MPHR - 129 (Clinical Trial Managment)

MPHR-129 CLINICAL TRIAL MANAGEMENT
1. Introduction to Pharmaceutical Medicine

• The Drug Development Process
• New Drug Discovery
• Clinical Development of Drug
• Essential Clinical Trial Documents
• Clinical Trials Terminology
2. Good Clinical Practice (GCP) Foundations
• History of GCP - milestones in the evolution of GCP
• Principles of GCP
• Applicable GCP Guidelines
• Declaration of Helsinki
• Clinical Study Process
• The Management of Clinical Studies (Sponsor)
• Ethics in Clinical Research
• Informed Consent process
• Challenges in the Implementation of GCP Guidelines
• Creation of Trial Master File(s)
3. Drug Regulatory Affairs (Clinical Trials)
• Overview of Regulatory Environment in USA, Australia, Europe and India
• Clinical Trial Application Requirements in India
• Import- Export of Clinical Trial Drugs in India
• Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule.
• IND/ANDA/New Drug Application
• Investigator Site Evaluation/Selection Process
• Audits and Quality Assurance etc
4. Roles and Responsibilities of Clinical Trial Personnel
• Roles and Responsibilities of Sponsor
• Roles and Responsibilities of Investigator
• Roles and Responsibilities of ERB/IRB/IEC
• Roles and Responsibilities of CRA /Monitor
• Roles and Responsibilities of Auditor
• Roles and Responsibilities of Clinical Research Coordinator or Site Manager
• Roles and Responsibilities of CRO’s
• Roles and Responsibilities of Regulatory Authorities
• Roles and Responsibilities of Clinical Data Manager (CDM )
• Roles and Responsibilities of Clinical Biostatistician
5. Clinical Trial Monitoring
• Development of Monitoring Plan
• Site Initiation Visit, Review of Essential Trial Documents, Delegation of Duties and
• Responsibilities at Individual Site
• Routine Monitoring Visit
• Inventory Planning and Tracking
• Source Document Verification (SDV)
• CRF Review, Collection and Co-ordination of Data Management Activities
• Serious Adverse Event (SAE) Review and Regulatory Compliance
• Investigational Product Accountability and Management
• Escalation, Management and Prevention of Violations/Deviations
• Tracking of Enrolments, Payments and Ongoing Correspondence
• Site Closure Monitoring Visit etc.
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1. INTRODUCTION TO PHARMACEUTICAL MEDICINE
DRUG DEVELOPMENT PROCESS
Drug development is a precarious pharmaceutical business with risks outweighing benefits. Though
risky, many major pharmaceutical companies are involved in drug development process, as it is essential
for the survival of pharmaceutical companies and for the betterment of people with newer therapy for
treating diseases that afflict millions of people worldwide.
Thus, Leveraging new drug development and registration programs internationally has become a
survival imperative for today's pharma industry. Billions of dollars are invested every year by pharma
companies worldwide to develop new drugs.
Success Rate of Developing a New Drug

Not every compound that is tested in lab is marketed. Before a drug is marketed, it has to undergo
several stages of development. A company has to screen through many thousand compounds that show
promising result before it could take on the task of development of a promising compound. This
eventually increases the cost of development of drug as many compounds that are tested are discarded in
the preliminary stages of development. For every 1,000 compounds that are identified by a company,
only about 30 show promising results. And for every 30 compounds that show promise, three get past
the first round of clinical trials and finally, only one hit the market. Sometimes compounds are to be
dropped off during regulatory approval process. Thus, to introduce one new drug, a company needs to
start with many thousands of compounds.
Time Required Developing a New Drug:

It is very known that drug development is very sluggish process which is scrutinized at every stage of
development by the USFDA in the US and respective regulatory agencies in various countries. It may
take anywhere between 12 to 15 years to develop a new drug according to PhRMA (Pharmaceutical
Research and Manufacturers of America - pharma industry trade group of America). This slowness of
drug development is attributed to numerous steps a drug has to go through before it is ultimately
launched in the market.
Drug development includes about six-and-a-half years of discovery, preclinical testing, and toxicity
studies; one-and-a-half years in Phase I trials to assess safety in healthy volunteers; then two years in
Phase II trials with a few hundred patients to evaluate the drug's effectiveness and side effects. The
development process continues with three-and-a-half years in Phase III trials involving thousands of
patients and scores of research centers to confirm effectiveness and evaluate long-term effects, then one-
and-a-half years of Food & Drug Administration review, where all the clinical trial data are presented.
Even after the drug is approved, it may undergo further Phase IV testing so more safety and efficacy
data can be collected. The drug development stages explained below can be shown in figure 1.
Cost of Developing New Drug:

Drug development in addition to taking longer time for marketing approval (12 to 15 years as discussed
above) requires mammoth investment from pharmaceutical companies. It is estimated, according to
various sources that cost of developing a single new drug including commercialization varies from US $
800 million to US $ 1.7 billion. Thus, in addition to increasing approval time for a single drug, cost of
development is also escalating. This is partly attributed to scrutiny by regulatory agencies and
lengthening time for review of applications. It is quite possible that during the stage of development, a
drug under review may not make to next stage due to reasons like quality, safety, toxicity or efficacy and
thereby increasing the cost of development. The money invested by the company for such unsuccessful
molecules is sunk cost and cannot be recovered.
Figure 1 - The New Drug Development Process - Steps from Test Tube to New Drug Application Review
Various Stages of Development of a New Drug:
Preclinical stage: This stage comprises of study on animals to find out various parameters for a drug
under development. During preclinical drug development, a sponsor evaluates the drug's toxic and
pharmacological effects through in vitro and in vivo laboratory animal testing. Genotoxicity screening is
performed, as well as investigations on drug absorption and metabolism, the toxicity of the drug's
metabolites, and the speed with which the drug and its metabolites are excreted from the body.
At the preclinical stage, the FDA will generally ask, at a minimum that sponsors:
(1) Develop a pharmacological profile of the drug;
(2) Determine the acute toxicity of the drug in at least two species of animals, and
(3) Conduct short-term toxicity studies ranging from 2 weeks to 3 months, depending on the proposed
duration of use of the substance in the proposed clinical studies.
Clinical Stages:
Phase I: Perform initial human testing in a small group of healthy volunteers
Phase-I studies are carried out in healthy volunteers, which are small in number – usually 20 to 100. The
purpose of phase-I studies is to identify metabolic and pharmacological effects of drug in humans and to
determine the side effects associated with increasing doses, and, if possible, to gain early evidence on
effectiveness. During Phase-I, sufficient information about the drug's pharmacokinetics and
pharmacological effects is required. The purpose of phase I studies is to mainly determine safety profile.
Phase II: Test in a small group of patients
Phase-II includes the early controlled clinical studies conducted to obtain some preliminary data on the
effectiveness of the drug for a particular indication or indications in patients with the disease or
condition. This phase of testing also helps determine the common short-term side effects and risks
associated with the drug. Phase-II studies are typically well-controlled, closely monitored, and
conducted in a relatively small number of patients, usually involving several hundred people.
Phase III: Test in a large group of patients to show safety and efficacy
Phase-III studies are expanded controlled and uncontrolled trials. They are performed after preliminary
evidence suggesting effectiveness of the drug has been obtained in Phase-II, and are intended to gather
the additional information about effectiveness and safety that is needed to evaluate the overall benefit-
risk relationship of the drug. Phase-III studies also provide an adequate basis for extrapolating the results
to the general population and transmitting that information in the physician labeling. Phase-III studies
usually include several hundred to several thousand people.
Phase IV: In addition to these three phases, Phase IV, also known as Post Marketing Surveillance is
also carried out once the drug is approved and marketed. The aim of Phase IV is to find out safety
profile in large patient pool across the world and to establish the safety profile of the drug. It is estimated
that success rate of drugs making to market from lab is very less. One drug, from among the thousands
tested, makes it to the market.
Table 1: Various stages of Preclinical and Clinical testing with purpose and success rate
Getting Regulatory Approval At Each Stage Of Drug Development:
Investigational New Drug (IND): Once the compound is tested in animals (preclinical testing), a
company files IND with FDA for getting approval for testing drug in humans. The IND shows results of
previous experiments, how, where and by whom the new studies will be conducted; the chemical
structure of the compound; how it is thought to work in the body; any toxic effects found in the animal
studies; and how the compound is manufactured. In addition, the IND must be reviewed and approved
by the Institutional Review Board where the studies are to be conducted, and progress reports on clinical
trials is required to be submitted to FDA periodically.
IND application contains information in three broad areas:
1. Animal Pharmacology and Toxicology Studies
2. Manufacturing Information of drug including manufacturer, composition, stability and controls
3. Clinical Protocols and Investigator Information
New Drug Application (NDA):

