REGULATORY INTERFACE

For decades, regulation and control of new drugs in the United States have been based on NDAs to the Food and Drug Administration (FDA) (http://www.fda.gov).

FDA regulates the development of new drugs and their subsequent marketing. The agency is divided into various centers, including the Center for Biologic Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), the Center for Devices and Radiological Health (CDRH), and the Center for Food Safety and Nutrition (CFSAN). The CDER evaluates prescription, generic, and OTC drug products for safety and efficacy before they can be marketed. It also monitors all human drugs and biopharmaceuticals once they are in the market and removes prod-ucts from the market that may not be manufactured properly or may cause harm to patients. The CBER regulates biologics not reviewed by the CDER, such as vaccines, blood and blood products, gene therapy products, and cellular and tissue transplants.

Many biopharmaceuticals fall under the responsibilities of both the CBER and the CDER. The Office of Regulatory Affairs (ORA) is responsible for monitoring sites and facilities in which pharmaceuticals are manufactured. For those interested in the roles of the various centers in the FDA, the FDA provides links to the centers and their mission statements at http://www.fda.gov

The marketing of a new pharmaceutical product in the United States requires the following:

• Preclinical laboratory tests and in vivo preclinical studies

• Submission of an IND application to the FDA for clinical testing

• Clinical trials for establishing product safety and efficacy

• Submission of an NDA to the FDA for a biologics license application (BLA)

• FDA approval of the NDA or BLA before any commercial sale

1.6.1  inveStigational new Drug aPPlication

After completing preclinical testing, a decision is made about whether or not the drug has enough potential to proceed to in vivo studies in humans. Assuming that the sponsor wishes to push the drug forward, an IND application is then reviewed and approved by an Institutional Review Board (IRB) at the site (e.g., a hospital and medical center) where the proposed clinical trials will be conducted. The IND application is then filed with FDA to begin testing of the drug in humans. By law, the IND application consists of a chemistry section, a preclinical result section (i.e., pharmacology), and a medical review section in which protocols for first-time testing in humans are presented. The FDA has 30 days to respond to this initial admission.

The IND becomes effective if FDA does not disapprove it within that time. The IND shows results of previous experiments; how, where, and by whom the new studies will be conducted; the chemical structure of the compound; its mechanism of action in the body; any toxic effects found in animal studies; and how the compound is manufactured. In addition, the IND must be reviewed and approved by the IRB in whose geographic jurisdiction the studies will be conducted, and progress reports on clinical trials must be submitted at least annually to the FDA.

1.6.2  new Drug aPPlication

After successful completion of phase I through phase III clinical development, a drug’s sponsor will submit the result of all of the studies to the FDA to obtain an NDA. The NDA application is a formal request to the FDA to approve a new drug product for sale and marketing in the United States. NDAs are usually comprehen-sive documents detailing all studies carried out and can run over 100,000 pages in print, although recent electronic submissions have eliminated the need for printing.

The average NDA review time for NMEs approved in 2001 was 16.4 months. The NDA must contain all of the scientific information that the company has gathered.

The data gathered during the animal studies and human clinical trials of an IND become part of the NDA. The goals of the NDA are to provide enough information to permit the FDA reviewers to reach the following key conclusions:

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

• Whether the drug’s proposed labeling is appropriate and what it should contain

• Whether the methods used in manufacturing the drug and the controls used to assure the drug’s quality are adequate to preserve the drug’s identity, strength, quality, and purity

The FDA often constitutes advisory committees consisting of experts in respective areas in several disciplines to assist in the review of an NDA. The primary role of an advisory committee is to provide independent advice that will contribute to the quality of the agency’s regulatory decision making and lend credibility to the drug product review process. In this way, the FDA can make sound decisions about new medical products and other public health issues. Although advisory committees have a prominent role in the product approval stage, they are sometimes included earlier in the product development cycle and are asked to consider issues relating to prod-ucts already on the market. Committees typically are asked to comment on whether adequate data supports approval, clearance, or licensing of a medical product for marketing. Advisory committees also may recommend that the FDA request addi-tional studies or suggest changes to a product’s labeling. Their recommendations are nonbinding advice to the agency. While committee discussions and final votes are very important to the FDA, the final regulatory decision rests with the agency.

1.6.3  aPProval anD PoSt-marketing Surveillance

Once the FDA approves an NDA, the drug’s sponsor can market the new medicine to the public. FDA approval for marketing of a new drug product does not end a sponsor’s responsibility toward clinical investigation of the drug. Continued clinical investigation, often called phase IV studies, may contribute to the understanding of the drug’s mechanism or scope of action, indicate possible new therapeutic uses, and/

or demonstrate the need for additional dosage strengths, dosage forms, or routes of administration. Phase IV studies may also reveal additional side effects, and rare,

12 Pharmaceutical Dosage Forms and Drug Delivery serious, and unexpected adverse effects. The sponsor is required to submit periodic reports to the FDA, including any adverse event reports, internal quality investiga-tions, and/or changes since the NDA approval. If an adverse effect is identified with a marketed drug, the Office of Drug Safety (ODS) in the CDER can take one or more of the following actions: labeling changes, boxed warnings, product withdrawals, and medical and safety alerts.

1.6.4  a^bbreviateD n^ew D^rug a^PPlication

An abbreviated new drug application (ANDA) is used to gain approval for a generic equivalent of a drug product that is already approved and is being marketed by the pioneer or original sponsor of the drug. Generic drugs are defined as products con-taining the same active ingredient as the branded drug, but likely having different inactive ingredients. In order to be marketed, the generic drug must have the same quality, efficacy, and safety as the branded drug. In contrast, equivalence require-ments for generic biologics, or follow-on biological products, are still evolving. In case of ANDA, nonclinical laboratory and clinical studies may be exempted, except those pertaining to the drug’s bioavailability.

1.6.5  a^ccelerateD D^eveloPment/r^eview

Accelerated development/review is a highly specialized mechanism for speeding the development of drugs that promise significant benefit over existing therapy for serious or life-threatening diseases for which no therapy exists. This process incor-porates several elements aimed at making sure that rapid development and review is balanced by safeguards to protect the patients and the integrity of the regula-tory process. 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.

1.6.6  r^ole of fDa’^S a^DviSory c^ommitteeS

The primary role of an advisory committee is to provide independent advice that will contribute to the quality of the agency’s regulatory decision making and lend credibility to the product review process. In this way, the FDA can make sound decisions about new medical products and other public health issues. Although FDA’s advisory committees have a prominent role in the product approval stage, they are sometimes included earlier in the product development cycle and are asked to consider issues relating to products already on the market. Committees typically are asked to comment on whether the approval, clearance, or licensing of a medical product for marketing is supported by adequate data. Advisory commit-tees may also recommend that the FDA request additional studies or may suggest changes to a product’s labeling. Their recommendations are just that—advice—

and do not bind the agency to any decision. Although committee discussions and final votes are very important to the FDA, the final regulatory decision rests with the agency.