Drug Information Journal. Vol. 31, pp. 805-823.

1997 0092-8615/97
Rioted in the USA.All rights reserved. Copyright 0 1997 Drug Information Association Inc.

THE REGULATORY AFFAIRS

PROFESSIONAL IN THE “HOT SEAT” IN
THE DRUG DEVELOPMENT PROCESS
LORENL. MILLER,PHD
Executive Director, Drug Regulatory Affairs, PPD Pharmaco, Morrisville, North Carolina
DAVIDM. C O C C H E ~PHD
O,
Regulatory Affairs Department, Glaxo Wellcome Inc., Research Triangle Park, North Carolina

I%e role of regulatory affairs in the drug development process must and has expanded
to meet the goals of quicker and more eficient drug development. The regulatory affairs
professional participating in the process of development will be to a greater degree
placed in the proverbial “hot seat” to achieve expedited clinical development and rapid
review. To achieve this goal, the regulatory affairs professional needs to be proactive
and futuristic in hisher thinking, be able to monitor regulatory trends, possess scientific
expertise in one or more therapeutic areas, maintain constructive relations with regulatory
authorities, work effectively with project t e a m , and develop an international perspective
on drug development issues. This manuscript will explore these increasingly important
issues and illustrate their application to various case studies of drug development.

Key Work: Regulatory affairs professional; Regulatory trends; International perspective;

Regulatory strategy

INTRODUCTION drug development has been discussed re-

THE ROLE OF DRUG regulatory affairs in cently (1,2).
new drug development has evolved over re- The regulatory affairs professional (RAP)
cent years to the point that regulatory affairs should optimize drug development primarily
professionals are widely perceived to provide at the planning stages of development (being
“added value” to the drug development pro- proactive) rather than at the end stage of the
cess. The perception of the drug regulatory process in which the RAP is often placed in
affairs department as a “storage facility,” the unenviable position of “making do with
“document archives,” “mail drop,” burden- what you have,” “putting pressure on the
some “paper pusher,” or at best a “quality Food and Drug Administration,” offering ul-
control” unit has now been altered in most timatums to the division or office directors,
companies as the complexities of drug devel- and writing letters of protest to the Food and
opment have increased and changes in the Drug Administration (FDA) commissioner or
regulatory environment are recognized and ombudsman. The latter strategies are reactive
felt throughout the industry. The role of regu- in nature. As a RAP, and given the choice,
latory affairs in achieving optimized, rapid a proactive regulatory strategy is a far more
effective approach to drug development than
reactive strategies. This may be easier said
Reprint address: Dr.Loren L. Miller, PPD Pharmaco, than done given the current whirlwind of
1400 Perimester Park Drive, Morrisville, NC 27560. scientific, economic, and political influences
805
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806 Loren L. Miller and David M. Cocchetto

on the drug industry. The RAP, like other amendments, and recommend projects ap-
drug industry professionals, is always con- propriate for submission of pre-IND pack-
fronted with the drug development para- ages. These are all essential activities involv-
dox-“do it faster and do it with less”-and ing regulatory hardware.
is ultimately placed in the proverbial “hot Software is less tangible than hardware
seat” as the critical liaison to FDA in the and consists of such factors as breadth of
drug development process. regulatory experiences, including ability to
For the RAP to operate effectively within predict and interpret regulatory trends,
this contentious environment, he/she must knowledge of preferences and idiosyncrasies
think and plan not only in terms of interpreta- of regulatory authorities, and ability to serve
tion and implementation of regulations (ie, as a productive, constructive, and credible
the formal written rules or “hardware” of liaison between sponsor and regulators. The
regulatory affairs), but in terms of experi- importance of regulatory input in these areas
ences, productive relationships, interactions, cannot be overstated.
and evolving trends in the regulatory envi- Effectively operating within the software
ronment (ie, the “software” of regulatory af- environment entails collecting, analyzing,
fairs). Clearly, the RAP must handle the hard- and disseminating information pertinent to
ware issues with accuracy and timeliness. the development and approval of drugs by
The software defines added value in the cur- regulatory authorities. In this sense, the RAP
rent regulatory environment, however, be- must become an information specialist in an
cause in the long haul of drug development, effort to provide regulatory intelligence.
the sponsor which has taken advantage of Regulatory intelligence pertains to any infor-
available regulatory intelligence and prop- mation that is pertinent to the review and
erly anticipated evolving trends will ulti- approval of a drug. This may include infor-
mately be more efficient in the drug develop- mation on competitive products, especially
ment process and hence faster to the market the basis on which they were approved. Any
than its competitors (3,4). information collected must be assessed and
analyzed to determine if it has strategic sig-
nificance. Thus, the RAP in the current regu-
HARDWARE AND SOFTWARE
latory environment must play an additional
Hardware consists of formal regulatory input role over and above the purveyor of hardware
from regulatory authorities such as the FDA (regulations), that is, hdshe must provide the
and is usually presented as a law, regulation, software (intelligence and strategy) upon
directive, or guideline. The Code of Federal which the engine of drug development can
Regulations (CFR) is a good example of a run more efficiently.
directive that outlines carefully defined pro- Most often, the impact of software knowl-
cedures regulating the conduct of clinical re- edge is that the RAP can offer the project
search and the required contents of formal team multiple options to achieve a develop-
applications. The code is open to interpreta- ment goal. For example, a project team may
tion to some extent, but, for the most part, have sufficient clinical data to justify ex-
CFR regulations must be complied with by panding access to the investigational drug
industry, investigators, and institutional re- and possibly offering it for treatment use in
view boards. All RAPS are expected to have some settings. In such a case, knowledge of
knowledge of and be able to interpret regula- the software may lead the RAP to suggest
tions comprising the CFR. For example, the taking advantage of the regulations govern-
RAP on a multidisciplinary project team ing accelerated approval of certain new drug
must be able to inform the team of the re- products, as well as considering one or more
quired contents for its initial Investigational options for expanded access, including:
New Drug (IND), provide a draft table of
contents for the IND, define the necessary 1. Filing a treatment protocol to the current
timing for submission of various information IND,
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Regulatory Affairs in the Drug Development “Hot Seat” 807

