Food and Drug Administration: Decision Process to Deny Initial	 
Application for Over-the-Counter Marketing of the Emergency	 
Contraceptive Drug Plan B Was Unusual (14-NOV-05, GAO-06-109).	 
                                                                 
In April 2003, Women's Capital Corporation submitted an 	 
application to the Food and Drug Administration (FDA) requesting 
the marketing status of its emergency contraceptive pill(ECP),	 
Plan B, be switched from prescription to over-the-counter (OTC). 
ECPs can be used to prevent an unintended pregnancy when	 
contraception fails or after unprotected intercourse, including  
cases of sexual assault. In May 2004, the Acting Director for the
Center for Drug Evaluation and Research (CDER) issued a 	 
"not-approvable" letter for the switch application, citing safety
concerns about the use of Plan B in women under 16 years of age  
without the supervision of a health care practitioner. Because	 
the not-approvable decision for the Plan B OTC switch application
was contrary to the recommendations of FDA's joint advisory	 
committee and FDA review staff, questions were raised about FDA's
process for arriving at this decision. GAO was asked to examine  
(1) how the decision was made to not approve the switch of Plan B
from prescription to OTC, (2) how the Plan B decision compares to
the decisions for other proposed prescription-to-OTC switches	 
from 1994 through 2004, and (3) whether there are age-related	 
marketing restrictions for prescription Plan B and other	 
prescription and OTC contraceptives. To conduct this review, GAO 
examined FDA's actions prior to the May 6, 2004, not-approvable  
letter for the initial application.				 
-------------------------Indexing Terms------------------------- 
REPORTNUM:   GAO-06-109 					        
    ACCNO:   A41397						        
  TITLE:     Food and Drug Administration: Decision Process to Deny   
Initial Application for Over-the-Counter Marketing of the	 
Emergency Contraceptive Drug Plan B Was Unusual 		 
     DATE:   11/14/2005 
  SUBJECT:   Children						 
	     Comparative analysis				 
	     Contraception					 
	     Decision making					 
	     Drugs						 
	     Evaluation methods 				 
	     Internal controls					 
	     Marketing						 
	     Pharmaceutical industry				 
	     Pregnancy						 
	     Product safety					 
	     Public health research				 
	     Teenagers						 
	     Prescription drugs 				 

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GAO-06-109

     

     * Results in Brief
     * Background
          * Studies for Prescription-to-OTC Switches
          * FDA Process for Switching First-in-a-Class Prescription Drug
          * Contraceptives
          * Emergency Contraceptive Plan B
     * Aspects of FDA's Review of the Plan B Switch Application Wer
          * The Acting Director of CDER Rejected the Recommendations of
          * Four Aspects of FDA's Review of the Plan B OTC Switch Applic
               * FDA Officials Normally Responsible for Signing the Action Le
               * High-Level FDA Management Was More Involved Than Usual in th
               * FDA Officials Gave Conflicting Accounts of When the Decision
               * The Acting Director's Rationale for the Not-Approvable Decis
                    * The Acting Director's Rationale Was Based on His
                      Concerns ab
                    * FDA Review Officials Disagreed with the Acting
                      Director's Ra
     * Plan B Decision Was Not Typical of Other Proposed Prescripti
          * Plan B Was the Only Prescription-to-OTC Switch Decision from
          * Plan B Was the Only Prescription-to-OTC Switch Decision from
     * There Are No Age-Related Restrictions for Safety Reasons for
     * Agency Comments and Our Evaluation
     * GAO Contact
     * Acknowledgments
     * GAO's Mission
     * Obtaining Copies of GAO Reports and Testimony
          * Order by Mail or Phone
     * To Report Fraud, Waste, and Abuse in Federal Programs
     * Congressional Relations
     * Public Affairs

Report to Congressional Requesters

United States Government Accountability Office

GAO

November 2005

FOOD AND DRUG ADMINISTRATION

Decision Process to Deny Initial Application for

Over-the-Counter Marketing of the Emergency Contraceptive Drug Plan B Was
Unusual

GAO-06-109

Contents

Letter 1

Results in Brief 5
Background 7
Aspects of FDA's Review of the Plan B Switch Application Were Unusual 13
Plan B Decision Was Not Typical of Other Proposed Prescription-to-OTC
Switch Decisions 29
There Are No Age-Related Restrictions for Safety Reasons for Any
FDA-Approved Contraceptives 30
Agency Comments and Our Evaluation 31
Appendix I Scope and Methodology 36
Appendix II Not-Approvable Letter for the Prescription-to-OTC Switch
Application of Plan B, May 6, 2004 38
Appendix III Timeline of Major Plan B Events Related to the Initial OTC
Switch Application 42
Appendix IV Acting Director of CDER's Official Memorandum Explaining His
Not-Approvable Decision, May 6, 2004 47
Appendix V Director of the Office of New Drugs' Official Memorandum on His
Decision on the Plan B Application, April 22, 2004 50
Appendix VI Comments from the Food and Drug Administration 53
Appendix VII GAO Contact and Staff Acknowledgments 57

Table

Table 1: Brief Timeline of Major Plan B Events Related to the Initial OTC
Switch Application 15

Figure

Figure 1: Flow of an OTC Switch Application through the Decision Process
within CDER for First-in-a-Class Drug 9

Abbreviations

ACRHD Advisory Committee for Reproductive Health Drugs CDER Center for
Drug Evaluation and Research ECP emergency contraceptive pill FDA Food and
Drug Administration NDA new drug application NDAC Nonprescription Drugs
Advisory Committee OTC over-the-counter PDUFA Prescription Drug User Fee
Act PREA Pediatric Research Equity Act sNDA supplemental new drug
application STD sexually transmitted disease WCC Women's Capital
Corporation

This is a work of the U.S. government and is not subject to copyright
protection in the United States. It may be reproduced and distributed in
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separately.

United States Government Accountability Office

Washington, DC 20548

November 14, 2005

Congressional Requesters

In April 2003, Women's Capital Corporation (WCC) submitted an application
to the Food and Drug Administration (FDA) requesting that the marketing
status of its emergency contraceptive pill (ECP), Plan B, be switched from
prescription to over-the-counter (OTC).1 ECPs can be used to prevent
unintended pregnancy when contraception fails or after unprotected
intercourse, including cases of sexual assault. Plan B had been approved
for use as a prescription drug by FDA in 1999 and is most effective when
taken as soon as possible, but no later than 72 hours, after intercourse.
By law, FDA may approve the switch of a prescription drug to OTC status if
use of the drug is safe and effective for self-medication in accordance
with proposed labeling.2 Since 1975, when FDA formalized the current
process for approving prescription-to-OTC switches, FDA has approved
approximately 90 applications to change the marketing status of a
prescription drug to OTC.

According to FDA's operational policies, reviews of OTC switch
applications occur in its Center for Drug Evaluation and Research (CDER).3
OTC switch applications for drugs that are "first-in-a-class,"4 such as
Plan B, are reviewed by two of the six offices of drug evaluation within
CDER-including the Office of Drug Evaluation V, which reviews all OTC
switch applications, and the office of drug evaluation that has the
relevant expertise for the proposed switch drug.5 In addition, CDER can
request a joint meeting of advisory committees that it has established to
seek scientific advice about its decisions from outside experts. The joint
advisory committee meeting is conducted by the advisory committee that has
expertise in OTC drugs and the advisory committee that has relevant
expertise for the proposed OTC switch drug. After review of the OTC switch
application and advice of the joint advisory committee, the directors of
both offices of drug evaluation make a decision. If the directors of the
offices concur on the decision for the application, they generally will
both sign and issue an action letter.6 If the directors do not concur with
one another, the application is sent to the next level of review, the
Director of the Office of New Drugs within CDER, who then makes the
decision and signs and issues the action letter. However, the Director of
CDER can also decide on an application and sign and issue the action
letter.

1FDA defines prescription-to-OTC switch as the OTC marketing of a product
that was once a prescription drug product for the same indication,
strength, dose, duration of use, dosage form, population, and route of
administration. In this report, the phrase "OTC switch" refers to a
prescription-to-OTC switch.

2See 21 U.S.C. S: 353(b)(1); 21 C.F.R. S: 310.200(b) (2005).

3FDA's operational policies are in its manuals of policies and procedures.

4A class of drugs refers to a category based on the chemical ingredients
of the drugs. "First-in-a-class" refers to the first drug to be reviewed
for an OTC switch within a class of drugs.

5In this report, FDA review staff refers to the staff in the Offices of
Drug Evaluation III and V who reviewed the Plan B OTC switch application.
The CDER structure described in this report is the one that existed at
that time.

The Plan B application went to the Office of Drug Evaluation V, which
includes the Division of Over-the-Counter Drug Products, and the Office of
Drug Evaluation III, which includes the Division of Reproductive and
Urologic Drug Products, where it was reviewed. In December 2003, a joint
meeting of two FDA advisory committees, the Nonprescription Drugs Advisory
Committee (NDAC) and the Advisory Committee for Reproductive Health Drugs
(ACRHD), recommended in a vote of 23 to 4 that the proposed OTC switch for
Plan B be approved. FDA review staff also agreed that Plan B should be
granted OTC status. On May 6, 2004, the Acting Director of CDER7 signed a
"not-approvable" letter for the switch to OTC,8 citing safety concerns
about the use of Plan B in women under 16 years of age without the
supervision of a practitioner licensed by law to administer the drug.9 On
July 22, 2004, Barr Pharmaceuticals, Inc.,10 submitted an amended
application for the proposed Plan B switch to market Plan B OTC for women
16 years of age and older and as a prescription drug for those under 16
years of age.11

6An action letter is a written communication to the sponsor from FDA
stating the outcome of the review of an application. The sponsor or
applicant is the person or entity that assumes responsibility for the
marketing of a new drug, including responsibility for compliance with
applicable provisions of the Federal Food, Drug, and Cosmetic Act and
related regulations.

7The current Director of CDER was appointed to this position on July 29,
2005. However, he held the title of Acting Director from fall 2003 until
his appointment. Prior to his appointment to Acting Director, he was
Deputy Director of CDER. Because he was Acting Director during most of the
time covered by this report-for those events associated with the initial
Plan B OTC switch application through the May 6, 2004, decision-we use the
title of Acting Director for him in this report.

Because the not-approvable decision for the initial Plan B OTC switch
application was contrary to the recommendations of the joint advisory
committee and the FDA review staff, you raised questions about FDA's
process for arriving at its decision on the initial application. In this
report, for the initial Plan B OTC switch application, we examined (1) how
the decision was made to not approve the switch of Plan B from
prescription to OTC, (2) how the Plan B decision compares to the decisions
for other proposed prescription-to-OTC switches from 1994 through 2004,
and (3) whether there are age-related marketing restrictions for
prescription Plan B and other prescription and OTC contraceptives.

8A not-approvable letter is a letter to the sponsor from FDA stating that
the agency does not consider the application approvable because of one or
more deficiencies in the application. See 21 C.F.R. S: 314.120. There are
two other types of action letters: the approval letter and the approvable
letter. The approval letter indicates that the application is approved and
the drug may go OTC. An approvable letter is similar to the not-approvable
letter in that there are one or more deficiencies in the application
precluding its approval. See 21 C.F.R. S: 314.110. FDA officials stated
that the difference between a not-approvable letter and an approvable
letter is that a not-approvable letter is generally issued when more
studies are required and an approvable letter is generally issued if there
are sufficient data, but some outstanding concerns still exist.

9Besides physicians, other health care providers, such as nurse
practitioners and physicians' assistants, may be licensed by law to
administer drugs. While only FDA may change a drug's status from
prescription to OTC, the practice of pharmacy is state controlled,
allowing each state to decide who may prescribe a drug. While most states
do not allow pharmacists to prescribe drugs, eight states (Alaska,
California, Hawaii, Maine, Massachusetts, New Hampshire, New Mexico, and
Washington) allow pharmacists to prescribe ECPs or provide them in
accordance with approved physician protocols.

10In February 2004, WCC sold the rights to market Plan B to Barr
Pharmaceuticals, Inc. In October 2003, as the purchase of Plan B by Barr
Pharmaceuticals, Inc., was being finalized, Barr began acting as the agent
for WCC regarding Plan B.

11On August 26, 2005, FDA announced it had completed its review of the
amended application and concluded that the scientific data were sufficient
to support the safe use of Plan B in an OTC setting for women 17 years of
age and older. However, FDA delayed taking action on the amended
application to seek public comment on marketing issues related to this
decision. See also Drug Approvals: Circumstances Under Which an Active
Ingredient May Be Simultaneously Marketed in Both a Prescription Drug
Product and an Over-the-Counter Drug Product, 70 Fed. Reg. 52050 (2005).
Accordingly, as of November 4, 2005, Plan B may not be legally marketed
OTC.

