GAO-06-109, Food and Drug Administration: Decision Process to Deny Initial Application for Over-the-Counter Marketing of the Emergency Contraceptive Drug Plan B Was Unusual


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entitled 'Food and Drug Administration: Decision Process to Deny 
Initial Application for Over-the-Counter Marketing of the Emergency 
Contraceptive Drug Plan B Was Unusual' which was released on November 
14, 2005. 

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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: 

GAO Highlights: 

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

Why GAO Did This Study: 

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. 

What GAO Found: 

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. 

What GAO Recommends: 

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

To view the full product, including the scope and methodology, click on 
the link above. For more information, contact Marcia Crosse at (202) 
512-7119 or crossem@gao.gov. 

[End of section] 

Contents: 

Letter: 

Results in Brief: 

Background: 

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

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

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

Agency Comments and Our Evaluation: 

Appendix I: Scope and Methodology: 

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

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

Appendix VI: Comments from the Food and Drug Administration: 

Appendix VII: GAO Contact and Staff Acknowledgments: 

Table: 

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

Figure: 

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

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: 

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).[Footnote 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.[Footnote 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).[Footnote 3] OTC switch applications for drugs that are "first- 
in-a-class,"[Footnote 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.[Footnote 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.[Footnote 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. 

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 CDER[Footnote 7] signed a "not-approvable" letter 
for the switch to OTC,[Footnote 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.[Footnote 9] On 
July 22, 2004, Barr Pharmaceuticals, Inc.,[Footnote 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.[Footnote 11] 

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. 

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.[Footnote 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. 

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,[Footnote 
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. 

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.[Footnote 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; 
[Footnote 15] (2) it has a low potential to be abused; (3) it has an 
appropriate safety and therapeutic index;[Footnote 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,[Footnote 17] and 
requires minimal intervention by a health care practitioner for 
treatment.[Footnote 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).[Footnote 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. 

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.[Footnote 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. 

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

[See PDF for image] 

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. 

[End of figure] 

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 package[Footnote 21] 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. 

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.[Footnote 22] ECPs are high dose birth control 
pills and have been available by prescription since 1998, when FDA 
approved Preven, a dedicated[Footnote 23] combined ECP containing the 
hormones estrogen and progestin.[Footnote 24] Prior to 1998, many 
physicians instructed patients to take higher doses of oral 
contraceptive pills for emergency contraception, an "off-label" 
use.[Footnote 25] 

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.[Footnote 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,[Footnote 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.[Footnote 28] 

ECPs have not been shown to cause a postfertilization event--a change 
in the uterus that could interfere with implantation of a fertilized 
egg.[Footnote 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.[Footnote 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.[Footnote 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. 

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.[Footnote 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. 

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

Date: July 28, 1999; 
Event: FDA approved Plan B as a prescription form of emergency 
contraception. 

Date: April 18, 2002; 
Event: 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]. 

Date: June 5, 2002; 
Event: 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. 

Date: September 23, 2002; 
Event: 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]. 

Date: April 16, 2003; 
Event: WCC submitted an sNDA to FDA to allow Plan B to be sold OTC. 

Date: June 9, 2003; 
Event: FDA set a Prescription Drug User Fee Act (PDUFA) goal date of 
February 22, 2004, to reach a decision on the application.[D]. 

Date: December 16, 2003; 
Event: 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. 

Date: January 15, 2004; 
Event: 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. 

Date: January 21, 2004; 
Event: 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. 

Date: January 23, 2004; 
Event: 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. 

Date: February 2, 2004; 
Event: 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. 

Date: February 13, 2004; 
Event: 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. 

Date: February 18, 2004; 
Event: 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. 

Date: February 26, 2004; 
Event: Barr Pharmaceuticals, Inc., completed acquisition of the 
marketing rights of Plan B from WCC. 

Date: April 2, 2004; 
Event: 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. 

Date: April 22, 2004; 
Event: 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. 

Date: May 2, 2004; 
Event: 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. 

