Drug Safety

The first pure food and drug law-Dr. Wiley's law-was passed in 1906. It provided very limited Federal controls of interstate traffic in drugs. Its prohibitions were few; its exemptions were many. Judged by today's standards, it was a totally inadequate statute. Yet, judged by the standards of 1906, it was a landmark law of first importance.

Very slowly over the following years, some improvements were made in the 1906 statute and also very slowly there were some notable advances in drug therapy. An outstanding improvement in the law was the addition of a provision that made it possible for the Government to take action against false therapeutic claims for drugs, provided it could prove that they were made deliberately; that is, that the claims were fraudulent. This still had serious drawbacks; the more ignorant the promoter of a drug, the harder it was for Government to prove he knew the claim was false.

Some of these early drugs were found to have adverse effects, sometimes after years of use in which the adverse effects were unrecognized, or unrelated to drug use. For example, an antisyphilis preparation containing arsenic, widely used in World War I, was recognized almost from the outset as an extremely toxic drug that would kill a certain percentage of people on whom it was used. But the advantages to be derived from curing syphilis so far outweighed the lethal character of the drug that medicine was justified in using it until a safer product was discovered.

At one time, chloroform was widely used as an anesthetic during childbirth. It has been discarded by the medical profession because of its ability to cause liver damage and kill a significant number of the women.

A chemical called dinitrophenol, was used as a reducing agent. It increases the metabolism of the body and literally causes patients to burn up excess fat. It was prescribed rather extensively in some areas before doctors realized that it had two major disadvantages. Sometimes it stepped up the metabolic rate so much that it killed the patient and ofttimes its use resulted in cataracts and blindness. We forced this drug off the market when the 1938 amendments to the law gave us greater power over drugs.

During the first four decades of this century, there was no established mechanism for determining in advance of marketing whether the anticipated harm from a drug outweighed the anticipated good. New chemicals were marketed entirely at the will of the manufacturer, and their bad effects might not be discovered until years later. In many instances, the ill effects could have been shown by relatively simple tests on laboratory animals before they were ever administered to man.

"Elixir of sulfanilamide" was such a drug. In 1937, a manufacturer used an untested solvent for sulfanilamide in order to produce a more attractive dosage form. The solvent, diethylene glycol, turned out to be a deadly poison. The new product killed over a hundred people, many of them children, before we could get it off the market. And, we had to act on technical charges drawn under the 1906 act-alleging that the word "elixir" implied that the drug was an alcoholic solution whereas it actually was a diethylene glycol solution. We could not charge directly that it was dangerous, or that it had been illegally shipped without proper prior testing, because neither of these were Federal offenses.

As a result, Congress added a new drug section to the pure food and drug law when it modernized the statute in 1938. Under this section a manufacturer had to test any new drug for safety, report the results to the Government, and if the Government took no action to prevent marketing within 60 or 180 days, the drug could be marketed. Congress also added a factory inspection section to the law.

The new drug and factory inspection provisions of the 1938 law contributed to far-reaching, even revolutionary, changes in drug research and production whose beneficial effects are still with us.

In the first place, the new drug safety provisions required those manufacturers who wished to develop new drugs to strengthen their staffs by adding more scientists capable of making reliable studies of drug safety.

This increased emphasis on modern scientific methods equipped the firms to make the most of the outpouring of new discoveries accompanying and following World War II. Thus, in our opinion, the 1938 law played a major role in helping the U.S. pharmaceutical industry reach its present position of world leadership.

In the second place, the factory inspection provisions enabled the Food and Drug Administration to assist and in some cases to require the industry to develop and adopt improved methods of manufacturing and laboratory control.

In 1940 a manufacturer inadvertently got some phenobarbital in sulfathiazole tablets. The tablets were distributed on a worldwide basis. This and certain other mixups showed that new techniques were needed to insure the safety of drugs in an era of mass production. Government and industry worked together to improve the situation. Our inspectors developed better methods of making control drug inspections. The responsible drug manufacturers enlarged their control laboratories, tightened their supervision of incoming raw materials, manufacturing processes, finished materials and labeling operations. Thus the reliability of our drug supply and public confidence in it were enhanced.

Nonetheless, experience from 1938 to 1962 showed the 1938 law to be defective in several important respects:

The producer of a new drug did not have to establish that his drug would be effective, as well as safe, for its intended uses. We were forced to work against deadlines of 60 and 180 days to prevent the automatic approval of the new drug.

