GAO

United States General Accounting Office

Report to Congressional Requesters

August 2000 PRESCRIPTION

DRUGS

Many Factors Affected

FDA’s Approval of

Selected “Pipeline”

Drugs

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Contents

Letter 3

Appendixes Appendix I: Scope and Methodology 26

Appendix II: Approval Time Comparisons 29

Appendix III: Approval Process for Claritin 32

Appendix IV: Approval Process for Relafen 45

Appendix V: Approval Process for Cardiogen-82 49

Tables Table 1: Pipeline Drug Approval Times in Months 29

Table 2: Average Total Approval Time for Drugs Approved 1983-85 in

Months 31

Figures Figure 1: Timeline of Events Affecting Claritin’s Approval, 1986-93 10

Figure 2: Timeline of Events Affecting Relafen’s Approval, 1982-91 15

Figure 3: Timeline of Events Affecting Cardiogen-82’s Approval,

1984-89 18

Abbreviations

CAC Carcinogenicity Assessment Committee

FDA Food and Drug Administration

IND investigational new drug

NDA new drug application

NSAID nonsteroidal anti-inflammatory drug

OTA Office of Technology Assessment

PDUFA Prescription Drug User Act of 1992
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United States General Accounting Office

Washington, D.C. 20548

Health, Education, and

Human Services Division

B-283293 Letr

August 10, 2000

Congressional Requesters

The Drug Price Competition and Patent Term Restoration Act of 1984, also

known as the Waxman-Hatch Act, sought to improve public health by

encouraging the availability of more effective and affordable drugs while

balancing the interests of generic and brand name pharmaceutical

manufacturers.1 The act provided the generic drug industry a simplified and

faster review process for generic versions of brand drugs that are typically

available to consumers at lower prices. The act also provided brand name

drug companies an extension of the existing 17-year patent protection as an

incentive to develop innovative new medications. For drugs that were not

yet patented, or were patented but had not yet begun human clinical trials

at the time of the law’s enactment, the act provided up to a 5-year patent

extension. However, the law limited the extension to 2 years if a patent for

a drug had been issued and human clinical trials had begun at the time of

the law’s enactment. The 122 drugs that were limited to the 2-year

extension are commonly referred to as “pipeline” drugs.

Recently, legislation (H.R. 1598 and S. 1172) was introduced to institute a

process by which the manufacturers of pipeline drugs that took longer than

5 years to be approved and whose patents were still in effect could apply

for a patent extension. Seven of the 122 pipeline drugs would be eligible for

review under this proposal.2 To assist the Congress as it considers this

1

A brand name drug company manufactures drugs that are sold under a registered brand

name either by its innovator (that is, the manufacturer that holds the patent on the drug) or

by a company that has an exclusive license from the innovator to sell the drug. Generic drug

companies sell equivalent versions of brand name drugs. A generic drug contains a

biologically active drug identical to its brand name counterpart; however, the inactive

ingredients and manufacturing process may differ. A generic drug, which cannot be

marketed until the exclusive patent period for the brand name drug has expired, is normally

sold under the drug’s generic (that is, scientific) name.

2

The seven drugs are Claritin (an antihistamine manufactured by the Schering-Plough

Corporation), Relafen (a nonsteroidal anti-inflammatory drug used for relieving pain made

by the SmithKline Beecham Corporation), Cardiogen-82 (a diagnostic imaging agent

marketed by Bracco Diagnostics), Dermatop (a corticosteroid for skin conditions

manufactured by Aventis Pharmaceuticals), Eulexin (a prostate cancer drug manufactured

by the Schering-Plough Corporation), Nimotop (a calcium channel blocker made by the

Bayer Corporation), and Penetrex (an antibiotic made by Aventis Pharmaceuticals).
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proposal, you asked us to examine the Food and Drug Administration’s

(FDA) review and approval of the manufacturers’ applications to market

seven drugs that would be covered by the proposed legislation. Specifically,

we examined (1) the review and approval times for the seven pipeline

drugs in comparison with other drugs and the factors that contributed to

the time FDA required to approve the three of the seven drugs for which

the manufacturers agreed to supply us information and (2) whether the

Congress based the 2-year patent extension granted to pipeline drugs on

the assumption that FDA action on these drugs’ applications would occur

within the average length of time for FDA approval of new drug

applications.

To examine these issues, we obtained information from FDA on drug

approval times, reviewed drug files at FDA, and examined material

provided by the drug companies that hold the patents for three of the seven

pipeline drugs that would be covered by the proposal. Our examination of

the factors that affected approval times for the four other drugs was limited

because the manufacturers were either unable to supply or uninterested in

supplying information we needed for our study.3 We also reviewed the

legislative history of the Drug Price Competition and Patent Term

Restoration Act of 1984 and spoke with government and industry officials

about the drug review process. (Detailed information about our

methodology is in appendix I.) We conducted our work between October

1999 and June 2000 in accordance with generally accepted government

auditing standards.

Results in Brief The times taken to approve the seven pipeline drugs that would be eligible

for review under the proposed legislation were significantly longer than the

corresponding average approval times for pipeline drugs of the same

chemical type and potential therapeutic benefit.4 In all cases, the time from

submission of applications to approval for the seven pipeline drugs ranged

from 17 to 65 months longer than the average time for comparable pipeline

3

The manufacturer of one drug could not provide us with information on its product while a

second did not intend to request a patent extension. The two other companies said that the

effort necessary to gather the data we needed would not be worthwhile.

4

FDA classifies each product according to chemical type and therapeutic potential when it

receives an application. In order to make our comparison groups as similar to the pipeline

drugs as possible, we compare drugs only of the same chemical type and therapeutic

potential. More information on these categorizations is in appendix I.
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drugs. In general, the delays in FDA’s approving the new drug applications

for the three pipeline drugs on which our study focused were a result of

concerns about the safety and efficacy of the drugs, as well as their

chemical properties and manufacturing procedures. In addition, the

applications for two of the drugs filed by the manufacturers lacked

essential information. However, the specific concerns varied by drug. For

Claritin, there was debate within FDA and with Schering-Plough on the

significance of the animal carcinogenicity data for humans. FDA and

Schering-Plough also disagreed on how the equivalence of two forms of the

drug should be established. Regarding Relafen, FDA was concerned about

adverse events associated with similar medications and believed there was

a lack of information in the manufacturer’s new drug application (NDA) on

the chemical properties of the drug, including its composition and how it

was manufactured. For Cardiogen-82, FDA found the NDA to be

incomplete. The agency believed that the data that were initially submitted

were insufficient to establish the efficacy of the drug and did not

adequately describe the components of the drug and the manufacturing

process.

The legislative history of the Waxman-Hatch Act does not explain the basis

for the patent extension time periods and discusses the use of different

extension periods only in general terms. The overall purpose of the patent

extensions, according to the House Energy and Commerce committee

report, was to create incentives for increased expenditures for research

and development.5 There is no explicit explanation, however, why a 2-year

limit was chosen for pipeline drugs or why a 5-year limit was chosen for

other drugs. A congressional staff member and pharmaceutical industry

representative who were involved in the development of the act have

written that the 2-year limit was originally suggested, in part, because it

reflected the average NDA approval time.6 However, we cannot

substantiate that contention from the legislative history, and other possible

explanations exist.

5

H. Rep. No. 98-857, Part I, at 15, 40-41 (1984), reprinted in 1984 U.S.C.C.A.N. 2648, 2674.

There was no conference report and no relevant Senate report language.

6

A report issued by the Office of Technology Assessment (OTA) in 1981 stated that the

average review time for NDAs “is frequently about 2 to 3 years.” OTA, Patent-Term

Extension and the Pharmaceutical Industry (Washington, D.C.: 1981), p. 66.
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Background In the development of a new drug, much happens before FDA becomes

directly involved. Companies search for promising chemical entities, test

them in their laboratories, and conduct animal studies using them,

generally without FDA’s direct involvement and often without FDA’s

knowledge. This is the “preclinical” stage of drug development. FDA must

be directly involved before any testing on human subjects can begin in the

United States. To get FDA’s permission to begin clinical trials (studies in

humans), a company must sponsor an investigational new drug (IND)

application that summarizes the data that have been collected on the

potential new drug and outlines the plans for the clinical trials. FDA does

not approve INDs. Rather, an IND goes into effect and clinical trials can

begin 30 days after FDA receives the IND, unless FDA objects to the

clinical trials and places a clinical hold on it. Companies that develop

innovator or brand-name drugs generally obtain a patent on the active

ingredient used in the drug. They also obtain patents on the uses of drugs to

treat certain diseases and conditions. Generally, patents are obtained

before a company submits an IND to begin clinical trials.7

Before marketing a new prescription drug in the United States, the

pharmaceutical company sponsoring the drug must obtain approval from

FDA. To receive approval, the sponsor must demonstrate that the drug is

both safe and effective for its intended use. It is the sponsor’s responsibility

to assemble all the evidence concerning the drug’s safety and efficacy and

supply it to FDA in an NDA. The NDA includes information on the drug’s

safety and efficacy, manufacturing procedures, and proposed labeling,

which includes prescribed uses, warnings, and side effects. It is FDA’s

responsibility to conduct a comprehensive review of the NDA and to make

decisions regarding approval of the new drug for marketing. Within FDA,

the Center for Drug Evaluation and Research is responsible for reviewing

new drugs. After an NDA is submitted, it is assigned to a specific review

division in the center that has responsibility for the appropriate drug class.

Within the division, reviewers from various disciplines such as medicine,

chemistry, and pharmacology are assigned to the drug. These specialists

evaluate the drug in terms of their own expertise. For example,

pharmacologists evaluate test results on animals while medical reviewers

7

When the Waxman-Hatch Act of 1984 was enacted, the term of a U.S. patent was 17 years,

measured from the date of its grant (or issuance). As a result of the Uruguay Round of the

General Agreement on Tariffs and Trade, the Uruguay Round Agreements Act was enacted

in 1994, which lengthened the U.S. patent term to 20 years, measured from the date of the

earliest application.
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evaluate clinical test results in humans. The review process includes not

only an ascertainment of the efficacy and safety of the drug but also an

assessment of the quality of the methods, facilities, and controls used for

manufacturing, processing, and packaging the drug.

At the beginning of the review process, a drug is assigned a review priority

that is based on its potential therapeutic benefit to the public. This allows

FDA to set priorities for reviews for different drugs, depending on their

potential importance. As a result, NDAs for drugs receiving a high

therapeutic ranking generally move more rapidly than others through the

review process.

One factor that led to longer drug approval times in the 1980s and early

1990s was a lack of resources at FDA. To resolve this problem, the

Congress enacted the Prescription Drug User Fee Act of 1992 (PDUFA),

which authorizes FDA to charge drug manufacturers specified fees.8 These

fees were to be used to augment FDA resources devoted to reviewing

NDAs in order “to significantly expedite the drug approval process.”

However, because the law was not passed until October 1992, the act had at

most a minor effect on the majority of pipeline drugs.9

The Drug Price Competition and Patent Term Restoration Act of 1984

provided patented drug products with an extended term of protection to

compensate for delays occurring as a result of regulatory review. At the

same time, the process for approving and marketing generic drugs was

made easier and quicker. The legislation granted patent extensions of up to

5 years for nonpipeline drugs and up to 2 years for pipeline drugs. The total

of a drug’s remaining patent life after FDA approval and any patent

extension could not exceed 14 years.

8

FDA was permitted to assess three types of fees on drug companies: (1) a one-time fee for

the submission of a human drug application, (2) an annual fee for each prescription drug

product being marketed, and (3) an annual fee for each establishment manufacturing

prescription drugs.