The NDA application is the vehicle through which drug sponsors formally propose that the FDA
approve a new pharmaceutical for sale and marketing in the U.S. The goals of the NDA are to provide
enough information to permit FDA reviewer to reach the following key decisions:
 Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug
outweigh the risks.
 Whether the drug's proposed labeling (package insert) is appropriate, and what it should contain.
 Whether the methods used in manufacturing the drug and the controls used to maintain the drug's
quality are adequate to preserve the drug's identity, strength, quality, and purity.
The documentation required in an NDA is supposed to tell the drug's whole story, including what
happened during the clinical tests. After completion of all phases of clinical trials as mentioned above, a
company files NDA with FDA if the data demonstrates safety and efficacy of the compound. NDA
mentions all the relevant scientific information pertaining to drug that is gathered during the
investigation period. As NDA runs in several thousands pages, FDA requires time to review each and
every detail of the information submitted. The relation of each stage of drug development and getting
regulatory approval at each stage is explained in table 2.
Table 2 - Phases of Product Development, Years, Test Population, Purpose and Success Rate
Conclusion: Drug development is a costly and risky affair and involves lot of money and time. Many
compounds that are screened initially fail to make it to next stage of development. If FDA decides, after
review of applications filed at each stage of drug development, that the benefits of drug outweigh the
risks associated with it, a drug is given marketing approval. But the road to success is painstaking and
companies have to take the risk associated with drug development.
References:
1. http://www.mindbranch.com/products/R198-014 (accessed 30-09-2005)
2. http://www.businessworldindia.com/ (accessed 15-06-06)
3. http://www.pubs.acs.org/cen/coverstory/8004/8004pharmaceuticals.html (accessed 30-08-2005)
4. http://www.pharmaquality.com/Cover%20Story5.htm (accessed 11-05-06)
5. CDER handbook, published by Department of Health and Human Services, Food and Drug Administration,
pg. 5, accessed at http://www.fda.gov/cder/handbook/index.htm (accessed 24-11-2005)
6. http://www.allp.com/drug_dev.htm (accessed 15-06-06)
7. http://www.fda.gov/cder/regulatory/applications/ind_page_1.htm (accessed 19-05-06)
8. http://www.fda.gov/cder/regulatory/applications/NDA.htm (accessed 19-05-06)
NDA Review Process
Applicant (Drug Sponsor): An applicant, or drug sponsor, is the person or entity who assumes
responsibility for the marketing of a new drug, including responsibility for compliance with applicable
provisions of the Federal Food, Drug, and Cosmetic Act and related regulations. The "sponsor" is
usually an individual, partnership, corporation, government agency, manufacturer or scientific
institution.
New Drug Application: For decades, the regulation and control of new drugs in the United States has
been based on the New Drug Application (NDA). Since 1938, every new drug has been the subject of an
approved NDA before U.S. commercialization. The data gathered during the animal studies and human
clinical trials of an Investigational New Drug (IND) become part of the NDA.
The NDA has evolved considerably during its history. When the Food, Drug, and Cosmetic Act (FD&C
Act) was passed in 1938, NDAs were only required to contain information pertaining to the
investigational drug's safety. In 1962, the Kefauver-Harris Amendments to the FD&C Act required
NDAs to contain evidence that a new drug was effective for its intended use as well, and that the
established benefits of the drug outweighed its known risks.
The NDA was again the subject of change in 1985, when the FDA completed a comprehensive revision
of the regulations pertaining to NDAs. While this revision, commonly called the NDA Rewrite,
modified content requirements, it was mainly intended to restructure the ways in which information and
data are organized and presented in the NDA to expedite FDA reviews.
Fundamentals of NDA Submissions: Although the quantity of information and data submitted in
NDAs can vary significantly, the components of NDAs are more uniform. The components of any NDA
are, in part, a function of the nature of the subject drug and the information available to the applicant at
the time of submission. As outlined in Form FDA-356h, Application to Market a New Drug for Human
Use Or As An Antibiotic Drug For Human Use, NDAs can consist of as many as 15 different sections:
 Index;
 Summary;
 Chemistry, Manufacturing, and Control;
 Samples, Methods Validation Package, and Labeling;
 Nonclinical Pharmacology and Toxicology
 Human Pharmacokinetics and Bioavailability;
 Microbiology (for anti-microbial drugs only);
 Clinical Data;
 Safety Update Report (typically submitted 120 days after the NDA's submission);
 Statistical;
 Case Report Tabulations;
 Case Report Forms;
 Patent Information;
 Patent Certification; and
 Other Information.
NDA Content and Format Requirements: Although the exact requirements are a function of the
nature of a specific drug, the NDA must provide all relevant data and information that a sponsor has
collected during the product's research and development.
The FDA has numerous guidelines that relate to NDA content and format issues. These guidelines can
be obtained from CDER's Drug Information Branch (DIB). Below is a partial list of some newer
Guidance of interest. See DIB's Guidance Documents for a complete list of available guidelines online
and instructions on how to obtain them.
Subject-Related CDER Guidance of Interest (examples)

Drug Master Files: See Appendix-I
NDA Classifications: CDER classifies new drug applications with a code that reflects both the type of
drug being submitted and its intended uses. The numbers 1 through 7 are used to describe the type of
drug:
1- New Molecular Entity
2- New Salt of Previously Approved Drug (not a new molecular entity)
3- New Formulation of Previously Approved Drug (not a new salt OR a new molecular entity)
4- New Combination of Two or More Drugs
5- Already Marketed Drug Product - Duplication (i.e., new manufacturer)
6- New Indication (claim) for Already Marketed Drug (includes switch in marketing status from
prescription to OTC)
7- Already Marketed Drug Product - No Previously Approved NDA
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The following letter codes describe the review priority of the drug:
S- Standard review for drugs similar to currently available drugs.
P- Priority review for drugs that represent significant advances over existing treatments.
Application Fileable?
After a New Drug Application (NDA) is received by the agency, it undergoes a technical screening
generally referred to as a completeness review. This evaluation ensures that sufficient data and
information have been submitted in each area to justify "filing" the application--that is, justifying
initiating CDER's formal review of the NDA.
Refuse-to-File Letter Issued

New Drug Applications that are incomplete become the subject of a formal "refuse-to-file" action. In
such cases, the applicant receives a letter detailing the decision and the deficiencies that form its basis.
This decision must be forwarded within 60 calendar days after the NDA is initially received by CDER.
Medical: Medical/clinical reviewers, often called medical officers, are almost exclusively physicians.
Medical reviewers are responsible for evaluating the clinical sections of submissions, such as the safety
of the clinical protocols in an IND or the results of this testing as submitted in the NDA. Within most
divisions, clinical reviewers take the lead role in the IND or NDA review, and are responsible for
synthesizing the results of the animal toxicology, human pharmacology and clinical reviews to formulate
the overall basis for a recommended Agency action on the application.
Pharmacology/ Toxicology: The pharmacology/toxicology review team is staffed by pharmacologists

and toxicologists who evaluate the results of animal testing and attempt to relate animal drug effects to
potential effects in humans.
Pharmacology and Drug Distribution (21 CFR 312.23(a)(8)(I)): This section of the application
should contain, if known: 1) a description of the pharmacologic effects and mechanism(s) of action of
the drug in animals, and 2) information on the absorption, distribution, metabolism, and excretion of the
drug. The regulations do not further describe the presentation of these data, in contrast to the more
detailed description of how to submit toxicologic data. A summary report, without individual animal
records or individual study results, usually suffices.
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To the extent that such studies may be important to address safety issues, or to assist in the evaluation of
toxicology data, they may be necessary; however, lack of this potential effectiveness should not
generally be a reason for a Phase-I IND to be placed on clinical hold.
Toxicology Data: Present regulations (21 CFR 312.23(a)(8)(ii)(a)) require an integrated summary of the
toxicologic effects of the drug in animals and in vitro. The particular studies needed depend on the
nature of the drug and the phase of human investigation. When species specificity, immunogenicity, or
other considerations appear to make many or all toxicological models irrelevant, sponsors are
encouraged to contact the agency to discuss toxicological testing.
Subject-Related CDER Guidance of Interest