2. Filing a separate Treatment IND, or that held real promise for treatment of pa-
3. Discussing with FDA a proposal to initiate tients with various forms of hepatitis. Clini-
a parallel track program. cal trials were underway or planned with
several nucleoside analogues, including fia-
The RAP, as other pharmaceutical special- luridine (FIAU). Other nucleoside analogues
ists, also seeks to cut drug development time following FIAU (eg, lamivudine, famciclo-
by minimizing delays that can occur in clini- vir) had hopes for fast-track development.
cal testing. Their development and all existing data,
however, had to be reassessed in view of
changing program risk once it was reported
RISKS IN DRUG DEVELOPMENT
that the predecessor drug, FIAU, was associ-
Drug development is an expensive, arduous ated with severe hepatic and pancreatic toxic-
process which increases in complexity as ity, as well as death, in several patients (6,7).
new regulations are introduced and as novel The evaluations triggered by this finding and
products are developed. There are at least multiple communications with FDA required
three major types of risk in drug develop- extensive effort and communication by regu-
ment: program risk, market risk, and expan- latory affairs personnel to assure that FDA
sion risk (5). was fully informed of all heightened safety
monitoring.
Program Risk
Market Risk
The challenges to the development of many
drugs are formidable depending on a host of Are there currently marketed products or
factors including the disease state, class of products under development which decrease
drugs under development, and proposed for- the value of a company’s product currently
mulations of the product. At the beginning under development? This is a question which
of the drug development process, there is a marketing units usually address early as the
pervasive optimism that any hurdle can be market for a product is being assessed. The
overcome; there appears to be an inherent RAP should provide information on the prod-
enthusiasm concerning the product, espe- ucts reviewed and approvednot approved by
cially on the part of the preclinical scientists FDA, as well as provide the basis for the de-
responsible for elevating a compound to de- cision. Importantly, the RAP must also pro-
velopmental status. Drug discovery is an ex- vide a realistic assessment of the type of la-
citing process, but the nuances of the regula- beling and claims that will be supported by
tory factors governing the drug development the intended clinical mals. It should be noted
process are often unrecognized at early that the clinical trial designs which are con-
stages. Invariably, optimism about a new sidered necessary and sufficient for regula-
drug outweighs a truly objective evaluation tory approval may not necessarily meet the
of its potential value. The RAP should have needs of the marketplace. For example, clini-
an idea of what regulatory hurdles a given cal trials may establish that a drug is safe
product may face based on experience and and effective, but not establish how it com-
knowledge of the regulatory authorities who pares with competitive products. At least
will ultimately be responsible for the regula- some placebo-controlled trials conducted in
tory oversight and review of a product appli- support of a marketing application should
cation. How is a given product likely to be contain a third arm, that is, treatment with
viewed by regulatory authorities? What is a marketed product approved for the same
the experience of the regulatory authorities indication. There is much to be gained from
with similar products? including the additional arm. First, if market-
An example may illustrate program risk. ing applications will eventually be submitted
In the last few years, considerable enthusi- internationally, many countries require com-
asm has existed for several novel compounds parison against a therapeutic standard as an
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808 Loren L.. Miller and David M. Cocchetto

active control. Second, the use of a standard within a pharmaceutical company and who
comparator allows for a relative risk-benefit now has a daunting responsibility for a major
assessment of the investigational drug and clinical development program. Yet, these fac-
established product. In addition, having some tors are extremely important in assessing the
comparative data at the time of application breadth, duration, and ultimate supported
filing may allow marketing units to design claims from a development program. For ex-
promotional pieces which support compara- ample, developing a lipid lowering agent
tive claims. The RAP must inform the mar- based on the endpoint of drug-associated re-
keting groups that a desire to promote on the duction in cholesterol or triglycerides in-
basis of comparative claims has significant volves a development program very different
ramifications for clinical development plans than one geared toward achieving changes in
prior to filing a New Drug Application morbidity or mortality endpoints. Similarly,
(NDA). The RAP must make marketing and clinical research personnel and investigators
clinical personnel aware that current FDA may be confident in the scientific validity
policy (“software”) requires at least two sup- of using reduction of hepatitis B viral DNA
portive adequate and well-controlled trials to (HBV DNA) or seroconversion as an ade-
establish a comparative superiority claim that quate endpoint for clinical trials of a new
is acceptable to FDA for use in advertising drug for chronic hepatitis B. The RAP, how-
and promotional labeling. The RAP should ever, must locate and share the historical
strive to reconcile the voices of the market, precedent that the regulatory approval of In-
regulations, and company. In this way, the tron A@(interferon alfa-2b) by FDA for se-
RAP represents the interest of the company lected patients with chronic hepatitis B was
by assuring that overall expectations are es- based not on serologic endpoints, but rather
tablished and met, rather than meeting the on demonstrating beneficial drug-associated
expectations of only the clinical research de- changes in liver histology.
partment by providing efficacy, but failing The RAP must have critical input to the
to meet the expectations of the marketing project team to assure selection of robust
department since product labeling can make endpoints that meet both scientific and regu-
no comparative claims with competitive latory needs. This may be accomplished by
products. helping to build consensus among scientists,
providing the scientists on the team with
summaries of regulatory precedents, seeking
Expansion Risk
advice from knowledgeable expertdconsul-
Does a sponsor have the necessary expertise tants, and fostering direct communication be-
to develop a drug in a given area of drug tween the sponsor’s technical staff and FDA
development? The RAP is often confronted scientists.
with the problem of communicating with sci-
entists who may be the clinical experts in a REGULATORY INTELLIGENCE
therapeutic area, but who have little or no
insight into regulatory issues that will heavily “Intelligence is the best defense against wishful
impact the development of a product. A good thinking.”
example is the choice of relevant endpoints Winston Churchill
for clinical trials. While many endpoints
have academic and scientific validity, drugs The goal of collecting intelligence and de-
are ultimately approved on the basis of veloping strategies is to influence tactical
proven or perceived clinical benefit. There- decision making. To achieve this goal, the
fore, clinically relevant endpoints must be RAP must monitor the regulatory environ-
employed in clinical trials. Sometimes this ment in which the company, as well as the
issue is lost on the academic clinician who pharmaceutical industry in general, operates,
works in a clinical research department gather and analyze information concerning

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Regulatory Affairs in the Drug Development “Hot Seat” 809

strategic changes in that environment, and opment and to offer alternatives to current
keep abreast of regulatory trends, assessing strategic plans when regulatory flaws are
their implications for future drug develop- identified. Being aware and prepared allows
ment. In Figure 1, a general information the RAP to proactively prepare contingency
model for the RAP is presented. In the model, plans for various development and registra-
the RAP filters needed regulatory informa- tion strategies, then take action quickly to
tion and fuses that information to make it remedy problems or seize opportunities. In
more manageable. Information should be fo- a word, the RAP should provide insight into
cused, evaluated, and synthesized before dis- the drug development process at multiple
semination. Types of projects where compet- levels and, therefore, in the future, avoid say-
itive and regulatory information is most ing: “I told you so” and avoid being asked:
useful is in the introduction of in-licensing “Why didn’t you tell us?’ Effective regula-
candidates, competitor company profiles, tory intelligence involves the ability to ana-
and benchmarking. This information should lyze regulatory trends, the knowledge of and
facilitate communications among groups ability to cooperate with regulatory authorities,
critical to the development of a product, es- and the ability to draw on a wide variety of
pecially marketing, clinical research, project regulatory experiences to create “actionable”
management, and senior management. behavior in the drug development arena.
The goal of the RAP is to create “action-
able” intelligence (8). Before dissemination, Regulatory ’ h n d s
the question should be asked: “can someone
use and act on this information?’ If so, the “What we anticipate seldom arrives;what we least
RAP has provided “added value” to the drug expect generally happens.”
development process. If the information pro- Benjamin Disraeli
vided by the RAP is valuable, decisions that
are likely to be influenced by external regula- Ten years ago, only a few of the topics
tory factors should be improved. An effective listed in Table 1 had substantial relevance to
RAP should influence the key players in the the existing drug development process and
drug development process, enjoining them to to product marketing. As issues associated
face critical issues impacting product devel- with each of these topics unfolded, they have

Filter Fuse Facilitate

Regulatory T d r
b

Product Data
b

Evaluate

Integrate Senior
Management
Focus

Synthesize
Noise
D
IntemSmn mth Disseminate
Regulatory Authonber
Adwsory CommMee
Acbons 6 Premdenta

FIGURE 1. Model for processing of regulatory intelligence and strategic planning.

