A Legislative History of the Federal Food, Drug, and Cosmetic Act and Its ...

drug section of the law for the purposes of requiring manufacturers to furnish adequate information for the professional use of prescription drugs and devices and to keep new drugs off the market until the adequacy of manufacturing methods, facilities, and controls have been confirmed by establishment inspection, when required.

Portions of the order were to become effective on January 8, 1961, and other portions were scheduled to become effective on March 9, 1961.

Representatives of the industries involved have demonstrated to the Commis sioner that it is impracticable to effect full compliance with those portions of the order scheduled to become effective on January 8, 1961. Additionally, the Commissioner concludes that certain portions of the published regulations require clarifying revisions. Therefore, It is ordered:

1. That the requirements of § 1.106 (b) (2) (ii), (iii), (iv), and (v) and 1.108 (c) (ii), (iii), (iv), and (v) shall not, until January 1, 1962, be applicable to drugs bearing labels printed prior to January 8, 1961, if the information required by these sections is contained in the labeling within the package from which the drugs are to be dispensed.

2. That the requirements of § 1.106(b) (2) (vi) and 1.106 (c) (2) (vi) shall not be applicable, until June 6, 1961, to any carton of a drug packaged prior to January 8, 1961, if the identifying lot or control number appears on the label of the drug contained in that carton.

3. That the provisions of §1.106(b) (4), (c) (4), and (d) (4) shall not apply to catalogs and price lists distributed to pharmacists and wholesale druggists (but not to physicians or other practitioners), until January 1, 1962.

4. Section 1.106 Drugs and devices; directions for use is amended in the following respects:

a. Paragraph (b) (2) (v) is amended to read as follows:

(b) *** (2)

(v) If it is for other than oral use, the names of all inactive ingredients, except that:

(a) Flavorings and perfumes may be designated as such without naming their components.

(b) Color additives may be designated as coloring without naming specific color components unless the naming of such components is required by a color additive regulation prescribed in Part 8 of this chapter.

(vi) If it is intended for administration by parenteral injection, the quantity or proportion of all inactive ingredients except that ingredients added to adjust the pH or to make the drug isotonic may be declared by name and a statement of their effect; and if the vehicle is water for injection it need not be named. b. Paragraph (c) (2) (v) is amended to read as follows:

(v) If it is for other than oral use, the names of all inactive ingredients, except that:

(a) Flavorings and perfumes may be designated as such without naming their components.

(vi) If it is intended for administration by parenteral injection, the quantity or proportion of all inactive ingredients, except that ingredients added to adjust the pH or to make the rug isotonic may be declared by name and a statement of their effect; and if the vehicle is water for injection, it need not be named.

c. Paragraphs (b)(4) and (c) (4) are amended by inserting in the first sentence, just before the last word "contain", the parenthetical phrase "(other than dose information required by § 1.106 (b) (2) (ii) and 1.106 (c) (2) (i))",

5. That effective date for the amendments published December 9, 150, scheduled to become effective on January 8, 1961, is hereby changed to February 7, 1961.

Notice and public procedure are not necessary prerequisites to the promulgation of this order since the changes in effective dates and other amendments relax existing requirements.

Effective date. This order shall be effective on the date of signature.
Dated: January 9, 1961.

JOHN L. HARVEY,

Deputy Commissioner of Food and Drug2.

Mr. LARRICK. 2. In August 1962, 2 months before the new law was passed, we announced proposed revisions of our investigational use regulations. These proposals gave rise to many comments and objections from the regulated industry, the medical profession, and the interested public. They were finalized on January 8, 1963, and were fully effective as to all investigations in progress by June 7, 1968. Briefly, these regulations were drawn to require the sponsor of an investigational drug distribution to prepare and present to us an acceptable plan to show that a rational program was to be carried out and that the program would be reasonably safe. Regular reports were required, and we retained the right to terminate the investigation when it could no longer be safely continued.

This is that regulation for the record, if you please.

Mr. FOUNTAIN. If there is no objection, that will be inserted in the record.

(The proposed and final regulations and explanatory press releases follow:)

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFAR

For Immediate Release

Thursday, August 9, 1962

OFFICE OF THE SECRETARY
Washington 25, D.C.

Secretary of Health, Education, and Welfare Anthony J. Celebrezze today announced the issuance of proposed regulations strengthening control over testing of new drugs in clinical trials.

Interested persons have 60 days in which to comment on the proposed regulations. Final regulations will not be issued until these comments have been considered.

The new regulations would require:

-That the Food and Drug Administration be put on notice and given the full details about the distribution of drugs for investigational use.

-That clinical investigations be based on adequate preclinical studies to assure safety.

-That the clinical investigations themselves be properly planned, executed by qualified investigators, and that the Food and Drug Administration be kept fully informed during the progress of the investigations.

Present regulations require that drugs used in clinical trials be labeled for "investigational use" only and that manufacturers keep records of distribution. The regulations also require that investigators have adequate facilities and that names of investigators be made available to FDA on request.

