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Asian J. Pharm. Res. 2011; Vol. 1: Issue 1, Pg 01-06 [AJPRes.]

1

ISSN- 22315683 (Print) www.asianpharmaonline.orgISSN- 22315691 (Online) 0974-3618

REVIEW ARTICLE

Regulatory Requirements for Drug Development and Approval in United

States: A Review

Swati Rawat1* and Akhilesh Gupta

2

1Shri Bhagwan College of Pharmacy Aurangabad (M.S.)

2Kunwar Haribansh Singh College of Pharmacy Jaunpur (U.P.)

*Corresponding Author E-mail: [email protected]

ABSTRACT:In this paper a brief history and an overview of the regulatory process for drug approval in the United States through

illustrations of Investigational New Drug (INDs) Applications and New Drug Applications (NDAs), abbreviated newdrug applications (ANDAs) and supplemental new drug applications (SNDAs) are provided. For INDs, the regulatory

requirements for a well-designed protocol, the role and responsibility of institutional review boards, and the

applicability of treatment INDs are discussed. For NDAs, issues regarding the application of expanded access, the

submission of abbreviated NDAs for a generic drug, the submission of supplemental NDAs for labeling changes, and

the role and responsibility of advisory committees are addressed. Along with this a brief description of review steps

taken by FDA is provided.

KEYWORDS: Investigational New Drug Application; New Drug Application; International Conference onHarmonization.

INTRODUCTION:HISTORY:

The research, development, and approval of a drug productis a continuous but lengthy process involving drug

discovery, laboratory development, animal studies, clinical

trials, and regulatory registration. This lengthy process is

necessary to assure the effectiveness and safety of the drug

product. In the United States, however, no regulations were

put forth until the Pure Food and Drug Act was passed by

Congress in 1906. The purpose of this act is to prevent

misbranding and adulteration of food and drugs yet it does

not give the government any authority to inspect food and

drugs. The act was amended in 1912 (the Sherley

Amendment) to prohibit labeling medicines with false and

fraudulent claims. In 1931, the United States Food and

Drug Administration (FDA) was formed. The provisions of

the FDA are intended to ensure that:1. Food is safe and wholesome,

2. Drugs, biological products, and medical devices are safe

and effective,

3. Cosmetics are unadulterated,

4. The use of radiological products does not result in

unnecessary exposure to radiation, and

5. All of these products are honestly and informatively

labeled (1).

Received on 21.02.2011 Accepted on 15.03.2011

Asian Pharma Press All Right ReservedAsian J. Pharm. Res. 1(1): Jan.-Mar. 2011; Page 01-06

Late 1930s, when the Elixir Sulfanilamide disaster

occurred. The disaster was a safety concern of a liquid

formulation of a sulfa drug which caused more than 100

deaths. This drug had never been tested in humans before it

was marketed. This safety concern led to the passage of the

Federal Food, Drug and Cosmetic Act (FDandC Act) in

1938. The FDandC Act extended its coverage to cosmetics

and therapeutic devices. More importantly, the FDandC Act

requires pharmaceutical companies to submit full reports of

investigations regarding the safety of new drugs. In 1962,

the significant Kefauver-Harris Drug Amendments to the

FDandC Act were passed which not only strengthened the

safety requirements for new drugs but also established an

efficacy requirement for new drugs for the first time. In

1984, Congress passed the Price competition and Patent

Term Restoration Act to provide for increased patent

protection to compensate for patent life lost during the

approval process. Based on this act, the FDA was

authorized to approve generic drugs through the evaluation

of bioequivalency on healthy male subjects. In addition, the

FDA also has the authority to designate prescription drugs

or over-the-counter (OTC) drugs1.

REGULATORY PROCESS:

For approval of drug products, each country and/or region

such as the European Community (EC), Japan, and the

United States has similar but slightly different regulatory

processes and requirements for the conduct of clinical trials

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and the submission, review, and approval of clinical results.

This section, for illustration purpose, will focus on the

regulatory process and requirements adopted in the United

States.

For evaluation and approval of drugs, sponsors are requiredto submit to the FDA substantial evidence of effectiveness

and safety accumulated from adequate and well controlled

clinical trials. The current regulations for conducting

clinical trials and the submission, review, and approval of

clinical results for pharmaceutical compounds in the United

States can be found in the Code of Federal Regulations

(CFR) (see, eg, 21 CFR Parts 50, 56, 312, and 314).