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810 Loren L. Miller and David M. Cocchetto

TABLE 1
Regulatory Trends with Increasing Impact In the Last 10 Years

0 Evolution of expedited approval regulations 0 Toxicokinetics

0 Advertisinglpromotional standards 0 Environmental assessment
0 Chirality 0 GCP regulationdcompliance/enforcement

0 Electronic submissions 0 Product diversion

0 Adverse event monitoringlreporting 0 Rx-to-OTC switch

0 International harmonization 0 User feedFDA resources

0 Health economics and cost-effectiveness EMEA

0 Direct-to-consumer advertising 0 Preapproval inspection

0 Expanded access regulations 0 Quality of life assessments

0 Treatment IND 0 Rapporteur

0 Pre-IND package 0 Export petition

0 SUPAC (scale-upand postapproval change) 0 Parallel track

affected drug development, regulatory com- ditional preclinical and/or clinical studies
munications, and product marketing to a sig- prior to drug approval. Moreover, although
nificant degree. It is the responsibility of the FDA guidelines on stereochemistry were not
RAP not only to disseminate new regula- available, concerns and scientific recommen-
tions, proposed new rules, and guidelines as- dations on this issue were voiced in publi-
sociated with these topics to the affected per- cations and at professional meetings long
sonnel within the company, but also to before issuance of guidelines on stereochem-
interpret their impact on drug development istry.
and make this new knowledge actionable. Another problematic area of more recent
More importantly, the proactive RAP should vintage is the interpretation and enforcement
monitor regulatory trends well before laws of regulations governing advertising and pro-
and regulations are codified. This is because motional materials. In recent years, FDA has
ongoing drug development programs are not enacted and enforced guidelines and policies
immune to changes in regulations codified on advertising and promotion zealously, es-
after a development program is halfway pecially in the areas of off-label usage and
through the process. Although regulatory promotion based on comparative claims (9-
trends are not laws or regulations, regulatory 12). The RAP should make it clear to market-
authorities may act as if they are, and incor- ing staff that data available to support ap-
porate these “proposals” into the review of proval of an NDA may have limited utility
an application or into a general evaluation of from a marketing perspective unless ade-
a specific development program. For exam- quate and well-controlled clinical trials
ple, only a few years ago, many sponsors against competitor products have been in-
developing a chemical racemate did not rou- cluded in the NDA and accepted in FDA’s
tinely characterize individual stereoisomers. review. Promotional material making claims
The ramification of not adequately character- of comparative superiority will be vigorously
izing isomers was not often felt until the NDA reviewed and may be criticized by the
review was in progress and questions arose agency. A company’s marketing plan can be
regarding specific safety issues and activity doomed to fail unless sufficient regulatory
associated with the individual isomers. Some input is present to assure that the desired
basic pharmacology, toxicology, and/or me- claims are adequately supported by clinical
tabolism work conducted earlier to character- trials and the proposed labeling.
ize the isomers might have resolved such The evolution of expedited review and
issues and prevented delays in the review approval regulations allows sponsors devel-
process due to the unanticipated need for ad- oping “breakthrough” compounds for life-

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Regulatory Affairs in the Drug Development “Hot Seat” 811

threatening and severely debilitating diseases formation to key research and marketing
to obtain early feedback and cooperation by groups which may speed andor cut costs in
the FDA in the review and approval of a development.
development program leading to an NDA.
Regulations such as Subparts E and H facili-
Regulatory Interactions
tate drug development in the United States
by allowing the sponsor early interactions The ability to interact with FDA staff on a
with the agency to obtain feedback on a pro- regular basis above the level of the consumer
posed clinical development plan and design safety officer (CSO) or project manager has
of pivotal clinical trials. Subpart H regula- been attenuated in recent years. Drop-in vis-
tions, also known as the accelerated approval its, while never enthusiastically supported by
regulations, provide a means for sponsors to FDA, were acceptable on short notice in
obtain an initial approval for marketing based years past. Increased need for security and
on supportive clinical trials showing benefi- the desire by FDA to be more insulated from
cial changes in surrogate endpoints. The de- industrial influence have limited more per-
velopment plan for such drugs may be sonal interactions. Today, most interactions
streamlined with some of the usual regula- with the FDA occur through the CSO by way
tory requirements such as completion of spe- of voicemail. Nonetheless, all interactions
cific clinical trials, the need for large num- with the agency are very important and must
bers of patient exposures, or the completion be valued by sponsors (13). The RAP must
of specific toxicology studies (eg, carcinoge- remember that drug development is for the
nicity studies) being deferred until after drug “long haul” and that a sponsor may develop
approval. Taking advantage of these regula- multiple drugs that are evaluated by the same
tions is important to any sponsor attempting reviewing division. Learning about and un-
to expedite the development process. The derstanding FDA review staff allows the
RAP must anticipate the use of regulations RAP to anticipate the needs, standards, idio-
which will provide for faster development, syncracies, and preferences of reviewers. For
more frequent interaction with FDA’s review example, a reviewing chemist may be very
team, and quicker review. particular about specification limits on water
One manner in which the RAP may antici- content of the drug substance, whereas chem-
pate evolving changes in regulations is to ists in other reviewing divisions may be more
attend professional meetings in which poten- lenient about this factor. Also, trust between
tial changes in regulations are discussed and the reviewer and RAP is very important be-
debated in an open public forum prior to cause reviewers often request commitments
issuance. Meetings sponsored by profes- from sponsors verbally that need not be com-
sional organizations such as the Drug Infor- pleted before a drug is approved. Making
mation Association, Food and Drug Law In- sure that these types of commitments are
stitute, Regulatory Affairs Professionals honored is the responsibility of the RAP who
Society, Parenteral Drug Association, and must remind and cajole research and devel-
Pharmaceutical Research and Manufacturers opment staff to provide reviewers with re-
of America are ideal for this purpose. Other quested information even though the sponsor
special scientific meetings which may be at- is no longer “under the gun” to do so based
tended by FDA staff are also useful. on any formal FDA correspondence. Being
A goal for any RAP is to monitor the effective in these situations calls for a degree
regulatory environment and keep abreast of of salesmanship and credibility both within
potential changes in the regulations which the sponsoring company and at FDA.
may influence drug development. Anticipat- The RAP must be wary of being placed
ing the changing trends in regulatory require- between the proverbial “rock and hard place”
ments allows the RAP to provide critical in- in dealing with regulatory authorities. This

