemed to include any requirement
relating to public information or any other form of
public communication relating to the safety or
effectiveness of a drug or cosmetic.
(d) No Effect on Product Liability Law.--Nothing in this
section shall be construed to modify or otherwise affect any
action or the liability of any person under the product
liability law of any State.
* * * * * * *
SEC. 903. [393] FOOD AND DRUG ADMINISTRATION.
(a) In General.--* * *
* * * * * * *
(b) Mission.--
(1) In general.--The Administration shall protect the
public health by ensuring that--
(A) foods are safe, wholesome, sanitary, and
properly labeled;
(B) human and veterinary drugs are safe and
effective;
(C) there is reasonable assurance of safety
and effectiveness of devices intended for human
use;
(D) cosmetics are safe; and
(E) public health and safety are protected
from electronic product radiation.
(2) Special rules.--The Administration shall promptly
and efficiently review clinical research and take
appropriate action on the marketing of regulated
products in a manner that does not unduly impede
innovation or product availability. The Administration
shall participate with other countries to reduce the
burden of regulation, to harmonize regulatory
requirements, and to achieve appropriate reciprocal
arrangements with other countries.
(3) Interagency Collaboration.--The Secretary shall
implement programs and policies that will foster
collaboration between the Administration, the National
Institutes of Health, and other science-based Federal
agencies, to enhance the scientific and technical
expertise available to the Secretary in the conduct of
the duties of the Secretary with respect to the
development, clinical investigation, evaluation, and
postmarket monitoring of emerging medical therapies,
including complementary therapies, and advances in
nutrition and food science.
(4) Agency plan for statutory compliance.--
(A) In general.--Not later than 180 days
after the date of enactment of this paragraph,
the Secretary, after consultation with relevant
experts, health care professionals,
representatives of patient and consumer
advocacy groups, and the regulated industry,
shall develop and publish in the Federal
Register a plan bringing the Secretary into
compliance with each of the obligations of the
Secretary under this Act and other relevant
statutes. The Secretary shall biannually review
the plan and shall revise the plan as
necessary, in consultation with such persons.
(B) Objectives of agency plan.--The plan
required by subparagraph (A) shall
establishobjectives, and mechanisms to be used by the Secretary, acting
through the Commissioner, including objectives and mechanisms that--
(i) minimize deaths of, and harm to,
persons who use or may use an article
regulated under this Act;
(ii) maximize the clarity of, and the
availability of information about, the
process for review of applications and
submissions (including petitions,
notifications, and any other similar
forms of request) made under this Act,
including information for potential
consumers and patients concerning new
products;
(iii) implement all inspection and
postmarket monitoring provisions of
this Act by July 1, 1999;
(iv) ensure access to the scientific
and technical expertise necessary to
ensure compliance by the Secretary with
the statutory obligations described in
subparagraph (A);
(v) establish a schedule to bring the
Administration into full compliance by
July 1, 1999, with the time periods
specified in this Act for the review of
all applications and submissions
described in clause (ii) and submitted
after the date of enactment of this
paragraph; and
(vi) reduce backlogs in the review of
all applications and submissions
described in clause (ii) for any
article with the objective of
eliminating all backlogs in the review
of the applications and submissions by
January 1, 2000.
(5) Annual report.--
(A) Contents.--The Secretary shall prepare
and publish in the Federal Register and solicit
public comment on an annual report that--
(i) provides detailed statistical
information on the performance of the
Secretary under the plan described in
paragraph (4);
(ii) compares such performance of the
Secretary with the objectives of the
plan and with the statutory obligations
of the Secretary;
(iii) analyzes any failure of the
Secretary to achieve any objective of
the plan or to meet any statutory
obligation;
(iv) identifies any regulatory policy
that has a significant impact on
compliance with any objective of the
plan or any statutory obligation; and
(v) sets forth any proposed revision
to any such regulatory policy, or
objective of the plan that has not been
met.
(B) Statistical information.--The statistical
information described in subparagraph (A)(i)
shall include a full statistical presentation
relating to all applications and submissions
(including petitions, notifications, and any
other similar forms of request) made under this
Act and approved or subject to final action by
the Secretary during the year covered by the
report. In preparing the statistical
presentation, the Secretary shall take into
account the date of--
(i) the submission of any
investigational application;
(ii) the application of any clinical
hold;
(iii) the submission of any
application or submission (including a
petition, notification, and any other
similar form of request) made under
this Act for approval or clearance;
(iv) the acceptance for filing of any
application or submission described in
clause (iii) for approval or clearance;
(v) the occurrence of any
anapprovable action;
(vi) the occurrence of any approvable
action; and
(vii) the approval or clearance of
any application or submission described
in clause (iii).