The FDA has jurisdiction over administration of regulation

and approval of drug products. These regulations cover

Investigational New Drug Applications, and New Drug

Applications for new drugs, orphan drugs, and over-the-

counter human drugs, Abbreviated New Drug Applications

for generic drugs, Establishment License Applications orProduct License Applications for biological products, and

Investigational Device Exemptions, and Premarket

Approval of Medical Devices for medical devices.

A treatment consisting of a combination of drugs, biological

products, and/or medical devices is usually referred to as

combined therapy. If a treatment consists of a combination

of drugs, biologics, and/or devices, such as a drug with a

device, a biologic with a device, a drug with a biologic, or a

drug with a biologic in conjunction with a device, then it is

defined as a combined product. For a combined product

consisting of different pharmaceutical entities, FDA

requires that each of the entities be reviewed separately by

appropriate centers at the FDA. In order to avoid confusionof jurisdiction over a combination product and to improve

the efficiency of the approval process, the principle of

primary mode of action of a combination product was

established in the Safe Medical Devices Act (SMDA) in

1990 (21 U.S.C. 353). In 1992, based on this principle,

three intercenter agreements were signed between the

Center for Drug Evaluation and Research (CDER) and

Center for Biologics Evaluation and Research (CBER),

between CDER and Center for Devices and Radiological

Health (CDRH) and between CBER and CDRH to establish

the ground rules for assignment of a combined product and

intercenter consultation (2).

As described earlier, different regulations exist for differentproducts. The spirit and principles for the conduct,

submission, review, and approval of clinical trials, however,

are the same. Therefore, for the purpose of illustration, a

detailed discussion will be provided only on INDs and

NDAs for drug products2.

INVESTIGATIONAL NEW DRUG APPLICATION

(IND):

The FDA first enters the picture when a drug sponsor

submits an IND to the agency. Sponsors--companies,

research institutions, and other organizations that take

responsibility for marketing a drug--must show the FDA

results of pre-clinical testing they've done in laboratory

animals and what they propose to do for human testing. At

this stage, the FDA decides whether it is reasonably safe to

move forward with testing the drug on humans.

Before a drug can be studied in humans, its sponsor must

submit an IND to the FDA. Unless otherwise notified, the

sponsor may begin to investigate the drug 30 days after the

FDA has received the application. The IND requirements

extend throughout the period during which a drug is under

study. As mentioned in Section 312.1 and 312.3 of 21 CFR,

an IND is synonymous with the Notice of Claimed

Investigational Exemption for a New Drug. Therefore, an

IND is, legally speaking, an exemption to the law that

prevents the shipment of a new drug for interstate

commerce. Consequently, the drug companies which file an

IND have the flexibility of conducting clinical

investigations of products across the United States.

Kessler indicated that there are two types of INDs:

commercial and noncommercial (3). A commercial IND

permits the sponsor to gather the data on clinical safety and

effectiveness that are needed for an NDA. If the drug is

approved by the FDA, the sponsor is allowed to market the

drug for specific uses. On the other hand, a noncommercial

IND allows the sponsor to use the drug in research or early

clinical investigation to obtain advanced scientific

knowledge of the drug. Note that the FDA itself does not

investigate new drugs or conduct clinical trials.

Pharmaceutical manufacturers, physicians, and other

research organizations such as the National Institutes of

Health (NIH) may sponsor INDs. If a commercial IND

proves successful, the sponsor ordinarily submits an NDA.During this period, the sponsor and the FDA usually

negotiate over the adequacy of the clinical data and the

wording proposed for the label accompanying the drug

which sets out description, clinical pharmacology,

indications and usage, contraindications, warnings,

precautions, adverse reactions, and dosage and

administration.

By the time an IND is filed, the sponsor should have

enough information about chemistry, manufacturing, and

controls (CMC) of the drug substance and drug product to

assure the identity, strength, quality, and purity of the

investigational drug covered by the IND. In addition, the

sponsor should provide adequate information aboutpharmacological studies for absorption, distribution,

metabolism, and excretion (ADME) and acute, subacute,

and chronic toxicological studies and reproductive tests in

various animal species to support that the investigational

drug is reasonably safe to be evaluated in clinical trials of

various durations in humans.

The central focus of the initial IND submission should be

on the general investigational plan and protocols for

specific human studies. Therefore, a copy of protocol(s)

which include study objectives, investigators, criteria for

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inclusion and exclusion, study design, dosing schedule,

endpoint measurements, and clinical procedure should be

submitted along with the investigational plan and other

information such as chemistry, manufacturing, and controls,

pharmacology and toxicology, previous human experiences

with the investigational drug, and any additional andrelevant information related to the investigational drug.