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812 Loren L. Miller and David M. Coccheno

is especially true with respect to issues of a total of 109 interactions between sponsor
compliance. For example, if a reviewer from and FDA.
FDA’s Division of Drug Marketing, Adver- Drug B was a drug for treatment of a life-
tising, and Communications informs a RAP threatening disease and, therefore, the drug
that a promotional piece is violative and re- was developed and reviewed under the Sub-
quests that the piece be voluntarily with- part E regulations. Although not reviewed
drawn, thereby avoiding a warning letter, it and approved as quickly as Drug A, Drug B
is damaging to the RAP’S relationship with progressed from submission to approval in
that reviewer when it is found weeks or 483 days with a total of 150 interactions be-
months later that the sponsor’s marketing tween sponsor and FDA.
group has failed to withdraw the promotional Drug C was a drug with no review priority
piece in question. and no early, formal FDNsponsor inter-
The RAP has considerable impact in those change during development, as for Subpart
situations in which the agency and sponsor E drugs. Drug C progressed from submission
are very interactive. This may occur if the to approval in 913 days with a total of 220
sponsor is developing a drug for a life threat- interactions between sponsor and FDA.
ening illness (eg. AIDS), is involved in an These data in Figure 2 illustrate three key
interactive review process such as that pio- points:
neered by the Pilot Drug Evaluation staff, or
is assisting with development of an electronic 1. FDA does have the ability to speed medi-
submission (eg, computer-assisted NDA). In cally important new drugs through review
these instances, when departure from the to approval. The more important the drug
usual review process is the norm, the RAP to decreasing mortality and morbidity, the
may be involved in numerous and extensive more accelerated the development, review,
interactions with agency staff. Accurately and approval process can become. Opera-
communicating requests from the FDA to the tionally within FDA, drug reviews are as-
sponsor becomes a crucial task for the RAP. signed a “priority” or “standard rating at
The RAP plays a special role in negotiations the time of NDA review. If the drug under
with FDA and may become the “pivotal” review is deemed by FDA to offer a signif-
player in the whole process. The pivotal na- icant therapeutic advance, a priority (P)
ture of this liaison function becomes clear review status is assigned. In accordance
when one considers the number and fre- with the Prescription Drug User Fee Act
quency of interactions between sponsor and (PDUFA), priority status provides a six-
FDA from the time of submission of an NDA month period for FDA to take action on
to the date of approval. Figure 2 illustrates the application. All other NDAs for drugs
the number of interactions between sponsor that are substantially equivalent to avail-
and FDA from times of submission to a p able treatments are given standard (S) re-
proval for three actual new chemical entities view status which, in accordance with
in the authors’ experience. All three applica- PDUFA, provides a 12-month period for
tions were subject to the Prescription Drug FDA to take action on the application,
User Fee Act. The differences among these 2. The sponsor must be prepared for numer-
three profiles are related principally to the ous and frequent interactions with FDA
type of drug and, therefore, the category of after submission of the NDA. In the case
FDA review. Drug A was a drug for use in of drugs for which accelerated approval is
patients with HIV infection; it was catego- sought (eg. Drug A), these interactions
rized by FDA as a 1-AA/E product (ie. a will be frequent (ie, daily), multidiscipli-
drug used in patients with HIV and a drug nary in nature (ie, address topics in multi-
with Subpart E status). Drug A progressed ple technical disciplines), and intensive. In
from submission to approval in 141days with the case of nonpriority drugs, interactions

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Regulatory Affairs in the Drug Development “Hot Seat” 813

FIGURE2. Exampiesof comparative frequencies and time coursesof interaction between

sponsor and FDA for three different types of drugs proceeding from NDA submission
to NDA approval (one Interaction was counted for each amendment, response to FDA
request for information, teleconference, meeting, and ietter/FAX to or from FDA).

will be less frequent (eg. weekly), often new dosage form for a drug product based
limited to one technical discipline at a on supporting chemistry/manufactng/con-
time, and protracted over a much longer trols data and a human bioequivalence study.
period of time, and FDA supports this view, but has the addi-
3. The ability to progess to approval rapidly tional expectation that the sponsor will not
depends on sufficient resources being promote the new product using clinical data
available at FDA to conduct the necessary collected on the original approved product,
review with follow-up interactions with but rather would collect new clinical data for
the sponsor, as well as depending on suffi- promotion of this new dosage form. Obvi-
cient resources being available at the spon- ously, the RAP must assure agreement of
sor to provide rapid, accurate, and com- these expectations long before an application
plete responses to FDA’s inquiries. is submitted.
Regulatory interactions are not limited to
In all interactions between sponsor and FDA if the RAP has international responsibil-
FDA, the RAP has the critical responsibility ities. Usually, larger sponsoring firms have
of assuring that both the sponsor and FDA active regulatory groups in Europe and Ja-
share a mutual understanding of the expecta- pan. The United States RAP must assure that
tions for the drug development program. As close contacts are maintained with interna-
in any interpersonal communication, a mis- tional regulatory colleagues to meet world-
match of expectations can be very costly. For wide goals for the submission of marketing
example, a sponsor believes that FDA has applications. It is important that the United
agreed to accept a Supplemental NDA for a States RAP is aware of regulatory issues af-

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814 Loren L. Miller and David M. Cocchetto

fecting product development worldwide. point, lowered serum cholesterol, is valid

