Department of Health and Human Services 

OFFICE OF 

INSPECTOR GENERAL 

POSTMARKETING STUDIES OF 

PRESCRIPTION DRUGS 
OFFICE OF INSPECTOR GENERAL 

The mission of the Office of Inspector General (OIG), as mandated by Public Law 95-452, as 

amended, is to protect the integrity of the Department of Health and Human Services’ (HHS) 

programs as well as the health and welfare of beneficiaries served by those programs. This 

statutory mission is carried out through a nationwide network of audits, investigations, and 

inspections conducted by three OIG operating components: the Office of Audit Sefices, the 

Office of Investigations, and the Office of Evaluation and Inspections. The OIG also informs 

the Secretary of HHS of program and management problems and recommends courses to 

correct them. 

OFFICE OF AUDIT SERVICES 

The OIGS Office of Audit Services (OAS) provides all auditing services for HHS, either by 

conducting audits with its own audit resources or by overseeing audit work done by others. 

Audits examine the performance of HHS programs and/or its grantees and contractors in 

carrying out their respective responsibilities and are intended to provide independent 

assessments of HHS programs and operations in order to reduce waste, abuse, and 

mismanagement and to promote economy and efficiency throughout the Department. 

OFFICE OF INVESTIGATIONS 

The OIG’S Office of Investigations (01) conducts criminal, civil, and administrative 

investigations of allegations of wrongdoing in HHS programs or to HHS beneficiaries and of 

unjust enrichment by providers. The investigative efforts of 01 lead to criminal convictions, 

administrative sanctions, or civil money penalties. The 01 also oversees State Medicaid fraud 

control units which investigate and prosecute fraud and patient abuse in the Medicaid program. 

OFFICE OF EVALUATION AND INSPECI’IONS 

The OIGS Office of Evaluation and Inspections (OEI) conducts short-term management and 

program evaluations (called inspections) that focus on issues of concern to the Department, 

the Congress, and the public. The findings and recommendations contained in these inspection 

reports generate rapid, accurate, and up-to-date information on the efficiency, vulnerability, 

and effectiveness of departmental programs. 

This report was prepared in the Philadelphia regional office of OEI, under the direction of 

Robert A Vito, Regional Inspector General. Project staffi 

REGIONAL HEADQUARTERS 

Isabelle Buonocore, Project Leader Mary Beth Clarke, Program Specialist


Nancy J. Molyneaux, Program Analyst


WonJong Oh, Intern


Emily Tseng, Intern


For additional copies of this report, please call the Philadelphia office (215-596-0606).

Department of Health and Human Services 

OFFICE OF


INSPECTOR GENERAL


POSTMARKETING STUDIES OF


PRESCRIPTION DRUGS


# SERVICE$ 

J+ %’
‘t


w JUNE GIBBS BROWN $ 

< Inspector General 2

% #
 ‘%++, Mi4Y 1996 

%’dga > 0EI-03-94-O0760 
EXECUTIVE SUMMARY


PURPOSE 

Our report describes the effectiveness of the Food and Drug Administration’s (FDA) 

monitoring of postmarketing studies for prescription drugs. 

BACKGROUND 

Postmarketing studies--investigational drug studies conducted after FDA marketing 

approval--can have an impact on how drugs are prescribed and used. A company’s 

agreement to conduct an FDA-requested postmarketing study is called a 

postmarketing or phase iv commitment. 

Responsibility for monitoring phase iv commitments lies with the Offices of Drug 

Evaluation in the Center for Drug Evaluation and Research (CDER). A division in 

the CDER’S Office of Management was assigned the responsibility of identi&ing 

commitments for all new drugs and tracking their status. The tracking results are 

published for CDER’S internal use as the Phase IV Postapproval Research List. 

Our report provides FDA management with an overview of monitoring procedures 

and outcomes, focusing on new molecular entities. 

FINDINGS 

% number of new dregs with postmarking commitmerm k increasing. In the 1970s, 

the highest annual percentage of such dregs was 33 percent compared to a high of 70 

percent in the XWOs. 

l%ere are no formal standurds and procedures for monitotig or for establishing whether a 

postmurkdng commitment k nu%. 

W%ik the Phase IV PostapprovalResearchList contains important and usefid 

informutio~ it is not a@@ flective management tool in iti cument form Its fonnut 

preclidx summarization of records, it k not u.ted regukdy, and s&nificant data 

elementi are not captured cons&mtly. 

