PERSPECTIVES OF DRUG

MANUFACTURERS

INVESTIGA TIONAL NEW DRUG AND NEW DRUG APPLICA TIONS 
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OFFICE OF INSPECTOR GENERAL 
OFFICE OF EV ALVA TION AND INSPECTIONS 
FEBRUARY 1990  PERSPECTIVES OF DRUG

MANUFACTURERS

INVESTIGATIONAL NEW DRUG AND NEW DRUG APPLICATIONS 
Richard P. Kusserow 
INSPECTOR GENERAL 
OEI-12-90-00771  FEBRUARY 1990
 ...
EXECUTIVE SUMMARY 
PURPOSE 
The purose of this report is to describe the perspectives of selected drg manufacturers 
regarding Foo and Drug Admnistration (FA) review of investigational new drg (INDs) 
and new drg applications (NAs). This is one of several reports being issued by the Offce 
of Inspector General (OIG) in connection with FDA's approval of new drgs. 
This report contans the accounts of manufactuers regarding their 
experiences and opinions of 
INs 
FDA' s review of  and NDAs. For maximum benefit, the reader should consider this 
information along with the results of independent analysis conducte by the OIG regardig 
FDA' s approval of new drgs. 
BACKGROUND 
Under the Federa Foo, 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 for use under the conditions 
perscribed, recommended, or suggested in the labeling...." (21 U.  C. section 321.) The FDA 
is charged with ensurg that the drgs it approves are both safe and effective for their 
intended uses. 
Investigational New Drug Application (IND) 
To begin clinical studies on a drg product for human use, a sponsor (generaly a 
pharaceutical company or a research organization) must receive an exemption from FDA 
from the Act s provisions prohibiting distrbution of new drgs not having approval from 
FDA. (21 U.  C. 355(i).) To obtan this exemption, the sponsor supplies the FDA with a 
Investigational New Drug (IND) application containing all of the known information on the 
priary 
drg. This information is  data from studies conducted on animals, unless the drg 
has been used in Europe or elsewhere. Additionally, the sponsor must provide the FDA with 
detailed protocols, describing how the proposed human clinical trals 
wil be conducted. 
Generaly, clinical trals are cared out in thee phases. Phase 1 trals are conducted primarly 
to determne the safety of the drg and generally contain a small number of healthy 
volunteers, from 20 to 100. Phase 2 trals involve admnistering the drg to patients with the 
disease or condition for which the drg is intended to treat to determine whether the drg is
effective. Phase 3 clinical trals are the most extensive of all, involving up to several thousand  patients. These trals provide information such as dosage rates and schedules that wil alow 
the drg to be marketed and used safely and effectively. 
New Drug Application (NDA) 
A New Drg Application (NA) is a sponsor s request to the FDA for approval to maket a 
new drg. The NDA is the compilation of all of the clinical data regarng the safety and
effcacy of the drg, as well as manufacturing information. 
METHODOLOGY 
To assess manufacturers ' perspectives regarding FDA drg approval, the DIG invited 24 firms 
to discuss their experiences with, assessments of, and suggestions for improving FDA drg
fis 
approval. All 24 firms agreed; the  parcipating in the study are listed in appendix A. 
fis 
Of the 24  listed, representatives of 15 discussed their professional experiences with the
IN 
and NDA review process. The results of those discussions are described in this report. 
FINDINGS 
All 15 manufacturers interviewed concerning FDA review of INs and NDAs 
consider the Agency effective in ensuring that drugs entering the marketplace 
Overall, respondents we interviewed concerning FDA' 
are safe and effective. 