To address our objectives, we examined documents, including the official
minutes from meetings of FDA staff and the written reviews of the adequacy
of the Plan B OTC switch application prepared by FDA staff in the Offices
of Drug Evaluation III and V and the Office of New Drugs, related to the
review of, and decision on, the Plan B OTC switch application, and we
interviewed FDA staff and officials who conducted the reviews and were
involved in the decision. We also reviewed FDA's manuals of policies and
procedures and The CDER Handbook to determine how FDA considers an
application to switch a drug from prescription to OTC.12 We interviewed
members of FDA's two advisory committees that met jointly to discuss the
Plan B OTC switch application, and we reviewed the transcript of its
meeting. We compared the FDA decision for Plan B to FDA's decisions for
other proposed prescription-to-OTC switch applications from 1994 through
2004. We interviewed officials from Barr Pharmaceuticals, Inc., the
company currently sponsoring the Plan B application for the
prescription-to-OTC switch, and WCC, the original sponsor of the Plan B
switch application. In addition, we reviewed documents and interviewed FDA
officials regarding age-related marketing restrictions for prescription
Plan B and other prescription and OTC contraceptives. We also interviewed
representatives from the American College of Obstetricians and
Gynecologists, the American Academy of Pediatrics, Concerned Women for
America, and the Planned Parenthood Federation of America, Inc., regarding
FDA's safety concerns for Plan B and other contraceptives. Our work
examined only events and communications within FDA and between FDA and the
Plan B sponsor; we did not consider any communications that may have
occurred between FDA officials and other executive agencies. Our work
examined only FDA's actions prior to the May 6, 2004, not-approvable
letter for the initial application, and we did not examine aspects of
FDA's subsequent deliberations about Plan B. (See app. I for details
regarding our scope and methodology and app. II for a copy of the May 6,
2004, not-approvable letter for the initial application.) We conducted our
work from September 2004 through November 2005 in accordance with
generally accepted government auditing standards.

12The CDER Handbook contains information on the center's processes and
activities. It was created for industry officials, health professionals,
academics, and the general public, and it is available at
www.fda.gov/cder/handbook/startpag.htm (downloaded Dec. 8, 2004).

                                Results in Brief

On May 6, 2004, the Acting Director of CDER rejected the recommendations
of the joint advisory committee and FDA review officials by signing the
not-approvable letter for the Plan B switch application, concluding a
review process that began on April 16, 2003, when WCC submitted a standard
supplemental new drug application (sNDA) requesting that Plan B be made
available without a prescription. While FDA followed its general
procedures for considering the application, four aspects of FDA's review
process were unusual. First, the Directors of the Offices of Drug
Evaluation III and V, who would normally have been responsible for signing
the Plan B action letter, disagreed with the decision and did not sign the
not-approvable letter for Plan B. The Director of the Office of New Drugs
also disagreed and did not sign the letter. Second, FDA's high-level
management was more involved in the review of Plan B than in those of
other OTC switch applications. For example, FDA review staff told us that
they were told early in the review process that the decision would be made
by high-level management. Third, as documented in the reviews of FDA staff
and in our interviews with FDA officials, there are conflicting accounts
of whether the decision to not approve the application was made before the
reviews were completed. Fourth, the rationale for the Acting Director of
CDER's decision was novel and did not follow FDA's traditional practices.
Specifically, the Acting Director was concerned about the potential impact
that the OTC marketing of Plan B would have on the propensity for younger
adolescents to engage in unsafe sexual behaviors because of their lack of
cognitive maturity compared to older adolescents. He also stated that it
was invalid to extrapolate data from older to younger adolescents in this
case. FDA review officials noted that the agency has not considered
behavioral implications due to differences in cognitive development in
prior OTC switch decisions and that the agency has considered it
scientifically appropriate to extrapolate data from older to younger
adolescents.

The decision to not approve the Plan B OTC switch application was not
typical of the other 67 prescription-to-OTC switch decisions made from
1994 through 2004. FDA's joint advisory committee considered 23 OTC switch
applications during this period; the Plan B OTC switch application was the
only 1 of those 23 that was not approved after the joint committee voted
to recommend approval of the application. Also, the Plan B action letter
was the only one signed by the Director of CDER, in this case the Acting
Director of CDER, instead of the directors of the offices or divisions
that reviewed the application, who would normally sign an action letter.

There are no age-related marketing restrictions for safety reasons for any
of the prescription or OTC contraceptives that FDA has approved, and FDA
has not required pediatric studies for them. All FDA-approved OTC
contraceptives are available to anyone, and all FDA-approved prescription
contraceptives are available to anyone with a prescription. For hormonal
contraceptives, FDA assumes that suppression of ovulation would be the
same for any female after menarche,13 regardless of age. FDA did not
identify any issues that would require age-related restrictions in its
review of the original application for prescription Plan B, and
prescription Plan B is available to women of any age.

In its comments on a draft of this report, FDA disagreed with three of our
findings. First, FDA disagreed with our finding that the involvement of
high-level management in the Plan B decision was unusual because their
involvement is likely in high-profile and controversial regulatory
decisions. Although we agree that high-level management involvement is
more likely to occur with high-profile regulatory decisions, we found that
the level of high-level management involvement for the Plan B decision was
unusual for OTC switch applications. The other examples of high-level
management involvement given to us by FDA officials during the course of
our work involved decisions about the marketing of prescription drugs.
Second, FDA disagreed with our discussion about when the decision to deny
the switch application was made. We maintain that the draft report
accurately noted that FDA officials gave us conflicting accounts about
when they believed the not-approvable decision was made. Third, FDA
disagreed with our finding that the Acting Director of CDER's rationale
for denying the application was novel and did not follow FDA's traditional
practices. We found that the Acting Director's rationale was novel because
it explicitly considered the differing levels of cognitive maturity of
adolescents of different ages, and that, because of the Acting Director's
views about these differences in cognitive maturity, he concluded that it
was inappropriate to extrapolate data related to risky sexual behavior
from older to younger adolescents. The Acting Director acknowledged to us
that considering adolescents' cognitive development as a rationale for a
not-approvable decision was unprecedented for an OTC application. In
addition, other FDA officials told us that the agency had not previously
considered whether younger adolescents would use a product differently
than older adolescents. Therefore, we believe that our finding is correct
and we have revised the report to more clearly describe the reasons for
our finding.

13Menarche is the initial menstrual period, normally occurring between a
female's 9th and 17th year.

                                   Background

Within FDA, CDER oversees the switch of drugs from prescription to OTC.
Generally, prescription drugs are drugs that are safe for use only under
the supervision of a health care practitioner. Approved prescription drugs
that no longer require such supervision may be marketed OTC.14 In applying
this standard, FDA will authorize a prescription-to-OTC switch only after
it is determined that the drug in question has met the following FDA
criteria: (1) it has an acceptable safety profile based on prescription
use and experience;15 (2) it has a low potential to be abused; (3) it has
an appropriate safety and therapeutic index;16 (4) it has a positive
benefit-risk assessment; and (5) it is needed for a condition or illness
that is self-recognizable, self-limiting,17 and requires minimal
intervention by a health care practitioner for treatment.18 FDA tries to
determine if the OTC availability of a prescription drug will prevent or
delay someone from seeking needed medical attention.

One class of OTC drugs switched from prescription status, the nicotine
products (such as Nicorette gum), has restricted access based on age-they
are available OTC only to persons 18 years of age or older.

Studies for Prescription-to-OTC Switches

Generally, drugs considered for a prescription-to-OTC switch involving the
same indication, strength, dose, duration of use, dosage form, patient
population, and route of administration as the prescription drug require
fewer new studies regarding safety and efficacy because such studies have
already been submitted as part of the original new drug application
(NDA).19 FDA also requires sponsors to address concerns related to
consumers' ability to self-diagnose and self-treat the condition. Thus,
sponsors generally submit additional studies, such as an actual use study,
which examines consumers' ability to self-diagnose, and a label
comprehension study, which examines how consumers interpret the drug's
proposed label. In addition to these actual use and label comprehension
studies, FDA requires sponsors to submit updated safety information on
adverse events reported for the prescription form of the drug.

14See 21 U.S.C. S: 353(b)(1), 21 C.F.R. S: 310.200(b).

15An appropriate safety profile means that a drug that has been on the
market has proven that it continues to be safe.

16The safety and therapeutic index is the ratio between the toxic dose and
the therapeutic dose of a drug and is used as a measure of the relative
safety of the drug for a particular treatment.

17A self-limiting condition or illness is one that without treatment runs
a definite course within a limited period.

18These criteria are from the transcript of the joint advisory committee
meeting held on December 16, 2003, to discuss the Plan B OTC switch
application. They were presented by an FDA official at the meeting.

FDA Process for Switching First-in-a-Class Prescription Drug to OTC

Figure 1 shows the flow of an OTC switch application of a first-in-a-class
drug through the decision process within CDER. To begin the process for a
prescription-to-OTC switch, the sponsor submits an efficacy supplement to
an approved NDA.20 This sNDA is sent to the FDA Office of Drug Evaluation
that oversaw the original NDA and usually is the office with relevant
expertise. This Office of Drug Evaluation is generally responsible for
reviews of the primary effectiveness data and safety results. After an
application has been determined to be complete, a reviewer from this
office assesses the design, general effectiveness, and safety of the
product. If the application is determined to be incomplete, this office
will issue a "refusal to file" letter to the sponsor, detailing the
omissions or inadequacies that led to this decision.

19Drugs that involve a different indication, strength, dose, duration of
use, dosage form, patient population, or route of administration may
require additional efficacy and safety studies. For example, the OTC
switch of ibuprofen in 1984 was for a lower dose than prescription
ibuprofen and, therefore, required new studies showing the efficacy of the
lower dose.

20An efficacy supplement may include a submission for proposed changes in
the labeling of an approved product for a new indication, new dosage
regimen, or significant alteration in the patient population.

Figure 1: Flow of an OTC Switch Application through the Decision Process
within CDER for First-in-a-Class Drug

Note: As part of their decision process, the Offices of Drug Evaluation
also get input from CDER's Office of Drug Safety. They also may convene a
meeting of advisory committees.

When an Office of Drug Evaluation with relevant expertise receives a
fileable sNDA for an OTC drug switch, it notifies the Office of Drug
Evaluation V and its Division of Over-the-Counter Drug Products, which has
relevant expertise in OTC drug products. Generally, the Office of Drug
Evaluation V oversees the review of (1) the suitability of the product for
OTC use and (2) safety experiences during the marketing of the
prescription product. A reviewer from this office assesses studies related
to OTC marketing, including the actual use and label comprehension
studies. CDER's Office of Drug Safety conducts additional reviews of the
label comprehension studies, reviews postmarketing safety data of the
prescription drug, and provides reports to reviewing staff in other
offices upon request.

FDA can convene advisory committee meetings for prescription-to-OTC switch
applications. Advisory committees include outside experts, such as medical
professionals and researchers, who provide FDA with independent advice and
recommendations. Members review data submitted by the sponsor or presented
by FDA review staff, address questions, and vote, either supporting or
opposing a switch from prescription-to-OTC status. Advisory committees
conduct open meetings and offer members of the public the opportunity to
express their views. FDA considers the advisory committees'
recommendations in its deliberations. However, the agency decides whether
to adopt these recommendations on a case-by-case basis and is not required
to follow the committees' recommendations.

FDA review staff from the appropriate offices of drug evaluation review
the data presented, interpret the findings, and make recommendations to
the respective office directors on whether the proposed OTC switch should
be approved. Once these reviews are completed, they are sent to the
directors of both the office of drug evaluation with relevant expertise
and the Office of Drug Evaluation V. If both directors agree with each
others' review recommendation, the directors of the relevant offices of
drug evaluation prepare an action package21 and an appropriate action
letter for review, concurrence, and their final signatures. If the office
directors do not concur on the decision, the application is reviewed by
the Office of New Drugs. The Director of CDER is not directly involved in
the approval of all drugs, but may overrule the decisions of subordinate
officials.

21An action package is a compilation of (1) FDA-generated documents
related to the review from submission to final action of an NDA or
efficacy supplement from the sponsor; (2) documents, such as meeting
minutes and pharmacology reviews, pertaining to the format and content of
the application; and (3) labeling submitted by the sponsor.

The authority to approve an OTC switch application ultimately rests with
the Secretary of Health and Human Services. This approval authority is
delegated to the Commissioner of FDA, then to other high-level management
officials, and eventually to other FDA officials within lower levels of
the agency. This delegated authority allows decisions to be made at lower
levels within the agency but assumes that management agrees with these
decisions. The FDA Commissioner and other officials within the Office of
the Commissioner usually do not have a role in OTC switch decisions, but
have the authority to overrule the decisions of other FDA officials.

Contraceptives

There are several types of contraceptive drugs and devices, including
barrier methods, intrauterine devices, spermicides, and hormonal methods.
Several types of hormonal methods of contraception are available,
including birth control pills, injectable hormones, hormonal implants, and
ECPs. FDA has approved two ECPs, Preven and Plan B, for use by
prescription, and Plan B is the first drug in its class to go through the
review process by FDA to determine whether it should be allowed to be sold
OTC.22 ECPs are high dose birth control pills and have been available by
prescription since 1998, when FDA approved Preven, a dedicated23 combined
ECP containing the hormones estrogen and progestin.24 Prior to 1998, many
physicians instructed patients to take higher doses of oral contraceptive
pills for emergency contraception, an "off-label" use.25

22In 1997, a notice in the Federal Register stated that the Commissioner
of FDA had concluded that certain combined oral contraceptives containing
ethinyl estradiol and norgestrel or levonorgestrel are safe and effective
for use as emergency contraception, and requested submission of NDAs for
this use. See Prescription Drug Products; Certain Combined Oral
Contraceptives for Use as Postcoital Emergency Contraception, 62 Fed. Reg.
8610 (1997). In 2004, the manufacturer stopped production of Preven.

23A dedicated ECP is a drug expressly meant for use as an ECP;
levonorgestrel is a synthetic progestin commonly used in birth control
pills.

24Estrogen is a hormone that is responsible for cyclic changes in the
vagina and uterus. Progestin is a hormone that prepares the endometrium
for implantation of the fertilized egg. These hormones in oral birth
control pills suppress ovulation.

