21 CFR Part 312
Proposed New Drug, Antibiotic, and Biologic Drug Product Regulations
[Docket No. 82N-0394]
48 FR 26720 (continued)

PART 312 -- INVESTIGATIONAL NEW DRUG APPLICATION

Subpart A -- General Provisions

Sec.
312.1 Scope.
312.2 Applicability.
312.3 Definitions and interpretations.
312.6 Labeling of an investigational new drug.
312.7 Promotion and sale of investigational drugs.
312.10 Waivers.

Subpart B -- Investigational New Drug Application (IND)

312.20 Requirement for an IND.
312.21 Phases of an investigation.
312.22 General principles of the IND submission.
312.23 IND content and format.
312.30 Protocol amendments.
312.31 Information amendments.
312.32 IND safety reports.
312.33 Annual reports.
312.34 Treatment use of an investigational new drug.
312.36 Emergency use of an investigational new drug.
312.38 Withdrawal of an IND.

Subpart C -- Administrative Actions

312.40 General requirements for use of an investigational new drug in a clinical investigation.
312.41 Comment and advice on an IND.
312.42 Clinical holds and request for modification.
312.44 Termination.
312.45 Inactive status.
312.47 Meetings.
312.48 Request for reconsideration or clarification of technical requirements or informal opinions.

Subpart D -- Responsibilities of Sponsors and Investigators

312.50 General responsibilities of sponsors.
312.53 Selecting investigators and monitors.
312.55 Informing investigators.
312.56 Monitoring investigations.
312.58 Inspection of sponsor's records and reports.
312.60 General responsibilities of investigators.
312.62 Investigator records and reports.

Subpart E -- Miscellaneous

312.110 Import and export requirements.
312.120 Foreign clinical studies not conducted under an IND.
312.130 Availability for public disclosure of data and information in an IND.
312.140 Address for correspondence.
312.145 Guidelines.

Subpart F -- Drugs for Investigational Use in Laboratory Research Animals or In Vitro Tests

312.160 New drugs for investigational use in laboratory research animals or in vitro tests.

Authority: Secs. 501, 502, 503, 505, 506, 507, 701, 52 Stat. 1049-1053 as amended, 1055-1056 as amended, 55 Stat. 851, 59 Stat. 463 as amended (21 U.S.C. 351, 352, 353, 355, 356, 357, 371); sec. 351, 58 Stat. 702 as amended (42 U.S.C. 262).

Subpart A -- General Provisions

§ 312.1 Scope.

(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 exempts the drug from the premarketing approval requirements that are otherwise applicable and permits the drug to 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.

§ 312.2 Applicability.

(a) Except as provided in this section, this part applies to all clinical investigations of drugs that are subject to section 505 or 507 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. 201 et seq.)).

(b)(1) Exemptions. The following categories of drugs are exempt from the requirements of this part:

(i) a lawfully marketed drug product used in a clinical investigation, if all the following apply:

(a ) 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 advertising or labeling for the drug:

(b ) The investigation does not involve a route of administration or dosage level or use in a patient population that significantly increases the risks associated with use of the drug product;

(c) 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

(d ) The investigation is conducted in compliance with the requirements of § 312.7.

(ii) A biological drug intended for in vitro diagnostic use 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 ) The investigational drug is shipped in compliance with § 312.160.

(iii) A drug intended solely for tests in laboratory research animals, if shipped in accordance with § 312.160.

(2) FDA will not accept an application for an investigation that is exempt under the provisions of paragraph (b)(1) of this section.

(c) For the applicability of this part to in vivo bioavailability studies in humans, see § 320.31.

(d) This part does not apply to the use in the practice of medicine for an unlabeled indication of a new drug or antibiotic drug product approved under Part 314 or of a licensed biological product.

(e) 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.

§ 312.3 Definitions and interpretations.

(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 (sections 201-902, 52 Stat. 1040 et seq., as amended (21 U.S.C. 301-392)).

"Clinical investigation" means any experiment in which an investigational new 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.

"FDA" means the Food and Drug Administration.

"IND" means an investigational new drug application.

"Investigational new drug" means a new drug, antibiotic drug, or biological drug (including a biological product that is used in vitro for diaganostic purposes) that: is not marketed under an approved marketing application; or is a marketed drug that is used for any purpose or in any way other than that described in its labeling, except when such use is carried out by a licensed practitioner in the course of medical practice. 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.

"Marketing application" means an application for a new drug submitted under section 505(b) of the act, a request to provide for certification of an antibiotic submitted under section 507 of the act, or a product 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 ot 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.

§ 312.6 Labeling of an investigational new drug.

(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.

§ 312.7 Promotion and sale of investigational drugs.

(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 shall not commercially distribute or test market an investigational new drug.

(c) Prolonging an investigation. A sponsor shall not unduly prolong an investigation, but shall submit a marketing application for the drug, with reasonable promptness after finding that the results of the investigation appear to establish sufficient data to support a marketing application, or within 60 days of receipt of a request for such application by FDA. If the sponsor determines that the data obtained will support a marketing application, the sponsor shall promptly discontinue the investigation and withdraw the IND.

(d) Sale of an investigational drug. The sale of an ivestigational new drug is not permitted except upon the written approval of the Director of the National Center for Drugs and Biologics. To obtain approval for the sale of a drug, the sponsor shall submit a full written explanation why sale is required and why the sale should not be regarded as the commercialization of an investigational drug. No sale will be permitted except in the context of an acceptable investigation.

§ 312.10 Waivers.

(a) A sponsor may request FDA to waive any applicable requirement under this part. A waive request may be submitted either in an initial 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.

Subpart B -- Investigational New Drug Application (IND)

§ 312.20 Requirement for an IND.

(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 effective IND in accordance with § 312.40.

§ 312.21 Phases of an investigation.

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 as 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.

(b) Phase 3. Phase 3 studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence of effectiveness of the drug has been established, 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.

§ 312.22 General principal of the IND submission.

(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 investigation 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 first 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. To aid communication and minimize paperwork, information and data in IND's should, with some exceptions, be submitted only in summary form.

(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 contest 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 should follow the same general format, but ordinarily may refer to the manufacturer's IND in providing the technical information supporting the proposal clinical investigation. A sponsor-investigator who uses an investigational drug not subject to a manufacturer's IND is ordinarily required to submit all technical information supporting the IND, unless, such information may be referenced from the scientific literature.

§ 312.23 IND content and format.

(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 clincial investigation, that investigators will report to the IRB all proposed changes in the research activity and all unanticipated problems involving risks to human subjects or others, and that investigators will not make any deviations from the research plan without IRB approval, except where necessary to eliminate apparent immediate hazard to human subjects.

(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) If the sponsor is not a sponsor-investigator, the name and title of the individual responsible for evaluating adverse reactions or other evidence of risk when such information is received from the clinical investigators.

(vii) 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. (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 relevent to the safety of the proposed clinical investigation(s).

(iii) If the drug has been withdrawn from investigation or marketing in any country for any reason related to safety or effectiveness, identification of the country(ies) where the drug was withdrawn and the reasons for the withdrawal.

(4) General investigational plan. A brief description of the overall plan for investigating the drug product, including: (i) The rationale for the drug or the research study; (ii) the indication(s) to be studied; (iii) the general approach to be followed in evaluating the drug; (iv) the kinds of clinical trials to be conducted in the first year following the submission; (v) the estimated number of patients to be given the drug in those studies, and (vi) any special risks anticipated on the basis of the toxicological data in animals or prior studies in humans with the drug or related drugs.

(5) Investigator's brochure. If required under § 312.55, a copy of the investigator's brochure, containing the following information.

(i) A brief description of the drug substance and the formulation, including the structural formula, if known.

(ii) A summary of the pharmacological and toxicological effects of the drug in animals and, to the extent know, in humans.

(iii) A summary of the pharmacokinetics and biological disposition of the drug in animals and, if known, in humans.

(iv) A summary of information relating to safety and effectiveness in humans obtained from prior clinical studies. (Reprints of published articles on such studies may be appended when useful.)