approval process for new drg products were less critical of the Agency than 
those we interviewed concerning FDA's approval for generic products. 
For the following points, a majority of respondents 
believe FDA provides adequate guidance to manufacturers on how to develop 
and submit successful INDs and NDAs; 
have found the IND rewrite useful; 
were generally satisfied with communication between their  FDA; 
firm and  are satisfied with FDA' s decisions regarding IND and NDA submissions; and 
consider FDA staff qualifed, competent, andfair-minded. 
Respondents are mixed regarding 
whether FDA pays suffcient attention to the need for timely action on original 
NDAs. However, most respondents believe the agency pays 
insuffcient attention 
to the need for timely action on supplemental NDAs. 
Respondents also believe 
FDA review is inconsistent and il-planned. 
Respondents suggested a numer of  to improve the IND and NDA approval processes. 
changes 
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 
surey and our briefing are 
attached at appendix B.  . . . ..  ...   ...   ...   ...   .....    ....    ....    ...   ...   ...
. . . ..  ...   ...   ....    .....     .....     .....     .....     .....     .....     .....     .....     .....     .....     .....     .....     .....     .....     .....     .....     .....     .....     .....     .....     .....     .....     .....     .....     ..... .   . ... .   . ....     .....     .....    . ... .   . .. .. .   . .. ..   . .. .  . ..  . .. .  . ..   ..  ..  ..  ..  . . . 
TABLE OF CONTENTS 
EXECUTIVE SUMMARY 
INTRODUCTION. 
Purpose 
. . . . . . . . . . . . . . . 1

Background. 
Methodology 
FINDI NGS 
 ....................................................... 6

ENDNOTES. 
APPENDIX A 
LISTING OF PARTICIPANTS. . . . . . . . . . . . . 
. . . . . . . . . . . . . . . . . . . A -
APPENDIX B

