Source: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=312&showFR=1
Timestamp: 2013-12-05 06:57:42
Document Index: 240454577

Matched Legal Cases: ['art 56', 'art 50', 'art 314', 'art 56', 'art 56', 'art 56']

(a) This part contains procedures and requirements governing the use of investigational new drugs, including procedures and requirements for the submission to, and review by, the Food and Drug Administration of investigational new drug applications (IND's). An investigational new drug for which an IND is in effect in accordance with this part is exempt from the premarketing approval requirements that are otherwise applicable and may be shipped lawfully for the purpose of conducting clinical investigations of that drug.(b) References in this part to regulations in the Code of Federal Regulations are to chapter I of title 21, unless otherwise noted.
Sec. 312.2 Applicability.
(a)Applicability. Except as provided in this section, this part applies to all clinical investigations of products that are subject to section 505 of the Federal Food, Drug, and Cosmetic Act or to the licensing provisions of the Public Health Service Act (58 Stat. 632, as amended (42 U.S.C. 201et seq .)).(b)Exemptions. (1) The clinical investigation of a drug product that is lawfully marketed in the United States is exempt from the requirements of this part if all the following apply:(i) The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication for use nor intended to be used to support any other significant change in the labeling for the drug;(ii) 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;(iii) The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product;(iv) The investigation is conducted in compliance with the requirements for institutional review set forth in part 56 and with the requirements for informed consent set forth in part 50; and(v) The investigation is conducted in compliance with the requirements of 312.7.(2)(i) A clinical investigation involving an in vitro diagnostic biological product listed in paragraph (b)(2)(ii) of this section is exempt from the requirements of this part if (a ) it is intended to be used in a diagnostic procedure that confirms the diagnosis made by another, medically established, diagnostic product or procedure and (b ) it is shipped in compliance with 312.160.(ii) In accordance with paragraph (b)(2)(i) of this section, the following products are exempt from the requirements of this part: (a ) blood grouping serum; (b ) reagent red blood cells; and (c ) anti-human globulin.(3) A drug intended solely for tests in vitro or in laboratory research animals is exempt from the requirements of this part if shipped in accordance with 312.160.(4) FDA will not accept an application for an investigation that is exempt under the provisions of paragraph (b)(1) of this section.(5) A clinical investigation involving use of a placebo is exempt from the requirements of this part if the investigation does not otherwise require submission of an IND.(6) A clinical investigation involving an exception from informed consent under 50.24 of this chapter is not exempt from the requirements of this part.(c)Bioavailability studies. The applicability of this part to in vivo bioavailability studies in humans is subject to the provisions of 320.31.(d)Unlabeled indication. This part does not apply to the use in the practice of medicine for an unlabeled indication of a new drug product approved under part 314 or of a licensed biological product.(e)Guidance. FDA may, on its own initiative, issue guidance on the applicability of this part to particular investigational uses of drugs. On request, FDA will advise on the applicability of this part to a planned clinical investigation.[52 FR 8831, Mar. 19, 1987, as amended at 61 FR 51529, Oct. 2, 1996; 64 FR 401, Jan. 5, 1999]
(a) The definitions and interpretations of terms contained in section 201 of the Act apply to those terms when used in this part:(b) The following definitions of terms also apply to this part:Act means the Federal Food, Drug, and Cosmetic Act (secs. 201-902, 52 Stat. 1040et seq ., as amended (21 U.S.C. 301-392)).Clinical investigation means any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this part, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice.Contract research organization means a person that assumes, as an independent contractor with the sponsor, one or more of the obligations of a sponsor, e.g., design of a protocol, selection or monitoring of investigations, evaluation of reports, and preparation of materials to be submitted to the Food and Drug Administration.FDA means the Food and Drug Administration.IND means an investigational new drug application. For purposes of this part, "IND" is synonymous with "Notice of Claimed Investigational Exemption for a New Drug."Independent ethics committee (IEC) means a review panel that is responsible for ensuring the protection of the rights, safety, and well-being of human subjects involved in a clinical investigation and is adequately constituted to provide assurance of that protection. An institutional review board (IRB), as defined in 56.102(g) of this chapter and subject to the requirements of part 56 of this chapter, is one type of IEC.Investigational new drug means a new drug or biological drug that is used in a clinical investigation. The term also includes a biological product that is used in vitro for diagnostic purposes. The terms "investigational drug" and "investigational new drug" are deemed to be synonymous for purposes of this part.Investigator means an individual who actually conducts a clinical investigation (i.e. , under whose immediate direction the drug is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. "Subinvestigator" includes any other individual member of that team.Marketing application means an application for a new drug submitted under section 505(b) of the act or a biologics license application for a biological product submitted under the Public Health Service Act.Sponsor means a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator. A person other than an individual that uses one or more of its own employees to conduct an investigation that it has initiated is a sponsor, not a sponsor-investigator, and the employees are investigators.Sponsor-Investigator means an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. The term does not include any person other than an individual. The requirements applicable to a sponsor-investigator under this part include both those applicable to an investigator and a sponsor.Subject means a human who participates in an investigation, either as a recipient of the investigational new drug or as a control. A subject may be a healthy human or a patient with a disease.[52 FR 8831, Mar. 19, 1987, as amended at 64 FR 401, Jan. 5, 1999; 64 FR 56449, Oct. 20, 1999; 73 FR 22815, Apr. 28, 2008]