(v) A description of possible risks and side effects to be anticipated on the basis of prior experience with the drug under investigation or with related drugs, and of precautions or special monitoring to be done as part of the investigational use of the drug.

(6) Protocols. (i) A protocol for each planned study. In general, protocols for Phase 1 studies may be less detailed and more flexible than protocols for Phase 2 and 3 studies. Phase 1 protocols should be directed primarily at providing an outline of the investigation -- an estimate of the number of patients to be involved, a description of safety exclusions, and a description of the dosing plan including duration, dose, or method to be used in determining dose -- and should specify in detail only those elements of the study that are critical to safety, such as necessary monitoring of vital signs and blood chemistries. Modifications of the experimental design of Phase 1 studies that do not affect critical safety assignments are required to be reported to FDA only in the annual report.

(ii) In Phases 2 and 3, detailed protocols describing all aspects of the study should be submitted. A protocol for a Phase 2 or 3 investigation should be designed in such a way that, if the sponsor anticipates that some deviation from the study design may become necessary as the investigation progresses, alternatives or contingencies to provide for such deviation are built into the protocols at the outset. For example, a protocol for a controlled short-term study might include a plan for an early crossover of nonresponders to an alternative therapy.

(iii) A protocol is required to contain the following, with the specific elements and detail of the protocol reflecting the above distinctions depending on the phase of study:

(a ) A statement of the objectives and purpose of the study.

(b ) The name and address and curriculum vitae of each investigator, and the name of each subinvestigator (e.g., research fellow, resident) working under the supervision of the investigators; the name and address of the research facilities to be used; and the name and address of each reviewing Institutional Review Board.

(c ) The criteria for patient selection and for exclusion of patients and an estimate of the number of patients to be studied.

(d ) A description of the design of the study, including the kind of control group to be used, if any, and a description of methods to be used to minimize bias on the part of subjects, investigators, and analysts.

(e ) The method for determining the dose(s) to be administered, the planned maximum dosage, and the duration of individual patient exposure to the drug.

(f ) A description of the observations and measurements to be made to fulfill the objectives of the study.

(g ) A description of clinical procedures, laboratory tests, or other measures to be taken to monitor the effects of the drug in human subjects and to minimize risk.

(7) Chemistry, manufacturing, and control information. (i) As appropriate for the particular investigations covered by the IND, a section describing the composition, manufacture, and control of the drug substance and the drug product. Although in each phase of the investigation sufficient information is required to 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, and the amount of information otherwise available. FDA recognizes that modifications to the method of preparation of the new drug substance and dosage form and changes in the dosage form itself are likely as the investigation progresses. Therefore, the emphasis in an initial Phase 1 submission should generally be placed on the identification and control of the raw materials and the new drug substance. Final specifications for the drug substance and drug product are not expected until the end of the investigational process.

(ii) It should be emphasized that the amount of information to be submitted depends upon the scope of the proposed clinical investigation. For example, although stability data are required in all phases of the IND to demonstrate that the new drug substance and drug product are within acceptable chemical and physical limits for the planned duration of the proposed clinical investigation, if very short-term tests are proposed, the supporting stability data can be correspondingly limited.

(iii) As drug development proceeds and as the scale of production is changed from the pilot-scale production appropriate for the limited initial clinical investigations to the larger-scale production needed for expanded clinical trials, the sponsor should submit information amendments to supplement the initial information submitted on the manufacturing and control processes with information appropriate to the expanded scope of the investigation.

(iv) Reflecting the distinctions described in this paragraph (a)(7), and based on the phase(s) to be studied, the submission is required to contain the following:

(a ) Drug substance. A description of the drug substance, including its physical, chemical, or biological characteristics; the name and address of its manufacturer; the general method of preparation of the drug substance; the acceptable limits and analytical methods used to assure the identity, potency, quality, and purity of the drug substance; and information sufficient to support stability of the drug substance during the toxicological studies and the planned clinical studies. Reference to the current edition of the U.S. Pharmacopeia and the National Formulary may be made to satisfy relevant requirements in this paragraph.

(b ) Drug product. A list of all components, whic may include reasonable alternates for inactive compounds, used in the manufacture of the investigational drug product, including both those components intended to appear in the drug product and those which may not appear but which are used in the manufacturing process, and, where applicable, the quantitative composition of the investigational drug product, including any reasonable variations that may be expected during the investigational stage; the name and address of the drug product manufacturer; a brief general description of the manufacturing and packaging procedure as appropriate for the product; the acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug product; and information sufficient to assure the product's stability during the planned clinical studies. Reference to the current edition of the U.S. Pharmacopeia and the National Formulary may be made to satisfy relevant requirements in this paragraph.

(c ) Labeling. A copy of all labels and labeling to be provided to each investigator.

(d ) Environmental impact analysis report. If requestd by FDA, environmental impact analysis report under § 25.1 analyzing the environmental impact of the manufacturing process and the ultimate use of the drug product.

(8) Pharmacology and toxicology information. Adequate information about pharmacological and toxicological studies of the drug involving laboratory animals or in vitro, on the basis of which the sponsor has concluded that it is reasonably safe to conduct the proposed clinical investigations. The kind, duration, and scope of animal and other tests required varies with the duration and nature of the proposed clinical investigations. Guidelines are available from FDA that describe ways in which these requirements may be met. Such information is required to include the identification and qualifications of the individuals who evaluated the results of such studies and concluded that it is reasonably safe to begin the proposed investigations and a statement of where the investigations were conducted and where the records are available for inspection. As drug development proceeds, the sponsor is required to submit informational amendments, as appropriate, with additional information pertinent to safety.

(i) Pharmacology and drug disposition. A section describing the pharmacological effects and mechanism(s) of action of the drug in animals, and information on the absorption, distribution, metabolism, and excretion of the drug, if known.

(ii) Toxicology. (a) An integrated summary of the toxicological effects of the drug in animals and in vitro. Depending on the nature of the drug and the phase of the investigation, the description is to include the results of acute, subacute, and chronic toxicity tests; tests of the drug's effects on reproduction and the developing fetus; any special toxicity test related to the drug's particular mode of administration or conditions of use (e.g., inhalation, dermal, or ocular toxicology); and any in vitro studies intended to evaluate drug toxicity.

(b) For each toxicology study that is intended primarily to support the safety of the proposed clinical investigation, a full tabulation of data suitable for detailed review.

(iii) For each toxicology study submitted to support the safety of a proposed clinical study that was not conducted in compliance with Part 58 relating to good laboratory practices, a description of each difference between the practices used in the study and those required under Part 58.

(9) Previous human experience with the investigational drug. A summary of previous human experience, if any, with the investigational drug. The information is required to include the following:

(i) If the investigational drug has been investigated or marketed previously, either in the United States or other countries, detailed information about such experience that is relevant to the safety of the proposed investigation or to the investigation's rationale. If the drug has been the subject of controlled trials, detailed information on such trials that is relevant to an assessment of the drug's effectiveness for the proposed investigational use(s) should also be provided. Any published material that is relevant to the safety of the proposed investigation or to an assessment of the drug's effectiveness for its proposed investigational use should be provided in full. Published material that is less directly relevant may be supplied by a bibliography.

(ii) If the drug is a combination of drugs previously investigated or marketed, the information required under paragraph (a)(9)(i) of this section should be provided for each component.

(iii) If the drug has been marketed outside the United States, a list of the countries in which the drug has been marketed and a list of the countries in which the drug has been withdrawn from marketing for reasons potentially related to safety or effectiveness.

(10) Additional information. In certain applications, as described below, information on special topics may be needed. Such information shall be submitted in this section as follows:

(i) Drug dependence and abuse potential. If the drug is a psychotropic substance or otherwise has abuse potential, a section describing relevant clinical studies and experience and studies in test animals.

(ii) Radioactive drugs. If the drug is a radioactive drug, sufficient data from animal or human studies to allow a reasonable calculation of radiation-absorbed dose to the whole body and critical organs upon administration to a human subject. Phase 1 studies of radioactive drugs must include studies which will obtain sufficient data for dosimetry calculations.

