PUBLIC HEALTH
DRUG
CONTROL
IN THE
UNITED
STATES
George P. Larrick
Food and Drug Administration, U.S. Department of health, Education, and \Velfare
The Food and Drug Administration has received unusual notice in recent months. It is
de-sirable for pediatricians to be properly informed of the nature and functions of this agency and
of its important contributions to physicians and the public health. The following recent address h)y the Commissioner of the Food and Drug Administration, along with the attached Appendix,
provi(les a brief account of the current activities. The FDA has earned our full support and
co-Address delivered at the Pan American Congress of Pharmacy and Biochemistry, Santiago, Chile, November 15, 1960.
ADDRESS: Washington 25, D.C.
PEDIAmIc5, March 1961
CONTRIBUTORS’
SECTION
peratio11 at all times.
I
N THE United States, government controlof drug manufacture is accomplished
largely through application of the Federal
Food, Drug, and Cosmetic Act. This is a
law of broad scope, which deals with such important matters as the purity, potency,
safety, labeling and methods of distribution
of drugs imported into the country or
shipped from one state to another. The
Food and Drug Administration administers
this law. I shall describe the drug control
provisions of the law, discuss briefly the
de-velopment of some of its more important aspects, and mention some current
prob-hems with which we in the Food and Drug Administration are now dealing.
The United States law provides three principal types of control over drugs. These are 1) the certification procedures; 2) the new drug procedures; and 3) the general procedures applicable to drugs that do not fall into the first two groups.
The certification procedures apply to drugs that require the most exacting gov-ernment control. Presently, insulin and five
types of antibiotics are involved. These
products may not be shipped in interstate commerce unless each batch has been tested in our laboratories and a certificate
THE EDITOR
issued for the particular batch. Thus, we
are able to control the purity, potency and
labeling of the certified drug. We require the manufacturer to have adequate produc-tion and control facilities, and we require him to show that the drug will accomplish the therapeutic benefits claimed in its
label-ing before we certify a batch of the drug.
Many other products are classified as
“new drugs,” and are subject to a different
type of regulation. Under the Act, a “new
drug” is defined as one which has been
pro-posed for medical use but which is not yet
generally recognized as safe by medical
ex-perts. The manufacturer of a “new drug”
must file with us, an application containing
all available data concerning the safety of
the drug, copies of its proposed labeling, and full information as to the
manufactur-ing and control procedures that will be
used in preparing the drug.
If our scientists agree that the article is safe for the intended uses, and the pro-posed manufacturing and control
proced-ures appear adequate, the new-drug
appli-cation is allowed to become effective. This
means that the drug may be shipped
com-mercially. I stress that the sponsor of the
his proposed manufacturing and control procedures before making commercial ship-ments of the product.
Both the “new drug” and certification procedures have proved of great value. Over 75% of the drugs prescribed by physi-cians in the United States today were not available 20 years ago. Most of these are subject to one of the controls just described.
Other drugs, generally the older prod-ucts, are only required to meet the general drug provisions of the law. These do not re-quire the pre-marketing, governmental eval-uation of safety and efficacy required of certified drugs, or the pre-marketing check on safety required of new drugs. But the general provisions of the law do require the manufacturer to give label information as
to the composition of the drug and to give
in the labeling adequate directions for use and warnings against misuse of the product. Label claims for therapeutic value must be truthful. The drug must not be dangerous to health when used according to direc-tions. And there are other requirements too numerous to be covered here.
Standards of composition and purity for drugs are established in several ways: 1. The FDA issues regulations that
estab-lish standards for drugs that are certi-fled.
2. Each new drug application contains
standards for the drug it refers to. We
will not allow an application to become
effective if the standards in it are not adequate.
3. Each drug must comply with the
com-position its label declares.
4. Many of the commonly used drugs are described in official compendiums.
The principal compendiums are the
United States Pharmacopeia (U.S.P.), and
The National Formulary (N.F.). The law
requires any drug purporting to be a U.S.P.
or N.F. article to comply with the standards
of strength, quality and purity set forth in
the official compendium. In some cases, var-iations are permitted, but in this event the label must clearly state how the article
dif-fers from the U.S.P. or N.F. requirements. The great value of the
United
StatesPharmacopeia, and
The
National
Formu-lary
arises from their providing official tests, specifications and standards for a number of important drugs not subject to the more direct control of the certification, or “new drug” provisions.Neither of these compendiums is promul-gated or printed by the United States Gov-ernment. Each is prepared by an
independ-ent group.