* * * * * * *
[(b)] (c) Commissioner.--
(1) Appointment.--* * *
* * * * * * *
[(c)] (d) Technical and Scientific Review Groups.--The
Secretary through the Commissioner of Food and Drugs may,
without regard to the provisions of title 5, United States
Code, governing appointments in the competitive service and
without regard to the provisions of chapter 51 and subchapter
III of chapter 53 of such title relating to classification and
General Schedule pay rates, establish such technical and
scientific review groups as are needed to carry out the
functions of the Administration, including functions under the
Federal Food, Drug, and Cosmetic Act, and appoint and pay the
members of such groups, except that officers and employees of
the United States shall not receive additional compensation for
service as members of such groups.
* * * * * * *
SEC. 906. CONTRACTS FOR EXPERT REVIEW.
(a) In General.--
(1) Authority.--The Secretary may enter into a
contract with any organization or any individual (who
is not an employee of the Department) with expertise in
a relevant discipline, to review, evaluate, and make
recommendations to the Secretary on part or all of any
application or submission (including a petition,
notification, and any other similar form of request)
made under this Act for the approval or classification
of an article or made under section 351(a) of the
Public Health Service Act (42 U.S.C. 262(a)) with
respect to a biological product. Any such contract
shall be subject to the requirements of section 708
relating to the confidentiality of information.
(2) Increased efficiency and expertise through
contracts.--The Secretary shall use the authority
granted in paragraph (1) whenever the Secretary
determines that a contract described in paragraph (1)
will improve the timeliness or quality of the review of
an application or submission described in paragraph
(1). Such improvement may include providing the
Secretary increased scientific or technicalexpertise
that is necessary to review or evaluate new therapies and technologies.
(b) Review of Expert Review.--
(1) In general.--Subject to paragraph (2), the
official of the Food and Drug Administration
responsible for any matter for which expert review is
used pursuant to subsection (a) shall review the
recommendations of the organization or individual who
conducted the expert review and shall make a final
decision regarding the matter within 60 days after
receiving the recommendations.
(2) Limitation.--A final decision under paragraph (1)
shall be made within the applicable prescribed time
period for review of the matter as set forth in this
Act or in the Public Health Service Act (42 U.S.C. 201
et seq.).
(3) Authority of secretary.--Notwithstanding
subsection (a), the Secretary shall retain full
authority to make determinations with respect to the
approval or disapproval of an article under this Act,
the approval or disapproval of a biologics license with
respect to a biological product under section 351(a) of
the Public Health Service Act, or the classification of
an article as a device under section 513(f)(1).
* * * * * * *
SEC. 907. INTRAMURAL RESEARCH TRAINING AWARD PROGRAM.
(a) In General.--The Secretary, acting through the
Commissioner of Food and Drugs, may, directly or through
grants, contracts, or cooperative agreements, conduct and
support intramural research training in regulatory scientific
programs by predoctoral and postdoctoral scientists and
physicians, including the support through the use of
fellowships.
(b) Limitation on Participation.--A recipient of a
fellowship under subsection (a) may not be an employee of the
Federal Government.
(c) Special Rule.--The Secretary, acting through the
Commissioner of Food and Drugs, may support the provision of
assistance for fellowships described in subsection (a) through
a Cooperative Research and Development Agreement.
* * * * * * *
PUBLIC HEALTH SERVICE ACT
* * * * * * *
Part F--Licensing--Biological Products and Clinical Laboratories
Subpart 1--Biological Products
REGULATION OF BIOLOGICAL PRODUCTS
Sec. 351. [262] [(a) No person shall sell, barter, or
exchange, or offer for sale, barter, or exchange in the
District of Columbia, or send, carry, or bring for sale,
barter, or exchange from any State or possession into any other
State or possession or into any foreign country, or from any
foreign country into any State or possession, any virus,
therapeutic serum, toxin, antitoxin, vaccine, blood, blood
component or derivative, allergenic product, or analogous
product, or arsphenamine or its derivatives (or any other
trivalent organic arsenic compound), applicable to the
prevention, treatment, or cure of diseases or injuries of man,
unless (1) such virus, serum, toxin, antitoxin, vaccine, blood,
blood component or derivative, allergenic product, or other
product has been propagated or manufactured and prepared at an
establishment holding an unsuspended and unrevoked license,
issued by the Secretary as hereinafter authorized, to propagate
or manufacture, and prepare such virus, serum, toxin,
antitoxin, vaccine, blood, blood component or derivative,
allergenic product, or other product for sale in the District
of Columbia, or for sending, bringing, or carrying from place
to place afore-said: and (2) each package of such virus, serum,
toxin, antitoxin, vaccine, blood, blood component or
derivative, allergenic product, or other product is plainly
marked with the proper name of the article contained therein,
the name, address, and license number of the manufacturer, and
the date beyond which the contents cannot be expected beyond
reasonable doubt to yield their specific results. The
suspension or revocation of any license shall not prevent the
sale, barter, or exchange of any virus, serum, toxin,
antitoxin, vaccine, blood, blood component or derivative,
allergenic product, or other product aforesaid which has been
sold and delivered by the licensee prior to such suspension or
revocation, unless the owner or custodian of such virus, serum,
toxin, antitoxin, vaccine, blood, blood component or
derivative, allergenic product, or other product aforesaid has
been notified by the Secretary not to sell, barter, or exchange
the same.] (a)(1) Except as provided in paragraph (4), no
person shall introduce or deliver for introduction into
interstate commerce any biological product unless--
(A) a biologics license is in effect for the
biological product; and
(B) each package of the biological product is plainly
marked with--
(i) the proper name of the biological product
contained in the package;
(ii) the name, address, and applicable
license number of the manufacturer of the
biological product; and
(iii) the expiration date of the biological
product.