Single Dose Acute Toxicity Testing for Pharmaceuticals
Content and Format of Investigational New Drug Applications (INDs) for Phase-I Studies of Drugs
Chemistry Review: Each review division employs a team of chemists responsible for reviewing the
chemistry and manufacturing control sections of drug applications. In general terms, chemistry
reviewers address issues related to drug identity, manufacturing control, and analysis. The reviewing
chemist evaluates the manufacturing and processing procedures for a drug to ensure that the compound
is adequately reproducible and stable. If the drug is either unstable or not reproducible, then the validity
of any clinical testing would be undermined because one would not know what was really being used in
the patients, and, more importantly, the studies may pose significant risks to participants.
At the beginning of the Chemistry and Manufacturing section, the drug sponsor should state whether it
believes the chemistry of either the drug substance or the drug product, or the manufacturing of either
the drug substance or the drug product, present any signals of potential human risk. If so, these signals
should be discussed, with steps proposed to monitor for such risks.
In addition, sponsors should describe any chemistry and manufacturing differences between the drug
product proposed for clinical use and the drug product used in the animal toxicology trials that formed
the basis for the sponsor's conclusion that it was safe to proceed with the proposed clinical study. How
these differences might affect the safety profile of the drug product should be discussed. If there are no
differences in the products, that should be stated.
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Biopharmaceutical: Pharmacokineticists evaluate the rate and extent to which the drug's active
ingredient is made available to the body and the way it is distributed in, metabolized by, and eliminated
from the human body.
Statistical: Statisticians evaluate the statistical relevance of the data in the NDA with the main tasks of
evaluating the methods used to conduct studies and the various methods used to analyze the data. The
purpose of these evaluations is to give the medical officers a better idea of the power of the findings to
be extrapolated to the larger patient population in the country.
Microbiology: The Clinical Microbiology information is required only in NDAs for anti-infective
drugs. Since these drugs affect microbial, rather than human physiology, reports on the drug's in vivo
and in vitro effects on the target microorganisms are critical for establishing product effectiveness.
An NDA's Microbiology section usually includes data describing:
 The biochemical basis of the drug's action on microbial physiology;
 The drug's antimicrobial spectra, including results of in vitro preclinical studies demonstrating
concentrations of the drug required for effective use;
 Any known mechanisms of resistance to the drug, including results of any known epidemiologic
studies demonstrating prevalence of resistance factors; and
 Clinical microbiology laboratory methods needed to evaluate the effective use of the drug.
Advisory Committees: CDER uses advisory committees to obtain outside advice and opinions from
expert advisors so that final agency decisions will have the benefit of wider national expert input.
Committee recommendations are not binding on CDER, but the agency considers them carefully when
deciding drug issues.
CDER may especially want a committee's opinion about a new drug, a major indication for an already
approved drug, or a special regulatory requirement being considered, such as a boxed warning in a
drug's labeling. Committees may also advise CDER on necessary labeling information, or help with
guidelines for developing particular kinds of drugs. They may also consider questions such as whether a
proposed study for an experimental drug should be conducted or whether the safety and effectiveness
information submitted for a new drug are adequate for marketing approval.
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Meetings with Sponsor: During the course of reviewing an application, CDER usually communicates
often with sponsors about scientific, medical, and procedural issues that arise during the review process.
Communications may take the form of telephone conversations, letters, faxes or meetings (either face-
to-face or via videoconferencing).
Notification of Easily Correctable Deficiencies

CDER makes every effort to communicate promptly to applicants easily correctable deficiencies found
during the review of an application. CDER also informs applicants of the need for more data or
information, or for technical changes in the application needed to facilitate the agency's review. This
type of early communication would not ordinarily apply to major scientific issues, which require
consideration of the entire pending application by agency final decision makers as well as by reviewing
staff. Instead, major scientific issues are usually addressed in an action letter at the end of the initial
review process.
End of Review Conference: At the conclusion of CDER's review of an application, there are three
possible action letters that can be sent to the sponsor:
Not Approvable Letter: Lists the deficiencies in the application and explains why the application cannot
be approved.
Approvable Letter: Signals that, ultimately, the drug can be approved. Lists minor deficiencies that
can be corrected, often involves labeling changes, and possibly requests
commitment to do post-approval studies.
Approval Letter: States that the drug is approved. May follow an approvable letter, but can also be
issued directly.
If the action taken is either an approvable or a not approvable action (as opposed to an approval action),
CDER provides applicants with an opportunity to meet with Agency officials and discuss the
deficiencies. The purpose of this "end of review conference" is to discuss what further steps are
necessary before the application can be approved. This meeting is available on all applications, with
priority given to applications for priority review drugs and major new indications for marketed drugs.
Requests for such meetings are directed to the director of the division responsible for reviewing the
application.
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Other Meetings
Other meetings between CDER and applicants may be held to discuss scientific, medical, and other
issues that arise during the review process. CDER makes every effort to grant requests for meetings that
involve important issues and that can be scheduled at mutually convenient times.
Reviews Complete and Acceptable?

Much of the primary review process involves reviewer attempts to confirm and validate the sponsor's
conclusion that a drug is safe and effective for its proposed use. The review is likely to involve a
reanalysis or an extension of the analyses performed by the sponsor and presented in the NDA. For
example, the medical reviewer may seek to reanalyze a drug's effectiveness in a particular patient
subpopulation not analyzed in the original submission. Similarly, the reviewer may disagree with the
sponsor's assessment of evaluable patients and seek to retest effectiveness claims based on the reviewer-
defined patient populations.
There is also extensive communication between review team members. If a medical reviewer's
reanalysis of clinical data produces results different from those of the sponsor, for example, the reviewer
is likely to forward this information to the statistical reviewer with a request for a statistical reanalysis of
the data. Likewise, the pharmacology reviewer may work closely with the statistical reviewer in
evaluating the statistical significance of potential cancer-causing effects of the drug in long-term animal
studies.
When the technical reviews are completed, each reviewer develops a written evaluation of the NDA that
presents their conclusions and their recommendations on the application. The division director or office
director then evaluates the reviews and recommendations and decides the action that the division will
take on the application. The result is an action letter that provides an approval, approvable or non-
approvable decision and a justification for that recommendation.
Additional Information (Amendment)

In some cases, an applicant may seek to augment the information provided in the original NDA during
the review process. For example, the applicant may submit a new analysis of previously submitted data
or information needed to address a deficiency in the drug application.
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Any such information provided for an unapproved application is considered an NDA amendment. The
submission of a significant amendment may result in an extension of FDA's time line for application
review.
Submitter Revises: When an NDA nears approval, agency reviewers evaluate draft package labeling
for accuracy and consistency with the regulatory requirements for applicable prescription or over-the-
counter drugs. Each element of the proposed labeling, including indications, use instructions, and
warnings, is evaluated in terms of conclusions drawn from animal and human testing. All claims,
instructions, and precautions must accurately reflect submitted clinical results.
If CDER has concerns about the draft labeling, the Center will contact the submitter detailing suggested
revisions. CDER comments can relate to almost any aspect of the proposed labeling. For example,
CDER can comment upon drug indications and warnings, or suggest general changes in wording and
format.
The labeling "negotiation process," through which a drug's final approved labeling is agreed upon, can
take a few weeks to many months. The length of the process depends upon the number of agency
comments and an applicant's willingness to reach agreement. Sometimes a submitter will submit several
revisions of labeling before agreement with FDA on the labeling can be reached.
Labeling Review Acceptable?

Each statement proposed for drug labeling must be justified by data and results submitted in the NDA.
The Code of Federal Regulations (CFR) describes labeling requirements in 21 CFR Part 201- Labeling.
The labeling is organized in the following sections:
Description: Proprietary and established name of drug; dosage form; ingredients; chemical
name; and structural formula.
Clinical Pharmacology: Summary of the actions of the drug in humans; in vitro and in vivo actions in
animals if pertinent to human therapeutics; pharmacokinetics.
Indications & Usage: Description of use of drug in the treatment, prevention or diagnosis of a
recognized disease or condition.
Contraindications: Description of situations in which the drug should not be used because the risk of
use clearly outweighs any possible benefit.
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Warnings: Description of serious adverse reactions and potential safety hazards, subsequent
limitation in use, and steps that should be taken if they occur.
Precautions: Information regarding any special care to be exercised for the safe and effective
use of the drug. Includes general precautions and information for patients on drug
interactions, carcinogenesis/mutagenesis, pregnancy rating, labor and delivery,
nursing mothers, and pediatric use.
Adverse Reactions: Description of undesirable effect(s) reasonably associated with the proper use of
the drug.
Drug Abuse/Dependence: Description of types of abuse that can occur with the drug and the averse
reactions pertinent to them.
Over-dosage: Description of the signs, symptoms and laboratory findings of acute overdosage
and the general principles of treatment.
Dosage/Administration: Recommendation for usage dose, usual dosage range, and, if appropriate, upper
limit beyond which safety and effectiveness have not been established.
How Supplied: Information on the available dosage forms to which the labeling applies.
Inspection Acceptable?
A division's decision to file an NDA begins the review process and, when needed, initiates a request for
a preapproval inspection of the sponsor's manufacturing facilities and clinical trial sites. During such
inspections, FDA investigators audit manufacturing-related statements and commitments made in the
NDA against the sponsor's manufacturing practices. More specifically, the FDA conducts inspections to:
 Verify the accuracy and completeness of the manufacturing-related information submitted in the
NDA;
 Evaluate the manufacturing controls for the preapproval batches upon which information provided in
the NDA is based;
 Evaluate the manufacturer's compliance with Current Good Manufacturing Practices (CGMPs) and
manufacturing-related commitments made in the NDA; and
 Collect a variety of drug samples for analysis by FDA field and CDER laboratories. These samples
may be subjected to several analyses, including methods validation, methods verification, and
forensic screening for substitution.
According to CDER policy, product-specific preapproval inspections generally are conducted for
products: (1) that are new chemical or molecular entities; (2) that have narrow therapeutic ranges; (3)
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that represent the first approval for the applicant; or (4) that are sponsored by a company with a history
of CGMP problems or that has not been the subject of a CGMP inspection over a considerable period.
More specific guidance on CDER's preapproval inspection program is available from CDER's
Compliance Program Guide 7346.832.
The results of the preapproval inspection may also affect the final approval decision. When such
inspections discover significant CGMP problems or other issues, the reviewing division may withhold
approval until these issues are addressed and corrected. The division's response to such deficiencies is
likely to depend on several factors, including the nature of the problem, the prognosis for the problem's
correction, and the potential effect of the problem on the safety and efficacy of the drug.
NDA Actions: Once an approval, approvable, or non-approvable recommendation is reached by the

reviewers and their supervisors, the decision must be evaluated and agreed to by the director of the
applicable drug review division or office. For the director's review, the consumer safety officer
assembles an "action package" that contains the action letter and any data, CDER reviews and memos,
and other information supporting the reviewers' recommendation.
Following his/her review of the action package, the division director may begin a dialogue with the
reviewers and their supervisors. The division director generally serves as the final FDA ruling. In this
sense, the division director is said to have "sign-off" authority for such drugs. The level of "sign-off"
authority needed is determined by the classification of the drug under consideration. Class 1 drugs, for
example, cannot be "signed off" by division directors; they require office level "sign-off" on action
letters.
Once the division director (or office director, as appropriate) signs an approval action letter, the product
can be legally marketed starting that day in the United States.
Source: U.S. Food and Drug Administration Center for Drug Evaluation and Research Handbook.
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NEW DRUG DISCOVERY
THE DISCOVERY PROCESS