Date: May 5, 2004; 
Event: 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]. 

Date: May 6, 2004; 
Event: 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. 

[A] See 21 U.S.C. § 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. 

[B] On 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. 

[C] Behind-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. 

[D] FDA, 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. 

[E] See 21 C.F.R. § 314.430(d)(1). 

[End of table] 

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.[Footnote 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.[Footnote 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.[Footnote 
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]."[Footnote 
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.[Footnote 
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. 

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.[Footnote 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.[Footnote 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.[Footnote 40] 

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. 

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 1998[Footnote 41] and the approval of 
mifepristone for the termination of early pregnancy in 2000.[Footnote 
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 Operations[Footnote 43] 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. 

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).[Footnote 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.[Footnote 45] 

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." 

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.[Footnote 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.[Footnote 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. 

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.[Footnote 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. 

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.[Footnote 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. 

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.[Footnote 50] 

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.[Footnote 51] 

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.[Footnote 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. 

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 crossem@gao.gov. 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. 

Signed by: 

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: 

[End of section] 

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. 

[End of section] 

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

DEPARTMENT OF HEALTH & HUMAN SERVICES: 

Public Health Service: 

Food and Drug Administration: 
Rockville, MD 20857: 

NDA 21-045/S-011: 

Barr Research, Inc. 
Attention: Joseph A. Carrado, M.Sc., Ph.D. 
Senior Director, Regulatory Affairs: 
One Bala Plaza, Suite 324: 
Bala Cynwyd, PA 19004-1401: 

Dear Dr. Carrado: 

Please refer to your supplemental new drug application dated April 16, 
2003, received April 22, 2003, submitted under section 505(b) of the 
Federal Food, Drug, and Cosmetic Act for Plan B® (0.75 mg 
levonorgestrel) tablets. 

We acknowledge receipt of your submissions dated July 25 (3) and 31, 
August 8 (2), September 4, 8, 9, and 15, October 6, 10, 15 (2), 17, 21, 
24, 29, 30 and 31, December 3 and 9, 2003; and January 9 and 30, 
February 6, 10, 13, 20 and 24, and March 11 and 26, 2004. 

This supplemental new drug application proposes nonprescription (over- 
the-counter (OTC)) availability of Plan B (0.75 mg levonorgestrel) 
tablets for emergency contraception to reduce the chance of pregnancy 
after unprotected sex (if a contraceptive failed or if birth control 
was not used). 

We have completed our review of this supplement and, for the reasons 
described below, find that the supplemental application is not 
approvable at this time under section 505(d) of the Act and 21 CFR 
314.125(b). 

You propose OTC status for Plan B for both adults and children based 
primarily on an actual use study in 585 subjects. Only 29 of the 585 
subjects enrolled in the study were 14-16 years of age, and none was 
under 14 years of age. 

In a December 16, 2003 joint meeting, the Nonprescription Drugs 
Advisory Committee and the Reproductive Health Drugs Advisory Committee 
considered your proposal to switch Plan B to nonprescription status. 
Although the Joint Committee recommended that your proposal to switch 
Plan B be approved, some members of the Joint Committee, including the 
Chair, raised questions concerning whether the actual use data were 
generalizable to the overall population of nonprescription users, 
chiefly because of inadequate sampling of younger age groups. 

Based on a review of the data, we have concluded that you have not 
provided adequate data to support a conclusion that Plan B can be used 
safely by young adolescent women for emergency contraception without 
the professional supervision of a practitioner licensed by law to 
administer the drug. In your March 11, 2004, amendment, you proposed to 
change the indication to allow for marketing of Plan B as a 
prescription-only product for women under 16 years of age and a 
nonprescription product for women 16 years and older. This preliminary 
proposal did not include draft product labeling to demonstrate how you 
propose to comply with both the prescription and nonprescription 
labeling requirements in a single packaging configuration. Because of 
the preliminary and incomplete nature of the proposal, we did not 
conduct a complete review of this amendment during this review cycle. 