(a) The immediate package of an investigational new drug intended for human use shall bear a label with the statement "Caution: New Drug--Limited by Federal (or United States) law to investigational use."(b) The label or labeling of an investigational new drug shall not bear any statement that is false or misleading in any particular and shall not represent that the investigational new drug is safe or effective for the purposes for which it is being investigated.(c) The appropriate FDA Center Director, according to the procedures set forth in 201.26 or 610.68 of this chapter, may grant an exception or alternative to the provision in paragraph (a) of this section, to the extent that this provision is not explicitly required by statute, for specified lots, batches, or other units of a human drug product that is or will be included in the Strategic National Stockpile.[52 FR 8831, Mar. 19, 1987, as amended at 72 FR 73599, Dec. 28, 2007]
(a)Promotion of an investigational new drug. A sponsor or investigator, or any person acting on behalf of a sponsor or investigator, shall not represent in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation or otherwise promote the drug. This provision is not intended to restrict the full exchange of scientific information concerning the drug, including dissemination of scientific findings in scientific or lay media. Rather, its intent is to restrict promotional claims of safety or effectiveness of the drug for a use for which it is under investigation and to preclude commercialization of the drug before it is approved for commercial distribution.(b)Commercial distribution of an investigational new drug. A sponsor or investigator shall not commercially distribute or test market an investigational new drug.(c)Prolonging an investigation. A sponsor shall not unduly prolong an investigation after finding that the results of the investigation appear to establish sufficient data to support a marketing application.[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 19476, May 22, 1987; 67 FR 9585, Mar. 4, 2002; 74 FR 40899, Aug. 13, 2009]
Sec. 312.8 Charging for investigational drugs under an IND.
(a)General criteria for charging . (1) A sponsor must meet the applicable requirements in paragraph (b) of this section for charging in a clinical trial or paragraph (c) of this section for charging for expanded access to an investigational drug for treatment use under subpart I of this part, except that sponsors need not fulfill the requirements in this section to charge for an approved drug obtained from another entity not affiliated with the sponsor for use as part of the clinical trial evaluation (e.g., in a clinical trial of a new use of the approved drug, for use of the approved drug as an active control).(2) A sponsor must justify the amount to be charged in accordance with paragraph (d) of this section.(3) A sponsor must obtain prior written authorization from FDA to charge for an investigational drug.(4) FDA will withdraw authorization to charge if it determines that charging is interfering with the development of a drug for marketing approval or that the criteria for the authorization are no longer being met.(b)Charging in a clinical trial --(1)Charging for a sponsor's drug . A sponsor who wishes to charge for its investigational drug, including investigational use of its approved drug, must:(i) Provide evidence that the drug has a potential clinical benefit that, if demonstrated in the clinical investigations, would provide a significant advantage over available products in the diagnosis, treatment, mitigation, or prevention of a disease or condition;(ii) Demonstrate that the data to be obtained from the clinical trial would be essential to establishing that the drug is effective or safe for the purpose of obtaining initial approval of a drug, or would support a significant change in the labeling of an approved drug (e.g., new indication, inclusion of comparative safety information); and(iii) Demonstrate that the clinical trial could not be conducted without charging because the cost of the drug is extraordinary to the sponsor. The cost may be extraordinary due to manufacturing complexity, scarcity of a natural resource, the large quantity of drug needed (e.g., due to the size or duration of the trial), or some combination of these or other extraordinary circumstances (e.g., resources available to a sponsor).(2)Duration of charging in a clinical trial . Unless FDA specifies a shorter period, charging may continue for the length of the clinical trial.(c)Charging for expanded access to investigational drug for treatment use . (1) A sponsor who wishes to charge for expanded access to an investigational drug for treatment use under subpart I of this part must provide reasonable assurance that charging will not interfere with developing the drug for marketing approval.(2) For expanded access under 312.320 (treatment IND or treatment protocol), such assurance must include:(i) Evidence of sufficient enrollment in any ongoing clinical trial(s) needed for marketing approval to reasonably assure FDA that the trial(s) will be successfully completed as planned;(ii) Evidence of adequate progress in the development of the drug for marketing approval; and(iii) Information submitted under the general investigational plan (312.23(a)(3)(iv)) specifying the drug development milestones the sponsor plans to meet in the next year.