INTRODUCTION:

HISTORY:

The research, development, and approval of a drug product is 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).

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 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 required to 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 or Product 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 confusion of 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 different products. 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 about pharmacological 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 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 and relevant 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 no comparable 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 withdrawn because 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 in writing 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 under investigation. 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 the opportunity 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 the type 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.

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 decide whether 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, but the 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 drug application 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 up of 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 are laboratory 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."

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 how people 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 be manufactured 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 condition of 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 for assessment 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 the characteristics 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 the application⁸.

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 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 for the 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) outlines what 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 about 300 people).

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

6. The pre-NDA period, just before a new drug application (NDA) is submitted.
A common time for the FDA and drug sponsors to meet.

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

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

9. If the FDA files the NDA, an FDA review team is assigned to evaluate the sponsor's research on the drug's safety and effectiveness.

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

11. The FDA inspects the facilities where the drug will be manufactured 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 a strong 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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10. http://www.fda.gov, accessed on 21/12/2007.

Received on 21.02.2011 Accepted on 15.03.2011

Asian J. Pharm. Res. 1(1): Jan.-Mar. 2011; Page 01-06

*Corresponding Author E-mail: swati_r@k.st