Emergency Contraceptive Plan B

Plan B is a dedicated ECP containing only levonorgestrel, a type of
progestin. The Plan B regimen is a two-pill dose of levonorgestrel (0.75
mg each) that is most effective when the first pill is taken as soon as
possible, but no later than 72 hours, after contraceptive failure or
unprotected intercourse. The second pill is taken 12 hours after the first
pill. Research suggests that a levonorgestrel-only hormone regimen, such
as Plan B, can reduce the risk of pregnancy by 89 percent if taken within
the 72-hour window.26 The time constraint for maximum effectiveness
associated with Plan B has led many in the medical community and some
reproductive health advocates to support switching Plan B to OTC, making
it more readily available when needed. In addition, levonorgestrel-only
regimens, such as Plan B, have fewer side effects than the combined ECP,
reducing the incidence of two common side effects, nausea and vomiting, by
50 percent and 70 percent, respectively.

Research has shown that levonorgestrel-only hormonal emergency
contraception, such as Plan B,27 interferes with prefertilization events.
It reduces the number of sperm cells in the uterine cavity, immobilizes
sperm, and impedes further passage of sperm cells into the uterine cavity.
In addition, levonorgestrel has the capacity to delay or prevent ovulation
from occurring.28

25Off-label drug use occurs when physicians prescribe a drug for clinical
indications other than those listed on the label.

26World Health Organization, "Randomized Controlled Trial of
Levonorgestrel Versus the Yuzpe Regimen of Combined Oral Contraceptives
for Emergency Contraception," The Lancet, vol. 352 (1998): 428-433.

27Horacio B. Croxatto and others, "Mechanism of Action of Hormonal
Preparations Used for Emergency Contraception: A Review of the
Literature," Contraception, vol. 63 (2001): 111-121; and H.B. Croxatto and
others, "Pituitary-Ovarian Function Following the Standard Levonorgestrel
Emergency Contraceptive Dose or a Single 0.75-mg Dose Given on the Days
Preceding Ovulation," Contraception, vol. 70 (2004): 442-450.

28Ovulation occurs when a mature egg is released from the ovary, is pushed
down the fallopian tube, and is available to be fertilized.

ECPs have not been shown to cause a postfertilization event-a change in
the uterus that could interfere with implantation of a fertilized egg.29
Some researchers argue that an interference with the implantation of a
fertilized egg is unlikely to happen because progestins, whether natural
or synthetic, help to sustain pregnancy.30 In addition, there is no
evidence that one burst of levonorgestrel without estrogen can prevent
implantation. However, researchers have concluded that the possibility of
a postfertilization event cannot be ruled out, noting that it would be
unethical and logistically difficult to conduct the necessary research.31
ECPs, including Plan B, do not interfere with an established pregnancy.

     Aspects of FDA's Review of the Plan B Switch Application Were Unusual

On May 6, 2004, the Acting Director of CDER rejected the recommendations
of a joint advisory committee and FDA review officials and signed the
not-approvable letter for the Plan B OTC switch application. Four aspects
of FDA's review process were unusual: officials who would normally have
been responsible for signing an action letter disagreed with the decision
and did not sign the not-approvable letter for Plan B; high-level
management was more involved than for other OTC switch applications;
conflicting accounts exist of whether the decision to not approve the
application was made before the reviews were completed; and the rationale
for the not-approvable decision was novel and did not follow FDA's
traditional practices.

The Acting Director of CDER Rejected the Recommendations of a Joint Advisory
Committee and FDA's Review Officials

On May 6, 2004, the Acting Director of CDER rejected the recommendations
of a joint advisory committee and FDA review officials by signing the
not-approvable letter for the Plan B OTC switch application. This action
concluded a review process that began on April 16, 2003, when WCC
submitted a standard sNDA requesting that Plan B be made available without
a prescription. In the OTC switch application, the proposed OTC dose and
administration schedule were identical to that for Plan B's prescription
use. The application also included an actual use study and a label
comprehension study to assess potential users' understanding of how to
administer the product.

29Implantation is the embedding of the fertilized egg in the uterus six or
seven days after fertilization. See A.L. Muller and others, "Postcoital
Treatment with Levonorgestrel Does Not Disrupt Postfertilization Events in
the Rat," Contraception, vol. 67 (2003): 415-419.

30Horacio B. Croxatto, Maria E. Ortiz, and Andres L. Muller, "Mechanisms
of Action of Emergency Contraception," Steroids, vol. 68 (2003):1095-1098.

31It has not been possible to identify groups of women who had taken ECPs
after fertilization so as to assess their effect on the establishment of a
pregnancy. Therefore, there is no direct evidence, either for or against,
the hypothesis that ECPs prevent pregnancy by affecting postfertilization
events. See Croxatto, Ortiz, and Muller, "Mechanisms of Action of
Emergency Contraception," 1096.

Following FDA's procedures for a review of an OTC switch application, the
sNDA was submitted to the Office of Drug Evaluation III-which includes the
Division of Reproductive and Urologic Drug Products, whose staff also
reviewed the prescription Plan B application. Table 1 includes a brief
timeline of events involving Plan B and the initial OTC switch
application. (See app. III for a more detailed timeline.) On June 9, 2003,
review staff within the Office of Drug Evaluation III determined the Plan
B sNDA to be fileable and accepted it for review. The sNDA was then
submitted to the Office of Drug Evaluation V-which includes the Division
of Over-the-Counter Drug Products, whose staff have expertise with OTC
drugs-for concurrent review, also in accordance with FDA's review
procedures. FDA also convened a joint public meeting of two of its
advisory committees-the NDAC and the ACRHD-during which the committees'
members reviewed documentation and voted on answers to specific questions
asked by FDA review staff from both offices, including whether Plan B
should be granted OTC marketing status. On December 16, 2003, the members
of the joint advisory committee voted 23 to 4 to recommend approving a
switch in Plan B's marketing status from prescription to OTC.32 Members of
the joint advisory committee also voted on other aspects of the Plan B
application. For example, members voted 27 to 1 that Plan B could be
appropriately used as recommended by the label and that the actual use
data were generalizable to the overall population, including adolescents.

32For this particular vote, 12 out of 13 members on the NDAC voted in
favor of the proposed OTC switch for Plan B and 11 out of 15 members on
the ACRHD also supported the switch (the final vote was 23 to 4 because 1
of the committee members of the ACRHD left before the vote). In addition,
1 advisory committee member submitted a letter to FDA, outlining why Plan
B should not be approved for OTC use. Media reports have suggested that
this letter was requested by someone within FDA. In its technical comments
on a draft of this report, FDA stated that this letter was not solicited
by the agency and noted that the letter itself does not represent that the
agency requested the letter. We found that all of the points raised in the
letter were already part of the public record because they had been
discussed at the advisory committee meeting.

Table 1: Brief Timeline of Major Plan B Events Related to the Initial OTC
Switch Application

Date               Event                                                   
July 28, 1999      FDA approved Plan B as a prescription form of emergency 
                      contraception.                                          
April 18, 2002     Review staff within the Office of Drug Evaluation III   
                      denied WCC's proposal that FDA request that it conduct  
                      two pediatric studies-a pharmacokinetic study and a     
                      safety study-on the use of prescription Plan B in       
                      subjects as young as 12 years of age in exchange for    
                      extending the drug's market exclusivity for 6 months,   
                      as permitted under the Federal Food, Drug, and Cosmetic 
                      Act.a                                                   
June 5, 2002       A briefing for the Office of the Commissioner was held  
                      to discuss the expected application to switch Plan B to 
                      OTC. Meeting attendees included the Deputy              
                      Commissioner,b the agency's Chief Counsel, the          
                      then-Director of CDER, the Director of the Office of    
                      New Drugs, and review staff within the Offices of Drug  
                      Evaluation III and V.                                   
September 23, 2002 FDA officials within the Office of New Drugs and the    
                      Offices of Drug Evaluation III and V and the sponsor    
                      held a meeting during which FDA officials provided      
                      guidance on the OTC switch application, which was to be 
                      submitted. According to meeting minutes, FDA officials  
                      and the sponsor discussed behavioral issues in          
                      adolescents and the possibility of a behind-the-counter 
                      option or a possible age restriction.c                  
April 16, 2003     WCC submitted an sNDA to FDA to allow Plan B to be sold 
                      OTC.                                                    
June 9, 2003       FDA set a Prescription Drug User Fee Act (PDUFA) goal   
                      date of February 22, 2004, to reach a decision on the   
                      application.d                                           
December 16, 2003  At a joint meeting of the NDAC and the ACRHD, members   
                      voted 23 to 4 to recommend approving the switch of Plan 
                      B from prescription to OTC.                             
January 15, 2004   A meeting was held during which the Acting Director of  
                      CDER informed review staff within the Offices of Drug   
                      Evaluation III and V that a not-approvable decision was 
                      "recommended" by the Office of the Commissioner.        
                      Minutes from this meeting also noted that attendees     
                      agreed that review staff would complete their reviews   
                      and collect additional data to be presented to the      
                      Commissioner and the Acting Director of CDER some time  
                      in February.                                            
                                                                              
                      Review staff within the Offices of Drug Evaluation III  
                      and V later noted in their completed reviews of the     
                      Plan B application that they were told at this meeting  
                      that the decision on the Plan B application would be    
                      made at a level higher than the Offices of Drug         
                      Evaluation.                                             
January 21, 2004   A memorandum from the Director of the Office of Drug    
                      Evaluation V concluded that adequate data had been      
                      submitted to approve Plan B for OTC marketing.          
January 23, 2004   A meeting was held between FDA officials within the     
                      Office of New Drugs and the Offices of Drug Evaluation  
                      III and V and Barr Pharmaceuticals, Inc./WCC. According 
                      to meeting minutes, FDA officials told the sponsor that 
                      the decision on the application would be made at a      
                      level higher than the Offices of Drug Evaluation. The   
                      Director of the Office of New Drugs told the sponsor    
                      that such a high-level decision was not typical.        
February 2, 2004   Review staff within the Office of Drug Evaluation III   
                      requested that the sponsor reanalyze the adolescent     
                      data of the Plan B actual use study for those under 18  
                      years of age.                                           
February 13, 2004  FDA confirmed that it had extended the PDUFA goal date  
                      for a decision on the Plan B switch application for 90  
                      days due to the submission of the requested reanalysis  
                      of adolescent data from the actual use study by the     
                      sponsor. The extended PDUFA goal date was May 21, 2004. 
February 18, 2004  A briefing was held during which review staff within    
                      the Offices of Drug Evaluation III and V presented      
                      their analysis of additional summary data to the        
                      Commissioner on the use and behavior of adolescents in  
                      association with increased access to ECPs. According to 
                      meeting minutes, review staff recommended that Plan B   
                      have an OTC marketing status without restriction. The   
                      meeting minutes also noted that the Commissioner        
                      directed CDER to work with the sponsor on a marketing   
                      plan to limit the availability of Plan B in an OTC      
                      setting and to consider the most appropriate ages that  
                      should be restricted from OTC access.                   
February 26, 2004  Barr Pharmaceuticals, Inc., completed acquisition of    
                      the marketing rights of Plan B from WCC.                
April 2, 2004      The Deputy Director of the Office of Drug Evaluation    
                      III completed the office's review of the Plan B         
                      application in which she recommended that the product   
                      be approved for use as an emergency contraceptive in    
                      the OTC setting without age restriction.                
April 22, 2004     The Director of the Office of New Drugs issued his      
                      review, in which he concurred with the recommendations  
                      of both Offices of Drug Evaluation III and V. In his    
                      review, he recommended that the application be approved 
                      to permit OTC availability of Plan B without age        
                      restriction.                                            
May 2, 2004        According to an internal FDA e-mail, the Acting         
                      Director of CDER contacted the Director of the Office   
                      of Pediatric Therapeutics, requesting assistance on     
                      language regarding cognitive development in             
                      adolescents.                                            
May 5, 2004        A teleconference was held during which the Acting       
                      Director of CDER informed Barr Pharmaceuticals, Inc.,   
                      officials of the not-approvable action and asked        
                      permission to release the not-approvable letter.        
                      According to FDA regulations, without consent of the    
                      sponsor, the agency cannot publicly release data or     
                      information contained in an application before an       
                      approval letter is issued.e                             
May 6, 2004        FDA issued a not-approvable letter, denying Plan B OTC  
                      marketing status, citing a lack of adequate data        
                      regarding safe use among younger adolescents.           

Source: GAO analysis of FDA data.

aSee 21 U.S.C. S: 355a(b), (c). FDA may request that manufacturers of new
or already-marketed drugs conduct studies of their drugs in pediatric
populations where it believes that such studies will lead to additional
health benefits. Studies completed in accordance with FDA requirements
entitle the manufacturer to an additional 6 months of marketing
exclusivity. In its technical comments on the draft of this report, FDA
stated that it did not ask for pediatric data for the prescription version
of Plan B because the product's physiological effects are the same in
younger and older women and because a health care practitioner is involved
in dispensing prescription drugs.

bOn September 23, 2005, the Commissioner of FDA, who was appointed on July
18, 2005, resigned from his position. He held the title of Deputy
Commissioner from February 24, 2002, until March 26, 2004, when he was
named Acting Commissioner. Because he was Deputy Commissioner during most
of the time covered by this report-for those events associated with the
initial Plan B switch application through the May 6, 2004, decision-we use
the title of Deputy Commissioner for him in this report.

cBehind-the-counter is defined as a classification of drug products that
do not require a prescription but are also unlike OTC products in that
there is a measure of clinical oversight in their use. For
behind-the-counter products, pharmacists are able to intervene by advising
patients on the product's proper use and associated risks and by referring
them to their physicians when appropriate. See Robert I. Field, "Support
Grows for a Third Class of `Behind-the-Counter' Drugs," Pharmacy and
Therapeutics, vol. 30, no.5 (2005): 260-261.

dFDA, in collaboration with various stakeholders, including
representatives from consumer, patient, and health care provider groups
and the pharmaceutical and biotechnology industries, has developed
performance goals for the time to complete the review of an application
submitted to the agency. These goals have been incorporated by reference
into PDUFA.

eSee 21 C.F.R. S: 314.430(d)(1).