% FDA k taking some steps to improve the tracking of phase iv comrnitmeruk 

RECOMMENDATIONS 

We recognize there are limited resources and FDA’s priority is the review of 

premarketing studies. This is especially true with the shorter time frames in which 

FDA reviews premarketing studies under the Prescription Drug User Fee Act of 1992. 

i 
We also recognize FDA is interested in improving data management for 

postmarketing commitments and is taking steps in that direction. 

As our report indicates, FDA is requesting postmarketing studies for an increasing 

number of drugs. We believe it is reasonable to expect FDA to determine whether or 

not submitted studies fulfill the commitments. Until commitments are more 

systematically monitored and brought to closure, FDA is not availing itself of a 

management tool with which to assess the appropriateness of its requests and plan for 

the future. 

We recommend that FDA: 

F� establish stanch-.., prvcedums, or guidelines for canying out monitoring and 

tracking objecthm; and 

�� establkh accountability for monitoring tracking and btiging comrnitmen@ to 

cihure. 

Below are some ideas for FDA to consider in order to streamline data management: 

.� Assign authority to specific personnel for carrying out management’s objectives. 

Establish a coordinator with authority to (1) represent all offices involved in 

monitoring, tracking, and bringing commitments to closure; and (2) ensure that 

there is a quality control system for the commitments database. 

.� Reduce the number of documents that have to be researched in order to 

identi~ the status of commitments; and use standard notations on these 

documents to signify how each document affects the status of the commitment. 

.� Establish descriptive categories for (1) types of studies requested and (2) status 

of commitments. 

.� Put the database of postmarketing commitments on-line in the review divisions 

and allow authorized individuals to update records as soon as an action occurs 

or a determination is made. 

FDA COMMENTS 

The FDA agrees with this report’s findings and recommendations. A draft directive 

that establishes procedures and provides guidance is undergoing review within CDER 

is expected to be finalized by the end of June 1996. (Appendix C contains FDA’s 

comments in full.) 

11 
TABLE OF CONTENTS


EXECUTIVE SUMMARY


INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1


FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...5


� Quantity and status ofpostmarketing commitments . . . . . . . . . . . . . . . . . 5


� Monitoring and bringing commitments to closure . . . . . . . . . . . . . . . . . . . 7


c The Phase IVList . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...9


� Improvements to the tracking system . . . . . . . . . . . . . . . . . . . . . . . . . . . 10


RECOMMENDATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11


ENDNOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13


APPENDICES


k. Categories for the status ofcommitments . . . . . . . . . . . . . . . . . . . . . . . . . ..A-1


B: Number of commitments in each status as of 1995 . . . . . . . . . . . . . . . . . . . . B-1


C Comments from the Food and Drug Administration . . . . . . . . . . . . . . . . . . . C-1

INTRODUCTION


PURPOSE 

This report describes the effectiveness of the Food and Drug Administration’s (FDA) 

monitoring of postmarketing studies for prescription drugs. 

BACKGROUND 

Definition of Postmarketirw Studies 

Before drug companies can market new drugs in the United States, they must apply to 

FDA and receive approval. Normally, drug manufacturers test new drugs in three 

phases of studies prior to applying for marketing approval. The premarketing studies 

determine the drug’s safety and efficacy under controlled conditions. 

Prior to or after granting marketing approval, FDA may ask the manufacturer to 

conduct a “phase iv” or “postmarketing” study--synonymous terms in this report. This 

request is made if FDA concludes that additional information, while not essential for 

approval, will improve the prescribing and use of the drug. Postmarketing studies may 

confirm existing data, raise questions, or provide new data. Drug companies may 

initiate postmarketing studies without an FDA request, but in this report we are only 

addressing studies requested by FDA. 

As of the early 1990s, new regulations at 21 CFR 314.500, make it possible for FDA 

to grant marketing approval under an accelerated review process for a small number 

of drugs that treat serious and life-threatening illnesses.l When FDA uses the 

accelerated review process, the drug is available sooner but with less immediate 

clinical and safety information than the normal review process requires. When using 

the accelerated process, FDA can require postmarketing studies and can withdraw 

marketing approval if the studies are not completed with due diligence. 

