. 

PERSPECTIVES OF DRUG


MANUFACTURERS


ABBREVIA TED NEW DRUG APPLICA TIONS 

t\lVICE$' CtJ' 

'0 

1t"dIQ 

OFFICE OF INSPECTOR GENERAL 

OFFICE OF EV ALVA TION AND INSPECTIONS 

FEBRUARY 1990 
PERSPECTIVES OF DRUG


MANUFACTURERS


ABBREVIATED NEW DRUG APPLICATIONS


Richard P. Kusserow 

INSPECTOR GENERAL 

OEI-12-90-00770 FEBRUARY 1990 
... , 

EXECUTIVE SUMMARY 

PURPOSE 

The purpose of this report is to describe the perspectives of selected drug manufacturers 

regarding the Food and Drug Admnistration s (FA) review of market applications for 

generic products. This is one of several reports being issued by the Offce of Inspector 

General (OIG) in connection with FDA's approval of generic drgs. 

This report contains the accounts of manufacturers regarding their experiences and opinions of 

FDA' s review of market applications for generic products. For maximum benefit, the reader 

should consider this information along with the results of independent analysis conducted by 

the OIG regarding FDA's approval of generic products. 

BACKGROUND 

Under the Federal Food, Drug, and Cosmetic Act ("the Act ), as amended, the FDA, U. Deparent of Health and Human Services, is responsible for approving new drgs before 

they can be marketed in the United States. The Act defines a new drg as " any drg (that).. .is not generally recognized...as safe and effective under the conditions prescribed 

recommended, or suggested in the labeling.... " (21 U. C. section 321.) The FDA is charged 

with ensurng that the drgs it approves are both safe and effective for its intended uses. 

New drgs include both "innovator" drgs and "generic" drgs. Innovator drgs, or drgs newly discovered, are generally developed under patent by the manufactuer. Generic drgs, 

or copies of drgs curently on the market, are developed by competitors after a patent has 

expired, or if the innovator patent wil not be infringed or is invalid. Unless a suitability 

petition has been approved exempting the manufacturer from this requirement, generic drgs must contain the same active ingredients and be manufacturd in the same strength and dosage 

form as the innovator drg. 

METHODOLOGY 

To assess manufacturers ' perspectives regarding FDA drg approval, the OIG invited 24 firms 

to discuss their experiences with, assessments of, and suggestions for improving FDA drg approval. All 24 firs agreed; the firms paricipating in the study are listed in appendix A. 

Of the 24 firms listed, representatives of 16 discussed their professional experiences with the 

generic drg approval process. The results of those discussions are described in this report. 
FINDINGS 

Virally all of the manufacturers we interviewed consider FDA effective in 

ensuring that drugs entering the marketplace are safe and effective. At the

same time, the respondents were generally critical of FDA's drg approval process for generic products-much more so than the respondents we 

interviewed concerning FDA's approval of innovator drgs. 

For each of the following, a majority of respondents in our surey believed that: 

FDA is ineffective in ensuring that safe and effective drugs enter the market in a timely 

manner; 

FDA provides inadequate guidance on how to develop and submit a successful ANDA; 

communication between the Agency and industry regarding ANDAs is often inadequate 

ineffective, or untimely; 

FDA is inconsistent when reviewing ANDAs and making decisions; 

FDA provides insuffcient justifcation for the decisions it makes on ANDAs; 

it is difcult to appeal decisions made by the Agency on ANDAs; and 

there is inadequate stafng at FDA, or ineffcient use of staff to deal with the current 

workload of ANDAs. 

Respondents disagreed on whether two recent FDA initiatives, establishing the Offce of 

Generic Drugs and creating an FDA Ombudsman, would help address the concerns they discussed. Respondents did believe, however, that FDA should continue sampling drgs on the market, to ensur the quality of drgs sold to consumers. Finaly, respondents suggested changes in FDA generic drug approval. 
AGENCY COMMENTS,


The OIG briefed FDA offcials on the findings and manufacturer recommendations from this 

surey. The FDA offcials provided a number of clarfying technical comments to the report. 

A copy of the Agency s comments regarding the results of the survey and our briefing are 

attached at appendix B. 
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . 

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

TABLE OF CONTENTS 

EXECUTIVE SUMMARY 

INTRODUCTION 

Purpose . . . . . . . . . . . . . . . . . . . . I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1


Background. . . . . . . . . . . . . 1 

Methodology 

FINDINGS 

ENDNOTES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

APPENDIX A 

LISTING OF PARTICIPANTS. . . . . . . . .. A - 1 

APPENDIX B 

AGENCY COMMENTS.. .. .. .. .. .. .. .. .. .. .. .. .. .. . .. .. .. .. B­
...