Given that the International Conference on from a purely scientific perspective, the use
Harmonization process will be ongoing for of cholesterol level as an endpoint may be
some time, the RAP must be aware that an acceptable only if the drug under develop-
international clinical trial program is subject ment falls within a chemical class of lipid
to individual countrys’ clinical application lowering agents already approved for this
requirements for study initiation, supporting indication. If the compound under develop-
preclinical information, and adverse event re- ment represents a new class of chemical
porting requirements. agents having no established safety record,
the agency may require the use of more clini-
cally relevant long-term endpoints such as
REGULATORY EXPERIENCE
cardiovascular morbidity or mortality. There
When considering regulatory experiences, is no automatic buy-in to the use of a surm-
the RAP should think in terms of “hoops gate endpoint with lipid lowering agents by
and hurdles.” The RAP must define for the the FDA, even though several drugs in the
sponsoring company the regulatory con- past have been approved on this basis. This
straints and roadblocks that face the drug type of nuance may not be immediately ap-
development team. As is well-known, drug parent to medical and marketing groups
development is truly a team process. Regula- without conducting research into the basis
tory information and expertise should always of approval by FDA for similarly marketed
be supplied within a team context. A RAP drugs.
should not only have regulatory experience Thus, recognizing the scientific require-
but scientific experience within a therapeutic ments that regulatory authorities may specify
area, because most clinical research depart- has significant ramifications for the design
ments and hence many regulatory depart- of clinical trials, thereby affecting the size
ments are now organized by therapeutic area. and duration of the whole development pro-
Many RAPS are now recruited from clinical gram. For example, clinical trials designed
research departments in contrast to labora- using a mortality endpoint will be powered
tory and manufacturing departments which differently than those employing a surrogate
have been the more traditional roads into reg- endpoint. In addition, the duration of clinical
ulatory affairs. In addition, more RAPS have trials with mortality endpoints can be quite
advanced degrees which allow for greater extensive, lasting years. These types of facts
acceptance within multidisciplinary research should be provided by the RAP so that the
and development teams. duration and costs of drug development are
The RAP should develop sufficient scien- clearly understood.
tific expertise within a therapeutic area to General knowledge of how each of the
understand regulatorylscientific requirements FDA reviewing divisions is managed pro-
to obtain approval for a given drug. Regula- vides important information for the sponsor.
tory/scientific must be distinguished from the A useful source of information about review-
purely scientific. Regulatory/scientific refers ing divisions can be obtained by attending
to those scientific requirements that must be Pharmaceutical Research and Manufacturers
met to obtain regulatory approval. of America dialogue sessions in which staff
from a specific reviewing division are present
Case Study 1. A sponsor decides to develop along with industry representatives. An over-
a unique chemical entity for the treatment of view of division philosophy and managerial
elevated cholesterol. It is decided to perj4orm style is presented by FDA’s staff at these
two multicenter studies in asymptomatic pa- meetings. The managerial style and interac-
tients with elevated cholesterol levels with tiveness of most divisions is governed princi-
the goal of reducing lipid levels to some pres- pally by the philosophy of the division direc-
pecified criteria. While the choice of end- tor. If reviewing divisions within CDER

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Regulatory Affairs in the Drug Development “Hot Seat” 815

could be placed on a “continuum of interac- which there are differences across divisions.
tiveness,” the continuum would reflect spon- As another example, reviewing divisions at
sors’ perceptions in the differences across FDA differ in their historical experience with
reviewing divisions in the amount of direct various types of computer-assisted applica-
feedback received both during the drug de- tions. A useful overview of these differences
velopment phase and during NDA review. in experience has been published (11) and is
For example, on the one end of the contin- shown in Figure 3. These differences affect the
uum, one would probably find the Pilot Drug division’sreceptiveness to receiving computer-
Evaluation staff (with the reorganization of assisted New Drug Applications (CANDAs)
FDA’s reviewing divisions, the Pilot Drug offered by sponsors and, in the case of divi-
Evaluation staff no longer exists) which sions with extensive successful experience
stressed early interactions with the sponsor with CANDAs, this experience often leads
and provided significant input into drug de- the division to proactively request that the
velopment plans. In this same part of the sponsor provide a CANDA.
continuum, one would probably also find the
highly interactive Division of Antiviral Drug
REGULATORY INPUT AND STAGES
Products which deals with AIDS drugs
OF PRODUCT DEVELOPMENT
which have a high public health priority. In-
teractions during the drug development The type of regulatory information and ad-
phase are frequent and often informal. Infor- vice provided by the RAP will differ depend-
mation is frequently submitted quickly to ing on the particular stage of product devel-
these divisions via FAX and other less formal opment. The type of information provided
communication avenues. On the other end of varies by research and development disci-
the continuum, one would probably find the plines, that is, clinical, preclinical, chemistry,
Division of Neuropharmacological Drug microbiology, and so forth.
Products which tends to be more traditional The RAP in the current regulatory envi-
in its review of NDAs and more formal and ronment must think of drug development in
infrequent in its interactions with sponsors. international terms. For pharmaceutical com-
Such interdivisional variation can be quite panies to survive, products must penetrate
confusing to a company’s project managers international markets as soon as possible
who on the one hand obtain considerable after an initial registration. With the advent
feedback from one RAP on the status of re- of the International Conference on Harmoni-
view of an NDA submitted for an antiviral zation (ICH) and resulting guidelines, prog-
product, but little or no feedback from the ress has been made to harmonize regulations
RAP on the status of review of an antidepres- worldwide, but local regulatory as well as
sant drug. Sponsors developing drugs in spe- cultural differences will exist for the foresee-
cific therapeutic areas need to be aware of able future. The well-informed RAP must be
divisional idiosyncracies. Making corporate able to provide regulatory information which
management aware of these differences be- cuts across international regulations and
tween FDA reviewing divisions in manage- guidelines.
ment and review style is critical in terms of
expected feedback from FDA on the planning
Product InceptionPre-IND Stage
and execution of a project plan and the re-
view of major submissions. These differ- Early planning is the key to efficient drug
ences among divisions may, in the long run, development. The RAP at the pre-IND stage
be reduced with the advent of fixed review must define the local and international regu-
clocks which may promote greater scientific latory requirements. Clinically, the RAP
interchange and more open communications should help to determine the basis of ap-
between FDA and sponsor. proval for similar products under develop-
Interactiveness is only one dimension on ment around the world. In the United States,

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816 Loren L Miller and David M . Cocchetto

16

Rovimlng Dlvl8ion at FDA

FIGURE 3. interdivisional variation in the Center for Drug Evaluationand Research (FDA)
in historical experience with CANDAs over a fivayear period (198S1992)
(reference 14).

information on the basis of approval for com- On the nonclinical side, the ICH guide-
petitive products is available through FDA’s lines have gone a long way in harmonizing
Freedom of Information (FOI) Office and global toxicology requirements. The goal of
publications such as “The Pink Sheet,” as the RAP, however, should be to assure that
well as through other sources. One of the all requirements for major applications are
best sources of information is summaries of met. Some basic questions that a RAP should
advisory committee deliberations on similar ask at the pre-IND stage are:
products. These may be prepared by a RAP
who attends advisory committee meetings, 1. Is the margin of cover provided by toxicol-
most of which are open to the public. Infor- ogy studies adequate for initial and future
mation from sources in Europe and Japan on human testing?
the basis of approval for competitive prod- 2. Are findings in toxicology studies dose
ucts is less readily obtainable relative to related? Are findings reversible? How
sources in the United States. Many sponsors, does the AUC at which toxicity is noted
however, make use of local experts in foreign relate to intended exposure in humans?
countries who may have close interactions 3. If no target organ toxicity was observed
with regulatory authorities. The development using the intended clinical route of admin-
and approval process in Japan is a case in istration (eg, oral), have toxicity studies
point in which regulatory authorities seek out been done using alternative routes of ad-
expertise from local medical experts who ministration (eg, IV)?
provide advice to the Koseisho. Sponsors de- 4. Have species been used that are likely to
veloping drugs in Japan must seek out these produce metabolites similar to those in
experts to develop a comprehensive clinical man?
plan. 5 . What is the timing for completion of fertil-

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Regulatory Affairs in the Drug Development “Hot Seat” 817

ity and teratology studies to support inclu- off drug. Anticipating that this type of infor-
sion of women of child-bearing potential mation is required is critical to assuring that
in clinical trials? and initiation of clinical trials is not delayed.
6. Have appropriate special studies been On the chemistry side, numerous factors
done to explore any known class-related need to be considered prior to filing an IND
toxicities of the drug? or CTX. Key issues include:

