PERSPECTIVES OF DRUG


MANUFACTURERS


INVESTIGA TIONAL NEW DRUG AND NEW DRUG APPLICA TIONS 

"ERVICE$. i-

'0 

IiVd:m 

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 

FDA' s review of INs 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 

drg. This information is priary 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 approval. All 24 firms agreed; the fis parcipating in the study are listed in appendix A. 

Of the 24 fis 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 

are safe and effective. 
 Overall, respondents we interviewed concerning FDA' 

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 firm 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 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 changes to improve the IND and NDA approval processes. 

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 

FDA' s review of INs 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 

drg. This information is priary 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 communication stating that the Agency wil approve the application if certn 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. 

Of the 24 fi 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 

are safe and effective. 
 Overal, respondents we interviewed concerning FDA' 

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.


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

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. 

All 15 respondents interviewed concerning IN 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 

their INs 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 

considered FDA guidance on developing an IN submission adequate added, "While the 

guidelines ar 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 

become a bigger problem since the IN 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. 

Checking on the status of applications. 
 Two-thirds of the respondents (10) considered it fairly 

easy to check on the progress of an IN 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. 

Communicating with FDA during clinical trials. 
 Almost al of the respondents indicated that 

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 review. Nine respondents had attended a "ninety-day 

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 

regarding their IN 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 

usually influences review tie 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 

the course of the IN 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. 

The majority of respondents (9) also considered the review ofINs il-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 

lacking on-going review of clinical information in the IN 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 

the data we send in. FDA is innundated with paper and has no time to pull the entire IN 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.


Update guidelines. Respondents would lie to see guidelines updated, 

especially those relating to clinical trals. 

Earlier-or later-involvement by FDA in the IND process. Some of the 

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 

equal number of manufactuers would like to see the IN 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. 

Complete review of data as it is submitted during the IND phase. 
 Respondents 

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 

aleady been approved once. Respondents feel that too much tie is spent 

re-reviewing data. 

Develop standard operating procedures for review. 
 Respondents would like to 

see more consistency from reviewer to reviewer and among diferent divisions. 

Manufacturers suggested developing standad operating procedures and 

guidelines for reviewers to reduce inconsistency. 

Hold to review clocks. 
 Manufacturers acknowledged it would be diffcult for 

FDA to complete NDA reviews within the current 180-day tie 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. 
Change the way supplemental NDAs are handled. Manufacturers would like to 

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. 

Improve management. 
 Respondents would like to see some changes in the 

management strcture at FDA. It was Ii frequently expressed opinion that 

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 

overrde the decisions of the reviewers under them and are afd to do so. 

Respondents would like to see more managerial control over individual 

reviewers. 

Increase staffng. 
 Several manufacturers expressed the feeling that even if all 

management and procedural concerns could be resolved, insuffcient personnel 

would still prevent FDA from being able to ensure timely approval of new drgs. 

Better understanding ofpharmceuticaZ manufacturing issues. 
 Respondents 

suggested exchange progrs 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 applications. For the results of these discussions, see Offce of 

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

Manufacturers: Abbreviated New Drug Applications, OEI; 12-90-00770, Februar 1990. 

2. See Foo and Drug Admnistration, Offce of the Commssioner, Offce of Planning and 

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

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

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


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. 

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

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

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


interactions and exchanges between our staffs. 

fjs S. Benson