Present regulations, however, do not require either an initial notice to FDA of a clinical trial of a new drug or subsequent reports on such use.

Once a clinical investigation had been undertaken, if a substantial doubt developed as to the safety of the drug, the Food and Drug Administration and all investigators using the drug would be notified immediately. If necessary, the trial would be halted by FDA.

Similarly, if a plan proved to be inadequate to assure safety or if the plan as presented was not being followed, FDA could require corrective action and, if necessary, could terminate the study.

Secretary Celebrezze said that the new regulations were drawn with the purpose clearly in mind of imposing no unneeded restrictions on the conduct of investigational research, while providing assurance that the public will be fully protected against risks that may attend the development of new drugs.

In notifying the FDA of his intention to begin a clinical investigation with new drug, the manufacturer or other sponsor would be required to provide the following:

-A summary of all the preclinical investigations, including animal studies which had been undertaken, to show that it is reasonably safe to test the drug on human patients. Where the clinical investigation involves use on infants or pregnant women, special assurances of safety for such use would be required. -Copies of the complete information about the preclinical investigation and experience with the drug that will be, supplied to each investigator, including all that is known about the relevant side effects and precautions suggested by the preclinical data.

-The names and a summary of the training and experience of each person who will participate in the investigation and an outline of what is planned in the clinical trials, how long they will take, how many patients will be involved, and when progress reports will be made.

Once an investigation was undertaken, the sponsors would be required to maintain complete records covering the distribution of the investigational drug and to closely monitor the progress of the investigation.

Each investigator in the clinical trial would be required to supply the sponsor with a full statement of his education and experience, a description of the hospital, institutional, and laboratory facilities available to him, and an outline of the plan that he intends to follow. He must fully inform himself about all the preclinical investigations before giving the drug to any patient, maintain complete records of his disposition of the drug and case histories of the patients to whom it is administered, and furnish adequate reports to the sponsor promptly after the completion of the clinical trials. These records must be open to inspection by the Food and Drug Administration on request.

The regulations would not require advance Government approval of the preclinical investigation, the qualifications of the investigators, or the plan of the clinical investigation. The Commissioner of Food and Drug would be authorized, however, to terminate any investigational use if the new requirements were not being met.

As to the investigations of new drugs already underway, the proposed regulations would require prompt reporting to the FDA of information showing that the investigation may be safely continued. Failure to submit such a report would automatically terminate the authority under which clinical investigations are now conducted.

Where the investigational use would be limited to laboratory research and animal experimentation, all that would be required is that the drug bear on its label, "Caution: New Drug-Limited by Federal law to laboratory research and tests on animals. Not for human use."

The proposed regulations were published with an invitation for all interested persons to comment within 60 days. Secretary Celebrezze said he hopes that the medical profession, the drug industry, scientific societies, members of the public, and all others interested in this important problem will offer constructive comments for any needed improvement in the proposed regulations.

[Published in the Federal Register of Aug. 10, 1962] DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE FOOD AND DRUG ADMINISTRATION

[21 CFR PART 130]

NEW DRUGS FOR INVESTIGATIONAL USE

NOTICE OF PROPOSAL TO AMEND REGULATIONS

The Commissioner of Food and Drugs, pursuant to the provisions of the Federal Food, Drug, and Cosmetic Act (secs. 505, 701, 52 Stat. 1052, 1055; 21 U.8.C. 355, 371) and under the authority delegated to him by the Secretary of Health, Education, and Welfare (25 F.R. 8625), proposes to amend the new drug regulations (21 CFR 130.3) as hereinafter set forth. The Commissioner hereby offers an opportunity to all interested persons to submit their views in writing with reference to this proposal to the Hearing Clerk, Department of Health, Education, and Welfare, Room 5440, 330 Independence Avenue SW., Washington 25, D.C., within 60 days from the date of publication of this notice in the Federal Register. Views and comments should be submitted in quintuplicate.

DRUG SAFETY

It is proposed to amend § 130.3 to read as follows:

§130.3 New drugs for investigational use; exemptions from section 505(a). (a) A shipment or other delivery of a new drug shall be exempt from section 505 (a) of the act if all the following conditions are met:

(1) The label of such drug bears the statement "Caution: New drug-Limited by Federal (or United States) law to investigational use."

(2) The person seeking the exemption has filed with the Food and Drug Administration a completed and sigued “Notice of Claimed Investigational Exemp tion for a New Drug" in triplicate, with the following information:

[Form FD 1571]

Department of Health, Education, and Welfare, Food and Drug Administration NOTICE OF CLAIMED INVESTIGATIONAL EXEMPTION FOR A NEW DRUG

Name of investigational drug

TO THE SECRETARY OF HEALTH, EDUCATION, AND WELFARE,

For the Commissioner of Food and Drugs, Washington 25, D.O.
DEAR SIR: The undersigned

submits this notice

of claimed investigational exemption for a new drug under the provisions of section 505 (i) of the Federal Food, Drug, and Cosmetic Act and § 130.3. Attached hereto are:

1. Name of drug and description of dosage form.

2. Complete list of components of drug.

3. Complete statement of quantitative composition of drug.

4. Description of source and preparation of any new-drug substances used as components, including the name and address of each supplier or processor, other than the undersigned, of each new-drug substance.