Before this application can be approved, you would have to provide data 
demonstrating that Plan B can be used safely by women under 16 years of 
age without the professional supervision of a practitioner licensed by 
law to administer the drug. Alternatively, you could supply additional 
information in support o^ the revised indication to allow for marketing 
of Plan B as a prescription-only product for women under the age of 16 
years and a nonprescription product for women 16 years and older, 
including draft product labeling. If you take the latter approach, your 
response to this letter would have to include details of how you 
propose to implement simultaneous prescription and nonprescription 
marketing of Plan B for women of different ages in a single packaging 
configuration while complying with all relevant statutory and 
regulatory requirements for labeling and marketing of this product. We 
will have to assure ourselves that your proposed approach is consistent 
with our statutory authority. If you pursue the alternative approach, 
we also would request details of your proposed program to educate 
consumers, pharmacists, and physicians about the dual marketing of Plan 
B as both a prescription and nonprescription product, as well as your 
proposed program to monitor implementation of this novel approach. 

Wide availability of safe and effective contraceptives is important to 
public health. We look forward to continuing to work with you if you 
decide to pursue either of these options. 

When you respond to the above deficiencies, include a safety update as 
described at: 

21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from 
all non-clinical and clinical studies of the drug under consideration 
regardless of indication, dosage form, or dose level. 

1. Describe in detail any significant changes or findings in the safety 
profile. 

2. When assembling the sections describing discontinuations due to 
adverse events, serious adverse events, and common adverse events, 
incorporate new safety data as follows: 

* Present new safety data from the studies for the proposed indication 
using the same format as the original NDA submission. 

* Present tabulations of the new safety data combined with the original 
NDA data. 

* Include tables that compare frequencies of adverse events in the 
original NDA with the retabulated frequencies described in the bullet 
above. 

* For indications other than the proposed indication, provide separate 
tables for the frequencies of adverse events occurring in clinical 
trials. 

3. Present a retabulation of the reasons for premature study 
discontinuation by incorporating the drop-outs from the newly completed 
studies. Describe any new trends or patterns identified. 

4. Provide case report forms and narrative summaries for each patient 
who died during a clinical study or who did not complete a study 
because of an adverse event. In addition, provide narrative summaries 
for serious adverse events. 

5. Describe any information that suggests a substantial change in the 
incidence of common, but less serious, adverse events between the new 
data and the original NDA data. 

6. Provide a summary of worldwide experience on the safety of this 
drug. Include an updated estimate of use for drug marketed in other 
countries. 

7. Provide English translations of current approved foreign labeling 
not previously submitted. 

Within 10 days after the date of this letter, you are required to amend 
the supplemental application, notify us of your intent to file an 
amendment, or follow one of your other options under 21 CFR 314.120. If 
you do not follow one of these options, we will consider your lack of 
response a request to withdraw the application under 21 CFR 314.65. Any 
amendment should respond to all the deficiencies listed. We will not 
process a partial reply as a major amendment nor will the review clock 
be reactivated until all deficiencies have been addressed. 

Under 21 CFR 314.102(d), you may request an informal meeting or 
telephone conference with the Divisions of Over-the-Counter Drugs and 
Reproductive and Urologic Drug Products to discuss what steps need to 
be taken before the application may be approved. 

This product may be considered to be misbranded under the Federal Food, 
Drug, and Cosmetic Act if it is marketed with this change before 
approval of this supplemental application. 

If you have any questions, call the Regulatory Project Manager at (301) 
827-4260. 

Sincerely, 

Electronically signed by: 

Steven Galson, M.D., M.P.H.: 
Acting Director: 
Center for Drug Evaluation and Research: 

[End of section] 

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

Date: February 25, 1997; 
Event: 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. 

Date: July 28, 1999; 
Event: FDA approved Plan B as a prescription form of emergency 
contraception. 

Date: February 14, 2001; 
Event: A citizens' petition for direct over- the-counter (OTC) access 
to Plan B was filed, requesting that FDA grant Plan B OTC status. 