A meeting was held on January 15, 2004, between officials within the
office of the CDER Director and review staff within the Offices of Drug
Evaluation III and V about the Office of the Commissioner's position on
the acceptability of the Plan B OTC switch application. FDA's minutes from
this meeting stated that the Acting Director of CDER informed review staff
that a not-approvable letter was "recommended" based on the need for more
data to clearly establish appropriate use in younger adolescents.33
Meeting minutes also stated that the Acting Director of CDER raised
multiple issues, including the "very limited data" on younger adolescents
in the actual use and label comprehension studies and concerns about
younger adolescents' ability to appropriately use Plan B without a learned
intermediary, such as a physician.34 The minutes also noted that the
Acting Director of CDER raised possible options to address these concerns,
including asking the sponsor to collect more data to show appropriate use
by those 18 years of age and under or by limiting the availability of the
product by, for example, restricting distribution to minors or restricting
pharmacy access to a behind-the-counter option.35 According to review
staff within the Offices of Drug Evaluation III and V who we spoke with
and as documented in their respective reviews, at this January 2004
meeting the Acting Director of CDER also told them that the decision on
the Plan B OTC switch application would be made at a "level higher than
them [the Offices of Drug Evaluation]."36

At this January 2004, meeting, review staff said they also told the Acting
Director of CDER that they had not yet completed their reviews and that
additional data existed on the use of ECPs in younger adolescents of which
high-level management might not be aware. According to meeting minutes, it
was agreed that review staff would complete their reviews as well as
obtain these data and present them to the Commissioner, who had expressed
a willingness to meet with review staff to further discuss the data and
these concerns. Review staff told us they then requested additional data
from the sponsor and contacted academic researchers in the United States
as well as international researchers about ongoing studies examining
younger adolescents and behavioral changes associated with increased
access to ECPs.37 Review staff identified five additional studies in which
ECPs were provided in advance to study participants. Review staff also
reevaluated data previously submitted with the Plan B OTC switch
application.

33Minutes of internal FDA meetings discussed in this report were written
either by a staff member within the Office of Drug Evaluation III or by
the Executive Secretariat within the Office of the Commissioner. For
meeting minutes written by the staff member within the Office of Drug
Evaluation III, attendees either reviewed or concurred with the minutes
and documented this by including their names at the end of the minutes.
For summaries written by the Executive Secretariat, there was no
documentation of a review or of concurrence by attendees. FDA officials
told us that summaries from meetings within the Office of the Commissioner
are not reviewed or concurred with by attendees. The minutes for the
January 15, 2004, meeting were written by a staff member within the Office
of Drug Evaluation III.

34For this report, "younger adolescents" refers to postmenarcheal women 16
years of age and under.

35Behind-the-counter is defined as a classification of drug products that
do not require a prescription but are also unlike OTC products in that
there is a measure of clinical oversight in their use. For
behind-the-counter products, pharmacists are able to intervene by advising
patients on the product's proper use and associated risks and by referring
them to their physicians when appropriate. See Field, "Support Grows for a
Third Class of `Behind-the-Counter' Drugs," 260.

36According to FDA officials we spoke with and FDA's manuals of policies
and procedures we reviewed, because Plan B is a first-in-the-class drug,
authority for deciding the action on the application would normally be
delegated to the directors of the reviewing offices of drug evaluation.

On February 18, 2004, review staff within the Offices of Drug Evaluation
III and V presented their findings to high-level management, including the
Commissioner and the Acting Director of CDER. According to interviews with
officials from the Office of New Drugs and review staff within the Offices
of Drug Evaluation III and V, and as documented in their respective
reviews of the Plan B application, they said these data provided
sufficient evidence that there was neither an increase in risky behaviors
nor any difference in appropriate use between younger adolescents and
older populations. According to FDA's minutes of this meeting, the
Commissioner expressed multiple points, including the potential for
changes in future contraceptive behaviors after adolescents took Plan B
and that counseling by a learned intermediary might be beneficial,
particularly for adolescents.38 He also noted that he was not convinced
that the additional studies used as evidence had "enough power" to
determine if behavioral differences existed between adults and
adolescents.39 According to the minutes, the meeting ended with the
conclusion that CDER staff would continue working with the sponsor on a
"marketing plan to limit availability of the product over the counter and
to consider the most appropriate age groups to be restricted from access
to the product." In addition, according to meeting minutes, the
Commissioner requested a "rapid action" on the Plan B OTC switch
application.40

37When FDA requested additional adolescent-use data from the sponsor,
review staff determined that the data submitted were sufficient to warrant
a major amendment to the sNDA. Thus, on February 13, 2004, FDA confirmed
that it had extended the PDUFA goal date for the decision on the Plan B
OTC switch application by 90 days from its original PDUFA goal date of
February 22, 2004. The extended PDUFA goal date was May 21, 2004.

38These meeting minutes were written by a staff member within the Office
of Drug Evaluation III.

39Having enough power means having a sample size large enough to
statistically detect actual differences between two groups.

Four Aspects of FDA's Review of the Plan B OTC Switch Application Were Unusual

Aspects of FDA's review of the Plan B OTC switch application were unusual
compared to the agency's regular review process. First, the FDA officials
who would normally sign an action letter for an OTC switch application
disagreed with the decision and did not sign the Plan B not-approvable
letter; as a result, the Acting Director of CDER did so. Second, the
review process for the Plan B OTC switch application was marked by a level
of involvement by FDA high-level management that has not been typical for
OTC switch applications. Third, conflicting accounts exist regarding when
the decision to deny the application was made. Finally, the Acting
Director of CDER's rationale for denying the application was novel for an
OTC switch decision.

  FDA Officials Normally Responsible for Signing the Action Letter Did Not Do So

By early April 2004, the reviews from the Offices of Drug Evaluation III
and V were completed. The directors of these offices agreed with the
recommendations of the joint advisory committee and review staff that Plan
B should be made available without a prescription. Nonetheless, the office
directors told us that they were asked by high-level management to draft a
not-approvable letter. Both office directors also told us they did not
agree with a not-approvable action and did not sign the not-approvable
letter.

The issue was then raised to the Office of New Drugs. The Director of the
Office of New Drugs reviewed the staff's analysis of the application and
concurred with the recommendations of both office directors. He also did
not sign the not-approvable letter. The Director of the Office of New
Drugs told us that it was "very, very rare" that his office would become
involved in the signing of an action letter. According to FDA manuals of
policies and procedures and The CDER Handbook, the Office of New Drugs
would review decisions from the offices of drug evaluation only if there
was disagreement between these two reviewing offices. In the case of Plan
B, there was no disagreement between the two reviewing offices of drug
evaluation on the approvability of the application.

40We attempted to interview the individual who had been the Commissioner
of FDA until March 2004. We were unable to arrange an interview, and he
did not respond to written questions we submitted. However, he did provide
a written comment to us. The former Commissioner noted that the initial
Plan B decision was made after he left FDA and that his interactions with
the Acting Director of CDER and other FDA staff in this case were
consistent with his usual practices. We also attempted to interview the
individual who had been the Deputy Commissioner until March 2004, when he
became the Acting Commissioner (we refer to him as Deputy Commissioner in
this report). We were unable to arrange an interview with him or obtain a
response to our written questions prior to his departure from FDA in
September 2005. His attorney subsequently provided a written statement on
his behalf. According to the statement: (1) the Deputy Commissioner did
not have a role in the review of the Plan B switch application; (2) the
Acting Director of CDER briefed him after he became Acting Commissioner on
the Acting Director's conclusions regarding Plan B, and he concurred with
the Acting Director's decision; and (3) the Deputy Commissioner did not
read the reviews of the application by the staff from the Offices of Drug
Evaluation III and V and by the Director of the Office of New Drugs, and
therefore, could not have any comments or concerns.

The Acting Director of CDER signed the not-approvable letter, which was
issued on May 6, 2004. According to FDA, the Acting Director of CDER did
not ask the Directors of the Offices of Drug Evaluation III and V or the
Director of the Office of New Drugs to sign the not-approvable letter, nor
was the letter presented to them for their signature, because it was known
that they did not agree with the not-approvable action.

  High-Level FDA Management Was More Involved Than Usual in the Review Process
  for the Plan B Prescription-to-OTC Switch Application

High-level FDA management became more involved than usual in the review
process for the Plan B OTC switch application. According to review staff
within the Offices of Drug Evaluation III and V that we spoke with and as
documented in their respective reviews, at a meeting held on January 15,
2004, the Acting Director of CDER informed them that the decision for the
Plan B OTC switch application would be made by high-level management. This
action removed decision-making authority from the directors of the
reviewing offices who would normally make the decision. According to
minutes from a subsequent meeting between review officials and the sponsor
on January 23, 2004, the Director of the Office of New Drugs informed the
sponsor that such a high-level decision was not typical of CDER's
procedures for drug approvals.

The Acting Director of CDER told us that management needed to be
comfortable with review staff's final decision because of the high
visibility and sensitivity of the Plan B OTC switch application. He and
other senior FDA officials told us that involvement by high-level
management stemmed from the agency's practice of delegated authority. In
addition to highly visible and sensitive cases, they said that the
Commissioner and the Director of CDER would also generally become involved
in cases that would potentially have a far-reaching impact or in cases in
which management had a different view or disagreed with review staff.
Although such cases are rare, FDA officials cited other examples when
high-level management was more involved in the review process for a drug
application than normal-the approval of thalidomide for the treatment of
leprosy in 199841 and the approval of mifepristone for the termination of
early pregnancy in 2000.42 Unlike Plan B, the examples FDA officials
provided us did not involve OTC switch applications.

  FDA Officials Gave Conflicting Accounts of When the Decision to Not Approve
  Plan B Was Made

FDA officials gave conflicting accounts of when the not-approvable
decision for the Plan B OTC switch application was made. FDA officials,
including the Director and Deputy Director of the Office of New Drugs and
the Directors of the Offices of Drug Evaluation III and V, told us that
they were told by high-level management that the Plan B OTC switch
application would be denied months before staff had completed their
reviews of the application. The Director and Deputy Director of the Office
of New Drugs told us that they were told by the Acting Deputy Commissioner
for Operations43 and the Acting Director of CDER, after the Plan B public
meeting in December 2003, that the decision on the Plan B application
would be not-approvable. They informed us that they were also told that
the direction for this decision came from the Office of the Commissioner.
The Acting Deputy Commissioner for Operations and the Acting Director of
CDER denied that they had said that the application would not be approved.
In addition, although minutes of the January 15, 2004, meeting stated that
the Acting Director told review staff that a not-approvable decision was
"recommended," review staff documented that they were told at this meeting
that the decision would be not-approvable. Both office reviews were not
completed until April 2004.

41Leprosy is a chronic bacterial infection that primarily affects the
skin, nerves, and mucus membranes and causes deformities of the face and
extremities. For the thalidomide NDA, the Director of CDER at that time
disagreed with review staff on whether the NDA should be approved. Review
staff were concerned about the potential off-label use of the drug.
However, the Director disagreed and overruled review staff and approved
the thalidomide NDA.

42For mifepristone, there was no disagreement between high-level
management and the review staff on whether the NDA should be approved.
Rather, the Commissioner at that time signed the approval letter out of
concern regarding the protection of the identities of staff that had
reviewed the application.

43The Acting Deputy Commissioner for Operations was the Director of CDER
when the initial Plan B OTC switch application was submitted in April
2003. She told us that she became the Acting Deputy Commissioner for
Operations in March 2004, and that her role in the review of the initial
Plan B OTC switch application was as a consultant to the Acting Director
of CDER.

However, the Acting Director of CDER told us that he made the decision to
not approve the Plan B OTC switch application shortly before signing the
action letter. He also informed us that his decision was made in
consultation with other high-level management officials, including the
Commissioner and the Acting Deputy Commissioner for Operations, but that
he was not directed to reach a particular decision. The Acting Director
also told us that these high-level management officials agreed with his
decision. When we asked the Acting Director about his meeting with
officials from the Office of New Drugs in December 2003, he told us that
he might have indicated to the Director and Deputy Director that the
agency was "tending" or "thinking of going" in the direction of a
not-approvable decision, but that this was not the final decision.
Furthermore, although he told us that he was "90 percent sure" as early as
January 2004, that the decision would be not-approvable, the Acting
Director told us he made his final decision only in the last few weeks
prior to issuing the action letter, after he had reviewed all of the
documentation associated with the application.

The Acting Director of CDER told us that the rationale for his decision
was not fully developed until a few days before the action letter was
issued on May 6, 2004. According to internal FDA e-mails we reviewed, the
Acting Director of CDER contacted the Director of the Office of Pediatric
Therapeutics on May 2, 2004, requesting assistance on language regarding
cognitive development during early adolescence to support his decision.
According to these e-mails, the Director of the Office of Pediatric
Therapeutics responded that she would consult with another official with a
background in developmental pediatrics and would follow up with
"behavioral science information as to why one cannot extrapolate decision
making on safety issues" from older to younger adolescents.

