[Federal Register Volume 66, Number 12 (Thursday, January 18, 2001)]
[Proposed Rules]
[Pages 4688-4706]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-1048]


 ========================================================================
 Proposed Rules
                                                 Federal Register
 ________________________________________________________________________
 
 This section of the FEDERAL REGISTER contains notices to the public of 
 the proposed issuance of rules and regulations. The purpose of these 
 notices is to give interested persons an opportunity to participate in 
 the rule making prior to the adoption of the final rules.
 
 ========================================================================
 

  Federal Register / Vol. 66, No. 12 / Thursday, January 18, 2001 / 
Proposed Rules  

[[Page 4688]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 20, 312, and 601

[Docket No. 00N-0989]


Availability for Public Disclosure and Submission to FDA for 
Public Disclosure of Certain Data and Information Related to Human Gene 
Therapy or Xenotransplantation

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
the biologics licensing regulations regarding confidentiality of 
information. The amendments would add provisions that would make 
available for public disclosure, and require submission for public 
disclosure of, certain data and information related to human gene 
therapy or xenotransplantation. The proposed regulation would apply 
specifically to the areas of human gene therapy and xenotransplantation 
because these areas of clinical research have the potential for unique 
public health risks and modification of the human genome. The proposed 
rule would provide for public disclosure of certain data and 
information related to an investigational new drug application (IND), 
to provide an opportunity for public education on, and discussion and 
consideration of, public health and safety issues. In addition, the 
proposed rule would require sponsors of clinical trials on human gene 
therapy or xenotransplantation to submit to FDA for public disclosure 
certain data and information that has been redacted to remove or 
obscure all information defined as confidential commercial or trade 
secret, or names and other personal identifiers of patients and certain 
other third parties.

DATES: Submit written comments on this proposed rule on or before April 
18, 2001. Submit written comments on the information collection 
provisions by February 20, 2001.

ADDRESSES: Submit written comments on this proposed rule to the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers 
Lane, rm. 1061, Rockville, MD 20852. Submit written comments on the 
information collection requirements to Wendy Taylor, FDA Desk Officer, 
Office of Information and Regulatory Affairs, Office of Management and 
Budget (OMB), New Executive Office Building, 725 17th St. NW., 
Washington, DC 20503, Attn: Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT: Steven F. Falter, Center for Biologics 
Evaluation and Research (HFM-17), Food and Drug Administration, 1401 
Rockville Pike, suite 200N, Rockville, MD 20852-1448, 301-827-6210.

SUPPLEMENTARY INFORMATION:

I. Background Information

A. Current FDA Policies Regarding Disclosure of Information

    FDA regulations in part 312 (21 CFR part 312) provide procedures 
that govern the use of investigational new drugs, including new 
biological drugs, in humans. Under part 312, the sponsor of a clinical 
study in humans must submit to FDA an IND which provides specific 
information regarding the investigational new drug and the clinical 
study. The IND must be authorized by FDA and approved by the local 
institutional review board (IRB) before the clinical study may begin. 
The provisions of this rulemaking do not alter the procedures specified 
in part 312 for submission of an IND. A manufacturer requesting 
approval to market a biological product in interstate commerce must 
submit a biologics license application (BLA) to FDA before the product 
may be introduced into interstate commerce (42 U.S.C. 262). Among other 
things, the BLA contains information and data resulting from the 
clinical studies performed under an IND (Sec. 601.2 (21 CFR 601.2(a))). 
All information and data concerning the product, including those 
submitted in applicable IND's and in the BLA, are held by FDA in a 
biological product file (see definition of ``biological product file'' 
in Sec. 601.51(a) (21 CFR 601.51(a)) throughout the lifetime of the 
product.
    The general requirements related to disclosure of information for 
all types of commodities regulated by FDA and for all types of 
documents are provided in part 20 (21 CFR part 20). Under these 
regulations, certain categories of information are exempt from 
mandatory disclosure. The categories of information relevant to human 
gene therapy and xenotransplantation clinical trials that have 
historically been exempt from public disclosure include trade secrets 
and commercial or financial information which is privileged or 
confidential (Sec. 20.61); personnel, medical, and similar files, the 
disclosure of which constitutes a clearly unwarranted invasion of 
personal privacy (Sec. 20.63); and at the discretion of FDA, 
interagency or intra-agency memoranda or letters, except for factual 
information which is reasonably segregable (Sec. 20.62).
    Specific requirements for the availability for public disclosure of 
data and information in an IND, including those IND's relating to 
biological drug products, are included in Sec. 312.130. FDA's policy 
for the confidentiality of data and information contained in an IND for 
a biological product and in a biological product file is provided in 
Secs. 601.50 and 601.51 (21 CFR 601.50 and 601.51). Under Secs. 601.50 
and 601.51, and consistent with the other referenced disclosure 
regulations, FDA has not routinely publicly disclosed any data or 
information contained in an IND or a pending biological product file. 
FDA has not even acknowledged the existence of the IND or a pending 
biologics license application, unless its existence has previously been 
publicly acknowledged. Because the agency has no mechanism for reliably 
tracking what information concerning an unapproved, investigational 
product has been publicly acknowledged, the agency generally provides 
no information to the public concerning an investigational product, 
including information concerning any IND or pending BLA submissions, 
and refers the public to the sponsor of the IND or the pending 
biological license for further information. In some cases, FDA may 
publicly disclose selected portions of safety and effectiveness data, 
such as summary information for consideration at an open session of a 
Federal advisory

[[Page 4689]]

committee meeting, or other public workshops or meetings 
(Sec. 601.51(d)(1)). Once a biological license has been approved, 
certain information, as specified in Sec. 601.51(e), concerning the 
approved product and the clinical investigation of the product may be 
publicly disclosed.

B. Issues Related to Human Gene Therapy and Xenotransplantation

    As a result of rapid advances in molecular biology, genomics, 
immunology, and transplant biology, new classes of biological 
therapeutics are being developed with the goal of providing future 
treatment options for genetic disease, cancer, and organ failure. Novel 
therapeutic approaches currently under consideration include the areas 
of human gene therapy and xenotransplantation. Human gene therapy and 
xenotransplantation are being proposed to treat genetic diseases such 
as cystic fibrosis, cardiovascular insufficiency, metabolic diseases 
such as diabetes, neurologic diseases such as Parkinson's and 
Huntington's disease, cancer, acquired immune deficiency syndrome 
(AIDS), and organ failure.
1. Definitions
    Human gene therapy is defined as the administration of genetic 
material to modify or manipulate the expression of a gene product or to 
alter the biological properties of living cells for therapeutic use. 
Cells may be modified ex vivo for subsequent administration to the 
subject or altered in vivo by gene therapy products given directly to 
the subject. Human gene therapy includes, but is not limited to, 
autologous or allogeneic bone marrow stem cells modified with a viral 
vector, intramuscular or intravascular injection of a therapeutic 
plasmid deoxyribonucleic acid (DNA) or a therapeutic viral vector, 
ribozyme technology, and use of sequence specific oligonucleotides to 
correct a genetic mutation. For the purposes of this regulation, gene 
therapy is not intended to include the administration of viral or 
cellular products (e.g., blood or unmodified bone marrow), or their 
derivatives, that do not contain genetic material that has been 
specifically engineered into the product for therapeutic purposes. 
While prophylactic vaccines, including plasmid DNA vaccines and 
genetically modified viral vector vaccines, and some replication 
competent viruses are excluded under this regulation from the gene 
therapy definition, they are similar in nature to gene therapy 
products. Issues relevant to gene therapy products, such as vector 
integration and biodistribution, also apply to prophylactic vaccines. 
Therefore, the agency requests comment on whether such products should 
be included under this rulemaking to allow information related to these 
products to be available for public disclosure.
    The use of antisense oligonucleotides to block gene transcription 
is not intended to be included under gene therapy; however, as noted 
above, the use of sequence specific oligonucleotides to correct a 
genetic mutation would be included. The proposed mechanism of action of 
sequence specific oligonucleotides is to irreversibly change, insert, 
or delete a single base in the genome of a cell. This raises questions 
of whether base changes may result in mutations that may cause cancer, 
or express an immunogenic protein or have other adverse health affects. 
In addition, their use in vivo raises issues of activity in tissues 
other than the target and the risk of gonadal biodistribution leading 
to germ line changes.
    Xenotransplantation refers to any procedure that involves the 
transplantation, implantation, or infusion into a human recipient of 
either: (1) Live cells, tissues, or organs from a nonhuman animal 
source; or (2) human body fluids, cells, tissues, or organs that have 
had ex vivo contact with live nonhuman animal cells, tissues, or 
organs. The live cells, tissues, or organs used in xenotransplantation 
are referred to as xenotransplantation products. Xenotransplantation 
products include those from transgenic or nontransgenic animals, as 
well as combination products that contain xenotransplantation products 
in combination with drugs or devices. These include, but are not 
limited to, porcine fetal neuronal cells, encapsulated porcine islet 
cells, encapsulated bovine adrenal chromaffin cells, baboon bone 
marrow, and external liver assist devices employing porcine liver, or 
porcine hepatocytes. Nonliving biological products or materials from 
animals, such as porcine heart valves and porcine insulin, are not 
classified as xenotransplantation products for the purposes of this 
rulemaking.
2. Public Health Issues
    While human gene therapy offers great promise for improving the 
lives of patients with serious, life-threatening diseases and 
disorders, there are several risks inherent in its use as a medical 
intervention. These risks include the inadvertent infection of 
patients, and potentially their contacts, with replication competent 
virus present in gene therapy vector preparations. For example, 
infection with type C murine retroviruses, which could contaminate 
retroviral vector preparations, is known to cause a range of diseases 
in animals including spongiform encephalopathy, anemia, and neoplastic 
disease. In addition, these risks include the risk of infection with 
novel infectious agents generated by recombination in vivo, the 
consequences of which are unknown; the risk of insertional mutagenesis 
through disruption of the normal genetic sequence, resulting in altered 
gene expression; and the risk of inadvertent modification of the 
patient's germline and its effect on future offspring.
    Although xenotransplantation provides a potential approach to 
address the shortage of human organs and for treatment of disease, the 
use of xenotransplantation products raises concerns about possible 
infection of the recipient and, subsequently, the public at large with 
both known and as-yet- unrecognized infectious agents. Experience with 
human allograft transplantation has demonstrated the potential for 
transmissibility of infections from donor to recipient through 
transplants (Refs. 1 to 3). The direct contact resulting from 
implantation of a xenotransplantation product into a recipient, with 
the associated disruption of anatomical barriers and the 
immunosuppression of the recipient, may facilitate interspecies 
transmission of xenogeneic infectious agents. The potential for 
subsequent transmission of a xenogeneic infectious agent from the 
recipient to the recipient's close contacts, and propagation through 
the general human population, is an additional risk and a recognized 
public health concern.
    Insertional mutagenesis is a risk potentially associated with the 
infection of xenotransplant recipients and their close contacts and the 
general population with xenogeneic retroviruses. In addition to 
potential horizontal transmission of infectious agents from the 
recipient of a xenotransplantation product to the recipient's contacts, 
there is concern regarding vertical transmission of infectious agents 
from the recipient to progeny during gestation (e.g., transmission from 
mother to fetus of infectious agents across the placenta or during 
parturition). Vertical transmission of xenogeneic infectious agents 
could result in the development of infectious disease in progeny. In 
addition, vertical transmission of xenogeneic viruses can result in 
insertional mutagenesis with disruption of normal human development or 
integration into the germline resulting in transmission to future 
generations.

[[Page 4690]]