Date: April 18, 2002; 
Event: 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. 

Date: May 28, 2002; 
Event: 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. 

Date: June 5, 2002; 
Event: 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. 

Date: July 10, 2002; 
Event: 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. 

Date: September 23, 2002; 
Event: 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]. 

Date: April 16, 2003; 
Event: WCC submitted an sNDA to FDA to allow Plan B to be sold OTC. 

Date: June 9, 2003; 
Event: 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]. 

Date: August 22, 2003; 
Event: 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. 

Date: September 11, 2003; 
Event: 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. 

Date: September 26, 2003; 
Event: 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. 

Date: October 2003; 
Event: 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. 

Date: October 9, 2003; 
Event: 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. 

Date: November 5, 2003; 
Event: 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. 

Date: December 2, 2003; 
Event: 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. 

Date: December 10, 2003; 
Event: 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. 

Date: December 16, 2003; 
Event: 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. 

Date: December 2003/January 2004; 
Event: The Director and the Deputy 
Director of the Office of New Drugs told GAO they were told by the 
Acting Deputy Commissioner for Operations[E] 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. 

Date: January 15, 2004; 
Event: 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. 

Date: January 16, 2004; 
Event: 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. 

Date: January 21, 2004; 
Event: 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. 

Date: January 23, 2004; 
Event: 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. 

Date: February 2, 2004; 
Event: 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." 

Date: February 13, 2004; 
Event: 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. 

Date: February 18, 2004; 
Event: 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. 

Date: February 19, 2004; 
Event: 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. 

Date: February 22, 2004; 
Event: This was the original PDUFA goal date for the initial Plan B OTC 
switch application. 

Date: February 26, 2004; 
Event: Barr Pharmaceuticals, Inc., completed acquisition of the 
marketing rights for Plan B from WCC. 

Date: March 11, 2004; 
Event: 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. 

Date: April 2, 2004; 
Event: 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. 

Date: April 22, 2004; 
Event: 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. 

Date: May 2, 2004; 
Event: 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. 

Date: May 3, 2004; 
Event: 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." 

Date: May 5, 2004; 
Event: 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. 

Date: May 6, 2004; 
Event: 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. 

[A] See 21 U.S.C. § 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. 

[B] On 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. 

[C] Behind-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. 

[D] FDA, 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. 

[E] The 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. 

[F] See 21 C.F.R. § 314.430(d)(1). 

[End of table] 

[End of section] 

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. 

MEMORANDUM: 

DATE: May 6, 2004: 

FROM; [Text Redacted] 

Acting Director, Center for Drug Evaluation and Research: 

TO: NDA 21-045: 

SUBJECT: Review of NDA for Rx to Over the Counter Switch for Plan B: 

I have read and carefully considered all of the reviews in the action 
package for this application. I do not concur with the recommendation 
by the Office of New Drugs to approve Barr's application to switch Plan 
B to over-the-counter (OTC) status. My decision is based on the lack of 
available data relevant to OTC use of the product by adolescents 
younger than 14 and very limited data in the 14-16 age group. Without 
data in the application on OTC use in this age group, and lacking 
confidence that data from older adolescents can be confidently 
extrapolated to this age group, I find the proposal to switch Plan B 
from Rx to OTC use-thus making it available to very young adolescents- 
to be unsupported. Specific concerns regarding the application include 
the following: 

* Sexual activity among 11-to 14-year-old females in the United States 
is well documented.[NOTE 1] Despite the urgent need to prevent 
pregnancy in these young adolescents, the application contained no data 
in subjects under 14 years of age. 

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. 
For example, during early adolescence (10-13), this age group 
experiences the emergence of impulsive behavior without the cognitive 
ability to understand the etiology of their behavior. During mid- 
adolescence (14-16), youth begin to develop the capacity to think 
abstractly; however, their ability to integrate their emerging 
cognitive skills into their real-life experiences is immature and 
incomplete. The capacity to understand complex concepts, which develops 
during middle adolescence, allows adolescents to modulate their 
impulsive behavior. [NOTE 2] 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. 