  The Acting Director's Rationale for the Not-Approvable Decision Was Novel and
  Varied from FDA's Traditional Practices

The rationale for the Acting Director of CDER's decision was novel and did
not follow FDA's traditional practices. The Acting Director was concerned
about the potential impact that the OTC marketing of Plan B would have on
the propensity for younger adolescents to engage in unsafe sexual
behaviors because of their lack of cognitive maturity. The Acting Director
further concluded that because these differences in cognitive development
made it inappropriate to extrapolate data from older to younger
adolescents in this case, there was insufficient data on the use of Plan B
among younger adolescents. FDA review officials disagreed with the Acting
Director's rationale and noted that the agency had not considered
behavioral implications resulting from differences in cognitive
development in prior OTC switch decisions.

    The Acting Director's Rationale Was Based on His Concerns about Risk-Taking
    in Younger Adolescents

The Acting Director of CDER told us he signed the not-approvable letter
because of his concerns about the lack of cognitive development and the
potential for risky behaviors among younger adolescents resulting from
increased access to Plan B. For example, he noted increased access to Plan
B could potentially result in an increase in unsafe sexual activity,
particularly among younger adolescents-an age group, he noted, that has a
tendency to engage in risky behaviors because of their level of cognitive
development. This change in behavior could be represented by changes in
measurable indicators, such as a decrease in condom use or an increase in
the transmission of sexually transmitted diseases (STD).44

In his memorandum on his review of the Plan B OTC switch application, the
Acting Director of CDER also stated that because younger adolescents'
cognitive maturity related to controlling impulsive behavior is less
developed than older adolescents', he did not consider it appropriate to
extrapolate data from older to younger adolescents in this case. (See app.
IV for a copy of the Acting Director of CDER's memorandum.) He
specifically noted the following:

"In making decisions about pediatric use, it is often possible to
extrapolate data from one age group to another, based on knowledge of the
similarity of the condition. However, in this case, adolescence is known
to be a time of rapid and profound physical and emotional change. . . .
Because of these large developmental differences, I believe that it is
very difficult to extrapolate data on behavior from older ages to younger
ages. I am uncomfortable with our current level of knowledge about the
potential differential impact of OTC availability of Plan B on these age
subsets."

Some other officials we spoke with supported the Acting Director's
concerns about extrapolating data from older to younger adolescents. For
example, the Director of the Office of Pediatric Therapeutics told us and
noted in e-mails to the Acting Director of CDER, which we reviewed, that
the difference in cognitive development and maturity between older and
younger adolescents and the potential impact this would have on behaviors
warranted a separate analysis of this latter age group. In addition, one
of the members of the joint advisory committee we spoke with said he was
also concerned about extrapolating data from older to younger age groups
because he perceived weaknesses in the actual use and label comprehension
studies submitted by the sponsor.45

44For the actual use study for the Plan B OTC switch application, an
additional observation was included along with the two study objectives.
This observation involved collecting and comparing data from study
participants on the use of emergency and regular contraception, such as a
change in condom use. These data were collected at the time participants
enrolled in the study and compared to data collected during a follow-up, 4
weeks later. However, although these data were considered relevant to the
application by the sponsor and FDA officials, the sponsor noted that the
actual use study was not primarily designed for assessing the potential
risk behaviors of potential users of Plan B in an OTC setting.

Because of these concerns, the Acting Director concluded that the Plan B
OTC switch application needed more data specific to younger adolescents.
In the not-approvable letter, the Acting Director stated there were too
few younger adolescents in the sponsor's actual use study to support the
Plan B OTC switch application. Specifically, he highlighted that only 29
of 585 participants in the study were 14 years to 16 years of age and none
were under 14 years of age. Although he acknowledged concerns about the
difficulty of including younger adolescents in actual use studies, he told
us that it was not impossible to enroll younger adolescents in studies,
noting that studies for other products have been conducted involving
younger participants, including those as young as infants. Some of the
Acting Director's concerns regarding the low number of younger adolescents
were also raised by other review staff and members of the joint advisory
committee. For example, one FDA reviewer who recommended an approvable
action on the Plan B OTC switch application noted that despite a
reanalysis of the actual use study data of subjects aged 14 years to 17
years, the sample size was too small and "significantly limit[ed]
assessment of potential risky/unsafe sexual behavior associated with OTC
accessibility of Plan B."

Although review staff within the Offices of Drug Evaluation III and V
presented him with additional data on sexual behaviors of younger
adolescents in association with increased access to ECPs, the Acting
Director of CDER determined that these data were not adequate to support
the approval of Plan B for OTC use. He provided his reasoning in his
memorandum, stating that these studies were either "not conducted in the
general population or they provide[d] product education assistance beyond
what adolescents would receive in an OTC situation, where no contact with
a health care professional is expected."

45This committee member told us he was specifically concerned that the
actual use study was largely conducted in family planning clinics, saying
this could bias the results of the study by potentially introducing study
participants to health care professionals who could educate them on the
use of ECPs. For the label comprehension study, he was concerned about the
poor results among lower-educated participants. This committee member told
us that literacy and age were a concern because younger age groups are by
definition considered among the lower educated.

The Acting Director of CDER's rationale varied from FDA's traditional
practices by considering the potential implications OTC access of Plan B
would have on the sexual behavior of younger adolescents based on their
lack of cognitive maturity and by not accepting the validity of
extrapolating data from older to younger adolescents. Although he
acknowledged to us that considering adolescents' cognitive development as
a rationale for a not-approvable decision was unprecedented, the Acting
Director also told us that FDA had recently increased its focus on
pediatric issues. He noted that pediatric issues were currently being
raised in prescription drug reviews and believed the same should occur in
OTC drug reviews.

    FDA Review Officials Disagreed with the Acting Director's Rationale for the
    Not-Approvable Decision

FDA review staff, the Directors of the Offices of Drug Evaluation III and
V, and the Director of the Office of New Drugs disagreed with the Acting
Director of CDER's rationale for not approving the Plan B OTC switch
application. FDA review officials, including those from the Office of New
Drugs, noted that traditionally FDA has not considered whether younger
adolescents would use an OTC product differently than older adolescents,
and the Director of the Office of New Drugs told us that it was "atypical"
to raise the question of maturity during a drug review. These officials
also noted that FDA does not attempt to determine how a patient arrived at
the need for a drug. Rather, drug evaluations usually begin with the need
for a potential treatment already existing.

Review staff we spoke with acknowledged that certain behavioral concerns
and unintended consequences are examined for an OTC switch application,
such as whether making a drug OTC would delay a person from seeking
medical treatment or if the drug would potentially be abused if it were
more readily available. They told us that these issues are usually
examined during a benefit-risk review, which is an analysis of potential
medical outcomes. Review staff told us they examined benefit-risk issues
for Plan B, and they concluded that concerns regarding the potential for
unsafe sexual behaviors among adolescents could not be supported.46 In
addition, the review of the label comprehension study from the Office of
Drug Safety noted that potential users of the product would be able to
appropriately use it if the sponsor made its suggested changes to the
proposed labeling.47 Also, at the public meeting, members of the joint
advisory committee voted 27 to 1 that the actual use study demonstrated
that consumers could properly use Plan B as recommended by the label. The
members of the joint advisory committee also voted 28 to 0 that the
literature review of Plan B included in the actual use study did not show
that Plan B would be used as a regular form of contraception.

Furthermore, the review of the application from the Office of Drug
Evaluation III, which included the benefit-risk assessment for Plan B,
noted that having Plan B in an OTC setting would "pose little risk" to the
potential user and that the risk of an adverse pregnancy outcome, such as
lower birth weight babies and premature delivery, is much higher among
younger adolescents. The review concluded that OTC access to Plan B in
helping younger adolescents avoid unintended pregnancies would be "of
particular value given the greater risk of an adverse pregnancy outcome in
this high risk group." This review also noted that even for a large dose
of the hormone used in Plan B, the "margin of safety appear[ed] to be
high."

In an attempt to further address the Commissioner's and Acting Director's
concerns about the potential for increased risky behavior by younger
adolescents resulting from increased access to Plan B, review staff
requested additional data from the sponsor and reviewed ongoing studies
examining these concerns. FDA's reviewers concluded that increased access
to ECPs did not result in (1) inappropriate use by adolescents as a
substitute form of contraception, (2) an increase in the number of sexual
partners or the frequency of unprotected intercourse, or (3) an increase
in the frequency of STDs.

46Only one of the review staff for the Plan B OTC switch application
raised concerns regarding behaviors of younger adolescents. Recommending
an approvable decision, he concluded in his written review of the
application that (1) the actual use study had insufficient data on whether
OTC accessibility of Plan B might be associated with risky (or unsafe)
sexual behaviors over the long term, particularly among adolescents; (2)
the behavioral literature did not provide strong evidence to address the
inadequacies in the actual use study in assessing risky sexual behaviors
in the target OTC populations; and (3) some behavioral studies in the
literature suggested that providing ECPs in advance could encourage unsafe
sexual behaviors in the study populations.

47The changes proposed by the Office of Drug Safety were included as
attachments to the office's review of the label comprehension study.

To reach these conclusions, review staff examined the five studies that
provided supplies of ECPs in advance to study participants to assess the
behavioral impact of OTC access. In one study, which included 2,090 women
aged 15 years to 24 years, there was a decrease in unprotected sex among
all age groups and no increase in the incidence of STDs compared to the
baseline. Another study of 160 adolescent mothers included participants
aged 14 years to 20 years. Although there were limited data available,
this study concluded that there was no increase in unprotected intercourse
and no decrease in condom use among participants. A third study of 301
adolescent women, aged 15 years to 20 years, showed similar results, with
no increase in unprotected intercourse or STDs and no decrease in condom
use.

FDA officials, including those from the Office of New Drugs, also
disagreed with the Acting Director's determination that extrapolating data
from older populations to younger adolescents was inappropriate. In their
reviews, officials noted that data they reviewed showed that younger
adolescents had outcomes similar to those of older populations. For
example, the actual use study found that 82 percent of participants 16
years of age or under correctly took the second dose 12 hours later,
compared to 78 percent of those 17 years and older.48 Also, review staff
said that overall the number of participants who were younger adolescents
was adequate to draw conclusions about potential use among the adolescent
population. Review staff told us they encouraged the sponsor to not limit
enrollment or exclude adolescents from the actual use study and felt the
study included a representative population of women that would potentially
use Plan B. Some of the members of the joint advisory committee we spoke
with also said they considered the number of younger adolescents in the
actual use study as adequate.

In addition, the Director of the Office of New Drugs told us that the
agency has not requested age-specific data often and that FDA often
extrapolates findings, including findings on behaviors, from adults to
adolescents. He added that given the agency's traditional processes and
the data provided in the Plan B OTC switch application, there was no
reason to consider the extrapolations done in the staff's reviews as
inappropriate.

48Although there were 29 younger adolescents aged 16 years or under
enrolled in the actual use study, only 22 used the product and provided
follow-up data for this specific question. Of the 22 study participants
who used the product and provided follow-up data, 18 reported that they
correctly took the second dose 12 hours after the first. The total number
of study participants aged 17 years or older who also used the product and
provided follow-up data was 46. Of these 46 study participants, 36
reported that they correctly took the second dose 12 hours after the
first.

Based on the reviews conducted by review staff and on the recommendations
of the joint advisory committee, the Director of the Office of New Drugs
concluded the following in his memorandum of his review of the Plan B OTC
switch application, issued April 22, 2004 (a copy of this memorandum can
be found in app. V):

"In my opinion, these studies provide adequate evidence that women of
childbearing potential can use Plan B safely, effectively, and
appropriately for emergency contraception in the non-prescription setting.
The data submitted by the sponsor in support of non-prescription use of
Plan B are fully consistent with the Agency's usual standards for meeting
the criteria for determining that a product is appropriate for such use. .
. . Such a conclusion is consistent with how the Agency has made
determinations for other OTC products, including other forms of
contraception available without a prescription. Further, I believe that
greater access to this drug will have a significant positive impact on the
public health by reducing the number of unplanned pregnancies and the
number of abortions."

In his memorandum, the Director of the Office of New Drugs also noted that
FDA has a "long history" of extrapolating findings from older populations
to younger adolescents. He wrote that this type of extrapolation from
older populations to younger adolescents had been done in clinical trials
for both prescription and OTC drug approvals and that this practice was
incorporated into the Pediatric Research Equity Act (PREA)-the law
authorizing FDA to require pediatric studies in certain defined
circumstances.49 According to PREA, if the disease and the effects of the
drug are "sufficiently similar" between adult and pediatric populations,
it can be concluded that the effectiveness can be extrapolated from
"adequate and well-controlled studies in adults" usually in conjunction
with supplemental studies in pediatric populations. In addition, PREA
provides that studies may not be necessary for all pediatric age groups,
if data from one age group can be extrapolated to another.

Members of the joint advisory committee expressed similar conclusions to
those of FDA review officials earlier at the public meeting in December
2003. During the public meeting, committee members voted 27 to 1 that the
actual use study data were generalizable to the overall population of OTC
users, including adolescents.

49See 21 U.S.C. S: 355c(a)(2)(B).

  Plan B Decision Was Not Typical of Other Proposed Prescription-to-OTC Switch
                                   Decisions

The decision to not approve the Plan B OTC switch application was not
typical of the other 67 proposed prescription-to-OTC switch decisions made
from 1994 through 2004. The decision of the Plan B application stands out
from these other OTC switch applications for two reasons: it was the only
decision that was not approved after the members of the joint advisory
committee voted to recommend approval of the application, and the action
letter was signed by the Acting Director of CDER instead of the directors
of the offices where the application was reviewed.