(iii) Other information. A brief statement on any other information that would aid evaluation of the proposed clinical investigations with respect to their safety or their design and potential as controlled clinical trials to support marketing of the drug.

(11) If requested by FDA, any other relevant information needed for review of the application.

(b) Information previously submitted. The sponsor ordinarily is not required to resubmit information previously submitted, but may incorporate the information by reference. A reference to information submitted previously must identify the file by name, reference number, volume, and page number where the information can be found. A reference to information submitted to the agency by a person other than the sponsor is required to contain a written statement that authorizes the reference and that is signed by the person who submitted the information.

(c) Material in a foreign language. The sponsor shall submit an accurate and complete English translation of each part of the IND that is not in English. The sponsor shall also submit a copy of each original literature publication for which an English translation is submitted.

(d) Number of copies. The sponsor shall submit an original and two copies of all submissions to the IND file, including the original submission and all amendments and reports.

§ 312.30 Protocol amendments.

Once an IND is in effect, a sponsor shall amend it as needed to ensure that the clinical investigations are conducted according to protocols included in the application. This section sets forth the provisions under which new protocols may be submitted and changes in previously submitted protocols may be made.

(a) New protocol. Whenever a sponsor intends to conduct a study that is not covered by a protocol already contained in the IND, the sponsor shall submit to the IND a protocol amendment containing the protocol for the study. Such study may begin provided two conditions are met: (1) The sponsor has submitted the protocol to FDA for its review; and (2) the protocol has been approved by the institutional review board (IRB) with responsibility for review and approval of the study in accordance with the requirements of Part 56. The sponsor may comply with these two conditions in either order.

(b) Changes in a protocol. A sponsor shall submit a protocol amendment describing any change in a Phase 1 protocol that significantly affects the safety of subjects or any change in a Phase 2 or 3 protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study. Such change may be made after the sponsor has submitted the amendment to the IND following completion of review of the change by the IRB that is responsible for review and approval of the study that is the subject of the protocol. Examples of changes requiring an amendment under this paragraph include:

(1) Any increase in drug dosage or duration of exposure of individual subjects to the drug beyond that in the current protocol, or any significant increase in the number of subjects under study.

(2) Any significant change in the design of a protocol (such as the addition or dropping of a control group).

(3) The addition of a new test or procedure that is intended to improve monitoring for, or reduce the risk of, a side effect or adverse event; or the dropping of a test intended to monitor safety.

(c) New investigator. A sponsor shall submit a protocol amendment when a new investigator is added to carry out a previously submitted protocol, except that a protocol amendment is not required when a licensed practitioner is added in the case of a treatment protocol under § 312.34. The sponsor shall notify FDA of the new investigator within 30 days of the investigator being added.

(d) Content and format. A protocol amendment is required to be prominently identified as such (i.e., "Protocol Amendment: New Protocol", "Protocol Amendment: Change in Protocol", or "Protocol Amendment: New Investigator"), to be serially numbered, and to contain the following:

(1)(i) In the case of a new protocol, a copy of the new protocol and a description of how it differs from previous protocols.

(ii) In the case of a change in protocol, a brief description of the change and reference (date and number) to the submission that contained the protocol.

(iii) In the case of a new investigator, the investigator's name and qualifications to conduct the investigation.

(2) Reference to the specific information in the IND or in a concurrently submitted information amendment to the IND that the sponsor relies on to support the new or amended protocol. If the reference is made to supporting information already in the IND, the sponsor shall identify by name, reference number, volume, and page number the location of the information.

(3) If the sponsor desires FDA to comment on the submission, a request for such comment and the specific questions FDA's response should address.

(e) When submitted. A sponsor shall submit a protocol amendment for a new protocol or a change in protocol before its implementation. Protocol amendments to add a new investigator or to provide additional information about investigators may be grouped and submitted at 30-day intervals. When several submissions of new protocols or protocol changes are anticipated during a short period, the sponsor is encouraged, to the extent feasible, to include these all in a single submission.

§ 312.31 Information amendments.

(a) Requirement for information amendment. A sponsor shall report in an information amendment essential information on the IND that is not within the scope of a protocol amendment, IND safety reports, or annual report. Examples of information requiring an information amendment include:

(1) New toxicology, chemistry, or other technical information; or

(2) A report regarding the discontinuance of a clinical investigation.

(b) Content and format of an information amendment. An information amendment is required to bear prominent identification of its contents (eg., "Information Amendment: Chemistry, Manufacturing, and Control"), to be numbered serially by discipline, and to contain the following:

(1) A statement of the nature and purpose of the amendment.

(2) An organized submission of the data in a format appropriate for scientific review.

(3) If the sponsor desires FDA to comment on an information amendment, a request for such comment.

(c) When submitted. Information amendments to the IND should be submitted as necessary but, to the extent feasible, not more often than every 30 days.

§ 312.12 IND safety reports.

(a) Review of safety information. The sponsor shall immediately review all information relevant to the safety or the drug obtained or otherwise received by the sponsor from any source, foreign or domestic, including information derived from clinical investigations, animal investigations, commercial marketing experience, reports in the scientific literature, and unpublished scientific papers. For purposes of this paragraph, "information relevant to the safety of the drug" includes information about related drugs.

(b) IND safety reports. (1) The sponsor shall notify FDA and all participating investigators in an IND safety report of the following:

(i) Any serious adverse experiences or other information associated with the use of the drug not previously reported (in nature, severity, or incidence) that may suggest significant hazards, contraindications, side effects, or precautions. Such notification shall be made as soon as possible and in no event later than 10 working days after the sponsor's initial receipt of the information;

(ii) Any fatal or life-threatening clinical experiences associated with the use of the drug not previously reported (in nature, severity, or incidence). Such notification shall be made as soon possible and in no event later than 3 working days after the sponsor's initial receipt of the report.

(iii) For purposes of this paragraph, "associated with the use of the drug" means there is a reasonable possibility that the event may have been caused by the drug.

(2) The sponsor shall transmit each IND safety report by telephone within the time frames specified in paragraph (b)(1) of this section and shall concurrently submit a written notification. Each written notification shall bear prominent indentification of its contents, i.e., "10-Day IND Safety Report" or "3-Day IND Safety Report." Each written notification and telephone call to FDA shall be transmitted to the FDA division with responsibility for review of the IND.

(c) Followup. The sponsor shall promptly investigate all safety information received by it. Followup information to 3-day and 10-day reports shall be submitted promptly in an information amendment, as soon as the relevant information is available. Results of sponsor's investigation of other safety information shall be submitted, as appropriate, in an information amendment or annual report.

§ 312.33 Annual reports.

A sponsor shall submit, at intervals of 1 year after the date of submission of the IND, a brief report on the progress of the investigation containing the following:

(a) A brief summary of the status of each of the clinical studies in progress, including the name of the investigator and the approximate number of patients under study.

(b) A brief summary of information obtained during the previous year's clinical and nonclinical investigations that is relevant to assessing the drug's safety, including: (1) A summary of all IND safety reports submitted during the past year in accordance with § 312.32; (2) a list of subjects who died during participation in an investigation, with the cause of death for each subject; and (3) a list of subjects who dropped out of an ongoing investigation.

(c) A description of the general investigational plan for the coming year to replace that submitted 1 year earlier. The general investigational plan shall contain the information required under § 312.23(a)(4).

(d) If the investigator brochure has been revised, a description of the revision and a copy of the new brochure.

(e) A description of any significant Phase 1 protocol modifications made during the previous year and not previously reported to the IND in a protocol amendment.

(f) A brief summary of significant foreign marketing developments with the drug during the past year, such as approval for marketing in any country or withdrawal from marketing in any country.

(g) If desired by the sponsor, a log of any outstanding business with respect to the IND for which the sponsor requests or expects a reply, comment, or meeting.

§ 312.34 Treatment use of an investigational new drug.

