2

Compliance Requirements Duringthe Drug

Development Process
Martin D. Hynes III
Eli Lilly and Company, Indianapolis, Indiana, U.S.A.
1 INTRODUCTION
The development of a new drug is a long, complex, and costly process. Cur-
rent estimates show that it can take up to 14.7 years [1] and cost in excess of
$800 million [2]. This complexity is a result of the large number of studies
that need tobe performed prior tothe submission of a marketing application.
Additionally, the complexity comes in part fromthe large number of regula-
tions that governthe preclinical andclinical studies that support a NewDrug
Application (NDA). The U.S. compliance regulations that govern the pre-
clinical and clinical studies that make up an NDA include Good Laboratory
Practices (GLPs), Good Manufacturing Practices (GMPs), and Good
Clinical Practices (GCPs). These regulations were written in the late 1970s
and early 1980s to specify how preclinical safety studies, clinical trials, and
development operations were to be conducted in support of an NDA.
1.1 Compliance Regulations
The understanding of these compliance regulations has evolved since their
inception 20 years ago. In part, this evolution has resulted from how the
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Food and Drug Administration (FDA) has interpreted these regulations
through its inspection activities. During the early 1990s, FDAenforcement
activities increased markedly [3]. This was evidenced by increases in warn-
ing letters, product seizures, injunctions, prosecutions, and recalls [4]. This
increase in FDAenforcement activities was similarly observed across all of
the regulations under which pharmaceutical companies work as they
develop new drugs. For example, the FDA increased the number of clinical
trial sites that it audited. In the GLPs area, there was an increase in the num-
ber of GLPs studies rejected by the FDA. This trend of evolving interpreta-
tions and heightened enforcement activity in the area of GMPs was
evidenced by the initiation of pre-NDAapproval inspections [3,5,6].
1.2 Drug Development
Another driver of complexity in the drug development process is the fact
that most pharmaceutical companies are global; that is, drug therapies
are being developed for patients on a worldwide basis. To do this means
dealing with GLPs, GCPs, and GMPs that dier on a country-by-country
basis.The dierences inthese regulations were frequently signicant enough
to warrant repeating many studies to meet local requirements. This had the
impact of adding to the time and expense of introducing a new drug to
patients in need in particular parts of the world without necessarily provid-
ing any signicant new knowledge about the drugs. As a result, there has
been an eort to harmonize these compliance regulations on a global
basis through the International Conference on Harmonization (ICH).
The ICH was instituted as a forum for the creation of viable alter-
natives to the country-by-country regulatory requirements. The ICH
membership consists of representatives from the Commission of the Eur-
opean Communities, the European Federation of Pharmaceutical Industry
Associations, the Japanese Pharmaceuticals Manufacturers Association,
the Japanese Ministry of Health and Welfare, the U.S. FDA, the Pharmaceu-
tical Research and Manufacturers of America, and the International Federa-
tion of the Pharmaceutical Manufacturers Association. These groups
represent both the industry and regulatory agencies for the participating
countries [7]. The outcome from the various ICH working groups has
impacted all of the compliance regulations (GLPs, GCPs, and GMPs). The
regulatory need toconduct separate studies tomeet the needs of local regula-
tory requirements has been dramatically reduced as a result of the
harmonization activities. Whether this translates into a real decrease in the
number of studies that companies have to conduct to register drugs on a
global basis remains to be seen. This chapter will provide a brief overview
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of the GLP, GCP, and GMP requirements as they relate to the drug develop-
ment process as well as present critical compliance issues related to these
requirements.
2 GOOD LABORATORY PRACTICES
Good laboratory practices regulations are published in the U.S. Code of
Federal Regulations (CFR), Title 21, Part 58 [8], and Title 40, Part 160
[9], for the FDA and the Environmental Protection Agency (EPA), respec-
tively. The GLPs became an ocial requirement in the United States on June
20, 1979. The GLPs provide standards for the planning, performance, moni-
toring, recording, and reporting of preclinical safety studies conducted in
support of an application to market a new drug [8]. It is only after the FDA
reviews the results of the preclinical studies that the product can be judged
to be safe. The FDAthus has the responsibility to review the data submitted
in the NDA, while the burden for proving safety rests with the sponsor of the
NDA submission. Sponsors can perform the needed studies in their own
laboratory facilities, in those of a contract research organization, or in a uni-
versity laboratory.