9

For more information on the act, see FDA User Fees: Current Measures Not Sufficient for

Evaluating Effect on Public Health (GAO/PEMD-94-26, July 22,1994).
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Lengthy Review Times

Were Caused by a

Number of Factors

The seven pipeline drugs covered by the proposed legislation had longer

approval times than comparable products.10 The long approval times of the

three pipeline drugs we examined in detail generally resulted from

concerns about the safety and efficacy of the products as well as their

chemical properties and manufacturing procedures. However, the specific

reasons for their longer approval times varied considerably for Claritin,

Relafen, and Cardiogen-82.

The Approval Times for the

Seven Pipeline Drugs

Exceeded the Times for

Other Drugs

The approval times for the seven pipeline drugs covered by the proposed

legislation were longer than those for comparable drugs. The approval time

for each of the seven drugs ranged from 17 to 65 months longer than the

average approval time for all pipeline drugs of the same chemical type and

therapeutic potential. The fastest of the seven drugs to be approved,

Cardiogen-82, had a longer approval time than about 85 percent of

comparable pipeline drugs. We also found that the seven drugs had longer

approval times than all but four comparable drugs approved between 1983

and 1985, around the time Waxman-Hatch was passed. Finally, we

compared the approval times for the seven pipeline drugs with the approval

times for comparable drugs in the same therapeutic class (for example,

nonsteroidal anti-inflammatory drugs). Because of the small number of

drugs in five of the classes, we were able to compare approval times in only

two classes. The average approval times for Relafen and Cardiogen-82 were

longer than those for similar products. More information on approval time

comparisons is given in appendix II.

Several Factors Delayed

FDA’s Approval of Claritin

The Claritin NDA was submitted on October 31, 1986, and approved on

April 12, 1993, a total approval time of 77.4 months. This was almost 3 years

longer than the average 42.5 months for similarly classified pipeline

drugs—new molecular entities that offered little or no therapeutic gain

compared with existing therapies.

10In this report, “comparable” refers to drugs that FDA classified as being of the same

chemical type and therapeutic potential. See appendix I for a discussion of the

categorizations.
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Two principal concerns about Claritin contributed to the delay. First, FDA

and Schering-Plough disagreed about whether the safety of Claritin had

been adequately demonstrated.11 Specifically, they held different views on

how the results of animal carcinogenicity tests should be interpreted.12

Second, FDA and Schering-Plough disagreed on whether or not the tablet

form of the drug that the company wanted to market had been shown to be

equivalent to the capsule form that had been tested. In addition to these

issues, FDA raised questions about whether or not Claritin induced

drowsiness and its effectiveness. Figure 1 is a timeline showing the major

events in the approval of Claritin. See appendix III for more information on

the Claritin approval process.

11The name of the company when the NDA was submitted was Schering Corporation. The

name was later changed to Schering-Plough Corporation.

12Carcinogenicity refers to the ability of a chemical or other substance to produce cancer.
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Figure 1: Timeline of Events Affecting Claritin’s Approval, 1986−93
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Carcinogenicity Studies The major issue that delayed the approval of Claritin was the potential

significance of animal carcinogenicity data for humans. The studies

Schering-Plough submitted in the Claritin NDA showed evidence of

increased tumors in male mice and male and female rats. After receiving

and analyzing additional data from Schering-Plough, the FDA reviewers

concluded that these findings should not delay approval of the drug. Thus,

in April 1988, about 18 months after the NDA was filed, the carcinogenicity

questions appeared to have been resolved. However, in spring 1989,

following an FDA reorganization, the Claritin NDA was transferred to a

new division and new reviewers were assigned. While we have no evidence

that the reorganization affected the approval of Claritin, Schering-Plough

contends that the reorganization resulted in inefficiencies and delay when

new reviewers re-reviewed data that had been accepted by the first

reviewers.

FDA’s new concerns regarding the animal carcinogenicity data from the

Claritin studies may have been affected by the findings of unpublished

animal tumor studies on another company’s antihistamine, doxylamine.

Schering-Plough officials believe that FDA officials were influenced by

these studies that indicated that doxylamine was associated with liver

tumors in rats and mice. Schering-Plough contends that this may have

heightened FDA’s concerns about the significance of animal tumor findings

in other antihistamines. Schering-Plough acknowledges that the tumor

issues FDA raised in 1989 regarding Claritin dealt with the same type of

data discussed in the doxylamine study. Moreover, FDA records indicate

that much of FDA’s review from 1989 to 1992 was conducted in the context

of the doxylamine findings and what these indicated about the safety of

other antihistamines.

When the carcinogenicity study issue was reopened in 1989, there was

considerable discussion between FDA and Schering-Plough on the proper

interpretation of the animal findings. In 1991, an FDA advisory committee

concluded that Claritin was unlikely to be carcinogenic. Despite this

conclusion, some FDA officials were still concerned about the significance

of the animal carcinogenicity data. Eventually, this issue was resolved in

the summer of 1992 when FDA requested and Schering-Plough agreed to

redo a previously submitted test at a higher dose. The results of this test

were negative.

Schering-Plough officials believe that FDA’s reevaluation of the

carcinogenicity issue was unnecessarily prolonged. They note that the

labeling requirements for carcinogenicity in 1993 were very similar to those
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that FDA recommended and Schering-Plough agreed to in 1989. However,

FDA officials told us that simply because the results of FDA’s

reexamination did not ultimately produce any changes in the label does not

mean that the inquiry was inappropriate. The information resulting from

the inquiry in this case could have contributed to FDA’s conclusion that the

original labeling requirements were appropriate.

FDA’s resolution of the carcinogenicity issue was made more difficult by

the large amount of controversy in the field of toxicology regarding animal

carcinogenicity studies. Expert opinion was divided on the relevance of

particular tests and how other tests should be conducted and analyzed.

Thus, when FDA was attempting to reach a decision on the approval of

Claritin, there was no consensus in the scientific community about how

best to develop and evaluate animal carcinogenicity data.

Bioequivalence The carcinogenicity issue might not have resurfaced if the approval of

Claritin had not been delayed by concerns about the bioequivalence of the

capsule used in the clinical trials and the tablet form of the drug that the

company planned to market. Schering-Plough contends that FDA’s

concerns were unfounded. After FDA biopharmaceutics experts reviewed

the 13 studies Schering-Plough submitted to establish the bioequivalence of

the tablet and capsule, they concluded that the data did not support that

they were equivalent. This issue arose because of disagreement between

FDA and Schering-Plough about how to demonstrate bioequivalence. Once

ingested, Claritin is rapidly converted to a primary metabolite that is largely

responsible for the drug’s effectiveness.13 Consequently, Schering-Plough

believed that the bioequivalence of the parent drug should be ignored and

only the metabolite should be studied for bioequivalence. FDA disagreed,

noting that the drug is not completely metabolized and that the

bioequivalency for both the parent and metabolite needed to be

established. Schering-Plough and FDA agreed that the bioequivalence of

the metabolite had been shown. Schering-Plough acknowledged that it

could not show the bioequivalence of the parent compound with its

studies, and the company decided to conduct a study in which the tablet,

capsule, and a placebo were compared in approximately 450 patients. The

study was conducted in fall 1988 and submitted to FDA in November 1988.

After reviewing these data, FDA concluded that the equivalence of the

13A metabolite is any substance produced or used during metabolism (digestion). In drug

use, a metabolite usually refers to the end product (what remains after metabolism).
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tablet and capsule had been established. Thus, approximately 2-1/2 years

after the NDA was submitted, the bioequivalency issue was resolved.

Sedation and Effectiveness Concurrent with the bioequivalence issue, FDA also raised questions about

the claim that Claritin was nonsedating and about the drug’s effectiveness.

FDA reviewers saw indications in the NDA that drowsiness was among the

most frequent adverse reactions from Claritin. They eventually concluded

that the 10 milligram dose Schering-Plough intended to market was no

more sedating than a placebo but that the 40 milligram dose was more

sedating. Soon after receiving the NDA, FDA reviewers raised a number of

issues with Schering-Plough about the design and results of the studies

submitted in the NDA, including indications that the 10 milligram doses

were not very effective while the 40 milligram doses were effective. After

further analysis of the data, FDA concluded that the 10 milligram dose was

effective. The resolution of these issues meant that if other concerns were

addressed, the 10 milligram dose of Claritin could be marketed and labeled

as nonsedating.

Safety and Manufacturing

Concerns Delayed the

Approval of Relafen

The total approval time for Relafen was 70.5 months, from February 6,

1986, to December 24, 1991. This was more than a year longer than the 57.6

month average for other drugs in the same therapeutic class (nonsteroidal

anti-inflammatory drugs, or NSAIDs) that were approved between 1975 and

1993 and that FDA classified as new molecular entities that offered little or

no therapeutic gain. The approval time for Relafen was greater than about

67 percent of NSAIDs.

Questions regarding Relafen’s safety and its manufacturing process were

the principal factors that delayed its approval. In the early 1980s, several

NSAIDs were associated with severe adverse reactions, including fatal and

nearly fatal events. These adverse reactions received a significant amount

of media coverage and congressional hearings were held. While these

events did not involve Relafen and occurred before the Relafen NDA was

filed, SmithKline Beecham officials suggested that adverse reactions in

these other NSAIDs were unfairly associated with Relafen and slowed its

approval.14 FDA officials acknowledged that they became more cautious in

their review of new NSAIDs following the disclosure of the adverse events.

However, FDA officials told us that missing and incomplete information in

14The Relafen NDA was originally submitted by the Beecham Group. In 1989, the company

merged with SmithKline Beckman to form SmithKline Beecham.
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the Relafen application slowed the approval process. Although FDA then

allowed incomplete applications to be filed (before PDUFA was enacted in

1992), agency officials said that the Relafen NDA was of especially poor

quality. FDA repeatedly requested additional information from SmithKline

Beecham about several issues regarding Relafen’s manufacturing process.

For example, FDA requested information about the quality of the

substances used in the drug. The company did not always address these

concerns in a timely and complete manner. Because the additional

submissions did not always adequately address the issues FDA raised,

SmithKline Beecham had to submit more data on a number of occasions

before a resolution was reached. These issues persisted over a fairly long

time and, according to FDA documents, delayed the approval of the

application. However, SmithKline Beecham officials suggested that the

review of these issues was an ongoing process that did not delay the review

of the drug. They stated that FDA did not communicate with company

officials during the first 3 to 4 years of the Relafen review about clinical

issues. While there was no documentation of such reviews being done

during this period in the FDA files, we cannot conclude with certainty that

these reviews did not occur because the information may have been

missing. (Figure 2 shows the major events in the review of Relafen.)
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Figure 2: Timeline of Events Affecting Relafen’s Approval, 1982−91
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According to SmithKline Beecham officials, FDA policy delayed the review

of the efficacy and safety of Relafen. Company officials told us that they

received unofficial oral comments from an FDA division director that the

agency was reviewing only one NSAID at a time after the Relafen

application was submitted. However, FDA officials we spoke with were

unaware of such a policy for NSAIDs. We located only a summary

document prepared after the NDA was approved that described the

efficacy of the drug and did not find documents in FDA’s Relafen files that

indicated when the agency’s safety and efficacy review began. We did find a

pharmacology review conducted within 6 months of the NDA submission

date that addressed carcinogenicity data in animals, but the document did

not indicate whether or not a medical officer had been assigned. See

appendix III for a complete discussion of Relafen’s approval.

Efficacy and Manufacturing

Issues Delayed the Approval

of Cardiogen-82

The NDA for Cardiogen-82, a radioactive diagnostic agent, was submitted

to FDA on December 28, 1984, and approved on December 29, 1989.15 The

average total approval time for new molecular entities that offered little or

no therapeutic gain in this therapeutic class (radioactive diagnostic aids)

approved between 1975 and 1993 was 49.3 months, 11 months shorter than

the review time for Cardiogen-82. Approximately 60 percent of drugs in this

therapeutic class were approved faster than Cardiogen-82.