(a) General. A drug that is not approved for marketing may be under clinical investigation for a serious disease condition in patients for whom no satisfactory alternative drug or other therapy is available. During the clinical investigation of the drug, it may be appropriate to use the drug in the treatment of patients after sufficient evidence of the drug's safety and effectiveness has been obtained to warrant such use. Ordinarily, a drug may be made available for treatment under this section only after Phase 2 investigations have been completed, but FDA may permit such use earlier in the investigational process if compelling circumstances warrant. Administration of an investigational drug under this section serves both to provide treatment and the investigational purpose of gathering additional data on the drug's safety and effectiveness.

(b) Treatment protocol submitted by IND sponsor. A sponsor of a clinical investigation of a drug who intends to sponsor a treatment use for the drug under this section shall submit to FDA a treatment protocol. A treatment use under a treatment protocol may begin 30 days after FDA receives the protocol or on earlier notification by FDA that the treatment use described in the protocol may begin.

(1) A treatment protocol is required to contain the following:

(i) The intended use of the drug.

(ii) An explanation of the rationale for use of the drug, including, as appropriate, either a list of what available regimens ordinarily should be tried before using the investigational drug or an explanation of why the use of the investigational drug is preferable to the use of available marketed treatments.

(iii) A brief description of the criteria for patient selection.

(iv) The method of administration of the drug and the dosages to be used.

(v) A description of clinical procedures, laboratory tests, or other measures to be taken to monitor the effects of the drug and to minimize risk.

(2) A treatment protocol is required to be supported by the following information:

(i) A copy of the informational brochure that is to be supplied to each treating physician.

(ii) The technical information that is relevant to determining the safety and effectiveness of the drug for the intended treatment purpose. Information that is already contained in the sponsor's IND may be incorporated by reference.

(iii) If a waiver from IRB review an approval requirements is desired, a request for the waiver. (FDA may on its own initiative waive IRB review under Part 56 if it finds such review unnecessary for the protection of subjects to be treated.)

(c)(1) Treatment IND submitted by licensed practitioner. If a sponsor of a clinical investigation of a drug has not established a treatment protocol for the drug under paragraph (b) of this section, but the drug is being investigated by the sponsor under an effective IND, a licensed medical practitioner may seek to obtain the drug from such sponsor and submit a treatment IND to FDA requesting authorization to use the investigational drug for treatment use. A treatment use under a treatment IND may begin 30 days after FDA receives the IND or on earlier notification by FDA that the treatment use under the IND may begin. A treatment IND is required to contain the following:

(i) A cover sheet (Form FDA-1571) meeting the requirements of § 312.23(a)(1).

(ii) Information on the drug's chemistry, manufacturing, and control, and prior clinical and nonclinical experience with the drug submitted in accordance with the requirements of § 312.23. The provision of an investigational drug to a licensed medical practitioner by a sponsor of a separate clinical investigation that is subject to an IND shall be deemed to authorize the incorporation by reference of the technical information contained in the sponsor's IND into the medical practitioner's treatment IND.

(iii) A treatment protocol containing the following:

(a ) The intended use of the drug.

(b ) An explanation of the rationale for use of the drug, including, as appropriate, an explanation of the regimens that have perviously been tried or why use of the investigational drug is preferable to the use of available marketed treatments.

(c ) A brief description of the criteria for patient selection.

(d ) The method of administration of the drug and the dosages to be used.

(e ) A description of clinical procedures, laboratory tests, or other measures to be taken to monitor the effects of the drug and minimize risks.

(iv) If a waiver from IRB review and approval requirements is desired, a request for the waiver. (FDA may on its own initiative waive IRB review requirements under Part 56, if it finds such review unnecessary for protection of subjects to be treated.)

(v) A statement of the practitioner's qualifications to use the investigational drug for the intended treatment use.

(vi) A statement that the practitioner has read or is otherwise familiar with information on the drug's safety and effectiveness derived from previous clinical and nonclinical experience with the drug.

(vii) A commitment to report to FDA adverse drug effects in accordance with § 312.56(c).

(2) A licensed practitioner who submits a treatment IND under this section is the sponsor-investigator for such IND and is responsible for meeting all applicable sponsor and investigator responsibilities under this part and Parts 50, 52, 54, and 56.

(d) Criteria. FDA may permit an investigational drug to be used for a treatment use under a treatment protocol or treatment IND unless it finds one of the following:

(1) The application does not fall within the terms of this section as it does not involve the treatment use of an investigational new drug intended for a serious disease condition in patients for whom no satisfactory alternative drug or other therapy is available.

(2) The potential risks outweigh the potential benefits of the drug in the treatment of patients.

(3) There is not sufficient evidence of the drug's safety and effectiveness to justify its intended treatment use.

(e) Agency assistance. FDA will provide assistance to persons interested in submitting an application under this section.

§ 312.36 Emergency use of an investigational new drug.

Need for an investigational drug may arise in an emergency situation that does not allow time for submission of an IND in accordance with § 312.23. In such a case, FDA may authorize shipment of the drug for a specified use in advance of submission of an IND. A request for such authorization may be transmitted to FDA by telephone or other rapid communication means. Except in extraordinary circumstances, such authorization will be conditioned on the sponsor making an appropriate IND submission as soon as practicable after receiving the authorization.

§ 312.38 Withdrawal of an IND.

(a) At any time a sponsor may withdraw an effective IND without prejudice.

(b) If an IND is withdrawn, FDA shall be so notified, all clinical investigations conducted under the IND shall be ended, all current investigators notified, and all stocks of the drug returned or otherwise disposed of in accordance with the requirements of Part 52.

(c) If an IND is withdrawn because of a safety reason, the sponsor shall promptly so inform FDA, all participating investigators, and all reviewing Institutional Review Boards, together with the reasons for such withdrawal.

Subpart C -- Administrative Actions

§ 312.40 General requirements for use of an investigational new drug in a clinical investigation.

(a) An investigational new drug may be used in a clinical investigation if the following conditions are met:

(1) The sponsor of the investigation submits an IND for the drug to FDA; the IND is in effect under paragraph (b) of this section; and the sponsor complies with all applicable requirements in this part and Parts 50, 52, 54, and 56 with respect to the conduct of the clinical investigations, and

(2) Each participating investigator conducts his or her investigation in compliance with the requirements of this part and Parts 50, 54, and 56.

(b) An IND goes into effect

(1) 30 days after FDA receives the IND, unless FDA notifies the sponsor that the investigations described in the IND are subject to a clinical hold under § 312.42, or

(2) on earlier notification by FDA that the clinical investigations in the IND may begin. FDA will notify the sponsor in writing of the date it receives the IND.

(c) A sponsor may ship an investigational new drug to investigators named in the IND:

(1) 30 days after FDA receives the IND; or

(2) on earlier FDA authorization to ship the drug.

Investigators may not, however, administer the investigational new drug to human subjects until the IND goes into effect under paragraph (b) of this section.

§ 312.41 Comment and advice on an IND.

(a) FDA may at any time during the course of the investigation communicate with the sponsor orally or in writing about deficiencies in the IND or about FDA's need for more data or information.

(b) On the sponsor's request, FDA will provide advice on specific matters relating to an IND. Such advice may include, for example, advice on the adequacy of technical data to support an investigational plan, on the design of a clinical trial, or on whether proposed investigations are likely to produce the data and information that is needed to meet requiremnts for a marketing application.

(c) FDA communications with a sponsor under this section are solely advisory and do not require any modification in the planned or ongoing clinical investigations or response to the agency, unless the communication is accompanied by a clinical hold order under § 312.42.

§ 312.42 Clinical holds and requests for modification.

(a) General. A clinical hold is an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. The clinical hold order may apply to one or more of the investigations covered by an IND. When a proposed study is placed on clinical hold, subjects may not be given the investigational drug by the clinical investigator conducting the study. When an ongoing study is placed on clinical hold, no new subjects may be recruited to the study and placed on the investigational drug; patients already in the study should be taken off therapy under the protocol unless specifically permitted by FDA in the interest of patient safety.

