mphr - 129 (clinical trial managment)

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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




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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




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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.




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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.




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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




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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)




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NDA Review Process




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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;




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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.




20

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.




22

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




25

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




26

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.




29

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

R E F E R E N C E S

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 Number

The institution is responsible for obtaining and maintaining a current Health and Human Services (HHS) Federal Wide Assurance Number through the Office of Human Research Protection (OHRP)

The PI is responsible for ensuring that a current Assurance Number is in effect while conducting research on human subjects

All sites must maintain the Assurance Number on file and obtain renewal prior to expiration.

In a Regulatory Binder at the site

A copy of the

Assurance number must be on file with

the sponsor Auditing Reports

1. Copies of all monitor visit findings. 2. Document audit visits and findings of the auditor. 3. Copies of all monitor visit reports are filed at the site and sent to the sponsor

In the Regulatory Binder at the site

Case Report Form

1. Signed, dated, and completed Case Report Forms (CFRs): Document that the investigator or authorized member of the investigators

staff confirms the observations recorded 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

In the patient’s research record at

the site

Communications 1. Document all relevant communications/correspondence other than site visits, for example:

Letters Meeting notes 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,

In the appropriate Regulatory Binder

or patient’s research record at the site




31

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 must be dated prior to participation of each subject in a trial. 2. Save all versions submitted and approved by site’s institutional review board (IRB). 3. Document revisions of the trial-related documents that take effect during the trial; save any revisions to:

Informed consent Any other written information provided to the subjects

4. Retain consents obtained for screening purposes even if the subject was not enrolled in the study 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.

IRB approved copies in the

Regulatory Binder at the site and signed original consents in the

patient’s research record or the

research Regulatory Binder at the site.

Curriculum Vitae

1.Document the qualification and eligibility of investigator(s) sub-investigator(s), and other key personnel to conduct a trial and/or to provide medical supervision 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 according to the obligations stated in the form 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 Monitoring

Report

Final report by investigator is sent to the IRB where required and, where applicable, to the regulatory authorities, to document completion of the trial. 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 Disclosure

1. Document the financial aspects of the trial and the financial agreement between the investigator/institution and the sponsor for the trial 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 Drug Brochures

(IDBs) and Safety Package

Inserts

1. Document that relevant and current scientific information about the investigational product has been provided to the investigator 2. Include updates to document that investigator is informed in a timely manner of relevant information as it becomes available 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.


and in the pharmacy

Investigational Product/Study

Drug Accountability

1. The Pharmacist of Record must keep records to account for the disposition of investigational products/study drugs by documenting the following:

Shipment dates 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

In the Pharmacy records at the site

R&D all Human Studies

Subcommittee

1. Copies of all materials submitted to the IRB with dated proof of submission and IRB approval (when appropriate) for the following:

Advertisements: document that recruitment measures are appropriate and

In Regulatory Binder at the site




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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 Laboratory

1. Document competence of facility to perform required tests, and support reliability of results of medical/laboratory/technical procedures/tests:

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 Enrollment

Randomization Logs

1. Document identification of subjects who entered pretrial screening 2. Document chronological enrollment of subjects by number 3. Screening and enrollment/randomization logs may be separate or Combined 4. Include the following information:

Initials of all patients screened for each study PID number Date screened Date randomized

If not randomized, indicate reason

In the screening files or protocol files at the site

Subject Identification

Code List

1.Document that the investigator keeps a confidential list of names of all subjects allocated to trial numbers upon enrolling in a trial. 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

In the protocol file at site

Serious Adverse Events (SAE)

1. Notification by originating investigator to sponsor of Serious Adverse Events, related reports, and other safety information 2. Notification by sponsor to investigators of safety information

In Regulatory Binder at the site




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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 and/or corrections on CFRs. Include all site staff working on a study, such as:

Clinicians Physicians Pharmacists Data Personnel

2. Include in log: Initials Legal signature, including first and last name Printed signature Credentials (if appropriate)


Source Documents

1. Document the existence of the subject and substantiate integrity of trial data collected 2. Original documents and/or certified copies of documents related to the trial, medical treatment, and history of the subject 3. Must be signed and dated

Regulatory Binder at the site, or per

IRB SOP

Scopes of Practice/Work

Copies of scope of work, competencies, and training for each member of the 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 emergency, identity of blinded investigational product can be revealed without breaking the blind for the remaining subjects’ treatments 2. Document any decoding that may have occurred at the site during the trial

In the protocol files at the site or in the pharmacy files and 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




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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.




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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.




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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.




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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.




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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.




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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.




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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




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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.