I also have the following concerns: 

* The additional studies cited in the Office of New Drugs reviews do 
not approximate actual OTC use sufficiently to support approval. 
Although the studies are relevant, none tests the hypothesis that 
typical adolescent consumers with no extra information will use the 
product correctly. The studies are either not conducted in the general 
population or they provide product education assistance beyond what 
adolescents would receive in an OTC situation, where no contact with a 
heath care professional is expected. Likewise, the literature review 
submitted to address questions of important potential behavioral 
changes associated with availability of an emergency contraceptive 
(e.g., substitution of the product for routine and more effective 
contraception, or increased medically risky sexual behavior) did not 
contain studies that mimic what would be actual OTC availability. 

* The number of adolescent participants in the actual use study is too 
small to generalize to the U.S. population of adolescents. I do not 
believe the data set on this age group is large enough to reach valid 
conclusions from the study. 

Some staff have expressed the concern that this decision is based on 
non-medical implications of teen sexual behavior, or judgments about 
the propriety of this activity. These issues are beyond the scope of 
our drug approval process, and I have not considered them in this 
decision. 

The need for data on young adolescent behavior discussed in this memo 
does not apply to prescription contraceptive products because use of 
prescription products involves monitoring by health care practitioners 
and, most-likely in this age group, parents. 

(Remaining Text Redacted] 

NOTES: 

[1] "14 and Younger. The Sexual Behavior of Young Adolescents," The 
National Campaign to Prevent Teen Pregnancy, May 2003. 

[2] Rudolph's Pediatrics, 21st edition, Chapter 3.1, Growth and 
Development, Psychological Development During Adolescence. 

[End of section] 

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. 

MEMORANDUM: 

DATE: April 22, 2004: 

FROM: [Text Redacted] 

Director, Office of New Drugs: 

TO: NDA 21-045: 

SUBJECT: Review of NDA for Rx to OTC Switch for Plan B: 

This memorandum is intended to summarize my review, conclusions, and 
recommendations regarding the pending application submitted by Barr 
Laboratories proposing a switch to non-prescription status for Plan B 
(levonorgestrel) for emergency contraception. I have read and carefully 
considered the reviews in the action package written by [Text Redacted] 

I also attended the December 16, 2003, joint meeting of the Non- 
Prescription Drugs Advisory Committee and the Reproductive Health Drugs 
Advisory Committee at which this application was presented for 
discussion and public input. 

The drug product and indication proposed by the sponsor for non- 
prescription marketing (also known as over-the-counter or OTC) are 
identical to the approved prescription product. Plan B has previously 
been proven to be effective for emergency contraception, and has a well-
documented safety profile. Therefore, the primary regulatory issue in 
considering the potential non-prescription use of this product is 
whether it can be used safely, effectively, and appropriately by women 
of child-bearing potential without need for a learned intermediary 
(e.g., counseling from a physician). In support of this application the 
sponsor submitted a label comprehension study and an actual use study, 
both of which have been extensively reviewed by the staff in the two 
divisions. 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. This conclusion is supported by the fact that 
both divisions and offices responsible for the review of this 
application have recommended approval and the fact that the joint 
Advisory Committee voted 23 to 4 in favor of recommending that Plan B 
be switched to non-prescription status. 