For most new drugs, FDA does not have the same kind of legal authority to require 

completion of postmarketing studies, Nevertheless, there is a tradition of FDA 

requesting studies and companies agreeing to conduct them. A company’s agreement 

to conduct a study is called a phase iv or postmarketing commitment. In this report 

we use the term commitment when discussing agreed-upon phase iv studies for drugs 

approved under the normal and accelerated processes. 

Who Does the Monitoring 

Monitoring includes following-up on a phase iv commitment, reviewing any data the 

company submits, and tracking the status of the commitment until closure is reached.2 

1

Primary responsibility for monitoring commitments lies with the reviewers handling a 

drug company’s application for marketing approval. The reviewers are located in 

divisions of the Offices of Drug Evaluation in FDA’s Center for Drug Evaluation and 

Research. (Hereinafter the name of the Center is abbreviated as the Center for 

Drugs). In the course of analyzing a drug company’s application, a reviewer may 

request that the company conduct one or more postmarketing studies. If the drug 

under review is a not a new molecular entity,3 the request is cleared by the review 

division director. Requests relative to a new molecular entity are cleared at the level 

of office director. The company also enters into discussions about the request before 

making a commitment to conduct any studies. 

The FDA usually enumerates a company’s postmarketing commitments in a letter to 

the company. Then, as the company submits data relative to its commitments, 

reviewers (ideally the same ones that requested the phase iv study) determine if any 

action is necessary. The kind of action depends on the submission and might include 

a labeling change. 

While reviewers keep track of the phase iv commitments for drugs they reviewed, a 

division in the Office of Management, Center for Drugs, was given the responsibility 

for tracking the status of commitments for all drugs approved in the Center. This is 

the Division of Drug Information Resources (DDIR). Periodically, DDIR staff 

research documents in the review divisions to identi@ commitments and their status. 

Data extracted from the documents are organized in a word-processing file, and the 

file is published for the Center’s internal use under the title, Phase IV Pmtappmval 

Research list (hereinafter abbreviated as Phase IV List). 

What the Phase IV List Contains 

The Phase IV List contains a record for each drug (both prescription and over-thecounter) that has postmarketing commitments. Records are only of commitments 

made on original drug applications. There is no Centerwide tracking of commitments 

for supplementary applications or for postmarketing studies that were not requested 

by FDA. 

Each drug record briefly describes the commitments and their status as of the last data 

collection period, and cites the documentary sources of that information. Sources used 

to identify the commitments are generally one of two types of form letters review 

divisions send to drug companies, but other documents are also used. The status is 

derived from drug company correspondence, supplements, progress reports, periodic 

reports, annual reports, and from FDA correspondence, reviewer reports, meeting 

minutes, and telephone or electronic contact reports. 

There may be any number of commitments per drug, and they are listed together in 

the drug’s record. When all the commitments for a particular drug are met, the 

record for that drug moves from the Phase IV List’s Pending Commitments List to its 

Commitments Met or Released List. 

2

In 1988, DDIRconducted the first andonly internal analysis ofinforrnation in the 

Phase IV List. The result was a description of drugs with postmarketing commitments 

between 1972 and 1988, types of studies agreed to, and drug company compliance.4 

SCOPE AND METHODOLOGY 

We conducted our data collection and analysis between February and October of


1995. All data is from FDA’s Center for Drugs in Rockville, MD.


We focused on all new molecular entities (NMEs) approved from January 1, 1987 to


December 31, 1993, including NMEs approved under the accelerated review process.


We limited our analysis to NMEs to focus on drugs most likely to have postmarketing


commitments. New molecular entities are usually under 30 percent of all new drug


approvals, and they are prescription drugs which have never been marketed as a single


entity or as part of a combination product. We selected 1993 as the cutoff year for


drug approval because it left 2 years--from 1993 to 1995--to show if companies took


action on their commitments.


We used the most recent version (1993) of the Phase IV List to determine which of


the NMEs had phase iv commitments. Our identifications were verified by DDIR.


Since DDIR was planning to update the Phase IV List in 1995, it agreed to update the


status of the commitments in our study’s universe and send them to us in advance of


its completing the update for all its records, As a result, we were able to analyze the


status of commitments as of August 1995. The status categories we created for the


analysis are similar to those used by DDIR in 1988 but are somewhat more


explanatory. Both sets of status categories are in Appendix A.


We (1) quantified the number and type of postmarketing studies for NMEs; (2)


identified the pharmacologic-therapeutic classification of the NMEs; (3) categorized


each phase iv study according to its current status; and (4) when possible, determined


the length of time between a company’s submission of a study and FDA’s


determination of closure. The tables and figure in this report are the result of our


analysis of data in FDAs Phase IV List and Management Information System.