AGENCY COMMENTS. . . . . . . . . . . . . . . . . . . . . . . . . .  B-1  ...
INTRODUCTION

PURPOSE 
The purose of this report is to describe the perspectives of selected drg manufacturers 
regarding Foo and Drug Admnistration (FA) review of investigational new drg (INDs) 
and new drg applications (NAs). This is one of severa report being issued by the Offce 
of Inspector General (OIG) in connection with FDA's approval of new drgs. 
This report contains the accounts of manufactuers regarding their experiences and opinions of 
INs 
FDA' s review of  and NDAs. For maximum benefit, the reader should consider this 
information along with the results of independent analysis conducte by the DIG regardig 
FDA' s approval of new drgs. 
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 for use under the conditions 
perscribed, recommended, or suggested in the labeling...." (21 U.  C. section 321.) The FDA 
is charged with ensurig that the drgs it approves ar both safe and effective for their 
intended uses. 
Investigational New Drug Application (IND) 
To begin clinical studies on a drg product for human use, a sponsor (generaly a 
pharaceutical company or a research organization) must receive an exemption from FDA 
from the Act s provisions prohibiting distrbution of new drgs not having approval from 
FDA. (21 U.  C. 355(i).) To obtan this exemption, the sponsor supplies the FDA with a 
Investigational New Drug (IND) application containing all of the known information on the 
priary 
drg. This information is  data from studies conducted on animals, unless the drg
has been used in Europe or elsewhere. Additionally, the sponsor must provide the FDA 
with 
detailed protocols, describing how the proposed human clinical trals 
wil be conducted. 
The FDA reviews the initial IND application requesting the exemption to determe if studies 
may proceed safely using human subjects. The FDA has 30 days in which to make its initial 
safety assessment and notify the sponsor of any concerns. After this time and if no safety 
concerns have arsen, the sponsor may proceed with clinical trals in humans. If FDA has 
safety concerns regarding the drg product at this time or at later points durng clinical testing, 
it places a clinical hold on the trals. For later phases of drg testing, FDA may also place a  tral on clinical hold if the tral' s design is inadequate to meet its stated objectives. Once FDA 
places a clinical hold, sponsors suspend clinical trals until the safety concern has been 
resolved to FDA's satisfaction. 
Generaly, clinical trals ar cared out in thee phases. Phase 1 trals are conducted primarly 
to determne the safety of the drg and generaly contain a smal number of healthy 
volunteers, from 20 to 100. Phase 2 trals involve admnistering the drg to patients with the 
disease or condition for which the drg is intended to treat to determne whether the drg is 
effective. Phase 3 clinical trals are the most extensive of all, involving up to several thousand 
patients. These trals provide information such as dosage rates and schedules that wil alow 
the drg to be marketed and used safely and effectively. 
When sponsors submit an application for an IND exemption to FDA, it must contain certai 
information  This information includes: (1) a cover sheet containing pertinent information 
about the sponsor, name of the investigational 
drg, and information on the Institutional 
Review Board and any contract research organizations; (2) table of contents; (3) introductory 
statement and general investigational plan; (4) investigator s brochure containing summares 
of pharacological and toxicological effects, pharcokinetics and biological disposition, as 
well as human safety and effectiveness information and a description of risks; (5) protocols 
outlining each study; (6) chemistr, manufacturing, and control information; (7) 
pharacology and toxicology information; (8) previous human experience with the 
drg; and 
(9) additional information on drg dependence and abuse potential of the drg. (21 CFR 
section 312.23. 
In 1987, regulations concerning the submission of INDs were revised. These new regulations 
are referred to as the "IN rewrte." The IN rewrte established deadlines for safety reports, 
encouraged meetings between FDA and the sponsor to discuss concerns, and alowed 
increased autonomy of sponsors in Phase 1 clinical trals. The IND rewrte also required 
sponsors to provide the FDA with an annual report which would, among other things, detail 
the plans for the drg s clinical development during the upcomig year and describe any 
safety problems that the sponsor has discovered. 
The sponsor may meet with the FDA at certain points during clinical development. An 
end-of-Phase 2" meeting taes place before large-scale testing in Phase 3 is begun. This 
meetig allows the FDA and the sponsor an opportunity to discuss data that 
wil be required 
from the Phase 3 trals to complete the safety and efficacy profie of the drg. At the 
completion of Phase 3 trals and before filing the New Drug Application (NDA), the sponsor 
may also meet with the FDA. This is called the "pre-NDA" meeting. This meeting allows the 