(b) Grounds for imposition of clinical hold. -- (1) Clinical hold of a Phase 1 study under an IND. FDA may place a proposed or ongoing Phase 1 investigation on clinical hold if it finds that:

(i) Human subjects are or would be exposed to an unreasonable and significant risk of illness or injury:

(ii) The clinical investigators named in the IND are not qualified by reason of their scientific training and experience to conduct the investigation described in the IND;

(iii) The investigator brochure is misleading, erroneous, or materially incomplete; or

(iv) The IND does not contain sufficient information required under § 312.23 to assess the risks to subjects of the proposed studies.

(2) Clinical hold of a Phase 2 or 3 study under an IND. FDA may place a proposed or onging Phase 2 or 3 investigation on clinical hold if it finds that:

(i) Any of the conditions in paragraph (b)(1)(i) through (iv) of this section apply, or;

(ii) The plan or protocol for the investigation is clearly deficient in design to meet its stated objectives.

(c) Discussion of deficiency. Whenever FDA concludes that a deficiency exists in a clinical investigation that may be grounds for the imposition of a clinical hold, FDA will, before issuing the clinical hold order, attempt to discuss and satisfactorily resolve the matter with the sponsor.

(d) Imposition of clinical hold. The initial clinical hold order may be made by telephone or other means of rapid communication or in writing. The clinical hold order shall be made by or on behalf of the Division Director with responsibility for review of the IND. Within 15 days of the imposition of the clinical hold, the Division Director will provide the sponsor a written explanation of the basis for the hold.

(e) Resumption of clinical investigations. If, by the terms of the clinical hold order, resumption of the affected investigation is permitted without prior notification by FDA once a stated correction or modification is made, the investigation may proceed as soon as the correction or modification is made. In all other cases, an investigation may only resume after the Division Director with responsibility for review of the IND has notified the sponsor that the investigation may proceed. In these cases the Division Director will authorize resumption of the affected investigation(s) when the sponsor corrects the deficiency(ies) previously cited by the Division Director or otherwise satisfies the Division Director that the investigation(s) can proceed.

(f) Appeal. If the sponsor disagrees with the reasons cited for the clinical hold, the sponsor may request reconsideration of the decision in accordance with § 312.48.

(g) Conversion of IND on clinical hold to inactive status . If all investigations covered by an IND remain on clinical hold for 1 year or more, the IND may be placed on inactive status by FDA under § 312.45.

§ 312.44 Termination.

(a) General . This section describes the procedures under which FDA may terminate an IND. If an IND is terminated, the sponsor shall end all clinical investigations conducted under the IND and recall or otherwise provide for the disposition of all unused supplies of the drug. A termination action may be based on deficiencies in the IND or in the conduct of an investigation under an IND. Except as provided in paragraph (d) of this section, a termination shall be preceded by a proposal to terminate by FDA and an opportunity for the sponsor to respond. FDA will, in general, only initiate an action under this section after first attempting to resolve differences informally or, when appropriate, through the clinical hold procedures described in § 312.42.

(b) Grounds for termination. -- (1) Phase 1 . FDA may propose to terminate a Phase 1 IND if it finds that:

(i) Human subjects would be exposed to an unreasonable and significant risk of illness or injury.

(ii) The IND does not contain sufficient information required under § 312.23 to assess the safety to subjects of the clinical investigations.

(iii) The methods, facilities, and controls used for the manufacturing, processing, and packing of the investigational drug are inadequate to establish and maintain appropriate standards of identity, strength, quality and purity as needed for subject safety.

(iv) The clinical investigations are not being conducted in accordance with the plan or protocols submitted in the IND.

(v) The drug is being promoted or distributed for commercial purposes not justified by the requirements of the investigation or permitted by § 312.7.

(vi) The IND, or any amendment or report to the IND, contains an untrue statement of a material fact or omits material information required by this part.

(vii) The sponsor fails promptly to investigate and inform the Food and Drug Administration and all investigators of newly found serious or potentially serious hazards, contraindications, side effects, and precautions pertinent to the safety of the new drug or fails to make any other report required under this part.

(viii) The sponsor fails to submit an accurate annual report of the investigations in acordance with § 312.33.

(ix) The sponsor fails to comply with any other applicable requirement of this part or Part 50, 52, 54, or 56.

(x) The IND has remained on inactive status for 5 years or more.

(2) Phase 2 or 3 . FDA may propose to terminate an IND during Phase 2 or Phase 3 if FDA finds that:

(i) Any of the conditions in paragraph (b)(1)(i) thorugh (x) of this section apply; or

(ii) The investigational plan or protocol(s) is not reasonable as a bona fide scientific plan to determine whether or not the drug is safe and effective for use; or

(iii) There is convincing evidence that the drug is effective for the purpose for which it is being investigated.

(c) Opportunity for sponsor response . (1) If FDA proposes to terminate an IND, FDA will notify the sponsor in writing, and invite correction or explanation within a period of 30 days.

(2) On such notification, the sponsor may provide a written explanation or correction or may request a conference with FDA to provide the requested explanation or correction. If the sponsor does not respond to the notification within the allocated time, the IND shall be terminated.

(3) If the sponsor responds but FDA does not accept the explanation or correction submitted, FDA shall inform the sponsor in writing of the reason for the nonacceptance and provide the sponsor with an opportunity for a regulatory hearing before FDA Under Part 16 on the question of whether the IND should be terminated. The sponsor's request for a regulatory hearing must be made within 10 days of the sponsor's receipt of FDA's notification of nonacceptance.

(d) Immediate termination of IND. Notwithstanding paragraphs (a) through (c) of this section, if at any time FDA concludes that continuation of the investigation presents a significant danger to the public health, the agency shall immediately, by written notice to the sponsor from the Director of the National Center for Drugs and Biologics, terminate the IND. An IND so terminated is subject to reinstatement by the Director on the basis of additional submissions that eliminate such danger. If an IND is terminated under this paragraph, the agency will afford the sponsor an opportunity for a regulatory hearing under Part 16 on the question of whether the IND should be reinstated.

§ 312.45 Inactive status.

(a) If no subjects are entered into clinical studies for a period of 2 years or more under an IND, or if all investigations under an IND remain on clinical hold for 1 year or more, the IND may be placed by FDA on inactive status. This action may be taken by FDA either on request of the sponsor or on FDA's own initiative. If FDA seeks to act on its own initiative under this section, it shall first notify the sponsor in writing of the proposed inactive status. Upon receipt of such notification, the sponsor shall have 30 days to respond as to why the IND should continue to remain active.

(b) If an IND is placed on inactive status, all investigators shall be so notified and all stocks of the drug shall be returned or otherwise disposed of as described in Part 52.

(c) A sponsor is not required to submit annual reports to an IND on inactive status. An inactive IND is, however, still in effect for purposes of the public disclosure of data and information under § 312.130.

(d) A sponsor who intends to resume clinical investigation under an IND placed on inactive status shall submit a protocol amendment under § 312.30 containing the proposed general investigational plan for the coming year and appropriate protocols. If the protocol amendment relies on information previously submitted, the plan shall reference such information. Additional information supporting the proposed investigation, if any, shall be submitted in an information amendment. Notwithstanding the provisions of § 312.30, clinical investigations under an IND on inactive status may only resume (1) 30 days after FDA receives the protocol amendment, unless FDA notifies the sponsor that the investigations described in the amendment are subject to a clinical hold under § 312.42, or (2) on earlier notification by FDA that the clinical investigations described in the protocol amendment may begin.

(e) An IND that remains on inactive status for 5 years or more may be terminated under § 312.44.

§ 312.47 Meetings.

(a) General. Meetings between a sponsor and the agency are frequently useful in resolving questions and issues raised during the course of a clinical investigation. FDA encourages such meetings to the extent that they aid evaluation of the drug and the solution of scientific problems concerning the drug and to the extent that FDA's resources permit. The general principle underlying the conduct of such meetings is that there should be free, full, and open communication about any scientific or medical question that may arise during the clinical investigation. These meetings shall be conducted and documented in accordance with Part 10.