INTRODUCTION


PURPOSE 

The purose of this report is to describe the perspectives of selected drg manufacturers 

regarding the Foo and Drug Admnistration s (FA) review of market applications for 

generic products. This is one of several reports being issued by the Office of Inspector 

General (OIG) in connection with FDA's approval of generic drgs. 

This report contains the accounts of manufacturers regarding their experiences and opinions of 

FDA' s review of market applications for generic products. For maximum benefit, the reader 

should consider this information along with the results of independent analysis conducted by 

the OIG regarding FDA's approval of generic products. 

BACKGROUND 

Under the Federal Foo, Drug, and Cosmetic Act (lithe Act ), as amended, the FDA, U. Deparent of Health and Human Services, is responsible for approving new drgs before 

they can be marketed in the United States. The Act defines a new drg as " any drg 

(that).. .is not generally recognized...as safe and effective under the conditions prescribed, 

recoriended, or suggested in the labeling...." (21 U. C. section 321.) The FDA is charged 

with ensurng that the drgs it approves are both safe and effective for its intended uses. 

New drgs include both "innovator" drgs and "generic" drgs. Innovator drgs, or drgs 

newly discovered, ar generally developed under patent by the manufactuer. Generic drgs, 

or copies of drgs currently on the market, ar developed by competitors after a patent has 

expird, or if the innovator patent wil not be infringed or is invald. Unless a suitability 

petition has been approved exempting the manufacturer from this requirement, generic drgs must contain the same active ingredients and be manufactured in the same strength and dosage 

form as the innovator drg. 

Until its patent expires, the manufacturer of the innovator drg enjoys a virual monopoly in 

manufacturg and sellng its patented invention. Manufacturers of the generic version of the 

drg generaly price their product lower than the innovator firm s product to compete with 

other manufacturrs producing generic versions of the drg and the innovator firm. The lower 

cost of generics can make them attractive to cost-conscious health care consumers and 

third-pary payors. 
The 1984 Drug Price Competition and Patent Restoration Act 

In 1984, the Congress passed the Drug Prce Competition and Patent Restoration Act, which 

amended the Act. Among other things, this law stramined the requirements for approving 

generic products. 

Pror to passage of the Drug Prce Competition and Patent Restoration Act, manufacturers 

seeking to market a generic version of drg marketed between 1938 and 1962 could submit an 

abbreviated application to FDA to obtain approval of their product. Manufacturers seeking 

approval of generic versions of drgs marketed after 1962 were requird to submit

application to FDA to demonstrate that the active ingredients in their product were both safe


and effective, based either on their own clinical trals (described in a New Drug Application


(NDA)) or on the basis of published reports of well-controlled studies (described in a "paper
 NDA"


The Drug Prce Competition and Patent Restoration Act alowed manufacturers to submit an 

Abbreviated New Drug Application (ANDA), rather than an NDA or "paper NDA" to obtain 

approval of the generic version of a drg marketed after 1962, as well as those marketed 

between 1938 and 1962. Since the generic contais the same active ingredients previously 

demonstrted safe and effective to the FDA by the innovator, Congrss reasoned that there 

was no need for retesting. Rather, Congress required manufacturers of generic drgs to 

demonstrate that their product worked in the same way in the body as the innovator

drg-in other words, that it is "bioequivalent. 

The ANDA differs from the NDA in that the manufacturr is not required to conduct and 

report results of animal and human clinical trals to demonstrate the drg s safety and 

effectiveness. Instead, the manufacturer must include data in the ANDA to demonstrate that 

(1) the generic drg contans the same active ingredients as the innovator product; (2) the 

generic drg is identical in strength, dosage, and route of admnistration as the innovator 

product; and (3) the generic drg is bioequivalent to the innovator product. l (21 U. 

355G)(2)(A). Because the manufacturer of a generic drg does not have to conduct the more 

costly and time consuming clinical trals required of the innovator fInn, ANDAs are less 

costly for manufacturers to prepare and submit to FDA than NDAs. 

Not surprisingly, FDA experienced a substantial surge in the number of ANDAs submitted to 

the Agency after passage of the 1984 law. According to FDA testiony before the 

Subcommttee on Oversight and Investigations, Committee on Energy and Commerce, the 

Agency has seen a theefold increase in number of both original ANDAs (those ANDAs 

submitted for the first approval of the manufacturer s generic) and supplemental ANDAs 

(those AND As submitted to obtain approval in a change in manufacturing, labeling, or other 

aspect of the production and marketing of the drg) submitted to the Agency since 1984. 
Submitting and Reviewing ANDAs 

When manufacturers submit an ANDA for FDA' s review and approval, it must contain certain 

information. Recently FDA has issued a Proposed Rule which would implement the 1984 

law. The FDA proposed that ANDAs submitted to the Agency include, among other things, 

the following: (1) an application form, containing identifying data such as the name and 

address of applicant, a statement of how the drg wil be marketed, and the signature of an 

authorized offcial; (2) a discussion of the basis for the ANDA; (3) a discussion of conditions 

of use; (4) a listing of active ingredients of the drg; (5) a discussion of the route of

admnistration, dosage form, and strength; (6) bioequivalence data; (7) a chemistr, maimfacture, and controls section, describing the composition, manufactur, and specification 

of the drg substance and the drg product; and (8) proposed labeling. (54 Fed. Reg. 28,872 

28,921 (1989) (to be codfied at 21 CFR 314.94) (proposed July 10, 1989). 