(3) The authorization to charge is limited to the number of patients authorized to receive the drug under the treatment use, if there is a limitation.(4) Unless FDA specifies a shorter period, charging for expanded access to an investigational drug for treatment use under subpart I of this part may continue for 1 year from the time of FDA authorization. A sponsor may request that FDA reauthorize charging for additional periods.(d)Costs recoverable when charging for an investigational drug . (1) A sponsor may recover only the direct costs of making its investigational drug available.(i) Direct costs are costs incurred by a sponsor that can be specifically and exclusively attributed to providing the drug for the investigational use for which FDA has authorized cost recovery. Direct costs include costs per unit to manufacture the drug (e.g., raw materials, labor, and nonreusable supplies and equipment used to manufacture the quantity of drug needed for the use for which charging is authorized) or costs to acquire the drug from another manufacturing source, and direct costs to ship and handle (e.g., store) the drug.(ii) Indirect costs include costs incurred primarily to produce the drug for commercial sale (e.g., costs for facilities and equipment used to manufacture the supply of investigational drug, but that are primarily intended to produce large quantities of drug for eventual commercial sale) and research and development, administrative, labor, or other costs that would be incurred even if the clinical trial or treatment use for which charging is authorized did not occur.(2) For expanded access to an investigational drug for treatment use under 312.315 (intermediate-size patient populations) and 312.320 (treatment IND or treatment protocol), in addition to the direct costs described in paragraph (d)(1)(i) of this section, a sponsor may recover the costs of monitoring the expanded access IND or protocol, complying with IND reporting requirements, and other administrative costs directly associated with the expanded access IND.(3) To support its calculation for cost recovery, a sponsor must provide supporting documentation to show that the calculation is consistent with the requirements of paragraphs (d)(1) and, if applicable, (d)(2) of this section. The documentation must be accompanied by a statement that an independent certified public accountant has reviewed and approved the calculations.[74 FR 40899, Aug. 13, 2009]
(a) A sponsor may request FDA to waive applicable requirement under this part. A waiver request may be submitted either in an IND or in an information amendment to an IND. In an emergency, a request may be made by telephone or other rapid communication means. A waiver request is required to contain at least one of the following:(1) An explanation why the sponsor's compliance with the requirement is unnecessary or cannot be achieved;(2) A description of an alternative submission or course of action that satisfies the purpose of the requirement; or(3) Other information justifying a waiver.(b) FDA may grant a waiver if it finds that the sponsor's noncompliance would not pose a significant and unreasonable risk to human subjects of the investigation and that one of the following is met:(1) The sponsor's compliance with the requirement is unnecessary for the agency to evaluate the application, or compliance cannot be achieved;(2) The sponsor's proposed alternative satisfies the requirement; or(3) The applicant's submission otherwise justifies a waiver.[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67 FR 9585, Mar. 4, 2002]
(a) A sponsor shall submit an IND to FDA if the sponsor intends to conduct a clinical investigation with an investigational new drug that is subject to 312.2(a).(b) A sponsor shall not begin a clinical investigation subject to 312.2(a) until the investigation is subject to an IND which is in effect in accordance with 312.40.(c) A sponsor shall submit a separate IND for any clinical investigation involving an exception from informed consent under 50.24 of this chapter. Such a clinical investigation is not permitted to proceed without the prior written authorization from FDA. FDA shall provide a written determination 30 days after FDA receives the IND or earlier.[52 FR 8831, Mar. 19, 1987, as amended at 61 FR 51529, Oct. 2, 1996; 62 FR 32479, June 16, 1997]
An IND may be submitted for one or more phases of an investigation. The clinical investigation of a previously untested drug is generally divided into three phases. Although in general the phases are conducted sequentially, they may overlap. These three phases of an investigation are a follows:(a)Phase 1. (1) Phase 1 includes the initial introduction of an investigational new drug into humans. Phase 1 studies are typically closely monitored and may be conducted in patients or normal volunteer subjects. These studies are designed to determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. During Phase 1, sufficient information about the drug's pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid, Phase 2 studies. The total number of subjects and patients included in Phase 1 studies varies with the drug, but is generally in the range of 20 to 80.(2) Phase 1 studies also include studies of drug metabolism, structure-activity relationships, and mechanism of action in humans, as well as studies in which investigational drugs are used as research tools to explore biological phenomena or disease processes.(b)Phase 2. Phase 2 includes the controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks associated with the drug. Phase 2 studies are typically well controlled, closely monitored, and conducted in a relatively small number of patients, usually involving no more than several hundred subjects.(c)Phase 3. Phase 3 studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labeling. Phase 3 studies usually include from several hundred to several thousand subjects.
