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PERSPECTIVES OF DRUG

MANUFACTURERS

ABBREVIA TED NEW DRUG APPLICA TIONS 
t\lVICE$' 
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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 
At the
effective. 
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. 
disagreed on whether two recent FDA initiatives, establishing the Offce of 
Respondents 
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.  Drug Price Competition and Patent Restoration Act 
The  1984 
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  approve the application if certain conditions are 
the Agency  wil 
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 
and well over 1,00 abbreviated new drg applications and abbreviated antidbrigo taicp pdlricgations
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 
study team did not attempt to veriy or validate the 
manufacturers. In addition, the  OIG 
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 
consider FDA effective in 
Virually all of the manufacturers we interviewed 
ensuring that drugs entering the marketplace are safe and  At the 
effective. 
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. 
disagreed on whether two recent FDA initiatives, establishing the Offce 
Respondents 
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  suggested 
sold to consumers. Finaly, respondents 
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: 
far (we) haven t found anything that was grossly missed. 
So 
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 
example 
of the kind of guidance they would like to see for all generic products: " 
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'  the guidance. As one respondent said, "
s inconsistency in  applying  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 
priary 
had not done so  , believing "FDA has a long. 
because they feared retaiation
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 
" thought another respondent. 
clerical staf
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
, establishing of the Office of
Generic Drugs and creating of an FDA ombudsman, would help address the concerns they 
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 
believed it would not help, and six were unsure. Those wDhrog tsh owuoguhltd s ubceh  bae mneofvicei awl,o tuhlede b
e 
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,  acnre eaqtiunagl  snuucmhb ae
r

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

release valve between FDA industr, pressure 
" but stressed that autonomy was critical. 
respondent takng the view that an  Another

ombudsman would not help stated 
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 ,e imf pohnalys itzoed the 
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 Sfoorm  e
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 
Respondents
proceduresforreviewers. 
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. 
Respondents suggesting this change desire 
Communicate more with industry. 
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. 
Respondents suggesting increased staff for ANDA review

Increase FDA staff 

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 
Hold to time frames. 

restart the review clock.  ENDNOTES

1. Except in those instaces where a manufacturer has an approved suitabilty petition to 
drg. 
seek approval of a product that differs from the listed 
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  Management Advisory Report: 
of Audit Services, 
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  see Offce of 
discussions, 
Inspector Genera, Offce of Evaluation and  Perspectives of Drug 
Inspections, 
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 
5. 
Agency Impact Analysis: Fruit Juice, The Perceptions ofTen Firms,  OPE 
Evaluation, 
Study 70, June 1984 Agency Impact Analysis: Salad Dressings, The Perceptions of 
, and 
OPE Study 64, May 1983. 
Ten Firm," 
 . .
APPENDIX A 
PARTICIPANTS 
LISTING  OF 
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 
Acting Commissioner of Food and Drugs 
From 
eIG Research on Perceptions of Drug Approval Processes 
Subject 
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 
' I 
the drug approval processes last Fall, and am pleased that 
pyour rstafof wasc ablee to scollsect ethiss inf.or mation for us so soon 
after Dr. Sullivan announced the various initiatives to 
s drug review processes. 
strengthen FDA'  This information gives 
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

staffs. 
interactions and exchanges between our 
/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 
firms. 
officials at 24 drug manufacturing  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 
reports. 
suggestions are contained in the  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