Note that the FDA requires that all sponsors submit an

original and two copies of all submissions to the IND file,

including the original submission and all amendments and

reports3.

TREATMENT INDs:

During the clinical investigation of the drug under an IND,

it may be necessary and ethical to make the drug available

to those patients who are not enrolled in clinical trials.

Since 1987, the FDA permits an investigational drug to be

used for treatment under a treatment protocol or treatment

IND if the drug is intended to treat a serious or immediately

life-threatening disease, especially when there is nocomparable or satisfactory alternative drug or other therapy

available to treat that stage of the disease in the intended

patient population. The FDA, however, may deny a request

for treatment use of an investigational drug under a

treatment protocol or treatment IND if the sponsor fails to

show that the drug may be effective for its intended use in

its intended patient population or the drug may expose the

patients to an unreasonable and significant additional risk of

illness or injury.

At any time a sponsor may withdraw an effective IND

without prejudice. If an IND is withdrawn, however, FDA

shall be notified and all clinical investigations conducted

under the IND shall be stopped. If an IND is withdrawnbecause of a safety reason, the sponsor shall promptly

inform the FDA, all investigators, and all reviewing IRBs

with the reasons for the withdrawal.

If there are any deficiencies in an IND or in the conduct of

an investigation under an IND, the FDA may terminate the

IND. If an IND is terminated, the sponsor shall end all

clinical investigations conducted under the IND and recall

or dispose of all unused supplies of the drug. Some

examples of deficiencies in an IND are discussed under 21

CFR 312.44. For example, the FDA may propose

terminating the IND if it finds that human subjects would

be exposed to an unreasonable and significant risk of illness

or injury. In such a case, the FDA will notify the sponsor inwriting and invite correction or explanation within a period

of 30 days. A terminated IND is subject to reinstatement

based on additional submissions that eliminate such risk. In

this case, a regulatory hearing on the question of whether

the IND should be reinstated will be held.

COMMUNICATION WITH THE FDA:

FDA encourages open communication regarding any

scientific or medical question that may arise during the

clinical investigation. Basically, it is suggested that such

communication be arranged at the end of the Phase II study

and prior to a marketing application. The purpose of an end-

of-Phase II meeting is to review the safety of a drug

proceeding to Phase III. This meeting is helpful not only

because it evaluates the Phase III plan and protocols but it

also identifies any additional information necessary to

support a marketing application for the uses underinvestigation. Note that a similar meeting may be held at the

end of Phase I to review results of tolerance/safety studies

and to review the adequacy of the remaining development

program. At the end of Phase I a meeting would be

requested by a sponsor when a drug or biologic product is

being developed for a life-threatening disease and the

sponsor wishes to file under the expedited registration

regulations. The purpose of pre-NDA meetings is not only

to uncover any major unresolved problems but also to

identify those studies that are needed for establishment of

drug effectiveness. In addition, the communication enables

the sponsor to acquaint FDA reviewers with the general

information to be submitted in the marketing application.

More importantly, the communication provides theopportunity to discuss:

1. Appropriate methods for statistical analysis of the data,and

2. The best approach to the presentation and formatting of

the data4.

CLINICAL TRIALS:Drug studies in humans can begin only after an IND is

reviewed by the FDA and a local institutional review board

(IRB). The board is a panel of scientists and non-scientists

in hospitals and research institutions that oversees clinical

research.

IRBs approve the clinical trial protocols, which describe thetype of people who may participate in the clinical trial, the

schedule of tests and procedures, the medications and

dosages to be studied, the length of the study, the study's

objectives, and other details. IRBs make sure the study is

acceptable, that participants have given consent and are

fully informed of their risks, and that researchers take

appropriate steps to protect patients from harm.

Phase 1 studies are usually conducted in healthy

volunteers. The goal here is to determine what the drug's

most frequent side effects are and, often, how the drug is

metabolized and excreted. The number of subjects typically

ranges from 20 to 80.

Phase 2 studies begin if Phase 1 studies don't reveal

unacceptable toxicity. While the emphasis in Phase 1 is on

safety, the emphasis in Phase 2 is on effectiveness. This

phase aims to obtain preliminary data on whether the drug

works in people who have a certain disease or condition.