Pre-discovery: Understand the disease
Before any potential new medicine can be discovered, scientists work to understand the disease to be
treated as well as possible, and to unravel the underlying cause of the condition. They try to understand
how the genes are altered, how that affects the proteins they encode and how those proteins interact with
each other in living cells, how those affected cells change the specific tissue they are in and finally how
the disease affects the entire patient. This knowledge is the basis for treating the problem. Researchers
from government, academia and industry all contribute to this knowledge base. However, even with new
tools and insights, this research takes many years of work and, too often, leads to frustrating dead ends.
And even if the research is successful, it will take many more years of work to turn this basic
understanding of what causes a disease into a new treatment.
“Some ideas may just stay on paper forever, but others have a way forward to make it into a pill, into a
bottle at the pharmacy.”
PUBLIC AND PRIVATE- Collaborations

Modern drug discovery is the product of cooperation. Many sectors contribute, particularly in building
the basic science foundations. Both public and private organizations play unique but increasingly
interdependent roles in translating basic research into medicine.
 Major Biopharmaceutical companies are the primary source of R&D funding for new medicines,
both for projects in their own laboratories as well as for research licensed from other sectors.
 Smaller companies also drive innovation, conducting basic research, drug discovery, preclinical
experiments and, in some cases, clinical trials.
 The National Institutes of Health (NIH) provides leadership and funding support to universities,
medical schools, research centers and other nonprofit institutions, and stimulates basic research and
early stage development of technologies that enable further targeted drug discovery and
development.
HOW DRUGS WORK- The basics
The cells in our bodies carry out complex molecular reactions to perform every function - from digesting
your lunch, to moving your finger, to regulating cell growth and transmitting thoughts in your brain.
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One type of molecule interacts with another which, in turn, affects another, and so on down the line.
These cascades of molecular changes are called chemical pathways.
In many different and extremely complex ways, these pathways are involved in disease. A mistake in one
reaction might stop an important protein from being produced or lead to too much production. These
molecular imbalances can have big consequences. Maybe they will cause extra cells to grow - like in
cancer - or perhaps cause the person’s body to not produce enough insulin - like in diabetes.
Drug molecules affect these pathways by interacting with certain molecules along the pathway, making
them more active or less active, or changing their activity all together.
Target Identification: Choose a molecule to target with a drug

Once they have enough understanding of the underlying cause of a disease, pharmaceutical researchers
select a “target” for a potential new medicine. A target is generally a single molecule, such as a gene or
protein, which is involved in a particular disease. Even at this early stage in drug discovery it is critical
that researchers pick a target that is “drugable,” i.e., one that can potentially interact with and be affected
by a drug molecule.
Target Validation: Test the target and confirm its role in the disease
After choosing a potential target, scientists must show that it actually is involved in the disease and can
be acted upon by a drug. Target validation is crucial to help scientists avoid research paths that look
promising, but ultimately lead to dead ends. Researchers demonstrate that a particular target is relevant
to the disease being studied through complicated experiments in both living cells and in animal models
of disease.
Drug Discovery: Find a promising molecule (a “lead compound”) that could become a drug
Armed with their understanding of the disease, scientists are ready to begin looking for a drug. They
search for a molecule, or “lead compound,” that may act on their target to alter the disease course. If
successful over long odds and years of testing, the lead compound can ultimately become a new
medicine. There are a few ways to find a lead compound:
(a). Nature: Until recently, scientists usually turned to nature to find interesting compounds for fighting
disease. Bacteria found in soil and moldy plants both led to important new treatments, for example.
Nature still offers many useful substances, but now there are other ways to approach drug discovery.
(b). De novo: Thanks to advances in chemistry, scientists can also create molecules from scratch. They
can use sophisticated computer modeling to predict what type of molecule may work.
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(c). High-throughput Screening: This process is the most common way that leads are usually found.
Advances in robotics and computational power allow researchers to test hundreds of thousands of
compounds against the target to identify any that might be promising. Based on the results, several lead
compounds are usually selected for further study.
(d). Biotechnology: Scientists can also genetically engineer living systems to produce disease-fighting
biological molecules.
“If at the end of my career, I can look back and know that something I did made a difference in one
patient somewhere in the world, that’ll be more satisfying and more gratifying than anything I can
possibly imagine.”
Early Safety Tests: Perform initial tests on promising compounds

Lead compounds go through a series of tests to provide an early assessment of the safety of the lead
compound. Scientists test Absorption, Distribution, Metabolism, Excretion and Toxicological
(ADME/Tox) properties, or “pharmacokinetics,” of each lead. Successful drugs must be:
• Absorbed into the bloodstream,
• Distributed to the proper site of action in the body,
• Metabolized efficiently and effectively,
• Successfully excreted from the body and
• Demonstrated to be not toxic.
These studies help researchers prioritize lead compounds early in the discovery process. ADME/Tox
studies are performed in living cells, in animals and via computational models.
Lead Optimization: Alter the structure of lead candidates to improve properties

Lead compounds that survive the initial screening are then “optimized,” or altered to make them more
effective and safer. By changing the structure of a compound, scientists can give it different properties.
For example, they can make it less likely to interact with other chemical pathways in the body, thus
reducing the potential for side effects.
Hundreds of different variations or “analogues” of the initial leads are made and tested. Teams of
biologists and chemists work together closely: The biologists test the effects of analogues on biological
systems while the chemists take this information to make additional alterations that are then retested by
the biologists. The resulting compound is the candidate drug.
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Even at this early stage, researchers begin to think about how the drug will be made, considering
formulation (the recipe for making a drug, including inactive ingredients used to hold it together and
allow it to dissolve at the right time), delivery mechanism (the way the drug is taken - by mouth,
injection, inhaler) and large-scale manufacturing (how you make the drug in large quantities).
LEAD OPTIMIZATION- At the molecular level