    Thus, human gene therapy and xenotransplantation investigative 
approaches individually pose: (1) Risks that extend beyond the 
individual (e.g., public health risks, including the potential for the 
transmission of infectious agents from the recipient to the public at 
large); and (2) risks of inadvertent modification of the germline 
(alterations of the genetic material of the progeny). Moreover, these 
approaches may also be used in combination (e.g., xenotransplantation 
products genetically modified before implantation), resulting in 
complex questions and issues for consideration and discussion prior to 
and during human clinical trials.
3. Public Education and Informed Consent Issues
    Human gene therapy and xenotransplantation investigations call for 
additional mechanisms to provide the public access to clinical trial 
information relevant to the assessment of risks and benefits, and to 
informed consent. Special care is needed to ensure that individual 
subjects understand the experimental nature of the procedures and their 
known and unknown risks and burdens. Human gene therapy and 
xenotransplantation require the evaluation of risks to third parties 
such as health care workers, close contacts of the recipient, and the 
community. The informed consent process should address the need for 
long-term surveillance and post-mortem analysis and potential 
infectious disease risks to recipients and their contacts.
    These investigative approaches raise new challenges for the local 
review bodies responsible for ensuring the safe and ethical conduct of 
this research. Local IRB's are responsible for reviewing biomedical and 
behavioral research involving human subjects, to protect the rights of 
human subjects (45 CFR part 46, Protection of Human Subjects, and 21 
CFR part 56, Institutional Review Boards). Institutional Biosafety 
Committees (IBC's) are responsible for reviewing and overseeing basic 
and clinical research conducted at their institutions. The IBC assesses 
the safety of the research and identifies any potential risk to public 
health or the environment (section IV-B-2 National Institutes of Health 
(NIH) Guideline for Research Involving Recombinant DNA Molecules). This 
proposed rule would provide a mechanism for public access to human gene 
therapy and xenotransplantation clinical trial information and for 
public education, informed discussion and participation that can form a 
foundation for safe and ethical research in these innovative areas.
    The proposed rule would enhance the development of related Federal 
initiatives that provide for public access to clinical trial 
information through national data bases: There are also a number of 
Internet sites sponsored by associations, clinical centers or academic 
institutions, and nonprofit organizations that provide public access to 
similar types of clinical trial information. Examples include: Center 
Watch Clinical Trials Listing Service at http://www.centerwatch.com, a 
resource both for patients interested in participating in clinical 
trials and for research professionals; http://www.HealthAtoZ.com, a 
search engine for health and medical Internet resources; the Musella 
Foundation for brain tumor research and information, at 
http://www.virtualtrials.com; the National Alliance of Breast Cancer 
Organizations, at http://www.nabco.org, which, in an effort to increase 
awareness of clinical trials, lists brief descriptive summaries of 
clinical trials in the National Cancer Institute Physician Data Query 
(NCI PDQ) data base; the University of Michigan, at http://www.cancer.med.umich.edu, which lists clinical trials at the University 
of Michigan Cancer Center (UMCC) and supplies links to external 
clinical trials and resources; the former Surgeon General C. Everett 
Koop's Internet site, at 
http://www.drkoop.com, which allows the public to browse through a 
listing of therapeutic areas where volunteers are being sought for 
clinical trials; Biotechnology Industry Organization, a trade 
association, at http://www.bio.org, which lists press releases and 
industry news, and provides links to patient groups and professional 
medical societies; and http://www.investor.biospace.com, which has not 
only a biotechnology search engine that links to hundreds of companies, 
but also extensive information on the latest technologies and clinical 
trials, as a basis for investment. The proposed rule should facilitate 
the development of similar data bases, either publicly or privately 
sponsored, with information concerning the study of gene therapy and 
xenotransplantation. As provided under section 113 of the Food and Drug 
Modernization Act of 1997 (Public Law 105-115), NIH, through its 
National Library of Medicine, has created a national clinical trials 
data base at http://clinicaltrials.gov to provide patients, family 
members, and other members of the public with current information about 
clinical research studies.
4. Basis for Disclosure
    Historically, public disclosure of information with regard to human 
gene therapy and xenotransplantation has assisted FDA in performing its 
duties and has benefitted the public. The categories of information 
that may be made publicly available by FDA as a result of this 
disclosure rule include information currently made public by other 
Federal agencies in connection with advisory committee meetings or 
other public workshops or meetings, and through general commercial 
disclosure.
    The NIH Office of Biotechnology Activities (OBA; formerly the 
Office of Recombinant DNA Activities) administers the Recombinant DNA 
Advisory Committee (RAC). This committee was established in October 
1975, in response to concerns about the potential public health risks 
and environmental hazards posed by recombinant DNA research, as well as 
the significant ethical, legal, and societal issues associated with 
this emerging technology. The RAC has met quarterly in open public 
session to discuss these issues and, since the first human gene 
transfer clinical trial was proposed in 1988, the committee has 
publicly reviewed selected human gene transfer clinical trial 
protocols. The minutes of RAC discussions of human gene transfer 
clinical trials and related issues are accessible to the public via the 
OBA website (http://www.nih.gov/od/oba/index.htm). RAC review and 
public discussions provide an important mechanism for receiving public 
input into Federal policy development and for making the public aware 
of potential toxicities and adverse events associated with gene 
transfer products. As one example, when a participant in a cystic 
fibrosis gene transfer clinical trial required intensive care treatment 
for an acute adverse event suffered shortly after administration of an 
adenoviral gene transfer product, the investigator was invited to 
discuss the occurrence with other experts in the field at the next 
public RAC meeting. This public discussion and analysis facilitated 
both dissemination of important information about this toxicity and 
enhanced understanding of its pathogenesis, thereby contributing to the 
safety of patients in other gene therapy trials.
    NIH also collects information on gene transfer studies and makes it 
available to the public. Appendix M of the ``NIH Guidelines for 
Research Involving Recombinant DNA Molecules'' (Ref. 4) requires that 
investigators provide specific information for the purposes of protocol 
registration, RAC review, and

[[Page 4691]]

potential public discussion, and that this information should not 
contain confidential commercial information or trade secrets, enabling 
all aspects of RAC review to be open to the public. The required 
information includes scientific and nontechnical abstracts, the 
informed consent document, statements on privacy and confidentiality, 
reports of serious adverse events, protocol amendments, and annual 
followup reports. Public disclosure of this information has facilitated 
progress and has contributed to improved patient safety in the field of 
human gene transfer by providing public access to clinical trial 
information, rapid dissemination of adverse event information, and 
summary information regarding outcomes of gene therapy clinical trials 
and adverse events.
    All investigators receiving any NIH funds for basic and/or clinical 
research involving recombinant DNA molecules, and all investigators 
affiliated with institutions receiving any NIH funds for basic and/or 
clinical research involving recombinant DNA molecules, must comply with 
the NIH Guidelines. The NIH Guidelines also apply to collaborations 
between NIH-funded or affiliated researchers and privately funded 
investigators. In addition, commercial sponsors not affiliated with a 
NIH-funded institution have voluntarily submitted materials to OBA for 
RAC review. Therefore, the general practice in the field of human gene 
transfer has been to submit to NIH, OBA the information required under 
NIH Guidelines with the understanding that the information will be 
available for RAC review and potentially public discussion. This 
suggests that the information specified in Appendix M is not generally 
considered to be proprietary and that its disclosure does not impede 
commercial development.
    The categories of information that would be disclosed as a result 
of this rulemaking include information that generally has been made 
public for xenotransplantation protocols. Sponsors of 
xenotransplantation IND's have publicly disclosed information regarding 
the scope of xenotransplantation clinical trials and the development of 
public health safeguards through: (1) Open public sessions of the 
Xenotransplantation Subcommittee of the Biologics Response Modifiers 
Advisory Committee (BRMAC) for the Center for Biologics Evaluation and 
Research (CBER), FDA (December 17, 1997, June 3 and 4, 1999, and 
January 13, 2000), and (2) Public Health Service (PHS) sponsored public 
workshops, including the workshop entitled ``Developing U.S. Public 
Health Policy in Xenotransplantation,'' January 21 and 22, 1998, at 
which xenotransplantation clinical trials under FDA IND's were 
summarized by the sponsor or by a sponsor's designee. Transcripts of 
these meetings can be found on the CBER Internet site at http://www.fda.gov/cber. At these public meetings, FDA scientists and others 
presented data demonstrating that porcine endogenous retroviruses could 
be activated and could infect human cells in vitro, and the 
implications of these data for porcine xenotransplantation product 
development and regulation were discussed. Based on these discussions, 
the BRMAC concurred with FDA's decision to place all porcine 
xenotransplantation clinical trials on clinical hold. During these 
meetings, FDA publicly discussed testing requirements and results 
needed by manufacturers in order to address and remove the clinical 
hold, and allowed sponsors of porcine xenotransplantation IND's the 
opportunity to present testing strategies, assuring the industry of 
consistency in regulation. The public as well was assured that Federal 
oversight was being conducted in a responsible manner.
    Information related to the categories of information FDA proposes 
to disclose is available through publicly accessible filings to the 
Securities and Exchange Commission (SEC). The Securities Act of 1933 
requires that investors receive financial and other significant 
information concerning securities being offered for public sale. In an 
annual filing, a company must provide a comprehensive overview of its 
business. This includes a description of ongoing research programs 
including discussion of clinical study safety and efficacy results, 
disclosure of investigational sites and the investigators involved, 
plans for product development and commercialization, and financial 
information. This information may be found on the SEC Internet site at 
http://www.sec.gov/edgarhp.htm.
    In addition, voluntary disclosure of information regarding clinical 
trials of unapproved products and therapies by individual sponsors over 
the Internet has become widespread. Company Internet sites often 
provide this information in the form of descriptive summaries of 
clinical trials, press releases, recruitment opportunities for 
patients, investment opportunities, and general awareness material.
    Thus, information of the kind FDA proposes to disclose concerning 
clinical trials on human gene therapy and xenotransplantation is 
already widely disclosed. This disclosure has not impeded commercial 
development of these products. In addition, the agency considers public 
disclosure of data and for information from human gene therapy or 
xenotransplantation clinical trials essential for public education, and 
for informed discussion and consideration of the public health and 
safety risks associated with the use of these investigational 
therapies.

II. Overview of Proposed Rule

A. Scope

    The scope of this proposed rule is limited to disclosure of 
information related to human gene therapy and xenotransplantation. 
Confidential commercial information, such as information regarding 
commercial licensing agreements or the identification of suppliers, 
trade secret manufacturing information, names and other personal 
identifiers of patients and, except as specifically provided in the 
regulations, names and personal identifiers of third parties, such as 
physicians, hospitals, etc., and, at FDA's discretion, interagency or 
intra-agency memoranda and letters would not be disclosed. FDA is 
proposing only to disclose certain information necessary to ensure a 
continued mechanism for public education and input, which FDA believes 
is essential to the evaluation of the public health impact of these new 
technologies. FDA believes that these categories of information have 
not been considered to be proprietary, since they have been made 
publicly available through various mechanisms and their disclosure has 
not impeded commercial development. The public expects the current 
level of information disclosure and public review to continue in the 
areas of human gene therapy and xenotransplantation where there is 
potential risk to the public health.
    The categories of information related to an IND that would be 
disclosed under this regulation include: (1) Product and patient safety 
data and related information, including results from preclinical and 
clinical studies and tests that demonstrate the safety and/or 
feasibility of the proposed procedures; (2) the name and address of the 
sponsor; (3) the clinical indications to be studied; (4) the protocol 
for each planned study, to include a scientific abstract and a 
nontechnical abstract, a statement of the objectives, purpose, and 
rationale of the study, the name and address of each investigator, the 
name and address of the official contacts of each local review body as 
appropriate (IRB, IBC) and dated copies of approval by each group, the 
criteria for patient selection and

[[Page 4692]]

exclusion, an estimate of the number of patients to be studied, a 
description of the treatment that will be administered to patients, and 
the clinical procedures, laboratory tests, or other measures to be 
taken to monitor the safety and effects of the drug in human subjects 
and to minimize risk; (5) written informed consent forms; (6) 
identification of the biological product(s) and a general description 
of the method of production, including a description of product 
features that may affect patient safety; (7) IND safety reports; (8) 
information submitted to FDA in the annual report; (9) the regulatory 
status of the investigation, the date of such action, and the reason 
for such action; and (10) other relevant data and information that the 
Director, CBER, determines are necessary for the appropriate 
consideration of the public health and scientific issues, including 
relevant ethical issues, raised by human gene therapy or 
xenotransplantation.
    To facilitate public disclosure of this information, FDA proposes 
to require sponsors of human gene therapy and xenotransplantation 
clinical trials to submit to FDA the information defined above upon 
submission of: (1) The initial IND, (2) any amendment documenting 
changes or additions to the IND, at the time the amendment goes into 
effect, (3) IND safety reports, and (4) annual reports. FDA is not 
proposing to require the submission of any new information not 
previously submitted as part of the IND process. For example, FDA is 
not proposing that all variations and updates of informed consent forms 
be submitted to FDA for public disclosure; however, under the proposed 
rule, FDA would disclose any sample informed consent forms generally 
submitted with an initial IND submission.
    The agency requests comment on whether this rulemaking should apply 
to information as defined above that is submitted in a BLA. Public 
disclosure of information in a BLA would provide a continuation of the 
availability of information for public disclosure up until the time of 
license approval. A disadvantage would be the amount of documentation 
that would be required to be submitted in order to support this 
initiative.
    The proposed provisions of this rulemaking do not alter the 
procedures specified in part 312 for submission of an IND. However, 
with regard to clinical holds of an IND (Sec. 312.42), FDA would be 
able to place a human gene therapy or xenotransplantation investigation 
on clinical hold if the sponsor does not submit to the agency the 
redacted version of data and information for public disclosure, or if 
the redacted version submitted is incomplete or not properly redacted.

B. Legal Authority

    The proposed regulation would make available for public disclosure 
specified safety and effectiveness information submitted in support of 
an IND \1\ involving either a human gene therapy or xenotransplantation 
protocol. This information, discussed thoroughly in section II.C of 
this preamble, includes protocols, criteria for patient selection and 
exclusion, summary results of preclinical and clinical studies of the 
investigational article, a summary of the treatment that will be 
administered and the measures that will be taken to minimize risk to 
human subjects, safety reports, informed consent documentation, and 
information concerning the regulatory status of the product, such as 
whether it is on clinical hold and the reason for the hold. While such 
information relating to human gene therapy protocols has routinely been 
made available to the public through the NIH RAC process for the last 
20 years, FDA regulations have consistently provided that similar 
information submitted to FDA as part of an IND is not publicly 
available. (See Secs. 601.50 and 601.51.) This proposed rule is an 
attempt to harmonize these approaches for public review of important, 
new, but potentially hazardous and controversial, therapies. In this 
way, FDA will be able to more fully participate in existing and future 
venues for obtaining educated public input and discussion that could 
inform the agency's deliberations. The agency believes that there is 
great benefit in having human gene therapy and xenotransplantation 
products scrutinized, as they are being developed, by individuals with 
a wide variety of perspectives, including scientists from different 
disciplines, biomedical ethicists, patient advocacy organizations, and 
the general public, because of the unique blend of proposed benefit as 
well as potential risk to society that these products possess. 
Investigations of these types of products raise serious ethical and 
scientific issues, and, therefore, the decisionmaking process should be 
as transparent and fully informed as possible.
---------------------------------------------------------------------------

    \1\While human gene therapy and xenotransplantation protocols 
are generally regulated by CBER as biological products, it is 
possible that some of these products may be combination products 
consisting of biological components, drug components, and device 
components. The same rules of disclosure will apply to the drug or 
device components of combination products under the same theories 
discussed later in this section.
---------------------------------------------------------------------------

    The proposed rule would formalize the existing practice of making 
certain specified types of safety and effectiveness information in 
IND's for human gene therapy and xenotransplantation publicly 
available. Such disclosure is necessary in order to protect the public 
health by informing the research community and the public of the nature 
and the hazards of the proposed research and by permitting comment on 
the merits of the proposed research.
    The Freedom of Information Act (FOIA), 5 U.S.C. 552, generally 
provides that Federal agencies must disclose information in their files 
to the public on request. FOIA is designed to make federal agency 
records or information available to the public. The Supreme Court has 
stated that, ``The basic purpose of [the] FOIA is to ensure an informed 
citizenry, vital to the functioning of a democratic society, needed to 
check against corruption and to hold the governors accountable to the 
governed.'' (See NLRB v. Robbins Tire & Rubber Co., 437 U.S. 214, 242 
(1978).)
    The statute provides nine exemptions and three law enforcement 
exclusions that agencies may use to protect specific categories of 
information from disclosure (5 U.S.C. 552(b)). These exemptions are the 
only basis for withholding information requested by the public under 
the FOIA \2\ and are discretionary, not mandatory. (See Chrysler Corp. 
v. Brown, 441 U.S. 281 (1979).) One of these exemptions is particularly 
relevant to this proposed rule and the disclosure of information in 
applications to investigate and market human gene therapy and 
xenotransplantation products.
---------------------------------------------------------------------------