FDA questioned information in the chemistry and manufacturing section of

the Cardiogen-82 NDA and the section assessing the efficacy of the drug.

These concerns resulted in FDA’s sending a “not approvable” letter to the

manufacturer in July 1986 stating that the drug could not be approved

without additional information being submitted. The manufacturer

submitted information to address some of the issues raised by FDA.

However, in January 1988, FDA asked the company to withdraw the NDA

from consideration until it was ready to complete the application. The

company withdrew the NDA from consideration for approval in March 1988

and then resubmitted it in July 1988 with new information. Thus, while the

drug took 60 months to be approved from its original submission, FDA

spent 24 months (from July 1986 to July 1988) waiting for the company to

submit a complete response to issues raised in the not approvable letter.

Similar calculations for other radioactive diagnostics that were new

molecular entities that offered little or no therapeutic gain indicate that this

15Cardiogen-82 is a radioactive dye that is injected into a patient’s bloodstream to distinguish

normal from abnormal middle muscular layers of the heart wall.
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adjusted average review time was 35.5 months, approximately the same as

for Cardiogen-82.16 Approximately 50 percent of these drugs were reviewed

faster than Cardiogen-82. (See figure 3 for a timeline of the Cardiogen-82

approval.) More detail on the approval of Cardiogen-82 is given in appendix

V.

16This alternative measure of approval time is calculated by FDA and does not include the

time it takes a manufacturer to resubmit an NDA after a not approvable letter is issued, the

length of time a drug is withdrawn by the manufacturer from consideration for approval,

and the time it takes a manufacturer to resubmit an application when FDA “refuses to file”

the NDA as well as the time from FDA’s receipt of the application to the refusal to file action.

FDA can refuse to file an application if it finds that the NDA is not sufficiently complete to

permit a substantive review.
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Figure 3: Timeline of Events Affecting Cardiogen-82’s Approval, 1984−89

FDA found that the NDA did not contain a full statement of the components

and quantitative composition of the drug and lacked adequate information

on the methods used in the synthesis, extraction, isolation, and purification

of the drug product. Although FDA had informed Squibb of these problems

in August 1985, the company had not addressed them when the not
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approvable letter was issued in July 1986.17 New chemistry data were

submitted in response to the not approvable letter in May 1988 and more

information was submitted in October of that year. However, FDA found

that there were still deficiencies in the NDA regarding the composition and

manufacturing of the drug. These were sent to the company in December

1988 and resolved in March 1989.

In the not approvable letter, FDA cited several concerns about the

adequacy of the testing that was done to show the efficacy of Cardiogen-82

in humans. For example, the studies that were submitted to support

efficacy and safety used a specific method for injecting Cardiogen-82 into

the body. However, different methods were described in the proposed

package insert for the drug, and these methods had not been tested in the

clinical trials. FDA believed that an additional study was needed to show

that the patient would receive the prescribed dose using these other

methods. Also, the design and analysis of the studies were problematic as

FDA was concerned that there were inadequate numbers of patients and no

justification was given for excluding some of them from the analyses.

Finally, FDA noted that the results of the studies varied according to what

device was used to judge the effectiveness of Cardiogen-82. Different

devices gave different indications of how well the drug worked.

After receiving the not approvable letter in July 1986, Squibb made several

submissions to address the issues FDA raised and met with agency officials

in May 1987 to specifically discuss several of them. However, FDA found

these responses to be incomplete and informed Squibb in March 1989 that

some of the clinical data would need to be reanalyzed.

FDA’s concerns with data showing the efficacy of the drug continued in the

summer of 1989. Squibb officials then suggested approving the drug on the

basis of its general usefulness in evaluating heart attacks rather than the

purpose described in the NDA, assessing the specific location of heart

problems. While FDA did not believe it was ideal to approve the drug for

the alternative use, it noted that as long as the drug is of some value it could

be approved. It was agreed that Cardiogen-82 was useful in evaluating and

17The Cardiogen-82 NDA was filed by Squibb Diagnostics, the manufacturer of the drug.

Bracco Diagnostics Inc. purchased the NDA from Squibb in July 1994 and now markets the

drug. However, since Squibb was solely involved in the NDA review process, we refer to

Squibb in our discussion of Cardiogen-82’s approval.
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diagnosing heart attacks, and in December 1989, Cardiogen-82 was

approved for this purpose.

Bracco officials have suggested two reasons to help explain the lengthy

approval time for Cardiogen-82. First, the FDA officials doing the chemistry

and medical reviews changed during the approval process. While this could

lengthen the approval time as new reviewers evaluated the data, we were

unable to determine how much, if at all, it did so. Second, Bracco has stated

that a 5-year FDA approval time was not unusual for medical imaging

products that were being reviewed around the time Cardiogen-82 was

evaluated and that the dialogue between the company and FDA was typical

of that for NDAs. We found that 40 percent of comparable radioactive

diagnostics were approved more slowly than Cardiogen-82 in the years we

examined (1975–93). Also, an FDA official told us that there was a backlog

of NDAs in FDA’s Division of Medical Imaging and Surgical-Dental Drug

Products in the late 1980s and early 1990s.

The Legislative History

Does Not Indicate a

Basis for a 2-Year

Patent Extension Limit

The legislative history of the Drug Price Competition and Patent Term

Restoration Act of 1984 explains only in general terms why an extension

was authorized for pipeline drugs and does not explain why it was limited

to 2 years. Testimonial evidence, outside the legislative history, from the

counsel to the Pharmaceutical Manufacturers Association (now the

Pharmaceutical Research and Manufacturers of America) when the

Waxman-Hatch Act was being considered as well as the Counsel to the

House Energy and Commerce Committee’s Subcommittee on Health and

the Environment suggests that the 2-year extension may have been based

on an assumption that drugs in the FDA pipeline would likely be approved

within 2 years of their NDA’s filing. However, there is no explicit

recognition in the history that the Congress adopted the provision for this

reason.

Before Waxman-Hatch was enacted, the Congress had debated the need for

a patent term extension law for a number of years. Two issues that were

debated concerned the limit of the extension period and whether or not

drugs that were already patented should be eligible for an extension. One

proposal would have authorized an extension equal to the regulatory

review period with a limit of 7 years and would have applied to drugs

regardless of when they were patented. Another proposal would have

allowed the same extension period but would have limited the extension to

drugs patented after a law was enacted. The provision that was ultimately

enacted established two limits: a 2-year limit for drugs that had already
B-283293

Page 21 GAO/HEHS-00-140 Pipeline Drugs

been patented and were undergoing clinical trials (pipeline drugs) and a 5-

year limit for drugs patented after enactment or patented before if they

were not yet undergoing clinical trials.18

The legislative history of the Waxman-Hatch Act offers no explanation for

why the Congress set the patent extension for pipeline drugs to 2 years

rather than some other period. The only relevant committee report, by the

House Energy and Commerce Committee, states generally that the overall

purpose of providing additional patent protection was “to create a new

incentive for increased expenditures for research and development of

certain products which are subject to premarket government approval.”

The report adds that different maximum periods of extension were

established “to provide greater incentive for future innovations.” 19 There is

no specific explanation for why a 2-year limit was chosen for pipeline drugs

and why a 5-year limit was chosen for other drugs.20 If the 2-year period

was originally suggested by one or more of the parties involved in the

negotiations because it reflected the average NDA approval time, as some

now maintain, the legislative history does not indicate that the Congress

adopted it for that reason.21 The 2-year extension could also have been the

result of a compromise between some seeking extensions for all products

and others opposed to any extensions. Moreover, the courts warn that

when attempting to determine the purpose of a law, one must use

information that is not part of the history generated by the Congress during

18The Counsel for the Generic Pharmaceutical Industry Association has described the

evolution of the bill as “a unique legislative process which, in reality, was a congressionally

supervised negotiation between the generic and brand-name pharmaceutical industries in

which the parties were compelled to reach a compromise by the legislature.” See Alfred B.

Engelberg, “Special Patent Provisions for Pharmaceuticals: Have They Outlived Their

Usefulness?” Journal of Law and Technology, Vol. 39 (1999), p. 389.

19H. Rep. No. 98-857, Part I, at 15, 40-41 (1984), reprinted in 1984 U.S.C.C.A.N. 2648, 2674.

20References throughout the legislative history justify patent extensions on the basis that

they will motivate future innovation generally but do not explain the distinction between the

2-year period for pipeline drugs and the 5-year period for other products. See, for example,

S. Rep. No. 97-138, pp. 6-7: “[The bill] will provide added cash flow to finance the costly

future research efforts. Moreover, it will increase the expected returns from new drug

innovations, thereby providing both the incentive and economic capability to conduct

expensive long-term research and development.”

21An FDA report issued in 1985 stated that the average approval time for all new molecular

entities in 1984 was about 31⁄4 years. If the average time needed by an applicant to respond to

an FDA action is subtracted from this length, the average approval time is approximately 21⁄4

years. HHS, New Drug Evaluation: Statistical Report (Washington, D.C.: 1985), p. 53.
B-283293

Page 22 GAO/HEHS-00-140 Pipeline Drugs

consideration of the bill with great caution, if at all.22 This is in part

because, as here, it is not possible to establish that the information was

known to the legislators considering and voting on the bill.

Agency and Drug

Manufacturers’

Comments

We provided a complete draft of this report to the Commissioner of FDA

and relevant parts of the draft to the companies whose drugs we reviewed

in depth. The companies were given only the parts of the draft that dealt

specifically with their drug or that cut across all the pipeline drugs. The

companies were not given the sections of the report that dealt specifically

with other manufacturers’ drugs. FDA responded that the report accurately

reflects the facts of the cases and is fairly presented. The agency also

provided technical comments that we incorporated as appropriate. The

manufacturers generally found our characterization of the major issues in

the review processes of the drugs to be accurate. However, there was some

concern that certain issues were not explained completely enough. We

revised sections of the report to include more detail where appropriate.

Other comments led us to make clarifications to the text. Schering-Plough

officials were concerned that our discussion of the delay in Claritin’s

approval caused by FDA’s investigation of the potential carcinogenicity of

the drug might lead readers to believe that there were lingering concerns

about the drug’s safety. The company wanted to emphasize that FDA

determined the drug to be safe and effective and that there are no

remaining carcinogenicity concerns.

We are sending copies of this report to the Honorable Donna E. Shalala,

Secretary of Health of Human Services, and the Honorable Jane E. Henney,

Commissioner of FDA. We are also sending copies to appropriate

congressional committees and others who are interested.

22Cavallo v. Utica-Watertown Health Insurance Company, 3 F. Supp. 2d 223, 230 (D.N.Y.

1998). See HHS v. Finkelstein, 496 U.S. 617, 631, 632 (Justice Scalia, concurring in part,

stated that “arguments based on subsequent legislative history ... should not be taken

seriously, not even in a footnote”).
Page 23 GAO/HEHS-00-140 Pipeline Drugs

If you or your staff have any questions, please contact me at (202) 512-7114

or John Hansen, Assistant Director, at (202) 512-7105. Robert M. Copeland,

Julian Klazkin, and Lawrence S. Solomon were the major contributors to

this report.

Janet Heinrich

Associate Director, Health Financing

and Public Health Issues
B-283293

Page 24 GAO/HEHS-00-140 Pipeline Drugs

List of Requesters

The Honorable Orrin G. Hatch

Chairman

The Honorable Patrick Leahy

Ranking Minority Member

Committee on the Judiciary

United States Senate

The Honorable Richard J. Durbin

The Honorable Paul Wellstone

United States Senate

The Honorable Sherrod Brown

The Honorable John Conyers, Jr.