Other senior officials within the Agency, including the former 
Commissioner [Text Redacted] and the Acting Center Director [Text 
Redacted], have expressed concerns about the potential for unsafe, 
ineffective, or inappropriate use of Plan B by adolescents if it were 
to be made available without a prescription. These concerns appear to 
have been based primarily on the limited number of adolescent women 
included in the sponsor's label comprehension and actual use studies. 
While it is true that the number of adolescents enrolled in the 
sponsor's studies was relatively small, these studies did not exclude 
adolescent women from enrollment and were conducted in settings that 
would be expected to capture a representative population of women who 
currently seek emergency contraception. Therefore, it is likely that 
the percentage of patients enrolled in these studies is an accurate 
reflection of the potential users of Plan B in an OTC setting. 
Furthermore, the data from these studies do not suggest that adolescent 
women are significantly different from older women in their 
comprehension of the labeling or appropriate use of the product in the 
OTC setting, and for some analyses the adolescent women actually 
performed better than older women. I, therefore, believe that the data 
from the studies submitted by the sponsor are sufficient and adequate 
on which to base a regulatory decision on whether Plan B can be used 
safely, effectively, and appropriately by women of childbearing 
potential, regardless of age, in the OTC setting. The Agency has not 
heretofore distinguished the safety and efficacy of Plan B and other 
forms of hormonal contraception among different ages of women of 
childbearing potential and I am not aware of any compelling scientific 
reason for such a distinction in this case. I would also note 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, and this practice was recently incorporated 
into the Pediatric Research and Equity Act (PREA). 

As detailed in the reviews prepared by [Text redacted], in addition to 
the studies submitted by the sponsor there exists a substantial body of 
data from recently completed published and unpublished studies on 
emergency contraception that have enrolled a substantial number of 
adolescent women. While none of the studies directly mimic the OTC 
setting for access to Plan B, I believe that these data are relevant 
and help to address whether adolescents can use Plan B in the OTC 
setting. Taken together, these additional studies do not support a 
concern that adolescent women are less able to understand the label 
directions or less likely to appropriately use the product than older 
women. Further, these studies found that increased access for 
adolescents to emergency contraception did not result in inappropriate 
use of Plan B as a routine form of contraception, an increase in the 
number of sexual partners, an increase in the frequency of unprotected 
intercourse, or an increase in the frequency of sexually transmitted 
diseases. 

In summary, I concur with the recommendations from the review divisions 
and offices that the sponsor has provided adequate data to demonstrate 
that Plan B can be safely, effectively, and appropriately used by women 
of childbearing potential for the indication of emergency contraception 
without a prescription. I, therefore, recommend that this application 
be approved to permit availability of Plan B without a prescription and 
without restrictions regarding the availability of the product to 
adolescent women. 

I am sensitive to and respect the concerns that some may have regarding 
non-prescription access to Plan B by adolescents. Products that are 
indicated for uses related to sexual activity in adolescents raise 
concerns for some people that go beyond a finding based on clinical 
trial data that the product is safe and effective for its intended use 
in adolescents. These concerns are derived from individual views and 
attitudes about the morality of adolescent sexual behavior and also 
overlap with concerns about the role for parents and health care 
professionals in decisions about contraceptive use in adolescents. 
While acknowledging these concerns, I believe that the available data 
clearly support a conclusion that Plan B meets the statutory and 
regulatory requirements for availability without a prescription for all 
age groups. 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. While OTC access to Plan B for adolescents may 
be controversial from a societal perspective, I cannot think of any age 
group where the benefit of preventing unplanned pregnancies and 
abortion is more important and more compelling. 

The sponsor is aware of the societal issues related to OTC access for 
Plan B, particularly to adolescents. They initially proposed a 
voluntary marketing plan called CARE (Convenient Access Responsible 
Education), which was designed to increase awareness of appropriate use 
of Plan B through education while increasing availability through OTC 
access. The joint Advisory Committee voted 22 to 5 (with one 
abstention) that this program was adequate for introduction of Plan B 
into the OTC setting. [Remaining Text Redacted] 

[End of section] 

Appendix VI: Comments from the Food and Drug Administration: 

DEPARTMENT OF HEALTH & HUMAN SERVICES: 
Public Health Service: 

Food and Drug Administration: 
Rockville MD 20857: 

October 28, 2005: 

Marcia Crosse: 
Director, Health Care: 
United States Government Accountability Office: 
441 G Street, NW: 
Washington, DC 20548: 

Dear Ms. Crosse: 

Please find enclosed the Food and Drug Administration's general 
comments in response to the Government Accountability Office's draft 
report entitled, "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." 