In an effort to initiate clinical trials quickly, 1. Sourcing of drug substance and clinical
there sometimes is a tendency to submit a trial material,
minimalistic package of toxicology data in 2. Are available stability data compatible
the initial IND. This can lead to considerable with the duration of proposed use in the
problems in the review of the IND and may clinical trial setting?
result in a “clinical hold” on the conduct of 3. Is there sufficient experience with multiple
clinical trials. This may occur for any number batches of drug substance and drug prod-
of reasons including not fully explaining uct to support the IND?
deaths in toxicology studies, a need for addi- 4. Has there been a change in the impurity
tional mutagenicity trials, a need for special profile of drug substance due to a change
toxicity studies due to the proposed route of in chemical synthesis or degradation-re-
administration, or providing toxicology stud- lated impurities identified during stability
ies based on one route of administration testing of the drug product which may re-
when dosing by another route is planned in quire additional toxicology studies to char-
clinical studies. A major toxicology issue acterize the impurities?
that sponsors too often overlook is that drug 5 . Are there sufficient data to support that
exposure in humans in early clinical trials the clinical trial material has the identity,
will be limited to the duration of drug expo- purity, quality, and strength that is claimed
sure in toxicology studies. In certain circum- for it?
stances, the FDA will allow a pre-IND meet-
ing with a sponsor to work out issues related A key factor in a number of clinical holds
to the toxicity of the compound or FDA may that have been imposed by FDA is a lack of
be willing to have a pre-IND teleconference sufficient stability data for drug substance
to discuss toxicology issues related to IND and formulation. Typically, a sponsor should
filing. Other international regulatory authori- have stability data on multiple batches of
ties are also open to dialogue on these impor- drug substance and drug product for at least
tant issues. three months under various storage condi-
tions to support an acceptable IND.
Case Study 2. A sponsor files an IND for a
compound used to treat colorectal cancel:
IND/Clinical ’Ma1 Application Stage
The initial Phase I trial in humans will be a
chronic dosing study in which cancer pa- If clinical development plans are internation-
tients will be administered escalating doses alized, the RAP must make the project team
of the drug for five-day periods separated aware that the amount of information re-
by five-day nontreatment periods. The IND quired and the time to approve clinical trial
contained a one-weekescalating dose animal applications differ across different countries.
study.with dosing well beyond the proposed For example, both Canada and Denmark re-
maximum dose in humans. The toxicology quire 60 days to review an investigational
data, while acceptable in the United States, drug application once it is filed, whereas Italy
were not acceptable in a European country. can take up to three months and Spain six
A toxicology study was required in which months. Therefore, it is difficult to initiate
dosing in animals had to mimic human dos- international clinical trials simultaneously
ing, that is, five days on drug and five days unless careful planning occurs regarding the

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818 Loren L Miller and David M. Cocchetto

timing of submission of international appli- ulatory requirements in different countries is

cations. to review available guidelines such as the
For international clinical trial programs, Committee for Proprietary Medicinal Prod-
a decision needs to be made as to whether ucts guidelines on clinical evaluation of
all clinical trials (both United States and non- drugs (16). Often, these guidelines are less
United States) will be conducted under the specific than United States guidelines regard-
United States IND or not. There are pros and ing clinical trial specificity, design, and end-
cons of both approaches. If trials are done points (eg, Guidelines for the Study of Anti-
under the United States IND, clinical trial hypertensive Drugs), but are specific in terms
material may be exported under the IND reg- of expected duration of efficacy and safety
ulations to any country without additional testing and use of standard comparators.
documentation required by FDA. If trials are Clinical development plans can no longer be
not conducted under a United States IND, set up only to meet the requirements of single
clinical trial material may be exported to any markets (eg, United States), but must be de-
of 24 specific countries without prior FDA signed to meet worldwide requirements so
approval, as long as FDA is notified of expor- that prospective markets may be established
tation. This provision of allowing exporta- as early as possible and maximal use can be
tion of investigational drugs to certain coun- made of each clinical study.
mes without prior FDA approval became
effective on April 26, 1996 when President Case Study 3. A sponsor is developing an
Clinton signed into the law the FDA Export oncolytic compound for the treatment of co-
Reform and Enhancement Act. Of course, lon cancer. An international clinical trial is
exportation to any country other than 24 planned which employs the investigational
specified countries requires FDA’s prior ap- agent versus a standard comparative drug.
proval of a drug export petition filed through A study is designed and filed to the United
the Office of International Affairs at FDA. States IND and a CIX is alsofiled in Europe.
The Office of International Affairs may take The study drug is sourced in the United States
up to two months to complete the review and an export notijkation is prepared. The
of an export petition. Some sponsors may standard drug used as a comparative agent
expedite this process by using the legal certi- is marketed in Europe as well as in the United
fication option for export petitions (15). States. What is the potential pitfall in this
If conducted under an IND, both sponsor situation? Answer: In a cancer trial con-
and investigator are subject to United States ducted in the United States, the comparative
good clinical practice (GCP) requirements. drug would be ahinistered according to the
On an international level, it may be difficult dosage regimen in FDA’s currently approved
for foreign investigators to meet the specific labeling. It is important in such a trial to
letter of the United States GCP requirements, dose the comparative drug at a level which
especially those related to informed consent is considered to be clinically effective so that
and composition of the ethics committee. the investigational versus standard drug
A key task of the RAP at or about the comparison is considered to be a “air test”
time of submission of an IND/(JTX is to of the investigational drug ’s effectiveness.
provide input into the international clinical Belatedly, it is found out that while the stan-
development plan (ICDP). A well-conceived dard drug is approved in Europe, the recom-
ICDP which includes regulatory information mended dosage regimen is much lower than
and a submission strategy is paramount to in the United States. Under these circum-
successful worldwide drug development. stances, it may be dificult to perform a
Regulatory input into the ICDP is important combined multicenter study with different ap-
because of the different requirements interna- proved dosing regimens. Unless the Euro-
tionally as to what might constitute a suffi- pean study is conducted with adequate dos-
cient clinical plan. One way to anticipate reg- ages of the comparator, the European data

