An overview of the drug approval process. (FDA Overview).

FDA overview. The Food and Drug Administration (FDA) is one of several government agencies charged with protecting, promoting, and enhancing the health of the American people. The statutory authority of the agency is the Food and Drug Administrative Modernization Act enacted in November 1997 that amended the Federal Food, Drug, and Cosmetic Act. In the broader sense, the FDA is charged with ensuring that food and cosmetic products, as well as radiation-emitting products, are safe. In addition, it regulates feed and drugs for pets and farm animals. With respect to the development of drugs and vaccines for HIV/AIDS, the FDA's mission under the Modernization Act includes:

* Promptly and efficiently reviewing clinical research and taking appropriate action on the marketing of regulated products in a timely manner;

* Ensuring that drugs are safe and effective; and

* Carrying out these actions in consultation with experts in science, medicine, and public health, and in cooperation with consumers, users, and manufacturers.

In completing this and other parts of its mission, the FDA strives to:

* Enforce laws and regulations through legal means;

* Base regulatory decisions on strong science, analysis, and the law;

* Be a positive force in making safe and effective products available to the consumer, focusing special attention on life-threatening diseases like AIDS;

* Provide clear standards of compliance to regulated industry and advise industry on how to meet those standards; and

* Identify and effectively address critical public health problems arising from the use of FDA-regulated products.

According to the "FDA Regulatory Primer" of the Office of Special Health Issues, the FDA regulates over $1 trillion worth of products, which account for 25 cents of every dollar spent annually by American consumers. The FDA is one of the country's oldest consumer protection agencies, employing approximately 9000 scientists, investigators, inspectors, and enforcement officers.

The organization of the FDA. The organization of the FDA is outlined at the end of this article. As noted, the FDA has several centers that deal with everything from toxicological research to veterinary medicine. The center most involved in the approval process of HIV-related drugs is the Center for Drug Evaluation and Research (CDER). In addition, the Center for Biologics Evaluation and Research regulates the blood supply, biological therapeutics, and vaccines. Finally, the FDA has an Office of Special Health Issues that answers questions about the agency's activities related to HIV/AIDS, cancer, patient representative programs, and other special health issues.

Initial evaluation. Drug evaluation and approval for marketing is the primary activity of the CDER. While it is the drug sponsor's obligation to do the research to identify and test the clinical safety and efficacy of a new compound, it is CDER's obligation to evaluate the drug and determine whether the benefits of the drug outweigh its risks.

The drug development process begins with the identification or the design of a compound that shows promise in treating a specific illness (see p. 6). Once that compound is identified, the sponsor will evaluate it through in vitro (laboratory) and in vivo (animal) testing. Testing in animals will determine, among other things, how the compound is metabolized, absorbed, and excreted, and what types of toxicities are associated with it. During this initial stage, the drug sponsor will determine 1) the pharmacologic profile of the drug, 2) acute toxicities associated with drug in at least 2 species of animals (generally 1 rodent and 1 non-rodent species), and 3) the short-term (2 weeks to 3 months) toxicities of the drug. (Additional animal testing may continue after human testing is begun to determine whether long-term use of the compound may cause cancer or birth defects.)

Preliminary meetings with the FDA are usually conducted at an early stage to discuss the testing phases, data requirements, and any scientific issues that may need to be resolved prior to animal testing and formal filing with the FDA. At these meetings the FDA and the sponsor may decide the type and length of animal studies needed prior to the initiation of human testing.

Preparing for human testing. A local institutional review board (IRB) will review the protocol for testing the drug in humans. The IRB is usually made of a panel of scientists, ethicists, and non-scientists who oversee clinical research at medical centers throughout the country. The drug developer next approaches the FDA with the plan for testing the compound in humans. The testing plan takes the form of an Investigational New Drug (IND) application, which consists of the plan for the study, a complete picture of the drug (including its structural formula), results of animal tests, and manufacturing information.

Phase 1. Once the FDA and the IRB approve the protocol, testing will begin in a small number of volunteers, usually healthy, to determine primarily pharmacologic and metabolic effects and toxicities. This initial testing is referred to as phase 1 (also see p. 5) and may take several months or longer. Approximately 70% of drugs tested are successful at the end of this phase and proceed to phase 2.