(b) "End-of-Phase 2" meetings and meetings held before submission of a marketing application. At specific times during the drug investigation process, meetings between FDA and a sponsor can be especially helpful in minimizing wasteful expenditures of time and money and thus in speeding the drug development and evaluation process. In particular, FDA has found that meetings at the end of Phase 2 of an investigation (end-of-Phase 2 meetings) are of considerable assistance in planning later studies and that meetings held near completion of Phase 3 and before submission of a marketing application ("pre-NDA" meetings) are helpful in developing methods of presentation and submission of data in the marketing application that facilitate review and allow timely FDA response.

(1) End-of-Phase 2 meetings. -- (i) Purpose. The purpose of an end-of-Phase 2 meeting is to determine the safety of proceeding to Phase 3, to evaluate the Phase 3 plan and protocols, and to identify any additional information necessary to support a marketing application for the uses under investigation.

(ii) Eligibility for meeting. The end-of-Phase 2 meeting is designed primarily for IND's involving new molecular entities or major new uses of marketed drugs. However, a sponsor of any IND may request and obtain an end-of-Phase 2 meeting.

(iii) Timing. To be most useful to the sponsor, end-of-Phase 2 meetings should be held before major commitments of effort and resources to specific Phase 3 tests are made. The scheduling of an end-of-Phase 2 meeting is not, however, intended to delay the transition of an investigation from Phase 2 to Phase 3.

(iv) Advance information. At least 1 month in advance of an end-of-Phase 2 meeting, the sponsor should submit background information on the sponsor's plan for Phase 3, including summaries of the Phase 1 and 2 investigations, the specific protocols for Phase 3 clinical studies, plans for any additional nonclinical studies, and, if available, tentative labeling for the drug. The recommended contents of such a submission are described more fully in an FDA Staff Manual Guide (NCDB 4850.6) that is publicly available under FDA's public information regulations in Part 20.

(v) Conduct of meeting. Arrangements for an end-of-Phase 2 meeting are to be made with the division responsible for review on the IND. The meeting will be scheduled by FDA at a time convenient to both FDA and the sponsor. Both the sponsor and FDA may bring consultants to the meeting. The meeting should be directed primarily at establishing agreement between FDA and the sponsor of the overall plan for Phase 3 and the objectives and design of particular studies. The adequacy of technical information to support Phase 3 studies and/or a marketing application may also be discussed. Agreements reached at the meeting on these matters will be recorded in minutes of the conference that will be taken by FDA in accordance with § 10.65 and provided to the sponsor. The minutes along with any other written material provided to the sponsor will serve as a permanent record of any agreements reached. Barring a significant scientific development that requires otherwise, studies conducted in accordance with the agreement shall be presumed to be sufficient in objective and design for the purpose of obtaining marketing approval for the drug.

(2) "Pre-NDA" meetings. FDA has found that delays associated with the initial review of a marketing application may be reduced by exchanges of information about a proposed marketing application. The primary purpose of this kind of exchange is to acquaint FDA reviewers with the general information to be submitted in the marketing application, to uncover any major unresolved problems, to identify those studies that the sponsor is relying on as adequate and well-controlled to establish the drug's effectiveness, to discuss appropriate methods for statistical analysis of the data, and to discuss the best approach to the presentation and formatting of data in the marketing application. Arrangements for such a meeting are to be made by the sponsor with the division responsible for review of the IND. To permit FDA to provide the sponsor with the most useful advice on preparing a marketing application, the sponsor should submit to FDA's reviewing division at least 1 month in advance of the meeting the following information:

(i) A brief summary of the clinical studies to be submitted in the application.

(ii) A Proposed format for organizing the submission, including methods for presenting the data.

§ 312.48 Request for reconsideration or clarification of technical requirements or informal opinions.

FDA is committed to resolving differences between sponsors and FDA reviewing divisions with respect to IND's as quickly and amicably as possible through the cooperative exchange of information and views. That exchange may take place through written correspondence, telephone conversations, or informal meetings. In addition, FDA has established administratively a specific procedure under which a sponsor may ask the agency to reconsider or clarify an agency action or an informal opinion expressed to a sponsor by an agency employee with respect to an IND. Examples of issues contemplated for resolution under the procedure include requests by FDA for specific studies or information, requests to modify or delay a study, and unfavorable responses by FDA to requests from sponsors for waivers or special technical approaches to a scientific problem. The procedure will be marked by the sponsor's submission of a written request for reconsideration of clarification to the division that is responsible for reviewing the application, the division's prompt response to the applicant, and, if the division's response is not acceptable to the applicant, automatic review of the issue by managment to the National Center for Drugs and Biologics. FDA will attempt to issue a final decision within 60 days of the applicant's request. This procedure is described more fully in an FDA Staff Manual Guide (NCDB 4820.5) that is publicly available under FDA's public information regulations in Part 20.

Subpart D -- Responsibilities of Sponsors and Investigators

§ 312.50 General responsibilities of sponsors.

Sponsors are responsible for selecting qualified investigators, providing them with the information they need to conduct an investigation properly, ensuring proper monitoring of the investigation(s), ensuring that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the IND, maintaining an effective IND with respect to the investigations, and ensuring that FDA and all participating investigators are promptly informed of significant new adverse effects or risks with respect to the drug. Additional specific responsibilities of sponsors are described elsewhere in this part and in Part 52.

§ 312.53 Selecting investigators and monitors.

(a) Selecting investigators. A sponsor shall select only investigators qualified by training and experience as appropriate experts to investigate the drug.

(b) Control of drug. A sponsor shall ship investigational new drugs only to investigators participating in the investigation.

(c) Obtaining information from the investigator. The sponsor shall obtain from each clinical investigator the following:

(1) A signed investigator statement (Form FDA-1572) containing:

(i) The name and address of the investigator;

(ii) The name and code number, if any, of the protocol(s) in the IND identifying the study(ies) to be conducted by the investigator.

(iii) The name and address of any medical school, hospital, or other research facility where the clinical investigation(s) will be condicted;

(iv) The name and address of any clinical laboratory facilities to be used in the study;

(v) The name and address of the IRB that is responsible for review and approval of the study(ies);

(vi) A commitment by the investigator that he or she --

( a ) Will conduct the study(ies) in accordance with the relevant, current protocol(s) and will only make changes in a protocol after consultation with the sponsor;

( b ) Will comply with all requirements of Part 54 regarding the obligations of clinical investigators and all other pertinent requirements in this part;

( c ) Will personally conduct or supervise the described investigation(s);

( d ) Will ensure that the requirements relating to obtaining informed consent and institutional review board review and approval are met;

(e ) Will report to the sponsor immediately any unsuspected or serious side effects that occur in the course of the investigation(s);

(f ) Has read and understands the information in the investigator's brochure, including the potential risks and side effects of the drug; and

(g ) Will ensure that all associated, colleagues, and employees assisting in the conduct of the study(ies) are informed about their obligations in meeting the above commitments.

(vii) A list of the names of the subinvestigators (e.g., research fellows, residents, colleagues) who will be assisting the investigator in the conduct of the investigation(s).

(2) Curriculum vitae. A curriculum vitae for the investigator showing the education, training, and experience that qualifies the investigator as an expert in the clinical investigation of the drug for the use under investigation.

(3) Clinical plan. (i) For Phase 1 investigations, a general outline of the planned investigation including the estimated duration of the study and the maximum number of subjects that will be involved.

(ii) For Phase 2 or 3 investigations, an outline of the plan of investigation including an approximation of the number of subjects to be treated with the drug and the number to be employed as controls, if any; the clinical uses to be investigated; characteristics of subjects by age, sex, and condition; the kind of clinical observations and laboratory tests to be conducted; the estimated duration of the study; and copies or a description of case report forms to be used.

(d) Selecting monitors. A sponsor shall select a monitor qualified by training and experience to monitor the investigation in accordance with this part and Part 52.

§ 312.55 Informing investigators.

(a) Before the investigation begins, a sponsor (other than a sponsor-investigator) shall give each participating clinical investigator an investigator brochure containing the information described in § 312.23(a)(5).

