(13) The sponsor shall obtain from each investigator involved in clinical trials a signed statement in the following form:

[Form FD 1573]

Department of Health, Education, and Welfare, Food and Drug Administration

by section 505(i) of the Federal Food, Drug, and Cosmetic Act and § 130.3 of title 21 of the Code of Federal Regulations as a condition for receiving and conducting clinical investigations with a new drug limited by Federal (or United States) law to investigational use.

1. The following is a statement of my education and experience:

a. Colleges, universities, and medical or other professional schools attended, with dates of attendance, degrees, and dates degrees were awarded.

b. Postgraduate medical or other professional training: Dates, names of institutions, and nature of training.

c. Teaching or research experience: Dates, institutions, brief description of experience.

d. Experience in medical practice or other professional experience: Dates, institutional affiliations, nature of practice, or other professional experience. e. Representative list of pertinent medical or other scientific publications: Titles of articles, names of publications and volume, page number, and date.

(If this information has previously been submitted to the sponsor, it may be referred to and any additions made to bring it up to date.)

2. If any hospital, institutional, and clinical laboratory facilities, etc., are available and will be employed in connection with the investigation, an identification of each follows:

(If this information has previously been submitted to the sponsor, reference to the previous submission will be adequate.)

3. The investigational drug will be used by the undersigned or under his supervision in accordance with the plan of investigation described, as follows: (Outline the plan of investigation, including approximation of the number of subjects to be treated with the drug and the number to be employed as controls, if any; clinical uses to be investigated; characteristics of subjects by age, sex, and condition; the kind of clinical observations and laboratory tests to be undertaken prior to, during, and after administration of the drug; the estimated duration of the investigation; and a description or copies of report forms to be used to maintain an adequate record of the observations and test results obtained. This plan may include reasonable alternates and variations, and should be supplemented or amended when any significant change in direction or scope of the investigation is undertaken.)

4. The undersigned understands that the following conditions, generally applicable to new drugs for investigational use, govern his receipt and use of this investigational drug:

a. The sponsor is required to supply the investigator with full information concerning the preclinical investigations that justify clinical trials, together with fully informative material describing any prior investigations and experience and any possible hazards, contraindications, side-effects, and precautions to be taken into account in the course of the investigation.

b. The investigator is required to maintain adequate records of the disposition of all receipts of the drugs, including dates, quantities, and use by subjects, and if the investigation is terminated to return to the sponsor any unused supply of the drug.

c. The investigator is required to prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to the investigation on each individual treated with the drug or employed as a control in the investigation.

d. The investigator is required to furnish his reports to the sponsor of the drug who is responsible for collecting and evaluating the results obtained by various investigators. The sponsor is required to present progress reports to the Food and Drug Administration at appropriate intervals not exceeding 1 year. Any adverse effect that may reasonably be regarded as caused by, or probably caused by, the new drug shall be reported to the sponsor promptly, and if the adverse effect is alarming, it shall be reported immediately. An adequate report of the investigation should be furnished to the sponsor shortly after completion of the investigation.

e. The investigator shall maintain the records of disposition of the drug and the case histories described above for a period of 2 years following the date a new-drug application is approved for the drug; or if the application is not approved, until 2 years after the investigation is discontinued. Upon the request of a scientifically trained and properly authorized employee of the Department, at reasonable times, the investigator will make such records available for inspection and copying. The subjects' names need not be divulged unless the records of particular individuals require a more detailed study of the cases, or unless there is reason to believe that the records do not represent actual cases studied, or do not represent actual results obtained.

f. The investigator certifies that the drug will be administered only to subjects under his personal supervision or under the supervision of the following investigators responsible to him, and that the drug will not be supplied to any other investigator or to any clinic for administration to subjects.

11)

g. The investigator certifies that he will inform any subjects, including subjects used as controls, or their representatives, that drugs are being used for investigational purposes, and will obtain the consent of the subjects, or their representatives, except where this is not feasible or, in the investigator's professional judgment, is contrary to the best interests of the subjects.

Very truly yours,

(Name of investigator)

(Address)

(This form should be supplemented or amended from time to time if new subjects are added or if significant changes are made in the plan of investigation.)

(b) A shipment or other delivery of a new drug that is being imported or is offered for importation into the United States shall be exempt from the requirements of section 505(a) of the act if the following conditions are complied with: (1) The label of such drug bears the statement "Caution: New drug-Limited by Federal (or United States) law to investigational use"; and

(2) The importer of all such shipments or deliveries is an agent of the foreign exporter residing in the United States or the ultimate consignee, which person has prior to such shipments and deliveries completed and submitted signed copies to the Food and Drug Administration of the "Notice of claimed investigational exemption for a new drug"; and acts as the sponsor of the clinical investigation to assure compliance with the conditions prescribed by paragraph (a) of this section; or

(3) The drug is shipped directly to a scientific institution with adequate facilities and qualified personnel to conduct clinical pharmacology and is intended solely for such use in such institutions and a "Notice of claimed investigational exemption for a new drug" covering this activity has been filed.