New techniques have revolutionized the ability of researchers to optimize potential drug molecules.
Thanks to technologies such as magnetic resonance imaging and X-ray crystallography, along with
powerful computer modeling capabilities, chemists can actually “see” the target in three dimensions
and design potential drugs to more powerfully bind to the parts of the target where they can be most
effective. In addition, new chemistry techniques help scientists to synthesize the new compounds quickly.
“The number of people involved in getting a drug to the first patient is a small phonebook. It’s hundreds
to even a thousand or two thousand, depending on the nature of the work. It requires people from a
whole set of different disciplines, ranging from a geneticist who may be that person who makes the first
link of a gene with a disease, to the chemist who tried to understand how to make a chemical that will
interact with a protein, that a biochemist will have isolated, to a pharmacist who will figure out how to
take that chemical and put it into some kind of delivery device, what we call a pill or injection, to
computer scientists who work to try to predict how that drug is going to behave in a patient or in a large
population, and so on. The set of disciplines is immense.”
Preclinical Testing: Lab & animal testing to determine if the drug is safe enough for human testing
With one or more optimized compounds in hand, researchers turn their attention to testing them
extensively to determine if they should move on to testing in humans. Scientists carry out in vitro and in
vivo tests. In vitro tests are experiments conducted in the lab, usually carried out in test tubes and
beakers (“vitro” is “glass” in Latin) and in vivo studies are those in living cell cultures and animal
models (“vivo” is “life” in Latin).
Scientists try to understand how the drug works and what its safety profile looks like. The U.S. Food and
Drug Administration (FDA) require extremely thorough testing before the candidate drug can be studied
in humans.
During this stage researchers also must work out how to make large enough quantities of the drug for
clinical trials. Techniques for making a drug in the lab on a small scale do not translate easily to larger
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production. This is the first scale up. The drug will need to be scaled up even more if it is approved for
use in the general patient population.
At the end of several years of intensive work, the discovery phase concludes. After starting with
approximately 5,000 to 10,000 compounds, scientists now have winnowed the group down to between
one and five molecules, “candidate drugs,” which will be studied in clinical trials.
“The challenge of finding a new drug is an incredible thing. You’re trying to solve a complex disease
with a single molecule. It’s an incredible challenge. We employ technologies that are just unbelievable
in their depth and their complexity. At the end of day, we do this to bring some comfort to people who
are suffering and dealing with the anguish and despair of a chronic disease. It’s to bring some hope to
them.”
“I think we’ve only begun to scratch the surface in our understanding of disease and the way we’re
going to be able to treat diseases. Many of us that are in the industry now... I don’t think we can even
conceive of where it’s all going to go in the future, but there’s a long, long way to go. We’ve only just
begun.”
Investigational New Drug (IND) Application and Safety: File IND with the FDA before clinical
testing can begin; ensure safety for clinical trial volunteers through an Institutional Review Board
Before any clinical trial can begin, the researchers must file an Investigational New Drug (IND)
application with the FDA. The application includes the results of the preclinical work, the candidate
drug’s chemical structure and how it is thought to work in the body, a listing of any side effects and
manufacturing information. The IND also provides a detailed clinical trial plan that outlines how, where
and by whom the studies will be performed.
The FDA reviews the application to make sure people participating in the clinical trials will not be
exposed to unreasonable risks.
In addition to the IND application, all clinical trials must be reviewed and approved by the Institutional
Review Board (IRB) at the institutions where the trials will take place. This process includes the
development of appropriate informed consent, which will be required of all clinical trial participants.
Statisticians and others are constantly monitoring the data as it becomes available. The FDA or the
sponsor company can stop the trial at any time if problems arise. In some cases a study may be stopped
because the candidate drug is performing so well that it would be unethical to withhold it from the
patients receiving a placebo or another drug.
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Finally, the company sponsoring the research must provide comprehensive regular reports to the FDA
and the IRB on the progress of clinical trials.
CLINICAL TRIAL DESIGN

An incredible amount of thought goes into the design of each clinical trial. To provide the highest level
of confidence in the validity of results, many drug trials are placebo controlled, randomized and double-
blinded. What does that mean?
 Placebo-controlled: Some subjects will receive the new drug candidate and others will receive a
placebo. (In some instances, the drug candidate may be tested against another treatment rather than
a placebo.)
 Randomized: Each of the study subjects in the trial is assigned randomly to one of the treatments.
 Double-blinded: Neither the researchers nor the subjects know which treatment is being delivered
until the study is over.
This method of testing provides the best evidence of any direct relationship between the test compound
and its effect on disease because it minimizes human error.
The number of subjects enrolled in a trial (the “power” of the trial) also has to be carefully considered:
In general, enrolling more subjects’ results in greater statistical significance of the results, but is also
more expensive and difficult to undertake.
Phase-I Clinical Trial: Perform initial human testing in a small group of healthy volunteers
In Phase-I trials the candidate drug is tested in people for the first time. These studies are usually
conducted with about 20 to 100 healthy volunteers. The main goal of a Phase-I trial is to discover if the
drug is safe in humans. Researchers look at the pharmacokinetics of a drug: How is it absorbed? How is
it metabolized and eliminated from the body? They also study the drug’s pharmacodynamics: Does it
cause side effects? Does it produce desired effects? These closely monitored trials are designed to help
researchers determine what the safe dosing range is and if it should move on to further development.
Phase-II Clinical Trial: Test in a small group of patients

In Phase-II trials researchers evaluate the candidate drug’s effectiveness in about 100 to 500 patients
with the disease or condition under study, and examine the possible short-term side effects (adverse
events) and risks associated with the drug. They also strive to answer these questions: Is the drug
working by the expected mechanism? Does it improve the condition in question? Researchers also
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analyze optimal dose strength and schedules for using the drug. If the drug continues to show promise,
they prepare for the much larger Phase-III trials.
Phase-III Clinical Trial: Test in a large group of patients to show safety and efficacy
In Phase-III trials researchers study the drug candidate in a larger number (about 1,000-5,000) of
patients to generate statistically significant data about safety, efficacy and the overall benefit-risk
relationship of the drug. This phase of research is key in determining whether the drug is safe and
effective. It also provides the basis for labeling instructions to help ensure proper use of the drug (e.g.,
information on potential interactions with other medicines). Phase-III trials are both the costliest and
longest trials. Hundreds of sites around the United States and the world participate in the study to get a
large and diverse group of patients. Coordinating all the sites and the data coming from them is a
monumental task. During the Phase-III trial (and even in Phases I and II), researchers are also
conducting many other critical studies, including plans for full scale production and preparation of the
complex application required for FDA approval.
PHASE 0, 2A & 2B TRIALS

Scientists are always working to identify ways to improve the R&D process and exploring new methods
to help reduce the costs and length of clinical trials. Restructured trials help researchers get as much
information as possible in the earliest stages and eliminate compounds that are more likely to fail only
after longer, more expensive trials.
Phase 0 Trial: The FDA has recently endorsed “micro-dosing,” or the “Phase 0 trial,” which allows
researchers to test a small drug dose in fewer human volunteers to quickly weed out drug candidates
that are metabolically or biologically ineffective.
Phase-IIa & 2b Trials: Sometimes combined with a Phase-I trial, a Phase-IIa trial is aimed not only at
understanding the safety of a potential drug, but also getting an early read on efficacy and dosage in a
small group of patients. The resulting Phase-IIb trial would be designed to build on these results in a
larger group of patients for the sake of designing a rigorous and focused Phase-III trial.
New Drug Application (NDA) and Approval: Submit application for approval to FDA
Once all three phases of the clinical trials are complete, the sponsoring company analyzes all of the data.
If the findings demonstrate that the experimental medicine is both safe and effective, the company files a
New Drug Application (NDA) - which can run 100,000 pages or more - with the FDA requesting
25
approval to market the drug. The NDA includes all of the information from the previous years of work,
as well as the proposals for manufacturing and labeling of the new medicine.
FDA experts review all the information included in the NDA to determine if it demonstrates that the
medicine is safe and effective enough to be approved (see sidebar - “How does the FDA decide to
approve a new drug?”). Following rigorous review, the FDA can either 1) approve the medicine, 2) send
the company an “approvable” letter requesting more information or studies before approval can be
given, or 3) deny approval.
Review of an NDA may include an evaluation by an advisory committee, an independent panel of FDA-
appointed experts who consider data presented by company representatives and FDA reviewers.
Committees then vote on whether the FDA should approve an application, and under what conditions.
The FDA is not required to follow the recommendations of the advisory committees, but often does.
BEN
How does the FDA decide to approve a new drug? VS. RISK
BENEFIT VS. RISK: After close to a decade of testing, the company files a New Drug Application
(NDA) with the FDA. Reported in the NDA are all the data gathered from all studies of the potential
new drug, including the preclinical as well as clinical findings. The FDA then scrutinizes all the data
carefully to determine if the medicine should be approved.
In particular, it uses the information in the NDA to try to address three major concerns:
1. Because no drug has zero risk, the FDA must determine whether the benefits of the drug outweigh
the risks, i.e., is the drug effective for its proposed use, and has an acceptable balance between
benefits and risks been achieved?
2. Based on its assessment of risk and benefit, the FDA must decide what information the package
inserts should contain to guide physicians in the use of the new drug.
3. Finally, the FDA must assess whether the methods used to manufacture the drug and ensure its
quality are adequate to preserve the drug's identity, strength and purity.
“I will never forget seeing the patients explain their experience because they were taking our drugs.
That's wonderful. That's a gift. And that is something that nobody can understand if you haven't
experienced it. That is the benefit that working in this industry provides. And it has been wonderful for
me.”
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Manufacturing
Going from small-scale to large-scale manufacturing is a major undertaking. In many cases, companies
must build a new manufacturing facility or reconstruct an old one because the manufacturing process is
different from drug to drug. Each facility must meet strict FDA guidelines for Good Manufacturing
Practices (GMP).
Making a high-quality drug compound on a large scale takes great care. Imagine trying to make a cake,
for example, on a large scale - making sure the ingredients are evenly distributed in the mix, ensuring
that it heats evenly. The process to manufacture most drugs is even more complicated than this. There
are few, if any, other businesses that require this level of skill in manufacturing.
Ongoing Studies and Phase-IV Trials