(b) The sponsor shall, as the overall investigational plan proceeds, keep each participating investigator informed of new observations discovered by or reported to the sponsor on the drug, particularly with respect to adverse effects and safe use. Such information may be distributed to investigators by means of periodically revised investigator brochures, reprints or published studies, reports or letters to clinical investigators, or other appropriate means. Important safety information should be relayed orally, but shall be followed as soon as practicable by a written communication.

§ 312.56 Monitoring investigations.

(a) A sponsor who discovers that an investigator is not complying with the signed agreement (Form FDA-1572), the general investigational plan, or the requirements of this part or other applicable parts shall promptly either secure compliance or discontinue shipments of the investigational new drug to the investigator and end the investigator's participation in the investigation. If the investigator's participation in the investigation is ended, the sponsor shall require that the investigator dispose of or return the investigational drug in accordance with the requirements of Part 52 and shall notify FDA.

(b) The sponsor shall monitor the progress of all clinical and nonclinical investigations and evaluate the evidence relating to the safety and effectiveness of the drug as it is obtained from the investigators. The sponsors shall make such reports to FDA regarding adverse drug experiences as are required under § 312.31.

(c) A sponsor who determines that safety information presents an unreasonable and significant risk to subjects shall discontinue those investigations that present the risk, notify FDA, all institutional review boards, and all investigators who have at any time participated in the investigation of the discontinuance, assure the disposition of all stocks of the drug outstanding as required by § 52.41, and furnish FDA with a full report of the sponsor's actions. The sponsor shall discontinue the investigation as soon as possible, and in no event later tha 5 working days after making the determination that the investigation should be discontinued. Upon request, FDA will confer with a sponsor on the need to discontinue an investigation.

§ 312.58 Inspection of sponsor's records and reports.

(a) Upon the request at reasonable times of a scientifically trained and properly authorized employee of FDA, the sponsor shall make available for inspection and copying the records and reports required to be maintained under this part and under other applicable parts of this chapter. Upon written request by FDA, the sponsor shall submit the records or reports (or copies of them) to FDA. The sponsor shall discontinue shipments of the drug to any investigator who has failed to maintain or make available records or reports of the investigation as required by this part or Part 54.

(b) If an investigational new drug is a substance listed in any schedule of the Controlled Substances Act (21 U.S.C. 801; 21 CFR 1308), records concerning shipment, delivery, receipt, and disposition of the drug, which are required to be kept under this part or other applicable parts of this chapter shall, upon the request of a properly authorized employee of the Drug Enforcement Administration of the U.S. Department of Justice, be made available by the investigator or sponsor to whom the request is made, for inspection and copying.

§ 312.60 General responsibilities of investigators.

An investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan and applicable regulations, for protecting the rights, safety, and welfare of subjects under the investigator's care and for the control of drugs under investigation. Specific responsibilities of clinical investigators are set forth in Parts 54 and 56.

§ 312.62 Investigator records and reports.

An investigator shall make such reports and maintain such records as are required in accordance with Part 54.

Subpart E -- Miscellaneous

§ 312.63 Import and export requirements.

(a) Imports. An investigational new drug offered for import into the United States complies with the requirements of this part if it is subject to an effective IND under § 312.40 and either (1) the consignee in the United States is the sponsor of the IND or (2) the consignee is a qualified investigator named in the IND.

(b) Exports. An investigational new drug intended for export from the United States complies with the requirements of this part as follows:

(1) If an IND is in effect for the drug under § 312.40 and each person who receives the drug is an investigator named in the application; or

(2) If FDA authorizes shipment of the drug for use in clinical investigation. Authorization may be obtained as follows:

(i) Through submission to FDA of a written request from the person that seeks to export the drug. A request must provide adequate information about the drug to satisfy FDA that the drug is appropriate for the proposed investigational use in humans, that the drug will be used for investigational purposes only, and that the drug may be legally used by that consignee in the importing country for the proposed investigational use. The request shall specify the quantity of the drug to be shipped per shipment and the frequency of expected shipments. If FDA authorizes exportation under this subparagraph, the agency shall concurrently notify the government of the importing country of such authorization.

(ii) Through submission to FDA of a formal request from an authorized official of the government of the country to which the drug is proposed to be shipped. A request must specify that the foreign government has adequate information about the drug and the proposed investigational use, that the drug will be used for investigational purposes only, and that the foreign government is satisfied that the drug may legally be used by the intended consignee in that country.

(iii) Authorization to export an investigational drug under paragraph (b)(2) (i) or (ii) of this section may be revoked by FDA if the agency finds that the conditions underlying its authorization are no longer met.

(3) This paragraph applies only where the drug is to be used for the purpose of clinical investigation. Export of an investigational drug for commercial marketing or for use in routine medical practice is not permitted.

§ 312.120 Foreign clinical studies not conducted under an IND.

(a) Introduction. This section describes the criteria for acceptance by FDA of foreign clinical studies not conducted under an IND. In general, FDA accepts such studies provided they are well designed, well conducted, performed by qualified investigators, and conducted in accordance with ethical principles acceptable to the world community. Studies meeting these criteria may be utilized to support clinical investigations in the United States and/or marketing approval. Marketing approval of a new drug or antibiotic drug based solely on foreign clinical data is governed by § 314.106 (proposed in the Federal Register of October 19, 1982; 47 FR 46622, 46655).

(b) Data submissions. A sponsor who wishes to rely on a foreign clinical study to support a U.S. study in the IND shall submit to FDA the following information:

(1) A description of the investigator's qualification;

(2) A description of the research facilities;

(3) A detailed summary of the protocol and results of the study, and, should FDA request, case records maintained by the investigator or additional background data such as hospital or other institutional records;

(4) A description of the drug substance and drug product used in the study, including a description of components, formulation, specifications and bioavailability of the specific drug product used in the clinical study, if available; and

(5) If the study is intended to support the effectiveness of a drug product, information showing that the study is adequate and well controlled under § 314.126 (proposed in the Federal Register of October 19, 1982; 47 FR 46622, 46656).

(c) Conformance with ethical principles. (1) Foreign clinical research is required to have been conducted in accordance with the ethical principles stated in the "Declaration of Helsinki" (see paragraph (c)(5) of this section) or the laws and regulations of the country in which the research was conducted, whichever represents the greater protection of the individual.

(2) For each foreign clinical study submitted under this section, the sponsor shall explain how the research conformed to the ethical principles contained in the "Declaration of Helsinki" or the foreign country's standards, whichever were used. If the foreign country's standards were used, the sponsor shall explain in detail how those standards differ from the "Declaration of Helsinki" and how they offer greater protection.

(3) When the research has been approved by an independent review committee, the sponsor shall submit to FDA documentation of such review and approval, including the names and qualifications of the members of the committee. In this regard, a "review committee" means a committee composed of scientists and, where practicable, individuals who are otherwise qualified (e. g., other health professionals or laymen). The investigator may not vote on any aspect of the review of his or her protocol by a review committee.

(4) When the research has not been approved by a review committee, the sponsor shall describe how the research conformed to the ethical standards in the country in which the research was conducted, so as to meet the goals of the "Declaration of Helsinki" In compensating for the lack of review committee approval.

(5) The "Declaration of Helsinki" states as follows:

Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects

I. Basic Principles

1. Biomedical research involving human subjects must conform to generally accepted scientific principles and should be based on adequately performed laboratory and animal experimentation and on a thorough knowledge of the scientific literature.

2. The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol which should be transmitted to a specially appointed independent committee for consideration, comment and guidance.

3. Biomedical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medical person. The responsibility for the human subject must always rest with a medically qualified person and never rest on the subject of the research, even though the subject has given his or her consent.

4. Biomedical research involving human subjects cannot legitimately be carried out unless the importance of the objective is in proportion to the inherent risk to the subject.

5. Every biomedical research project involving human subjects should be preceded by careful assessment of predictable risks in comparison with foreseeable benefits to the subject or to others. Concern for the interests of the subject must always prevail over the interests of science and society.

6. The right of the research subject to safeguard his or her integrity must always be respected. Every precaution should be taken to respect the privacy of the subject and to minimize the impact of the study on the subject's physical and mental integrity and on the personality of the subject.