(c) Whenever a sponsor submits to the Commissioner the name of an investigator known to the Commissioner as having repeatedly or deliberately failed to comply with the conditions of these exempting regulations, the Commissioner will notify the sponsor that the investigator is not entitled to receive investigational-use drugs, and such investigator shall not be supplied any investigational-use drug until adequate assurance is provided to and accepted by the Commissioner that the conditions of the exemption will be met. The Food and Drug Administration will be prepared to confer with the sponsor or the investigator, or both, on this point.

(d) If the Commissioner of Food and Drugs finds that

(1) The submitted "Notice of claimed investigational exemption for a new drug" contains an untrue statement of a material fact or omits material information required by said notice; or

(2) The results of prior investigations made with the drug are inadequate to support a conclusion that it is reasonably safe to initiate or continue the intended clinical investigations with the drug; or

(3) There is substantial evidence to show that the drug is unsafe for the purposes and in the manner for which it is offered for investigational use; or

(4) There is convincing evidence that the drug is ineffective for the purposes for which it is offered for investigational use; or

(5) 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 safety and to give significance to clinical investigations made with the drug; or

(6) The plan for clinical investigations of the drug described under section 10 of the "Notice of claimed investigational exemption for a new drug" is not a reasonable plan in whole or in part, solely for a bona fide scientific investigation to determine whether or not the drug is safe and effective for use; or

(7) The clinical investigations are not being conducted in accordance with the plan submitted in the "Notice of claimed investigational exemption for a new drug"; or

(8) The drug is not intended solely for investigational use, since it is being or is to be sold or otherwise distributed for commercial purposes not justified by the requirements of the investigation; or

(9) The labeling or other informational material submitted for the drug as required by section 7 of the "Notice of claimed investigational exemption for a new drug" or any other labeling of the drug disseminated within the United States by or on behalf of the sponsor fails to contain an accurate description of prior investigations or experience and their results pertinent to the safety and possible usefulness of the drug, including all relevant hazards, contraindications, side-effects, and precautions; or any promotional material disseminated within the United States by or on behalf of the sponsor contains any representation or suggestion that the drug is safe or that its usefulness has been established for the purposes for which it is offered for investigations; or

(10) The sponsor fails to submit accurate reports of the progress of the investigations with significant findings at intervals not exceeding 1 year;

or

(11) 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;

he shall notify the sponsor and invite his immediate correction. A conference will be arranged if requested. If the conditions of exemption are not immediately met, the Commissioner shall notify the sponsor of the termination of the exemption and the sponsor shall recall the unused supplies of the drug.

(e) Where drugs were under clinical trial on man on or after August 10, 1962, the sponsor shall, within 30 days after these regulations become effective, submit a list of such investigational drugs, and within 120 days after such effective date shall submit to the Food and Drug Administration the completed "Notice of claimed investigational exemption for a new drug" or a new-drug application. Failure to do so shall automatically terminate the exemption. If any such clinical trials have been discontinued, the sponsor is requested to submit a statement of why the investigation was discontinued.

(f) (1) A shipment or other delivery of a new drug for laboratory study or animal tests only shall be exempt from section 505 (a) of the act if it is labeled: "Caution: New drug-Limited by Federal (or United States) law to laboratory studies and tests on animals. Not for human use." No animals used in such tests, or their products such as milk or eggs, shall be used for food purposes unless the sponsor or the investigator has submitted to the Commissioner data demonstrating that such use will be consistent with the public health, and the Commissioner, proceeding as he would in a matter involving section 409 (i) of

the act, has notified said sponsor or investigator that the proposed disposition for food purposes is authorized.

(2) The person or firm shipping a new drug for laboratory study or animal tests under this section shall use due diligence to assure that the consignee is regularly engaged in conducting laboratory studies or animal tests and that the shipment of the new drug will actually be used for laboratory studies or animal testing.

(3) The person who introduced such shipment or who delivered the drug for introduction into interstate commerce maintains adequate records showing the name and post office address of the expert to whom the drug is shipped, date, quantity, and batch or code mark of each shipment and delivery for a period of 2 years after such shipment and delivery. Upon the request of a properly authorized employee of the Department at reasonable times he makes such records available for inspection and copying.