Research on a new medicine continues even after approval. As a much larger number of patients begin
to use the drug, companies must continue to monitor it carefully and submit periodic reports, including
cases of adverse events, to the FDA.
In addition, the FDA sometimes requires a company to conduct additional studies on an approved drug
in “Phase-IV” studies. These trials can be set up to evaluate long-term safety or how the new medicine
affects a specific subgroup of patients.
“I find it very exciting to be involved with the drug in its final stages... after so many years of waiting.
The patients are finally getting access to the drug that potentially is going to help them.”
Conclusion
The discovery and development of new medicines is a long, complicated process. Each success is built
on many, many prior failures. Advances in understanding human biology and disease are opening up
exciting new possibilities for breakthrough medicines. At the same time, researchers face great
challenges in understanding and applying these advances to the treatment of disease. These possibilities
will grow as our scientific knowledge expands and becomes increasingly complex. Research-based
pharmaceutical companies are committed to advancing science and bringing new medicines to patients.
“Patients are not an abstract concept to those who work in research. We know patients, our parents are
patients, our friends are patients, our children are patients and sometimes we are patients.”
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FOR SHORT TERM REVIEW
DISCOVERY
Pre-discovery
Goal: Understand the disease and choose a target molecule.
How: Scientists in pharmaceutical research companies, government, academic and for-profit research
institutions contribute to basic research.
Discovery
Goal: Find a drug candidate.
How: Create a new molecule or select an existing molecule as the starting point. Perform tests on that
molecule and then optimize (change its structure) it to make it work better.
Preclinical
Goal: Test extensively to determine if the drug is safe enough for human testing.
How: Researchers test the safety and effectiveness in the lab and in animal models.
Total Duration: 3 - 6 years
DEVELOPMENT
IND
Goal: Obtain FDA approval to test the drug in humans.
How: FDA reviews all preclinical testing and plans for clinical testing to determine if the drug is safe
enough to move to human trials.
Clinical Trials
Goal: Test in humans to determine if the drug is safe and effective.
How: Candidate drug is tested in clinical setting in three phases of trials, beginning with tests in a small
group of healthy volunteers and moving into larger groups of patients.
Total Duration: 6 - 7 years
Review
Goal: FDA reviews results of all testing to determine if the drug can be approved for patients to use.
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How: The FDA reviews hundreds of thousands of pages of information, including all clinical and
preclinical findings, proposed labeling and manufacturing plans. They may solicit the opinion of an
independent advisory committee.
Manufacturing
Goal: Formulation, scale up and production of the new medicine.
Total Duration: 0.5 - 2 years
Ongoing Studies
Goal: Monitor the drug as it is used in the larger population to catch any unexpected serious side effects.
TOTAL
How much: $800 million – $1 billion
How long: 10 – 15 years
REFERENCES
 J.A. DiMasi, “New Drug Development in the United States from 1963-1999,” Clinical Pharmacology and
Therapeutics 69, no. 5 (2001): 286-296.
 J.A. DiMasi, R.W. Hansen and H.G. Grabowski, “The Price of Innovation: New Estimates of Drug
Development Costs,” Journal of Health Economics 22 (2003): 151-185.
 Pharmaceutical Research and Manufacturers of America, based on data from Tufts University, Tufts Center
for the Study of Drug Development (1995).
 Meadows, M. (2002) The FDA’s Drug Review Process: Ensuring Drugs are Safe and Effective. FDA
Consumer 36: (revised September 2002, http://www.fda.gov/fdac/features/2002/402_drug.html)
 Pharmaceutical Research and Manufacturers of America, Pharmaceutical Industry Profile 2006,
(Washington, DC: PhRMA, March 2006).
 Tufts Center for the Study of Drug Development, "Average Cost to Develop a New Biotechnology Product Is
$1.2 Billion, According to the Tufts Center for the Study of Drug Development," 9 November 2006,
http://csdd.tufts.edu/NewsEvents/NewsArticle.asp?newsid=69 (accessed 18 December 2006).
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ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL
Essential documents are those documents that individually and collectively evaluate the conduct of a
trial and the quality of the data produced. These documents demonstrate the compliance of the
investigator and sponsor with the standards of Good Clinical Practice (GCP) and all applicable
regulatory requirements. Note: The ICH Guidelines have been adopted by the FDA as guidances, not
regulations.
The Office of Human Research Protection (OHRP) and Health and Human Services (HHS) regulations
(45 CFR 46) and Good Clinical Practice recommendations apply for all trials that receive funding from a
Health and Human Service agency. Trials with a Food and Drug Administration (FDA) Investigational
Drug Application (IND) must additionally comply with 21CFR regulations.
Document Purpose File