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Regulatory Affairs in the Drug Development “Hot Seat” 819

may not be acceptable to support an efSicacy before plans for international development
claim in the United States. are finalized.
Regulatory agencies around the world
Case Study 4. A sponsor is developing a drug have found ways to collaborate to achieve
for a life-threatening illness (eg, AIDS) in drug approvals if the disease in question is
the United States. The compound is eligible considered to be a widespread public health
f o r Subpart E status and the completion of problem. For example, in the case of some
only one well-controlled trial is required f o r AIDS drugs, some regulatory authorities in
approval in the United States. In addition, different countries have agreed to joint re-
the review of the NDA will be expedited and view, acceptance of a single marketing appli-
the agency agrees to defer completion of car- cation with only minor variations from coun-
cinogenicity studies until afrer the time of try to country, and the deferral or elimination
NDA submission. The company’s vice presi- of some regulatory requirements for initial
dent for marketing is ecstatic about this state approval (17).
of affairs and requests that the RAP provide
a timetablefor international submissions and
IND (CTX) to NDA (MAA) Stage
also suggests that these submissions occur
within three months of the United States sub- During this phase of the drug development,
mission. It is deemed that the United States the RAP must anticipate issues likely to im-
formulation would be acceptable f o r interna- pede development, product approval, and in-
tional registrations. What is the piqall in this ternational registrations. The most signifi-
plan? Answer: The expedited review and ap- cant factor that a RAP should attend to is
proval procedure based on surrogate end- whether communication between regulatory
points is not yet a standard regulatoryproce- authorities and sponsor are as open as possi-
dure in Europe. Therefore, the clinical data ble. The RAP must assure that available fo-
generated for the United States submission rums for communication are used by the
(one study) and the deferral of completion sponsor in the most effective way. Meetings
of carcinogenicity studies may not be accept- with the FDA, when available, are useful for
able as a basis for the Marketing Authoriza- this purpose. One critical meeting is the End
tion Application (MAA) in Europe. The key of Phase I1 meeting. The End of Phase I1
advice the RAP should give is that clinical meeting is important because its purpose is
development may need to be expanded, espe- to inform FDA about the preliminary efficacy
cially the completion of an additional well- and safety of the compound under study and
controlled trial and more drug exposures f o r to receive feedback on the proposed future
European registrations. The timetable for development plan. This meeting offers the
submissions internationally following sub- possibility of obtaining feedback on a variety
mission of the United States NDA may be of issues and sponsors should prepare exten-
much longer than the three months requested sively for such a meeting. In preparing for
by the marketing division. This is one case these meetings, there is a temptation to “hold
in which the United States plan does not lend back” information which might be perceived
itself well to coordinated international regis- as detrimental to drug development if there
trations based solely on the contents of the is a probability that FDA may require addi-
NDA. tional information in the NDA. One can
Access to regulatory authorities world- imagine conversations between medical and
wide is much better now than it was a few marketing groups prior to such a meeting in
years ago. European authorities are willing which reference is made to adverse reaction
to meet and discuss issues relevant to filing data, the discussion of which might be “de-
CTXs or MAAs. Thus, in addition to input ferred” to another time, or efficacy findings
from FDA, it is important to consult with which might not be as robust as thought on
regulatory authorities on a worldwide basis initial examination.

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820 Loren L. Miller and David M. Cocchetto

If issues critical to the development and Throughout development, the RAP and
eventual approval of a product are not dealt FDA’s review team should adhere to the basic
with in interactions with regulatory agencies principle of discovery, that is, all information
as early as possible, these same issues are or regulatory opinions held by FDA person-
likely to be a problem at the later stages of nel must be shared in a timely manner with
product development. Thus, in an effort to the sponsor and, similarly, all information
save time on one end, sponsors will avoid and the latest development plan by the spon-
facing certain realities, thereby providing the sor must be shared in a timely manner with
illusion that time is saved in development, FDA (20). Such “discovery” is an essential
only to see time added on after submission prerequisite to establishing shared expecta-
of the NDA when a major deficiency letter tions for the drug between the sponsor and
is issued by the agency which entails signifi- FDA.
cant remedial work. Nowhere is this more During Phase 11-111 clinical testing, the
apparent than in how sponsors treat and inter- RAP should be aware that events in any area
pret adverse experience data. It is extremely of drug development (preclinical, clinical,
important to evaluate adverse experience and development) can impact heavily on
data as they are collected and then determine other areas, that is, the RAP must operate on
whether additional clinical trials are needed the interface among all technical areas. For
to address specific safety issues. Although example, scale-up from the pilot plant to
such a strategy may result in the conduct of commercial-scale synthesis may result in a
a few additional safety studies and therefore change in impurity profile such as an increase
be rate-limiting to the completion of the over- in the amount of previously known impuri-
all development program, the agency is likely ties or the introduction of new impurities.
to pose questions about the safety profile of Or, a change in the formulation (eg, capsule
the drug and require additional studies follow- to tablet) may result in a degradation profile
ing NDA review. If the compound is consid- that is different than previously seen on sta-
ered to be a therapeutic breakthrough, the bility testing. This may mgger additional
agency may require that the sponsor complete toxicology studies to characterize the effects
special safety studies following approval. Not of the impurities. Ongoing stability testing
including key safety data in the NDA, how- may reveal a lack of effectiveness of the pre-
ever, tempts fate and may result in a marked servative in a solution formulation, thereby
delay in product approval. It is disconcerting necessitating a thorough investigation and,
to go into an advisory committee hearing and potentially, reformulation with a different
have this type of deficiency discussed in an preservative. Or, because of a change in the
open public forum when the sponsor has had route of synthesis with consequent physico-
adequate opportunity to address safety issues chemical changes in the drug, the product
during the development phase. profile may change enough that a human bi-
During Phases I1 and 111, the RAP with oequivalence study is required to “bridge”
other members of the sponsor’s team should the formulation used in clinical trials to the
critically assess certain key aspects of their new intended commercial formulation. This
development program. Two key aspects are: is work not previously anticipated, but which
may need to be completed prior to submis-
1. Whether or not the dose-response relation- sion of the NDA. Failure to provide these
ships are adequately characterized, and additional studies could result in a “Refuse
2. Whether or not the benefivrisk issues are to File” action by FDA or a rejection by other
adequately addressed. regulatory authorities resulting in a consider-
able delay in the initiation of application re-
Case examples illustrating the regulatory view.
perspective on these issues have been pre- Another area of interface occurs when
sented in previous papers (18,19). new preclinical findings arising from a sec-

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Regulatory Affairs in the Drug Development “Hot Seat” 821