(2)(A) The Secretary shall establish, by regulation,
requirements for the approval, suspension, and revocation of
biologics licenses.
(B) The Secretary shall approve a biologics license
application on the basis of a demonstration that--
(i) the biological product that is the subject of the
application is safe, pure, and potent; and
(ii) the facility in which the biological product is
manufactured, processed, packed, or held meets
standards designed to assure that the biological
product continues to be safe, pure, and potent.
(3) A biologics license application shall be approved only
if the applicant (or other appropriate person) consents to the
inspection of the facility that is the subject of the
application, in accordance with subsection (c).
(4) The Secretary shall prescribe requirements under which
a biological product undergoing investigation shall be exempt
from the requirements of paragraph (1).
[(b) No person shall falsely label or mark any package or
container or any virus, serum, toxin, antitoxin, vaccine,
blood, blood component or derivative, allergenic product, or
other product aforesaid; nor alter any label or mark on any
package or container of any virus, serum, toxin, antitoxin,
vaccine, blood, blood component or derivative, allergenic
product, or other product aforesaid so as to falsify such label
or mark.]
(b) No person shall falsely label or mark any package or
container of any biological product or alter any label or mark
on the package or container of the biological product so as to
falsify the label or mark.
(c) Any officer, agent, or employee of the Department of
Health and Human Services, authorized by the Secretary for the
purpose, may during all reasonable hours enter and inspect any
establishment for the propagation or manufacture and
preparation of any [virus, serum, toxin, antitoxin, vaccine,
blood, blood component or other product aforesaid for sale
barter, or exchange in the District of Columbia, or to be sent,
carried, or brought from any State or possession into any other
State or possession or into any foreign country, or from any
foreign country into any State or possession.] biological
product.
[(d)(1) Licenses for the maintenance of establishments for
the propagation or manufacture and preparation of products
described in subsection (a) of this section may be issued only
upon a showing that the establishment and the products for
which a license is desired meet standards, designed to insure
the continued safety, purity, and potency of such products,
prescribed in regulations, and licenses for new products may be
issued only upon a showing that they meet such standards. All
such licenses shall be issued, suspended, and revoked as
prescribed by regulations and all licenses issued for the
maintenance of establishment for the propagation or manufacture
and preparation, in any foreign country, of any such products
for sale, barter, or exchange in any State or possession shall
be issued upon condition that the licensees will permit the
inspection of their establishment in accordance with subsection
(c) of this section.]
[(2)(A) Upon] (d)(1) Upon a determination that a batch,
lot, or other quantity of a product licensed under this section
presents an imminent or substantial hazard to the public
health, the Secretary shall issue an order immediately ordering
the recall of such batch, lot, or other quantity of such
product. An order under this paragraph shall be issued in
accordance with section 554 of title 5, United States Code.
[(B)] (2) Any violation of [subparagraph (A)] paragraph (1)
shall subject the violator to a civil penalty of up to $100,000
per day of violation. The amount of a civil penalty under [this
subparagraph] this paragraph shall, effective December 1 of
each year beginning 1 year after the effective date of [this
subparagraph] this paragraph, be increased by the percent
change in the Consumer Price Index for the base quarter of such
year over the Consumer Price Index for the base quarter of the
preceding year, adjusted to the nearest \1/10\ of 1 percent.
For purposes of [this subparagraph] this paragraph, the term
``base quarter'', as used with respect to a year, means the
calendar quarter ending on September 30 of such year and the
price index for a base quarter is the arithmetical mean of such
index for the 3 months comprising such quarter.