For controlled trials, patients receiving the drug are

compared with similar patients receiving a different

treatment--usually a placebo or a different drug. Safety

continues to be evaluated, and short-term side effects are

studied. Typically, the number of subjects in Phase 2

studies ranges from a few dozen to about 300.

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Phase 3 studies begin if evidence of effectiveness is shown

in Phase 2. These studies gather more information about

safety and effectiveness, studying different populations and

different dosages and using the drug in combination with

other drugs. The number of subjects usually ranges from

several hundred to about 3,000 people.

Phase 4 studies occur after a drug is approved. They may

explore such areas as new uses or new populations, long-

term effects, and how participants respond to different

dosages.

NEW DRUG APPLICATION (NDA):This is the formal step a drug sponsor takes to ask that the

FDA consider approving a new drug for marketing in the

United States. An NDA includes all animal and human data

and analyses of the data, as well as information about how

the drug behaves in the body and how it is manufactured.

When an NDA comes in, the FDA has 60 days to decidewhether to file it so that it can be reviewed. The FDA can

refuse to file an application that is incomplete. For example,

some required studies may be missing. In accordance with

the Prescription Drug User Fee Act (PDUFA), the FDA's

Center for Drug Evaluation and Research (CDER) expects

to review and act on at least 90 percent of NDAs for

standard drugs no later than 10 months after the

applications were received. The review goal is six months

for priority drugs. The Tufts Center for the Study of Drug

Development in Boston estimates that about 1 in 5 drugs

that enter clinical testing ultimately are approved by the

FDA.

How often the FDA meets with a drug sponsor varies, butthe two most common meeting points are at the end of

Phase 2 clinical trials and pre-NDA--right before a new

drug application is submitted.

At the end of Phase 2, the FDA and sponsors try to come to

an agreement on how the large-scale studies in Phase 3

should be done. The pre-NDA meeting is for discussing

what the FDA expects to see in the application.

There is also continuous interaction throughout the review

process5.

REVIEWING APPLICATIONS:

Though FDA reviewers are involved with a drug's

development throughout the IND stage, the official review

time is the length of time it takes to review a new drugapplication and issue an action letter, an official statement

informing a drug sponsor of the agency's decision.

Once a new drug application is filed, an FDA review team--

medical doctors, chemists, statisticians, microbiologists,

pharmacologists and other experts--evaluates whether the

studies the sponsor submitted show that the drug is safe and

effective for its proposed use. No drug is absolutely safe; all

drugs have side effects. "Safe" in this sense means that the

benefits of the drug appear to outweigh the risks.

The review team analyzes study results and looks for

possible problems with the application, such as weaknesses

of the study design or analyses. Reviewers determine

whether they agree with the sponsor's results and

conclusions, or whether they need any additional

information to make a decision.Each reviewer prepares a written evaluation containing

conclusions and recommendations about the application.

These evaluations are then considered by team leaders,

division directors, and office directors, depending on the

type of application.

Reviewers receive training that fosters consistency in drug

reviews, and good review practices remain a high priority

for the agency. For example, CDER recently held a two-day

retreat in which clinical reviewers discussed review

priorities, including improved communication between drug

review divisions in CDER regarding drugs being reviewed

for more than one indication.

Sometimes the FDA calls on advisory committees made upof outside experts who help the agency decide on drug

applications. Whether an advisory committee is needed

depends on many things.

ACCELERATED APPROVAL:

Traditional approval requires that clinical benefit be shown

before approval can be granted. Accelerated approval is

given to some new drugs for serious and life-threatening

illnesses that lack satisfactory treatments. This allows an

NDA to be approved before measures of effectiveness that

would usually be required for approval are available.

Instead, less traditional measures called "surrogate

endpoints" are used to evaluate effectiveness. These arelaboratory findings or signs that may not be a direct

measurement of how a patient feels, functions, or survives,

but are considered likely to predict benefit. For example, a

surrogate endpoint could be the lowering of HIV blood

levels for short periods of time with anti-retroviral drugs.

Most drugs to treat HIV have been approved under

accelerated approval provisions, with the company required

to continue its studies after the drug is on the market to

confirm that its effects on virus levels are maintained and

that it ultimately benefits the patient. Under accelerated

approval rules, if studies don't confirm the initial results, the

FDA can withdraw the approval.

Because premarket review can't catch all potential problems

with a drug, the FDA continues to track approved drugs for

adverse events through a postmarketing surveillance

program6.