Plan B Was the Only Prescription-to-OTC Switch Decision from 1994 through 2004
That Was Not Approved after the Joint Advisory Committee Voted to Recommend
Approval of the Application

From 1994 through 2004, Plan B was the only prescription-to-OTC switch
decision that was not approved after the joint advisory committee voted to
recommend approval of the application. FDA advisory committees considered
23 OTC switch applications during this period; the Plan B OTC switch
application was the only 1 of those 23 that was not approved after the
joint advisory committee voted to recommend approval of the application.
In addition, there has been only 1 other decision for an OTC switch
application that did not follow the recommendations of the joint advisory
committee. This other OTC switch application, for the drug Aleve, was
approved for OTC status by FDA in 1994, although the joint advisory
committee opposed the switch. The NDAC met jointly with the Arthritis
Drugs Advisory Committee to discuss the OTC switch application for Aleve
in June 1993 and recommended that the application not be approved.
Following this meeting, the sponsor made changes to address the joint
advisory committee's concerns, and as a result of these changes, FDA
decided to approve the application.50

50Reasons that the joint advisory committee gave for the recommendation
against the OTC switch included that the dose was too high, the labeling
for people over 65 years of age was incorrect, and no additional labeling
was included for children regarding the side effect of photosensitivity.

Plan B Was the Only Prescription-to-OTC Switch Decision from 1994 through 2004
in Which the Action Letter Was Signed by the Director of CDER

From 1994 through 2004, 94 action letters were issued during the review
processes for the 68 prescription-to-OTC switch applications, and only 1
action letter-the not-approvable letter for Plan B-was signed by the
Director, in this case the Acting Director, of CDER. Given that Plan B was
a first-in-a-class drug, the Directors of the Offices of Drug Evaluation
III and V would normally jointly sign the action letter. The Plan B
application was 1 of 68 proposed OTC switch applications decided by FDA
from 1994 through 2004, and 14 of those 68 applications, including the
Plan B application, were issued not-approvable letters. Eight of those 14
applications were eventually approved. Plan B was the only contraceptive
or emergency contraceptive proposed for an OTC switch during this period.
Thirty-eight OTC switch applications, including Plan B, were for the same
dose, population, and indication, and all but 3 applications were
eventually approved.

 There Are No Age-Related Restrictions for Safety Reasons for Any FDA-Approved
                                 Contraceptives

According to the Deputy Director of the Office of New Drugs, there are no
age-related marketing restrictions for any FDA-approved contraceptives,
and FDA has not required any pediatric studies. Condoms and spermicides
are available to anyone OTC, while intrauterine devices; diaphragms;
cervical caps; and hormonal methods of contraception, including ECPs, are
available to anyone with a prescription. For hormonal contraceptives, FDA
has assumed that suppression of ovulation is the same in all
postmenarcheal females, regardless of age. The Deputy Director of the
Office of New Drugs told us that all birth control pills, including ECPs,
contain the following class labeling: "Safety and effectiveness of [trade
name] have been established in women of reproductive age. Safety and
efficacy are expected to be the same for postpubertal adolescents under
the age of 16 and for users 16 years and older. Use of this product before
menarche is not indicated."

FDA officials from the Office of New Drugs explained that for an OTC
switch, the safety and effectiveness issues have already been addressed
during the initial approval process for the drug to become a prescription
drug. For an OTC switch application, the review process is primarily
focused on whether the drug meets the OTC switch criteria, specifically
whether it is safe and effective for use in self-medicating.51

51In its technical comments on the draft of this report, FDA said that it
also considers age in the labeling of OTC drug products. For example, FDA
stated that there are many OTC drugs that have labels with dosing
instructions based on age.

There were no safety issues that would require age-related restrictions
that were identified with the original NDA for prescription Plan B. FDA
approved this application upon determining that Plan B met the statutory
standards of safety and effectiveness, manufacturing and controls, and
labeling. The original NDA for Plan B for use as an emergency
contraceptive contained an extensive safety database that included
controlled trials and literature on over 15,000 women.52 The label for
prescription Plan B makes no age distinctions about the pharmacological
processes of the drug, and prescription Plan B is available to anyone with
a prescription.

                       Agency Comments and Our Evaluation

FDA reviewed a draft of this report and provided comments, which are
reprinted in appendix VI. FDA also provided technical comments, which we
incorporated as appropriate.

In its comments, FDA disagreed with our finding that three aspects of its
decision process for the May 2004, Plan B OTC switch application were
unusual. First, FDA said that the involvement of high-level management in
the Plan B decision was not as unusual as the draft report found. FDA
commented that the Director of CDER is ultimately responsible for all
decisions made within CDER, and that the Director of CDER is regularly
involved in regulatory decisions that are not routine, including those
that involve controversial issues. FDA also commented that the Director of
CDER typically discusses high-profile and controversial regulatory
decisions with officials within the Office of the Commissioner.

While we agree with FDA that the Director of CDER and other high-level
officials generally are more likely to become directly involved in
high-profile regulatory decisions and noted that in the draft of the
report, we found that this level of involvement is unusual for OTC switch
applications. The other examples of high-level management involvement
given to us by FDA officials during the course of our work involved
decisions about the marketing of prescription drugs. Also, it was unusual
for the Acting Director of CDER to inform FDA's review staff that it had
been determined that the Plan B decision would be made by high-level
management. The Acting Director did so on January 15, 2004, before the
review staff had completed their reviews of the application.

52The database included trials conducted in the United States and other
countries. Women in the study were above the age of consent for their own
countries.

Second, FDA took issue with what it characterized as the tone of our
discussion about when the decision was made to deny the Plan B OTC switch
application. FDA commented that discussions about alternative regulatory
actions ordinarily occur in the course of decision making within CDER and
that it is inaccurate to conclude that a decision to deny the application
was made several months before the not-approvable letter was issued.
However, the draft report did not assert that a decision was actually made
several months before the letter was issued. Rather, it accurately noted
that FDA officials gave us conflicting accounts of when the not-approvable
decision was made. The Director and Deputy Director of the Office of New
Drugs and other officials told us that they were informed during December
2003 and January 2004 that the application would not be approved. The
Acting Director of CDER denied this, and we reported that his rationale
for the not-approvable decision was not fully developed until early May
2004.

Third, FDA disagreed with our finding that the Acting Director's rationale
for denying the application was novel and did not follow FDA's traditional
practices. FDA commented that the Acting Director's focus on the potential
implications to the sexual behavior of adolescent women of approving the
Plan B OTC switch application was appropriate and consistent with FDA's
treatment of other OTC switch applications.

In response to this comment, we have revised the report to more clearly
describe the reasons for our finding. We found that the Acting Director's
rationale was novel because it explicitly considered the differing levels
of cognitive maturity of adolescents of different ages, and that because
of the Acting Director's views about these cognitive maturity differences,
he concluded that it was inappropriate to extrapolate data related to
risky sexual behavior from older to younger adolescents. In his May 6,
2004, memorandum, the Acting Director stated that "Because of these large
developmental differences, I believe that it is very difficult to
extrapolate data on behavior from older to younger ages." The Acting
Director acknowledged that considering adolescents' cognitive development
as a rationale for a not-approvable decision was unprecedented for an OTC
switch application. In addition, other FDA officials told us that the
agency had not previously considered whether younger adolescents would use
a product differently than older adolescents. For example, the Director of
the Office of New Drugs told us that it was "atypical" to raise the
question of maturity during a drug review and that FDA has traditionally
extrapolated findings from older to younger adolescents. Furthermore, in
his April 22, 2004, memorandum, the Director of the Office of New Drugs
said that "the Agency has a long history of extrapolating findings from
clinical trials in older patients to adolescents in both prescription and
non-prescription approvals."

In addition, FDA disagreed with our statement in the draft report that the
Directors of the Offices of Drug Evaluation III and V and the Director of
the Office of New Drugs refused to sign the not-approvable letter. We used
the term "refused" in the draft report because, in our interviews with
them, all three of the directors told us that they did not agree with the
not-approvable decision and did not sign the action letter, and one of the
directors told us that she had been given an opportunity to sign the
letter and refused to do so. However, in its comments, FDA said that the
directors were not asked to sign the action letter because it was known
that they disagreed with the Acting Director's decision. We have revised
the report to reflect this.

In its technical comments, FDA asked us to emphasize that safety concerns
regarding OTC use of drug would not be raised for prescription products
because of the involvement of health practitioners. The draft report noted
that prescription drugs are drugs that are safe for use only under
supervision of a health care practitioner and that approved prescription
drugs that no longer require such supervision may be marketed OTC.

We are sending copies of this report to the Acting Commissioner of the
Food and Drug Administration and other interested parties. We will also
provide copies to others upon request. In addition, the report will be
available at no charge on GAO's Web site at http://www.gao.gov .

If you or your staffs have any questions about this report, please contact
me at (202) 512-7119 or [email protected] . Contact points for our Offices
of Congressional Relations and Public Affairs may be found on the last
page of this report. GAO staff who made major contributions to this report
are listed in appendix VII.

Marcia Crosse Director, Health Care

List of Requesters

The Honorable Edward M. Kennedy Ranking Minority Member Committee on
Health, Education, Labor, and Pensions United States Senate

The Honorable Carl Levin Ranking Minority Member Permanent Subcommittee on
Investigations Committee on Governmental Affairs United States Senate

The Honorable John D. Dingell Ranking Minority Member Committee on Energy
and Commerce House of Representatives

The Honorable Henry A. Waxman Ranking Minority Member Committee on
Government Reform House of Representatives

The Honorable Jeff Bingaman The Honorable Barbara Boxer The Honorable
Maria Cantwell The Honorable Hillary Rodham Clinton The Honorable Jon
Corzine The Honorable Mark Dayton The Honorable Christopher J. Dodd The
Honorable Richard J. Durbin The Honorable Tom Harkin The Honorable Daniel
K. Inouye The Honorable James M. Jeffords The Honorable Frank R.
Lautenberg The Honorable Barbara A. Mikulski The Honorable Patty Murray
The Honorable Charles E. Schumer The Honorable Debbie Stabenow The
Honorable Ron Wyden United States Senate

The Honorable Tammy Baldwin The Honorable Sherrod Brown The Honorable Lois
Capps The Honorable Benjamin L. Cardin The Honorable Joseph Crowley The
Honorable Susan A. Davis The Honorable Lloyd Doggett The Honorable Sam
Farr The Honorable Bob Filner The Honorable Maurice D. Hinchey The
Honorable Rush D. Holt The Honorable Michael M. Honda The Honorable
Barbara Lee The Honorable Nita M. Lowey The Honorable Carolyn B. Maloney
The Honorable Edward J. Markey The Honorable James P. Moran, Jr. The
Honorable Jerrold Nadler The Honorable Eleanor Holmes Norton The Honorable
Janice D. Schakowsky The Honorable Louise M. Slaughter The Honorable Hilda
L. Solis The Honorable Edolphus Towns The Honorable Mark Udall The
Honorable Chris Van Hollen The Honorable Diane E. Watson The Honorable
Lynn C. Woolsey House of Representatives

Appendix I: Scope and Methodology Appendix I: Scope and Methodology

To examine how the decision was made to not approve the switch of Plan B
from prescription to over-the-counter (OTC), we reviewed documents, such
as the Plan B OTC switch action package related to the May 6, 2004,
decision from the Food and Drug Administration (FDA). We examined
documents produced by FDA, including official meeting minutes and the
reviews of the Plan B OTC switch application from the Offices of Drug
Evaluation III and V and the Office of New Drugs, related to the review of
the Plan B OTC switch application. FDA officials told us that
documentation was not available concerning some communications within FDA.
It was not possible to determine whether such communications may have
concerned the Plan B OTC switch application. However, we acquired
sufficient information from other FDA documents and our interviews with
FDA officials to fully address our objectives.

We interviewed FDA officials involved in the Plan B OTC switch application
review, including officials from the Office of Drug Evaluation III, Office
of Drug Evaluation V, Office of New Drugs, and Office of Drug Safety. We
also interviewed the Acting Director of the Center for Drug Evaluation and
Research (CDER), the Acting Deputy Commissioner for Operations, and the
Director of the Office of Women's Health. We interviewed members of FDA's
advisory committees that met jointly to discuss the Plan B OTC switch
application-the Nonprescription Drugs Advisory Committee (NDAC) and the
Advisory Committee for Reproductive Health Drugs (ACRHD)-and reviewed the
transcripts of the meeting. In addition, we interviewed officials from
Barr Pharmaceuticals, Inc., the company currently sponsoring the Plan B
application for the prescription-to-OTC switch, and Women's Capital
Corporation (WCC), the original sponsor of the Plan B OTC switch
application.

To examine how the Plan B decision compares to the decisions for other
proposed prescription-to-OTC switches made from 1994 through 2004, we
examined the recommendations of the joint advisory committee and if they
were followed for Plan B and the proposed OTC switch drugs that were
decided from 1994 through 2004. We reviewed action letters and interviewed
FDA officials and review staff as well as other outside experts involved
with the Plan B OTC switch application. We also interviewed officials from
the Consumer Healthcare Products Association (the association representing
OTC drug manufacturers) about the prescription-to-OTC switch process.

To determine if there were age-related marketing restrictions for
prescription Plan B and other prescription and OTC contraceptives, we
reviewed FDA documents and interviewed FDA officials and review staff
regarding safety concerns for prescription Plan B and the safety concerns
for other prescription and OTC contraceptives. We also interviewed
representatives from the American College of Obstetricians and
Gynecologists, the American Academy of Pediatrics, Concerned Women for
America, and the Planned Parenthood Federation of America, Inc., regarding
safety concerns for Plan B and other contraceptives.