    \2\ It should be noted here that section 301(j) of the act 
prohibits the public disclosure of information, obtained under 
certain sections of the act, ``concerning any method or process 
which as a trade secret is entitiled to protection.'' (See 21 U.S.C. 
331(j).) In addition, the so-called Federal Trade Secrets Act also 
contains certain restrictions on the public disclosure of trade 
secret and confidential commercial information. The Trade Secrets 
Act does provide for the disclosure of confidential commercial 
information where such disclosure is ``authorized by law.'' (See 18 
U.S.C. 1905.)
---------------------------------------------------------------------------

    Exemption 4 of the FOIA protects trade secrets and confidential 
commercial information from public disclosure. (See 5 U.S.C. 
552(b)(4).) While trade secret information, narrowly defined as secret, 
commercially valuable information related to manufacturing methods or 
processes, is present in all IND's and biological product files, 
including those subject to this proposed rule, this

[[Page 4693]]

proposal will not affect the confidentiality of such information, and 
therefore it will not be discussed. Confidential commercial information 
is defined under exemption 4 as ``commercial or financial information 
obtained from a person and privileged or confidential.'' Each element 
of the definition must be satisfied for information to be confidential 
commercial information entitled to protection under exemption 4.
    Historically, much of the data and information submitted in IND's 
and unapproved biological product files has been considered 
confidential commercial information. (See Public Citizen Health 
Research Group v. FDA, 704 F.2d 1280 (D.C. Cir. 1983); R & D 
Laboratories, Inc. v. FDA No. 00-CV-0165 (D.D.C. Sept. 7, 2000).) FDA's 
general information disclosure regulations define confidential 
commercial information, and provide that information submitted to FDA 
that falls within this definition is not disclosable. (See 21 CFR 
20.61.) Further, the regulations that apply to the submission of IND's 
and biological product files define the contents of these applications 
as confidential commercial information generally exempt from disclosure 
and, indeed, even prohibit the agency from acknowledging the existence 
of an application (prior to approval) if it has not already been 
publicly disclosed. (See 21 CFR 312.130, 601.50, and 601.51.) The 
regulations provide different rules for disclosure after an approval 
letter has been sent, and when the application has been terminated, 
abandoned, or otherwise no longer has commercial value.
    The agency is exercising its legal authority to promulgate new 
regulations that will make explicit and will formalize the 
circumstances and means by which certain safety and effectiveness 
information in these special types of applications will be made 
available for public disclosure. Such a change is especially warranted 
when, as here, the change is being made in large part to reflect the 
actual environment in which human gene therapy and xenotransplantation 
applications exist.
    As has been discussed elsewhere in this preamble (in section I.B, 
Issues Related to Human Gene Therapy and Xenotransplantation), sponsors 
of IND's pertaining to human gene therapy have publicly disclosed the 
types of information covered by this proposed rule for many years as 
part of the process overseen by the RAC. Likewise, there has been 
widespread practice in the field of xenotransplantation to make 
publicly available a great deal of information concerning details of 
trials of xenotransplantation products during public advisory committee 
meetings and workshops sponsored by FDA and by the U.S. PHS. 
Information that is publicly disclosed by its owner cannot be 
confidential within the meaning of the FOIA and, as a result, can be 
made available for public disclosure by FDA. (See CNA Fin. v. Donovan, 
830 F.2d 1132, 1154 (D.C. Cir. 1987).) The fact that these types of 
information cannot be considered confidential is the principal basis 
for issuing this proposed rule.
    This proposed rule contains the public disclosure procedures the 
agency will apply to the safety and effectiveness information in human 
gene therapy and xenotransplantation applications that has historically 
been treated as confidential commercial information by the agency. 
These procedures will follow the consistent practice in the fields of 
human gene therapy and xenotransplantation of making such information 
available to the public. It is important to note that while certain 
safety and effectiveness data and information will be publicly 
available under this proposed rule, FDA does not intend to disclose the 
full reports of safety and effectiveness on the basis of which the 
product may be approved. FDA believes that, prior to approval of a 
biological product file, the full reports constitute confidential 
commercial information, as they traditionally have under the agency's 
regulations, and should not be released. (See 21 CFR 601.51(d).) 
However, under Sec. 601.51(e), all safety and effectiveness data and 
information do become publicly available after a license is issued, and 
this practice will not be changed by this proposal.
    In addition to the full reports, the agency also wishes to make 
clear that it will continue its current policy of not releasing 
confidential commercial information that is contained in a human gene 
therapy or xenotransplantation IND or unapproved biological product 
file. Examples of confidential commercial information that may exist in 
these applications would include information concerning licensing 
agreements and information identifying suppliers. This information 
ordinarily will remain confidential under exemption 4 unless it has 
already been publicly disclosed by the sponsor. Such business-related 
information is also not the type of information that FDA believes 
should be disclosed to further the public discussion and evaluation of 
human gene therapy and xenotransplantation trials. In addition, this 
proposed rule will not affect the rules governing the disclosure of 
personal medical and other similar information, the disclosure of which 
would cause an unwarranted invasion of personal privacy. (See 21 CFR 
20.63.)
    Based on the authorities discussed, the agency proposes to require 
sponsors of IND's related to human gene therapy and xenotransplantation 
to disclose certain specified safety and effectiveness data and 
information. This proposal will formalize and codify the existing 
practice in these fields under which these data and information have 
been publicly disclosed by their sponsors. Disclosure is especially 
necessary regarding these new, important, and also controversial 
technologies so that the research community and the public can be 
assured of the safety of conducting clinical trials of these products.
    This proposal would require the sponsors of human gene therapy or 
xenotransplantation IND's to submit to FDA publicly available versions 
of information FDA requires in such IND's. The purpose of this 
requirement is to facilitate FDA's efforts to make important 
information concerning human gene therapy and xenotransplantation IND's 
available to the public in a timely and efficient manner. Sponsors 
would have to redact the information from IND submissions specified in 
proposed Sec. 601.53. Sponsors would redact trade secrets, confidential 
commercial information, such as licensing agreements and suppliers, and 
names and other personal identifiers of patients and, except as 
specifically provided in the regulations, names and personal 
identifiers of third parties, such as physicians, hospitals, etc. (See 
Secs. 20.61 and 20.63.) It would not be necessary for sponsors to 
redact the vast majority of the information in human gene therapy and 
xenotransplantation IND's since, as described in this proposal, such 
information would be publicly disclosable.
    The proposed rule would also specify that FDA may place a human 
gene therapy or xenotransplantation investigation on clinical hold if 
the sponsor has not submitted to the agency a redacted and thus 
disclosable version of the required IND information that complies with 
the requirements of proposed Sec. 601.53. A sponsor must properly purge 
its redacted version of trade secrets, confidential commercial 
information, and names and other personal identifiers and, except as 
specifically provided in the regulations, names and personal 
identifiers of third parties, such as physicians, hospitals,

[[Page 4694]]

etc. Section 505(i)(3) of the act authorizes FDA to prohibit a sponsor 
of an investigation from conducting that investigation if FDA 
determines that the drug involved represents an unreasonable risk to 
the safety of persons who are the subjects of the clinical 
investigation, or if there are other reasons that FDA has established 
by regulation for which the agency may issue a clinical hold. FDA 
recognizes that errors in redacting may occur and will provide sponsors 
with an opportunity to correct such errors. However, FDA will have the 
enforcement authority to place a human gene therapy and 
xenotransplantation investigation on clinical hold if resolution is not 
reached on any discrepancies found by FDA in the redacted versions, or 
if a redacted version is not submitted at all by the sponsor. As 
described in this proposal, it is important for proposed and ongoing 
human gene therapy and xenotransplantation investigations to be the 
subject of public education, discussion, and consideration in order for 
all relevant issues, including safety, to be explored.
    As stated above, FDA has tentatively concluded that the information 
that would be disclosed as a result of this rulemaking is, in fact, 
already being made public through a variety of mechanisms, and 
therefore cannot be considered confidential. As such, it does not 
constitute confidential commercial (or trade secret) information within 
the meaning of FOIA Exemption 4.
    However, FDA's issuance of this proposed rule is authorized even if 
the information to be disclosed could be considered confidential 
commercial information covered by Exemption 4 and within the scope of 
protection of the Trade Secrets Act (18 U.S.C. 1905). That statute 
prohibits the disclosure of confidential commercial or trade secret 
information, except as ``authorized by law.'' Because agency 
regulations that specifically provide for the disclosure of such 
information can supply the requisite legal authorization for release of 
the information for purposes of the Trade Secrets Act, that statute 
would not present a bar to any of the disclosures contemplated by this 
proposed rule. (See, e.g., CNA Financial Corp., 830 F.2d 1132, 1138-
1139 (D.C. Cir. 1987)).
    The broad rulemaking authority conferred on FDA by Congress under 
the act (21 U.S.C. 201 et seq.) permits the agency to amend its 
regulations as contemplated by this proposed rule.
    Section 505(i) of the act (21 U.S.C. 355(i)) gives FDA the 
authority to issue regulations imposing conditions on the investigation 
of new drugs. In addition to prescribing certain mandatory conditions, 
that section further provides that the agency may impose ``other 
conditions'' as necessary ``relating to the protection of the public 
health.'' (21 U.S.C. 355(i)). This language was added to the act as 
part of the Drug Amendments of 1962 (Public Law 87-781) to make it 
``clear that the conditions prescribed in the [bill] are not the sole 
conditions that may be imposed for the protection of public health.'' 
H.R. Conf Rep. No. 2526, at 20 (1962), reprinted in 1962 U.S.C.C.A.N. 
2927, 2929. Legislative history relating to these amendments also 
indicates that one purpose of the bill was to make ``information on 
drugs * * * more readily available to physicians and the general 
public.'' (S. Rep. No. 1744, at 1 (1962), 1962 U.S.C.C.A.N. 2884). 
FDA's broad discretion in adopting regulations under this language has 
been upheld by the courts. (United States v. Garfinkel, 29 F.3d 451 
(8th Cir. 1994)).
    The proposed amendments to FDA's regulations are within FDA's 
statutory discretion in imposing conditions on products under 
development to promote the public health. The public health often is 
served not only by collection of research data and information, but 
also by disclosure of such information. (See e.g., Dole v. United 
Steelworkers of America, 494 U.S. 26, 28 (1990)).
    The proposed rule would serve several significant public health 
goals. It would enhance the ability of patients with serious and life-
threatening diseases and others seeking information about emerging 
therapies to obtain critically important information from FDA about the 
existence of clinical trials in which they might participate, about 
possible safety problems associated with the products they are taking, 
and about the regulatory status of applications pending before the 
agency.
    As an aftermath of recent problems in clinical trials involving 
gene therapy products, FDA and NIH have launched two new initiatives to 
further strengthen the safeguards for individuals enrolled in clinical 
studies for gene therapy. One initiative, the Gene Therapy Clinical 
Trial Plan, would ensure: That sponsors meet their obligation to 
adequately monitor the clinical trials for which they are responsible; 
that there is appropriately independent oversight of such clinical 
trials; and that there is an increased level of government oversight, 
through increased inspection frequency and review of sponsors' 
monitoring plans and other clinical trial practices. Under the other 
initiative, FDA and NIH will, several times per year, convene Gene 
Transfer Safety Symposia to provide a critical forum with experts in 
gene transfer for the sharing and analysis of medical and scientific 
data from gene transfer research. FDA and NIH support will also be 
provided for professional organizations and academic centers to hold 
safety conferences focused on gene therapy. These safety symposia and 
educational outreach efforts are intended to guide the conduct of 
current clinical trials and enhance the design of future gene transfer 
trials to maximize public safety.
    The ready availability of information concerning clinical trials 
involving gene therapy is essential to the success of these efforts. 
For example, such information would be discussed at the government's 
safety symposia, may be made available for other scientific discussions 
and to the general public, and would be used in evaluating current gene 
therapy practices, including sponsor monitoring and informed consent 
standards. Likewise, FDA intends to continue to sponsor and support 
government, professional, and academic conferences related to 
xenotransplantation. Thus, FDA believes that the disclosure of 
information contained in INDs related to gene therapy and 
xenotransplantation trials is essential to patient safety and 
appropriate informed consent.
    In addition to section 505(i), section 701(a) of the act (21 U.S.C. 
371(a)) gives FDA general rulemaking authority to issue regulations for 
the efficient enforcement of the act. A regulation issued under section 
701 of the act will be sustained as long as it is reasonably related to 
the purposes of the act. (United States v. Nova Scotia Food Prod. 
Corp., 568 F.2d 240, 246 (2d Cir. 1977)). Section 903(b) of the act (21 
U.S.C. 393(b)) explicitly states that the mission of FDA includes the 
promotion and protection of the public health. It has long been 
recognized by the courts, including the Supreme Court, that the primary 
purpose of the act is the protection of public health (United States v. 
An Article of Drug, Bacto-Unidisk, 394 U.S. 784, 798 (1969)). As a 
result, FDA's rulemaking authority under section 701(a) of the act has 
been broadly construed to uphold a wide variety of the agency's 
rulemaking activities intended to protect the public health. (See e.g., 
National Ass'n of Pharmaceutical Mfrs. v. FDA, 637 F.2d 877 (2d Cir. 
1981)) (current good manufacturing practice regulations); 
Pharmaceutical Mfrs. Ass'n v. FDA, 484 F. Supp. 1179 (D. Del. 1980) 
(rule requiring disclosure of drug side effects to patients); American 
Frozen Food Inst.