7. Doctors should abstain from engaging in research projects involving human subjects unless they are satisfied that the hazards involved are believed to be predictable. Doctors should cease any investigation if the hazards are found to outweigh the potential benefits.

8. In publication of the results of his or her research, the doctor is obliged to preserve the accuracy of the results. Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication.

9. In any research on human beings, each potential subject must be adequately informed of the aims, methods, anticipated benefits and potential hazards of the study and the discomfort it may entail. He or she is free to withdraw his or her consent to participation at any time. The doctor should then obtain the subject's given informed consent, preferable in writing.

10. When obtaining informed consent for the reasearch project the doctor should be particularly cautious if the subject is in a dependent relationship to him or her or may consent under duress. In that case the informed consent should be obtained by a doctor who is not engaged in the investigation and who is completely independent of this official relationship.

11. In case of legal incompetence, informed consent should be obtained from the legal guardian in accordance with national legislation. Where physical or mental incapacity makes it impossible to obtain informed consent, or when the subject is a minor, permission from the responsible relative replaces that of the subject in accordance with national legislation.

12. The research protocol should always contain a statement of the ethical considerations involved and should indicate that the principles enunciated in the present Declaration are complied with.

II. Medical Research Combined With Professional Care (Clinical Research)

1. In the treatment of the sick person, the doctor must be free to use a new diagnostic and therapeutic measure, if in his or her judgment it offers hope of saving life, reestablishing health or alleviating suffering.

2. The potential benefits, hazards and discomfort of a new method should be weighed against the advantages of the best current diagnostic and therapeutic methods.

3. In any medical study, every patient -- including those of a control group, if any -- should be assured of the best proven diagnostic and therapeutic methods.

4. The refusal of the patient to participate in a study must never interfere with the doctor-patient relationship.

5. If the doctor considers it essential not to obtain informed consent, the specific reasons for this proposal should be stated in the experimental protocol for transmission to the independent committee (I, 2).

6. The doctor can combine medical research with professional care, the objective being the acquisition of new medical knowledge, only to the extent that medical research is justified by its potential diagnostic or therapeutic value for the patient.

III. Non-Therapeutic Biomedical Research Involving Human Subjects (Non-Clinical Biomedical Research)

1. In the purely scientific application of medical research carried out on a human being, it is the duty of the doctor to remain the protector of the life and health of that person on whom biomedical research is being carried out.

2. The subjects should be volunteers -- either healthy persons or patients for whom the experimental design is not related to the patient's illness.

3. The investigator or the team should discontinue the research if in his/her or their judgment it may, if continued, be harmful to the individual.

4. In research on man, the interest of science and society should never take precedence over considerations related to the well-being of the subject.

§ 312.130 Availability for public disclosure of data and information in an IND.

(a) The existence of an investigational new drug application will not be disclosed by FDA unless it has previously been publicly disclosed or acknowledged.

(b) The availability for public disclosure of all data and information in an investigational new drug application for a new drug or antibiotic drug file will be handled in accordance with the provisions established in § 314.430 (proposed in the Federal Register of October 19, 1982; 47 FR 46664) for the confidentiality of data and information in applications submitted under Part 314. The availability for public disclosure of all data and information in an investigational new drug application for a biological product will be governed by the provisions of § § 601.50 and 601.51.

(c) Notwithstanding the provisions of § 314.430 , FDA shall disclose upon request to an individual to whom an investigational new drug has been given a copy of any IND safety report relating to the use in that individual.

§ 312.140 Address for correspondence.

(a) Except as provided in paragraph (b) of this section, a sponsor shall send an initial IND to the Documents and Records Section (HFN-106), Office of New Drug Evaluation, National Center for Drugs and Biologics, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. On receiving the IND, FDA will inform the sponsor which one of the divisions in the Office of New Drug Evaluation is responsible for the IND. Amendments, reports, and other correspondence relating to matters covered by the IND should be directed to the appropriate division. The outside wrapper of each submission shall state what is contained in the submission, for example, "IND Application", "Protocol Amendment", etc.

(b) Applications for the products listed below should be submitted to the Office of Biologics (HFN-823), National Center for Drugs and Biologics, Food and Drug Administration, 8800 Rockville Pike, Bethesda, MD 20205: (1) Products subject to the licensing provisions of the Public Health Service Act of July 1, 1944 (58 Stat. 682, as amended (42 U.S.C. 201 et. seq.)) or subject to Part 600; (2) ingredients packaged together with containers intended for the collection, processing, or storage of blood or blood components; (3) urokinase products; (4) plasma volume expanders and hydroxyethyl starch for leukapheresis; and (5) coupled antibodies, i.e., products that consist of an antibody component coupled with a drug or radionuclide component in which both components provide a pharmacological effect but the biological component determines the site of action.

(c) All correspondence relating to biological products for human use which are also radioactive drugs shall be submitted to the Division of Oncology and Radiopharmaceutical Drug Products (HFN-150), Office of New Drug Evaluation, National Center for Drugs and Biologics, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, except that applications for coupled antibodies shall be submitted in accordance with paragraph (b) of this section.

(d) All correspondence relating to export of an investigational drug under § 312.110(b)(2) shall be submitted to the International Affairs Staff (HFY-50), Office of Health Affairs, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.

§ 312.145 Guidelines

(a) FDA has made available guidelines under § 10.90(b) to help persons to comply with certain requirements of this part.

(b) The National Center for Drugs and Biologics maintains a list of guidelines that apply to the Center's regulations. The list states how a person can obtain a copy of each guideline. A request for a copy of the list should be directed to the Assistant Director for Regulatory Affairs (HFN-7), National Center for Drugs and Biologics, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.

Subpart F -- Drugs for Investigational Use in Laboratory Research Animals or In Vitro Tests

§ 312.160 Drugs for investigational use in laboratory research animals or in vitro tests.

(a) Authorization to ship. (1) A person may ship a drug intended solely for tests in vitro or in animals used only for laboratory research purposes if it is labeled as follows:

Caution: Contains a new drug for investigational use only in laboratory research animals, or for tests in vitro. Not for use in humans.

(2) A person shipping a drug under paragraph (a) of this section shall use due diligence to assure that the consignee is regularly engaged in conducting such tests and that the shipment of the new drug will actually be used for tests in vitro or in animals used only for laboratory research.

(3) A person who ships a drug under paragraph (a) of this section shall maintain adequate records showing the name and post office address of the expert to whom the drug is shipped and the date, quantity, and batch or code mark of each shipment and delivery. Such records are to be maintained for a period of 2 years after the shipment. Upon the request of a properly authorized FDA employee at reasonable times, the person shall make such records available for inspection and copying.

(b) Termination of authorization to ship. FDA may terminate authorization to ship a drug under this section, if it finds that:

(1) The sponsor of the investigation has failed to comply with any of the conditions for shipment established under this section; or

(2) The continuance of the investigation is unsafe or otherwise contrary to the public interest or the drug is used for purposes other than bona fide scientific investigation. FDS will notify the person shipping the drug of its finding and invite immediate correction. If correction is not immediately made, the person shall have an opportunity for a regulatory hearing before FDA pursuant to Part 16. If authorization to ship the drug is terminated, the person shipping the drug shall recall or have destroyed the unused supplies of the drug.

Interested persons, may, on or before August 8, 1983, submit to the Dockets Management Branch (HFA-305), Food and Drug Administration, Rm. 4-62, 5600 Fishers Lane, Rockville, MD 20857, written comments regarding this proposal. Two copies of any comments are to be submitted, except that individuals may submit one copy. Comments are to be identified with the docket number found in brackets in the heading of this document. Received comments may be seen in the office above between 9 a.m. and 4 p.m., Monday through Friday.

Arthur Hull Hayes, Jr.,
Commissioner of Food and Drugs.

Richard S. Schweiker,
Secretary of Health and Human Services.

Dated: February 3, 1983.
[FR Doc. 83-15452 Filed 6-8-83; 8:45 am]

BILLING CODE 4160-01-M

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