Assurance The institution is responsible for obtaining and maintaining a current Health and In a Regulatory
Number Human Services (HHS) Federal Wide Assurance Number through the Office of Binder at the site
Human Research Protection (OHRP)
 The PI is responsible for ensuring that a current Assurance Number is in A copy of the
effect while conducting research on human subjects Assurance number
 All sites must maintain the Assurance Number on file and obtain renewal must be on file with
prior to expiration. the sponsor
Auditing 1. Copies of all monitor visit findings. In the Regulatory
Reports 2. Document audit visits and findings of the auditor. Binder at the site
3. Copies of all monitor visit reports are filed at the site and sent to the sponsor
Case Report 1. Signed, dated, and completed Case Report Forms (CFRs): In the patient’s
Form  Document that the investigator or authorized member of the investigators research record at
staff confirms the observations recorded the site
 Document all changes/additions or corrections made to CFR after initial
data were recorded
2. Site retains copy
3. Originals retained by sponsor after study completion and/or site closure
Communications 1. Document all relevant communications/correspondence other than site visits, In the appropriate
for example: Regulatory Binder
 Letters or patient’s research
 Meeting notes record at the site
 Notes or log of telephone calls with either subject or Sponsor
 E-Mail messages
2. Subject specific communications must be filed with source documents in the
subject’s research record
3. Document agreements or significant discussions regarding trial administration,
30
protocol violations, trial conduct, adverse event (AE) reporting, etc.
4. Save electronic media, originals, and/or certified copies
Consent Form 1. Obtain signed informed consent forms in accordance with the protocol. They IRB approved
must be dated prior to participation of each subject in a trial. copies in the
2. Save all versions submitted and approved by site’s institutional review board Regulatory Binder
(IRB). at the site and
3. Document revisions of the trial-related documents that take effect during signed original
the trial; save any revisions to: consents in the
 Informed consent patient’s research
 Any other written information provided to the subjects record or the
4. Retain consents obtained for screening purposes even if the subject was not research Regulatory
enrolled in the study Binder at the site.
5. Non-English speaking subjects must be consented in a language they can
understand.
6. Provide any changes in consent forms due to AEs, continuing review and or
safety memos according to IRB SOPs.
Curriculum 1.Document the qualification and eligibility of investigator(s) sub-investigator(s), In the Regulatory
Vitae and other key personnel to conduct a trial and/or to provide medical supervision Binder at the site
of subjects
2. Available for all investigators, sub-investigators, any other person listed on
Form FDA 1572 Form, and other key personnel at the site
3. Submit updated/revised investigator(s) and sub-investigator(s) CV to the
HRPP coordinator
FDA 1572 Form 1.Document that the Investigator of Record (IoR) agrees to conduct the trial In the Regulatory
according to the obligations stated in the form Binder at the site
2. Update as study personnel and/or other data on the form changes
3. The original version and any updated forms must be retained per regulatory
requirements
4. The Investigator in 1 box of form FDA 1572 is the individual who must sign
and date the signature box
5. Only laboratories specified in the protocol need to be listed in Section 4
6. Section 6 must list any individual:
 Responsible for conducting/performing study audits
 Authorized to prescribe study medication
This may include but is not limited to the following:
 MDs
 Pharmacist of Record
 Nurse practitioner
 Physician’s assistant
 Study coordinator
 Research nurse
If there are no individuals that need to be listed, then write “NONE”
Final Closeout Final report by investigator is sent to the IRB where required and, where In the Regulatory
Monitoring applicable, to the regulatory authorities, to document completion of the trial. Binder at the site
Report Included is the following information:
 Disposition of the subjects
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 Location of the research records
 Disposition of the specimens
 Disposition of the study drugs
 Other information as required by the institution or local IRB (e.g.,
number of patients screened, number enrolled, serious adverse
experiences)
Financial 1. Document the financial aspects of the trial and the financial agreement In the Regulatory
Disclosure between the investigator/institution and the sponsor for the trial Binder at the site
2. Certification or disclosure statement to:
 Certify that there is no financial interest or
 Disclosure specific financial interests on Investigators and
subinvestigators listed on Form FDA 1572, as well as their spouses and
dependent children
3. Proper procedure will be followed per IRB SOP.
Investigational 1. Document that relevant and current scientific information about the In the Regulatory
Drug Brochures investigational product has been provided to the investigator Binder at the site
(IDBs) and 2. Include updates to document that investigator is informed in a timely manner and in the pharmacy
Safety Package of relevant information as it becomes available
Inserts 3. Keep a copy on file for EACH study medication used within the protocol
4. Include the following:
 The most recent version
 Addendum
 Safety letters
5. Some IDBs must be shredded per protocol/sponsor. Some studies require that a
historical trial of IDBs and their individual IRB letters of acknowledgement be
retained.
Investigational 1. The Pharmacist of Record must keep records to account for the disposition of In the Pharmacy
Product/Study investigational products/study drugs by documenting the following: records at the site
Drug  Shipment dates
Accountability  Batch number
2. Document the tracking of:
 Product batch
 Review of shipping conditions
 Accountability
3. Document that the investigational products have been used according to the
protocol
4. Document the final accounting of investigational products:
 Received at the site; shipping invoices
 Dispensed to subjects; dispensing records
 Returned to subjects
 Returned to sponsor; drug disposition records
 Destroyed at the site
R&D all Human 1. Copies of all materials submitted to the IRB with dated proof of submission In Regulatory
Studies and IRB approval (when appropriate) for the following: Binder at the site
Subcommittee  Advertisements: document that recruitment measures are appropriate and
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Correspondence not coercive
 All versions of consent forms
 All protocols and amendments
 Annual reports to the IRB
 IND safety reports/Adverse Event Report
 Initial protocol submission
 Investigational drug brochure or safety package inserts
 Protocol specific education material
 Subject compensation
 Any other documents receiving IRB approval or their favorite opinion
 Any other written information to be provided to subjects will be given
appropriate written information (content and wording) to support their
ability to give fully informed consent
Any other pertinent communications with the IRB
Research 1. Document competence of facility to perform required tests, and support In the Regulatory
Laboratory reliability of results of medical/laboratory/technical procedures/tests: Binder at the site
 Certification or Accreditation
 Update when certifications expire or laboratory changes to document that
tests remain adequate throughout the trial period
 Established quality control and/or external quality assessment
2. Document normal values / ranges for medical / laboratory / technical
procedures / tests included in the protocol
3. Update documentation of normal values/ranges when they are revised during
the trial
4. The reference ranges and certifications must be on file for the following
listings:
 Local or central laboratories that analyze specimens for the study
 Any group central laboratory
Screening and 1. Document identification of subjects who entered pretrial screening In the screening
Enrollment 2. Document chronological enrollment of subjects by number files or protocol
Randomization 3. Screening and enrollment/randomization logs may be separate or Combined files at the site
Logs 4. Include the following information:
 Initials of all patients screened for each study
 PID number
 Date screened
 Date randomized
If not randomized, indicate reason
Subject 1.Document that the investigator keeps a confidential list of names of all subjects In the protocol file
Identification allocated to trial numbers upon enrolling in a trial. at site
Code List 2. Allows investigator/institution to permit identification of all subjects enrolled
in the trial in case follow up is required
3. List needs to be kept in a confidential manner and for agreed upon time
Serious Adverse 1. Notification by originating investigator to sponsor of Serious Adverse Events, In Regulatory
Events (SAE) related reports, and other safety information Binder at the site
2. Notification by sponsor to investigators of safety information
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3. Notification by sponsor and/or investigator, where applicable, to regulatory
authorities and IRB of unexpected serious adverse drug reactions and of other
safety information
Signature Log 1. Document signatures and initials of all persons authorized to make entries In the Regulatory
and/or corrections on CFRs. Include all site staff working on a study, such as: Binder at the site
 Clinicians
 Physicians
 Pharmacists
 Data Personnel
2. Include in log:
 Initials
 Legal signature, including first and last name
 Printed signature
 Credentials (if appropriate)
Source 1. Document the existence of the subject and substantiate integrity of trial data Regulatory Binder
Documents collected at the site, or per
2. Original documents and/or certified copies of documents related to the trial, IRB SOP
medical treatment, and history of the subject
3. Must be signed and dated
Scopes of Copies of scope of work, competencies, and training for each member of the
Practice/Work research team.
 Contact list of research team names, phone numbers, e-mails, pagers,
address.
Unbinding 1. Decoding procedures for blinded trials to document how, in case of an In the protocol files
emergency, identity of blinded investigational product can be revealed without at the site or in the
breaking the blind for the remaining subjects’ treatments pharmacy files and
2. Document any decoding that may have occurred at the site during the trial in the patient record
Sources: The International Conference on Harmonization, Topic E6: Good Clinical Practice: Consolidated
Guideline.http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002874.
pdf
34
CLINICAL TRIALS TERMINOLOGY
Adverse Event (AE) – Any untoward or unfavorable medical occurrence in a clinical research study
participant, including any abnormal sign (e.g. abnormal physical exam or laboratory finding), symptom,
or disease, temporally associated with the participants’ involvement in the research, whether or not
considered related to participation in the research.
Baseline – The initial time point in a clinical trial that provides a basis for assessing changes in
subsequent assessments or observations. At this reference point, measurable values such as physical
exam, laboratory tests, and outcome assessments are recorded.
Bias – A point of view or preference which prevents impartial judgment in the way in which a
measurement, assessment, procedure, or analysis is carried out or reported.
Case Report Form (CRF) – A printed, optical, or electronic (eCRF) document designed to capture all
protocol-required information for a study.
Coordinating Center (CC) – A group organized to coordinate the planning and operational aspects of a
multi-center clinical trial. CCs may also be referred to as Data Coordinating Centers (DCCs) or Data
Management Centers (DMCs).
Clinical Research or Study Coordinator (CRC) – An individual that handles the administrative and
day-to-day responsibilities of a clinical trial and acts as a liaison for the clinical site. This person may
collect the data or review it before it is entered into a study database.
Clinical Research – NIH defines clinical research as: (1) Patient-oriented research. Research conducted
with human subjects (or on material of human origin such as tissues, specimens and cognitive
phenomena) for which an investigator directly interacts with human subjects. Excluded from this
definition are in vitro studies that utilize human tissues that cannot be linked to a living individual.
Patient-oriented research includes: (a) mechanisms of human disease, (b) therapeutic interventions, (c)
clinical trials, or (d) development of new technologies. (2) Epidemiologic and behavioral studies. (3)
Outcomes research and health.
35
Clinical Trial – The NIH defines a clinical trial as a prospective biomedical or behavioral research study
of human subjects that is designed to answer specific questions about biomedical or behavioral
interventions (drugs, nutritional supplements, surgical intervention, or devices). Clinical trials are used
to determine whether new biomedical or behavioral interventions are safe, efficacious, and effective.
Behavioral clinical trials involving an intervention to modify behavior (diet, physical activity, cognitive
therapy, etc.) fit this definition of a clinical trial.
Concomitant Medication – Prescription and over-the-counter drugs and supplements a study participant
has taken along with the study intervention. This information may be collected as a history item as well
as during the study. Some studies may collect only those medications that may interact with the study or
intervention or that may exclude an individual from participating in a study.
Conflict of Interest – A conflict of interest occurs when individuals involved with the conduct,
reporting, oversight, or review of research also have financial or other interests, from which they can
benefit, depending on the results of the research.
Control Group – The group of individuals in a clinical trial assigned to a comparison intervention.
Controlled Clinical Trial – A clinical trial in which at least one group of participants is given a test
intervention, while at least one other group concurrently receives a control intervention.
Data Management – The processes of handling the data collected during a clinical trial from
development of the study forms/CRFs through the database locking process and transmission to
statistician for final analysis.
Data Management Plan (DMP) – A plan that documents the processes for handling the flow of data
from collection through analysis. Software and hardware systems along with quality control and
validation of these systems, as relevant are described.
Data and Safety Monitoring Board (DSMB) –A group of individuals independent of the study
investigators that is appointed by the NIA to monitor participant safety, data quality and to assess
clinical trial progress.
36
Efficacy – Indication that the therapeutic effect of a clinical trial intervention is acceptable; that is, at
least as good as the control intervention or standard of care to which it is compared.
Eligibility Criteria – List of criteria guiding enrollment of participants into a study. The criteria describe
both inclusionary and exclusionary factors, (e.g. inclusion criterion - participants must be between 55
and 85 years old; exclusion criterion – must not take drug X three month prior to the study).
Food and Drug Administration (FDA) – An agency within the U.S. Department of Health and Human
Services (DHHS) responsible for protecting the public health by assuring the safety, efficacy, and
security of human and veterinary drugs, biological products, medical devices, nation’s food supply,
cosmetics, and products that emit radiation.
Good Clinical Practice – A standard for the design, conduct, performance, monitoring, auditing,
recording, analyses, and reporting of clinical trials that provides assurance that the data and reported
results are credible and accurate, and that the rights, integrity, and confidentiality of trial participants are
protected.
Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule – The first comprehensive
Federal protection for the privacy of personal health information. The Privacy Rule regulates the way
certain health care groups, organizations, or businesses, called covered entities under the Rule, handle
the individually identifiable health information known as protected health information (PHI).
Human Subject – A patient or healthy individual who is or becomes a participant in research, either as a
recipient of the intervention or as a control.
Informed Consent – A process by which a participant or legal guardian voluntarily confirms his or her
willingness to participate in a particular trial, after having been informed of all aspects of the trial that
are relevant to the participant’s decision to take part in the clinical trial. Informed consent is usually
documented by means of a written, signed, and dated informed consent form, which has been approved
by an IRB/IEC.
37
Informed Consent Form – A document that describes the rights of a study participant and provides
details about the study, such as its purpose, duration, required procedures, and key contacts. Risks and
potential benefits are explained in the informed consent document.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) – An independent body