2.1 Historical Perspective
Until the mid-1970s, the assumption on the part of the FDA was that
preclinical studies submitted by the sponsor were well conducted, analyzed,
and reported. In the mid-1970s the FDA began to have questions about the
uniformityandqualityof thestudiessubmittedtoit aspart of anNDA. During
the process of reviewing study reports, scientists at the FDA observed data
inconsistencies and evidence of unacceptable laboratory practices [10].
As a result of these FDA observations, for-cause inspections were
performed at a number of institutions conducting preclinical safety studies.
The results of these inspections were reported to the U.S. Senate in July of
1975, by the then FDA commissioner, Dr. Alexander M. Schmidt. The
ndings for these for-cause inspections showed problems in the design, con-
duct, and reporting of preclinical safety studies. These problems were
deemed so serious as to question the validity of some studies. The following
examples are illustrative of the magnitude and seriousness of the problems
uncovered in these for-cause inspections carried out by the FDA.
One of the rms inspected by the FDAwas Industrial Bio-Test Labora-
tories (IBT). At the time it was one of the largest contract testing facilities
in the world. IBThad conducted literally thousands of preclinical safety stu-
dies that were submitted to the FDAto establish the safety of drugs awaiting
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approval to be marketed. The following is a partial list of the problems that
were identied in the for-cause FDA inspection [10]:
Physical conditions were very poor.
Reports were not consistent with the original data.
Peer reviewof pathology studies resulted in dierent conclusions, with
only the favorable one submitted to the FDA.
Food and water consumption was recorded as normal despite the fact
that the animals were dead.
Drug doses could not be determined.
Histopathology reports existed for animals when tissues were not
taken.
After reviewing these ndings, its easy to see why the FDAwas con-
cerned about the validity of the work conducted at IBT. As a result, the FDA
declared the majority of long-term studies done by IBT to be invalid. Spon-
sors were then required to repeat these invalidated studies at great
expense. IBTwent out of business and several company ocials were con-
victed of defrauding the government and jailed.
An audit at Searle found a number of similar problems. For example,
the audit or for-cause inspection carried out by the FDAshowed [10] the fol-
lowing:
Malignant mammary tumors were omitted froma statistical summary.
There were dierences between the rawdata and the nal report.
Animals were dropped fromthe study without explanation.
Written protocols for completed studies could not always be found.
2.2 Link to Phase of Development
These ndings, in conjunction with those from IBT, led the FDAto the con-
clusion that studies were poorly conceived, executed, documented, ana-
lyzed, and reported. Additionally, it was clear that the rms management
did not provide for adequate supervision and reviewof the data for accuracy
prior to submission. These conclusions, which basically served to invalidate
these preclinical safety studies, were deeply disturbing to the FDA, Con-
gress, the general public, and industry. As a result, FDA Commissioner
Schmidt established the Bioresearch Monitoring (BIMO) program in early
1976 to deal with the validity of data from both preclinical and clinical stu-
dies [11]. A toxicology monitoring task force set up by the BIMO dealt with
the validity and reliability of all nonclinical laboratory studies conducted
to support the safety of FDA-regulated products. As a result of its work,
it recommended the establishment of GLP regulations to ensure the
validity of preclinical safety studies. These regulations were drafted by a
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subcommittee composed of FDA and scientic personnel [10]. The group
started its work with a rough draft that was based upon two independent sets
of guidelines submitted by G.D. Searle and Company and the Pharmaceuti-
cal Manufacturers Association. After review and revision, the committees
work was published in 21CFR, Part 58 [8].