Once an application is submitted, FDA has 180 days to review an application and send the 

applicant either an "approved" letter, an "approvable" letter, or a "not approvable" letter. This 

180-day period is referrd to as the "review clock." 

An "approval" letter means a wrtten communication to the application from FDA approving 

an application. Only after receiving an "approval" letter from FDA may a manufacturer 

market the drg that is the subject of the application. An "approvable" letter means a wrtten 

communication statig that the Agency wil approve the application if certain conditions are 

met (such as changes in the manufacturing controls). A "not approvable" letter means that the 

Agency does not consider the application approvable due to deficiencies identified in the 

application. 

During review, communication takes place between FDA and the applicant. Industr officials 

may request meetings with the Agency if such requests are made in advance and an agenda is 

agreed upon. The FDA offers an "end-of-review" conference to applicants after they receive 

an "approvable" or "not approvable" letter to discuss what steps the manufacturer must take to 

get the application approved. 

Once an application is approved, certain changes may be made by the manufacturer in the 

course of manufacturing and marketing the drg. Depending on the type of change made 

(e.g., changes in drg substance or drg product that affect performance versus editorial 

change in labeling) the manufacturer must either submit (1) a supplement requirng FDA approval before changes can be made; (2) a supplement describing changes to FDA that have 

aleady been made; or (3) a description of the types of changes made in the next annual report 

to the Agency. Only information relating to the change must be included in the supplement. 
Recent Concerns Regarding FDA Review of ANDAs 

In the past year, substantial ,criticism has been directed at the FDA generic drg approval 

process. In 1988, the Subcommttee on Oversight and Investigations, Commttee on Energy 

and Commerce, U.S. House of Representatives, based on information it received from a 

generic drg manufacturer, asked the Offce of Inspector Genera (OIG) and the United States 

Attorney to conduct an investigation into allegations of favoritism on the par of certn FDA 

offcials responsible for reviewing and approving ANDAs. The OIG' s investigation resulted 

in corrption charges and criminal convictions of three former FDA employees, three generic 

drg company offcials, and two generic drg fis. 

In the wake of the corrption charges, FDA began to target, review and test generic drg products and related ANDAs in an effort to ensure the integrty of these products. This review 

disclosed manufacturing deficiencies and fraud involving a number of generic drg firms and 

their products. Where fraud appeared likely, the FDA with the assistace of the OIG initiated 

additional criminal investigations which ar continuing. 

In August 1989, the OIG completed an audit of the generic drg approval program to identify 

weakesses and vulnerabilties in the system which gave rise to the problems discussed above. 

The OIG audit team found, among other things, that FDA lacks adequate guidelines to ensure 

the consistent review of applications and needs a quality control system to ensure that 

applications are properly reviewed and that generic drg fIrms receive equitable treatment. 

Thrughout 1989, there was an unusualy high level of media and press attention devoted to 

concerns about the generic drg approval process. Reports appearng in major national 

newspapers and the pharaceutical trade press in August and September 1989 (the time of our 

survey) focused on the corrption allegations and subsequent investigations undertaken by the 

FDA and OIG; the OIG audit fmdings and recommendations; and FDA' s response, described 

below, which included procedural and organizational changes and product testing and site 

inspections affecting a large segment of the generic industr. 

FDA Response to Concerns 

In response to allegations of favoritism publicized by the Subcommittee, FDA conducted an 

internal assessment of the ANDA process in 1988. Among the reforms initiated as a result of 

this review were new procedures limiting and formalizing contacts between industr and 

reviewers. Industr representatives are no longer allowed to make unannounced visits; 

meetings are now held away from reviewer work space; and Consumer Safety Offcers , rather 

than reviewers, answer cals from firs concerning the status of applications. 

In 1989, FDA took additional steps to corrct the opportunities for abuse in approving generic 

drgs and to reestablish public confidence in the safety of generic drgs. These steps included: 
establishing a new Offce of Generic Drugs under a new management team; 

creating an ombudsman in the Office of Commssioner to mediate disputes 

between FDA and the firms it regulates; 

targeting, reviewing and testing generic drg products and related ANDAs; and 

conducting an internal audit of the generic drg approval process in accordance with the Federal Managers ' Financial Integrty Act of 1982 (FMFIA). 