The Honorable John D. Dingell

The Honorable Bart Gordon

The Honorable Jim McDermott

The Honorable Robert Menendez

The Honorable Ed Pastor

The Honorable Steven R. Rothman

The Honorable Pete Stark

The Honorable Ellen O. Tauscher

The Honorable Henry A. Waxman

House of Representatives
Page 25 GAO/HEHS-00-140 Pipeline Drugs
Page 26 GAO/HEHS-00-140 Pipeline Drugs

Appendix I

Scope and Methodology ApApenednxidexiIs

We assessed the factors that affected the approval times for three pipeline

drugs that were in regulatory review for more than 5 years. We studied in

detail the approval of only three of the seven drugs covered by the

proposed legislation because the manufacturers of the four other drugs

were unable either to provide us with review information or chose not to

have their drugs included in our study. The three drugs we studied are

Claritin (an antihistamine manufactured by the Schering-Plough

Corporation), Relafen (a nonsteroidal anti-inflammatory drug used for

relieving pain and made by the SmithKline Beecham Corporation), and

Cardiogen-82 (a diagnostic imaging agent marketed by Bracco Diagnostics

Inc). The four other drugs covered under the legislation are Dermatop (a

corticosteroid for skin conditions that is manufactured by Aventis

Pharmaceuticals), Eulexin (a prostate cancer drug manufactured by the

Schering-Plough Corporation), Nimotop (a calcium channel blocker made

by the Bayer Corporation), and Penetrex (an antibiotic made by Aventis

Pharmaceuticals).

We determined the factors that affected the amount of time the Food and

Drug Administration (FDA) took to approve Claritin, Relafen, and

Cardiogen-82 by reviewing relevant FDA division files. These files provide a

comprehensive account of FDA’s actions and company responses. For

additional information, we met with FDA officials who were involved in the

approval of these drugs and reviewed other files when necessary. In

addition, to the extent available, we obtained similar information from the

manufacturers of each of the three drugs. We also spoke with company

officials to obtain their positions.

We calculated the approval times of the seven pipeline drugs covered by

the proposed legislation. This time began when the sponsor submitted the

new drug application (NDA) to FDA in order to market the drug and ended

when FDA approved the application. We put these times into context by

comparing them with approval times for drugs of the same chemical type
Appendix I

Scope and Methodology

Page 27 GAO/HEHS-00-140 Pipeline Drugs

and therapeutic potential.1 Our analyses were limited to drugs approved

between January 1, 1975, and April 12, 1993. We began our analyses with

1975 because FDA began to classify drugs by therapeutic potential in that

year. We ended our analysis with drugs approved on April 12, 1993, because

that was the date Claritin was approved. In addition, the Prescription Drug

User Fee Act was enacted in 1992 in order to augment FDA’s resources

devoted to reviewing NDAs. Because this was so soon after the enactment

of the Prescription Drug User Fee Act of 1992 (PDUFA), it is unlikely that

the law had more than a minimal effect on the approval times for these

drugs. We included all drugs approved until April 12, 1993, in order to make

1

In order to make our comparison groups as similar as possible to the pipeline drugs, we

used FDA’s categorizations of drugs by chemical type and therapeutic potential to classify

all the drugs. We then compared only similarly classified products. FDA assigns each drug to

a chemical type category when it receives an application. FDA uses seven categories for

chemical type; however, the seven pipeline drugs fall into only two of the categories. Six of

the drugs are classified as a type 1 or “new molecular entity.” These are drugs that are not

marketed in the United States by any drug manufacturer. The seventh drug (Dermatop) is

classified as type 2, a “new ester, salt, or other noncovalent derivative.” For a type 2 drug,

the active component of the drug is marketed in the United States, but this particular salt,

ester, or derivative is not.

Similarly, FDA classifies each drug by its therapeutic potential when it receives an NDA. The

NDAs in this study were all submitted before 1992. At that time, therapeutic potential was

primarily classified according to three types:

“Type A, important therapeutic gain: the drug may provide effective therapy or diagnosis, by

virtue of greatly increased effectiveness or safety, for a disease not adequately treated or

diagnosed by any marketed drug. Or the drug may provide improved treatment of a disease

through improved effectiveness or safety, including decreased abuse potential.

“Type B, modest therapeutic gain: the drug has a modest, but real, potential advantage over

other available marketed drugs. Examples include greater patient convenience, elimination

of an annoying but not dangerous adverse reaction, potential for large cost reduction, less

frequent dosage schedule, or useful in a specific subpopulation of those with disease (for

example, those allergic to other available drugs).

“Type C, little or no therapeutic gain: the drug essentially duplicates in medical importance

and therapeutic usage one or more already marketed drugs, offering little or no therapeutic

gain over existing therapies.”

In 1992, FDA began to classify NDAs as eligible for priority (P) or standard (S) review. Most

NDAs that formerly would have been classified type A or B are now classified P, and those

that were formerly classified type C are now classified S.

The chemical type and therapeutic potential codes can be combined. For instance, a 1A drug

is a new molecular entity that offers an important therapeutic gain. We compare only

similarly classified drugs. For example, if a pipeline drug was classified 1C (new molecular

entity with little or no therapeutic gain) we compared it only to other 1C products.
Appendix I

Scope and Methodology

Page 28 GAO/HEHS-00-140 Pipeline Drugs

the comparisons as similar as possible. The few pipeline drugs that were

approved after April 12, 1993, and any other potential comparison drugs

approved after this date are not included in our analyses. We calculated

approval times for three comparison groups. First, we calculated the

approval times for 110 pipeline drugs.2 Second, we determined the approval

times for drugs that were approved in 1983, 1984, and 1985. These include

1984, the year Waxman-Hatch was enacted, and the years preceding and

following. These were included to provide an estimate of expected drug

approval times when the legislation was being considered. Finally, we

determined the average approval times for drugs in the same therapeutic

class as the seven pipeline drugs.

To determine the approval times for the seven pipeline drugs and the

comparison groups, we reviewed published FDA reports that summarize

drug approval information, including approval times. We also obtained

additional information from the agency, such as whether FDA had issued a

not approvable letter informing the company of the deficiencies in the

application. We then calculated average approval times and various

measures of the spread of the data.

To understand why the Congress limited the patent extension for pipeline

drugs to 2 years, we developed a detailed legislative history of the WaxmanHatch Act that we based on hearings, committee reports, and floor debate.

We also obtained related information from the drug manufacturers.

2

There were a total of 122 pipeline drugs. Twelve of them were biologics or were approved

after April 12, 1993, and therefore did not meet our criteria for inclusion.
Page 29 GAO/HEHS-00-140 Pipeline Drugs

Appendix II

Approval Time Comparisons ApendxiI

Each of the seven pipeline drugs covered by the proposed legislation

required more than 5 years to be approved. In order to provide the context

for the length of these approval periods, in this appendix we compare the

approval times for these seven drugs with three groups: (1) all comparable

pipeline drugs, (2) other drugs that were approved near the time WaxmanHatch was enacted, and (3) other drugs in the same therapeutic classes.

Comparison With

Other Pipeline Drugs

One of the criteria for a pipeline drug’s eligibility for a patent extension

under the proposed legislation is that the approval time must have been at

least 5 years. This review time is defined as the total period between

submission of the NDA and its final approval. As table 1 shows, the seven

pipeline drugs required longer approval times than did the average pipeline

drug. The approval time for each of the seven drugs ranged from 17 to 65

months longer than the average approval time for all pipeline drugs of the

same chemical type and therapeutic potential. We determined that the

percentile rankings for the seven drugs range from the 85th percentile for

Cardiogen-82 to the 100th for Dermatop, Eulexin, and Nimotop.1

Table 1: Pipeline Drug Approval Times in Months

Note: The average review time for all 122 pipeline drugs, including biologics and those approved after

Claritin, was 38.6 months.

a

The range of total approval times was 9.5 to 75.5 for 1A drugs, 13.0 to 100.0 for 1B drugs, 15.0 to

122.5 for 1C drugs, and 17.8 to 68.4 for 2C drugs.

1

A percentile divides a set of values into parts. For instance, the 85th percentile indicates

that about 85 percent of the pipeline drugs had shorter approval times and 15 percent had

longer approval times than the comparison drug.

Drug

Chemical type and

therapeutic potential

Number of pipeline

drugs of this type

and potential Approval time

Average approval time

for pipeline drugs of

this type and potentiala

Approval time

percentile for this

drug

Cardiogen-82 1C 67 60.1 42.5 85th

Claritin 1C 67 77.4 42.5 92nd

Dermatop 2C 4 68.4 35.3 100th

Eulexin 1B 29 100.0 35.5 100th

Nimotop 1A 10 75.4 29.9 100th

Penetrex 1C 67 62.3 42.5 86th

Relafen 1C 67 70.5 42.5 88th
Appendix II

Approval Time Comparisons

Page 30 GAO/HEHS-00-140 Pipeline Drugs

Comparison With

Drugs Approved Near

the Time WaxmanHatch Was Enacted

Only four drugs approved between 1983 and 1985 had longer approval

times than at least one of the seven pipeline drugs.2 As shown in table 2, the

average approval time decreases as FDA’s assessment of a drug’s

therapeutic potential increases. The only 1A medication (a new molecular

entity with the highest therapeutic potential) among the seven pipeline

drugs is Nimotop. Its approval time (75.4 months) was three times greater

than the average total approval time (25.2 months) for 1A drugs in 1983-85.

Moreover, its approval time was longer than for any 1A drug during that

period.3 The only 1B pipeline drug (a new molecular entity with moderate

potential) covered under the proposed legislation is Eulexin. Similarly, its

approval time (100 months) was greater than the longest 1B approval time

between 1983 and 1985.4 The four 1C pipeline drugs (new molecular

entities with little or no therapeutic gain over existing therapies) all

exceeded the average approval time (40.3 months) for 1C drugs in 1983 to

1985. However, none of the four exceeded the longest approval time during

that period for similarly classified products. The 68.4 month approval time

for Dermatop, the one 2C drug (a new ester, salt, or other noncovalent

derivative that offers little or no therapeutic gain over existing therapies)

covered under the proposed legislation, was longer than for any other 2C

drug approved between 1981 and 1986.

2

The four drugs were Glucotrol (104.2 months), Merital (72.1 months), Micronase (131.3

months), and Nenphroflow (69.3 months).

3

There were major disagreements between FDA and the sponsor about the adequacy of the

data in the Nimotop NDA. The sponsor withdrew the application twice for a total of 15.7

months. This accounts for part of but not all the lengthy review process.

4

Eulexin was never approved to be used alone, as was sought in the NDA. In September 1987

(7 years after the NDA was originally filed), the manufacturer of the drug submitted new

data to support the use of the drug as part of a combination product. If only the approval

time for Eulexin as part of combination product is considered, the approval time (16.0

months) is well within the range of total approval times between 1983 and 1985 for 1B drugs.
Appendix II

Approval Time Comparisons

Page 31 GAO/HEHS-00-140 Pipeline Drugs

Table 2: Average Total Approval Time for Drugs Approved 1983-85 in Months

a

Only two 2C drugs were approved in 1983-85. In order to have enough drugs to allow us to calculate

meaningful statistics for this classification, we used drugs that were approved in 1981-86.

Comparison With

Drugs in the Same

Therapeutic Class

We also compared the approval times for the seven pipeline drugs with the

approval times for drugs in the same therapeutic class that were classified

as the same chemical type and therapeutic potential. Because of the small

numbers of drugs in five of the classes, we were able to compare approval

times in only two classes. This analysis shows similar results to our

previous analyses. The approval times for Relafen (a nonsteroidal antiinflammatory drug) and Cardiogen-82 (a radioactive diagnostic agent) are

longer than average approval times for similar products.5 More information

on these comparisons is given in appendixes IV and V.