When the source of evidence we cited is from an interview, we identified
the respondent's title and FDA office. Whenever possible, we reviewed
documents to verify testimonial evidence from FDA officials. When this was
not possible, we attempted to corroborate testimonial evidence by
interviewing multiple people about the information we obtained. In
situations where there was no concurrence among the interviewees, we
presented all the information provided.

Minutes of the internal FDA meetings discussed in this report were written
either by a staff member within the Office of Drug Evaluation III or by
the Executive Secretariat within the Office of the Commissioner. For
meeting minutes written by the office staff member, attendees either
reviewed or concurred with the minutes and documented this by including
their names at the end of the minutes. For summaries written by the
Executive Secretariat, there was no documentation of a review or of
concurrence by attendees included with these summaries. FDA officials told
us that summaries from meetings within the Office of the Commissioner were
not reviewed or concurred with by attendees.

To verify data we received from FDA regarding proposed prescription-to-OTC
switch decisions made from 1994 through 2004 and the outcomes of advisory
committee meetings for these drugs, we compared FDA's data with
prescription-to-OTC switch data obtained from the Consumer Healthcare
Products Association on OTC drug switches.

Our work examined only events and communications within FDA and between
FDA and the Plan B sponsors; we did not consider any communications that
may have occurred between FDA officials and other executive agencies. Our
work examined only FDA's actions prior to the May 6, 2004, not-approvable
letter, and we did not examine any aspects of FDA's subsequent
deliberations about Plan B. We conducted our work from September 2004
through November 2005 in accordance with generally accepted government
auditing standards.

Appendix II: Not-Approvable Letter for the Prescription-to-OTC Switch
Application of Plan B, May 6, 2004 Appendix II: Not-Approvable Letter for
the Prescription-to-OTC Switch Application of Plan B, May 6, 2004

Appendix III: Timeline of Major Plan B Events Related to the Initial OTC
Switch Application Appendix III: Timeline of Major Plan B Events Related
to the Initial OTC Switch Application

Date                  Event                                                
February 25, 1997     A notice in the Federal Register stated that the FDA 
                         Commissioner had concluded that certain combined     
                         oral contraceptives are safe and effective for use   
                         as emergency contraception and requested submission  
                         of a new drug application (NDA) for this use.        
July 28, 1999         FDA approved Plan B as a prescription form of        
                         emergency contraception.                             
February 14, 2001     A citizens' petition for direct over-the-counter     
                         (OTC) access to Plan B was filed, requesting that    
                         FDA grant Plan B OTC status.                         
April 18, 2002        FDA review staff within the Office of Drug           
                         Evaluation III sent Women's Capital Corporation      
                         (WCC) a letter, denying its proposal that FDA        
                         request that it conduct pediatric studies on the use 
                         of prescription Plan B as an emergency contraceptive 
                         in exchange for extending the drug's marketing       
                         exclusivity for 6 months, as permitted under the     
                         Federal Food, Drug, and Cosmetic Act.a According to  
                         the letter to WCC and a memorandum by review staff   
                         within the Office of Drug Evaluation III, the        
                         proposed studies would have included a               
                         pharmacokinetic study and a safety study and would   
                         have used Plan B as an emergency contraceptive in    
                         subjects as young as 12 years of age. According to   
                         review staff within the Office of Drug Evaluation    
                         III, once a young female reached menarche, she was   
                         considered an adult for contraceptives and the       
                         condition for using an emergency contraceptive is    
                         not unique to the pediatric population. The letter   
                         concluded that trials could be conducted in the      
                         adult population and then extrapolated to the        
                         pediatric population.                                
May 28, 2002          A Center Director Informational Briefing was held in 
                         response to the citizens' petition, filed on         
                         February 14, 2001. Meeting attendees included the    
                         Center for Drug Evaluation and Research (CDER)       
                         Director and Deputy Director, the Director of Office 
                         of New Drugs, and review staff from the Offices of   
                         Drug Evaluation III and V.                           
June 5, 2002          A briefing for the Office of the Commissioner was    
                         held to discuss the expected application to switch   
                         Plan B to OTC. Attendees included the Deputy         
                         Commissioner,b the agency's Chief Counsel, the then  
                         Director of CDER, the Director of the Office of New  
                         Drugs, and review staff from the Offices of Drug     
                         Evaluation III and V. According to the executive     
                         summary of the briefing, issues discussed included   
                         (1) the political sensitivity of the application,    
                         (2) consumer understanding of the proposed           
                         nonprescription product label, (3) the results of    
                         actual use studies to adequately address safety      
                         issues, (4) the review status of the supplemental    
                         new drug application (sNDA) upon submission, and (5) 
                         regulatory issues.                                   
July 10, 2002         The Director of CDER provided the Deputy             
                         Commissioner and FDA's Chief Counsel with materials  
                         on the safety of emergency contraception and its     
                         mechanism of action, which were requested at the     
                         June 5, 2002, briefing.                              
September 23, 2002    FDA officials within the Office of New Drugs and the 
                         Offices of Drug Evaluation III and V and the sponsor 
                         held a meeting in which FDA provided guidance on the 
                         Plan B OTC switch application, which was to be       
                         submitted. According to meeting minutes, agency      
                         officials and the sponsor discussed behavioral       
                         issues in adolescents and the possibility of a       
                         behind-the-counter option or a possible age          
                         restriction.c                                        
April 16, 2003        WCC submitted an sNDA to FDA to allow Plan B to be   
                         sold OTC.                                            
June 9, 2003          FDA review staff from the Office of Drug Evaluation  
                         III determined that the sNDA was fileable and        
                         accepted it for review. FDA set a Prescription Drug  
                         User Fee Act (PDUFA) goal date of February 22, 2004, 
                         to reach a decision on the application.d             
August 22, 2003       A teleconference was held between review staff       
                         within Offices of Drug Evaluation III and V and the  
                         sponsor. According to minutes of this                
                         teleconference, review staff began working with the  
                         sponsor to prepare for the meeting of the joint      
                         advisory committee in December. Minutes also noted   
                         that FDA review staff suggested that the sponsor     
                         plan to address issues of age, literacy, or label    
                         comprehension regarding the administration of Plan   
                         B.                                                   
September 11, 2003    Review within the Office of Drug Evaluation V        
                         requested additional information on the label        
                         comprehension study results from WCC. According to   
                         the official request, review staff asked for         
                         information including results for each question      
                         asked in the label comprehension study based on      
                         literacy levels; details on what criteria were used  
                         to determine if a communication objective was met;   
                         and other specific points of clarification on how    
                         responses were scored.                               
September 26, 2003    A teleconference was held in which review staff      
                         within the Offices of Drug Evaluation III and V      
                         discussed the upcoming December 16, 2003, public     
                         meeting of its two advisory committees with WCC.     
                         According to teleconference minutes, review staff    
                         requested additional information on the labels used  
                         for the label comprehension and the actual use       
                         studies and on the label proposed for approval in    
                         the sNDA. Minutes also noted that WCC informed FDA   
                         that on September 23, 2003, a majority of its board  
                         voted to sell the marketing rights of Plan B to Barr 
                         Pharmaceuticals, Inc.                                
October 2003          Barr Pharmaceuticals, Inc., was finalizing the       
                         purchase of the marketing rights for Plan B from WCC 
                         and began to act as the agent for WCC for Plan B.    
October 9, 2003       At the request of Barr Pharmaceuticals, Inc., a      
                         teleconference was held to discuss the upcoming      
                         joint public meeting of FDA's advisory committees.   
                         Meeting participants from FDA included review staff  
                         within the Offices of Drug Evaluation III and V.     
                         According to teleconference minutes, review staff    
                         asked Barr Pharmaceuticals, Inc., about possible age 
                         restrictions for use of Plan B. Minutes also noted   
                         that Barr Pharmaceuticals, Inc., said that it        
                         intended to offer its product to women as young as   
                         15 years of age. Also, Barr Pharmaceuticals, Inc.,   
                         agreed to explore and report back to FDA on          
                         behind-the-counter marketing and the implementation  
                         of age limitations on the sale of Plan B.            
November 5, 2003      A reviewer within the Office of Drug Safety          
                         completed her review of the Plan B label             
                         comprehension study, which was initially submitted   
                         to review staff within the Office of Drug Evaluation 
                         III. According to the official memorandum on the     
                         review of the label comprehension study, the         
                         reviewer concluded that making the proposed changes  
                         to the Plan B label would likely result in           
                         acceptable levels of comprehension. Review staff     
                         within the Office of Drug Evaluation V told GAO they 
                         concurred with the reviewer's findings.              
December 2, 2003      A meeting was held between FDA officials within the  
                         Office of New Drugs and the Offices of Drug          
                         Evaluation III and V and the sponsor. According to   
                         meeting minutes, FDA officials informed Barr         
                         Pharmaceuticals, Inc., that the agency may not be    
                         able to present a clear regulatory path for          
                         alternate OTC distribution mechanisms for Plan B in  
                         time for the December 16, 2003, public meeting.      
December 10, 2003     A briefing for the Office of the Commissioner was    
                         held to discuss the upcoming public meeting of the   
                         Nonprescription Drugs Advisory Committee (NDAC) and  
                         Advisory Committee for Reproductive Health Drugs     
                         (ACRHD). FDA participants included the Commissioner, 
                         the Acting Director of CDER, the Director and Deputy 
                         Director of the Office of New Drugs, and review      
                         staff within the Office of Drug Safety and the       
                         Offices of Drug Evaluation III and V. According to   
                         the executive summary of the briefing, issues        
                         discussed included the sponsor's marketing and       
                         distribution plan and the effect making Plan B       
                         available OTC might have on consumers' behavior.     
December 16, 2003     At a joint meeting of the NDAC and the ACRHD,        
                         members voted 23 to 4 to recommend approving the     
                         switch of Plan B from prescription to OTC.           
December 2003/January The Director and the Deputy Director of the Office   
2004                  of New Drugs told GAO they were told by the Acting   
                         Deputy Commissioner for Operationse and the Acting   
                         Director of CDER that the Plan B application could   
                         not be approved. These officials said they were told 
                         that this direction came from the Office of the      
                         Commissioner. The Acting Deputy Commissioner for     
                         Operations and the Acting Director of CDER told GAO  
                         they did not say this.                               
January 15, 2004      A meeting was held between officials within the      
                         Office of the CDER Director and review staff within  
                         the Offices of Drug Evaluation III and V about the   
                         Office of the Commissioner's position on the         
                         acceptability of the Plan B OTC switch application.  
                         According to meeting minutes, the Acting Director of 
                         CDER said that a not-approvable decision was         
                         recommended by the Office of the Commissioner based  
                         on the need for more data to more clearly establish  
                         appropriate use in younger adolescents, the need to  
                         develop a restricted distribution plan, or both.     
                         Meeting minutes also indicated that review staff     
                         also informed the Acting Director that their reviews 
                         were not yet completed and that there were           
                         additional data regarding adolescent use of Plan B.  
                         It was then agreed that review staff would complete  
                         their reviews and collect the additional data and    
                         present them to the Commissioner and the Acting      
                         Director of CDER some time in February.              
                                                                              
                         Review staff within both Offices of Drug Evaluation  
                         III and V later noted in their completed reviews of  
                         the Plan B OTC switch application that they were     
                         told at this meeting that the decision on the Plan B 
                         application would be made at a level higher than the 
                         offices of drug evaluation.                          
January 16, 2004      A teleconference was held between review staff from  
                         the Office of Drug Evaluation V and the sponsor.     
                         According to meeting minutes, review staff informed  
                         the sponsor that a meeting was held with CDER        
                         management, including the Acting Director of CDER    
                         and the Director and Deputy Director of the Office   
                         of New Drugs, in which "some issues" were raised     
                         that would require review staff to "provide          
                         additional information and have additional           
                         discussions with CDER upper management." Minutes     
                         also noted that review staff told the sponsor they   
                         would not be discussing labeling revisions at that   
                         time and that they had been instructed by CDER       
                         management to complete their written reviews         
                         regarding the OTC switch application.                
January 21, 2004      A memorandum from the Director of Office of Drug     
                         Evaluation V indicated that she was in agreement     
                         with the favorable assessment of review staff and    
                         the majority votes by members of the joint advisory  
                         committee. Her memorandum concluded that adequate    
                         data had been submitted to approve Plan B for OTC    
                         marketing with certain product-labeling              
                         modifications-such as strengthening the message that 
                         Plan B is not for regular contraceptive use-included 
                         to address concerns raised at the public meeting and 
                         in the agency's reviews.                             
January 23, 2004      A meeting was held between FDA officials within the  
                         Office of New Drugs and the Offices of Drug          
                         Evaluation III and V and Barr Pharmaceuticals,       
                         Inc./WCC. According to meeting minutes, FDA          
                         officials told the sponsor that the decision on the  
                         application would be made at a level higher than the 
                         Offices of Drug Evaluation. The Director of the      
                         Office of New Drugs told the sponsor that such a     
                         high-level decision was not typical of CDER's        
                         procedures for drug approvals. The minutes also      
                         noted that review staff within the Offices of Drug   
                         Evaluation were in the process of completing their   
                         reviews and would forward them with their final      
                         recommendations to high-level management. Meeting    
                         minutes also indicated that FDA officials told the   
                         sponsor that they would need to request a meeting    
                         directly with the Office of the Center Director or   
                         the Office of New Drugs to understand high-level     
                         management's concerns.                               
                                                                              