The focus of these regulations was on the process that ensures the qual-
ity and integrity of the safety data. It should be noted that safety data were
dened asany in vivo or in vitro experiments inwhich test articles are studied
prospectively in test systems under laboratory conditions to determine their
safety[8]. It was not an attempt to ensure good science or interfere with the
judgment of scientists conducting the studies. These GLPs regulations cov-
ered the following topics [8]:
Subpart A
General provisions
Scope
Denitions
Inspection of a testing facility
Subpart B
Organization and personnel
Personnel
Testing facility management
Study director (SD)
Quality assurance unit (QAU)
Subpart C
Facilities
General
Animal care
Animal supply
Laboratory operation areas
Specimen and data storage facilities
Administrative and personnel facilities
Subpart D
Equipment
Equipment design
Maintenance and calibration of equipment
Computers
Subpart E
Testing facilities operation
Standard operating procedures (SOPs)
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Reagent and solutions
Animal care
Subpart F
Test and control articles
Characterization
Handling
Mixture with carriers
Subpart G
Protocols and study conduct
Protocol
Conduct
Subpart H^I
Records and reports
Reporting
Storage and retrieval
Retention
Subpart K
Disqualication of testing facilities
Disqualication
Suspensions or terminations
Reinstatement
The complete regulations as well as the post conference report fromthe
management brieng held in May 1979 can be found at http://www.fda.gov/
ora/compliance___ref/ or in the postconference report [11].
The FDA has the ability to ensure compliance to these regulations
through inspections conducted by its eld investigator. Routine facility
inspections are done every other year, while for-cause inspections can be
done at any time. A refusal on the part of a rm or sponsor to allow
the FDA to inspect can result in a disqualication of the studies. If during
the course of an inspection the FDA nds signicant deviations from the
GLPs, the studies can also be disqualied. In general, at the conclusion of
an FDA inspection it is more common for the FDA investigator to nd
deciencies that need to be corrected but that are not signicant enough
to question the validity of the work. In this case, the FDA investigator docu-
ments the observations of noncompliance to the GLPs on Form 483,
Notice of Inspectional Observation. In response to these ndings, rms
need to respond to the FDA as to how and when these observations of
noncompliance will be corrected.
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2.3 Evolution/ICH Harmonization
The implementation of GLPs regulations was not limited to the United
States. European GLPs were rst issued in1981and were revised in1997. The
Japanese also set standards for preclinical safety studies in 1983. Although
there is some similarity among these global GLPs, there are a sucient num-
ber of dierences, requiring additional studies to be performed, which in
turn increases drug development time lines and expense with minimal
return in terms of new information. These dierences were the result of var-
ious legislative mandates and regulatory agendas. A great deal of work has
been done within recent years to harmonize the GLPs regulations as a part
of ICH [7].
These harmonized GLPs regulatory expectations are a signicant
advantage to pharmaceutical companies doing business on a global basis in
that they allowthe design and implementation of one set of standardized stu-
dies to meet all worldwide regulatory requirements, thus reducing the total
number of preclinical safety studies on a drug candidate. One additional and
important benet is it helps rms in their eorts to minimize deviations from
GLPs, since there is one set of standards against which to assess GLPs com-
pliance throughout critical phase inspections and nal study reports [7]. It
is important to note, however, that there is a long way togo. Many dierences
still exist, such as the length of a chronic dog study, in vitro cardiac conduc-
tion, and Japan safety pharmacology.
3 GOOD CLINICAL PRACTICES
3.1 Overview
The federal regulation of drugs in the United States dates to the early 1900s.
Although the Pure Food and Drug Act of 1906 was in large measure directed
at the elimination of unclean and adulterated foods for the market, it also
dealt with controlling drugs. Additional regulations were issued in1923 that
were focused on the bioassay of important drugs and their preparation.
The Pure Food and Drug Act of 1906 was amended in 1938, following
the death of about 100 children. The deaths were the result of an elixir of sul-
fonamide, which utilized diethylene glycol, a highly toxic solvent. The elixir
of sulfonamide tragedy triggered the introduction of an administrative pro-
cedure for the approval of new drugs of unknown safety prior to market
introduction. Section 505 of the Food, Drug and Cosmetic Act of 1938
forbade the introduction of new drugs into interstate commerce without
FDA approval. In 1962, the Kefauver ^Harris amendments of the 1938 act
resulted in an increase in regulatory control over many aspects of clinical
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research. In large measure these amendments were the result of concerns
resulting from perceived deciencies on the part of the pharmaceutical
industry to adequately protect the public health in the thalidomide tragedy.