Drug classification

Number of drugs

approved

Total approval time for specific

pipeline drugs in this

classification

Average total approval

times for this

classification

Range of total approval

times for this

classification

1A 9 Nimotop: 75.4 25.2 6.1 to 39.8

1B 24 Eulexin: 100.0 27.5 10.6 to 58.7

1C 33 Cardiogen-82: 60.1

Claritin: 77.4

Penetrex: 62.3

Relafen: 70.5

40.3 15.0 to 131.3

2C (drugs approved

1981-86)a

7 Dermatop: 68.4 30.8 17.8 to 50.4

5

While we compared Cardiogen-82 with other radioactive diagnostic agents, the claim made

for it in the NDA was unique.
Page 32 GAO/HEHS-00-140 Pipeline Drugs

Appendix III

Approval Process for Claritin ApendxiI

Schering-Plough Corporation holds a patent for Claritin, a nonsedating

antihistamine used to prevent or relieve symptoms of hay fever and other

allergies. Claritin is the top-selling antihistamine in the United States, with

$1.5 billion in 1999 sales. The patent for Claritin was filed on June 18, 1980,

and issued on August 4, 1981. It is scheduled to expire on June 19, 2002.

When the Claritin NDA was submitted to FDA in 1986, there was one

nonsedating antihistamine on the market (Seldane) and another

(Hismanal) had been submitted for approval. (Hismanal was approved on

December 29, 1988.) On the basis of Claritin’s potential therapeutic benefit

to the public, FDA assigned Claritin its lowest review priority—a C ranking.

This means that FDA determined that there was little or no therapeutic gain

from the drug compared with already marketed drugs.

Schering-Plough contends that the lengthy review period (77.4 months)

FDA took to grant marketing approval for Claritin deprived the company of

a large period of patent protection. Schering-Plough contends that the

lengthy review process resulted from (1) FDA’s re-reviewing data from the

animal carcinogenicity studies, (2) FDA’s not accepting reasonable data

showing the bioequivalence of the capsule and tablet formulations, (3) an

insufficient number of reviewers at FDA to evaluate NDAs during this

period, and (4) a reorganization at FDA that resulted in the Claritin NDA

being transferred to a new division.1

The Approval Time for

Claritin Was Longer

Than Average

Schering-Plough submitted a new drug application to FDA on October 31,

1986, for approval to sell Claritin. The NDA was approved on April 12, 1993,

the approval process taking a total of 77.4 months. This was about 3 years

longer than the 42.5-month average approval time for 1C pipeline drugs.

The approval time for about 92 percent of these drugs was shorter than for

Claritin. In addition, the approval time was longer than that for all but 3 of

the 33 1C drugs approved between 1983 and 1985.

Because only three nonsedating antihistamines (and only one other 1C

antihistamine) were approved between January 1, 1975, and April 12, 1993,

we did not calculate average approval times for this therapeutic class.

However, Claritin had the longest approval time of all these drugs. The

1

Bioequivalence refers to whether drugs in different forms (in this case, tablets and

capsules) are absorbed into the human body in equivalent ways.
Appendix III

Approval Process for Claritin

Page 33 GAO/HEHS-00-140 Pipeline Drugs

other 1C nonsedating antihistamine (Hismanal) was approved in 46.1

months.

The Approval Process

Was Complex

Schering-Plough submitted 37 major amendments to the Claritin NDA

during the 77 months it was being considered by FDA. A major amendment

involves a relatively large amount of new data (for example, a reanalysis of

a completed study or results of an additional study) being submitted to the

agency. FDA decides whether an amendment is classified as major or

minor. The amendment may be submitted either at the sponsor’s own

initiative or in response to an issue raised by FDA. For Claritin, 30 of the

amendments were responses to FDA concerns. In an earlier report, we

found that 97 percent of approved NDAs submitted from 1987 to 1992 had

10 or fewer major amendments.2 While the number of amendments may

indicate problems with the NDA, FDA told us that it is not necessarily the

case. In our analysis of the Claritin NDA, we found that there were

substantial differences in the nature of the major amendments and the

amount of data submitted. Eighteen of the amendments dealt with

establishing the equivalence of the capsule and tablet forms of the drug or

the animal carcinogenicity studies and the remaining 19 covered a number

of topics including required safety updates, reports of studies completed

after the NDA was submitted, and foreign labeling. In addition, despite the

large number of major amendments, FDA neither refused to file the

application nor issued a not approvable letter, and the company never

withdrew the drug from consideration.3

There were indications from FDA during the approval process that

progress was being made. For instance, before an October 22-23, 1987,

meeting of the Pulmonary-Allergy Drugs Advisory Committee to discuss

the efficacy and sedative effects of the drug, an FDA official told a

Schering-Plough representative not to be concerned because the drug had

already been shown to be equivalent to Seldane (which had already been

approved). Also, before the Advisory Committee meeting, FDA officials

2

FDA Drug Approval: Review Time Has Decreased in Recent Years (GAO/PEMD-94-26,Oct.

20, 1995).

3

Once an NDA is received, FDA has 60 days to determine whether it will be officially filed.

FDA can refuse to file an application if it finds that the NDA is not sufficiently complete to

permit a substantive review. After reviewing the NDA, the agency can issue a not approvable

letter if it determines that NDA “does not provide the substantial evidence of safety and

effectiveness required.”
Appendix III

Approval Process for Claritin

Page 34 GAO/HEHS-00-140 Pipeline Drugs

told the company that they had not encountered any actual review

problems. The Advisory Committee recommended approval of the drug at

that meeting. In a March 13, 1989, letter to FDA, Schering-Plough wrote that

its understanding (based on a conversation with the Acting Division

Director) was that only a minor safety concern was holding up approval of

the drug. The company complained that this could easily be addressed in

the label. On March 23, 1989, the Acting Division Director at FDA

responded that it was attempting to make its part of the review process

final.

However, during this period FDA also gave indications to Schering-Plough

that it was having difficulty with the NDA. For instance, on June 13, 1988,

Schering-Plough called FDA to ask if FDA was ready to discuss labeling for

the drug. The FDA official responded that it usually has serious labeling

discussions only when the agency believes it is nearing an approvable letter

and that this was not yet the case with Claritin. On January 13, 1989,

Schering-Plough called FDA to schedule a meeting with the agency in order

to precipitate approval of the drug. It was told that the meeting should not

even be considered until completion of the medical, biopharmaceutical,

and biometrics reviews.

Despite these problems, the NDA appeared to be nearing approval in 1989.

The stated purposes of a meeting of FDA officials on February 28, 1989,

were to discuss particular issues raised in the biopharmaceutical review

and to “tie up loose ends” in it and the medical review before an anticipated

approval. In June 1989, FDA cancelled a meeting with Schering-Plough

because FDA officials believed that an “approvable” letter would soon be

issued.4 On July 21, 1989, an Acting Division Director held a meeting with

other FDA officials to discuss approvability and labeling with the intention

of moving toward a final action. In his September 11, 1989, review of the

NDA, the Acting Division Director wrote that the efficacy and safety of the

drug had been shown and the bioequivalence issues had been settled. He

noted that both the medical officer and group leader recommended

approval. The Acting Director concluded that, with recommended label

changes, the NDA was approvable.

4

FDA can issue an approvable letter when it has determined that the NDA has provided

substantial evidence of the safety and effectiveness of the drug but “additional information

must be submitted or a specific condition must be agreed to by the applicant” before the

NDA can be approved.
Appendix III

Approval Process for Claritin

Page 35 GAO/HEHS-00-140 Pipeline Drugs

Concerns About the

Results of Animal

Carcinogenicity

Studies Delayed the

Drug’s Approval

The principal issue that delayed Claritin’s approval was concern at FDA

about the potential significance of animal carcinogenicity studies. This

concern was raised early in the review process but appeared to have been

settled about 1-1/2 years after the NDA was submitted. The issue

resurfaced about a year later. While it is unclear exactly why this occurred,

one factor might have been the finding that another antihistamine was

associated with liver tumors in rats and mice. This was the primary issue

that FDA dealt with from 1989 until the drug was approved in 1993.

A number of tests are used to assess the carcinogenicity of a drug,

including ones with animals. Throughout this report, we refer to

carcinogenicity studies that have been conducted with animals. Substances

that cause or promote tumors in laboratory animals are not necessarily

carcinogenic in humans. Because of this uncertainty, a range of other

studies and information is used to assess the risk of tumors in humans, and

an assessment is made by examining the bulk of the evidence.

The Carcinogenicity Studies

Concern Appeared to Be

Settled but Then Resurfaced

FDA found indications of carcinogenicity in the studies Schering-Plough

submitted. In May 1987, the reviewing pharmacologist found some

evidence of carcinogenicity in mice and rats. On several occasions after

this, initially on August 17, 1987, FDA requested that Schering-Plough

retabulate existing data. After this additional information was reviewed, a

statistical review dated April 14, 1988, found some evidence that Claritin

led to increased liver adenomas and benign tumors in male mice when

administered at high doses but concluded that there was no increase in

carcinomas.5 Following this assessment, the reviewing pharmacologist

concluded in an April 26, 1988, memorandum that the drug was approvable

from a toxicology perspective if there was disclosure in the product

labeling of the findings from the rat and mouse carcinogenicity studies.

However, in August 1989, a new reviewing pharmacologist noted that

additional data were needed to properly evaluate the rat studies.

Schering-Plough contends that a spring 1989 FDA reorganization was a

major factor in delaying the Claritin approval process. When this

reorganization occurred, the Claritin NDA was transferred from the

Division of Surgical-Dental Drug Products to the Division of Oncology and

5

An adenoma is a noncancerous tumor or growth arising in the lining or inner surface of an

organ; a carcinoma is a cancerous tumor.
Appendix III

Approval Process for Claritin

Page 36 GAO/HEHS-00-140 Pipeline Drugs

Pulmonary Drug Products. While the medical officer remained the same,

new reviewers (including a new primary pharmacologist) were assigned to

examine other aspects of the NDA. Schering-Plough believes that the new

reviewers needed additional time to familiarize themselves with the data.

In so doing, issues were raised that appeared to have been settled about 16

months earlier.

Schering-Plough speculates that FDA officials may have been influenced by

then unpublished findings of a study by FDA’s National Center for

Toxicological Research on doxylamine, another antihistamine. The results

indicated that doxylamine was associated with liver tumors in rats and

mice. This could have heightened FDA’s concerns about the significance of

the animal tumor findings in other antihistamines for humans, since toxic

issues are sometimes common across entire drug classes.6 Schering-Plough

notes that the concerns FDA raised in 1989 related to findings of liver

toxicity in the long-term rat and mouse carcinogenicity studies, the same

type of data discussed in the doxylamine study.

We found evidence of the importance of the doxylamine study in the FDA

files on Claritin, although none of the evidence addresses whether this

caused the carcinogenicity studies issue to be reevaluated. It is unclear

when the results of the doxylamine study became known within FDA,

although we do know that the draft report was released in August 1990.

However, the importance of the study in the review of Claritin is clear. In

April 1991, FDA decided not to schedule a meeting with Schering-Plough

until the company had a chance to review the published doxylamine report.

Also, a meeting of the Pulmonary and Allergy Drug Product Advisory

Committee was held on June 13-14, 1991, in which the toxicology of

antihistamines was discussed with regard to the doxylamine data. Finally,

the division director noted in his final safety and efficacy summary October

19, 1992, that since his last review on September 11, 1989, there had been a

reconsideration of the carcinogenicity study results as similar findings had

been reported for other antihistamines.