METHODOLOGY 

To assess manufacturers ' perspectives regarding FDA drg approval, the OIG invited 24 firms to discuss their experiences with, assessments of, and suggestions for improving FDA drg approval. All 24 firs agreed; the firms paricipating in the study are listed in appendix A. 

Of the 24 firms listed, representatives of 16 discussed their professional experiences with 

the generic drug approval process. The results of those discussions are described in this 

repor . 

Previous work done by the Offce of Planning and Evaluation, Offce of the Commssioner FDA, formed the framework for conducting this study. Pror studies titled Agency Impact Analyses (AlAs) examned the effect of FDA practices and procedures on a regulated industr by collecting and analyzing the perspectives of executives of some of the regulated firms. 

About the Interviews 

The firms invited to paricipate in the OIG interviews were selected to ensure approximately 

equal distrbution of firms experienced in generic drg and new drg approval. Respondents from seven fmns had experience with both processes. Manufacturers interviewed were 

concentrated in New York, New Jersey, and Pennsylvania, although interviews also took place 

with manufacturers in Colorado, Delaware, Illinois, Ohio, and West Virginia. 

Generaly interviews were conducted with the chief executive offcer, president, and/or regulatory afais director and staff of the fmns selected. A total of 49 individuals were 

interviewed. The 24 firms visited durng the course of our study had by their own estimation submitted in excess of 450 investigational new drg applications, 150 new drg applications and well over 1,00 abbreviated new drg applications and abbreviated antibiotic drg applications in the past 5 years. 

Interviews were conducted in August and September, 1989. To conduct the interviews, all of 

which were conducted in person, the OIG used a strctued discussion guide askig respondents about their experiences and opinions regarding varous aspects of application 
review and approval. Respondents were asked how they view guidance from the agency, 

communication with the agency, review of applications by the agency, and decision-making 

by the agency. 

Because the manufactuers selected do not necessarly reflect a representative sample of all 

manufacturers, their views mayor may not constitute a consensus opinion of all 

manufacturers. In addition, the OIG study team did not attempt to veriy or validate the 

legitimacy of claims or concerns expressed by the fIrms. Consequently, we do not 

recommend specific action to the FDA based on the results of these interviews. Rather, we 

have presented the recommendations made by the manufacturers interviewed for FDA' 

information and consideration. 
FINDINGS 

Virually all of the manufacturers we interviewed consider FDA effective in 

ensuring that drugs entering the marketplace are safe and effective. At the 

same time, the respondents were generaly critical of FDA's drg approval 

process for generic products-much more so than the respondents we 

interviewed concerning FDA's approval of innovator drgs. 

For each of the following, a majority of respondents in our surey believed that: 

FDA is ineffective in ensuring that safe and effective drugs enter the market in a timely 

manner; 

FDA provides inadequate guidance on how to develop and submit a successful ANDA; 

communication between the Agency and industry regarding ANDAs is often inadequate, 

ineffective, or untimely; 

FDAis inconsistent when reviewing ANDAs and making decisions;


PDAprovides insuffcient justifcation for the decisions it makes on ANDAs;


it is difcult to appeal decisions made by the Agency on ANDAs; and


there is inadequate staffng at FDA, or ineffcient use of staff to deal with the current


workload of ANDAs. 

Respondents disagreed on whether two recent FDA initiatives, establishing the Offce 

Generic Drugs and creating an FDA Ombudsman, would help address the concerns they 

discussed. Respondents did believe, however, that FDA should continue sampling drgs on 

the market, to ensur the quality of drgs sold to consumers. Finaly, respondents suggested 

changes in FDA generic drug approval. 

Each of these findings is discussed in more detail below. 

Respondents believe that FDA is effective in ensuring that drugs entering the marketplace 

are safe and effective. 

Fifteen of the 16 respondents who had experience with the generic drg approval process felt 

that FDA does an effective job in ensuring that drgs entering the market are safe and 
, 

, 

effective. Most of the respondents felt that such assurance was FDA's charer or mandate and that the Agency took no shortcuts in meeting its obligations. "Lok at the record," one manufacturer said. "With very few exceptions there have been no catastrophes. I don 

quarel with the end result," said another respondent just the way they get there. Respondents viewed FDA as tang a "no risk" policy: "the process rewards people for creative ways of assurng that the most strgent standards ar (imposed). 

For these reasons, most respondents (10) also believe that FDA review of ANDAs is thorough. 

The review is very detailed " said one respondent. "Reviewers are known for lookig for uncrossed t s and undotted i' " Other respondents saw the results as proof of thoroughness: So far (we) haven t found anything that was grossly missed. 

At the same time, respondents belreve that FDA is ineffective at ensuring that safe and
 effective drugs enter the marketplace in a timely manner.


