FDA drug approval process

In this series , I will tell u detail about biotechnology sector ... perticularly abt bioinformatics sector
i will start by process of approval of drugs by FDA as all the money in the sector originates from drugs that need to be approved .....

FDA DRUG APPROVAL PROCESS

Clinical Studies (Overview)

The new drug application (NDA) is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale in the United States. To obtain this authorization, a drug manufacturer submits in an NDA nonclinical (animal) and clinical (human) test data and analyses, drug information, and descriptions of manufacturing procedures.

An NDA must provide sufficient information, data, and analyses to permit FDA reviewers to reach several key decisions, including:

Whether the drug is safe and effective for its proposed use(s), and whether the benefits of the drug outweigh its risks.

Whether the drug’s proposed labeling is appropriate, and, if not, what the drug’s labeling 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 purpose of preclinical work—animal pharmacology/toxicology testing—is to develop adequate data to undergird a decision that it is reasonably safe to proceed with human trials of the drug. Clinical trials represent the ultimate premarket testing ground for unapproved drugs. During these trials, an investigational compound is administered to humans and is evaluated for its safety and effectiveness in treating, preventing, or diagnosing a specific disease or condition. The results of this testing will comprise the single most important factor in the approval or disapproval of a new drug.

Although the goal of clinical trials is to obtain safety and effectiveness data, the overriding consideration in these studies is the safety of those in the trials. CDER monitors the study design and conduct of clinical trials to ensure that people in the trials are not exposed to unnecessary risks.

Pre-Clinical Research

Under FDA requirements, a sponsor must first submit data showing that the drug is reasonably safe for use in initial, small-scale clinical studies. Depending on whether the compound has been studied or marketed previously, the sponsor may have several options for fulfilling this requirement: (1) compiling existing nonclinical data from past in vitro laboratory or animal studies on the compound; (2) compiling data from previous clinical testing or marketing of the drug in the United States or another country whose population is relevant to the U.S. population; or (3) undertaking new preclinical studies designed to provide the evidence necessary to support the safety of administering the compound to humans.

During preclinical drug development, a sponsor evaluates the drug’s toxic and pharmacologic 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.

Phase 1 Clinical Studies

Phase 1 includes the initial introduction of an investigational new drug into humans. These studies are closely monitored and may be conducted in patients, but are usually conducted in healthy volunteer subjects. These studies are designed to determine the metabolic and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. During Phase 1, sufficient information about the drug’s pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid, Phase 2 studies.

Phase 1 studies also evaluate drug metabolism, structure-activity relationships, and the mechanism of action in humans. These studies also determine which investigational drugs are used as research tools to explore biological phenomena or disease processes. The total number of subjects included in Phase 1 studies varies with the drug, but is generally in the range of twenty to eighty.

In Phase 1 studies, CDER can impose a clinical hold (i.e., prohibit the study from proceeding or stop a trial that has started) for reasons of safety, or because of a sponsor’s failure to accurately disclose the risk of study to investigators. Although CDER routinely provides advice in such cases, investigators may choose to ignore any advice regarding the design of Phase 1 studies in areas other than patient safety.

Phase 2 Clinical Studies

Phase 2 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 2 studies are typically well-controlled, closely monitored, and conducted in a relatively small number of patients, usually involving several hundred people.

Phase 3 Clinical Studies

Phase 3 studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained in Phase 2, 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 3 studies also provide an adequate basis for extrapolating the results to the general population and transmitting that information in the physician labeling. Phase 3 studies usually include several hundred to several thousand people.

In both Phase 2 and 3, CDER can impose a clinical hold if a study is unsafe (as in Phase 1), or if the protocol is clearly deficient in design in meeting its stated objectives. Great care is taken to ensure that this determination is not made in isolation, but reflects current scientific knowledge, agency experience with the design of clinical trials, and experience with the class of drugs under investigation.

Animal Testing

In animal testing, drug companies make every effort to use as few animals as possible and to ensure their humane and proper care. Generally, two or more species (one rodent, one non-rodent) are tested because a drug may affect one species differently from another. Animal testing is used to measure how much of a drug is absorbed into the blood, how it is broken down chemically in the body, the toxicity of the drug and its breakdown products (metabolites), and how quickly the drug and its metabolites are excreted from the body.

Accelerated Development/Review

Accelerated development/review (Federal Register, April 15, 1992) is a highly specialized mechanism for speeding the development of drugs that promise significant benefit over existing therapy for serious or life-threatening illnesses for which no therapy exists. This process incorporates several novel elements aimed at making sure that rapid development and review is balanced by safeguards to protect both the patients and the integrity of the regulatory process.

Accelerated development/review can be used under two special circumstances: when approval is based on evidence of the product’s effect on a “surrogate endpoint,” and when the FDA determines that safe use of a product depends on restricting its distribution or use. A surrogate endpoint is a laboratory finding or physical sign that may not be a direct measurement of how a patient feels, functions, or survives, but is still considered likely to predict therapeutic benefit for the patient.

The fundamental element of this process is that the manufacturers must continue testing after approval to demonstrate that the drug indeed provides therapeutic benefit to the patient. If not, the FDA can withdraw the product from the market more easily than usual

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.

Institutional Review Boards

Institutional Review Boards (IRB) are used to ensure the rights and welfare of people participating in clinical trials both before and during their trial participation. IRBs at hospitals and research institutions throughout the country make sure that participants are fully informed and have given their written consent before studies ever begin. IRBs are monitored by the FDA to protect and ensure the safety of participants in medical research.

An IRB must be composed of no less than five experts and lay people with varying backgrounds to ensure a complete and adequate review of activities commonly conducted by research institutions. In addition to possessing the professional competence needed to review specific activities, an IRB must be able to ascertain the acceptability of applications and proposals in terms of institutional commitments and regulations, applicable law, standards of professional conduct and practice, and community attitudes. Therefore, IRBs must be composed of people whose concerns are in relevant areas.

For more information, see the IRB Operations and Clinical Requirements list provided by FDA’s Office of Health Affairs. This document is intended to help IRB’s carry out their responsibilities for protection of research subjects. Also see the March 13, 1975, Federal Register, and the Technical Amendments concerning “Protection of Human Subjects” (45 CFR Part 46).

Parallel Track

Another mechanism to permit wider availability of experimental agents is the “parallel track” policy (Federal Register of May 21, 1990) developed by the U.S. Public Health Service in response to AIDS. Under this policy, patients with AIDS whose condition prevents them from participating in controlled clinical trials can receive investigational drugs shown in preliminary studies to be promising.

Subpart E

Subpart E in Section 312 of the Code of Federal Regulations establishes procedures to expedite the development, evaluation, and marketing of new therapies intended to treat people with life-threatening and severely-debilitating illnesses, especially where no satisfactory alternatives exist (Federal Register, October 21, 1988).

Sponsor/FDA Meetings (Pre-NDA)

The purpose of a Pre-NDA meeting is to discuss the presentation of data (both paper and electronic) in support of the application. The information provided at the meeting by the sponsor includes:

A summary of clinical studies to be submitted in the NDA; the proposed format for organizing the submission, including methods for presenting the data; and other information needed to be discussed.

The meeting is conducted to uncover any major unresolved problems or issues, to identify studies the sponsor is relying on as adequate and well controlled in establishing the effectiveness of the drug, to help the reviewers to become aquainted with the general information to be submitted, and to discuss the presentation of the data in the NDA to facilitate its review.

Once the NDA is filed, a meeting may also occur 90 days after the initial submission of the application in order to discuss issues that are uncovered in the initial review.