In addition to the above, we conducted 45 on-site interviews with FDA’s professional,


scientific, and technical staff in the areas of drug review, drug information resources,


document management, and computer design. The respondents included office


directors, division directors, drug reviewers, project management staff (also known as


consumer safety officers), drug information officers, and technical information


specialists. Ninety-three percent of the respondents were in the review divisions and


DDIR. Each of those respondents received the interview questions in advance. .


When we began our study there were 10 review divisions, each specializing in certain


drugs.5 We conducted interviews in 6 of the 10 review divisions, including the two


3

that have used the accelerated approval process. The Center for Drugs has since 

undergone a reorganization, and the number of review divisions has changed. 

Under separate cover, we gave the Center for Drugs our data analysis that serves as 

an extension of DDIR’s 1988 analysis but which is not directly related to findings 

herein. 

Our study was conducted in accordance with the Qualiy Standards for Inspections 

issued by the President’s Council on Integrity and Efficiency. 

4

FINDINGS


THE NUMBER OF NEW DRUGS WITH POSTMARKEmG Co~~ 

IS INCREASING. 

Percentage of Drum with Postmarketin~ Commitments 

While the annual percentage of new molecular entities (NMEs) with commitments 

varies, there has been an upward trend as shown in Figure A. In the 1970s, the 

highest percentage of such drugs was 33 percent compared to a high of 70 percent in 

the 1990s. 

Figure A 

76-


71-


66-


61-


56-


51-


a-


41-


36-


31


26 -


21


Annual Percent of NMEs With 

Phase IV Commitments, 1972-1993 

16 lb I 

11)
 , 1 1 I 1 t I 1 I 1 1 1 1 ! I , 1 1 , 1 I 

72 74 76 78 80 82 64 86 88 90 92 

Year of Approval 

More than half of the NMEs in our study period, 1987-1993, have postmarketing 

commitments. For these years, FDA approved a total of 169 NMEs including 2 under 

the accelerated approval process. Fifty-three percent, or 90 of the 169 drugs had 

commitments. Table 1 on the next page shows the percent by year. 

There was a total of 385 commitments for the 90 drugs, and an average of 4 

commitments per drug as shown in Table 2. Twenty-five of the 90 drugs had only one 

5 
commitment each. Of the 385 commitments, 35 were for the 2 NMEs approved under

the accelerated process. 

Table 1 

PHASE IV NMIZ.s*AS A PERCENTAGE OF TOTAL NMEs 

1987-1993 

! 

Year Total NMEs Phase IV NMEs 

I I 

1987 

I 

21 

I 

9 (43%) 

1988 20 6 (30%) 

1989 24 12 (50%) 

1990 23 12 (52%) 

1991 30 21 (70%) 

1992 25 13 (52%) 

1993 26 17 (65%) 

TOTAL 169 90 (53%) 

~Mti wtth phase w (postmarketmg) commitments 

Table 2 

AVERAGE NUMBER OF PHASE IV COMMITMENTS 

PER PHASE IV NME* 

1987-1993 

Year of Number of Number of Phase Average Number 

Drug Phase IV NMEs IV Commitments of Commitments 

Approval Per NME 

1987 9 

I 

37 4 

I 

1989 

1 

12 36 3 

1990 I 12 I 44 14 

1991 21 96 5 

1992 13 80 6 

Status of PostmarketinE Commitments 

The FDA data indicates that out of the 385 phase iv studies it asked companies to 

conduct, 150 are currently in progress and 146 were completed and submitted to FDA. 

6 
In other words, 296 studies, or77percent of thestudies, areeither inprogress or have


been submitted. Thetable in Appendti Bshowsthe status ofcommitments as of


August 1995 for all NMEs approved between 1987 and 1993, including NMEs


approved under the accelerated review process.


Fifty-seven percent or880f the 150studies inprogress are actually underway. The


remaining 62 studies break out as follows. One study is perpetual (i.e., an ongoing


surveillance study); 11 were halted; and 50 were completed but a report has not yet


been submitted to FDA.


Of the 146 studies that were submitted to FDA FDA reviewed 40 and found 39


acceptable and only 1 not acceptable. It appears to have taken FDA an average of 16


months to determine that 25 studies were acceptable. Dates that would have allowed


us to calculate an average time for all 39 studies are missing from the Phase IV List.