5. A brief statement of the methods, facilities, and controls used for the manufacturing, processing, and packing of the new drug to establish and maintain appropriate standards of identity, strength, quality, and purity as needed to give significance to clinical investigations made with the drug. If any of these operations are performed by a person other than the undersigned, each such person is identified and his signed statement covering the part of the operations be performed is attached.

6. Adequate information about the preclinical investigations, including studies made on laboratory animals, which show that it is reasonably safe to initiate clinical investigations with the drug. Such information should include identification of the person who conducted each investigation; identification and qualification of the individuals who evaluated the results and concluded that it is reasonably safe to initiate clinical investigations with the drug; and an explanation of where the investigations were conducted and where the records are available for inspection. The preclinical investigations shall not be considered adequate to justify clinical testing unless they give proper attention to the conditions of proposed clinical testing such as, for example, whether the drug is for short or long-term administration or whether it is to be tested or used in infants, children, pregnant women, premenopausal women, or geriatric patients. 7. Five copies of all informational material to be supplied to each investigator. This shall include an accurate description of the prior investigations and experience and their results pertinent to the safety and possible usefulness of the drug under the conditions of the investigation. It shall not represent that the safety or usefulness of the drug has been established for the purposes to be inrestigated. It shall describe all relevant hazards, contraindications, side-effects, and precautions suggested by prior investigations and experience with the drug for the information of clinical investigators.

8. The scientific training and experience considered appropriate by the sponsor to qualify the investigators as suitable experts to investigate the safety of the drug, bearing in mind the pharmacological action of the drug and the conditions of use contemplated by the plan of clinical investigation.

9. The names and a summary of the training and experience of each investigator and of the individual charged with monitoring the progress of the investigation and evaluating the evidence of safety of the drug as it is received from the 37-272-64—pt. 1

investigators; together with a statement that the sponsor has obtained from each investigator a completed and signed form, as provided in subparagraph (12) of this paragraph and that the investigator is qualified by scientific training and experience as an appropriate expert to investigate the safety of the investigational drug under the criteria outlined in section 8 of the "Notice of Claimed Investigational Exemption for a New Drug."

10: An outline of the planned clinical investigations of the drug including the following:

a. Planned stages of investigation, if any, that will be completed and evaluated. prior to determining whether the next stage or stages will be initiated.

b. The names of the investigators to be engaged in each stage and kind of investigation.

c. The specific nature of the investigations to be conducted in each stage, together with the specific information or forms showing the scope and detail of the clinical observations and clinical laboratory tests to be made and reported. d. The approximate number and any specific criteria as to the selection of patients by age, sex, and condition, to be employed in each stage of the investigation.

e. The estimated duration of the clinical investigation by stage, and the intervals, not exceeding 1 year, at which progress reports showing the results of the investigations will be submitted to the Food and Drug Administration. (This part of the statement may be limited to the plan for one or more stages of the investigations, provided that shipments or deliveries of the drug for use in additional stages of the investigations are not made until a supplemental statement recording results of the prior investigations and outlining the plan for following stages of investigations has been submitted to the Food and Drug Adminis tration.)

Ordinarily a plan of investigation will not be regarded as reasonable unless, among other things, it provides for more than one independent competent investigator to maintain complete case histories of an adequate number of patients, designed to record observations and permit evaluation of any and all discernible effects of the drug on each individual treated, and comparable records on any individuals employed as controls. These records shall be individual patient records maintained to include full information pertaining to each individual, including age, sex, conditions treated, dosage, frequency of administration of the drug, results of all clinical observations and laboratory examinations made, full information concerning any other treatment given and a full statement of any adverse effects and useful results observed, together with an opinion as to whether such effects or results are attributable to the drug under investigation.

11. A statement as to whether or not the drug will be sold; and if so, a full explanation why sale is required and should not be regarded as the commercialization of a new drug for which an application is not effective.

Very truly yours,

Per

(Sponsor)

(Indicate authority)

(3) Each shipment or delivery is made in accordance with the commitments in the "Notice of Claimed Investigational Exemption for a New Drug."

(4) The sponsor maintains complete records showing the investigator to whom shipped, date, quantity, and batch or code mark of each such shipment and delivery, until 2 years after a new-drug application becomes effective for the drug; or, if an application does not become effective, until 2 years after shipment and delivery of the drug for investigational use is discontinued and the Food and Drug Administration has been so notified. Upon the request of any officer or employee of the Department at reasonable times, the sponsor makes the records referred to in this subparagraph and in subparagraph (2) of this paragraph available for inspection, and upon written request submits such records or copies of them to the Food and Drug Administration.

(5) The sponsor closely monitors the progress of the investigations and currently evaluates the evidence relating to the safety of the drug as it is obtained from the investigators. Accurate progress reports of the investigations and

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