There was no provision requiring regular recordkeeping and reporting of clinical and other experience, good or bad, with the new drugs.

We could not remove a new drug from the market unless we could prove that it was unsafe; it was not enough to show that new developments had drawn the question of its safety sharply into issue.

There were inadequate controls over the distribution and use of investigational drugs, as the thalidomide episode clearly

showed.

Prescription drug advertising, at an estimated expenditure of a quarter of a billion dollars per year-$1,000 for each physician in the United States-was virtually unregulated.

Trade names were being used without proper relationship to generic names, with resulting confusion to the profession."

The quality of "old drugs" was not assured, as it was with the "new drugs.

Only five of the classes of antibiotic drugs-used to treat life threatening infections-were subject to routine batch testing and certification by our laboratories.

And factory inspection authority was so limited as to seriously handicap our operations.

It was against this background that the Kefauver-Harris Drug Amendments of 1962 were enacted. This important public law plugged most of the known loopholes. But it was not self-executing. It required a series of administrative actions to make it a working instrument of public protection.

Mr. FOUNTAIN. At this point I note in your prepared statement, you have the language "plugged all of the loopholes."

Have you since decided you didn't plug them all?

Mr. LARRICK. We decided when we reviewed the testimony we were too inclusive. Both before and after the passage of the KefauverHarris drug amendments, we took the following significant steps:

1. As far back as 1961 we revised our labeling regulations for prescription drugs to require full disclosure of all the good and the bad about prescription drugs in all promotional pieces, except reminder pieces.

Here I would like to submit for your consideration the regulation to which I just referred.

Mr. FOUNTAIN. If there is no objection, it will be made a part of the record.

(The regulations follow :)

[Published in the Federal Register Dec. 9, 1960]

TITLE 21-FOOD AND DRUGS

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

SUBCHAPTER A-GENERAL

PART 1-REGULATIONS FOR THE ENFORCEMENT OF THE FEDERAL FOOD, DRUG, and COSMETIC ACT

SUBCHAPTER C-DRUGS

PART 130-NEW DRUGS

CHANGES IN DRUG-LABELING REQUIREMENT; CHANGES IN NEW-DRUG APPLICATIONS On July 22, 1960, the Commissioner of Food and Drugs, pursuant to section 701(a) of the Federal Food, Drug, and Cosmetic Act and under the authority delegated to him by the Secretary of Health, Education, and Welfare (25 F.R. 5611) published in the FEDERAL REGISTER (25 F.R. 6985) notice of a proposal to amend the regulations for the enforcement of the drug and device sections and the new-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.

In response to the Commissioner's invitation, numerous comments were received, and as a result of specific requests the time for the filing of comments on the proposed amendment of § 1.106 (b) (3), (c) (3), and (d) (3) was extended to December 22, 1960 (25 F.R. 9649). The data, comments and suggestions relative

to the remaining proposals have been evaluated, and as a result of this study, It is ordered, That the regulations be amended as set forth below:

1. Section 1.106 is amended in the following respects:

a. Paragraph (b) is amended by changing subparagraphs (1) and (2) to read as set forth below and by adding thereto new subparagraphs (4) and (5): § 1.106 Drugs and devices; directions for use.

(b) Exemption for prescription drugs. A drug subject to the requirements of section 503(b)(1) of the act shall be exempt from section 502(f) (1) if all the following conditions are met:

(1) The drug is :

(i) (a) In the possession of a person (or his agents or employees) regularly and lawfully engaged in the manufacture, transportation, storage, or wholesale distribution of prescription drugs; or

(b) In the possession of a retail, hospital, or clinic pharmacy, or a public health agency, regularly and lawfully engaged in dispensing prescription drugs;

(ii) It is to be dispensed in accordance with section 503(b).

(2) The label of the drug bears:

(i) The statement "Caution: Federal law prohibits dispensing without prescription"; and

(ii) The recommended or usual dosage; and

(iii) The route of administration, if it is not for oral use; and

(iv) The quantity or proportion of each active ingredient, as well as the information required by section 502 (d) and (e); and

(v) If it is for other than oral use, the names of all inactive ingredients; and if it is intended for administration by parenteral injection, the quantity or proportion of all inactive ingredients; and

(vi) An identifying lot or control number from which it is possible to determine the complete manufacturing history of the package of the drug; Provided, however, That in the case of containers too small or otherwise unable to accommodate a label with sufficient space to bear all such information, but which are packaged within an outer container from which they are removed for dispensing or use, the information required by subdivisions (ii), (iii), and (v) of this subparagraph may be contained in other labeling on or within the package from which it is to be dispensed, and the information referred to in subdivision (i) of this subparagraph may be placed on such outer container only, and the information required by subdivision (vi) of this subparagraph may be on the crimp of the dispensing tube.