FDA and the sponsor to discuss the nature and presentation of data to be included in the NDA.  New Drug Application (NDA) 
A New Drg Application (NA) is a sponsor s request to the FDA for approval to maket a 
new drg. The NDA is the compilation of all of the clinical data regarding the safety and 
efficacy of the drg, as well as manufacturing information. 
Specific information must be included in the NDA submitted by manufacturers to the FDA for 
approval to market a new drg. This information includes, among other things: (1) 
application form contaiing identifying data of the sponsor and drg; (2) index; (3) summar 
of submission contaning proposed labeling, statement of intended use, description of 
marketing history, and risk/enefit analysis; (4) chemistr, manufacture, and control section; 
(5) nonclinical pharcology and toxicology section; (6) human pharacokinetics and 
bioavailabilty; (7) microbiology section (for anti-infective drgs); (8) clinical data section; (9) 
statistical section contaiing statistical evaluation of the clinical data; and (10) case report 
tabulations contaiing tabulations of data from Phase 1  , and 3 trals. (21 CFR 314.50. 
FDA classifies submissions according to the chemical type and most importantly, the 
tratment potential, to determe review priorities. According to FDA procedures, innovative 
compounds that ar used to treat diseases and conditions for which there are no other 
tratments receive the fIrst priority in review. 
Once an application is submitted, FDA has 60 days to determne if the application may be 
fIed. This means that FDA has made a threshold determnation that the application is 
suffciently complete to allow a substantive review. Once the application is fIed, FDA then 
has 180 days to review an application and send the applicant either an "
approval" letter, an 
approvable" letter, or a "not approvable" letter. This 180-day period is referred 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 "approvSl" letter means a wrtten 
approve the application if certn 
communication stating that the Agency  wil  conditions are 
met (such as changes in the manufacturng controls). A "not approvable" letter means that the 
Agency does not consider the application approvable due to deficiencies identified in the 
application. 
Durig the review, communication takes place between FDA and the applicant. A "ninety-day
conference" is offered to applicants approximately 90 days after the agency has received the 
application, durig which FDA discusses with the applicant the status of the application 
progress made to date in the review of the application, and deficiencies identified thus far in 
the review. An "end of review conference" is offered 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, cenain changes may be made by the maufacturr in 
manufacturg 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 manufactuer must either submit (1) a supplement reuirng FDA approval before changes 
can be made; (2) a supplement describing changes to FDA that have alady been made; or (3) 
a description of the types of changes made in the next annual report to the Agency. Only 
information relatig to the change must be included in the supplement. 
Regulations concerning NDA submissions were updated in 1985. These revised regulations 
are referrd to as the "NDA Rewrte." The new regulations provided several additional safety 
featues including safety reports after submitting the application and strngthened monitoring 
of adverse drg reactions from marketed drgs. The revision also faciltated review by 
requirng more focused and better organized data, use of summares and tables, and allowance 
of approval on the basis of foreign studies alone. 
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 fIrms agreed; the firm paricipating in the study are listed in appendix A. 
fi 
Of the 24  listed, representatives of 15 discussed their professional experiences with the 
IND and NDA review process. The results of those discussions are described in this 
report. 1 
Prvious work done by the Office 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 parcipate in the OIG interviews were selected to ensure approximately 
equal distrbution of fIrms experienced in generic drg and new drg approval. Respondents 
from seven fIrms 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. 
Generally interviews were conducted with the chief executive offcer, president, and/or 
regulatory affais diector and staff of the fIrms selected. A total of 49 individuals were 
interviewed. The 24 fIrms visited durng the course of our surey had by their own estimation 
submitted in excess of 450 investigational new drg applications, 150 new drg applications,  and well over 1 000 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-makng 
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 al 
manufactuers. In adtion, 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 
All 15 manufactuers interviewed concerning FDA review of INDs and NDAs 
consider the Agency effective in ensuring that drugs entering the marketplace 
Overal, respondents we interviewed concerning FDA' 
are safe and effective. 