Phase 2. Phase 2 (also see p. 7) may involve several hundred patients and its primary purpose is to obtain short-term safety and effectiveness data in the setting of well-controlled, closely monitored clinical studies. Approximately 33% of the drugs that undergo phase 1 tests successfully complete phase 2.

At the end of phase 2 the sponsor will generally meet with the FDA to discuss plans for phase 3 testing. During this meeting additional information may be identified that is needed to support the final submission of a new drug application. The sponsor and the FDA may agree on the design and objectives of additional studies as a way to avoid unnecessary expenditure of time and money. One month prior to the meeting, the sponsor will generally submit data supporting claims of the new drug, chemistry data, animal data, proposed additional animal testing, results of phase 1 and 2 studies, statistical methodology being used, detailed protocol plans from phase 3 studies, and proposed labeling.

Phase 3. Phase 3 studies (also see p. 7) are intended to evaluate the overall risk-benefit relationship of the drug. These studies are conducted in several hundred to several thousand patients and may take several years to complete. These studies may be controlled or uncontrolled. In addition to evaluating the risk-benefit ratio, these studies may be used to extrapolate and possibly predict how the drug will affect the larger, general population of patients who may ultimately use the drug. Approximately 25% to 30% of the drugs that undergo phase 1 tests successfully complete phase 3.

New Drug Application. After these studies are completed, the sponsor may file a New Drug Application (NDA). Prior to 1962, NDAs were only required to contain information demonstrating the safety of investigational drugs. Since the passage of the Kefauver-Harris Amendments to the Food, Drug, and Cosmetic Act, sponsors have been required to submit evidence that new drugs are not only safe, but that they are effective for their intended use and that the benefits of their use outweigh the risks.

An NDA submission is generally a rather large set of documents that consists of several sections, including information on chemistry, manufacturing and control, non-clinical pharmacology and toxicology, human pharmacokinetics and bioavailability, clinical data, safety update reports, statistical analysis, case report tabulations, case report forms, patient information, etc.

CDER classifies NDAs according to the type of drug and its intended uses. The drug may be a new molecular entity, a new formulation of a previously approved drug, a new combination of 2 or more drugs, a new indication of an already marketed product, etc.

If the NDA is deemed "fileable" (i.e. it is complete and contains sufficient data and information for review), then the submission is sent to reviewers, who can be physicians, pharmacokineticists, statisticians, chemists, microbiologists, and pharmacologists. CDER may meet with sponsors during the review process to discuss scientific, medical, and procedural issues and give the sponsors an opportunity to correct deficiencies.

Advisory committees. CDER may call upon advisory committees to review submissions. Such committees allow for outside advice and opinions from experts in the field. The committees are usually made of a wide variety of members, including physicians; members of professional, scientific, and medical societies; academics; members of government agencies; members of industry and trade associations; and patients who have special insights into the disease that the drug is intended to treat. Special emphasis is placed on recruiting minorities and women to serve as part of these committees.

Committee meetings are usually open to the public unless issues of confidentiality; proprietary, commercial, or trade secret information; or law enforcement investigations are presented or discussed. A portion of the meeting is always reserved for public comment, during which any interested party may make presentations, ask questions, or take part in general discussions.

The decisions of the advisory committee are not binding on CDER, but the center gives them significant weight in making its own decisions. In the case of antivirals for the treatment of HIV/AIDS, the advisory committee involved in drug review is the Antiviral Drugs Advisory Committee. (See "Getting information about the FDA and its activities" on p. 17).

Review by CDER of an NDA submission involves attempts by the reviewer to confirm, validate, or refute the sponsor's conclusion that the drug is safe and effective for its intended use. Reviewers, often in consultation with each other, will write an evaluation of the NDA with their conclusion and recommendations. The division director or office director will go over the reviews and decide what action the division will take on the submission.

Label revision and onsite inspection. Prior to the final decision, CDER may require the sponsor to revise the package labeling of the drug to ensure that all claims, instructions, and precautions accurately reflect the results of the clinical trials. In addition, CDER may conduct onsite inspections of the manufacturing sites and clinical trials sites to verify completeness and accuracy of data, good manufacturing controls, compliance with Current Good Manufacturing Practices, and to collect drug samples for analysis.

