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In some instances, the FDA and drug sponsor (company/institution submitting the IND) will agree to hold a pre-IND meeting. This aims to acquaint the FDA officials with the background to/content of the IND application, and to get a feel for whether the IND application will be regarded as adequate (see below) by the FDA. An IND application can consist of up to 15 volumes of approximately 400 pages each. Once received by the FDA, it is studied to ensure that:
• it contains sufficient/complete information required;
• the information supplied supports the conclusion that clinical trial subjects would not be exposed to an unreasonable risk of illness/injury (the primary FDA role being to protect public health);
• the clinical investigator named is qualified to conduct the clinical trials;
• the sponsor’s product brochures are not misleading or incomplete.
Based on their findings, the FDA may grant the application immediately or may require additional information, which the sponsor then submits as IND amendments (Figure 2.11). Once clinical trials begin, the sponsor must provide the FDA with periodic updates, usually in the form of annual reports. Unscheduled reports must also be submitted under a variety of circumstances, including:
Figure 2.11. Outline of the IND application process
• if any amendments to the trial protocol are being considered;
• if any new scientific information regarding the product is obtained;
• if any unexpected safety observations are made.
During the clinical trial phase, the sponsor and FDA will meet on one or more occasions. A particularly important meeting is often the end of phase II meeting. This aims primarily to evaluate and agree upon phase III plans and protocols. This is particularly important, as phase III trials are the most costly and generate the greatest quantity of data used later to support the drug approval application.
The new drug application
Upon completion of clinical trials, the sponsor will collate all the pre-clinical, clinical and other pertinent data (Table 2.13) and submit this to FDA in support of an application to allow the new drug to be placed upon the market. For CDER-related drugs, this submission document is termed a new drug application (NDA).
The NDA must be an integrated document. It often consists of 200-300 volumes, which can represent a total of over 120000 pages. Several copies of the entire document, and sections thereof, are provided to CDER. The FDA then classify the NDA based upon the chemical type of the drug and its therapeutic potential. Generally, drugs of high therapeutic potential (e.g. new drugs capable of curing/alleviating serious/terminal medical conditions) are appraised by CDER in the shortest time.
After initial submission of the NDA, the FDA has 45 days in which to preliminarily inspect the document — to ensure that everything is in order. They then ‘file’ the NDA, or if more information/better information management is needed, they refuse to file until such changes are implemented by the sponsor.
Once filed, an NDA undergoes several layers of review (Figure 2.12). A primary review panel generally consists of a chemist, a microbiologist, a pharmacologist, a biostatistician, a medical officer and a biopharmaceutics scientist. Most hold PhDs in their relevant discipline. The team is organized by a project manager or consumer safety officer (CSO). The CSO initially forwards relevant portions of the NDA to the primary review panel member with the appropriate expertise.
Table 2.13. An overview of the contents of a typical new NDA. The multi-volume document is often organized into 15 different sections, the titles of which are provided below
2 Overall summary
3 Chemistry, manufacturing and control section
4 Sampling, methods of validation, package and labelling
5 Non-clinical pharmacology and toxicology data
6 Human pharmacokinetics and bioavailability data
7 Microbiology data
8 Clinical data
9 Safety update reports
10 Statistical section
11 Case report tabulations
12 Case report forms
13 and 14 Patent information and certification
15 Additional pertinent information
THE DRUG DEVELOPMENT PROCESS 83
Figure 2.12. The CDER review process for a typical NDA. In addition to the review stages described, the FDA also may consult with a technical advisory committee. The members of the advisory committee are not routinely involved in IND or NDA assessment. The FDA is not obliged to follow any advice given by the advisory committee, but it generally does so