approval process for new drg products were less critical of the Agency than 
those we interviewed concerning FDA's approval for generic products. 
ff1i 
For the following points, a majority of respondents 
believe FDA provides adequate guidance to manufacturers on how to develop 
and submit successful INDs and NDAs;

have found the IND rewrite useful;

were generally satisfied with communication between their firms and FDA;

are satisfied with FDA' s decisions regarding IND and NDA submissions; and

consider FDA staff qualifed, competent, andfair-minded.

Respondents are mixed regarding 
whether FDA pays suffcient attention to the needfor timely action on original 
NDAs. However, most respondents believe the agency pays 
insuffcient attention 
to the needfor timely action on supplemental NDAs. 
Respondents also believe

FDA review is inconsistent and il-planned.

to improve the IND and NDA approval processes. 
Respondents suggested a number of changes 

Each of the findings is discussed in more detal below.  All manufacturers interviewed regarding new drug approval believe FDA is effective in 
ensuring that drugs entering the marketplace are safe and effective. 
IN 
All 15 respondents interviewed concerning  and NDA review feel FDA does an effective 
job in ensurng that drgs entering the maket are safe and effective. One respondent who 
rated the agency as very effective, added, "They (FA) have fulf1led their charer well; in 
fact your scale is not high enough in this regard." Severa manufactuers observed that FDA 
is highly regarded worldwide for its safety stadards. 
The majority of respondents believe the Agency provides adequate guidance to 
manufacturers on how to develop and submit successful INDs and NDAs. 
The majority of respondents (11) rated the guidance from the FDA in preparg the original
IN 
as adequate or more than adequate. Guidance relied on by manufacturers to develop 
INs 
their  includes discussions with FDA staf, regulations, and guidelines. "The guidance is 
adequate," said one respondent "(We get it) both verbally and though documentation. 
Severa respondents believe that FDA should attempt to update guidelines for clinical 
development, which they considered to be out of date. For example, one respondent who 
IN 
considered FDA guidance on developing an  submission adequate added, "While the 
ar 
guidelines  clear, they re old..." Another respondent who considered agency guidance 
inadequate pointed to this as the reason: "Clinical guidelines have not been updated in alost 
13 years. 
Most respondents (13) also feel information provided by the agency on how to prepare and 
submit NDAs is adequate or more than adequate. Again, guidance relied on by maufacturers 
to develop their NDAs includes discussions with FDA staf, regulations, and guidelines. 
Most respondents have found the IND rewrite useful. 
The majority of respondents (9) reported that the 1987 rewrte has been very or moderately 
useful to them in preparg successful IND submissions. Five respondents consider the new 
regulations of little use; one respondent was unsure. "It codfied a lot of the process that 
people had previously guessed at based on past experience," said one respondent. Another 
respondent added, "It helped a lot; (FDA) really took the best practices of many companies 
and combined this in the regulation. One company does (one thing) really well, so FDA 
decided that everyone should adhere to that practice; one company does (another thing) really 
well, so FDA decided that everyone should adhere to that practice; and so on. 
Overall, respondents indicated that the rewrte has resulted in more work for sponsors since 
more information must be submitted. Most of the manufacturers indicated they had no 
problem with supplying the FDA with more information if it helped the reviewers. However 
several respondents wondered whether the additional information, especially the annual 
report, was being reviewed at FDA or simply fied.  Some manufacturers believe that the use of clinical holds has increased since the 
implementation of the IND rewrte. One respondent indicated that the 30-day review period is 
not allowing reviewers the tie they feel they need to perform a safety review, causing them 
to be overly cautious. He explained, "The regulations themselves ar very goo...(but) FDA 
does not seem to fully follow the intent of the regulations. The problem of clinical holds has 
IN 
become a bigger problem since the  rewrte. Since they only have 30 days, sometimes 
you get a 'knee-jerk' reaction if they have any question at all." 
Respondents were generally satisfied with communicaton between their firms and FDA. 
However, they emphasized that communication must be timely and accurate in conveying 
the agency 
s position in order to be most useful. 
Two-thirds of the respondents (10) considered it fairly 
Checking on the status of applications. 

IN 
easy to check on the progress of an  submission. Respondents indicated that Consumer 
Safety Offciers (CSOs) are generally eager to help and provide status repons. Slightly more 
than one-half of the respondents (8) considered it fairly easy to find out the progress of a NDA 
submission and its status. A few respondents (2) thought checkig on NDA status was 
diffcult and several (3) indicated it vares from division to division. 
Almost al of the respondents indicated that 
Communicating with FDA during clinical trials. 