Ten of 16 respondents thought that FDA was ineffective in ensuring that safe and effective


drgs enter the marketplace in a timely manner. Many attbuted this lack of timeliness to
 FDA's emphasis on safety: " Timeliness isn t one of FDA' s priorities," said one respondent. (FDA) is much more concerned with (keeping) a bad product (off) the market... The


commssioner says one priority is to cut the backlog but reviewers are more concerned with


makng a mistake. " Some respondents argued for a change in orientation by the agency:


FDA should help us get approval, not prevent or deter manufactuers (from getting our
 applications approved)," said one respondent.


Some respondents were perplexed that certn pars of the review that appear straightforward
 to them take, in their view, too much time. For example, the manufacturers we interviewed


were critical of the time required to review and approve labels.


Respondents believe that the Agency provides inadequate guidance on how to develop a


successful ANDA.


Nine of the 16 manufacturers interviewed believe that the guidance provided to them by the 

Agency on how to develop a successful ANDA is "inadequate." Manuf?Ctuers expressing this opinion argued that they needed more direction from the Agency in the form of standards 

and specifications before developing their ANDA. One respondent echoed the sentiments of 

several others when he said We need the blueprint ahead of time. " Several manufacturers pointed to the standards and specifcations that exist for approving antibiotics as an 

of the kind of guidance they would like to see for all generic products: " example 

We want to see the codfication of specifications and required method of testing, as it exists for antibiotics. If we 

have to meet a certai standard of testing, tell us what the stadard is in advance of our 

submission and work.


Even those respondents who viewed FDA guidance as adequate voiced concerns regarding 

FDA' s inconsistency in applying the guidance. As one respondent said, "The guidance is 
, 

adequate, just inconsistent...You ve got a regulation that is three sentences long that says, 

You ll do it right,' and hundrds of people interpreting what that means." Another respondent 

who considers FDA guidan e adequate added, "The regulations are pretty 

straightforward-but there are different requirements from diferent (FDA) divisions. 

Sometimes you wouldn t believe it s the same Agency. 

For this reason, more respondents said that they rely primarly on previous experience 

developing ANDAs (8) than regulations (3), guidelines (1), or discussions with FDA staff (3). 

Several respondents said that they review FDA comments made to previous submissions, 

evaluate those comments, and remember them in makng their next submissions. These 

respondents added that they specifically tailor their submission to the division and reviewers 

assigned to the application. "Requirements var ,from reviewer to reviewer " one respondent 

claimed. Another respondent said he said he considered guidelines irelevant: "Ignore the 

guidelines and listen to what the individual chemist wants. 

Respondents believe that communication between the Agency and industry is often 

inadequate, ineffective, or untimely. 

Most manufacturrs (10) felt it is diffcult to fmd out the progrss of review or the status of an 

ANDA. Respondents expressing this opinion were frustrated by their lack of access to 

reviewers as a result of the new FDA policy requirg applicants to contact Consumer Safety 

Officers (CSOs) rather than reviewers concerning their application. " s turning into a bad 

scene; what used to be a relatively informal process (of caling reviewers directly) is now very 

formal (caling Consumer Safety Offcers)." One respondent said, "We can t call reviewers, 

we can t meet with them... .It s impossible to fmd out the status of a review. We re told I can 

only tell you the review is in progress.' Consumer Safety Officers are hard to reach , don 

return phone calls, and don t have a lot to say to us when they do. 

Several respondents believed that communication has deteriorated in recent months. "In the 

past (communication) was spotty," said one respondent. "Now communication is nonexistent. 

s lie somebody put up a brick wal around the Agency." Another respondent echoed this 

sentiment: "(Finding out the status and progress of review) was very easy before the scandal. 

Now it is very diffcult. 

Most of the manufacturers we interviewed had not attended "end-of-review" conferences in 

connection with ANDAs, although several had done so in connection with NDAs. Many 

the manufactuers were not aware that such meetings took place in connection with generic 

drg review. However, some of the manufacturers we interviewed had requested meetings 

with FDA at varous stages in the review of their applications; one respondent thought these 

meetings were "granted reluctantly" and another who had requested numerous meetings said 

he often received the response, "Do you want a meetig or do you want an approval?" 
Two manufacturers specifcally expressed concern regarding their inabilty to obtain 

information from FDA on the "alert list," which they described as a listing of manufacturers 

with outstanding deficiencies in manufacturing plants. According to these respondents, a 

manufacturer s presence on the FDA' s "alert list" means that no ANDAs could be approved 

for that company until deficiencies were corrected. However, these offcials maintained that 

companies on the "alert list" were not told they were on the list and given an opportnity to 

appeal the decision or move to quickly correct their deficiencies. 

Respondents believe that FDA is inconsistent when reviewing ANDAs and making its 

decisions. 