6

Safety concerns in medications in a therapeutic class can lead to FDA’s investigating these

concerns more carefully in other drugs in that class. See, for example, FDA Premarket

Approval: Process of Approving Ansaid as a Drug (GAO/HRD-92-85, Apr. 17, 1992).
Appendix III

Approval Process for Claritin

Page 37 GAO/HEHS-00-140 Pipeline Drugs

FDA Questioned the

Adequacy of the

Carcinogenicity Testing

After the carcinogenicity study issue resurfaced, FDA became concerned

that the carcinogenicity testing for Claritin was inadequate. At a November

16, 1989, meeting with Schering-Plough, FDA officials informed the

company that they were concerned about the effects of Claritin on the

animal liver, including tumor formation. On January 19, 1990, at the request

of the Division of Oncology and Pulmonary Drug Products, the

Carcinogenicity Assessment Committee (CAC) reviewed the Claritin

carcinogenicity studies.7 The committee concluded that the studies showed

a possible increase in mouse and rat liver tumors but noted that it found the

data difficult to evaluate fully because of the way the tests were conducted

and analyzed. It recommended that, at a minimum, a complete rereading of

all the mouse and rat liver slides be conducted. CAC also suggested that a

repeat of the mouse carcinogenicity study might be necessary if the

approximate maximum tolerated dose was not used.8 The committee was

also concerned about the interpretation of the mouse lymphoma assay and

believed that if the data were important, the study might need to be

repeated. In March 1990, FDA requested carcinogenicity data from the rat

and mouse studies to address the issues CAC raised. Schering-Plough

submitted the information on June 19, 1990. FDA’s review of these data

concluded that the maximum tolerated dose had not been used in the

mouse toxicity study. The rereading of the slides essentially confirmed the

original findings. It showed increased liver adenomas and carcinomas in

male mice. The rat studies were found to be equivocal.

CAC met again on November 2, 1990, but reached no firm conclusions on

the significance of the animal liver tumor findings in the carcinogenicity

studies of Claritin. The committee was satisfied with the rereading of the

mouse and rat slides, and it was agreed that the reanalysis of the results did

not significantly alter the outcome of either study. However, although it

was agreed that the maximum tolerated dose was not used in the mouse

study, opinion was divided on the need to repeat it. The committee did

agree that the maximum tolerated dose had been used in the rat study.

7

CAC is made up of FDA staff members from several reviewing divisions and outside

consultants.

8

The maximum tolerated dose is the highest dose that causes no more than a 10 percent

weight decrement, compared with the appropriate control groups, and does not produce

mortality, clinical signs of toxicity, or pathologic lesions (other than those that may be

related to a neoplastic response) that would be predicted to shorten the animals’ natural life

span.
Appendix III

Approval Process for Claritin

Page 38 GAO/HEHS-00-140 Pipeline Drugs

Much of the discussion regarding the significance of the carcinogenicity

studies concerned the location and type of the animal tumors. There was a

significant increase in liver adenomas in male mice. There was much

debate in the CAC about the importance of such an increase at a site where

there is a high spontaneous rate of such tumors. It was agreed that an

increase in adenomas at such a site is not as serious as an equivalent

increase at a site with a low spontaneous incidence rate. There was also

disagreement about whether adenomas progress to carcinomas.

On June 13-14, 1991, the Pulmonary-Allergy Drugs Advisory Committee

(which had recommended approval of the drug in October 1987) met to

discuss the toxicology data in light of the doxylamine findings. ScheringPlough officials presented data from the Claritin rat and mouse studies,

concluding that the drug presented no cancer risk to humans. An FDA

official described the abnormalities that were found and expressed

concerns about the dosing levels used in the mouse study. The committee

voted five to one that Claritin was unlikely to be a human carcinogen,

although it unanimously agreed that the data were not sufficient to support

a conclusion regarding the drug’s human carcinogenic potential. On

September 9, 1991, the reviewing FDA pharmacologist wrote in his review

that the NDA was approvable from the standpoint of pharmacology and

toxicology.

Other FDA officials remained concerned about the implications of the

carcinogenicity study results of Claritin because of several findings. These

included, first, the mouse carcinogenicity study being done at a fourth to a

third of the maximum tolerated dose, doses that FDA was concerned might

be too low to fully evaluate the carcinogenic potential of the drug. Second,

there were three marginal findings of tumors in rats. Third, the mouse

lymphoma assay was positive in the absence of metabolic activity. Fourth,

there were positive findings of increased tumors in the mouse study.

Finally, although there was no clear increase in carcinomas in mice, FDA

did not find their absence reassuring because the tests were not done at the

maximum tolerated dose.

Some officials within FDA remained concerned about the maximum

tolerated dose not being used in the mouse studies. These officials believed

that because this dose had not been used, the findings in these studies were

suspect. However, Schering-Plough argued that the doses used in the study

were satisfactory. The company had told the Pulmonary-Allergy Drugs

Advisory Committee that for the long-term mouse carcinogenicity study it

used doses of up to 200 times the clinically effective dose, corresponding to
Appendix III

Approval Process for Claritin

Page 39 GAO/HEHS-00-140 Pipeline Drugs

blood levels of Claritin 4 times the level that would occur in humans and

blood levels of the metabolite 18 times the human level.

One component of FDA’s concern about the results of the carcinogenicity

studies of Claritin resulted from a genotoxicity test known as the mouse

lymphoma assay.9 Schering-Plough contended that the positive finding in

this assay in the absence of metabolic activity was in fact a false positive

and should be disregarded because of negative results in all other

genotoxicity screens. Furthermore, it believed that this assay might give an

inappropriately high incidence of false positive results and be highly

influenced by toxicity considerations. Some FDA officials did not believe

the findings should be dismissed. One FDA official noted that each

genotoxicity test asks a different question. Consequently, a different

genotoxicity that is negative cannot negate a positive finding in the mouse

lymphoma assay.

FDA raised another genotoxicity issue in May 1992. FDA determined that

the Ames/Salmonella test (another screen for genotoxicity) that ScheringPlough submitted in the original NDA was invalid because the doses that

had been used were too low. FDA believed that the repetition of the Ames

test with higher concentrations could lead to a final conclusion on Claritin’s

mutagenic activity. One reviewer noted that because of weak tumorcausing responses in the animal tests, Claritin’s potential for genotoxic

activity needed to be investigated fully before considering approval.

Schering-Plough believed that the original dosing was appropriate and

stated in a letter to FDA the rationale for the doses used in the Ames test.

However, FDA disagreed and on July 20, 1992, asked Schering-Plough to

conduct a second Ames test using higher doses of the drug, and the

company agreed to do so. The results were submitted in August and the

company reported that the results were negative. In September, FDA

informed Schering-Plough that the second Ames test was satisfactory and

that FDA wanted to move along with an approvable action after receipt and

approval of a new safety update. FDA and Schering-Plough then worked on

an appropriate label, and the drug was approved in April 1993.

Schering-Plough contends that FDA’s reevaluation of the carcinogenicity

study data resulted in the company’s losing about 4 years of effective patent

protection. The company notes that the labeling requirements for the

9

Genotoxicity refers to the adverse health effect a chemical has on genes and chromosomes.

Genotoxicity tests are used to identify carcinogens.
Appendix III

Approval Process for Claritin

Page 40 GAO/HEHS-00-140 Pipeline Drugs

animal tumor issue that was adopted in 1993 were very similar to those

FDA proposed and Schering-Plough agreed to in 1988. However, FDA

officials told us that the fact that the results of FDA’s investigation did not

lead to significant label changes does not necessarily mean that the inquiry

was inappropriate. FDA officials were uncertain that Claritin met the safety

requirements for its being approved and, consequently, investigated the

drug until they were convinced that the carcinogenicity data concerns

should not cause the drug to be kept off the market. The information

resulting from the inquiry could have contributed to FDA’s believing that

the original labeling requirements were appropriate. When FDA approved

the drug, it was implicitly acknowledging that the carcinogenicity issue had

been satisfactorily addressed.

FDA Needed to Develop a

Policy but Expert Opinion

Was Divided

The Claritin NDA appears to have been caught in an internal policy debate

at FDA regarding the marketing status of antihistamines with low-grade

positive carcinogenicity findings and whether these drugs were

approvable. The decision was made more difficult by the large amount of

controversy in the field of toxicology about animal carcinogenicity studies.

Opinion was divided regarding the relevance of animal carcinogenicity

studies for humans, including the high level of sensitivity of these studies,

the need to use the maximum tolerated dose in animal cancer studies, the

interpretation of marginal findings in animal studies, the importance of any

findings that might be based on physiologic mechanisms (which may or

may not be species-specific), and the relevance for humans of findings in

animal livers.10 Thus, FDA was in a position in which it needed to develop a

policy but could not look to the scientific community for consensus.

FDA and ScheringPlough Disagreed on

How to Demonstrate

Bioequivalence

Schering-Plough believes that FDA’s concerns about the bioequivalence of

the capsule and tablet forms of Claritin were unfounded and resulted in

unnecessary delay in the drug’s approval. The clinical trials of Claritin

tested a capsule rather than the tablet Schering-Plough planned to market.

Although this is not uncommon, the NDA sponsor needs to show that the

two dosage forms of the drug are equivalent in order to obtain FDA’s

approval.

10Sensitivity refers to an organism’s being highly responsive or susceptible. In this case,

animals were viewed as being highly likely to develop tumors.
Appendix III

Approval Process for Claritin

Page 41 GAO/HEHS-00-140 Pipeline Drugs

Before the NDA was filed, Schering-Plough informed FDA that it planned to

seek approval to market the tablet form of the drug instead of the capsule

that had been used in the clinical trials. FDA had no objections to ScheringPlough’s pursuing this strategy. However, after FDA biopharmaceutic

experts reviewed the 13 studies Schering-Plough submitted to establish the

bioequivalence of the tablet and capsule, they concluded that the data did

not support such a finding. In reviews dated May 25, 1988, and August 22,

1988, the FDA official reviewing these data wrote that the application was

unacceptable.

This issue arose because of disagreement between FDA and ScheringPlough on what needed to be done to demonstrate bioequivalence. Claritin

is rapidly converted to a primary metabolite.11 Consequently, ScheringPlough believed that the bioequivalence of the parent drug should be

ignored and only the metabolite should be studied for bioequivalence. FDA

disagreed, noting that the drug is not completely metabolized and that the

bioequivalency for both the parent and metabolite needed to be

established. The difficulty was establishing bioequivalence for the parent

compound because Schering-Plough and FDA agreed that the

bioequivalence of the metabolite had been shown.

Given this disagreement, the company decided to conduct a therapeutic

equivalence study in which the tablet, the capsule, and a placebo were

compared in approximately 450 patients. The study was conducted in the

fall of 1988 and the results were submitted to FDA on November 23, 1988.

FDA pharmacologists concluded in January 1989 that while bioequivalence

had not been shown with traditional methods, the point would be moot if

the therapeutic equivalence study was acceptable. Consensus was reached

at FDA in March 1989 that the results of the therapeutic equivalence study

adequately demonstrated equivalent efficacy. Thus, approximately 2-1/2

years after the NDA was submitted, the bioequivalency issue was resolved.

This position was confirmed by the responsible Acting Division Director at

FDA, who concluded in his September 11, 1989, review that the 450-person

clinical study established the equivalence of the tablet and capsule.

11A metabolite is any substance produced or used during metabolism (digestion). In drug

use, a metabolite usually refers to the end-product (what remains after metabolism).
Appendix III

Approval Process for Claritin

Page 42 GAO/HEHS-00-140 Pipeline Drugs

Other Issues That

Arose During the

Approval of Claritin

While not as significant as carcinogenicity and bioequivalence, several

other issues may have affected the approval of Claritin. FDA had some

concerns about the data that were submitted to support the claim that

Claritin was nonsedating, and there were also questions about the

effectiveness of the 10 milligram dose of the drug. In addition, there is

evidence to suggest that the 1989 reorganization resulted in Claritin’s

receiving a lower review priority in the new division than it would have had

in the original division. Conversely, it appears that the approval of Claritin

may have been given a higher priority at FDA when concerns about the

toxicity of already marketed antihistamines arose.