The U.S.P. is the product of a United States Pharmacopeial Convention. The Convention is composed of representatives from medical and pharmacy schools, or-ganized medical groups such as the Amen-can Medical Association, organized
phar-macy groups such as the American
Pharma-ceutical Association, and representatives from government organizations concerned with drugs. The Pharmacopeial Convention selects a Committee of Revision, and this Committee prepares and issues the U.S.P.
The
Nati#{252}nalForinulary
is prepared by the Committee on National Formulary tin-den the supervision of the Council of the American Pharmaceutical Association. Its promulgation proceeds along very much the same lines as those of the United StatesPharniacopeia.
There are a number of unofficial volumes listing drug standards and test methods for
drugs which have achieved wide recogni-tion and high status. Among these are the following publications:
1. New and NonofJicial Drugs (formerly
designated as New and Nonofficial
Rem-edies) published annually by the Council on Drugs of the American Medical As-sociation.
2. Official Methods of Analysis of the
Asso-ciation
of Official
Agricultural
Chemists.
This is published by the Association of Official Agricultural Chemists, which is comprised of chemists and other scien-tists holding official state or federal posi-tions.as the journals of the American
Pharma-ceutical Association and the Association of Official Agricultural Chemists.
The regulated drug industries in the United States have themselves contributed much to the development of reliable meth-ods for testing drugs. For more than 35
years, the trade associations representing
the majority of the drug manufacturers have sponsored a committee of their
scien-lists to help us determine what drug
stand-ards could be met in good commercial prac-tice. This group, cabled the Contact Com-mittee, is an example of fine industny-gov-ernment co-operation, which has worked
very successfully in our country.
The Food and Drug Administration has modern laboratories in Washington and 18 other principal cities in the United States. In these laboratories, pharmaceutical
chem-ists, biochemists, pharmacobogists,
bacteni-obogists, microanalysts, antibiotic specialists and other scientific personnel, test drugs for compliance with applicable standards. In addition, a staff of physicians and veteninar-ians gives advice regarding drug matters.
Our inspectors determine the quality of drug production by going into plants to examine manufacturing processes. Such visits are designed to help the firms by hay-ing the inspector provide comments and suggestions as to improvements in manu-facturing and control procedures, and at the same time to obtain information for use
by us for regulatory purposes.
Statistical data accumulated in the course
of our enforcement activities show that the
quality of the drugs on the United States market is generally high and that the drug supply of the country, with relatively few exceptions, is safe and effective. However, careful consideration of these data indicate that the drug manufacturing industry has expanded so greatly in recent decades that the facilities of the Food and Drug
Admin-istration have not kept pace. Thus our
coy-erage of the drug manufacturing industry through inspection and analyses of samples is not wholly adequate. Fortunately, the Congress is increasing our annual
appropni-ations so that we may be reasonably confi-dent that we shall be provided with the
necessary manpower and equipment re-quired to do a thorough job of checking drug supplies.
Further, we are now convinced that the current situation calls for extending the cer-tification provisions to cover all antibiotics. Only five types of antibiotics are now sub-ject to the rather complete controls pro-vided by the certification provisions of the Act. It is our anticipation that there will be considerable support for the proposal to ex-tend the certification requirements.
From a careful analysis of the current situation, we have concluded that our pres-ent jurisdiction over conditions at the man-ufacturing plant is in need of improvement, particularly with respect to products that
are not subject to the certification or new
drug requirements. We have recommended amending the law to give us a more positive degree of control which would enable us to prevent distribution of drugs by a manu-factuner lacking adequate manufacturing facilities, or adequate control procedures.
This proposal has already acquired
sub-stantial support and will undoubtedly be
given serious consideration by the
Con-gress.
In recent years, there has been consider-able criticism from independent medical authorities concerning the nature of the promotional material issued to physicians
by some drug manufacturing firms. These
critics believe that the manufacturers, at least in some cases, present the busy prac-titioner with a misleading impression of the usefulness of their drugs; the brochures and other promotional material describe the benefits of the drugs but fail to give proper emphasis to their shortcomings.
We have concluded that there may be
justification for this criticism. Therefore, we
are currently proposing regulations which
would have the effect of requiring drug firms to provide physicians with a com-pletely forthright presentation of the drug. This would require disclosure of its
483
informed and thus exercise proper judg-ment in prescribing the drug (see Appen-dix).
Another important regulatory problem
arises from illegal distribution of drugs that
should be dispensed only on prescription. Under the law, drugs are divided broadly into two categories-those that are safe enough to be sold directly to the public for self-administration and those that must be restricted for use by the physician or for
dispensing on the prescription of the
physi-cian. In this second category, of course, fall
many potent and important products that
may be quite harmful if made available to the laity for self-use. For example, the am-phetamines and barbiturates have proved troublesome in the United States. They are
legally in the prescription-drug class.