Nine of the 39 studies FDA found acceptable were studies for accelerated NMEs.


Five of these nine studies had determinations within 11 days to 21 months after the


date of the study’s submission.G


The FDA data does not indicate whether 106 out of the 146 submitted studies are


acceptable or not. Dates in the Phase IV Lz3t indicate that 30 of the 106 studies have


been without a determination for 2 to 7-1/2 years. Dates for the remaining 76 studies


are missing. One study for an accelerated NME has not had a determination for


almost 3 years.7


Thirty-five studies out of the total 385 have not yet begun, either because the company


(a) is postponing action until FDA reviews a supplement application, (b) did not agree


to conduct the study, or (c) plans to start the study in the future.


The FDA released companies from 23 of the 385 commitments. Twelve of these


released commitments were for drugs that are not marketed. For the remaining 11


studies in this status catego~, either (a) the studies were not feasible, (b) FDA’s


questions were answered by other studies, or (c) the reason for release was not clearly


explained in the Phase IV List,


There was no status information at FDA for 31 (eight percent) of the 385 studies. All


31 studies were for drugs approved from 1990 through 1993.


THERE ARE NO FORMAL STANDARDS AND PROCEDURES FOR 

MONITORING OR ESTABLISHING WHETHER A COMMITMENT IS MET. 

Review Divisions 

There are no formal Centerwide standards and procedures for monitoring 

postmarketing studies. Monitoring in the review divisions is up to individuals. 

Reviewers request postmarketing studies and review company submissions in their 

normal scope of work which is reviewing investigational new drug applications, new 
drug applications, and efficacy and labeling supplements. However, following-up on a


commitment and reviewing a phase iv submission are done as time allows and are


dependent on the commitment’s relative importance.


There is no formal mechanism for establishing whether a commitment is met and then


taking the commitment out of the pending section of the Phase IV List. There are


indications that in some cases someone has determined that phase iv studies were


acceptable and the commitments were met. For example, we found such


determinations for 39 of the 146 submitted studies. During our inteniews, most


review division respondents said the reviewer would, at least initially, decide whether a


commitment was met. However, no one has the formal responsibility of determining


and recording whether or not a company’s phase iv submission meets the commitment.


This may explain why data in the Phase IV List indicates that 106 submitted studies for


NMEs approved from 1987 through 1993 are still without determinations.


The review divisions have a procedure for advising drug companies of their


commitments around the time the new drug receives market approval. But, they do


not have a procedure for notifying a company when and whether their phase iv


submissions have been reviewed and accepted as fulfillment of the commitments.


While individual reviewers may relay this to drug companies, the records do not


indicate that such notification occurs.


Under the current monitoring which relies on individuals, reviewers may or may not


have ways of reminding themselves to contact a company about a commitment.


Reviewers either rely on reminders from project management staff, have their own


tickler system, or respond when a question arises. But reviewers and review division


directors alike believe the important studies are memorable and most companies meet


their commitments. Some respondents said relying on individuals within an informal


system could be a problem. They cited that a reviewer could leave the division and


remaining staff would not be aware of pending commitments.


While some review division respondents believe there should be guidelines regarding


phase iv monitoring, a greater number feel the current way things are done is good


enough given limited resources. Most of these respondents feel it is unnecessary to


have formal procedures because in most cases it is extremely difficult for FDA to


enforce compliance. They feel once the drug is approved, it is up to the company to


take the next step regarding their commitment.


Phase IV List 

While the Phase IV List is a tool the review divisions could use as a reminder of which 

commitments are pending, most reviewers and division directors were not aware of its 

existence. The office directors and project management staff knew of the Phase IV 

List but they did not make full use of it. 

8

The informality of phase iv tracking in the review divisions hampers DDIR in its 

ability to collect complete and timely phase iv data for the Centerwide F%ase IV L&. 

All sources of postmarketing data are located in review division documents. But 

because documents containing phase iv information are so numerous and are not 

indexed, identi&ing them is very time-consuming. In addition, there is no way for the 

tracking staff to be sure they have located all the relevant documents. It is only when 

documents indicate that a phase iv study fulfilled the commitment for a particular drug 

that DDIR removes it from the pending section of the Phase IV L&. 