[[Page 4695]]

v. Mathews, 413 F. Supp. 548 (D.D.C. 1976) (rule establishing common 
and usual names for certain nonstandard foods to provide consumers with 
relevant buying information), aff'd, 555 F.2d 1059 (D.C. Cir. 1977); 
National Nutritional Foods Ass'n v. Weinberger, 376 F. Supp. 142 
(S.D.N.Y.) (rule requiring that certain vitamin preparations be 
restricted to prescription sale and be labeled accordingly), aff'd, 512 
F.2d 688 (2d Cir. 1975)), cert. denied, 423 U.S. 827 (1975). FDA 
believes that its rulemaking authority under section 701(a) of the act 
supports the amendments proposed here because they advance public 
health goals concerning gene therapy and xenotransplantation studies.
    FDA is also proposing to issue this new regulation under the 
authority of section 361 of the Public Health Service Act (PHS Act) (42 
U.S.C. 264). Under section 361 of the PHS Act, FDA may make and enforce 
regulations necessary to prevent the introduction, transmission, or 
spread of communicable diseases between the States or from foreign 
countries into the States. (See sec. 1, Reorg. Plan No. 3 of 1966 at 42 
U.S.C. 202 for delegation of section 361 of the PHS Act authority from 
the Surgeon General to the Secretary, Health and Human Services; see 21 
CFR 5.10(a)(4) for delegation from the Secretary to FDA.) Intrastate 
transactions may also be regulated under section 361 of the PHS Act.
    This proposed regulation is part of a regulatory program that will 
further the goal of preventing the introduction, transmission, or 
spread of communicable disease. For this regulatory system to be 
effective in preventing the spread of disease, FDA must be able to 
regularly make publicly available information regarding these 
experimental procedures. By providing sponsors, clinical investigators, 
patients and their families, and the general public with access to the 
types of information proposed in this rule, FDA will be able to more 
rapidly identify and react appropriately to newly discovered or 
understood risks in order to prevent the spread of communicable 
disease.
    Studies in the areas of gene therapy and xenotransplantation are 
conducted to explore the potential for considerable benefits. However, 
use of these procedures, particularly in the case of 
xenotransplantation, poses potential risks for the transmission of 
infectious disease. Infectious disease public health concerns focus not 
only on the transmission of known zoonoses, but also on the 
transmission of infectious agents as yet unrecognized. The disruption 
of natural anatomical barriers and immunosuppression of the recipient 
increase the likelihood of interspecies transmission of xenogeneic 
infectious agents. An infectious agent may pose risks if it can infect, 
cause disease in, and transmit among humans, or if its ability to 
infect, cause disease in, or transmit among humans remains inadequately 
defined. The public availability of information this proposed rule 
envisions will permit public attention to any emerging risks associated 
with these experimental techniques, early detection and definition of 
which will permit the agency and sponsors to take steps to prevent or 
minimize the introduction of communicable disease.
    An additional concern is that these infectious agents could 
subsequently be transmitted from the patient to family members and 
other close contacts of the patients, to health care personnel, and to 
other members of the public. Because the potential risk of transmission 
of infectious disease extends beyond the patient receiving the 
treatment, it is vital that the public, as well as the patient, be 
informed and educated about potential infectious disease risks and 
methods for reducing those risks. Close contacts should understand the 
uncertainty regarding the risks of xenogeneic infections, behaviors 
known to transmit infectious agents from human to human (e.g., 
unprotected sex, breast feeding, intravenous drug use with shared 
needles, and other activities that involve potential exchange of blood 
or other body fluids) and methods to minimize the risk of transmission. 
Close contacts of recipients also need to know about the importance of 
reporting any significant unexplained illness through their health care 
provider to the research coordinator at the institutions where the 
xenotransplantation was performed. This broader concern for the spread 
of communicable disease is reflected in the proposed requirements 
providing for public disclosure. While informed consent procedures may 
try to address these educational needs, the public release and 
discussion of information that this proposed rule calls for is also 
necessary to ensure that all those potentially at risk have the 
information to manage these risks and so avoid or minimize the spread 
of communicable disease.
    For all the above reasons, to promote and protect the public 
health, FDA is proposing to issue this proposed rule providing for 
public disclosure of certain information relating to gene therapy and 
xenotransplantation.

C. Discussion of the Proposed Rule

    The proposed rule would create a new Sec. 601.52 entitled 
``Availability for public disclosure of certain data and information 
related to human gene therapy or xenotransplantation'' and Sec. 601.53 
entitled ``Submission to FDA of certain data and information related to 
human gene therapy or xenotransplantation for public disclosure.'' In 
addition, conforming amendments are proposed to Secs. 20.100, 312.42, 
312.130, 601.50, and 601.51. The provisions of this rulemaking do not 
alter the procedures specified in part 312 for submission of an IND. 
The proposed regulations are discussed below.
1. Sections 601.50 and 601.51
    Part 601 (21 CFR part 601) sets forth provisions that govern the 
licensing of biologic products by the FDA. Existing procedures and 
requirements regarding confidentiality of data and information 
contained in IND's for biological products or biologics license 
applications are described in Secs. 601.50 and 601.51. The proposed 
rule would amend Secs. 601.50 and 601.51 to include language that would 
reference the exceptions proposed in Sec. 601.52 regarding the 
availability for public disclosure of certain data and information 
related to human gene therapy or xenotransplantation. Specifically, 
Secs. 601.50(a) and 601.51(a) would be amended to add the words, 
``Except as provided in Sec. 601.52.''
    In addition, FDA is proposing to amend the Sec. 601.50 section 
heading and Sec. 601.50(a) to replace the word ``notice'' with 
``application'' to be consistent with other current regulations 
regarding investigational new drugs, i.e., part 312.
2. Proposed Sec. 601.52
    Proposed Sec. 601.52 would set forth the requirements regarding the 
availability for public disclosure of certain data and information 
related to human gene therapy or xenotransplantation. These provisions 
would define the therapies and scope of the proposed regulation, and 
describe the types of data and information related to human gene 
therapy and xenotransplantation that may be disclosed by FDA.
    a. Definitions. Proposed Sec. 601.52(a) would include definitions 
of human gene therapy and xenotransplantation that are consistent with 
existing agency policy and guidance regarding these therapies. Proposed 
Sec. 601.52(a)(1) would define ``human gene therapy'' to mean the 
administration of genetic material in order to modify or manipulate the 
expression of a gene

[[Page 4696]]

product or to alter the biological properties of living cells for 
therapeutic use. FDA interprets this definition to include both the ex 
vivo and in vivo modification of cells. Proposed Sec. 601.52(a)(2) 
would define ``xenotransplantation'' to mean any procedure that 
involves the transplantation, implantation, or infusion into a human 
recipient of either: (a) Live cells, tissues, or organs from a nonhuman 
animal source, or (b) human body fluids, cells, tissues, or organs that 
have had ex vivo contact with live nonhuman animal cells, tissues, or 
organs. This definition of xenotransplantation does not include the use 
of products that are nonliving, acellular products such as porcine 
heart valves, porcine insulin, or bovine serum albumin. The definition 
also does not include non-animal cells and tissues, such as bacteria 
and plant cells.
    Because the terms ``human gene therapy'' and 
``xenotransplantation'' are not currently used elsewhere in the 
regulations, FDA is proposing that, for the convenience of the user, 
the definitions be included in proposed Sec. 601.52. If, in the future, 
additional regulations are issued using these terms, FDA intends to 
move these definitions to the section of the regulations which 
currently includes definitions of other terms applicable to biological 
products (21 CFR 600.3).
    b. Scope. Proposed Sec. 601.52(b) would describe the scope of the 
proposed regulation. Consistent with the use of the terms ``human gene 
therapy'' and ``xenotransplantation,'' FDA intends that the proposed 
rule apply to the procedures, not specific products used in the 
therapies, although data and information regarding a product may be 
disclosed as proposed in Sec. 601.52(c). FDA intends with this broadly-
defined scope that the proposed regulation apply to any experimental 
use of human gene therapy and xenotransplantation, although the 
immediate impact of the proposed regulation would be on investigational 
products. For example, the proposed regulations would apply to any use 
of gene therapy or xenotransplantation in clinical studies in humans, 
including use of a licensed gene therapy or xenotransplantation product 
with an experimental drug or device being clinically studied for use in 
a gene therapy or xenotransplantation procedure.
    FDA believes it is not necessary to disclose for purposes of public 
education and discussion all the information which may be included in 
an IND. Except as specifically provided in the proposed rule, FDA 
intends that information regarding human gene therapy or 
xenotransplantation investigations will continue to be held 
confidential, consistent with existing regulations in Secs. 20.61, 
20.62, 20.63, 20.100, 312.130, 601.50, and 601.51. Accordingly, 
proposed Sec. 601.52(b) would specify that, except as specifically 
provided in proposed Sec. 601.52, the availability for public 
disclosure of data and information related to human gene therapy or 
xenotransplantation shall remain in accordance with Sec. 601.50 for 
IND's for a biological product.
    c. Information for public disclosure. Proposed Sec. 601.52(c) would 
specify the types of data and information related to human gene therapy 
or xenotransplantation that the FDA may make available for public 
disclosure. The types of information listed in proposed Sec. 601.52(c) 
are already required for submission under existing regulations (parts 
312 and 601) as part of an IND or BLA or as a supplement to a BLA.
    Under proposed Sec. 601.52(c)(1), FDA would make product and 
patient safety data and related information related to human gene 
therapy and xenotransplantation available for public disclosure. This 
proposed provision is similar to existing requirements in 
Sec. 601.51(e)(1), which require that all safety and effectiveness data 
and information contained in a biological product file be made 
available for public disclosure immediately after a license has been 
issued. The proposed provisions in Sec. 601.52, however, would extend 
this throughout the entire product development process for a product 
related to human gene therapy or xenotransplantation. The proposed rule 
further specifies in Sec. 601.52(c)(1) that for the purposes of this 
proposed regulation, product and patient safety data and related 
information include results of preclinical and clinical studies and 
tests that demonstrate the safety and/or feasibility of the proposed 
procedures. In addition, FDA proposes in Sec. 601.52(c)(1) to identify 
some of the types of product and patient safety data and related 
information that would be disclosed to the public that are particularly 
relevant or specific to human gene therapy and xenotransplantation. 
These types of product and patient safety data and related information 
are: (1) Analysis in animals, humans, or in vitro systems of gene 
transfer, expression, and persistence; (2) vector biodistribution; (3) 
evidence for immune response/anergy; (4) biological activity; (5) 
results of product safety testing including test results for known 
xenogeneic and human infectious agents and replication competent virus; 
(6) qualification of source herd, individual source animal, and source 
organ/tissue/cells for xenotransplantation in humans; and (7) 
information on monitoring or prevention of potential health risks to 
the recipient, close contacts, and health care workers. FDA does not 
intend this to be an exclusive list. In all cases, names and other 
personal identifiers of patients and, expect as specifically provided 
in the regulations, names and other personal identifiers of third 
parties, such as physicians or hospitals, would be removed. 
Furthermore, FDA does not intend product and patient safety data and 
related information under proposed Sec. 601.52(c)(1) to include IND 
safety reports and annual reports, as provided for in Secs. 312.32 and 
312.33. Rather, specific requirements for the public disclosure of 
these types of reports are proposed below in Sec. 601.52(c)(7) and 
(c)(8), respectively.
    Under proposed Sec. 601.52(c)(2) and (c)(3), FDA would make the 
name and address of the sponsor and the clinical indications to be 
studied available for public disclosure. The sponsor name and address 
and the indications to be studied are types of information that are 
consistent with information already required for submission to FDA in 
an IND under Sec. 312.23(a)(1)(i) and (a)(3)(iv)(b), respectively.
    Under proposed Sec. 601.52(c)(4), FDA would make the protocol for 
each planned study available for public disclosure. A study protocol is 
required for submission in an IND under Sec. 312.23(a)(6); proposed 
Sec. 601.52(c)(4) would specify that certain elements of the protocol 
be available for public disclosure. Proposed Sec. 601.52(c)(4)(i) 
through (c)(4)(vi) would describe the following specific elements of 
the protocol to be available for public disclosure: (1) A scientific 
abstract and a non-technical abstract; (2) a statement of the 
objectives, purpose, and rationale of the study (submitted in an IND 
under Sec. 312.23(a)(6)(iii)(a)); (3) the name and address of each 
investigator (submitted in an IND under Sec. 312.23(a)(6)(iii)(b)); (4) 
the name and address of the official contacts of each local review body 
as appropriate (IRB (submitted in an IND under 
Sec. 312.23(a)(6)(iii)(b)), and IBC (NIH Guidelines for Research 
Involving Recombinant DNA Molecules, revised April 1998)) and dated 
copies of each committee's approval of the study; (5) the criteria for 
patient selection and exclusion and an estimate of the number of 
patients to be studied (submitted in an IND under 
Sec. 312.23(a)(6)(iii)(c)); and (6) a description of the treatment that 
will be administered to patients and the clinical procedures, 
laboratory tests, or