Thalidomide is a hypnotic that was used in Europe in the early 1960s. Epi-
demiological research established that thalidomide taken early in the course
of pregnancy caused a rare birth defect, phocomelia.
The 1962 amendments required sponsors to do a number of things
including: demonstrate clinical ecacy in scientically valid studies, esta-
blish informal consent guidelines, generate preclinical safety data to support
clinical trials in humans, and report adverse events. The FDA was also
granted the authority to regulate clinical research by requiring investigators
and sponsors to maintain study records that must be made available for
inspection by the FDA. A key requirement of the 1962 amendments was the
need tole an Investigation NewDrug application (IND) prior to the initia-
tion of clinical trials with an experimental drug. Since that time the IND
regulations have been modied to provide additional detail as to the respon-
sibility of sponsors, investigators, and monitors. These modications were
made throughout the 1970s and1980s.
Good clinical practices govern the approval, conduct, review, and
reporting of clinical research intended for submission in an NDA. The U.S.
GCPs as enforced by the FDAare delineated in the following documents:
21 CRF, Part 50Protection of Human Subjects, Informed Consent.
Eective date July 27, 1981 [12].
21 CFR, Part 56Protection of Human Subjects; Standards for Insti-
tutional Review Boards for Clinical Investigations. Eective date
July 27, 1981 [13].
21 CFR, Part 312New Drug Product Regulations. Final rule issued
1987 [14].
21 CFR, Part 314Applications for FDA Approval to Market a New
Drug or an Antibiotic Drug [15].
Subpart CFDA Action on Applications
314.126Adequate and well-controlled studies
A general outline of the topics covered in the U.S. GCPs is as follows:
Part 50Protection of Human Subjects [12].
Subpart AGeneral Provisions
Subpart BInformed Consent of Human Subjects
50.20General requirements for informed consent
Subpart CProtections Pertaining to Clinical Investigations Involv-
ing Prisoners as Subjects
50.44Restrictions on clinical investigations involving prisoners
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50.46Composition of institutional reviewboards where prisoners
are involved
Part 56Institutional Review Boards
Subpart AGeneral Provisions
56.103Circumstances in which IRBreview is required
Subpart BOrganization and Personnel
Subpart CIRBFunctions and Operations
56.109IRBreviewof research
56.111Criteria for IRBapproval of research
Subpart DRecords and Reports
Subpart EAdministrative Actions for
56.121Disqualication of an IRBor an institution
Part 312Investigational New Drug Application
Subpart AGeneral Provisions
312.6Labeling of an investigational newdrug
Subpart BInvestigational New Drug application (IND)
312.20Requirement for an IND
312.22General principles of the INDsubmission
312.23INDcontent and format
312.32INDsafety reports
312.33Annual reports
Subpart CAdministrative Actions
312.40General requirements for use of an investigational new
drug in a clinical investigation
312.42Clinical holds and requests for modication
Subpart DResponsibilities of Sponsors and Investigators
312.50General responsibilities of sponsors
312.53Selecting investigators and monitors
312.56Reviewof ongoing investigations
312.57Record keeping and record retention
312.58Inspection of sponsors records and reports
312.60General responsibilities of investigators
312.61Control of the investigational drug
312.62Investigator record keeping and record retention
312.64Investigator reports
312.70Disqualication of a clinical investigator
Subpart EDrugs Intended to Treat Life-Threatening and Severely
Debilitating Illnesses
312.83Treatment protocols
312.84Risk benet analysis in review of marketing applications
for drugs to treat life-threatening and severely debilitating illnesses.
