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The major FDA responsibilities with regard to drugs include:
• to assess pre-clinical data, and decide whether a potential drug is safe enough to allow commencement of clinical trials;
• to protect the interests and rights of patients participating in clinical trials;
• to assess pre-clinical and clinical trial data generated by a drug and decide whether that drug should be made available for general medical use (i.e. whether it should be granted a marketing licence);
Figure 2.10. Partial organizational structure of the FDA, displaying the various centres primarily responsible for regulating drugs, devices and food
• to oversee the manufacture of safe effective drugs (inspect and approve drug manufacturing facilities on the basis of compliance to the principles of good manufacturing practice as applied to pharmaceuticals);
• to ensure the safety of the US blood supply.
In relation to the drug development process, CDER oversees and regulates the development and marketing approval of mainly chemical-based drugs. CBER is more concerned with biologics. ‘Biologic’ has traditionally been defined in a narrow sense and has been taken to refer to vaccines and viruses, blood and blood products, as well as antiserum, toxins and antitoxins used for therapeutic purposes. Because of this, many established pharmaceutical products (e.g. microbial metabolites and hormones) have come under appraisal by CDER, even though one might initially assume they would come under the biologics umbrella (Table 2.11).
Biopharmaceutical products have not fallen neatly into either category and the decision to refer any biotech-derived drug to CBER or CDER is taken on a case-by-case basis. Tissue plasminogen activator (tPA; Chapter 9), for example, is licensed as a biologic, whereas erythropoietin (EPO; Chapter 6) comes under the auspices of CDER. The majority of biopharmaceuticals, however, are assessed by CBER.
The criteria used by CBER and CDER regulators in assessing product performance during the drug development process are similar, i.e. safety, quality and efficacy. However, the administrative details can vary in both name and content. Upon concluding pre-clinical trials, all the data generated regarding any potential new drug are compiled in a dossier and submitted to CDER or CBER in the form of an investigational new drug application (IND application). The FDA assesses the application, and if it does not object within a specific time frame (usually 30 days), clinical trials can begin. The FDA usually meet with the drug developers at various stages, to be updated and often to give informal guidance/advice. Once clinical trials have been completed, all the data generated during the entire development process are compiled in a multivolume dossier.
The dossier submitted to CDER is known as a new drug application (NDA) which, if approved, allows the drug to be marketed. If the drug is a CBER-regulated one, a biologics licence application (BLA) is submitted.
The investigational new drug application
An investigational new drug (IND) is a new chemical-based, biologic or biopharmaceutical substance for which the FDA has given approval to undergo clinical trials. An IND application
Table 2.11 Some traditional pharmaceutical products produced by/extracted from biological sources, which come under the auspices of CDER for regulatory purposes. The specific reviewing divisions within CDER which deal with these products are also listed
Product Reviewing division
Most antibiotics Division of anti-infective drug products
Anticoagulants, fibrinolytics, prostaglandins Division of gastrointestinal and coagulation drug
Enzymes Division of medical imaging, surgical and dental drug
Insulin, somatostatin, growth hormone, Division of metabolic and endocrine drug products
gonadotrophins, vasopressin, oxytocin
THE DRUG DEVELOPMENT PROCESS 81
Table 2.12. The major itemized points which must be included/addressed in an IND application to CDER or CBER
FDA Form 1571 Table of (IND) contents Introduction
Proposed trial detail and protocol (general investigational plan)
Chemistry (or biology, as appropriate), manufacturing, and control detail Pharmacology and toxicology data
Any previous human experience regarding the drug substance Any additional information
should contain information detailing pre-clinical findings, method of product manufacture and proposed protocol for initial clinical trials (Table 2.12).