(a) FDA's primary objectives in reviewing an IND are, in all phases of the investigation, to assure the safety and rights of subjects, and, in Phase 2 and 3, to help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug's effectiveness and safety. Therefore, although FDA's review of Phase 1 submissions will focus on assessing the safety of Phase 1 investigations, FDA's review of Phases 2 and 3 submissions will also include an assessment of the scientific quality of the clinical investigations and the likelihood that the investigations will yield data capable of meeting statutory standards for marketing approval.(b) The amount of information on a particular drug that must be submitted in an IND to assure the accomplishment of the objectives described in paragraph (a) of this section depends upon such factors as the novelty of the drug, the extent to which it has been studied previously, the known or suspected risks, and the developmental phase of the drug.(c) The central focus of the initial IND submission should be on the general investigational plan and the protocols for specific human studies. Subsequent amendments to the IND that contain new or revised protocols should build logically on previous submissions and should be supported by additional information, including the results of animal toxicology studies or other human studies as appropriate. Annual reports to the IND should serve as the focus for reporting the status of studies being conducted under the IND and should update the general investigational plan for the coming year.(d) The IND format set forth in 312.23 should be followed routinely by sponsors in the interest of fostering an efficient review of applications. Sponsors are expected to exercise considerable discretion, however, regarding the content of information submitted in each section, depending upon the kind of drug being studied and the nature of the available information. Section 312.23 outlines the information needed for a commercially sponsored IND for a new molecular entity. A sponsor-investigator who uses, as a research tool, an investigational new drug that is already subject to a manufacturer's IND or marketing application should follow the same general format, but ordinarily may, if authorized by the manufacturer, refer to the manufacturer's IND or marketing application in providing the technical information supporting the proposed clinical investigation. A sponsor-investigator who uses an investigational drug not subject to a manufacturer's IND or marketing application is ordinarily required to submit all technical information supporting the IND, unless such information may be referenced from the scientific literature.
(a) A sponsor who intends to conduct a clinical investigation subject to this part shall submit an "Investigational New Drug Application" (IND) including, in the following order:(1)Cover sheet (Form FDA-1571). A cover sheet for the application containing the following:(i) The name, address, and telephone number of the sponsor, the date of the application, and the name of the investigational new drug.(ii) Identification of the phase or phases of the clinical investigation to be conducted.(iii) A commitment not to begin clinical investigations until an IND covering the investigations is in effect.(iv) A commitment that an Institutional Review Board (IRB) that complies with the requirements set forth in part 56 will be responsible for the initial and continuing review and approval of each of the studies in the proposed clinical investigation and that the investigator will report to the IRB proposed changes in the research activity in accordance with the requirements of part 56.(v) A commitment to conduct the investigation in accordance with all other applicable regulatory requirements.(vi) The name and title of the person responsible for monitoring the conduct and progress of the clinical investigations.(vii) The name(s) and title(s) of the person(s) responsible under 312.32 for review and evaluation of information relevant to the safety of the drug.(viii) If a sponsor has transferred any obligations for the conduct of any clinical study to a contract research organization, a statement containing the name and address of the contract research organization, identification of the clinical study, and a listing of the obligations transferred. If all obligations governing the conduct of the study have been transferred, a general statement of this transfer--in lieu of a listing of the specific obligations transferred--may be submitted.(ix) The signature of the sponsor or the sponsor's authorized representative. If the person signing the application does not reside or have a place of business within the United States, the IND is required to contain the name and address of, and be countersigned by, an attorney, agent, or other authorized official who resides or maintains a place of business within the United States.(2)A table of contents. (3)Introductory statement and general investigational plan. (i) A brief introductory statement giving the name of the drug and all active ingredients, the drug's pharmacological class, the structural formula of the drug (if known), the formulation of the dosage form(s) to be used, the route of administration, and the broad objectives and planned duration of the proposed clinical investigation(s).(ii) A brief summary of previous human experience with the drug, with reference to other IND's if pertinent, and to investigational or marketing experience in other countries that may be relevant to the safety of the proposed clinical investigation(s).(iii) If the drug has been withdrawn from investigation or marketing in any countr