FDA Questioned Whether

Claritin Was Nonsedating

Schering-Plough claimed that Claritin was a nonsedating antihistamine,

something that would distinguish it from all but one antihistamine on the

market when the NDA was filed. Soon after receiving the NDA, FDA

reviewers began to examine whether the drug had sedative effects. They

identified a number of issues regarding the availability and quality of the

data on sedation as well as indications that the drug might be sedating. For

instance, in an October 1987 review, an FDA official concluded that no

definitive conclusions on sedation resulting from the 10 milligram dose

could be drawn because of the flawed nature of the studies.

In spring and summer 1987, FDA reviewers raised concerns that the studies

submitted in the NDA did not show nonsedation. They found indications

that drowsiness was among the most common adverse reactions and was

somewhat dose-related—that is, the tendency to induce sedation increased

with larger doses. In November 1987, the FDA medical officer concluded

that sedation would have to be included in the label as an adverse reaction.

As FDA continued to assess this issue in 1988, it concluded that the 10

milligram dose was no more sedating than a placebo. However, it also

found that the 40 milligram dose was more sedating.12 In a letter to

Schering-Plough on May 16, 1988, the Acting Director of the Division of

Surgical-Dental Products informed the company of these conclusions.

12Schering-Plough had plans to market only the 10 milligram dose. Because of this, ScheringPlough officials questioned the appropriateness of FDA’s presenting data on the 40 milligram

dose to an advisory committee. FDA responded that it was primarily for completeness and

that the difference in efficacy and sedation between the two doses was a basic part of the

evaluation.
Appendix III

Approval Process for Claritin

Page 43 GAO/HEHS-00-140 Pipeline Drugs

FDA Questioned Claritin’s

Effectiveness

While FDA was assessing the bioequivalence and sedation issues, it was

also examining the efficacy of Claritin. Soon after the NDA was filed, FDA

reviewers began to examine the efficacy of the 10 milligram dose. In a

January 9, 1987, telephone conversation, the FDA medical officer told a

Schering-Plough official that it appeared that the 10 milligram dose was not

very effective but that the 40 milligram dose was effective. An FDA

statistical review completed in July 1987 raised a number of issues about

the design and results of the studies, including indications that the drug

was not effective. The reviewer concluded that the studies failed to provide

substantial evidence that the drug was effective. FDA sent these concerns

to the company on August 6, 1987, and the company responded by letter

later that month. At its October 22-23, 1987, meeting, the Pulmonary-Allergy

Drug Advisory Committee concluded that the minimum clinically effective

dose was 10 milligrams. As the review process continued in 1988 and 1989,

the FDA medical officer expressed his concern that 10 milligrams was not

the optimal dose. However, by July 1989, a consensus had developed at

FDA that 10 milligrams was effective.

Schering-Plough’s Response Schering-Plough believes that the issues of nonsedation and effectiveness

did not at all delay FDA’s approval of the Claritin NDA. We thought that it

was important to note that there were issues in addition to carcinogenicity

and bioequivalence about which FDA had concerns. FDA’s analysis of these

issues took up resources which, if used differently, could have decreased

the approval time. In addition, these concerns continued to be discussed

within FDA at least until 1988 for nonsedation and 1989 for effectiveness.

Consequently, an early resolution of the bioequivalence issue would not

necessarily have resulted in an earlier approval.

The FDA Reorganization

May Have Decreased the

Review Priority of Claritin

Schering-Plough contends that the spring 1989 FDA reorganization resulted

in Claritin’s receiving a lower review priority in the new reviewing division

than it would have had in the previous division. The evidence for this

position is mixed. The therapeutic potential classification of C for Claritin

stayed the same after it was transferred. However, the new division

approved more higher-priority A and B drugs than the old division, thus
Appendix III

Approval Process for Claritin

Page 44 GAO/HEHS-00-140 Pipeline Drugs

relatively de-emphasizing the C drugs. Therefore, relative to the other drugs

in the two divisions, Claritin’s priority decreased.13

Approval May Have Been

Aided by Toxicity Concerns

in Other Antihistamines

The approval of Claritin may have been aided by unexpected adverse

events being associated with other nonsedating antihistamines. In FDA’s

deliberations on the carcinogenicity studies of Claritin, it was noted that

marketed antihistamines did not produce the same animal tumor findings

as demonstrated in the Claritin studies. Consequently, because of these

safety concerns, FDA believed that the approval of Claritin might be

inappropriate since it offered limited or no benefit over the other drugs.

This view began to change in the early 1990s, when both Seldane and

Hismanal, the only nonsedating antihistamines on the market, were linked

to cardiac events. As this developed, FDA officials started to believe that it

would be beneficial to have Claritin for sale. The practical effect of this

development was to increase the therapeutic potential of Claritin, because

it now appeared to offer some benefit beyond previously approved drugs.

The Division Director wrote in his October 19, 1992, final safety and

efficacy summary that because Claritin at clinically useful doses is no more

sedating than placebo, a slight uncertainty regarding the mechanism by

which Claritin promotes animal tumors is acceptable, given the

cardiotoxicity associated with Seldane and Hismanal.

13Because the numbers of reviewers in the two divisions were comparable, differences

cannot be explained by staffing levels. However, because we have no information on drugs

that were not approved, we cannot ascertain the workload for each division.
Page 45 GAO/HEHS-00-140 Pipeline Drugs

Appendix IV

Approval Process for Relafen ApendxiIV

SmithKline Beecham Corporation holds the patent for Relafen, a

nonsteroidal anti-inflammatory drug (NSAID) that is used to relieve

symptoms of osteoarthritis and rheumatoid arthritis. Relafen had U.S. sales

of $405 million in 1999, making it the largest selling prescription NSAID in

the country. The patent for Relafen was issued on December 13, 1983, and

is scheduled to expire on December 13, 2002. The company filed a new

drug application with FDA on February 6, 1986, for approval to sell Relafen.

On the basis of Relafen’s therapeutic potential, FDA assigned Relafen its

lowest review priority, a C ranking. This means that FDA determined that

the medication would provide little or no therapeutic gain compared with

an already marketed drug. The NDA was approved on December 24, 1991.

SmithKline Beecham contends that the 71 month review period taken by

FDA to grant approval caused it to lose valuable patent life from the

marketing of the drug.

During the early 1980s, before the approval of Relafen, some NSAIDs

already on the market were associated with fatal and other serious adverse

reactions.1 SmithKline Beecham contends that these problems, in effect,

slowed down the review time of Relafen because FDA officials were

concerned that other drugs in the NSAID class might have similar

problems. In addition, SmithKline Beecham claims that there were

prolonged periods when FDA did not provide feedback regarding the

agency’s assessment of the safety and efficacy of the drug. Instead, the

company believes that FDA focused the majority of its resources on

reviewing the chemistry and bioequivalence data rather than on the clinical

information. Furthermore, SmithKline Beecham stated that only one NDA

was being reviewed at a time within the NSAID class. As a result, the

company claims that Relafen was placed in a queue and not reviewed in a

timely manner. It also argues that the lack of resources at FDA contributed

to delaying Relafen’s approval.

Approval Time for

Relafen

The approval time for Relafen was 70.5 months. This exceeded the average

approval time of 57.6 months for the 13 category 1C NSAIDs approved

during 1975 to 1993 (with a range of 20.3 to 122.5 months). As a result, the

approval time for Relafen was greater than about 67 percent of the NSAIDs.

The approval time for Relafen exceeded the longest approval time of all 1C

1

Oraflex was voluntarily withdrawn from the market by the manufacturer on August 5, 1982,

while Zomax was withdrawn in March 1983. Feldene is still available, although it was

relabeled in 1983.
Appendix IV

Approval Process for Relafen

Page 46 GAO/HEHS-00-140 Pipeline Drugs

drugs approved between 1983 and 1985, around the time the WaxmanHatch Act was passed.

However, the picture for Relafen changes if the drugs are divided into those

approved before and after 1984. In the early 1980s, several NSAIDs already

on the market were found to be associated with adverse reactions.

Consequently, FDA became cautious about approving new drugs in this

class. The average approval time for NSAIDs approved before 1984 was

30.8 months, with a low of 20.3 months and a high of 48.2. The average time

for drugs approved between 1984 and 1992 was 80.7 months, with a range

of 45.9 to 122.5.2 Relafen, which was approved in 1991 and had an approval

time of 70.5 months, is actually below the average for 1C NSAIDs approved

after the safety concerns were raised. Approximately half of these drugs

had shorter approval times than Relafen and half took longer to be

approved.

Missing and

Incomplete

Information in the

Relafen NDA

NDAs are complex documents that require a significant amount of

information from drug manufacturers. NDAs that are fairly complete can

lessen the time FDA requires for review. The FDA officials we spoke with

told us that the Relafen NDA had a significant amount of incomplete and

missing information.3 For example, the company was attempting to get a

specific type of liquid dose approved but did not supply complete

information that could validate the contents of this liquid. As a result of the

incomplete application, SmithKline Beecham had to submit several

amendments to the application and respond to FDA questions. According

to FDA officials, the submission and review of these amendments and

requests for additional information increased the review time of the NDA,

although the extent of this increase cannot be specifically quantified.

2

These times reflect that there were no 1C NSAID approvals from April 1982 until December

1985.

3

When the Relafen NDA was submitted, FDA allowed incomplete applications to be

submitted. However, FDA officials indicated that the Relafen NDA had more missing and

incomplete information than was usually found in other NDAs. With the passage of the

Prescription Drug User Fee Act of 1992, incomplete applications are no longer permitted.
Appendix IV

Approval Process for Relafen

Page 47 GAO/HEHS-00-140 Pipeline Drugs

FDA Efficacy and

Safety Review of

Relafen

FDA files contain little evidence of communication between the company

and FDA about drug efficacy during the approval process. SmithKline

Beecham suggested that FDA delayed the review of efficacy of the drug.

According to company officials, FDA did not communicate with SmithKline

Beecham about the drug’s clinical review for the first 3 to 4 years following

the submission of the NDA. While there was no documentation of such

reviews being done during this period in the FDA files, we cannot conclude

with certainty that these reviews did not occur because the information

may have been missing.

We located a comprehensive summary of the safety and efficacy of Relafen

that was developed after the final approval of the NDA, but it did not

chronicle the clinical review throughout the approval process. We did

identify a pharmacology review that was conducted about 6 months after

the NDA was submitted that dealt with animal tumors, but the review did

not indicate whether or not a medical officer had been assigned.

Serious Adverse

Reactions Among

Other NSAIDS

In many cases, adverse drug reactions are common within a drug class. As

a result, all NSAIDs could potentially share common adverse reactions. In

1982, more than 9 years before FDA approved Relafen, three of the NSAIDs

on the market (Feldene, Oraflex, and Zomax) had reports of fatal and

nearly fatal reactions. Oraflex and Zomax were subsequently removed from

the market, while Feldene was relabeled in 1983 and remains on the

market. Another NSAID (Suprol) was taken off the market in 1987 because

of adverse effects on the kidneys. SmithKline Beecham claims that the

close attention given to the adverse events of these other drugs caused

FDA to be overly cautious in its review of Relafen. Between 1982 and 1987,

the Congress held several hearings about the adverse reactions of NSAIDs.4

During these hearings, the FDA approval process was criticized. It was

noted that the manufacturers had not reported a large number of adverse

reactions to FDA. Because of the serious concerns over public health, FDA

began to review new NSAID applications in a more detailed manner to help

ensure that NSAIDs under review would not cause similar problems if they

were approved. However, according to SmithKline Beecham officials, the

resulting attention given to the problems of the other NSAIDs was unfairly

4

FDA Premarket Approval: Process of Approving Ansaid as a Drug (GAO/HRD-92-85, Apr. 7,

1992) and FDA Premarket Approval: Process of Approving Lodine as a Drug (GAO/HRD-93-

81, Apr. 13, 1993).
Appendix IV

Approval Process for Relafen

Page 48 GAO/HEHS-00-140 Pipeline Drugs

cast upon Relafen. The manufacturer of one of these other drugs stated

that the adverse drug reactions associated with NSAIDs on the market at

that time were not unknown before concern was raised in the Congress and

were not beyond what might be expected. However, these concerns led

FDA to examine the safety of new NSAIDs in more detail. As a result, there

were no 1C NSAID drug approvals from April 1982 until December 1985.