(g) When the Commissioner finds that the "Notice of claimed investigational exemption for a new drug" pertains to a product 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.), he will submit a copy of such notice, any amendment or supplement thereto, and any progress report or other communication pertinent to the investigational use of the drug to the Division of Biologics Standards, National Institutes of Health, Public Health Service, for review and the development and execution of a program to closely monitor and evaluate the clinical investigations. Consultation with the Division of Biologics Standards during the course of the investigation will be required so that appropriate data may be developed for licensure.

(h) Any requirements by this section for the submission of information or data that has been submitted previously may be incorporated by reference.

Effective date. This order shall become effective 30 days from the date of its publication in the Federal Register.

(Sees. 505, 701, 52 Stat. 1052 as amended 76 Stat. 784; 1055 as amended 70 Stat. 919, 72 Stat. 948; 21 U.S.C. 355, 371)

Dated: December 31, 1962.

GEO. P. LARRICK, Commissioner of Food and Drugs.

CHAPTER I-FOOD

TITLE 21-FOOD AND DRUGS

AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH,
EDUCATION, AND WELFARE

SUBCHAPTER C-DRUGS

PART 146 GENERAL REGULATIONS FOR THE CERTIFICATION OF ANTIBIOTIC AND ANTIBIOTIC-CONTAINING DRUGS

ANTIBIOTIC DRUGS FOR INVESTIGATIONAL USE

In the Federal Register of August 31, 1962 (27 F.R. 8744), notice was given that the Commissioner of Food and Drugs would consider views and comments submitted following publication of the proposed revision of § 130.3 in the Federal Register of August 10, 1962 (27 F.R. 7990), as applicable to all antibiotic drugs for investigational use.

Having considered the views and comments received, pursuant to the provisions of the Federal Food, Drug, and Cosmetic Act (secs. 507, 701, 52 Stat. 1055 as amended; 59 Stat. 463 as amended; 21 U.S.C. 357, 371), and under the authority delegated to the Commissioner by the Secretary of Health, Education, and Welfare, It is ordered, That § 146.23 of the antibiotic regulations be revised to read:

§ 146.23 Exemptions for investigational use.

A shipment or other delivery of a drug shall be exempt from § 502 (1) of the act if all the procedures outlined in § 130.3 of this chapter are complied with. For the purposes of this section, the references in § 130.3 of this chapter to "new drug" and "approved new-drug application" shall be deemed to read "antibiotic drug" and "approval for certification or exemption from certification," respectively.

37-272-64-pt. 1- -5

Effective date. This order shall become effective 30 days from the date of its publication in the Federal Register.

(Secs. 507, 701, 52 Stat. 1055 as amended; 59 Stat. 463 as amended; 21 U.S.C. 357, 371.)

GEO. P. LARRICK, Commissioner of Food and Drugs.

TITLE 21-FOOD AND DRUGS

CHAPTER I-FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE

SUBCHAPTER C-DRUGS

PART 130-NEW DRUGS

RADIOACTIVE NEW DRUGS FOR INVESTIGATIONAL USE

Following publication of the proposed revisions of the regulations dealing with new drugs for investigational use in the Federal Register of August 10, 1962 (27 F.R. 7990), a number of views and comments received recommended that special consideration be given to radioactive new drugs in this category, because of the dual control exercised.

The Commissioner of Food and Drugs has concluded that additional facts will be needed before any final decision is made on this point. Therefore, It is ordered, That § 130.3, promulgated in this issue of the Federal Register (27 F.R. —) shall not apply to radioactive new drugs until further notice, provided the radioactive new drugs for investigational use are being shipped in complete conformity with the regulations issued by the Atomic Energy Commission. (Secs. 505, 701, 52 Stat. 1052 as amended 76 State. 784; 1055 as amended 70 State. 919, 72 Stat. 984; 21 U.S.C. 355, 371)

Dated: December 31, 1962.

GEO. P. LARRICK, Commissioner of Food and Drugs.

Mr. LARRICK. 3. On February 14, 1963, we announced four groups of new proposed regulations. These were based on the KefauverHarris amendments. They covered:

(a) New labeling and advertising requirements for prescription drugs.

(b) Improved procedures and expanded data requirements for new drug applications. These regulations were blended in with the previously adopted investigational use regulations. They contained the new requirements for establishing effectiveness, for recordkeeping and reporting, and the new grounds for refusing to approve new drug applications and for withdrawing approval when safety or effectiveness could no longer be assured.

(c) Principles to be observed in producing drugs under standards of current good manufacturing practices.

(d) Registration of drug manufacturers.

Again we received comments and objections, but the registration regulations were finalized on April 3, 1963, and the others on June 20, 1963, except for the prescription drug advertising regulations which were the subject of formal objections and a public hearing.

I present, sir, for the record the regulations and the press releases relating to them, to which I have just referred.

Mr. FOUNTAIN. They will be inserted in the record.

(The above-mentioned material follows:)