[[Page 4697]]

other measures to be taken to monitor the safety and effects of the 
drug in human subjects and to minimize risk (similar to that submitted 
in an IND under Sec. 312.23(a)(6)(iii)(g)). FDA intends that the term 
``investigator' in proposed Sec. 601.52(c)(4)(iii) include ``sponsor-
investigators'' (individuals who have the responsibility for both the 
development and clinical investigation of the product) as well as 
``investigators,'' both of which are defined in existing Sec. 312.3(b). 
In proposed Sec. 601.52(c)(4)(iv), FDA intends to make available for 
public disclosure the dated copies of the IRB's and IRC's approval of 
the proposed clinical study to identify when the IRB or IBC assumed 
responsibility for the continued review and approval of the IND.
    Under proposed Sec. 601.52(c)(5), FDA would make sample informed 
consent forms available for public disclosure. FDA proposes to provide 
public access to human gene therapy and xenotransplantation clinical 
trial information relevant to informed consent to promote public 
education, discussion, and consideration of the unique challenges that 
these novel therapies present to assuring adequate informed consent, as 
discussed previously in this proposed rule.
    Under proposed Sec. 601.52(c)(6), FDA would make the identification 
of the biological product(s) and a general description of the method of 
production, including a description of product features that may affect 
patient safety, available for public disclosure. This proposed 
provision contains types of information that are required for 
submission to FDA in an IND under Sec. 312.23. FDA has modified the 
language taken from Sec. 312.23 to reflect information needs related to 
human gene therapy and xenotransplantation and specifies that only a 
``general'' description of the production method would be made 
available, excluding trade secret information. FDA does, however, 
propose to further specify in Sec. 601.52(c)(6) that the identification 
and description would include the following types of information, as 
applicable: (1) The vector name and type; (2) gene insert; (3) 
regulatory elements and their source; (4) intended target cells; (5) 
source of cells, tissues, or organ(s); (6) method used to prepare the 
vector containing cells; (7) method used to procure and prepare cells, 
tissues, or organ(s) for xenotransplantation; (8) purity of cells; (9) 
adventitious agent testing; (10) description of the delivery system; 
(11) ancillary products used during production; (12) herd colony and 
individual source animal health maintenance and surveillance records; 
and (13) biological specimens to be archived from source animals. These 
types of information are consistent with information that is already 
submitted to and publicly disclosed by OBA for human gene therapy.
    Under proposed Sec. 601.52(c)(7), FDA would make IND safety 
reports, as provided in Sec. 312.32, and other similar data and 
information available for public disclosure. Under Sec. 312.32, 
sponsors of investigational drugs, including biological drugs, are 
required to submit to FDA certain adverse reaction reports concerning 
their product. Under Sec. 601.51(e)(3), information concerning these 
adverse experience reports, excluding names and other identifiers of 
patients, health care facilities, and physicians, may be publicly 
disclosed after the licensure of the product. Under proposed 
Sec. 601.52(c)(7), such adverse experience reports and other safety 
reports related to an investigational product could be publicly 
disclosed at any time throughout the lifetime of the product. The same 
limitations for disclosure included in Sec. 601.51(e)(3) are included 
in proposed Sec. 601.52(c) to protect the privacy of patients and 
health care workers.
    Under Sec. 601.52(c)(8), FDA would make information submitted in 
the annual report available for public disclosure. Sponsors must submit 
to FDA annual reports of the progress of the investigations as required 
under Sec. 312.33. FDA proposes that the following types of information 
relevant to human gene therapy and xenotransplantation be included, as 
applicable, in the annual report submitted by the sponsor to FDA for 
public disclosure: (1) Evidence of gene transfer, gene expression in 
target cells, and biological activity; (2) assessment of immune 
response; (3) analysis of biodistribution; (4) significant preclinical 
and clinical toxicities; (5) evidence of infection by agents associated 
with the products; (6) adverse experiences; (7) number of subjects who 
died during participation in the investigation, with the cause of death 
for each subject and the status of autopsy requests; and (8) any 
available post mortem evidence of gene transfer, biodistribution, 
specifically including gonadal distribution. In all cases, names and 
other personal identifiers of patients and, except as specifically 
provided in the regulations, names and other personal identifiers of 
third parties, such as physicians or hospitals, would be removed.
    Under proposed Sec. 601.52(c)(9), FDA would make the regulatory 
status of the investigation, the date of a regulatory action, and the 
reason for an action available for public disclosure in order to 
identify to the public the current regulatory status of a clinical 
investigation. For example, FDA would disclose that an investigation is 
on clinical hold, or that an IND is inactive, withdrawn, or terminated. 
Additional information regarding the procedures and criteria for 
placing an investigation on clinical hold, withdrawal of an IND, 
inactive status for an IND, and IND termination may be found in 
Secs. 312.42, 312.38, 312.45, and 312.44, respectively.
    Under Sec. 601.52(c)(10), FDA would make available for public 
disclosure other relevant data and information that the Director, CBER, 
determines are necessary for the appropriate consideration of the 
public health and scientific issues, including relevant ethical issues 
raised by human gene therapy or xenotransplantation. This proposed 
provision is included because the investigational nature of these 
therapies and the continuing evolution of the science surrounding these 
therapies renders FDA unable to anticipate all of the types of 
information related to human gene therapy and xenotransplantation that 
may warrant public education, discussion, and consideration. Examples 
of other relevant data that FDA may disclose could, under certain 
circumstances, include the details of a test used to determine 
eligibility for trial entry or autopsy or biopsy information. However, 
in general, FDA intends to release only the information specifically 
identified in this proposed rule, except in unique conditions or 
circumstances. Proposed Sec. 601.52(c)(10) would provide that other 
relevant data and information may be approved for disclosure only by 
the Director of CBER.
3. Proposed Sec. 601.53
    Proposed Sec. 601.53 would require sponsors of human gene therapy 
and xenotransplantation clinical trials to submit to FDA for public 
disclosure a redacted version of certain data and information. These 
provisions would specify when and what types of submissions to make to 
FDA in a redacted version for public disclosure, and the requirements 
for identifying and certifying these submissions.
    Furthermore, proposed Sec. 312.42(b)(6) provides that a sponsor's 
failure to submit to FDA the data and information specified in 
Secs. 601.52 and 601.53 that has been properly redacted under 
Sec. 601.53(a) is a basis for FDA placing the investigation on clinical 
hold. FDA recognizes that errors in redacting may occur and will 
provide sponsors with an

[[Page 4698]]

opportunity to correct such errors. However, FDA will have the 
enforcement authority to place a human gene therapy and 
xenotransplantation investigation on clinical hold if resolution is not 
reached on any discrepancies found by FDA in the redacted versions, or 
if a redacted version is not submitted at all by the sponsor. It is 
important that FDA has the specific authority to place a human gene 
therapy or xenotransplantation investigation on clinical hold if the 
sponsor has not submitted required data and information to FDA in a 
form that FDA can make publicly available in a timely and efficient 
manner. As previously described in this proposal, due to the unique 
nature of human gene therapy and xenotransplantation, public 
participation in the consideration of proposed and ongoing clinical 
studies of such therapies is crucial. In order for such public 
education, discussion, and consideration to take place and be 
meaningful, FDA must be able to make all relevant and publicly 
disclosable data and information available to the public as soon as 
practicable. The agency has determined that having sponsors submit 
redacted versions that comply with proposed Secs. 601.52 and 601.53 is 
the most efficient means to accomplish this.
    Under proposed Sec. 601.53(a), FDA would require the sponsor of an 
IND to submit to FDA for public disclosure a redacted version of the 
types of submissions identified in Sec. 601.53(b)(1) through (b)(5). 
The sponsor would be required to include all applicable information 
identified as disclosable in Sec. 601.52 and redact all information 
considered confidential as trade secret, names and other personal 
identifiers of patients and, except as specifically provided in the 
regulations, names and personal identifiers of third parties, such as 
physicians, hospitals, etc., and certain confidential commercial 
information, such as information regarding commercial licensing 
agreements or the identification of suppliers. Sponsors would be 
permitted to redact either by removing or obscuring the information 
exempt from disclosure.
    Proposed Sec. 601.53(b)(1) through (b)(5) would list the types of 
submissions that the sponsor would be required to submit to FDA in 
duplicate and as a redacted version for public disclosure. FDA believes 
this information should be available for public disclosure as soon as 
possible and therefore, would require under this paragraph that the 
redacted version be submitted to FDA concurrently with the original 
unabridged submission or at the specific time points noted.
    Proposed Sec. 601.53(b)(1) would require submission for public 
disclosure a redacted version of the information defined under 
Sec. 601.52 to accompany the original unabridged IND submission.
    Proposed Sec. 601.53(b)(2) would require submission for public 
disclosure a redacted version of any amendment documenting changes or 
additions to the information defined under Sec. 601.52 that occur 
either during the IND review process or after the IND goes into effect. 
FDA recognizes that some amendments may require negotiation with FDA 
and subsequent revision by the sponsor. As such, FDA would require that 
the redacted version of any amendment be submitted at the time the 
amendment goes into effect.
    Proposed Sec. 601.53(b)(3) would require submission for public 
disclosure of a redacted version of any IND safety report at the time 
of submission of the original report to FDA. Sponsors are required 
under Sec. 312.32 to notify FDA in a written IND safety report of any 
serious and unexpected adverse experiences associated with the use of 
their drug no later than 15 days after the sponsor's initial receipt of 
the information. FDA believes that the timely availability of adverse 
experience information is essential for public education and informed 
discussion and consideration of the health and safety issues presented 
by the experiences.
    Proposed Sec. 601.53(b)(4) would require submission for public 
disclosure of a redacted version of the annual report, in accordance 
with Sec. 312.33. Consistent with Sec. 312.33, sponsors would be 
required to submit, within 60 days of the anniversary date that the IND 
went into effect, a redacted version of the annual report.
    Under proposed Sec. 601.53(b)(5), a sponsor would be required to 
submit for public disclosure a redacted version of other information 
upon specific request of the Director, CBER. For example, FDA may 
request that the sponsor submit information regarding a test used to 
determine eligibility for trial entry. This proposed provision is 
included because due to the investigational nature of these therapies 
and the continuing evolution of the science surrounding these 
therapies, FDA is not able to anticipate all of the types of 
information related to human gene therapy and xenotransplantation that 
may warrant public education, discussion, and consideration. However, 
in general, FDA does not intend to request information not identified 
in this proposed rule, except for unique conditions or circumstances.
    Proposed Sec. 601.53(c) would require that the sponsor submit the 
information identified in Sec. 601.53(b) in duplicate, in a form 
readily separable from the nonredacted or original unabridged version 
or submission and clearly marked as suitable for public disclosure on 
each page of the submission. This proposed provision would enable FDA 
to identify and provide this information more rapidly to the public and 
would help assure that only appropriate information is disclosed to the 
public.
    Proposed Sec. 601.53(d) would require that any copyrighted material 
be included in a single appendix to the submission and listed in a 
bibliography in the redacted version. The proposal would specify that 
any copyrighted material whose copyright is not owned by the applicant 
shall not be included in any other section of the redacted version. FDA 
is including this provision to facilitate timely release of the 
redacted version on the Internet. In response to an FOIA request, 
copyrighted materials can be included in the response. However, with 
regard to posting on the Internet, copyrighted material must be 
redacted prior to electronic disclosure as this is not considered a 
``fair use'' of copyrighted material. Therefore, FDA would not release 
the appendix containing copyrighted materials as part of the redacted 
version on the Internet, but may release the bibliography of materials 
included in the appendix.
    Proposed Sec. 601.53(e) would require that redacted versions be 
accompanied by the statement specified to ensure that the sponsor has 
redacted only the information identified in Sec. 601.53(a) as exempt 
from disclosure (confidential commercial, trade secret, or personal 
information). In addition, under proposed Sec. 601.53, the sponsor must 
include a declaration that the statement is true and correct, under 
penalty of perjury.
4. Conforming Amendments
    The proposed rule would make conforming amendments to parts 20 and 
312. Part 20 describes the procedures and policy regarding the 
availability and disclosure of information to the public. Section 
20.100 lists the cross-references to other sections of title 21 CFR 
that contain requirements on the availability of specific categories of 
FDA records and how these records are handled upon a request for public 
disclosure. The proposed rule would amend Sec. 20.100(c) by adding a 
paragraph (43) that would contain a cross-reference to the proposed 
Sec. 601.52 regarding the availability for public disclosure of certain 
data and information submitted

[[Page 4699]]

to FDA related to human gene therapy or xenotransplantation.
    Part 312 describes the procedures and requirements that govern the 
use of investigational new drugs, including provisions for submission 
to and review by FDA of IND's. The provisions of this rulemaking do not 
alter the procedures specified in part 312 for submission of an IND. 
Section 312.42, among other things, lists the grounds for which FDA may 
impose a clinical hold of an investigation. Proposed Sec. 312.42(b)(7) 
would amend Sec. 312.42 by adding an additional basis for clinical hold 
for human gene therapy and xenotransplantation investigations. Under 
this proposal, FDA could place a human gene therapy or 
xenotransplantation investigation on clinical hold if the sponsor has 
not submitted to the agency a redacted version for public disclosure 
that complies with the requirements of Sec. 601.53.
    Section Sec. 312.130 contains requirements regarding the 
availability for public disclosure of data and information in an IND. 
The proposed rule would amend Sec. 312.130 by revising paragraph (b) to 
include a reference to proposed Sec. 601.52, in addition to the 
existing references to Secs. 601.50 and 601.51, when listing the 
provisions of this chapter that govern the availability for public 
disclosure of all data and information in an IND.