(4) Any labeling, as defined in section 201 (m) of the act, whether or not it is on or within a package from which the drug is to be dispensed, distributed by or on behalf of the manufacturer, packer, or distributor of the drug, that furnishes or purports to furnish information for use or which prescribes, recommends, or suggests a dosage for the use of the drug contains:

(i) Adequate information for such use, including indications, effects, dosages, routes, methods, and frequency and duration of administration and any relevant hazards, contraindications, side effects, and precautions, under which practitioners licensed by law to administer the drug can use the drug safely and for the purposes for which it is intended, including all conditions for which it is advertised or represented; and if the article is subject to section 505, 506, or 507 of the act, the labeling providing such information is substantially the same as the labeling authorized by the effective new-drug application or required as a condition for its certification or exemption from certification; and

(ii) The same information concerning the ingredients of the drug as appears on the label and labeling on or within the package from which the drug is to be dispensed;

Provided, however, That the information required by subdivisions (i) and (ii) of this subparagraph is not required on the so-called reminder-piece labeling which calls attention to the name of the drug but does not include indications or dosage recommendations for use of the drug.

(5) All labeling, except labels and cartons, bearing information for use of the drug also bears the date of the issuance or the date of the latest revision of such labeling.

b. Paragraph (c) is amended by changing the introduction to the paragraph and subparagraphs (1) and (2) to read as set forth below and by adding thereto new subparagraphs (4), (5), and (6):

(c) Exemption for veterinary drugs. A drug intended for veterinary use which, because of toxicity or other potentiality for harmful effect, or the method of its use, is not safe for animal use except under the supervision of a licensed veterinarian, and hence for which "adequate directions for use" cannot be prepared, shall be exempt from section 502(f)(1) of the act if all the following conditions are met:

(1) The drug is :

(i) In the possession of a person (or his agents or employees) regularly and lawfully engaged in the manufacture, transportation, storage, or wholesale or retail distribution of veterinary drugs and is to be sold only to or on the prescription or other order of a licensed veterinarian for use in the course of his professional practice; or

(ii) In the possession of a licensed veterinarian for use in the course of his professional practice.

(2) The label of the drug bears:

(i) The statement "Caution: Federal law restricts this drug to sale by or on the order of a licensed veterinarian"; and

(ii) The recommended or usual dosage; and

(iii) The route of administration, if it is not for oral use; and

(iv) The quantity or proportion of each active ingredient as well as the information required by section 502 (e) of the act; and

(vi) An identifying lot or control number from which it is possible to determine the complete manufacturing history of the package of the drug;

Provided, however, That in the case of containers too small or otherwise unable to accommodate a label with sufficient space to bear all such information, but which are packaged within an outer container from which they are removed for dispensing or use, the information required by subdivisions (ii), (iii), and (v) of this subparagraph may be contained in other labeling on or within the package from which it is to be so dispensed, and the information referred to in subdivision (i) of this subparagraph may be placed on such outer container only, and the information required by subdivision (vi) of this subparagraph may be on the crimp of the dispensing tube.

(i) Adequate information for such use, including indications, effects, dosages, routes, methods, and frequency and duration of administration, and any relevant hazards, contraindications, side effects, and precautions, and including information relevant to compliance with the food additive provisions of the act, under which veterinarians licensed by law to administer the drug can use the drug safely and for the purposes for which it is intended, including all conditions for which it is advertised or represented; and if the article is subject to sections 505 and 507 of the act, the labeling providing such information is substantially the same as the labeling authorized by the effective new-drug application or required as a condition for its certification or exemption from certification; and

(ii) The same information concerning the ingredients of the drug as appears on the label and labeling on or within the package from which the drug is to be dispensed;

(5) All labeling, except labels and cartons, bearing information for use of the drug also bears the date of the issuance or the date of the latest revision of such labeling.

(6) A prescription drug intended for both human and veterinary use shall comply with paragraph (b) of this section and subparagraphs (4) and (5) of this paragraph.

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Drug Safety, Parts 1-2