The lack of consistency in review was a foremos concern of many respondents. Twelve of 

the 16 respondents considered FDA review of applications inconsistent, citing differences 

between reviewers and divisions in the amount and nature of information they require and the 

importance they attach to varous aspects of the application. Respondents sharng this opinion 

believed that inconsistency occurred due to a lack of standard operating procedures for 

reviewers to use in assessing ANDAs. "Different reviewers have diferent requirements, they 

emphasize different things," said one respondent. "It becomes a game." Another respondent 

thought that "you could submit the same fie to two diferent reviewers and get two different 

decisions (based on their review)....Different decisions ar made on diferent applications with 

the same data." Some respondents blamed this inconsistency on poor management of 

reviewers. "FDA runs from the bottom up, not from the top down " one respondent stated. 

A majority ofrespondents (10) also believed that review of ANDAs was not well-planned. 

These respondents complained that they would receive a deficiency letter with certain 

problems identified and then receive subsequent deficiency letters listing more FDA concerns. 

These respondents were frstrated that all deficiencies were not identifed sooner in the 

process. In addition, some respondents thought that FDA contrdicted or repeated itself by 

asking the same question in one letter that it did in another; or by asking a question the 

manufacturer believed was obviously addrssed in the application; or by askig for a change 

and later asking for another change back to the original position. In paricular, manufacturers 

we interviewed pointed to chemistr review and labeling review as inconsistent and 

il-planned. 

Respondents believe that the Agency provides insufficient justification for decisions it 

makes on ANDAs. 

Most respondents (11) have been dissatisfied with the decisions FDA has reached regarding 

the ANDAs they have submitted. Respondents expressing this view thought that " 

justification was presented for decisions" or "the decisions are very close to being arbitrar 

and unrasonable." Several respondents emphasized that they believe some FDA decisions on 

ANDAs lack scientific merit: "Small percentage differences can result in one application 

being approved and another (deemed) not approvable. Is (a certn percentage) goo and 

(another percentage) bad? FDA can t say. " Another respondent said, "We don t argue with 
(the justification), ' Science dictates you have to do this.' But that s not what we hear.... (We 

hear), ' Because I said so. 

Some respondents were also unclear about how policy decisions were made in FDA, or what 

constituted Agency policy. They are unhappy that "changes in policy ar transmitted in an 

ANDA letter" where "we have no chance to comment on it." One respondent said, "FDA is 

implementing new requirments without input from industr, and some appear to lack 

scientific merit. When these requirements (are communicated), it is diffcult to tell what 

represents Agency policy and what represents an individual reviewer s ' whim. ' Nor is it easy 

to tell if the new requirment is the result of a passing conversation with an academician or an 

intensive 5-year study.


Respondents consider it difficult to appeal decisions made by the Agency on ANDAs. 

Few respondents had ever formally complained to the Agency regardig the issues they 

discussed with us or concerning specifc problems with specific ANDAs. These respondents 

had not done so priary because they feared retaiation, believing "FDA has a long. 

memory." One respondent who had made a complaint to the Agency had felt that his 

company paid a price: "While the submission was approved, it created future problems 

because of the resentment that somebody went over (the reviewers ) heads to the director. 

Other respondents who complained or appealed decisions were frustrated by the Agency 

response. "The meeting (held) as a result of our complaint was not open but defensive," said 

one respondent. Another respondent said that his company had not "received a response up 

the ladder." Yet another offcial lamented, "There really is no tre appeals process. 

Respondents believe that there is inadequate staffng at FDA, or inefficient use of staff, to 

deal with the workload of ANDAs. 

While respondents had varing opinions on the qualifications, competence, dilgence, and 

fai-mindedness of FDA staf with whom they work on ANDAs, they pointed to a lack of 

resources or ineffcient use of resources as reasons for a lack of timeliness and consistency in 

ANDA review. "They don t have enough people," one respondent said. "They need more 

clerical staf" thought another respondent. 

Some respondents thought FDA could be more effcient in using its staf or organizing its 

review. Several respondents thought the Agency should take more advantage of field staff in 

conducting portons of the review: "They don t go to laboratories or plants as par of their 

review. They underutilze their field staf, one of their best assets, who have more hands-on 

experience." Another respondent who thought the review of ANDAs could be accomplished 

more effciently by avoiding the duplication of work said: "FDA works hard but not smar. 

