The Investigational New Drug (IND) Application is a major step in the drug approval process. It is a document that proves to the Food and Drug Administration (FDA) that a new drug is safe enough for testing in human subjects. In the stages leading to the submission of the IND application, the manufacturer is expected to carry out a preclinical investigation of the drug on an animal model. This is generally done in mice, pigs or dogs since their anatomy resembles that of humans. The objective of preclinical studies is to determine the safety and efficacy of the drug in a living organism.
Contents of the IND application:
Upon attaining positive results in preclinical studies, the manufacturer has to submit the IND application to the FDA. This document is a proposal for the initiation of clinical investigation in human subjects. It consists of information pertaining to the chemistry of the drug, the production processes involved and other data related to the safety and efficacy of the drug. The FDA requires all manufacturers to submit an IND application according to the specifications in Title 21 Part 312 of the Code of Federal Regulations. In brief, the contents of the application are as follows:
• Cover sheet-Form 1571 is used as a cover sheet. Apart from the name of the drug and the sponsor, it contains basic information such as the number of phases of clinical trials to be conducted and the application contents.
• Table of contents-Although Form 1571 consists of information of the application contents, a separate list of contents should be attached to the IND application.
• Investigational plan-This section should provide a description of the drug, such as its structural formula and route of administration.
• Investigator's brochure-A document presented to the institutional review board during a clinical trial that consists of nonclinical, clinical and quality data.
• Protocols-This section should give describe how the clinical trials should be carried out. Phase 1 protocols do not have to be very detailed, but attention should be given to Phase 2 and Phase 3 protocols. Protocols should contain details of the investigators as part of Form 1572, the purpose of the study and the observations to be made.
• Chemistry, Manufacturing and Controls (CMC) Information-This section must provide detailed information on the manufacturing and packaging procedures.
• Pharmacology and toxicology information-This section should prove that the drug is safe for human consumption. It must give a detailed description of the absorption, distribution, metabolism and excretion (ADME) of the drug.
• Previous human experience with the investigational drug-This section should extensively describe past experiences with the drug. E.g.: if clinical trials have already been conducted in other countries, the results should be shown here.
• Additional information-This section should address the potential for drug abuse and future clinical trials on children.
• Drug Master File (DMF)-A document that provides the FDA with confidential information about the drug, which will aid in the IND application.
After submission of the IND application:
Once the IND application has been submitted, the sponsor is expected to wait for 30 days before the initiation of clinical trials. If the FDA does not object to the IND application within this period, then the sponsor may immediately start the trials. However, if the FDA calls for a clinical hold, the sponsor may be requested to delay or suspend the clinical trials. The clinical hold letter will specify the reason why the hold was imposed.
In order to carry out a clinical investigation, a committee needs to be established to monitor the process. This committee is more formally known as the Institutional Review Board (IRB). Once the IRB is convinced that the clinical study protocol will sufficiently test the safety and efficacy of the drug, phase 1 of the trials may begin. These trials may last up to 12 years before the New Drug Application (NDA) can be submitted to the FDA requesting permission for the commercial sale of the product.
During clinical investigations:
It does not necessarily mean that experimental drugs cannot be used till they are approved for sale. In some cases, the FDA may grant the use of an experimental drug. In case of an emergency, the sponsor may submit an emergency-use IND application to the FDA in order to use the experimental drug. E.g.: In April 2009, the FDA granted the emergency use of Relenza and Tamiflu for the treatment of swine flu. Occasionally, the FDA may approve the use of an experimental drug for the treatment of a life-threatening condition also. The sponsor is required to submit a treatment IND application in order to do so. E.g.: In March 1988, the FDA approved the use of Anafranil for the treatment of the obsessive-compulsive disorder.
Thus, the IND application is more than just a booklet with various facts and figures. It helps pharmaceutical manufacturers inform the FDA that the experimental drug has shown positive results in animal models and is now ready for testing in humans. The drug can then be sent to various medical institutes where clinical trials are performed in three phases.
1) Pisano, D.J., Mantus, D.S., FDA Regulatory Affairs: A Guide for Prescription Drugs, Medical Devices, and Biologics, New York; Informa Healthcare, 2008, pp. 18-69.
2) Tobin, J.J., Walsh G., Medical Product Regulatory Affairs: Pharmaceuticals, Diagnostics and Medical Devices, Weiheim, Germany; Wiley-VCH, 2008, pp.91-95
3) Feinberg D.B., Pharmacy Law: Textbook and Review, New York; McGraw-Hill Medical, 2008, pp. 21-27
4) Dogramatzis D., Pharmaceutical Marketing: A Practical Guide, Boca Raton, FL; Taylor & Francis Group, 2002, pp. 12-13
5) United States Food & Drug Administration, Code of Federal Regulations Title 21 Part 312, Retrieved June 6, 2010, FDA Website
6) United States Food & Drug Administration, Investigational New Drug Application, Retrieved June 6, 2010, FDA Website
7) United States Food & Drug Administration, Treatment Investigational New Drugs (INDS): Allowed to Proceed, Retrieved June 6, 2010, FDA Website
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