they had attended the varous meetings made available by FDA durg the IN phase. The 
majority of respondents rated these meetings, which include the "End of Phase 2" and 
Pre-NDA" meetings, as very useful and generally indicated that they would take advantage 
of any opportunity presented to meet with reviewers. "You would be out of your mind not to 
sit down with reviewers and discuss the submission when given the opportunity," said one 
respondent. 
Respondents did note, however, that conclusions reached in "End of Phase 2" and "Pr-NDA" 
meetings could not always be considered final. "(You) can have a well-documented meeting 
but because division dictors aren t present, FDA doesn t feel obligated to adhere to 
agreements," one manufacturer said. "Sometimes you need to have certn individuals present 
to know that meeting results wil fly. 
VIrually all manufacturers had sought advice from FDA during the coure of clinical trals 
and found that advice useful. However, timeliness is crucial to sponsors, especialy when 
changes and additions are needed in clinical protocols and studies durng the IND phase. 
Severa respondents related incidents where FDA had contacted them with changes in the 
design of clinical trals only to fmd out the tral had already been completed. 
Communicating with FDA during NDA  Nine respondents had attended a "ninety-day 
review. 
conference" and 10 had attended an "end-of-review conference  - . '';-
Respondents who had attended a "ninety-day conference" were split on their usefulness. 
Accordig to several manufacturers, FDA frequently has not had suffcient time to even begin 
the review at the time of the "ninety-day conference  Some respondents thought that, for this 
reason, FDA often wil not grant requests for these meetigs. "We attended one 'ninety-day 
conference ' and found it very useful, said one manufacturer. "But we have...reueste 
numerous other ('ninety-day conferences ). These did not take place because FDA said, ' 
have nothing to tal about 
Nine of the 10 respondents who had attended an "end-of-review conference" found them 
useful. At these meetigs, manufactuers discussed with FDA continued testing for adverse 
drg reactions, final labeling, and other issues of interest. 
Respondents are generally satisfied with the Agency s decisions regarding IND and NDA 
submissions. 
The majority of respondents (13) were satisfied with the final decisions made by the FDA 
IN 
regarding their  submissions. Many manufactuers pointed out their concerns are with 
how FDA reaches their decisions, not what decisions are made. One respondent described 
himself as "ultiately satisfied with decisions, but frstrted along the way." Another 
respondent stated, "Decisions are always justifiable and based on some sound priniciples of 
science." However, this same respondent went on to point out that "what is missing is the 
discussion between industr and FDA on those scientic questions. 
Severa respondents expressed frustration with clinical holds. One manufacturer stated, 
There have been open-ended delays with clinical holds. FDA does not have a sense of 
urgency to remove clinical holds...during the course of an IND (phase), we can have formal 
and informal clinical holds. With informal clinical holds, we can have questions on a mior 
par of the protocol disrupt the program." Several manufacturers mentioned that they believe 
FDA is aware of the problem with "informal" clinical holds and is moving to address it. 
The majority of respondents (12) expressed simlar satisfaction with the decisions made by 
FDA regardig NDA submissions. Again, however, many of the respondents would like to 
see decisions reached more quickly on NDA submissions. One respondent stated, "(It) just 
taes them longer to reach the same decision (that we would have)." 
Respondents consider FDA staff qualifed, competent, andfair-minded. 
The majority of the respondents consider the FDA staf with whom they work to be qualified 
(11), competent (8), and fai-minded (12). Several respondents believe that these qualties 
var 
significantly from employee to employee. 
Several respondents mentioned several factors they feel affects the abilty of FDA staff 
car 
out their function, such as less than desirable working conditions, relatively low pay, and  insuffcient staffing. One respondent felt that the FDA staff "get a bum rap" and that

taxpayers are gettig a goo deal for their money." One respondent commented that the

workig conditions were bad and he "probably couldn't do a better job.

Another respondent felt that the work system at FDA does not reward industrousness:

(There are) no rewards in FDA for workig hard and goo. There are only penalties for

getting a drg out if anything goes wrong. If a reviewer works rapidly, they just get another

assignment. "