(We had) one experience where a reviewer approved one application with one drg master 

fie. Then he moved to review our (application) next. Our application had the same drg 

master fie, but the reviewer re-reviewed it allover again. " Other respondents thought there 

should be more communication and interaction between the staff which reviewed the NDA for 
, 

, 

the innovator product and the staf which reviews the applications for the generic equivalent 

to create and share expertise on simlar products; in fact, one respondent believed that FDA 

should co-locate the staf and make the same reviewers responsible for review of applications for both generic and innoyator products of the same type. Finally, respondents 

to what they see as management problems: " agai pointed There is no management control of FDA reviewers. " 

Respondents disagreed on whether two recent FDA initiatives

Generic Drugs and creating of an FDA ombudsman, would help address the concerns they , establishing of the Office of

discussed. Respondents did believe, however, that the FDA should continue sampling drugs on the market to ensure the quality of drugs sold to consumers. 

Seven respondents believe creating an Offce 
of Generic Drgs would be beneficial believed it would not help, and six were unsure. Those who thought such a move would be , thee


beneficial argued that "elevating (the offce) gives it more prestige and attacts higher caliber employees." Those respondents who were unsure about the effect of the move thought that it might help if it resulted in more or better staff, but believed it would not the address the main need for standard operating procedures or guidelines. The respondents who feel the new


offce wil not meet their concerns considered it "window drssing.


Seven respondents believe creating an FDA ombudsman would be helpful


said it would not help, and two were unsure. One respondent who feels the creating such a
 , an equal number


position would help meet his concerns argued that an ombudsman could serve as a "


release valve between FDA industr," but stressed that autonomy was critical. pressure 

respondent takng the view that an ombudsman would not help stated Another


open door policy, the codfication Unless you have an
 of specifications and requirements, an ombudsman is meaningless. What is he going to ombuds?" 

Most respondents believe that FDA should test samples of marketed drgs 

reestablish consumer confidence in generic products. Several respondents emphasized the , if only to

need for such testing to include innovator, or brand name, products. 

Respondents suggested changes in FDA generic drug approval. 

Some of the suggestions offered by respondents to improve FDA approval of generic products 

were to: 

Develop more guidelines; codify and standardize specifc requirements. 


of the respondents expressing this view want to see detailed specifications for Some

generic products, similar to those published now for approval of antibiotics. 

When a drg is coming off patent " said one respondent publish requirements in the Federal Register and let manufacturers comment on them. 
Develop standard operating proceduresforreviewers. Respondents recommending this change wish to address what they see as the inconsistency of 

review and decision makng. Standard operating procedurs would diect

reviewers in how to assess ANDAs, what to look for during review, and what constitutes an approvable or not approvable ANDA. 

Communicate more with industry. Respondents suggesting this change desire 

more discussion of policy with industr as it is being developed, formal 

communication of policy to industr once it is adopted, more informal


communication (e.g., telephone calls) with reviewers, availabilty of more
 information (e.g., alert list) to manufacturers, and development of a workable


appeals process. 

Increase FDA staff 
 Respondents suggesting increased staff for ANDA review


point to the increase in volume of submissions since 1984 and the need for the


Agency to process submissions in a timely manner.


Reorganize review structure. Some respondents suggested increased use of field 

staff to conduct portions of the review, such as validating production 

equipment, and the conformty of the drg product with data in the ANDA. 

Another suggestion was to use the same reviewers to assess both NDAs and

ANDAs for similar chemical compounds. 

Pre-approve drug master files. Several respondents thought that drg master


fies should be pre-approved, and simply referenced in the ANDA, rather than a


drg master fie reviewed and approved for each separte application.


Revisit supplemental requirements and review. Some respondents suggested 

that FDA reconsider what changes merit a supplement or if such reviews could 

be contracted out. One respondent said, "If a facility change affects 10 

applications, make 1 supplemental, not 10. 

Standardize and streamline labeling requirements. Some respondents thought that FDA should establish a "master" label for generic products. Others thought 

FDA should allow manufacturers to submit samples of labels to be marked up by 

reviewers, and then approve the label with changes to be incorporated in actual 

production. 

Increase management control of reviewers. Some respondents suggested that 

FDA should emphasize more the need for better supervision of reviewers, their 

quality of work and productivity, to reduce the varances and inconsistency in

reVIew. 
Respondents thought that minor deficiencies should not 

restart the review clock. 

Hold to time frames. 

ENDNOTES


1. Except in those instaces where a manufacturer has an approved suitabilty petition to 

seek approval of a product that differs from the listed drg. 

2. Testimony of Dr. Fran E. Young, M. , Ph.D., former Commssioner of Food and 

Drugs, before the Subcommttee on Oversight and Investigations, Commttee on Energy 

and Commerce, U.S. House of Representatives, on July 11, 1989. 

3. Offce of Inspector General, Offce of Audit Services, Management Advisory Report: 

Vulnerabilties in the Food and Drug Administration s Generic Drug Approval Process, 

15-89-0051, August 1989. 

4. Fifteen manufactuers dicussed their professional experiences with investigational new 

drg and new drg applications. For the results of these discussions, see Offce of 

Inspector Genera, Offce of Evaluation and Inspections, Perspectives of Drug 

Manufacturers: Investigational New Drug and New Drug Applications," 

OEI- 12-90-00771, Februar 1990. 