Currently, there is no formal mechanism by which DDIR can receive feedback from 

the review divisions about the Phase IV List. Respondents in DDIR say updating the 

Phase IVList requires a great deal of work and they hope their product is useful. But 

without feedback from end-users they do not know if the Phase IV List is addressing 

user needs. 

WHILE THE Phase lVL& CONTAINS IMPORTANT INFORMATION, IT IS NOT 

A FULLY EFFECTIVE MANAGEMENT TOOL IN ITS CURRENT FORM. 

Important Information 

The Phase IV LA is the only instrument containing postmarketing commitment data 

on every drug (including NMEs) approved by the Center for Drugs. The Phase IV 

List is made up of one record for each drug with commitments, and the records are 

grouped according to the review division handling the drug. A record contains 

identifiers for the drug, the drug’s approval date, a narrative description of the 

commitments, a narrative description of the status, the name and date of the sources 

of information, and the name of a contact person in the review division. We were 

able to use the Phase IV List for most of our analyses. 

Timeliness and Completeness 

The Phase IV List is not updated on a regular or frequent basis, and certain data 

elements are not captured consistently. At the time of our interviews in mid-1995, the 

Phase IV List was already 2 years old. Many of the dates that would give management 

time frames for company or FDA activity were missing. Also, drugs approved under 

the accelerated review process were not identified as such. However, the timeliness 

and completeness of data is affected by the lack of standards and procedures for 

monitoring phase iv studies in the review divisions. Without procedures to keep 

abreast of commitments and to record that activity in a standard way, the same phase 

iv data cannot be captured consistently Centerwide. 

Format 

The Phase IV List does not contain summarizations of the numerous records. Two 

factors can explain the absence of summaries. One factor is that extended narratives 

are used in each record to describe a commitment and its status. The narrative 

9 
format makes it hard to see patterns or anomalies in the types of studies requested or 

in company compliance. While an individual can manually go through each record in 

the Phase IV List, create categories, and then count up items in the categories (as we 

did), this is very time-consuming. Furthermore, narratives are subject to interpretation 

and categorizing them for analysis is a matter of individual judgment. 

The second factor is the type of computer software in which the information is stored. 

Currently, the information is in a word-processing program which cannot automatically 

summarize data. Given the nature of the data, the need for quick turn-around 

reporting, and the need for ease of data entry and changes, we believe more 

convenient software, such as a relational database, may be more appropriate. 

THE FDA IS TAKING SOME STEPS TO IMPROVE THE TRACKING OF 

COMMITMENTS. 

In late 1994, the Center for Drugs established a work group to look at tracking 

problems. As of September 1995 at least two improvements were being implemented. 

The first is that postmarketing commitments will be formally listed in a standard letter 

to the company. This will reduce the number of documents DDIR staff have to 

research in order to identify a new commitment. The second improvement is that the 

Phase IV List will be transferred from its current word-processing program to a 

database program. 

The Center plans to continue its efforts to improve the tracking system. One goal is 

to have the Phase IV List on-line for greater accessibility. Another is to make 

company submissions more easily identifiable for tracking purposes. 

10

RECOMMENDATIONS 

We recognize that FDA has limited resources and its priority is the review of 

premarketing drug studies. This is especially true with the shorter time frames FDA 

has to review premarketing studies and new drug applications under the Prescription 

Drug User Fee Act of 1992 (P.L. 102-571). Wealsorecognize that the Center for 

Drugs is interested in improving the data management system for postmarketing 

commitments and has started to do so. Since FDA work groups are currently meeting 

to improve tracking, this is an opportune time to make data collection less labor 

intensive and to create a system that meets the informational needs of senior 

management in the Center for Drugs. 

As our report indicates, FDA is requesting postmarketing studies for an increasing 

number of new drugs, and most of the commitments are long-term in nature. 

Furthermore, for drugs approved under the accelerated review process, FDA can 

move to withdraw the drugs from the market if the postmarketing studies are not 

completed with due diligence. 

Until the monitoring system is made less dependent on individual memory, FDA risks 

losing track of the commitments. Unless time frames are tracked and monitored, 

FDA cannot uniformly determine diligence on the part of drug companies. Until the 

commitments are monitored and tracked systematically, FDA is not availing itself of a 

management tool with which to assess the appropriateness of its requests and plan for 

the future. 

Lastly, FDA’s requests for postmarketing studies put added responsibilities on the 

drug companies. Therefore, it is reasonable to expect FDA to determine whether or 

not the studies fulfill the commitments and to noti~ the companies of the 

determination. 