III. Implementation

    Under the proposed rule, FDA would require that sponsors of human 
gene therapy and xenotransplantation clinical trials submit for public 
disclosure a redacted version of the information defined under 
Sec. 601.52 as contained in the initial IND submission, amendments 
documenting changes or additions to the information defined under 
Sec. 601.52 at the time the amendments go into effect, IND safety 
reports, and annual reports. The redacted version of these documents 
should be submitted to FDA in a form immediately releasable to the 
public, and clearly marked accordingly on each page of the submission 
as suitable for public disclosure. Acceptable approaches range from 
submitting a ``marked up'' version of the original that obscures the 
information which is not to be disclosed, to developing a separate 
document that abstracts the needed information for public disclosure 
from the original unabridged version submitted to FDA.
    Specifically, FDA is proposing that the redacted version of the 
information specified in the proposed rule be submitted to FDA 
concurrently with the original unabridged IND submission or at the 
specific time points noted in the provisions. Sponsors of human gene 
therapy and xenotransplantation clinical trials would send an original 
and two copies of the original unabridged version of the IND submission 
(as required under existing Sec. 312.23(d)) as well as one copy of the 
redacted version for public disclosure to FDA's CBER, where they would 
be received by the Document Control Center (DCC) to be logged, filed, 
and routed for appropriate documentation, review, and approval. DCC 
would route the submittals to the appropriate FDA reviewer, where, upon 
receipt, the redacted version for public disclosure would be reviewed 
for administrative completeness as well as to ensure that the 
submitting sponsor has appropriately redacted personal information 
regarding patients and third parties prior to release to the public. 
Once this review is complete, the redacted version for public 
disclosure would be sent to the Dockets Management Branch for public 
display where a docket number would be assigned. Each redacted version 
for public disclosure submitted to FDA would be tagged with the same 
docket number for that IND for reference. FDA is also proposing to make 
the redacted versions for public disclosure available to the public 
electronically on the Internet site according to the docket number.
    In addition, to facilitate timely release by FDA of the redacted 
version, FDA is proposing to require that all copyrighted materials 
submitted in accordance with Sec. 601.53 be placed in a single appendix 
and listed in a bibliography in the redacted version. Should an FOIA 
request be received for the data and information specified in 
Sec. 601.52, FDA would be able to include a copy of any copyrighted 
materials in its response. However, FDA would not be able to publicly 
release any copyrighted material on the Internet as electronic posting 
of such information is not a ``fair use'' of that copyrighted material 
and must be redacted prior to electronic release. In this case, FDA 
instead would disclose the bibliography of copyrighted materials 
contained in the appendix.
    FDA encourages, but would not require at this time, sponsors to 
submit the redacted version for public disclosure in electronic format. 
Pilot programs are currently underway regarding submission of 
electronic IND's and BLA's. (See 63 FR 29740 and 29741.) As such, FDA 
may, in the near future, implement electronic submission and disclosure 
of this information.
    Sponsors of human gene therapy or xenotransplantation clinical 
trials who submit an initial IND or an amendment to an existing IND on 
or after the effective date of the final rule resulting from this 
rulemaking would be required to submit a redacted version for public 
disclosure in conformance with the rule.
    Sponsors of xenotransplantation clinical trials who have submitted 
an IND to FDA prior to the effective date of the final rule resulting 
from this rulemaking would be required to submit for public disclosure 
a redacted version of the information defined under Sec. 601.52, 
reflecting all amendments to date, by a date specified in the final 
rule.
    Sponsors of human gene therapy clinical trials who have submitted 
IND's or amendments prior to the effective date of the final rule, need 
not submit redacted versions. For these IND's or amendments, FDA will 
rely on the existing OBA database as a source of the information that 
FDA will disclose.
    For additional information regarding the proposed effective dates 
for the final rule see the end of this preamble.

IV. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

V. Analysis of Impacts and Initial Regulatory Flexibility Analysis

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612) 
(as amended by subtitle D of the Small Business Regulatory Fairness Act 
of 1996 (Public Law 104-121)), and under the Unfunded Mandates Reform 
Act (UMRA) (Public Law 104-4). Executive Order 12866 directs agencies 
to assess all costs and benefits of available regulatory alternatives 
and, when regulation is necessary, to select regulatory approaches that 
maximize net benefits (including potential economic, environmental, 
public health and safety, and other advantages; distributive impacts; 
and equity). The Regulatory Flexibility Act requires agencies to 
analyze whether a rule may have a significant impact on a substantial 
number of small entities and, if it does, to analyze regulatory options 
that would minimize the impact. The UMRA requires that agencies prepare 
a written statement under section 202(a) of UMRA of

[[Page 4700]]

anticipated costs and benefits before proposing any rule that may 
result in an expenditure by State, local, and tribal governments, in 
the aggregate, or by the private sector, of $100 million (adjusted 
annually for inflation) in any one year.
    The agency believes that this final rule is consistent with the 
principles identified in Executive Order 12866. OMB has determined that 
the final rule is a significant regulatory action as defined by the 
Executive Order and so is subject to review. Because the rule does not 
impose mandates on State, local, or tribal governments, or the private 
sector, that will result in an expenditure in any one year of $100 
million or more, FDA is not required to perform a cost-benefit analysis 
according to the Unfunded Mandates Reform Act. Aggregate impacts of the 
rule, and aggregate expenditures caused by the rule, will not approach 
$100 million for either the public or the private sector. As discussed 
below, because of the limited information that can be used to 
characterize the entities that may qualify as small businesses, the 
impact on small business establishments is uncertain. FDA has therefore 
prepared an Initial Regulatory Flexibility Analysis.

A. Background

    In the discussion that follows, FDA will describe the purpose and 
requirements of the proposed rule, the estimated number of entities 
that will be affected, the estimated cost of compliance with the rule 
per IND, and a summary of estimated annual costs to industry.
    The purpose of the proposed rule is to make available for public 
disclosure and to require submission in redacted version for public 
disclosure, certain data and information related to human gene therapy 
and xenotransplantation investigations. These areas of clinical 
investigation have the potential for unique public health risks and 
modification of the human genome. The public health and safety risks 
require that FDA be able to make timely disclosures of adverse 
outcomes, such as the development of novel infectious agents, 
unanticipated alterations of a recipient's germline, and severe 
toxicity resulting from the therapy, in order to prevent or contain 
further adverse occurrences.
    These therapeutic research areas will effectively transform 
participating recipients into life-long research subjects. The length 
of commitment, coupled with the magnitude of potential risks to the 
recipients, their families and community, will present new challenges 
for risk assessment and the adequacy of informed consent. As noted 
earlier, these investigative approaches raise new challenges for 
Institutional Review Boards. The novelty and extent of the risk issues 
will call for expanded public access to clinical trial information 
relevant to assessment of risks and benefits, and public education and 
informed consent. These public information needs can only be addressed 
through disclosure of relevant information about the proposed and 
ongoing investigations.
    The information to come under this disclosure regulation includes: 
(1) Product and patient safety data and related information including 
results of preclinical and clinical studies and tests that demonstrate 
the safety and/or feasibility of the proposed procedures; (2) the name 
and address of the sponsor; (3) the clinical indications to be studied; 
(4) the protocol for each planned study to include a scientific 
abstract and a nontechnical abstract, a statement of the objectives, 
purpose, and rationale of the study, the name and address of each 
investigator and subinvestigator, the name and address of the official 
contacts of each local review body as appropriate (IRB, IBC) and the 
dated copies of approval by each group, the criteria for patient 
selection and exclusion, an estimate of the number of patients to be 
studied, and a description of the treatment that will be administered 
to patients, and the clinical procedures, laboratory tests, or other 
measures to be taken to monitor the safety and effects of the drug in 
human subjects and to minimize risk; (5) the informed consent 
documentation; (6) the identification of the biological product(s) and 
a general description of the method of production, including a 
description of product features that may affect patient safety; (7) the 
IND safety reports; (8) the information submitted to FDA in the annual 
report; (9) the regulatory status of the investigation, the date of an 
action, and the reason for an action; (10) and other relevant data and 
information that the Director, CBER, determines are necessary for the 
appropriate consideration of the public health and scientific issues, 
including relevant ethical issues, raised by human gene therapy or 
xenotransplantation. After a license has been issued, all safety and 
effectiveness data and information in the biological product file are 
immediately available for public disclosure unless extraordinary 
circumstances are shown (Sec. 601.51(e)(1)).
    The sponsor of an IND involving human gene therapy or 
xenotransplantation will be required to submit this information in 
redacted version for public disclosure, removing all information that 
would be defined as trade secret, or personal information. The redacted 
submissions would be as follows:
    1. Redacted version of information as defined under Sec. 601.52 at 
the time of the initial IND submission.
    2. Redacted version of any amendment documenting changes or 
additions to the information defined under Sec. 601.52, at the time the 
amendment goes into effect.
    3. Redacted version of IND safety reports at the time of submission 
of the initial report.
    4. Redacted version of the annual progress report within 60 days of 
the anniversary date that the IND went into effect.
    The redacted version would be submitted in a form that is readily 
identifiable and separable from the original unabridged submission to 
FDA.
    The proposed rule will affect sponsors of human gene therapy or 
xenotransplantation clinical trials. The agency estimates that, at any 
one time, a total of 147 sponsors will be affected by the proposed 
rule. This includes 134 sponsors that have submitted IND's in the area 
of human gene therapy, and an additional 13 sponsors that have 
submitted IND's for clinical trials involving xenotransplantation. The 
number of new IND's per year in these two research areas has remained 
relatively constant at the level of approximately 45 IND submissions 
per year, for the past several years.

B. Cost Impact

    Certain types of information have a substantial commercial value. 
This value may be particularly high for data pertaining to specific 
business plans, strategies, or lines of scientific research. The 
required disclosure of such information, however, imposes no economic 
impact where the relevant data are already available to competitors. As 
discussed earlier in this preamble, information that would be disclosed 
under this proposed rule is routinely examined and discussed by the 
RAC, in the case of gene therapy, and discussed at other public 
meetings addressing xenotransplantation issues, or through public 
filings with the SEC. Because the information proposed for disclosure 
has not been treated as confidential by industry, FDA finds that there 
is minimal incremental commercial value associated with the information 
that may be disclosed. The agency has, therefore, not attributed 
regulatory costs to its disclosure. The

[[Page 4701]]

agency requests public comment on the validity of this view.
    The proposed rule will require additional paperwork activities for 
affected firms. The primary impact on clinical trial sponsors will be 
the requirement for additional staff time to redact IND-related 
submissions, throughout the period in which the IND is active. Table 1 
of this document provides a summary of the types of submissions that 
will be required for public disclosure and the estimated number of such 
submissions that FDA expects to receive each year across all active 
IND's in the areas of human gene therapy and xenotransplantation. The 
estimated time required per redacted submission is also shown in table 
1. The numbers of submissions and redaction times are estimated by FDA 
staff involved in application review, based on their experience in 
recent years, and their familiarity with the content of the IND 
packages. The redaction is assumed to be performed by a relatively 
senior member of the scientific research staff at a sponsoring 
organization. The cost per hour of staff time is estimated to be 
approximately $38, based on the Bureau of Labor Statistics estimate of 
total hourly compensation for professional white-collar workers in the 
private goods-producing and service producing industries.\3\ The 
redacted documents listed in table 1 reflect a series of submissions 
that would typically occur over several years. Based on FDA's estimate 
of the total volume of submissions of each type per year, the agency 
estimates that the total cost to the industry will be approximately 
$123,880 [$41,040+$5,130+$1,710+$76,000]. This yields an average annual 
cost of $843 per sponsor [$123,880/147].
---------------------------------------------------------------------------

    \3\ U.S. Dept of Labor, Bureau of Labor Statistics, Employer 
Costs for Employee Compensation, March 1997.

Table 1.--Estimates Of Cost Per Year For Industry-Wide Redaction Efforts
------------------------------------------------------------------------
                    Total Industry                         Estimated
 Type of Redacted     Submissions   Average Redaction  Industry Cost per
    Submission         per Year      Time/Submission          Year
------------------------------------------------------------------------
New IND\1\--             45         24 hours           $41,040 [45 x 24
 initial and                                            x $38]
 authorized
 version
IND amendments          270         0.5 hour           $5,130 [270 x 0.5
                                                        x $38]
IND safety reports       90         0.5 hour           $1,170 [90 x 0.5
                                                        x $38]
Annual reports          100         20 hours           $76,000 [100 x 20
                                                        x $38]
------------------------------------------------------------------------
Total Annual Cost                                      $123,880
 to Industry
------------------------------------------------------------------------
Average Annual                                              $843
 Cost Per Sponsor
 (147 sponsors)
------------------------------------------------------------------------
\1\ Investigational new drug application.

C. Benefits

    Although human gene therapy offers the promise of more effective 
treatment, for diseases ranging from cystic fibrosis to human 
immunodeficiency virus (HIV), rapid progress and patient safety in 
research requires timely communication of new findings about the 
success or risks of candidate strategies. The key to success for any 
human gene therapy strategy is attaining a vector that can serve as a 
safe and efficient gene delivery vehicle (Ref. 5). In general, human 
gene therapy researchers work to maximize efficacy through the 
regulation of gene expression over long periods (Ref. 6). Simultaneous 
with this goal, researchers attempt to develop vectors and treatment 
strategies that will both minimize the patient's immune response (which 
counters the therapy) (Ref. 7) and minimize the toxicity of the gene 
therapy (Refs. 8 and 9). As different vectors are considered, it is 
critical that newly discovered risks be reported to alert other 
researchers considering similar vectors or developing therapies to 
treat similar conditions.
    As described earlier, the importance of timely communication of 
risks is clearly demonstrated by the cystic fibrosis patient who 
developed an acute adverse event requiring intensive care after 
receiving an adenoviral vector. In this case, public discussion of the 
adverse event at the RAC meeting facilitated rapid dissemination of 
important information about this toxicity, thereby contributing to the 
safety of patients in other gene therapy trials.
    For xenotransplantation, the disclosure of information is necessary 
for public education and more efficient product and recipient tracking. 
Communication of risks offers other benefits for recipients of 
xenotransplantation products, their families, and their communities. 
According to a recent World Health Organization report on 
xenotransplantation, ``The practice of xenotransplantation carries with 
it an unquantifiable risk of xenozoonotic infection and disease. 
Measures are required to minimize risk and maximize safety in the 
potential use of this technology'' (Ref. 10). The level of risk is 
particularly difficult to quantify since potential viruses may be 
unknown and ``silent'' in the donor species; that is, they may not be 
identified through the currently available battery of screening tests 
for known pathogens. In addition, the risk of infection in the 
recipient of a xenotransplantation product may be substantially 
increased as a result of the immunosuppressive drug therapy 
administered to prevent rejection of the transplanted 
xenotransplantation product.
    New evidence supporting the possibility of this risk is reported in 
a recent study (Ref. 11) showing that pig pancreatic islets 
transplanted into severely immunodeficient mice produce porcine 
endogenous retroviruses (PERV) that can infect human cells that had 
been transplanted into the same mice receiving the porcine pancreatic 
cells. Although pigs are considered a promising alternative source of 
organs for xenotransplantation, this study found that the PERV were 
trancriptionally active and infectious cross-species in vivo after 
xenotransplantation of the pig tissues. These findings bolster earlier 
concerns about PERV infection from pig islet