Respondents have mixed opinions on whether the Agency pays suffzcient attention to the 
need for timely action on original NDAs. However, most respondents believe the agency 
pays insuffzcient attention to the need for timely action on supplemental NDAs. 
A slight majority of respondents (8) believe that FDA is ineffective in ensurig that drgs 
enter the marketplace in a timely manner. However, almost as many (7) thought FDA is 
effective in getting applications processed in a timely manner. One respondent who considers 
FDA ineffective argued, "After five months they know (the drg) is safe and effective; the rest 
is unnecessar details, bureaucracy, and poor management." A few respondents thought FDA 
is too cautious in its review, expressing the opinion that FDA "goes overboard" in ensurng 
safety and over-emphasizing the risk side of the risk/enefit relationship. 
Another respondent 
disagreed, rating the agency as effective in ensuring the timely movement of drgs to market 
and arguing that delays were generaly the fault of industr: "The overwhelming factor that 
tie 
usually influences review  is the quality of the data sent to FDA" 
All of the manufactuers interviewed had submitted at least one supplemental NDA. The 
majority (11) believed that supplementas were reviewed less expeditiously and received a 
lower priority than NDAs. Several manufacturers expressed frustration with this situation 
saying that FDA had diected them to streamline original NDAs and pursue additional 
indications later in supplemental NDAs. The manufacturers we interviewed said that they 
understand that new drg approvals are the top priority at FDA, but they pointed out that 
expanded indications from aleady marketed drgs provides companies with revenue for 
research and development. 
Respondents disagreed on whether FDA is effective in establishing review priorities in order 
to expeditiously review certain applications. Most manufacturers agred that except in the 
case of l-AA compounds, such as those to treat AIDS, the classification a drg reeives has 
little bearng on review time. "The difference between a priority NDA and a nonpriority NDA 
in terms of average review time to approvable is only about three months," declard one 
respondent. 
Respondents believe that FDA review is inconsistent and il-planned. 
The majority of respondents consider FDA review of NDAs inconsistent (12) and FDA review 
of INDs inconsistent (13). Respondents characterized the review process as highly varable  from division to division and from reviewer to reviewer in a given division. Respondents 
attrbuted the varabilty to lack of guidelines and standard operating procedures for reviewers, 
as well as individual differences in background, interest, and dedication. One manufacturer 
reported, "We have cases in which the same set of data used to support 10 approved NDAs is 
suddenly found to be deficient by a reviewer in another division. 
Severa manufacturrs believed that the worst scenerio is having a change of reviewers durng 
IN 
the course of the  and NDA submission. According to respondents what was accepted and 
agreed upon for clinical studies may no longer be acceptable with a new reviewer. 
Inconsistency among divisions is especially apparent when a reviewer switches to a new 
division and tres to apply the standads of the former division to the review process. 
Respondents also pointed out that divisions use their advisory committees in differig 
capacities which results in diferences in some management practices. 
ofINs il-
The majority of respondents (9) also considered the review  planned. Respondents 
concerns about the lack of planning in the process focused on identifying deficiencies late in 
the review process, asking inappropriate questions early in the clinical development, and 
IN 
lacking on-going review of clinical information in the  phase. One manufactuer stated, 
you proceed until you hear but this often causes delays because you have not been informed 
early on." Another manufacturer noted, "(Review of) the original IND is well-planned, but 
the entie process is not. Throughout the process, we are not sure that anybody is looking at 
IN 
the data we send in. FDA is innundated with paper and has no time to pull the entire  and 
reflect on it as a whole. We get to a pre-NDA meeting and find out that we ar supposed to 
redo a toxicology study we did five years ago. FDA has had the data for five years; why are 
we just finding out about their concerns?" 
Comments were similar concerning the NDA process, with lO respondents feeling that the 
review process is il-planned. Severa manufacturers reported the same experience: receiving 
questions from reviewers that are addressed in the submission, to which the manufacturer 
replies, "See page 4, paragraph 2, of our submission  ; and receiving new questions after an 
initial letter stating the application s deficiencies have been received by the manufacturer and 
addressed. 
Respondents suggested a number of changes to improve the IND and NDA approval 
processes for innovator drugs.

Overall, respondents would like to see a less adversarial relationship with FDA. 
Several respondents indicated they feel FDA views their role as a policing job 
instead of a regulatory agency. Manufacturers would like to see an 
agency-industr "parnership" in getting new drgs to the market. 
Morefeedback to industry on protocols and submissions during the IND phase. 
The majority of the manufacturers interviewed would like to have more input  from FDA on the design of clinical trals. Respondents feel FDA should be 
wiling to look to the future and be more specific of what they wil require of 
future studies.