                         In addition, meeting minutes noted that FDA          
                         officials told the sponsor that the Office of the    
                         Commissioner and the Acting Director of CDER had     
                         raised concerns as to whether there were adequate    
                         data to establish that minors (i.e., those under 18  
                         years of age) would use Plan B appropriately in the  
                         absence of a learned intermediary. Potential options 
                         that were suggested from FDA and CDER management     
                         included the possible need to (1) collect additional 
                         data, perhaps from another actual use study targeted 
                         to minors, or (2) to impose an age restriction on    
                         the OTC sale of the product.                         
February 2, 2004      Review staff within the Office of Drug Evaluation    
                         III requested that the sponsor reanalyze the         
                         adolescent data of the Plan B actual use study.      
                         According to the official request, staff asked for a 
                         "[s]ummary presentation of the Actual Use data from  
                         the participants in the less than 18 years of age    
                         subset, including comparisons to the older subset    
                         within the study."                                   
February 13, 2004     FDA confirmed that it had extended the PDUFA goal    
                         date for a decision on the Plan B OTC switch         
                         application for 90 days due to the submission of the 
                         requested adolescent data from the actual use study  
                         by the sponsor. The extended PDUFA goal date was May 
                         21, 2004.                                            
February 18, 2004     A briefing was held during which review staff within 
                         Offices of Drug Evaluation III and V presented their 
                         analysis of additional summary data to the           
                         Commissioner on the use and behavior of adolescents  
                         in association with increased access to emergency    
                         contraceptive pills. Other attendees included the    
                         Acting Deputy Commissioner for Operations and the    
                         Acting Director of CDER. According to meeting        
                         minutes, included in the presentation were the       
                         review staff's recommendations that Plan B have an   
                         OTC marketing status without restriction. The        
                         meeting minutes also noted that the Commissioner     
                         raised concerns regarding adolescents, including the 
                         potential for changes in future contraceptive        
                         behaviors and the potential benefits of counseling   
                         from a learned intermediary for younger adolescents. 
                                                                              
                         In addition, the meeting minutes noted that CDER was 
                         directed by the Commissioner to work with the        
                         sponsor on a marketing plan to limit the             
                         availability of Plan B in an OTC setting and to      
                         consider the most appropriate ages that should have  
                         OTC access restricted. The Commissioner requested a  
                         "rapid action" on the application.                   
February 19, 2004     Review staff within the Offices of Drug Evaluation   
                         III and V met with the Acting Deputy Commissioner    
                         for Operations, the Acting Director of CDER, and the 
                         Director and the Deputy Director of the Office of    
                         New Drugs. According to a reviewer's memorandum, in  
                         part, during this meeting, the Acting Deputy         
                         Commissioner for Operations expressed her and the    
                         Commissioner's concerns regarding adolescents and    
                         the potential for adverse behaviors resulting from   
                         increased access to Plan B. The Acting Director of   
                         CDER concurred with these concerns.                  
February 22, 2004     This was the original PDUFA goal date for the        
                         initial Plan B OTC switch application.               
February 26, 2004     Barr Pharmaceuticals, Inc., completed acquisition of 
                         the marketing rights for Plan B from WCC.            
March 11, 2004        Barr Pharmaceuticals, Inc., submitted an amendment   
                         to its sNDA, proposing a dual-marketing strategy,    
                         making Plan B OTC for women 16 years of age and      
                         older and prescription only for women under 16 years 
                         of age.                                              
April 2, 2004         The Deputy Director of the Office of Drug Evaluation 
                         III completed her review of the Plan B OTC switch    
                         application and recommended that Plan B be approved  
                         for use as an emergency contraceptive in the OTC     
                         setting without age restriction. The review          
                         concluded there were sufficient data on the safety   
                         and effectiveness of Plan B to approve its use in    
                         the OTC setting.                                     
April 22, 2004        The Director of the Office of New Drugs issued his   
                         review of the Plan B application and concurred with  
                         the recommendations of the offices of drug           
                         evaluation that the sponsor had provided adequate    
                         data to demonstrate that Plan B could be safely,     
                         effectively, and appropriately used by women of      
                         childbearing potential for the indication of         
                         emergency contraception without a prescription. He   
                         recommended that this application be approved to     
                         permit availability of Plan B without a prescription 
                         and without age restriction.                         
May 2, 2004           The Acting Director of CDER contacted the Director   
                         of the Office of Pediatric Therapeutics, within the  
                         Office of the Commissioner, via e-mail requesting    
                         assistance on language regarding cognitive           
                         development among adolescents.                       
                                                                              
                         According to internal FDA e-mails, the Director of   
                         the Office of Pediatric Therapeutics responded that  
                         she would consult with another official with a       
                         background in developmental pediatrics and would     
                         follow up with "behavioral science information as to 
                         why one cannot extrapolate decision making on safety 
                         issues" from older populations to younger            
                         adolescents.                                         
May 3, 2004           According to internal FDA e-mails, the Director of   
                         the Office of Pediatric Therapeutics provided the    
                         Acting Director of CDER with information on brain    
                         development and the maturation of higher-order       
                         thinking among adolescents 10 years to 21 years of   
                         age. In her e-mail to the Acting Director, the       
                         Director of the Office of Pediatric Therapeutics     
                         included the statement that "[d]uring early          
                         adolescence (10-13) there is an emergence of         
                         impulsive behavior without the cognitive ability to  
                         understand the etiology of their behavior."          
May 5, 2004           According to teleconference minutes, the Acting      
                         Director of CDER called Barr Pharmaceuticals, Inc.,  
                         officials to inform them of the not-approvable       
                         action and asked permission to release the           
                         not-approvable letter. According to FDA regulations, 
                         without consent of the sponsor, the agency cannot    
                         publicly release data or information contained in an 
                         application before an approval letter is issued.f    
                                                                              
                         Minutes noted that the Acting Director told sponsor  
                         officials that (with their permission) he would      
                         conduct a press interview to discuss the             
                         not-approvable action and the staff's disagreement   
                         with the not-approvable action would be acknowledged 
                         publicly.                                            
May 6, 2004           FDA issued a not-approvable letter, denying Plan B   
                         OTC marketing status, citing a lack of adequate data 
                         regarding safe use among younger adolescents. The    
                         letter also stated that FDA was not able to conduct  
                         a complete review of the dual-marketing strategy in  
                         the amendment to the sNDA because of the absence of  
                         the draft product labeling describing how Barr       
                         Pharmaceuticals, Inc., would comply with both the    
                         prescription and OTC labeling requirements in a      
                         single package.                                      

Source: GAO analysis of FDA data.

aSee 21 U.S.C. S: 355a(b), (c). FDA may request that manufacturers of new
or already-marketed drugs conduct studies of their drugs in pediatric
populations where it believes that such studies will lead to additional
health benefits. Studies completed in accordance with FDA requirements
entitle the manufacturer to an additional 6 months of marketing
exclusivity. In its technical comments on the draft of this report, FDA
stated that it did not ask for pediatric data for the prescription version
of Plan B because the product's physiological effects are the same in
younger and older women, and because a health care practitioner is
involved in dispensing prescription drugs.

bOn September 23, 2005, the Commissioner of FDA, who was appointed on July
18, 2005, resigned from his position. He held the title of Deputy
Commissioner from February 24, 2002, until March 26, 2004, when he was
named Acting Commissioner. Because he was Deputy Commissioner during most
of the time covered by this report-for those events associated with the
initial Plan B OTC switch application through the May 6, 2004, decision-we
use the title of Deputy Commissioner for him in this report.

cBehind-the-counter is defined as a classification of drug products that
do not require a prescription but are also unlike OTC products in that
there is a measure of clinical oversight in their use. For
behind-the-counter products, pharmacists are able to intervene by advising
patients on the product's proper use and associated risks and by referring
them to their physicians when appropriate. See Robert I. Field, "Support
Grows for a Third Class of `Behind-the-Counter' Drugs," Pharmacy and
Therapeutics, vol. 30, no.5 (2005): 260-261.

dFDA, in collaboration with various stakeholders, including
representatives from consumer, patient, and health care provider groups
and the pharmaceutical and biotechnology industries, has developed
performance goals for the time to complete the review of an application
submitted to the agency, which have been incorporated by reference into
PDUFA.

eThe Acting Deputy Commissioner for Operations was the Director of CDER
when the initial Plan B OTC switch application was submitted in April
2003. She told GAO that she became the Acting Deputy Commissioner for
Operations in March 2004, and that her role in the review of the initial
Plan B OTC switch application was as a consultant to the Acting CDER
Director.

fSee 21 C.F.R. S: 314.430(d)(1).

Appendix IV: Acting Director of CDER's Official Memorandum Explaining His
Not-Approvable Decision, May 6, 2004 Appendix IV: Acting Director of
CDER's Official Memorandum Explaining His Not-Approvable Decision, May 6,
2004

The following is the official memorandum submitted to the record by the
Acting Director of CDER to explain his decision on the initial Plan B OTC
switch application. GAO has redacted information identifying specific
persons as well as information not directly related to the review of the
initial Plan B application.

Appendix V: Director of the Office of New Drugs' Official Memorandum on
His Decision on the Plan B Application, April 22, 2004 Appendix V:
Director of the Office of New Drugs' Official Memorandum on His Decision
on the Plan B Application, April 22, 2004

The following is the official memorandum submitted to the record by the
Director of the Office of New Drugs to explain his decision on the initial
Plan B OTC switch application. GAO has redacted information identifying
specific persons as well as information not directly related to the review
of the initial Plan B application.

Appendix VI: Comments from the Food and Drug Administration Appendix VI:
Comments from the Food and Drug Administration

Appendix VII: St Appendix VII: GAO Contact and Staff Acknowledgments

                                  GAO Contact

Marcia Crosse, (202) 512-7119 or [email protected]

                                Acknowledgments

In addition to the contact named above, Martin T. Gahart, Assistant
Director; Cathleen Hamann; Julian Klazkin; Gay Hee Lee; and Deborah J.
Miller made key contributions to this report.

(290410)

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www.gao.gov/cgi-bin/getrpt? GAO-06-109 .

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Highlights of GAO-06-109 , a report to congressional requesters

November 2005

FOOD AND DRUG ADMINISTRATION

Decision Process to Deny Initial Application for Over-the-Counter
Marketing of the Emergency Contraceptive Drug Plan B Was Unusual

In April 2003, Women's Capital Corporation submitted an application to the
Food and Drug Administration (FDA) requesting the marketing status of its
emergency contraceptive pill(ECP), Plan B, be switched from prescription
to over-the-counter (OTC). ECPs can be used to prevent an unintended
pregnancy when contraception fails or after unprotected intercourse,
including cases of sexual assault. In May 2004, the Acting Director for
the Center for Drug Evaluation and Research (CDER) issued a
"not-approvable" letter for the switch application, citing safety concerns
about the use of Plan B in women under 16 years of age without the
supervision of a health care practitioner. Because the not-approvable
decision for the Plan B OTC switch application was contrary to the
recommendations of FDA's joint advisory committee and FDA review staff,
questions were raised about FDA's process for arriving at this decision.
GAO was asked to examine (1) how the decision was made to not approve the
switch of Plan B from prescription to OTC, (2) how the Plan B decision
compares to the decisions for other proposed prescription-to-OTC switches
from 1994 through 2004, and (3) whether there are age-related marketing
restrictions for prescription Plan B and other prescription and OTC
contraceptives. To conduct this review, GAO examined FDA's actions prior
to the May 6, 2004, not-approvable letter for the initial application.

On May 6, 2004, the Acting Director of CDER rejected the recommendations
of FDA's joint advisory committee and FDA review officials by signing the
not-approvable letter for the Plan B switch application. While FDA
followed its general procedures for considering the application, four
aspects of FDA's review process were unusual. First, the directors of the
offices that reviewed the application, who would normally have been
responsible for signing the Plan B action letter, disagreed with the
decision and did not sign the not-approvable letter for Plan B. The
Director of the Office of New Drugs also disagreed and did not sign the
letter. Second, FDA's high-level management was more involved in the
review of Plan B than in those of other OTC switch applications. Third,
there are conflicting accounts of whether the decision to not approve the
application was made before the reviews were completed. Fourth, the
rationale for the Acting Director's decision was novel and did not follow
FDA's traditional practices. The Acting Director stated that he was
concerned about the potential behavioral implications for younger
adolescents of marketing Plan B OTC because of their level of cognitive
development and that it was invalid to extrapolate data from older to
younger adolescents. FDA review officials noted that the agency has not
considered behavioral implications due to differences in cognitive
development in prior OTC switch decisions and that the agency previously
has considered it scientifically appropriate to extrapolate data from
older to younger adolescents.

The Plan B decision was not typical of the other 67 proposed
prescription-to-OTC switch decisions made by FDA from 1994 through 2004.
The Plan B OTC switch application was the only one during this period that
was not approved after the advisory committees recommended approval. The
Plan B action letter was the only one signed by someone other than the
officials who would normally sign the letter. Further, there are no
age-related marketing restrictions for any prescription or OTC
contraceptives that FDA has approved, and FDA has not required pediatric
studies for them. FDA identified no issues that would require age-related
restrictions in the review of the original prescription Plan B new drug
application.

In its comments on a draft of this report, FDA disagreed with GAO's
finding that high-level management was more involved with the Plan B OTC
switch application than usual, with GAO's discussion about when the
not-approvable decision was made, and with GAO's finding that the Acting
Director of CDER's rationale for denying the application was novel.
However, GAO found that high-level management's involvement for the Plan B
decision was unusual for an OTC switch application and FDA officials gave
GAO conflicting accounts about when they believed the decision was made.
The Acting Director acknowledged to GAO that considering adolescents'
cognitive development as a rationale for a not-approvable decision was
unprecedented for an OTC application, and other FDA officials told GAO
that the rationale differed from FDA's traditional practices.
*** End of document. ***