* * * * * * *
(i) In this section, the term `biological product' means a
virus, therapeutic serum, toxin, antitoxin, vaccine, blood,
blood component or derivative, allergenic product, analogous
product, or arsphenamine or derivative of arsphenamine (or any
other trivalent organic arsenic compound), applicable to the
prevention, treatment, or cure of a disease or condition of
human beings.
* * * * * * *
TITLE IV--NATIONAL RESEARCH INSTITUTES
Part A--National Institutes of Health
organization of the national institutes of health
Sec. 401. (a) * * *
* * * * * * *
appointment and authority of director of nih
Sec. 402. (a) * * *
* * * * * * *
(j)(1) The Secretary, acting through the Director of the
National Institutes of Health and subject to the availability
of appropriations, shall establish, maintain, and operate a
program with respect to information on research relating to the
treatment, detection, and prevention of serious or life-
threatening diseases and conditions. The program shall, with
respect to the agencies of the Department of Health and Human
Services, be integrated and coordinated, and, to the extent
practicable, coordinated with other data banks containing
similar information.
(2)(A) After consultation with the Commissioner of Food and
Drugs, the directors of the appropriate agencies of the
National Institutes of Health (including the National Library
of Medicine), and the Director of the Centers for Disease
Control and Prevention, the Secretary shall, in carrying out
paragraph (1), establish a data bank of informationon clinical
trials for drugs, and biologicals, for serious or life-threatening
diseases and conditions.
(B) In carrying out subparagraph (A), the Secretary shall
collect, catalog, store and disseminate the information
described in such subparagraph. The Secretary shall disseminate
such information through information systems, which shall
include toll-free telephone communications, available to
individuals with serious or life-threatening diseases and
conditions, to other members of the public, to health care
providers, and to researchers.
(3) The Data Bank shall include the following:
(A) A registry of clinical trials (whether federally
or privately funded) of experimental treatments for
serious or life-threatening diseases and conditions
under regulations promulgated pursuant to sections 505
and 520 of the Federal Food, Drug, and Cosmetic Act
that provides a description of the purpose of each
experimental drug or biological protocol, either with
the consent of the protocol sponsor, or when a trial to
test efficacy begins. Information provided shall
consist of eligibility criteria, a description of the
location of trial sites, and a point of contact for
those wanting to enroll in the trial, and shall be in a
form that can be readily understood by embers of the
public. Such information must be forwarded to the Data
Bank by the sponsor of the trial not later than 21 days
after the approval by the Food and Drug Administration.
(B) Information pertaining to experimental treatments
for serious or life-threatening diseases and conditions
that may be available--
(i) under a treatment investigational new
drug application that has been submitted to the
Food and Drug Administration pursuant to part
312 of title 21, Code of Federal Regulations;
or
(ii) as a Group C cancer drug.
The Data Bank may also include information pertaining
to the results of clinical trials of such treatments,
with the consent of the sponsor, including information
concerning potential toxicities or adverse effects
associated with the use or administration of such
experimental treatments.
(4) The Data Bank shall not include information relating to
an investigation if the sponsor has certified to the Secretary
that disclosure of such information would substantially
interfere with the timely enrollment of subjects in the
investigation.
(5) For the purpose of carrying out this subsection, there
are authorized to be appropriated such sums as may be
necessary. Fees collected under section 736 of the Federal
Food, Drug, and Cosmetic (21 U.S. C. 379h) shall not be
authorized or appropriated for use in carrying out this
subsection.
[(j)] (k)(1) The Director of NIH may establish a program to
provide day care services for the employees of the National
Institutes of Health similar to those services provided by
other Federal agencies (including the availability of day care
service on a 24-hour-a-day basis).
* * * * * * *
[(k)] (l) The Director of NIH shall carry out the program
established in part F of title XII (relating to interagency
research on trauma).
* * * * * * *
CONTROLLED SUBSTANCES ACT
* * * * * * *
TITLE II--CONTROL AND ENFORCEMENT
Part A--Short Title; Findings and Declaration; Definitions
Short Title
Sec. 100. * * *
* * * * * * *
Definitions
Sec. 102. As used in this title
(1) * * *
* * * * * * *
(9) The term ``depressant or stimulant substance'' means
(A) a drug which contains any quantity of [(i)]
barbituric acid or any of the salts of barbituric acid;
or [(ii) any derivative of barbituric acid which has
been designated by the Secretary as habit forming under
section 502(d) of the Federal Food, Drug, and Cosmetic
Act (21 U.S.C. 352(d)); or]
* * * * * * *