CDER action. At the end of the review, CDER sends 1 of 3 possible action letters to the sponsor. A "Not Approvable Letter" lists the deficiencies of the application and explains why the application cannot be approved. An "Approvable Letter" lists minor deficiencies that can be corrected and generally indicates that the drug will ultimately be approved. An "Approval Letter" states the drug is approved.

CDER provides applicants receiving Approvable or Not Approvable Letters an opportunity to have an end-of-review conference to discuss what additional steps are necessary before an application might be approved. If approved (and made official through the decision of the division director), the product may be marketed immediately.

The FDA and the AIDS epidemic. For many years the review done by the FDA was considered the gold standard by which drugs should be measured for efficacy and safety. Despite this, the review process was often judged to be too slow, especially when it came to the approval of drugs for life-threatening illnesses.

The advent of the AIDS epidemic resulted in some changes in the way drugs for the treatment of life-threatening illnesses are made available and approved. These changes shortened the time required for approval, allowing patients to have earlier access to many more drugs in a shorter time. All Americans should be grateful for the advocacy of AIDS activists resulting in these dramatic and important changes.

Parallel track. The parallel track mechanism was developed by the US Public Health Service in response to the AIDS epidemic. The parallel track mechanism allowed patients with AIDS to receive investigational drugs that showed promise in preliminary studies when those patients were unable to participate in controlled clinical trials.

Treatment IND. The Treatment Investigational New Drug (or Treatment IND) allows investigational drugs to be given to desperately ill patients as early in the development process as possible. This process is intended to make drugs available to treat serious or life-threatening diseases, or diseases where no comparable alternative drug or therapy is available to treat that stage of the disease. The most famous case of the use of a Treatment IND was the advanced use of zidovudine (or AZT; later called Retrovir). In that case, an interim analysis of the phase 2 study of the drug was halted when it was discovered that 19 persons in the control group had died compared to 1 person in the zidovudine group. Within 1 week of receiving the information, the FDA authorized a Treatment IND for zidovudine that resulted in several thousand patients receiving the drug prior to its approval.

Accelerated approval. Finally, another mechanism that has been employed by the FDA to provide early access to investigational drugs in extraordinary circumstances has been "Accelerated Review" or "Accelerated Approval" (also see p. 18). This mechanism allows for speedier development of and access to investigational drugs that promise significant benefit over existing therapies for serious or life-threatening illnesses, or for serious or life-threatening illnesses where no therapy exists.

Accelerated approval can be used in 2 circumstances: when approval is based on evidence that the drug has an effect on surrogate markers or when the FDA determines that safe use of a product may be achieved by restricting its distribution or use. A surrogate marker is a laboratory finding or physical sign that is considered a likely indicator of therapeutic benefit (like decreased viral load), but is not a direct measure of the clinical state of the patient.

Accelerated approval is sometimes given with the understanding that the sponsor will carry out post-marketing studies to confirm that the drug does produce a clinical benefit. Additionally, distribution of accelerated approval drugs can at times be limited to institutions that have the capacity to use them safely and to physicians who have specialized training or experience in treating the disease. All drugs made available for clinical use prior to approval must be dispensed only with the written consent of the patient and cannot be otherwise promoted or commercialized.

Drug classification. Finally, another way the FDA has attempted to streamline the review process is by adopting the practice of classifying drugs under consideration as "Standard" or "Priority." Standard drugs are those that provide only minor or no improvement in therapeutics, whereas Priority drugs are those that have the potential to provide a major advance in care. The review of Priority drugs is accelerated and the FDA will mobilize available personnel to review the large amount of technical information contained in an NDA of a Priority drug.

In the case of AIDS therapies, the FDA has created an "AA" priority category to ensure that these drugs receive the highest priority in the review process. Additionally, in 1988 the FDA issued interim regulations that allowed expedited marketing approval of new drugs directly from phase 2, when sponsors had early consultation with the FDA and designed phase 2 clinical trials that provided sufficient data to prove efficacy and support approval.

Consequences of streamlining the system. The expedited methods devised to accelerate access to HIV/AIDS drugs have served to provide investigational drugs to many patients who might have otherwise died from the disease. However, there has been some concern that in the haste to provide access and approval of new therapies, the scientific and medical communities have not learned the best ways to use these drugs. Drugs approved on the basis of surrogate markers are often used without the benefit of knowing the long-term clinical consequence of their use. For this reason many advocates have determined that it may be time to require sponsors to conduct more long-term clinical endpoint studies that would give patients a better idea of how to use these drugs for the long haul.