We appreciate the opportunity to review and comment on this draft 
report before it is published, as well as the opportunity to work with 
your staff in its development. 

Sincerely, 

Signed by: 

Janet Woodcock, M.D. 

Deputy Commissioner for Operations: 

Enclosure: 

General Comments to GAO's Draft Report, Entitled, "FOOD AND DRUG 
ADMINISTRATION: Decision Process to Deny Initial Application for Over- 
the Counter Marketing of the Emergency Contraceptive Drug Plan B Was 
Unusual" 

We would first like to observe that the agency's opportunity to review 
this report was atypical. Usually, GAO provides the agency with copies 
of the report and gives the agency ample time for an internal review 
and for comment. In this case, we were not provided a copy of the 
report to review and discuss among ourselves. Instead, GAO offered 
various viewing times and required FDA personnel to sit in a room with 
a GAO representative in order to review the report. We were not 
permitted to copy portions of the report or to make telephone calls. 
Because of these restrictions, we have had to compile our comments 
based on our recollection and notes of what the report said during the 
limited time we had to review it. Our substantive comments are as 
follows: 

1. One of the principal findings in the report is that the decision 
process for issuance of the Not-Approvable letter for Plan B in May of 
2004 was unusual in that FDA high-level management was more involved in 
the Plan B decision than it has been in other over-the-counter (OTC) 
switch decisions. While it is true that management at the Center for 
Drug Evaluation and Research (CDER or Center) is not always involved in 
making decisions on OTC switch applications, the report suggests that 
the Center Director's involvement on the Plan B application was more 
unusual than it actually was. The report does not reflect the fact that 
Center management is ultimately responsible for all decisions made 
within CDER, and the Center Director is regularly apprised of, and 
involved in, regulatory decisions that are not routine, such as those 
that raise complicated scientific issues, are likely to be 
controversial, or those for which there is a difference of opinion in 
the Center. Because of the amount of public interest in the Plan B 
application, including the fact that two citizen petitions had been 
submitted regarding the OTC switch of Plan B, it was fairly typical 
that the Center Director was involved in the regulatory action on Plan 
B. In addition, the Center Director discussed the Plan B switch 
application with high-level management within the Office of the 
Commissioner. Such discussions are part of the Center Director's 
responsibilities (i.e., to keep his superiors within the agency 
apprised) and are typical for high-profile, controversial applications. 

2. The report also says that the issuance of a Not-Approvable letter in 
May of 2004 was unusual because there were conflicting accounts about 
whether the decision to not approve the supplemental application was 
made before the reviews were completed. The report discusses at length 
the communications between the review divisions and the Acting 
Director, CDER and the Acting Deputy Commissioner for Operations in the 
December 2003 and January 2004 timeframes. The tone of the discussion 
suggests that the decision to not approve Plan B that was reflected in 
the May 6, 2004, letter may have been made as early as December 2003 
before the reviews were completed, and that this was somehow improper. 
The report does not reflect that the ordinary course of making 
regulatory decisions in CDER almost always encompasses discussion of 
alternative regulatory courses of action over a period of time. A 
decision on an application is not considered to have been made until 
the chosen alternative is documented in an action letter, with 
supporting rationale. In the first cycle review of Plan B, regulatory 
alternatives were discussed as the original user fee performance goal 
date of February 20, 2004, approached. It was entirely normal for the 
Acting Center Director and others to convey to the review divisions 
their concerns regarding the application so the division could 
determine what communications with the applicant were appropriate as 
the goal date approached. It is inaccurate, however, to claim that a 
decision to issue a Not-Approvable letter was made several months 
before the action letter was issued. As the report itself indicates, as 
late as May 2, 2004, the Acting Director, CDER consulted with the 
Office of Pediatrics seeking more data on cognitive development in 
adolescents. The information received provided support for the 
conclusions reflected in the letter issued on May 6, 2004, documenting 
the action on the first review cycle of the application. 