"APPROVABLE" OR "NOT APPROVABLE"

If the FDA decides that the benefits of a drug outweigh the

risks, the drug will receive approval and can be marketed in

the United States. But if there are problems with an NDA,

the FDA may decide that a drug is "approvable" or "not

approvable."

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A designation of approvable means that the drug can

probably be approved, provided that some issues are

resolved first. This might involve the sponsor and the FDA

coming to a final agreement on what should go on the

drug's label, for example. It could also involve more

difficult issues, such as the adequacy of information on howpeople respond to various dosages of the drug.

A designation of "not approvable" describes deficiencies

significant enough that it is not clear that approval can be

obtained in the future, at least not without substantial

additional data.

Common problems include unexpected safety issues that

crop up or failure to demonstrate a drug's effectiveness. A

sponsor may need to conduct additional studies--perhaps

studies of more people, different types of people, or for a

longer period of time.

Manufacturing issues are also among the reasons that

approval may be delayed or denied. Drugs must bemanufactured in accordance with standards called good

manufacturing practices, and the FDA inspects

manufacturing facilities before a drug can be approved. If a

facility isn't ready for inspection, approval can be delayed.

Any manufacturing deficiencies found would need to be

corrected before approval.

The FDA outlines the justification for its decision in an

action letter to the drug sponsor. When the action is either

approvable or not approvable, CDER gives the sponsor a

chance to meet with agency officials to discuss the

deficiencies. At that point, the sponsor can choose to ask for

a hearing or correct any deficiencies and submit new

information.

ABBREVIATED NEW DRUG APPLICATIONS:

An abbreviated NDA (ANDA) is usually reserved for drug

products (eg, generics) which duplicate products previously

approved under a full NDA. For an ANDA, reports of

nonclinical laboratory studies and clinical investigations

except for those pertaining to in vivo bioavailability of the

drug product are not required. The information may be

omitted when the FDA has determined that the information

already available is adequate to establish that a particular

dosage form of a drug meets the statutory standards for

safety and effectiveness. The duplicate products are usually

referred to as products with the same active ingredient(s),

route of administration, dosage form, strength, or conditionof use which may be made by different manufacturers.

As mentioned earlier, under the Drug Price Competition

and Patent Term Restoration Act passed in 1984, the FDA

may approve generic drug products if the generic drug

companies can provide evidence that the rates and extents

of absorption of their drug products do not show significant

differences from those of the innovator drug products when

administered at the same molar dose of the therapeutic

moiety under similar experimental conditions (21 CFR

320). The Drug Price Competition and Patent Term

Restoration Act states that FDA has authority for all generic

drug approvals through an ANDA submission for

bioequivalence review. An ANDA submission should

include product information, pharmacokinetic data and

analysis, statistical analysis, analytical methodology and

validation, and clinical data.To ensure the validity of bioequivalence assessment, the

Division of Bioequivalence's Office of Generic Drugs of

CDER issued a "Guidance on Statistical Procedures for

Bioequivalence Studies Using a Standard TwoTreatment

Crossover Design" in July 1992. The guidance sets forth

regulations for valid statistical analysis for bioequivalence

assessment. In addition, any relevant clinical findings,

adverse reactions, and deviations from the protocol also

need to be included in the ANDA submission. Recently, to

assure drug interchangeability, a draft guidance on "In Vivo

Bioequivalence Studies Based on Population and Individual

Bioequivalence Approaches" was developed by the FDA

and is currently being circulated for public comments. The

draft guidance is intended to replace the 1992 guidance forassessment of bioequivalence for regulatory approval of

new dosage forms of an innovator drug and its generic

copies after it is finalized7.

SUPPLEMENTAL NEW DRUG APPLICATIONS:

A supplemental NDA (SNDA) is referred to as

documentation submitted to the FDA on a drug substance or

product which is already the subject of an approved NDA.

Supplements may be submitted for a variety of reasons such

as labeling changes, a new or expanded clinical indication,

or a new dosage form. For example, for labeling changes,

the sponsor may want to add a new specification or test

method or changes in the methods, facility, or controls to

provide increased assurance that the drug will have thecharacteristics of identity, strength, quality, and purity that

it purports to possess. For drug substance and/or drug

product, the sponsor may want to relax the limits for a

specification, establish a new regulatory analytical method,

or delete a specification or regulatory analytical method. In

addition, the sponsor may want to extend the expiration

date of the drug product based on data obtained under a new

or revised stability testing protocol that has not been

approved in the application or to establish a new procedure

for reprocessing a batch of the drug product that fails to

meet specification. It should be noted, however, that in an

SNDA, the sponsor is required to fully describe the change

in each condition established in an approved application

beyond the variation already provided for in theapplication

8.