Further, according to SmithKline Beecham officials, the Division Director

commented that a moratorium was placed on approvals because it was his

opinion that enough NSAIDs were already on the market.5 SmithKline

Beecham officials contend that only one NDA was then being reviewed at a

time, further slowing the approval of Relafen. However, FDA officials told

us that they did not recall such a policy.

Chemistry Issues

Delayed Approval

According to FDA’s files, several issues regarding the chemistry of Relafen

surfaced during the NDA approval process. For example, FDA officials

requested that SmithKline Beecham provide more complete information

about the purity and stability of the drug and various specifications used in

the manufacturing process to ensure the drug’s quality. Predominately, FDA

officials requested chemistry information from the company that was

missing or incomplete in the original NDA. FDA officials told us that these

chemistry concerns were “technical.”6 These concerns were a result of 11

separate chemistry reviews FDA conducted between February 1986 and

November 1991. SmithKline did not address many of the chemistry

concerns identified in the early FDA reviews to FDA’s satisfaction until the

latter part of the approval process. In some cases, FDA files show that

agency staff had to repeatedly ask the company to address certain issues

and that chemistry concerns persisted for more than 5 years. Although we

were unable to find documentation of the final resolution of these

chemistry concerns, we did locate information about an amendment

submitted on November 14, 1991, that contained responses regarding the

chemistry concerns. Given that the drug was approved within 6 weeks of

this date, we assume that FDA was satisfied with the company’s responses.

5

FDA questions whether such a moratorium was placed on NSAID approvals.

6

FDA uses technical comments to ask a drug manufacturer to clarify or provide more

information about a specific issue.
Page 49 GAO/HEHS-00-140 Pipeline Drugs

Appendix V

Approval Process for Cardiogen-82 ApendxiV

Cardiogen-82 is a radioactive diagnostic agent that is administered by

intravenous injection. It is used in adults with suspected heart attacks to

distinguish normal from abnormal middle muscular layers of the heart wall.

The patent for Cardiogen-82 was filed on November 21, 1980, and issued on

August 23, 1983. It is scheduled to expire on August 23, 2002.

FDA received the NDA from Squibb Diagnostics, the manufacturer of the

drug, on December 28, 1984.1 When the NDA was submitted, a number of

radioactive diagnostic products were already on the market. On the basis

of its assessment of the therapeutic potential of the drug, FDA assigned

Cardiogen-82 its lowest review priority, a C ranking.2 This means that FDA

believed that the medication would provide little or no gain compared with

an already marketed drug. The NDA was approved on December 29, 1989,

60 months after it was submitted. The average approval time during 1975 to

1993 for 1C drugs in this therapeutic class (radioactive diagnostic aids) was

49.3 months, with a low of 19.9 months and a high of 83.5. About 60 percent

of drugs in this class were approved faster than Cardiogen-82.

FDA had concerns with the chemistry and manufacturing section of the

NDA and the section assessing the efficacy of the drug. These concerns

resulted in FDA’s sending a not approvable letter to Squibb on July 3, 1986,

stating that the drug could not be approved without additional information

from the company. On February 26, 1987, Squibb submitted clinical

information to FDA and requested a meeting to discuss a subset of the

clinical issues raised by FDA in the not approvable letter. The meeting was

held on May 5, 1987. On January 5, 1988, Squibb submitted information

requested by FDA at the May 5 meeting. FDA wrote to Squibb on January

27, 1988, 19 months after the not approvable letter was issued, asking the

company to voluntarily withdraw the application until all requested

information was provided. FDA noted that Squibb had not yet provided a

complete response to the deficiencies discussed in the not approvable

letter. The manufacturer withdrew the application on March 3, 1988, and

then resubmitted it with additional information on July 11, 1988. Thus,

while the drug took 60 months to be approved from its original submission,

in effect, FDA waited 24 months from July 1986 to July 1988 for Squibb to

submit a complete response to the not approvable letter. FDA tracks the

1

The drug is manufactured by Bristol Myers Squibb Company and marketed by Bracco

Diagnostics Inc., which purchased the drug from Squibb in July 1994.

2

A C ranking was given, even though the claim being made for Cardiogen-82 was unique.
Appendix V

Approval Process for Cardiogen-82

Page 50 GAO/HEHS-00-140 Pipeline Drugs

time it takes companies to resubmit an application following a not

approvable letter or withdrawal of the drug. The agency subtracts this time

from the total approval time for a drug. The agency refers to this as “FDA

approval time.”3 The FDA approval time for Cardiogen-82 was 35.5 months.

The average FDA approval time for other 1C radioactive diagnostics was

also 35.5 months (with a range of 18.6 to 56 months). Approximately 50

percent of 1C radioactive diagnostics were approved faster than Cardiogen82 when FDA approval time is considered.

Bracco officials contend that one reason for the lengthy review process

was the change in FDA reviewers during the approval process. We found

that the individuals doing the chemistry and medical reviews did change.

However, while this could lengthen the review process, we were unable to

determine whether this had any effect on the approval period.

Bracco officials have also noted that a 5-year FDA approval time was not

unusual for medical imaging products that were being reviewed around the

time Cardiogen-82 was evaluated. Also, they believe that the dialogue

between the manufacturer and FDA was typical of that for NDAs. We found

that 40 percent of comparable radioactive diagnostics were approved more

slowly than Cardiogen-82 in the years we examined (1975-93). Also, an FDA

official told us that there was a backlog of NDAs in FDA’s Division of

Medical Imaging and Surgical-Dental Drug Products in the late 1980s and

early 1990s.

FDA Found the NDA

Difficult to Evaluate

Overall, FDA reviewers found the NDA to be confusing, incomplete, poorly

organized, and filled with unexplained discrepancies. They noted that the

case reports for individuals in the studies gave a different impression than

what was presented in the summaries and tables. Also, FDA found that it

was unable to determine how many patients were enrolled in the studies or

how many studies were conducted. FDA officials also noted that some

reports that the manufacturer had submitted to FDA were not referred to in

3

In addition to the time associated with a not approvable letter and a drug’s withdrawal, FDA

approval time does not include the time involved when the agency “refuses to file” an

application. FDA can refuse to file an application if it determines that the information

contained in the NDA is not sufficient to permit a substantive review. FDA approval time

excludes the time from FDA’s initial receipt of an NDA to the refusal to file action and the

time from refusal to file to resubmission.
Appendix V

Approval Process for Cardiogen-82

Page 51 GAO/HEHS-00-140 Pipeline Drugs

the NDA. Moreover, an FDA official concluded that none of the studies

were designed to examine the use of the drug as discussed in the NDA.

Deficiencies in the

Chemistry Section of

the NDA

The chemistry review of the Cardiogen-82 NDA began within 2 months of

the application’s being filed, and the deficiencies found in the chemistry

review were conveyed by letter to the manufacturer on August 15, 1985. In

the initial FDA chemistry review, the reviewer noted that FDA had found a

number of deficiencies before the NDA was submitted and the

manufacturer had been informed of these concerns at that time.4 The

reviewer also found a number of problems with the NDA, and the

manufacturer was informed of these concerns in the August 1985 letter.

Among these difficulties were (1) the lack of a full statement of the

components and quantitative composition of the drug product; (2)

inadequate manufacturing information, including information on the

methods used in the synthesis, extraction, isolation, and purification of the

drug product; (3) failure to include adequate laboratory test procedures to

ensure that the finished drug product conforms to appropriate standards of

strength, quality, and purity; (4) reservations about the adequacy of the

stability tests for the drug; and (5) shortcomings in the proposed label for

the drug. On July 3, 1986, FDA sent Squibb a not approvable letter citing the

same chemistry problems that had been sent to the manufacturer nearly 11

months earlier.

Squibb submitted a chemistry amendment on May 4, 1988, in response to

the issues FDA raised in the not approvable letter. An additional chemistry

amendment was submitted on October 3, 1988. However, after reviewing

the submissions, FDA found that a number of deficiencies remained. These

were sent to the company on December 15, 1988. Squibb discussed them

with FDA on February 24, 1989, and responded to them on March 3, 1989. A

chemistry review completed on March 10, 1989, concluded that there were

no remaining chemistry questions.

4

On September 9, 1982, FDA had sent the manufacturer a chemistry deficiencies letter.

According to FDA, these deficiencies were still present when the NDA was submitted on

December 24, 1984, and they persisted for some time.
Appendix V

Approval Process for Cardiogen-82

Page 52 GAO/HEHS-00-140 Pipeline Drugs

FDA Identified

Problems in Data

Supporting the

Efficacy of the Drug in

the Not Approvable

Letter

FDA also cited clinical deficiencies in the July 3, 1986, not approvable

letter. For example, the studies that were submitted to support the efficacy

and safety of the drug used a different method for injecting Cardiogen-82

into the body than were identified in the proposed package insert included

in the NDA. FDA believed that additional studies were needed to show the

proper use of these other methods. Also, FDA found problems with the

design of the submitted studies. Agency officials were concerned that there

were too few patients on which to base approval. In addition, the results of

the clinical trials varied according to what device was used to judge how

well the drug worked. Different devices gave different indications of the

effectiveness of the drug. FDA had previously informed Squibb about many

of these problems in a November 12, 1985, meeting.

Approximately a month after the not approvable letter was issued, the

company informed FDA that it intended to file an amendment addressing

FDA’s concerns. Squibb submitted clinical information to FDA in February

1987 and, at FDA’s request and in preparation for a meeting, submitted a

draft response to the efficacy concerns in April 1987. Agency and Squibb

officials met on May 5, 1987, to discuss several of the clinical issues raised

in the not approvable letter. The information requested by FDA was

submitted to the agency on January 5, 1988.

However, FDA still had concerns about the data that were used to support

the efficacy claims for Cardiogen-82. FDA reviewers found that they could

not determine how many patients had been studied. Also, FDA was

concerned that some patients were excluded from analyses without

appropriate justification. In addition, FDA found that the tabulated data

often seemed to give a picture of the effectiveness of the drug different

from that of the raw data.

In a March 29, 1989, letter, FDA informed Squibb that there were still a

number of problems with the NDA and that it would be necessary to

reanalyze and reorganize the clinical data. FDA and Squibb officials met on

April 3 and 13, 1989, to discuss the issues raised in the letter. At the April 13

meeting, Squibb noted that it no longer had the data and was unsure

whether they could be retrieved from the investigators because the studies

had been completed a number of years earlier. FDA told Squibb that it

should attempt to retrieve all the data. On June 9, 1989, Squibb informed

FDA that it had found all the original patient scans but that analysis would

be difficult because of necessary computer conversions.
Appendix V

Approval Process for Cardiogen-82

Page 53 GAO/HEHS-00-140 Pipeline Drugs

In June 1989, Squibb officials suggested approving the drug for a narrower

indication than was described in the NDA, with the promise that it would

analyze the data on the original claim within 6 months.5 While FDA did not

believe it was ideal to approve the drug for the alternative claim, the drug

could be approved as long as it was of some value. It was agreed at FDA

that Cardiogen-82 was useful in the evaluation and diagnosis of heart

attacks, and in December 1989 Cardiogen-82 was approved for this

purpose.

5

The use sought in the Cardiogen-82 NDA was for assessing the specific location of heart

problems. The new claim was for the drug to be used to distinguish normal from abnormal

middle muscular layers of the heart wall in patients with suspected heart attacks.

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