We recommend that FDA: 

�	 estabtih standkrds, procedures, or guidelines for individuals responsible for canying 

out trwnito~g and tracki%gobjectivm; and 

F	 establikh accountability for monitoring tracking and bringing com”tments to 

cihsure. 

Below are some ideas for FDA to consider in order to streamline data management: 

.� Assign authority to specific personnel for carrying out management objectives. 

Establish a coordinator with authority to (1) represent all offices involved in 

monitoring, tracking, and bringing commitments to closure; and (2) ensure that 

there is a quality control system for the commitments database. 

11 
.� Reduce thenumber ofdocuments that have to beresearched in order to 

identify the status of commitments; and use standard notations on these 

documents to signify how each document affects the status of the commitment. 

.� Establish descriptive categories for (1) types of studies requested and (2) status 

of commitments. 

.� Put the database of postmarketing commitments on-line in the review divisions 

and allow authorized individuals to update records as soon as an action occurs 

or a determination is made. 

FDA COMMENTS 

The FDA agrees with this report’s findings and recommendations. A draft directive 

that establishes procedures and provides guidance is undergoing review within CDER 

is expected to be finalized by the end of June 1996. (Appendix C contains FDA’s 

comments in full.) 

4.-I 

1A 
ENDNOTES


1. Accelerated approvals are possible in only two situations: 

(1)	 When approval can be based on a drug’s effect on a surrogate endpoint 

that is reasonably likely to predict clinical benefit, or on a drug’s effect 

on a clinical endpoint other than survival or irreversible morbidity. 

After approval, the a~plicant would be required to complete adequate 

and well-controlled clinical studies alreadv underwav at the time of 

aumoval, to confirm the predictive value of the surro~ate end~oint or 

other indicator. (21 CFR 314.510) 

(2)	 When FDA determines that an effective but highly toxic drug can be 

used safely only if distribution or use is modified or restricted. (21 CFR 

314.520) 

2. Closure is defined by FDA’s Division of Drug Information Resources as: 

(1)	 the drug product was not marketed or it was withdrawn from the market 

(closure would be void if the drug were re-marketed); 

(2) the drug company was released from all phase iv commitments by FDA; 

(3)	 the research was terminated for reasons mutually agreed to by the drug 

company and FDA or 

(4)� the research was completed and accepted by FDA as scientifically valid 

and in fulfillment of the commitment(s). 

3.	 Definition of new molecular entity: The active moiety (component or molecule) has 

not previously been approved or marketed in the United States by any drug 

manufacturer either as a single entity or as part of a combination product. 

4.	 The analysis was performed by staff in the Division of Drug Information Resources, 

Office of Management, Center for Drug Evaluation and Research. It was used in 

papers presented at (1) the 23rd Annual Meeting of the U.S. Public Health Service 

Professional Association in Scottsdale, AZ, May 1988, and (2) the 25th Annual 

Meeting of the Drug Information Association in Boston, ~ June 1989. 

5.� Review Divisions (as of May 1995): (1) Cardio-Renal, (2) Neuropharmacological, (3) 

Oncology and Pulmonary, (4) Medical Imaging and Surgical-Dental, (5) 

Gastrointestinal and Coagulation, (6) Metabolism and Endocrine, (7) Anti-infective, (8) 

Anti-Viral, (9) Topical Drug Products, and (10) Pilot Drug Evaluation Staff. 

6.	 We used the following method to calculate the time it took FDA to review and 

determine that studies were acceptable: Out of the 39 studies found acceptable, 25 

had submission and determination dates. We calculated the difference between the 

dates. The time ranged from 5 days to nearly 7 years, for an average of a little over 16 

months. 

13 
7.	 We used the following method to calculate the time that studies have been without a 

determination: Out of 106 studies without a determination, 30 had submission dates. 

We calculated the difference between those dates and August 31, 1995 which was when 

the studies’ status was most recently updated. The time periods for the 30 studies 

ranged from 2 to 7-1/2 years. 

14

APPENDIX A


CATEGORIES FOR THE STATUS OF POSTMARKETING CO~NTS 

On the left are the 15 categories we established in order to analyze status information 

in FDAs Phase IV Postapproval Research List. On the right are the eight categories 

established by FDA in 1988. 

See Appendix B for the number of commitments in each status category as of August 

1995. 