ondary pharmacology study or toxicology TABLE 2

study completed during the course of clinical Countries Participating in the
Centralized Registration Procedure
testing may trigger additional clinical safety
testing which was unanticipated. For exam- Austria Italy
ple, if secondary pharmacology studies re- Belgium Luxembourg
port cardiovascular sequelae in dogs at expo- Denmark Netherlands
Finland Portugal
sures comparable to clinical exposure, this France Spain
may call for a special clinical pharmacology Germany Sweden
study to clarify these findings. While this Greece United Kingdom
may not be rate limiting in terms of pro- Ireland
longed drug development time if not in-
cluded in the marketing application, it may
cause the review of an application to become are that a decision to approve a drug must
extended and labeling negotiations to inten- be unanimous and the rapporteur is chosen
sify because of the lack of human data which by the EMEA. The mutual recognition proce-
might put the nonclinical findings into clini- dure involves obtaining approval in a limited
cal perspective. number of countries. Choosing this proce-
Another example comes from new toxi- dure allows for consensus building across
cology findings. If a chronic toxicity study in countries for a given drug and may be benefi-
the dog, for example, shows coagulopathies cial to marketing and pricing strategies. Fur-
after extended exposure that were not appar- ther, the rapporteur is chosen by the pharma-
ent after one week and one month of dosing, ceutical company. Approval in all countries,
this may trigger the need for additional safety however, will take longer relative to the cen-
testing. Therefore, the project team may de- tralized procedure. In addition, the RAP must
cide to amend ongoing clinical trials to col- be aware that the review of certain classes
lect specimens for coagulation tests, thereby of drugs (eg, drugs for the treatment of AIDS
avoiding the possibility of leaving these or certain psychiatric disorders, as well as
questions in humans unanswered in the fu- biotechnology products) must automatically
ture. go through the centralized procedure.
One goal of the RAP is to develop consis-
tent worldwide product labeling. This is ap-
NDAMAA to Approval Stage
proached through the development of a core
Prior to filing an NDA/MAA, the RAP, espe- label which provides the basis for labels in
cially on the international level, must interact different countries. This is not always easily
with multiple regulatory authorities to achieved, however, because data collected in
achieve successful international registra- foreign populations such as the Japanese or
tions. A well-conceived filing strategy is es- African people may not match data collected
pecially important in Europe where a rappor- in a United States or western European popu-
teur country that will “champion” the product lation. A number of factors contribute to this,
must be identified and the choice of filing including:
strategy (the centralized, mutual recognition,
or national route) must be decided. With the 1. Diagnostic criteria for certain disorders
establishment of the European Medicines may differ across cultures,
Evaluation Agency (EMEA). the RAP must 2. Therapeutic practices and standards of
rapidly gain familiarity with the new Euro- care differ widely,
pean procedures and make recommendations 3. Concomitant therapies differ across coun-
regarding a filing strategy. The advantage tries,
of the centralized procedure is that product 4. Body size/mass differs across cultures
approval can occur across 15 different coun- which may affect dosing requirements,
tries at one time (Table 2); the disadvantages 5 . Genetic differences in drug metabolism

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822 Loren L. Miller and David M. Cocchetto

may differentially influence drug action velopment (1,2). Both authors identified the
and affect generalizability, and actual need for a RAP to be part of an inter-
6. General health and diet can influence disciplinary team and stressed the impor-
study results (21). tance of developing a regulatory strategy.
While both authors stressed speed and effi-
Any of these factors can influence study out- ciency in drug development, the present arti-
come across both efficacy and safety vari- cle expands on these concepts and stresses
ables and hence any of these factors can ulti- that to achieve speed and efficiency, the RAP
mately affect product labeling. must be proactive in the areas of interactions
A common problem in this area revolves with regulatory authorities and carefully
around establishing dose-effect data for effi- monitoring regulatory trends. The proactive
cacy. For example, dosing requirements be- approach should include a strong intema-
tween United States and Japanese popula- tional perspective and provide key regulatory
tions may be different because of weight and information at critical stages in drug develop
mass differences between the two popula- ment. Importantly, the proactive approach in-
tions. Invariably, dosing recommendations cludes efforts to assure integration and har-
do not match. In this case, dosing may be monization of the science across each of the
recommended in mgkg or by concentration- technical areas contributing to regulatory ap-
effect. In any event, the RAP must be aware plications.
that combining data from studies across dif- To meet these goals, pharmaceutical com-
ferent races and cultures will result in careful panies have taken different approaches. In
scrutiny by regulatory authorities, especially some pharmaceutical companies, an intelli-
in terms of subpopulation statistical analyses. gence function, including regulatory infor-
One area in which the RAP should play mation, has been centralized. Regulatory in-
a pivotal role is the establishment of a post- formation pertinent to drug development is
NDA team or “SWAT’ team which has the combined with information from a variety of
primary responsibility of rapidly supplying sources including marketing, clinical re-
responses to queries made by regulatory au- search, and project management and is in-
thorities. Many authorities require that re- cluded under the rubric of “competitive or
sponses to queries be addressed within a spe- strategic intelligence” (22,23). Groups pro-
cific time frame, sometimes the same day. viding this type of information may be cre-
This necessitates a coordinated effort by ated within business development units. In-
members of the project team to meet time- formation from these sources is often general
lines for responses to questions from regula- in nature and may be driven from a marketing
tory authorities. This activity is extremely or sales perspective. Specific and in-depth
important for successful international regis- regulatory information may not be obtainable
trations. from such sources. One approach to regula-
tory intelligence is to provide regulatory af-
fairs departments with an intelligence coor-
DISCUSSION dinator who is linked to information services,
the Internet, and various databases in order
This article describes several critical roles to track and synthesize critical information
for the RAP in the drug development process pertaining to product development. The es-
which, in some cases, exceed the usual or tablishment of a regulatory affairs library is
more traditional role played by regulatory also very useful (3).
affairs departments. Previous authors have The RAP, to be successful in the current
stressed that the RAP can provide added climate of drug development, must not only
value by speeding up the process, identifying be a document manager, but have a consider-
various acceptable regulatory options for able degree of scientific acumen (including
drug development, and optimizing drug de- therapeutic area expertise) in order to be

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Regulatory Aflairs in the Drug Development “Hot Seat” 823

credible with staff in scientific disciplines. 9. Kessler DA, Pines WL. The federal regulation of
Sometimes, this requires on-the-job training prescription drug advertising and promotion. JAMA.
1990;264:24O9-2415.
through attendance at professional scientific 10. Morris LA, Banks DB. New issues in drug advertis-
meetings and investigatorkonsultant meet- ing and labelling: the five advertising end-runs. Drug
ings. I f J. 1990;24:639-646.
Additionally, the RAP must be aware of 11. Kessler DA. Drug promotion and scientific ex-
international regulatory issues affecting change: the role of the clinical investigator. New
Engl J Med 1991;325:201-203.
product development. This can be achieved 12. Kessler DA, Rose JL, Temple RJ, Shapiro R, Griffin
within an international regulatory affairs JP. Therapeutic-class wars-dmg promotion in a
group with staff located in the United States, competitive marketplace. New Engl J Med. 1994;
Europe, and Japan. Close interactions and 331: 1350-1353.
collaboration among these regulatory groups 13. Given KM. Value the US pharmaceutical industry
places on early dialogue in the drug development
are a necessity. process. Drug Inf J. 1992;26:311-316.
In summary, the RAP in the current regu- 14. Lumley C, Walker S (editors). Improving the Regu-
latory environment must wear multiple hats latory Review Process: Industry and Regulatory Ini-
in the drug development scheme, including tiatives. Lancaster, U K Kluwer Academic Publish-
those of a scientist, document manager, inter- ers; 1996, page 77.
15. Food and Drug Administration. Guidance for sub-
national strategist, information specialist, li- mitting a request for FDA authorization to export a
aison, and negotiator. For drug development drug to be used in a clinical investigation not being
to be successful, the function and roles of pursued under an investigational new drug applica-
regulatory affairs departments must be more tion (Finn Request, Option 2). January 1993.
16. European Commission. The Rules Governing Medic-
defined with RAPS being key members of
inal Products in the European Union. Volume III.
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