Subpart FMiscellaneous
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312.110Import and export requirements
312.120Foreign clinical studies not conducted under an IND
Subpart GDrugs for Investigational Use in Laboratory Research
Animals or InVitroTests
Part 314Applications for FDA Approval to Market a New Drug [15]
Subpart CFDA Action on Applications
314.126Adequate and well-controlled studies
The requirements outlined in the CFR are legally enforceable by the
U.S. FDA. In addition to the above-mentioned documents, the FDAhas gui-
dance documents that are not legal requirements but do provide direction
on acceptable standards for clinical research. They are as follows:
FDA, Guidelines for Monitoring Clinical Investigators, January1988
FDA, Information Sheets for IRB and Clinical Investigators, October
1995
FDA, ICHGCPs Consolidated Guidelines, May1997
In order to enforce compliance with these U.S. regulations, the FDA
has a comprehensive program of on-site inspections of clinical trial investi-
gations and data audits. These compliance activities are designed to monitor
all aspects of the conduct of clinical studies intended for submission in the
NDA. The goal of these inspections and audits is to ensure data quality, data
integrity, and the protection of research subjects. This comprehensive pro-
gram of on-site inspections and data audits is known as the BIMO program
[16].
Despite the fact that the basics of GCPs have been in place for nearly 20
years, FDAinspections continue to identify compliance concerns. The most
frequent GCPs compliance issues identied through inspection are the fail-
ure of investigators to follow the protocol and failure to maintain adequate
and accurate case histories [17].
As part of the ICH eort, the FDA has been working on global GCPs
guidelines. The draft guidelines that resulted from this harmonization eort
were rst published in the Federal Register in1995 [18]. After a comment per-
iod, the modied guidelines, which included guidelines for investigator bro-
chures and essential documents for the conduct of a clinical study, were
submitted to the ICH steering committee in 1996. These ICH GCPs guide-
lines provide a unied standard for designing, conducting, recording, and
reporting trials that involve the participation of human subjects. The
expectation is that these guidelines will be followed when clinical trials are
being conducted in support of regulatory submissions. The goal of these
guidelines is the assurance that the rights, well-being, and condentiality of
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trial subjects are protected. Additionally, they are designed to ensure that the
data generated for an NDA submission are credible. (These guidelines can
be found in the Federal Register [19].)
The following is a brief overviewof the content of the ICHGCPs:
Introduction
1. Glossary
2. The Principles of ICHCGP
3. Institutional Review Board/Independent Ethics Committee
(IRB/IEC)
4. Investigator
Investigators Qualications and Agreements
Compliance with Protocol
Informed Consent of Trial Subjects
Records and Reports
5. Sponsor
QualityAssurance and Quality Control
Trial Management, Data Handling, Record Keeping, and Inde-
pendent Data Monitoring Committee
Investigator Selection
Manufacturing, Packaging, Labeling, and Coding Investiga-
tional Product(s)
Safety Information
Adverse Drug Reaction Reporting
Monitoring
Audit
6. Clinical Trial Protocol and Protocol Amendment(s)
Trial Objectives and Purpose
Trial Design
Ethics
Data Handling and Record Keeping
7. Investigators Brochure
Contents of the Investigators Brochure
8. Essential Documents for the Conduct of a Clinical Trial
For an extensive discussion regarding compliance requirements
during clinical activities, refer to Chap. 3, Role of Quality Assurance
Throughout Clinical Trials.
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4 GOOD MANUFACTURING PRACTICES
The fact that GMPs apply to drug products that are in clinical trials was set
out in the preamble to the GMPs (Federal Register, Sept. 1978). The part of
the preamble that is relevant to the application of GMPs to the development
of newdrugs reads as follows:
The commissioner nds that as stated in 211.1 these cGMPs
regulations apply to the preparation of any drug product for
administration to humans or animals, including those still in inves-
tigational stages. It is appropriate that the process by which a drug
product is manufactured in the development phase be well docu-
mented and controlled in order to assure the reproducibility of the
product for further testing and for ultimate commercial production.
The commissioner is considering proposing additional cGMPs reg-
ulations specically designed to cover drugs in research stages.