OIG -1995 

StudyNot Begun 

1.1Will begin in the future 

1.2 Company did not agree to 

conduct study 

1.3 Company awaiting approval 

of a supplement application 

studyinProgrW 

2.1 Underway 

2.2 Completed but not yet 

submitted to FDA 

2.3 Halted 

2.4 Perpetual 

Study Submittedto FDA


3.1 Accepted by FDA


3.2 Not accepted by FDA


3.3 No determination made


by FDA


ReleasedfromCommitment


4.1 Drug not marketed


4.2 Questions answered by


other studies


4.3 Reason unclear


4.4 Study not feasible


statusunknown 

5.1 No information 

FDA -1988 

A. Study not begun or status could 

not be determined 

B. Study in progress 

C. Study is perpetual 

D. Study submitted and FDA 

determined commitment is met 

E. Study submitted and was 

rejected by FDA 

F. Study submitted and FDA has not 

determined if commitment is met 

G. Company released from 

commitment 

H. Study not completed due to drug 

not being marketed 

A-1

APPENDIX B


NUMBER OF PHASE lV COMMHMENR IN EACH STATUS 

STATUS AS OF AUGUST 1995 \ YEAR OF DRUG APPROVAL II 

StudyNot Begun I ’87 

1.1 Will begin in future 11 

1.2� Company did not agree to 3 

conduct study 

1.3 Company awaiting approval of O 

supplement 

study in Progress 

2.1 Underway 

2.2� Completed but not yet 

submitted to FDA 

2.3 Halted 

2.4 Perpetual 

StudySubmitted 

3.1 Accepted by FDA 

3.2 Not accepted by FDA 

4.1 Drug not marketed 

4.2� Question answered by other 

studies 

4.3 Reason unclear 

4.4 Study not feasible 

status unknown 

I 

I 1 

10 

I o 

I 

\ 10 

11 

18 

1 

o 

1 

10 

I 

B-1

APPENDIX C 

COMMENTS FROM THE FOOD AND DRUG ADMINISTRATION 

c-1 
--

*4+’ 

*5W’OC,* ‘

% PubIii HealttI Service * 

:

-Y DEPARTMENT OF HliiMTH & HUMAN SERVICES Foodand Drug Administradon 

:

z 

%

%‘+

$

2

+.,w Memorandum 

Date .~ 28D%

From 

Deputy Commissioner for Management and Systems (Acting) 

Subject Food and Drug Administration’s (FDA) Comments on the OffIce of Inspector 

General’s (OIG) Draft Report, “Postmarketing Studies of Prescription Drugs, ” 

To (OEI-03-94-O0760), ACTION 

Deputy Inspector General for Evaluation and Inspections 

We reviewed the referenced draft report and prepared the attached comments. 

The FDA’s Center for Drug Evaluation and Research has agreed with the report’s 

recommendation and is beginning to implement it. 

If your staff has any questions, please have them contact Jim Dillon on (301) 443-6392. 

Attachment 

[C-2] 
COM MFNTS OF THF FOO17 AND DRUG A13MIN ISTRATION (FDA) ON THF OF FICF 

OF INSPECTOR GFNFRAI (OICJ) DRAF T RFPORT, s! OSTMARKF TING STUDIFS OF 

PRFSCRIP TION DRUGS. ” OFI-03-94-00760, FFBRUAR Y 1996 

General Commen& 

We appreciate the opportunity to review and comment on the referenced OIG draft report. 

The FDA’s Center for Drug Evaluation and Research (CDER) agrees with the report’s 

findings and recommendation. CDER wishes to express its gratitude to the OIG evaluators 

for considering their comments and suggestions on the working draft report. 

OIG RecQmmendatior’1 

We recommend that FDA establish standards, procedures, or guidelines for individuals 

responsible for carrying out monitoring and tracking objectives; and, establish 

accountability for monitoring, tracking, and bringing commitments to closure. 

FDA comment 

FDA concurs. CDER has formed a working group that is canying out the intent of the 

recommendation. This working group has drafted a directive that establishes procedures 

and provides guidance for resolving various issues. The draft directive tentatively entitled, 

“Tracking Phase 4 Commitments,” is undergoing review within CDER and should be 

finalized by end of June. CDER expects implementation shortly thereafter. The directive 

will become part of the Manual of Policies and Procedures and will be available for use by 

all CDER employees. 

[C-3]