[[Page 4702]]

xenotransplantation in immunosuppressed human patients.
    Recent experience with zoonotic viruses has demonstrated the 
potential lethality of these viruses. An example is the 1998 to 1999 
outbreak of a hendra-like virus in Malaysia and Singapore (Ref. 12). 
Documented cases occurred primarily among adults who had come in close 
contact with swine, which also showed signs of the illness. In some 
instances, illness in the pigs had occurred 1 to 2 weeks before illness 
in the humans. Illness in humans was characterized by 3 to 14 days of 
fever and headache followed by drowsiness and disorientation that often 
progressed to coma within 24 to 48 hours. During the period September 
1998 to April 1999, 229 human cases were reported, 111 of which (48 
percent) resulted in death. Although the first cases of human illness 
were reported in September 1998, the type and source of infection was 
initially unknown, so human exposures continued to occur, with the peak 
number of new cases occurring 6 months later, in March 1999. Once the 
type of virus was identified, through laboratory testing, and the 
source of infection (i.e., exposure to pigs) was serologically 
confirmed, public health measures were taken to prevent further 
outbreaks.
    Ebola hemorrhagic fever is another disease that is transferable 
from animals to humans (Ref. 13) and consequently illustrates the 
importance of timely tracking of and public communication about 
zoonotic viruses. In the period from January to July 1995, a total of 
316 persons became ill with hemorrhagic fever in Kikwit, Democratic 
Republic of the Congo (DRC) (Ref. 14). During the epidemic, a mortality 
rate of 60 to 80 percent was reported among hospital cases. After an 
incubation period of approximately 7 days, the early clinical features 
of the disease included fever, headache, sore throat, diarrhea and 
myalgias, followed by vomiting, worsening diarrhea, oliguria, shock and 
death after 7 to 14 days. In May of 1995, the month of peak onset of 
new cases, the DRC requested international assistance in investigating 
the cause of the outbreak. Laboratory testing by the Centers for 
Disease Control and Prevention (CDC) confirmed the presence of the 
Zaire subtype of Ebola hemorrhagic fever. Continued investigation and 
testing enabled the international team to identify modes of 
transmission and to specify the precautions necessary to prevent 
further spread of the virus. According to the CDC, prompt laboratory 
diagnosis is an essential component of the surveillance needed to 
maximize Ebola prevention and control measures (Ref. 15). In this 
instance, the lack of early detection and proper management of Ebola 
hemorrhagic fever patients resulted in numerous deaths among both 
health care personnel and patients (Rollin and Ksiazek, 1998). By 
hastening the disclosure of important risk information, the proposed 
rule would assist public health agencies and health care providers in 
more rapidly identifying and controlling any zoonotic viruses that 
might emerge following xenotransplantation.
    As of April 1999, the United Network for Organ Sharing (UNOS) 
reported a total of 62,443 patients on the waiting list for an organ 
transplant. This number far exceeds the total of approximately 20,000 
transplants performed each year (Ref. 16). In addition to bolstering 
the supply of viable organ transplants, patients may also benefit from 
cellular and tissue therapies involving a xenotransplantation product. 
Although the potential to fill unmet needs is great, the number of 
prospective xenotransplant recipients represents a sizeable population 
at potential risk of zoonotic infection. The proposed data disclosures 
would help to provide the information needed by the public to 
understand, manage, and minimize the risks associated with these 
advancing medical technologies.

D. Impact on Small Entities

    The agency has only limited information to estimate the number of 
small entities conducting clinical investigations of human gene therapy 
or xenotransplantation. As indicated in the cost analysis, the overall 
number of business entities sponsoring clinical trials is estimated to 
be 147. Although a few companies are a part of larger firms, many 
others may have annual revenues of less than $5 million, which is the 
revenue level that identifies a small business, according to the Small 
Business Administration. The estimated cost impact of $843 per sponsor 
per year reflects the staff time that would need to be allocated to 
produce redacted versions of the specified documents for the purpose of 
public disclosure.
    The proposed rule offers sponsors considerable flexibility in 
implementation by allowing for a range of approaches for preparing a 
redacted version. Under the proposed rule, acceptable approaches range 
from submitting a ``marked up'' version of the original that simply 
obscures the information not to be disclosed, to development of a 
separate document that abstracts the needed information for the public 
from the original unabridged version submitted to FDA. This flexibility 
will help to minimize the cost impact.
    The agency does not anticipate that the estimated cost will 
significantly burden any of the sponsors. However, because of the 
limited information available for establishments sponsoring clinical 
trials in human gene therapy and xenotransplantation, and its 
importance in developing estimates of the small entity impact, the 
agency requests detailed comment on the number and type of businesses 
sponsoring clinical trials in human gene therapy or 
xenotransplantation, and the expected impact of the proposed 
requirements on these entities.
    In developing the proposed rule, the agency considered but rejected 
two alternatives that might impose less burden on small businesses. The 
agency found, however, that these alternatives would be less effective 
in supporting the advancement of this research, because of unanswered 
concerns regarding patient safety and public health. One of the 
alternatives considered involved voluntary disclosure by clinical trial 
sponsors without a regulatory requirement. This alternative would 
reduce costs to industry only if establishments failed to voluntarily 
provide the needed information for disclosure. Moreover, while 
voluntary provision of this information would be no less burdensome for 
industry, it could prove inadequate in protecting public health, 
because the agency would have no means of assuring the quality and 
consistency of the content of the voluntarily disclosed information, or 
the timeliness of its reporting. The disclosure of timely, accurate, 
and complete information is critical to an appropriate agency response 
to adverse outcomes, including the emergence of novel and potentially 
life-threatening infectious agents, or the alteration of the germline 
in patients participating in the clinical study. Also, voluntary 
disclosure provides no means for the agency to ensure a balanced 
dissemination of information on identified risks and benefits. Such 
balance is central to an adequate public understanding of the 
technologies, and to an informed public discussion of the overall risk 
versus benefit to patients and communities.
    A second alternative to the proposed rule would require disclosure, 
but would have FDA assume the sole responsibility for redaction of 
documents submitted by the sponsor. Although this alternative would 
reduce the direct cost impact for sponsors, the limited number of 
agency staff available to perform this task would introduce the risk of 
delay in producing the redacted

[[Page 4703]]

version for public disclosure. This outcome could potentially result in 
delaying the research, or delaying the timely public availability of 
critical information.

VI. References

    The following references have been placed on display in the Dockets 
Management Branch and may be seen by interested persons between 9 a.m. 
and 4 p.m., Monday through Friday.
    1. Eastland, T., ``Infectious disease transmission through cell, 
tissue and organ transplantation: reducing the risk through donor 
selection,'' Cell Transplantation vol 4. pp. 455-477, 1995.
    2. Delmonico, F. L. and D. R. Snydman, ``Organ donor screening 
for infectious diseases'' Transplantation, vol. 65, pp. 603-610, 
1998.
    3. Regamey, N., M. Tamm, M. Wernil, A. Witschi, G. Thiel, G. 
Cathomas, and P. Erb, ``Tranmission of human herpesvirus 8 infection 
from renal-transplant donors to recipients.'' New England Journal of 
Medicine, vol. 339, pp.1358-1363, 1998.
    4. ``Guidelines for Research Involving Recombinant DNA 
Molecules,'' Appendix M-Points to Consider in the Design and 
Submission of Protocols for the Transfer of Recombinant DNA 
Molecules into One or More Human Subjects (PTC), http://www4.od.nih.gov/oba/guidelines.html.
    5. Friedmann, T., ``Overcoming the Obstacles to Gene Therapy,'' 
Scientific American, vol. 276, No. 6, pp. 96-101, June 1997.
    6. Haberman, R. P., T. J. McCown, and R. J. Samulski, 
``Inducible Long-Term Gene Expression in Brain With Adeno-Associated 
Virus Gene Transfer,'' Gene Therapy, vol. 5, No. 12, pp. 1604-1611, 
December 1998.
    7. Middleton, P. G. and E. W. F. W. Alton, ``Gene Therapy for 
Cystic Fybrosis: Which Postman, Which Box?'' Thorax, vol. 53, No. 3, 
pp. 197-199, March 1998.
    8. Krisky, D. M., D. Wolfe, W. F. Goins, P. C. Marconi, R. 
Ramakrishnan, M. Mata, R. J. D. Rouse, D. J. Fink, and J. C. 
Glorioso, ``Deletion of Multiple Immediate-Early Genes From Herpes 
Simplex Virus Reduces Cytotoxicity and Permits Long-Term Gene 
Expression in Neurons,'' Gene Therapy, vol. 5, No. 12, pp. 1593-
1603, December 1998.
    9. Yang, E.Y., D. L. Cass, K. G. Sylvester, J. M. Wilson, and N. 
S. Adzick, ``Fetal Gene Therapy: Efficacy, Toxicity, and Immunologic 
Effects of Early Gestation Recombinant Adenovirus,'' Journal of 
Pediatric Surgery, vol. 34, No. 2, pp. 235-241, February 1999.
    10. Report of WHO Consultation on Xenotransplantation, World 
Health Organization, Emerging and other Communicable Diseases 
Surveillance and Control, Geneva, Switzerland, pp. 28-30, October 
1997.
    11. Van der Laan, L. J., C. Lockey, B. C. Griffeth, F. S. 
Frasier, C. A. Wilson, D. E. Onions, B. J. Hering, Z. Long, E. Otto, 
B. E. Torbett, D. R. Salomon, ``Infection by Porcine Endogenous 
Retrovirus After Islet Xenotransplantation in SCID Mice,'' Nature, 
vol. 407 (6800), pp. 90-94, September 7, 2000.
    12. U.S. Department of Health and Human Services, Centers for 
Disease Control, ``Outbreak of Hendra-Like Virus--Malaysia and 
Singapore, 1998-1999,'' Morbidity and Mortality Weekly Report, vol. 
48, No. 13, April 9, 1999.
    13. Rollin, P. E. and T. G. Ksiazek, ``Ebola Haemorrhagic 
Fever,'' Transactions of the Royal Society of Tropical Medicine and 
Hygiene, vol. 92, pp. 1-2, 1998.
    14. Roels, T. H., A. S. Bloom, J. Buffington, G. L. Muhumgu, W. 
R. MacKenzie, A. S. Khan, R. Ndambi, D. L. Noah, H. R. Rolka, C. J. 
Peters, and T. G. Ksiazek, ``Ebola Hemorrhagic Fever, Kikwit, 
Democratic Republic of the Congo, 1995: Risk Factors for Patients 
with a Reported Exposure,'' The Journal of Infectious Diseases, vol. 
179 Supplement 1:S92-97, 1999.
    15. Centers for Disease Control, ``Update: Outbreak of Ebola 
Viral Hemorrhagic Fever--Zaire 1995,'' Journal of the American 
Medical Association, vol. 274, No. 5, August 1995.
    16. U.S. Facts About Transplantation, UNOS, (c) 1998, http://
www.unos.org/newsroom/critdata__main.htm.

VII. The Paperwork Reduction Act of 1995

    This proposed rule contains information collection provisions that 
are subject to review by OMB under the Paperwork Reduction Act of 1995 
(44 U.S.C. 3501-3520). The title, description, and respondent 
description of the information collection provisions are shown below 
with an estimate of the annual reporting burden. Included in the 
estimate is the time for reviewing instructions, searching existing 
data sources, gathering and maintaining the data needed, and completing 
and reviewing each collection of information.
    FDA invites comments on: (1) Whether the proposed collection of 
information is necessary for the proper performance of FDA's functions, 
including whether the information will have a practical utility; (2) 
the accuracy of FDA's estimate of the burden of the proposed collection 
of information, including the validity of the methodology and 
assumptions used; (3) ways to enhance the quality, utility, and clarity 
of the information to be collected; and (4) ways to minimize the burden 
of the collection of information on respondents, including through the 
use of automated collection techniques, when appropriate, and other 
forms of information technology.
    Title: Submission to FDA for Public Disclosure of Certain Data and 
Information Related to Human Gene Therapy or Xenotransplantation.
    Description: FDA is proposing new regulations to require that 
sponsors of IND's involving human gene therapy or xenotransplantation 
submit information related to the IND in redacted version for public 
disclosure, removing all information that would be defined as trade 
secret or personal information whose disclosure would constitute a 
clearly unwarranted invasion of privacy, and certain confidential 
commercial information. Each submission for public disclosure would be 
accompanied by a statement, signed by a responsible person, that the 
information has been suitably redacted. FDA would then publicly 
disclose the redacted version to provide an opportunity for public 
education, discussion, and consideration of public health and safety 
issues, as well as consideration of societal and ethical issues.
    FDA is also proposing to require that the sponsor submit any 
copyrighted material in a single appendix to each redacted version and 
any copyrighted material whose copyright is not owned by the sponsor 
not be included in any other section of the redacted version. The 
proposal would further require that the redacted version include a 
bibliography of the copyrighted material contained in the appendix. 
This provision would facilitate the timely public disclosure of the 
redacted version on the Internet, with the copyrighted information 
excluded. Making available copyrighted material on the Internet is not 
considered ``fair use'' of copyrighted material.
    Description of Respondents: Sponsors of clinical investigations 
involving human gene therapy or xenotransplantation.
    FDA has estimated the burden for each provision that describes a 
collection of information. The estimates are based on FDA's experience 
in reviewing IND submissions and in redacting documents related to an 
IND.
    Under proposed Sec. 601.53(b), approximately 147 sponsors of 
clinical investigations involving human gene therapy (134 sponsors) and 
xenotransplantation (13 sponsors) would be required to submit a 
redacted version of certain documents under the IND. For all 147 
sponsors, these documents include the original IND (45 submissions/
year), amendments to an IND (270 submissions/year), IND safety reports 
(90 submissions/year), and annual reports (100 submissions/year) for an 
estimated total of 505 submissions/year (45 + 270 + 90 + 100). FDA has 
estimated the time necessary to copy and redact each of the above types 
of submissions; i.e., IND submission, 24 hours/submission; amendments, 
.5 hour/per submission; IND safety reports, .5 hour/submission; and 
annual reports, 20 hours/submission. The total burden equals the sum of 
the burdens estimated for each type of submission (45x24 +

[[Page 4704]]

270x.5 + 90x.5 + 100x20 equals 3,260 hours).
    Under Sec. 601.53(c) all submissions under Sec. 601.53(b) must be 
readily separable from the original submission and clearly marked on 
each page as suitable for disclosure. Under Sec. 601.53(d) of the 
proposed rule, sponsors of human gene theraphy and xenotransplantation 
clinical studies would be required to submit copyrighted material in a 
single appendix to each redacted submission and include in the redacted 
version a bibliography of these materials. The hours per response, 
therefore, are an average estimate of the total time for redaction of 
the document, separation of copyrighted material and preparation of a 
bibliography, marking of each page as suitable for public disclosure, 
and submission to FDA, as provided in Sec. 601.53(b), (c), and (d). The 
information collection burdens associated with the submission of an IND 
as provided in part 312 are approved by OMB under OMB control number 
0910-0014.