4.1 Historical Perspective
In addition to stating that GMPs apply to clinical trial materials, the pre-
amble indicated that the regulations for clinical trial materials were dierent
fromthose for commercial products. This fact is evidenced by the statement
that the FDAwas considering proposing additional GMPs to cover drugs in
research. To date the FDA has not issued a separate set of GMPs for investi-
gational drugs. Expectations for investigational new drugs have been estab-
lished by the FDA through a combination of guidance documents,
compliance programs, inspection guidelines, and podium policy statements
[5,6].
4.2 Link to Phase of Development
Additional guidance on the application of GMPs to drug products used in
clinical trials can be found in the FDAs Guidelines on the Preparation of
Investigational New Drug (IND) Products. These guidelines clearly state that
compliance to GMPs was required at the stage at which the drug was to
be produced for clinical trials in humans (IND guidelines, March 1991).
These IND guidelines emphasized the need for proper documentation dur-
ing the drug development process. The need for control of components,
product controls, process controls, equipment identication, packaging,
and labeling also was covered in the IND guidelines [5,6]. The guidelines
also made clear that tighter controls were expected as experience was
gained with the product.
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4.3 Evolution/ICH Harmonization
The fact that the FDA had jurisdiction over clinical trial material and that
compliance to GMPs was expected once a drug entered human clinical trials
was rmly established by the preamble to the GMPs and the IND regula-
tions. After the generic drug scandal of 1989, however, the exceptions of com-
pliance to GMPs in the various phases of drug development took on new
importance. As a result of the generic drug scandal of 1989, the FDA issued
two new documents outlining their expectations during the drug develop-
ment process. They are as follows:
1. FDA Compliance Program Guidance Manual, Pre-Approval Inspec-
tions/Investigations (Program 7346.832), October 1990
2. FDA Compliance Program Guidance Manual, Pre-Approval Inspec-
tion of New Animal Drug Applications (NADA) (Program 7346.832),
February1991
The objectives of these compliance programs are as follows [5,6]:
1. Ensure that the facilities listed have the capabilities to fulll the
application commitments to manufacture, process, control, package,
and label a drug product following GMPs.
2. Ensure adequacy and accuracy of analytical methods by proper test-
ing.
3. Ensure correlation between manufacturing process for clinical trial
material, bioavailability study material, and stability studies and led
process.
4. Ensure that scientic evidence supports full-scale production proce-
dures and controls.
5. Have submitted factual data.
6. Ensure protocols are in place to validate the manufacturing pro-
cess.
Given that these compliance programs and FDA expectations for
clinical trial material are discussed in detail in Chap. 3 of this book, the
topics will not be further reviewed here. The importance of GMPs compli-
ance in development of a newdrug cannot be overemphasized, as the conse-
quences of noncompliance can be high in that the FDA can delay approval
of an NDA if signicant noncompliance is discovered during a preapproval
inspection.
5 ASSESSING COMPLIANCE THROUGH AUDITS
Compliance to GMPs, GLPs, and GCPs is clearly required during the
development of a new drug. Not only is this a regulatory requirement, it is
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also a good business practice. The failure to comply with these regulations
can result in the delay of regulatory approval, which results in delaying the
availability of important newdrugs to patients in need and the generation of
revenues for drug companies. It is thus in everyones best interest to comply
with these regulations during the development process. Compliance should
therefore be assessed throughout the drug development process rather than
waiting until an NDAsubmission has been made.
5.1 Internal Audits
The identication of areas of noncompliance by the FDA just prior to NDA
approval can be problematic for a rm at best. All of the compliance regula-
tions call for some type of internal quality assurance or quality control activ-
ity to ensure compliance. The purpose here is not to review these
requirements in detail, but rather to stress the importance of having internal
quality reviews in place to ensure a drug is being developed in compliance
with the GMPs, GLPs, and GCPs. One method that is widely used in the
industry is that of conducting a series of internal audits of specic areas and
critical documentation.