ADVISORY COMMITTEES:

The FDA has established advisory committees which

consist of clinical, pharmacological, and statistical experts

and one consumer advocate (not employed by the FDA) in

designated drug classes and subspecialities. The

responsibilities of the committees are to review data

presented in NDAs and to advise the FDA as to whether or

not substantial evidence of safety and effectiveness exists

based on adequate and well controlled clinical studies. In

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addition, the committee may also be asked at times to

review certain INDs, protocols, or important issues relating

to marketed drugs and biologics. The advisory committees

not only supplement the FDA's expertise but also allow an

independent peer review during the regulatory process9.

Note that the FDA usually prepares a set of questions forthe advisory committee to address at the meeting. For

example, the following is a list of some typical questions:

1. Are there two or more adequate and wellcontrolled trials?

2. Have the patient populations been well enough

characterized?

3. Has the dose-response relationship been sufficiently

characterized? and

4. Do you recommend the use of the drug for the indication

sought by the sponsor for the intended patient population?

DRUG REVIEW STEPS:

The review steps taken by FDA are as described in brief10

:

1 Pre-clinical (animal) testing.2. An investigational new drug application (IND) outlineswhat the sponsor of a new drug proposes for human testing

in clinical trials.

3. Phase 1 studies (typically involve 20 to 80 people).4. Phase 2 studies (typically involve a few dozen to about300 people).

5. Phase 3 studies (typically involve several hundred toabout 3,000 people).

6. The pre-NDA period, just before a new drugapplication (NDA) is submitted.

A common time for the FDA and drug sponsors to meet.

7. Submission of a new drug application is the formalstep asking the FDA to consider a drug for marketing

approval.

8. After an NDA is received, the FDA has 60 days todecide whether to file it so it can be reviewed.

9. If the FDA files the NDA, an FDA review team isassigned to evaluate the sponsor's research on the drug's

safety and effectiveness.

10. The FDA reviews information that goes on a drug'sprofessional labeling, guidance on how to use the drug.

11. The FDA inspects the facilities where the drug will bemanufactured as part of the approval process.

12. FDA reviewers will approve the drug or find it either"approvable" or "not approvable."

CONCLUSION:This paper provides a brief history and an overview of the

regulatory approval process in drug development currently

adopted in the United States. For drug sponsors and others

who want a basic understanding of the drug development

process, the FDA has published a series of articles in a

special report called From Test Tube to Patient: Improving

Health Through Human Drugs" These articles provide

background information on a broad range of topics from

laboratory and animal studies, to reporting unsafe medical

products already on the market. Another resource for drug

development information is an interactive chart which

graphically displays the process with an emphasis on

preclinical (animal) research and clinical (human) studies or

trials conducted by the drug's sponsor. It should be noted

that most regulatory authorities in different countries have

similar but slightly different requirements for approval of

drug products. In practice, similar studies may be

repeatedly conducted in order to fulfill regulatory

requirements in different marketplaces. Therefore, there is astrong desire to establish international standards for

regulatory requirements so that the information generated

from a specific region will be mutually accepted by other

regions. The necessity to standardize regulatory

requirements has been recognized by both regulatory

authories and the pharmaceutical industry. As a result, the

International Conference on Harmonization (ICH) which

consists of the European Community, the United States, and

Japan was formed to evaluate and develop technical

requirements for the registration of pharmaceuticals for

human use. A number of guidance and draft guidelines for

good pharmaceutical practices have been developed to

assist pharmaceutical companies in drug research and

development.

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2. Margolies ME Regulations of combination products. App ClinTrials. 1994; 3:50-65.

3. Kessler DA. The regulation of investigational drugs. New Eng JMed 1989; 320:281-288.

4. Petricciani JC. An overview of FDA, IRBs and regulations. IRB.1981; 3:1.

5. Barry MJ, Fowler Jr. FJ, O'Leary MP, Bruskewitz RC, HoltgreweHL, Mebust WK, Cockett AT. The American Urological

Association Symptom Index for Benign Prostatic Hyperplasia. JUrol. 1992; 148: 1549-1557.

6. Chow SC, Liu JP. Design and Analysis of Clinical Trials. NewYork, New York: John Wiley and Sons; 1998.

7. Kessler DA, Feiden KL. Faster evaluation of vital drugs.Scientific Am. 1995; 272:48-54.

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