constituted of medical, scientific, and nonscientific members whose responsibility it is to ensure the
protection of the rights, safety, and well-being of human subjects involved in a trial by, among other
things, reviewing, approving, and providing continuing review of trials, protocols and amendments, and
of the methods and material to be used to obtaining and documenting informed consent of the trial
participant.
Intervention – A procedure (e.g. venipuncture), drug, nutritional supplement, gene transfer, vaccine,
behavior or device modification that is performed for clinical research purposes (45 CFR 46.102(f)).
Investigational New Drug Application (IND) – An IND is a request for authorization from the Food
and Drug Administration (FDA) to administer an investigational drug or biological product to humans.
Such authorization must be secured prior to interstate shipment and administration of any new drug or
biological product that is not the subject of an approved New Drug Application or Biologics/Product
License Application (21 CFR 312).
Masking/Blinding – A procedure in which the investigator administering the assessments and

intervention as well as the participants in a clinical trial are kept unaware of the treatment assignment(s).
Single blinding usually refers to the study participant(s) being unaware, and double blinding usually
refers to the study participant(s) and any of the following being unaware of the treatment assignment(s):
investigator(s), monitor, and data analyst(s).
Manual of Procedures (MOP) – A set of procedures describing study conduct. A MOP is developed to
facilitate consistency in protocol implementation and data collection across study participants and
clinical sites.
New Drug Application (NDA) – An application submitted by the manufacturer of a drug to the FDA,
after the clinical trial has been completed, for a license to market the drug for a specified indication.
38
Office for Human Research Protection (OHRP) – A federal government agency within the Department
of Health and Human Services (DHHS) charged with the protection of human subjects participating in
government funded research. It issues assurances and oversees compliance of regulatory guidelines by
research institutions.
Open-Label Trial – A clinical trial in which investigators and participants know which intervention is
being administered.
Pharmacokinetics – The process (in a living organism) of absorption, distribution, metabolism, and
excretion of a drug or vaccine.
Phase I clinical trials test a new biomedical intervention in a small group of people (e.g., 20-80) for the
first time to evaluate safety (e.g., to determine a safe dosage range and to identify side effects). It can
include healthy participants or patients.
Phase II clinical trials study the biomedical or behavioral intervention in a larger group of people
(several hundred) to determine efficacy and to further evaluate its safety. It is conducted in participants
with the condition or disease under study and will determine common short-term side effects and risks.
Phase III studies investigate the efficacy of the biomedical or behavioral intervention in large groups of
human subjects (from several hundred to several thousand) by comparing the intervention to other
standard or experimental interventions as well as to monitor adverse effects, and to collect information
that will allow the intervention to be used safely.
Phase IV studies are done after the intervention has been marketed. These studies are designed to
monitor effectiveness of the approved intervention in the general population and to collect information
about any adverse effects associated with widespread use.
NIH-Defined Phase III - An NIH-defined Phase III clinical trial is a broadly based prospective Phase
III clinical investigation, usually involving several hundred or more human subjects, for the purpose of
evaluating an experimental intervention in comparison with a standard or controlled intervention or
comparing two or more existing treatments. Often the aim of such investigation is to provide evidence
leading to a scientific basis for consideration of a change in health policy or standard of care. The
definition includes pharmacologic, non-pharmacologic, and behavioral interventions given for disease
prevention, prophylaxis, diagnosis, or therapy. Community trials and other population-based
intervention trials are also included.
39
Placebo – A placebo is an inactive pill, liquid, powder, or other intervention that has no treatment
value. In clinical trials, experimental treatments are often compared with placebos to assess the
treatment's effectiveness.
Placebo Controlled Study – A method of investigation in which an inactive substance/treatment (the

placebo) is given to one group of participants, while the test article is given to another group. The results
obtained in the two groups are then compared to see if the investigational treatment is more effective in
treating the condition.
Protocol – A document that describes the objective(s), design, methodology, statistical consideration,
and organization of a trial.
Protocol Amendments – A written description of a change(s) to or formal clarification of a protocol.
Protocol Deviations – Failure to conduct a study as described in the protocol. The failure may be
accidental or due to negligence and in either case, the protocol deviation should be documented. This
also includes failure to comply with federal laws and regulations, the institution's commitments and
policies, and standards of professional conduct and practice. Examples of noncompliance include:
 Failure to obtain/maintain approval for research,
 Failure to obtain informed consent when required,
 Failure to file adverse event reports,
 Performance of an unapproved study procedure,
 Performance of research at an unapproved site,
 Failure to file protocol modifications and
 Failure to adhere to an approved protocol.
Protocol Deviations Report – Internal document created as part of the ongoing quality control process
summarizing compliance with the protocol and listing protocol deviations and/or violations.
Quality Assurance (QA) – Systematic approach to ensure that the data are generated, documented
(recorded), and reported in compliance with the protocol and good clinical practice (GCP) standards.
40
Quality Control (QC) – The internal operational techniques and activities undertaken within the quality
assurance system to verify that the requirements for quality of trial related activities have been fulfilled
(e.g., data and form checks, monitoring by study staff, routine reports, correction actions, etc.).
Randomization – The process of assigning clinical trial participants to treatment or control groups using
an element of chance to determine the assignments in order to reduce bias.
Recruitment Plan – The plan that outlines how individuals will be recruited for the study and how the
study will reach the recruitment goal.
Retention Plan – The plan that details the methods in which the study will use in order to retain study
participation in the clinical trial.
Safety Monitoring Plan – A plan that outlines the oversight of a clinical trial.
Screening Log – An essential document that records all individuals who entered the screening process.
The screening log demonstrates the investigator’s attempt to enroll a representative sample of
participants.
Screening Process – A process designed to determine individual’s eligibility for participation in a

clinical research study.
Serious Adverse Event (SAE) – Any adverse event that:

 Results in death
 Is life threatening, or places the participant at immediate risk of death from the event as it
occurred
 Requires or prolongs hospitalization
 Causes persistent or significant disability or incapacity
 Results in congenital anomalies or birth defects
 Is another condition which investigators judge to represent significant hazards
41
Site Signature Log/Delegation of Authority – A list of individuals authorized to execute specific
functions in a study. Authority to execute these functions is granted to the study staff by the principal
investigator and documented through signatures and initials in the log.
Source Document – Original documents, data, and records (e.g., hospital records, clinical and office
charts, laboratory notes, memoranda, participant diaries, recorded data from automated instruments, x-
rays, etc.) that are used in a clinical trial.
Standard Operating Procedure (SOPs) – Detailed written instructions to achieve uniformity of the
performance of a specific function across studies and patients at an individual site.
Stopping Rules – Established safety criteria that would either pause or halt a study because of futility or
risk(s) to the participants.
Stratification – Separation of a study cohort into subgroups or strata according to specific characteristics
such as age, gender, etc., so that factors which might affect the outcome of the study, can be taken into
account.
Unmasking/Unblinding – A procedure in which one or more parties to the trial are made aware of the
treatment assignment(s).
Sources: Clinical Trials.gov NINDS Glossary of Clinical Research Terms CenterWatch, Inc. Patient
Resources: Glossary. www.nia.nih.gov/.../NIAGlossaryofClinicalResearchTermsFINAL.doc - United States
NIH Definitions
Friedman LM, Furberg CD, DeMets DL. Fundamentals of Clinical Trials (3 ed.). Missouri: Mosby-
Year Book Inc., 1996.
Meinert CL. Clinical Trials: Design, Conduct, and Analysis. New York: Oxford University Press, Inc.,
1986.
42

MPHR - 129 (Clinical Trial Managment)

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MPHR-129 CLINICAL TRIAL MANAGEMENT

1. Introduction to Pharmaceutical Medicine

DRUG DEVELOPMENT PROCESS

Success Rate of Developing a New Drug

Time Required Developing a New Drug:

Cost of Developing New Drug:

Getting Regulatory Approval At Each Stage Of Drug Development:

New Drug Application (NDA):

Subject-Related CDER Guidance of Interest (examples)

Refuse-to-File Letter Issued

Pharmacology/ Toxicology: The pharmacology/toxicology review team is staffed by pharmacologists

Subject-Related CDER Guidance of Interest

Notification of Easily Correctable Deficiencies

Reviews Complete and Acceptable?

Additional Information (Amendment)

Labeling Review Acceptable?

NDA Actions: Once an approval, approvable, or non-approvable recommendation is reached by the

THE DISCOVERY PROCESS

PUBLIC AND PRIVATE- Collaborations

Target Identification: Choose a molecule to target with a drug

Early Safety Tests: Perform initial tests on promising compounds

Lead Optimization: Alter the structure of lead candidates to improve properties

LEAD OPTIMIZATION- At the molecular level

CLINICAL TRIAL DESIGN

Phase-II Clinical Trial: Test in a small group of patients

PHASE 0, 2A & 2B TRIALS

Ongoing Studies and Phase-IV Trials

Document Purpose File

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) – An independent body

Masking/Blinding – A procedure in which the investigator administering the assessments and

Placebo Controlled Study – A method of investigation in which an inactive substance/treatment (the

Protocol Amendments – A written description of a change(s) to or formal clarification of a protocol.

Screening Process – A process designed to determine individual’s eligibility for participation in a

Serious Adverse Event (SAE) – Any adverse event that:

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