                                 Table 2.--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                      Annual
         21 CFR Section               No. of       Frequency per   Total Annual      Hours per      Total Hours
                                    Respondents      Response        Responses       Response
----------------------------------------------------------------------------------------------------------------
601.53(b), (c), and (d)               147               3.4           505               6.5        3,282
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs and maintenance costs associated with this collection of information.

    In compliance with section 3507(d) of the Paperwork Reduction Act 
of 1995 (44 U.S.C. 3507(d)), FDA has submitted the information 
collection provisions of this proposed rule to OMB for review. 
Interested persons may submit comments on the information collection 
requirements of this proposal by February 20, 2001, to the Office of 
Information and Regulatory Affairs, OMB, New Executive Office Bldg., 
725 17th St. NW., Washington, DC 20503, Attn: Desk Officer for FDA.

VIII. Proposed Effective Dates

    FDA proposes that any final rule that may issue based on this 
proposal become effective 90 days after the date of its publication in 
the Federal Register. On or after that date, sponsors of human gene 
therapy or xenotransplantation clinical trials would be required to 
submit a redacted version of the data and information specified in the 
final rule as part of a submission into an IND. Sponsors may 
voluntarily submit a redacted version immediately upon the date of 
issuance of the final rule. FDA is proposing, for sponsors of 
xenotransplantation clinical trials who have submitted an IND prior to 
the effective date of the final rule, that the sponsor submit for 
public disclosure a redacted version of the information held under the 
IND, to contain the information specified in proposed Sec. 601.52. FDA 
invites comment on the length of time after issuance of the final rule 
that these sponsors should be provided to submit the redacted 
information.

IX. Request for Comments

    Interested persons may submit to the Dockets Management Branch 
(address above) written comments regarding this proposal by April 18, 
2001. Two copies of any comments are to be submitted, except that 
individuals may submit one copy. Comments are to be identified with the 
docket number found in brackets in the heading of this document. Submit 
written comments on the information collection provisions by February 
20, 2001. Received comments may be seen in the Dockets Management 
Branch between 9 a.m. and 4 p.m., Monday through Friday.

List of Subjects

21 CFR Part 20

    Confidential business information, Courts, Freedom of information, 
Government employees.

21 CFR Part 312

    Drugs, Exports, Imports, Investigations, Labeling, Medical 
research, Reporting and recordkeeping requirements, Safety.

21 CFR Part 601

    Administrative practice and procedure, Biologics, Confidential 
business information.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR parts 20, 312, and 601 be amended as follows:

PART 20--PUBLIC INFORMATION

    1. The authority citation for part 20 continues to read as follows:

    Authority: 5 U.S.C. 552; 18 U.S.C. 1905; 19 U.S.C. 2531-2582; 21 
U.S.C. 321-393, 1401-1403; 42 U.S.C. 241, 242, 242a, 242l, 242n, 
243, 262, 263, 263b-263n, 264, 265, 300u-300u-5, 300aa-1.

    2. Section 20.100 is amended by adding paragraph (c)(43) to read as 
follows:


Sec. 20.100  Applicability; cross-reference to other regulations.

* * * * *
    (c) * * *
    (43) Data and information submitted related to human gene therapy 
or xenotransplantation, in Sec. 601.52 of this chapter.

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

    3. The authority citation for part 312 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371; 42 
U.S.C. 262.

    4. Section 312.42 is amended by adding paragraph (b)(7) to read as 
follows:


Sec. 312.42  Clinical holds and requests for modification.

* * * * *
    (b) * * *
    (7) Clinical hold of any investigation, as defined in Sec. 601.52 
of this chapter, involving human gene therapy or xenotransplantation. 
FDA may place a proposed or ongoing investigation, as defined in 
Sec. 601.52 of this chapter, involving human gene therapy or 
xenotransplantation on clinical hold if it is determined that:
    (i) Any of the conditions in paragraph (b)(1) or (b)(2) of this 
section apply; or
    (ii) The sponsor has not submitted a redacted version of the data 
and information, as specified in Sec. 601.52 of this chapter, for 
public disclosure that complies with the requirements of Sec. 601.53 of 
this chapter.
* * * * *
    5. Section 312.130 is amended by revising paragraph (b) to read as 
follows:


Sec. 312.130  Availability for public disclosure of data and 
information in an IND.

* * * * *
    (b) The availability for public disclosure of all data and 
information in an investigational new drug application for a new drug 
or antibiotic drug will be handled in accordance with the provisions 
established in Sec. 314.430 of

[[Page 4705]]

this chapter for the confidentiality of data and information in 
applications submitted in part 314 of this chapter. The availability 
for public disclosure of all data and information in an investigational 
new drug application for a biological product will be governed by the 
provisions of Secs. 601.50, 601.51, and 601.52 of this chapter.
* * * * *

PART 601--LICENSING

    6. The authority citation for part 601 continues to read as 
follows:

    Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 
355, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216, 
241, 262, 263; sec. 122, Pub. L. 105-115, 111 Stat. 2322 (21 U.S.C. 
355 note).

    7. Section 601.50 is amended by revising the section heading and 
paragraph (a) to read as follows:


Sec. 601.50  Confidentiality of data and information in an 
investigational new drug application for a biological product.

    (a) Except as provided in Sec. 601.52, the existence of an IND 
application for a biological product will not be disclosed by the Food 
and Drug Administration unless it has previously been publicly 
disclosed or acknowledged.
* * * * *
    8. Section 601.51 is amended by revising the section heading and 
paragraph (a) to read as follows:


Sec. 601.51  Confidentiality of data and information in a biologics 
license application.

    (a) For purposes of this section the biological product file 
includes all data and information submitted with or incorporated by 
reference in any biologics license application, IND's incorporated in 
any such application, master files, and other related submissions. 
Except as provided in Sec. 601.52, the availability for public 
disclosure of any record in the biological product file shall be 
handled in accordance with the provisions of this section.
* * * * *
    9. Section 601.52 is added to subpart F to read as follows:


Sec. 601.52  Availability for public disclosure of certain data and 
information related to an IND concerning human gene therapy or 
xenotransplantation.

    (a) Definitions. The following definitions of terms apply to this 
section:
    (1) Human gene therapy means the administration of genetic material 
in order to modify or manipulate the expression of a gene product or to 
alter the biological properties of living cells for therapeutic use. 
Cells may be modified ex vivo for subsequent administration or altered 
in vivo by gene therapy products given directly to the subject.
    (2) Xenotransplantation means any procedure that involves the 
transplantation, implantation, or infusion into a human recipient of 
either: Live cells, tissues, or organs from a nonhuman animal source; 
or human body fluids, cells, tissues, or organs that have had ex vivo 
contact with live nonhuman animal cells, tissues, or organs.
    (b) Scope. Except as otherwise provided in this section, the 
availability for public disclosure of data and information related to 
human gene therapy or xenotransplantation shall be in accordance with 
Secs. 601.50 and 601.51.
    (c) Information for public disclosure. FDA will make available for 
public disclosure the following types of data and information related 
to an IND concerning human gene therapy or xenotransplantation. Names 
and other personal identifiers of patients and, except as specifically 
provided in this section, names and personal identifiers of and third 
party, such as physicians or hospitals, will not be made available for 
public disclosure.
    (1) Product and patient safety data and related information. For 
purposes of this section product and patient safety data and related 
information include results of preclinical and clinical studies and 
tests that demonstrate the safety and/or feasibility of the proposed 
procedures. This may include, but is not necessarily limited to, 
analysis in animals, humans, or in vitro systems of gene transfer, 
expression, and persistence; vector biodistribution; evidence for 
immune response/anergy; biological activity; and results of product 
safety testing including testing for known xenogeneic and human 
infectious agents and replication competent virus; and qualification of 
source herd, individual source animal, and source organ/tissue/cells 
for xenotransplantation in humans. Also included is information on 
monitoring or prevention of potential health risks to the recipient, 
close contacts, and health care workers, such as patient monitoring for 
replication competent retrovirus and viral shedding and measures taken 
to prevent transmission of infectious disease. The availability for 
public disclosure of data and information in an IND safety report or 
annual report, as provided under Secs. 312.32 and 312.33 of this 
chapter, will be governed by the provisions of paragraphs (c)(7) and 
(c)(8) of this section.
    (2) The name and address of the sponsor.
    (3) The clinical indications to be studied.
    (4) A protocol for each planned study, to include:
    (i) A scientific abstract and a nontechnical abstract.
    (ii) A statement of the objectives, purpose, and rationale of the 
study.
    (iii) The name and address of each investigator.
    (iv) The name and address of the official contacts of each local 
review body as appropriate (Institutional Review Board, Institutional 
Biosafety Committee) and the dated copies of each committee's approval 
of the study.
    (v) The criteria for patient selection and exclusion and an 
estimate of the number of patients to be studied.
    (vi) A description of the treatment that will be administered to 
patients and the clinical procedures, laboratory tests, or other 
measures to be taken to monitor the safety and effects of the drug in 
human subjects and to minimize risk.
    (5) Written informed consent form(s) as provided in Sec. 50.27 of 
this chapter.
    (6) Identification of the biological product(s) and a general 
description of the method of production, including a description of 
product features that may affect patient safety. The information shall 
include, as applicable, the vector name and type; gene insert; 
regulatory elements and their source; intended target cells; source of 
cells, tissues, or organ(s); method used to prepare the vector 
containing cells; method used to procure and prepare cells, tissues, or 
organs for xenotransplantation; purity of cells; adventitious agent 
testing; description of the delivery system; ancillary products used 
during production; herd colony and individual source animal health 
maintenance and surveillance records; and biological specimens to be 
archived from source animals.
    (7) IND safety reports, as provided in Sec. 312.32 of this chapter, 
and other similar data and information.
    (8) Information submitted in the annual report to include, as 
applicable, assessment of evidence of gene transfer, gene expression in 
target cells, biological activity, immune response, status of autopsy 
request and evidence of gene transfer and gonadal distribution upon 
autopsy, results from assessment for evidence of infection by agents 
associated with the product, adverse experiences, and a list of 
subjects who died during participation in the investigation, with the 
cause of death for each subject.
    (9) The regulatory status of the IND, such as on hold, in effect, 
inactive, or

[[Page 4706]]

withdrawn, the dates of these actions, and the reasons for these 
actions.
    (10) Other relevant data and information that the Director, CBER, 
determines are necessary for the appropriate consideration of the 
public health and scientific issues, including relevant ethical issues, 
raised by human gene therapy or xenotransplantation.
    10. Section 601.53 is added to subpart F to read as follows:


Sec. 601.53  Submission of certain data and information related to 
human gene therapy or xenotransplantation for public disclosure.

    (a) A sponsor of an IND shall submit to FDA for public disclosure 
in a redacted version the submissions identified in paragraphs (b)(1) 
through (b)(5) of this section. Each submission shall include all 
applicable information identified as disclosable in Sec. 601.52, but 
shall be redacted to remove or obscure all information considered 
confidential as a trade secret, certain confidential commercial 
information, such as information regarding commercial licensing 
agreements or the identification of suppliers, and names and other 
personal identifiers of patients and, except as specifically provided 
in this section, names and personal identifiers of any third party, 
such as physicians or hospitals, must be redacted.
    (b) The following shall be submitted in a suitably redacted version 
and in duplicate at the time points noted:
    (1) Information as defined under Sec. 601.52 at the time of initial 
IND submission.
    (2) Any amendment documenting changes or additions to the 
information as defined under Sec. 601.52 at the time the amendment goes 
into effect.
    (3) IND safety reports at the time of submission of the initial 
report to FDA.
    (4) The annual report, within 60 days of the anniversary date that 
the IND went into effect, in accordance with Sec. 312.33 of this 
chapter.
    (5) Other information upon the specific request of the Director, 
CBER.
    (c) The submissions identified in paragraph (b) of this section 
shall be submitted in a form readily separable from the original 
unabridged submission to FDA and clearly marked on each page of the 
redacted version as suitable for public disclosure.
    (d) Any copies of copyrighted material shall be submitted in a 
single appendix to each redacted version. Copyrighted materials whose 
copyright is not owned by the applicant shall not be included in any 
other section of the redacted versions. A bibliography of copyrighted 
materials contained in the appendix shall be included as part of each 
redacted version.
    (e) Any data or information submitted to FDA as a redacted version 
for public disclosure in accordance with paragraph (a) of this section 
shall be accompanied by the following statement signed by a responsible 
individual:
    The information contained herein has been redacted for public 
disclosure. The only material removed from these records is: 
Confidential commercial or trade secret information exempt from 
disclosure under the Freedom of Information Act (5 U.S.C. 552 (b)(4)) 
and the Food and Drug Administration's implementing regulations (21 CFR 
20.61); names and other personal identifiers of patients and, except as 
specifically provided in the regulations, names and other personal 
identifiers of any third party.

    I declare, under the penalty of perjury, that the foregoing is 
true and correct.
    Dated: December 20, 2000.
Jane E. Henney,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 01-1048 Filed 1-17-01; 8:45 am]
BILLING CODE 4160-01-F