These audits should be performed by an independent quality function
that has a staof well-trained auditors who are knowledgeable of the compli-
ance regulations as well as the clinical or preclinical operations they will be
inspecting. Firms must have documented internal audit procedures for these
auditors to follow. This starts with having a well-dened process for deter-
mining what will be audited or inspected. For example, the GLPs require
that all of the nal study reports submitted to the INDor NDAbe signed o
by the quality function. Other regulations lack this degree of prescriptive-
ness for what needs to be audited. Firms therefore need to decide what they
will audit. This is of particular importance because it is not possible to audit
or inspect every drug study or clinical trial site. Most rms thus need to have
a way of deciding which studies or facilities they want to audit. This can be
done by developing a risk prole so that those areas that have the highest
degree of risk and exposure can be audited.The areas of high risk with signif-
icant exposure should be prioritized and developed into an audit plan. Once
an audit plan for the year has been developed and approved by management
the auditors can execute the plan. As each audit is conducted, the auditor
needs to document his or her audit ndings in a formal report back to the
management of the area being audited. Once the audit report has been issued
it is uptothe site functionbeing audited torespond tothe audit.The response
needs to provide the details of managements plan for correcting the observa-
tion of noncompliance found during the audit. These responses need to be
contained in a formal written document. The audit group or function needs
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to follow up with the site management after an appropriate period of time to
ensure that all of the promised corrective actions have in fact been made.
Having a strong internal audit function throughout the drug develop-
ment process will help to ensure that all of the preclinical and clinical work
conducted for an NDA submission will be in compliance with the GMPs,
GLPs, and GCPs. This will go a long way toward eliminating any last minute
surprises during an FDA inspection just prior to NDAapproval.
6 CONCLUSION
The development of a new drug is a long and costly process that is governed
by myriad federal regulations. The GMPs, GLPs, and GCPs are the most
notable froma compliance standpoint. These regulations grewout of a num-
ber of concerns or situations that have occurred over the past century. They
include the ndings at IBTand Searle in the case of GLPs, the elixir of sulfo-
namide and thalidomide tragedies in the case of GCPs, and the generic drug
scandal of the late1980s inthe case of the GMPs for materials utilized inclin-
ical trials. These compliance regulations were developed in the United
States, as well as in a large number of countries around the world. Although
these regulations were similar in many aspects, there were signicant dier-
ences.These dierences were large enough in many cases towarrant the con-
duct of additional studies to obtain approval in specic countries. In
response to this the ICHwas established as a forumto deal with these dier-
ences and formulate one set of global compliance regulations. Muchprogress
has been made as a result of these eorts, which has led to the establishment
of one global quality standard.This has led to the acceleration of drug regula-
tions on a global basis and eliminated the need to conduct studies, which
added little to our knowledge of the drugs ecacy or safety.
The cost of not complying with the GMPs, GLPs, and GCPs can be
high for studies conducted in support of an NDA. Not only does a rm risk
receiving a list of deciencies from the FDA on a form 483, but much more
important, studies can be disqualied, or worse yet, the approval of an NDA
can be delayed.
Firms engaged in the development of a new drug should have strong
audit functions in place to monitor compliance to the GMPs, GLPs, and
GCPs throughout the development of a new drug. This will go a long way
toward ensuring compliance, minimizing FDA-483 observations, and elim-
inating the possibility that an NDAapproval will be delayed for noncompli-
ance. More important, it will ensure the safety of patients during the
development of a new drug and accelerate the ultimate approval of the drug
for patients in need.
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7 WORDS OF WISDOM
Drug development activities are covered by three important types of
compliance regulations: GMPs, GLPs, and GCPs.
Approval of the regulatory ling is inuenced by the documentation
eorts put forth during development.
Pervasive quality assurance monitoring of development activities (by
way of audits) will greatly impact the quality and success of the
development activities.
Development activities must be captured in an ocial development
report only for GMPs.
Noncompliance with GMPs, GCPs, and GLPs during the development
phase could result in both a failed preapproval inspection and a reg-
ulatory hold of the submissions.
REFERENCES
1. DiMasi, J.A., Hanson, R.W., Grabowski, H.G., Lasagna, L. Research and
development costs for new drugs by therapeutic category: A study of the U.S.
pharmaceutical industry. PharmacoEc 7; 152^169, 1995.