See Food and Drug Administration, Office of the Commssioner, Offce of Planning and 

Evaluation, Agency Impact Analysis: Fruit Juice, The Perceptions ofTen Firms, OPE 

Study 70, June 1984, and Agency Impact Analysis: Salad Dressings, The Perceptions of 

5. 

Ten Firm," 
 OPE Study 64, May 1983. 
APPENDIX A 

LISTING OF PARTICIPANTS 

Abbott Laboratories


Amersham Corporation 

American Cyanamd Company 

Bar Laboratories 

Biocraft Laboratories 

Bolar Pharaceuticals 

Eli Lily and Company 

D. Searle & Company 

Geneva Generics 

Hoechst-Roussel Pharaceuticals, Inc. 

Hoffmann-La Roche, Inc. 

ICI Pharaceuticals Group 

Lemmon Company


Lyphomed, Inc. 

Merck Shar & Dohme 

Mylan Laboratories 

Ortho Pharaceutical Corporation 

Pfizer Incorporated 

Roxane Laboratories, Inc. 

Rugby Laboratories, Inc. 

Sandoz Corporation 

Schein Pharaceutical, Inc. 

Schering-Plough Corporation 

Smith, Kline, & French 

A - 1

APPENDIX B


AGENCY COMMENTS

t8"C"" 

DEPARTMENT OF HEATH &. HUMAN SERVICES Public Health Service Foo and Dru Admnistration 

Memorandum 

Date . February 9, 1990 

From Acting Commissioner of Food and Drugs 

Subject eIG Research on Perceptions of Drug Approval Processes 

Inspector General


I want to thank your staff for sharing with FDA managers the


recent eIG research into the perceptions of pharmaceutical


executives regarding FDA' s new drug and generic drug approval
 processes. In my prior FDA experience, I have always found 

opinions and observations expressed by parties affected by FDA


to be a valuable source of feedback on agency performance. 

FDA was particularly interested in industry perceptions about 

the drug approval processes last Fall, and' I am pleased that 

your staff was able to collect this information for us so soon 

after Dr. Sullivan announced the various initiatives to 

strengthen FDA' s drug review processes. This information gives processes. FDA a very helpful insight as we proceed to strengthen these

In addition to receiving the information itself, the process of


sharing this information in a workshop setting with your staff


was a positive experience. I look forward to more such


interactions and exchanges between our staffs. 

/t 

fjs S. Benson 

, . . 

feD


FEB 2 7 199 

, R p. \(USSe O"'1 

Richard f Kusserow 

Inspector General


OIG Final Reports , "Perspectives of Drug Manufacturers: 

Abbreviated New Drug Applications " OEI-12-90-00770 and "Perspectives of Drug Manufacturers: Investigational New Drug 

and New Drug Applications " OEI-12-90-00771 

James o. Mason , M. D.


Assistant Secretary


for Health


Attached for your information are the above-referenced reports 

which discuss the findings from interviews conducted with 

officials at 24 drug manufacturing firms. This survey was 

conducted to assess the perspectives of industry in regard to 

new and generic drug approval in the Food and Drug

Administration (FDA). 

Respondents from 16 firms had experience with FDA' s review of 

abbreviated new drug applications (ANDAs). Respondents from 15 

firms had experience with FDA' s review of investigational new 

drug exemptions (INDs) and new drug applications (NDAs). 

FINDINGS 

Virtually all the respondents we interviewed believe that 

FDA is effective in ensuring that only safe and effective drugs enter the market. The 15 respondents who discussed 

FDA' s review of INDs and NDAs went on to say that they are 

generally satisfied with the decisions FDA reaches , the 

agency staff with whom they deal on their applications 

and the communication between their firms and the agency. 

The 16 respondents we interviewed concerning FDA' s review 

of ANDAs were generally dissatisfied with the agency 

performance. They were critical of FDA' s guidance communication , and decision making. 

Respondents in both categories identified inconsistency of 

FDA' s review of applications as their primary concern. 

Respondents felt that the information required on an application , and the amount and nature of evidence on 

safety and effectiveness required by the agency, differ according to reviewer and division. 

Respondents made a number of suggestions that they believe 

would improve agency performance if implemented. These 

suggestions are contained in the reports. 
Page 2 - James O. Mason , M. D.


Our staff discussed the findings and manufacturer


recommendations contained in these reports with FDA officials


in January 1990. The FDA provided us with technical comments


to the reports , which we incorporated to clarify points made by


the respondents , and a written response to the reports which we


have attached. 

Attachments 

cc: 

James S. Benson 

Acting Commissioner of Food and Drugs

Prepared by: PThompson: BMTelesford: 2-23-90