Antiretrovirals Currently Approved for HIV Infection

ANTIRETROVIRALS                   Submission   Approval   Approximate
Brand name (generic name/         Date of NDA  Date       Approval Time
original manufacturer)

Retrovir capsules (zidovudine,
  AZT / Glaxo Wellcome)           02 DEC 86    19 MAR 87  3.5 months
Retrovir syrup                    28 OCT 88    28 SEP 89  11 months
Retrovir injection                01 FEB 89    02 FEB 90  12 months
Videx (didanosine, ddI /
  Bristol-Myers Squibb)           06 APR 01    09 OCT 91  6 months
Hivid (zalcitabine, ddC /
  Hoffmann-La Roche)              31 OCT 01    19 JUN 92  8.5 months
Zerit (stavudine, d4T /
  Bristol-Myers Squibb            28 DEC 93    24 JUN 94  6 months
Epivir (lamivudine, 3TC /
  Glaxo Wellcome)                 30 JUN 05    17 NOV 95  4.5 months
Invirase (saquinavir /
  Hoffmann-La Roche)              08 AUG 95    06 DEC 95  3 months
Norvir (ritonavir / Abbott
  Laboratories)                   21 DEC 95    01 MAR 96  2.5 months
Crixivan (indinavir / Merck &
  Co., Inc)                       31 JAN 96    13 MAR 96  1.5 months
Viramune (nevirapine/Boehringer
  Ingelheim Pharmaceuticals,
  Inc)                            23 FEB 96    21 JUN 96  4 months
Viracept (nelfinavir / Agouron
  Pharmaceuticals)                26 DEC 96    14 MAR 97  3 months
Rescriptor (delavirdine /
  Pharmacia & Upjohn)             15 JUL 96    04 APR 97  9 months
Combivir (zidovudine and
  lamivudine / Glaxo Wellcome)    30 MAY 97    26 SEP 97  4 months
Fortovase (saquinavir, soft
  gelatin capsule / Hoffmann-La
  Roche                           12 MAY 97    07 NOV 97  6 months
Sustiva (efavirenz / DuPont
  Pharmaceuticals)                11 JUN 98    17 SEP 98  3 months
Ziagen (abacavir / Glaxo
  Wellcome)                       24 JUN 98    17 DEC 98  6 months
Agenerase (amprenavir / Glaxo
  Wellcome)                       16 OCT 98    15 APR 99  6 months
Norvir (ritonavir, soft gelatin
  capsule / Abbott Laboratories)  02 MAR 09    29 JUN 99  3 months
Kaletra (lopinavir, ritonavir /
  Abbott Laboratories)            01 JUN 00    15 SEP 00  3 months
Videx EC (enteric-coated
  didanosine / Bristol-Myers
  Squibb)                         31 JAN 00    31 OCT 00  9 months
Trizivir (abacavir, zidovudine,
  lamivudine / Glaxo Wellcome)    17 DEC 99    14 NOV 00  12 months
Viread (tenofovir disoproxil
  fumarate / Gilead Sciences,
  Inc)                            01 MAY 01    96 OCT 01  5.5 months

Why is an Investigational New Drug Application referred to as an "Exemption"?

Persons familiar with FDA workings will often refer to an Investigational New Drug (IND) application as an "exemption" or as an "IND exemption." The use of this terminology can be confusing to the uninitiated. The explanation for the use of this term is simple, but often not given.

The FDA has legal jurisdiction only over products shipped in interstate commerce. States have jurisdiction over products that are manufactured, shipped, and marketed within a state. US law requires that drugs must be approved for marketing prior to shipping over state lines. Since drugs are usually tested in multiple states, sponsors must obtain an exemption from the legal requirement of drug approval prior to shipping their drug to the various out-of-state investigators who are participating in the testing of the drug.

Thus, the IND is not an application for marketing approval even though it usually starts the mechanism towards that approval. Instead the IND is an application for exemption from the legal requirement that drugs be approved for marketing prior to being shipped across state lines. Despite this technical aspect of an IND application, the application is used primarily to obtain evidence that the drug is reasonably safe and that human studies should proceed.