How-ever, an extensive traffic has developed in their illegal sale without prescription to truck drivers, juveniles, criminals and
oth-ers. Abuse of amphetamines and
barbitu-rates by certain elements of the public is one of our serious problems.
We have done what we can to curb this illegal distribution of prescription drugs,
l)Ut it appears that we need greater
author-ity to do a better job. Some members of
Congress have proposed legislation to
strengthen our control in this area; the
pro-posals generally would require accurate
record keeping of the manufacture and dis-tribution of amphetamines and barbiturate drugs and would make possession of the
drugs by the general public, except when
dispensed on a bona fide prescription, a vio-lation of the Act. We have endorsed the principle involved in these bills.
In order to provide a comprehensive
pie-ture of the way drug control is exercised in
the United States, I point out that control over the manufacture and distribution of
vaccines and similar preparations, the
so-called “biological drugs,” is vested in the Public Health Service when the articles are intended for human use, and in the Depart-ment of Agriculture when the articles are intended for veterinary use. And junisdic-tion over drug advertising disseminated via
newspapers, magazines, radio and televi-sion is exercised by the Federal Trade Commission. As a last point, the Food and
Drug Administration has no jurisdiction
over shipments of a drug sent only to places located within the state in which the drug was manufactured. In most states, however, such local traffic in drugs is subject to laws adopted by the individual states, which are generally patterned after the federal law.
Appendix
The Food and Drug Administration, on Decem-ber 9, 1960, announced new regulations requiring changes in labeling used to promote the sale of prescription drugs to physicians.
The purpose of the new regulations is to insure
that such labeling discloses both the hazards and the advantages of the drugs. The new regulations are based on proposals published in the Federal
Register of July 22, 1960.
Commissioner of Food and Drugs, George P.
Larnick, pointed out that comments received on the
regulations as first proposed have resulted in some modifications, and that action on those parts of the original proposal relating to package inserts for prescription drugs has been deferred until after December 22, 1960, at the request of the Amen-can Medical Association, to permit further study of the proposal by the Association.
Major labeling changes are required by the new
regulations:
1. Labels of drugs for injection must declare the quantity or proportion of all inactive
ingnedi-ents. Previous regulations have required inactive ingredients to be named on such drugs, but re-quired quantitative declaration of only the active ingredients.
2. Labels of prescription drugs will have to bear identifying lot or control numbers from which it is possible to determine their manufacturing history.
3. Any labeling of prescription drugs or devices, including promotional literature mailed or given to physicians by company representatives, which fur-nish information about uses or dosage must contain complete information for professional use, includ-ing information about any relevant hazards and
conditions in which the drug should not be used. However, this will not apply to so-called “re-minder piece” literature that merely mentions the
name of the drug but does not give indications or dosage recommendations.
4. If the drug is new, information about uses,
Advertising or verbal detailing for a new drug may offer it only for use under the conditions spec-ified in the labeling contained in the application
to market the drug.
Labeling or advertising that goes beyond the claims approved in the original labeling must be resubmitted for approval in advance of use.
5. Labeling hearing information about uses and dosage must show the date of issuance or latest revision.
Changes in the regulations to assure the safety of new drugs would further provide that:
a) Permission to market a new drug may be denied if the manufacturer refuses to allow in-spection of his manufacturing methods, facilities, controls or any records pertaining to them.
b) The marketing of a new drug may be delayed by making an application conditionally effective until the adequacy of manufacturing methods,
fa-cihities and controls has been verified by inspection. However, the regulations allow such a delay only when it is not possible to complete an inspection within the time limit set by the law for processing an application.
The regulations as issued differ from the
pro-posals of July 22 ill the following respects, among others:
1. Labels for ophthalmic preparations need de-dare only the names of inactive ingredients and not the (luantities of such ingredients as originally proposed. The FDA said that it did not have cvi-dence to show that failure to declare the quantity would represent a hazard. Naming the inactive ingredients should enable the doctor to avoid a drug to which the patient is known to be sensitive. This was the original purpose of the proposal.
2. All prescription drugs are required to bear on their labels the quantity or proportion of the active ingredients. The original proposal was to call for such a label declaration only if the prescription drug was not one which was designated on its label solely by a name in the United States Pharma-copoeia or the National Formulary.
TItose parts of the regulations requiring full in-formation for use, including disclosure of hazards of the drug, in promotional labeling mailed and detailed to physicians, become effective on March 9. 1961.