Respondents would lie to see guidelines updated, 
Update guidelines. 
especially those relating to clinical trals. 
Earlier-or later-involvement by  Some of the 
FDA in the IND process. 
respondents would like to see FDA involved in the overall clinical development 
of the drg at an earlier point These manufactuers would like more security 
that the development coure they are following is one that FDA approves of. An 
IN 
equal number of manufactuers would like to see the  phase deregulated, 
. with less FDA involvement. These respondents feel that liabilty concerns 
sufficient to ensure that safety issues are adequately addresssed. Some 
manufacturers would also like to see detailed product formulation data and 
manufacturing information requested at a later point in time, not in the initial 
IND. 
Respondents 
Complete review of data as it is submitted during the IND phase. 

would like to see review of the NDA become more of a final formality in the 
review process. Manufacturers pointed out that generally the information 
submitted in the NDA has already been sent to the FDA and many times has 
tie 
aleady been approved once. Respondents feel that too much  is spent 
re-reviewing data. 
Respondents would like to 
Develop standard operating procedures for review. 

see more consistency from reviewer to reviewer and among 
diferent divisions. 
Manufacturers suggested developing standad operating procedures and 
guidelines for reviewers to reduce inconsistency. 
Manufacturers acknowledged it would be 
Hold to review clocks. 
 diffcult for 
tie 
FDA to complete NDA reviews within the current 180-day  frame. They 
would like to see more realistic time frames established and have FDA stay 
within them. Several manufacturers felt that reviewers did not feel bound by the 
curnt 180-day period because the tie frame is so unrealistic. 
Clarif regulations and role offoreign data.  Manufacturers would like to see a 
more accepting attitude from FDA towards foreign data. 
Severa respondents 
indicated they would like to see further clarfication in the regulations specifying 
exactly how much of the foreign data needs to be submitted and will be accepted 
by FDA.  Manufacturers would like to 
Change the way supplemental NDAs are handled. 
see more timely review of supplemental NDAs. They suggested the review time 
could be shortened by having the reviewer of the original NDA handle all 
supplements for that drg. This would prevent another reviewer from losing 
significant time reviewing the original NDA prior to looking at any supplements. 
Respondents would like to see some changes in the 
Improve management. 

management  was Ii frequently expressed opinion that 
strcture at FDA.  It 
divisional diectors were being asked to do too much in 
tring to be both 
scientist and manager. Respondents also felt that managers rarly contradict or 
afd 
overrde the decisions of the reviewers under them and are 
to do so. 
Respondents would like to see more managerial control over individual 
reviewers. 
Several manufacturers expressed the feeling that even if all 
Increase staffng. 

management and procedural concerns could be resolved, insuffcient personnel 
would still prevent FDA from being able to ensure timely approval of new drgs. 
Respondents 
Better understanding ofpharmceuticaZ manufacturing issues. 

progrs 
suggested exchange  with the industr as a method for FDA staff to 
become more famliar with the pharaceutical manufacturng process.  ENDNOTES

1. 
Sixteen manufacturs discussed their professional experiences with FDA review of 
abbreviated new drg  see Offce of 
applications. For the results of these discussions, 
Inspector General, Offce  Perspectives of Drug 
of Evaluation and Inspections, 
Manufacturers: Abbreviated New Drug Applications,  OEI; 12-90-00770, Februar 1990. 
See Foo and Drug Admnistration, Offce of the Commssioner, Offce of Planning and 
2. 
Agency Impact Analysis: Fruit Juice, The Perceptions ofTen Firm,  OPE 
Evaluation, 
Study 70 Agency Impact Analysis: Salad Dressings, The Perceptions of 
, June 1984, and 
Ten Firm,  OPE Study 64, May 1983.  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

Orho 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
 . ,. .-, '".  . =- .
"VlCU. 
DFEoPoA RanTMd EDNrTu O AF dHnEiAstTrHat &io. nH UMAN SERVICES  Public Health Service
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 
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 
s drug review processes. 
strengthen FDA'  This information gives
FDA a very helpful insight as we proceed to strengthen these 
processes. 
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 
fjs S. Benson