3. The third aspect of the action on Plan B that GAO found was 
"unusual" was that the rationale for the decision was "novel" and did 
not follow traditional practices, referring to the consideration of 
behavioral issues such as decreased use of condoms and increased risk 
of sexually transmitted diseases (STDs). This conclusion reflects a 
fundamental misunderstanding of the issues normally considered in OTC 
switch applications and the Acting Director's rationale supporting his 
action on the first cycle review of the Plan B supplemental 
application. First, all OTC switch applications require consideration 
of "behavioral" issues, including whether the disease or condition can 
be self-diagnosed and whether the drug can be used safely and 
effectively under actual conditions of use. Most switch applications 
are accompanied by actual use and label comprehension studies that 
examine such "behavioral" issues. In addition, the "behavioral" issues 
with regard to this application are directly related to safe use of the 
product. For example, if a woman chose not to use condoms and to rely 
on Plan B as her only form of contraception, she may be exposing 
herself to risks related to acquiring STDs, and if she relies on Plan B 
as her routine form of birth control, she would be exposing herself to 
the risks of regular oral contraceptives (which are only available Rx). 

In the case of Plan B, the behaviors that were appropriate for 
consideration included sexual behaviors such as condom use and 
increased risk of STDs. Furthermore, the report suggests that the 
Acting Director, CDER alone identified these behavioral issues as 
concerns in his review. In fact, the Acting Director, CDER was not the 
source of these issues in the review of the Plan B supplemental 
application. Regarding the studies that were submitted by Barr and 
reviewed by the Divisions, the actual use study included specific 
questions about condom use and the label comprehension study included 
data from questions that assessed women's understanding that Plan B 
does not protect against STDs. The Acting Director, CDER reviewing the 
data in the application concluded that the data on actual use and label 
comprehension were inadequate to allow a conclusion that Plan B could 
be used safely and effectively in women under 16 because women in that 
age group were inadequately represented in the actual use and label 
comprehension studies. Rather than introducing a "novel" approach to 
this OTC switch application, the Acting Director, CDER reached a 
different conclusion than that of the review Divisions based on his 
view of the adequacy of the data supporting the switch. 

4. The last aspect that GAO asserts was unusual (listed first in the 
GAO report) was that the Directors of the Offices of Drug Evaluation 
(ODE) III and V and the Director of the Office of New Drugs "refused to 
sign" the Not-Approvable letter. The Acting Director, CDER did not ask 
the ODE Directors or the OND Director to sign the letter, nor was the 
letter ever presented to them for signature. It would be more accurate 
to state that those FDA officials did not agree with the issuance of a 
Not-Approvable letter, and therefore were not asked to sign it. 

[End of section] 

Appendix VII: GAO Contact and Staff Acknowledgments: 

GAO Contact: 

Marcia Crosse, (202) 512-7119 or crossem@gao.gov: 

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. 

FOOTNOTES 

[1] FDA 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. 

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

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

[4] A 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. 

[5] In 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. 

[6] An 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. 

[7] The 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. 

[8] A 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. § 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. 
§ 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. 

[9] Besides 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. 

[10] In 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. 

[11] On 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. 

[12] The 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). 

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

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

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

[16] The 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. 

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

[18] These 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. 

[19] Drugs 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. 

[20] An 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. 

[21] An 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. 

[22] In 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. 

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

[24] Estrogen 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. 

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

[26] World 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. 

[27] Horacio 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. 

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

[29] Implantation 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. 

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

[31] It 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. 

[32] For 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. 

[33] Minutes 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. 

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

[35] Behind-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. 

[36] According 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. 

[37] When 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. 

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

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

[40] We 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. 

[41] Leprosy 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. 

[42] For 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. 

[43] The 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. 

[44] For 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. 

[45] This 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. 

[46] Only 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. 

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

[48] Although 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. 

[49] See 21 U.S.C. § 355c(a)(2)(B). 

[50] Reasons 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. 

[51] In 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. 

[52] The 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. 

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