2. Engel, S. R& Dcosts are staggering. R&DDirections p3, January 2002.
3. Hynes, M.D. III.The use of total quality principles toachieve regulatory compli-
ance in research laboratories. Qual Assur Good Prac and Law 4(1): 34^40,
March 1995.
4. Drug warning letters up, other enforcement actions down. Washington Drug
Letter, pp 2^3, March14, 1994.
5. Hynes, M.D. III. Developing a strategic approach to preparing for a successful
pre-NDA approval inspection. Hynes, M.D. III (ed.). Preparing for FDA Pre-
Approval Inspections. NewYork: Marcel Dekker, 1998; pp. 11^29.
6. Hynes, M.D. III. Introduction to food and drug administration pre-new drug
applications approval inspections. Hynes, M.D. III (ed.). Preparing for FDA
Pre-Approval Inspections. NewYork: Marcel Dekker, 1998; pp. 1^10.
7. Basarke, B.S., Jack, Hynes, M.D. III. Regulations, harmonization, and the
industry: Acomplementary triangle. Bhatt,V. (ed.).GCPs Compliance, Productiv-
ity, and Quality: Achieving Synergy in Healthcare Manufacturing. Vol. 12. Bualo
Grove, Ill.: Interpharm Press, 1998, pp. 399^423.
8. U.S. Department of Health and Human Services, Food and Drug Administra-
tion. 21 CFR 58. Food and Drugs Good Laboratory Practice Regulations. Final
Rule. Sept. 4, 1987 and Dec. 22, 1978.
9. U.S. Department of Health and Human Services, Environmental Protection
Agency. 40 CFR, 160. Protection of Environment, Good Laboratory Practice
Standards.
80 Hynes
Copyright 2004 Marcel Dekker, Inc.
10. Taylor, J.M., Stein, G.C. Historical Perspective. Weinberg, S. (ed.) Good
Laboratory Practice Regulations. 2nd ed., revised and expanded. New York:
Marcel Dekker, 1995, pp. 1^9.
11. U.S. Department of Health and Human Services, Food and Drug Administra-
tion, Oce of RegulatoryAairs,Guidance for Industry Good Laboratory Practice
Regulations Management Briengs Post Conference Report, Aug. 1979.
12. U.S. Department of Health and Human Services, Food and Drug Administra-
tion, 21 CFR 50, Food and Drugs, Protection of Human Subjects; Subpart B:
Informed Consent of Human Subjects.
13. U.S. Department of Health and Human Services, Food and Drug Administra-
tion, 21CFR56, (docket no. 77N0350) Food and Drugs, Protection of Human Sub-
jects; Standards for Institutional Review Boards for Clinical Investigations.
14. U.S. Department of Health and Human Services, Food and Drug Administra-
tion, 21 CFR 312, (docket no. 82N0394) Food and Drugs, New Drug Product
Regulations.
15. U.S. Department of Health and Human Services, Food and Drug Administra-
tion, 21 CFR 312, Food and Drugs, Applications for FDA Approval to Market a
New Drug; Subpart C: FDA Action on Applications.
16. U.S. Department of Health and Human Services, Food and Drug Administra-
tion, Oce of Regulatory Aairs, Bioresearch Monitoring (BIMO), Good
Laboratory Practice, Compliance Program 7348.808.
17. Lepay, M.D., David, A. GCPCompliance: FDAExpectations and Recent Findings,
slide presentation presented as part of the BIMOConference, June 9, 1998.
18. U.S. Department of Health and Human Services, Food and Drug Administra-
tion, Fed Reg. International Conference on Harmonization; Draft Guideline on
Good Clinical Practice, 60 (159):42947^42957, Aug. 17, 1995.
19. U.S. Department of Health and Human Services, Food and Drug Administra-
tion, Fed Reg. International Conference on Harmonization; Good Clinical Practice,
62 (90):25691^25709, May 9, 1997.
Compliance Requirements 81
Copyright 2004 Marcel Dekker, Inc.