Facilitated by: Mr. M.P.

Venkatesh Lecturer Department of Pharmaceutics Regulatory Affairs Group JSSCP, Mysore

Presented by: Mr. Srikanth Palle I M.Pharm - RA JSSCP, Mysore

An IND may be submitted to the FDA by the sponsor or by a clinical investigator. The results of the investigation appear to establish sufficient data to support a marketing application. According to 21 CFR Part 312.7, a sponsor may charge the patient for an investigational drug, but this is atypical and can be done only after written approval from the FDA.

General Information Regarding INDs

Exemptions
The clinical investigation of a drug product that is lawfully marketed in the U.S. is exempted from the requirements of an IND, providing all of the following apply:
(a) The investigation is intended to be reported to the FDA, as a wellcontrolled trial to support of a new indication for use & to be used to support any other significant change in the labeling for the drug. (b) If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, the investigation is not intended to support a significant change in the advertising for the product (c) The investigation does not involve a route of administration & dosage level or use in a patient population that significantly increases the risks associated with the use of the drug product. (d) The investigation is conducted requirements for IRB/IEC approval. in compliance with the

Labeling Requirements for an Investigational New Drug Labeling for a drug covered by an IND will be discussed under the CMC Caution: New Drug - Limited by Federal investigational use law to

Additionally, the label or labeling shall not bear any statement that is false or misleading to possibly represent the investigational new drug as being safe or effective

Waivers In rare instances, the FDA may grant a waiver to the requirements for an IND on the basis of a request from the sponsor. The FDA may grant such a request for a waiver if it determines that the sponsors noncompliance would not pose a significant risk to the human test subjects.

Pre-consultation Program The purpose of this is to introduce the sponsor and the drug to the FDA This meeting can help a sponsor design additional nonclinical studies or refine the clinical protocol prior to submitting the IND. The sponsor generally discusses the characterization of the drug, present mfg and nonclinical data The presentation should also address the proposed clinical investigational plan to get the desired labeling.

Binders for IND Submissions Presently the FDA has specific requirements for the type and color of binders in which an IND may be submitted. IND will be submitted in CTD format. All INDs and IND amendments are submitted to FDA in triplicate. The original IND submission copy1 in a red binder (form no.2675) copy2 in a green binder (form no.2675a) copy3 in a orange binder (form no.2675b) Address for IND Submissions An initial IND submission is to be sent in triplicate to the Central Document Room, CDER, Food and Drug Administration, 5901-B Ammendale Road, Beltsville, MD 207051266 The outside cover or cover letter of each submission should state what is contained in the submission, for example IND Application, Protocol Amendment.

Availability for Public Disclosure of IND Data: The manner in which FDA handles requests for disclosure of information to the public under the Freedom of Information Act is described in 21 CFR Part 312.130. The existence of an IND will not be disclosed by the FDA unless it has previously been publicly disclosed or acknowledged by the sponsor.

Phases of Clinical Investigations

INDs for Phase 1 Trials

The FDA has recently assessed means to increase the efficiency of the drug development process without sacrificing the long-standing safety and efficacy standards. In November 1995, CDER and CBER issued a Guidance for Industry entitled, Content and Format of Investigational New Drug Applications for Phase 1 Trials of Drugs. It contains the requirements for data and data presentation related to the initial entry into human trials in the U.S. of an investigational drug. The overall aim of this transparency of submission. guidance is increasing

According to the guidance, if the suggestions specified in the document are followed, typical IND submissions for phase 1 trials usually should not be larger than two to three 3-inch binders. The most significant clarifications in the guidance document are 1. FDA to accept an integrated summary report of toxicology information that as initial support for human trials. 2. Specific manufacturing data.

The regulation requires submission of a copy of the protocol for the conduct of each proposed clinical trial. The regulations state that phase 1 protocols should be directed primarily at providing an outline of the investigation: -- An estimate of the number of subjects to be included; -- A description of safety exclusions; -- A description of the dosing plan, including duration, dose, or method to be used in determining dose.

Requirements for CMC Information

Chemistry, manufacturing and control information is required for IND submission. Sufficient information should be submitted to assure the proper identification, quality, purity, and strength of the investigational drug The amount of information needed to make that assurance will vary with the phase of the investigation, the proposed duration of the investigation, the dosage form The identification of a safety concern or insufficient data to make an evaluation of safety is the only basis for a clinical hold based on the CMC section.

Reasons are (a) a product made with impure components, (b) a product possessing chemical structures of highly toxicity, (c) a product that cannot remain chemically stable throughout the testing program proposed, (d) a product with an impurity profile indicative of a potential health hazard Sponsors should be able to relate the drug product being proposed for use in a clinical trial to the drug product used in the animal toxicology trials that support the safety of the proposed human trial. Sponsors should describe any chemistry and manufacturing differences between the drug product proposed for clinical use and the drug product used in

Information on the drug substance should be submitted in a summary report containing the following items: 1. 2. 3. 4. 5. Description The name and address of its manufacturer Method of preparation Tests and analytical methods Stability data

Information on the drug product should be submitted in a summary report containing the following items 1. 2. 3. 4. 5. 6. 7. 8. A list of all components Quantitative composition The name and address of the manufacturer Method of manufacturing and packaging Acceptable limits and analytical methods Stability testing Labeling Environmental assessment

Pharmacology and Toxicology Information

Pharmacology This section of IND should contain, (a) a description of the pharmacologic effects and mechanism of action of the drug in animals (b) information on the absorption, distribution, metabolism, and excretion of the drug. Toxicology - integrated summary The IND regulations require an integrated summary of the toxicological effects of the drug in animals and in vitro. the IND regulations are silent on whether the submitted material should be based on (a) final, fully quality assured individual trial reports or (b) earlier, unaudited draft toxicologic reports of the completed trials.

The integrated summary of the toxicological findings of the completed animal studies to support the safety of the proposed phase 1 human investigation should ordinarily contain the following information 1. A brief description of the design of the trials, dates of performance 2. A systematic presentation of the animal toxicology and toxicokinetic trials 3. Identification and qualifications of the individual who evaluated the animal safety data and concluded that it is reasonably safe to begin the proposed human trial 4. A statement of where the animal trials were conducted 5. The trial should be comply with GLP. Toxicology- full tabulation: The sponsor should submit

The FDAs review of phase 1 submissions focuses on assessing the safety of those investigations. The central focus of the initial IND submission will be on the general investigational plan and the protocols for specific human trials. An IND goes into effect 30 days after the FDA receives the IND, unless the FDA notifies the sponsor that the investigations described in the IND are subject to a clinical hold. Form FDA 1571 INDs and each amendment to an IND are to be submitted in triplicate and must include a completed copy of the two-page Form FDA 1571.

New Drug Approval Process. Edited by Richard A. Guarino, Vol.190, 5th edition, Page No. 110-124

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