tributed batches to meet specifications established in the new-drug application or in the antibiotic regulations, this information shall be submitted as soon as the review reveals such facts. Any unresolved experience of the kinds listed in this paragraph shall be reported even though it occurred prior to the 2-year period.

(c) Such reports shall be addressed to the Secretary, Department of Health, Education, and Welfare, for the Commissioner of Food and Drugs, Washington, D.C., 20204, and shall be distinctly marked "New Drug (or Antibiotic) Report," together with the applicable new-drug application number or antibiotic account number on the envelope.

(d) Each such applicant shall maintain for inspection all records received or otherwise obtained by him containing any of the kinds of information described in § 130.13 (a).

(e) After the submission of the initial reports required by paragraphs (a) and (b) of this section, each such applicant shall, after 1 year, submit for the reporting period reports of the kinds required by § 130.13(b) (3), not later than each anniversary date of the effectiveness of the new-drug application or initial antibiotic form 5 or 6 approval.

(f) Each applicant shall submit all information reported to or received by him of the kinds required by § 130.13 (b) (1) and (2) as required in that section (g) Deliberate or repeated failure to make the reports required by paragraphs (a) and (b) of this section will be followed by written notice to the holder of the application and publication of such notice in the FEDERAL REGISTER, furnishing an opportunity for a hearing on a proposal to withdraw approval of the application. Any interested person who may be adversely affected by such an order may respond to such notice and avail himself of an opportunity to participate in such a hearing. This will allow any person distributing a drug that was covered by an application held by a person who did not make the required reports an opportunity to show cause why approval of the application should not be withdrawn and marketing of the drug discontinued.

(h) Reports showing that a new drug was not marketed or has been discontinued may be followed by publication in the FEDERAL REGISTER of a notice of a proposal to withdraw approval of such application, on any of the grounds specified in section 505 (e) of the Act, giving any interested person who would be adversely affected by such an order an opportunity to respond and avail himself of a hearing prior to the issuance of such order. This will allow any person distributing a new drug that was covered by an application held by a person who did not market the drug or who has abandoned marketing of the drug an opportunity to show cause why approval of the application should not be withdrawn and why marketing of the drug should not be discontinued.

(i) Exemptions from annual reporting will be considered on the basis of petitions therefor, giving reasons why annual reporting is not required to protect the public health. No exemption will be allowed from the reporting requirements of paragraph (f) of this section and of § 130.13 (b) (1) and (2).

Effective date. This order shall be effective on the date of its publication in the Federal Register.

(Secs. 505, 507, 701, 52 Stat. 1053, 1055, as amended; 59 Stat. 463 as amended; 21 U.S.C. 355, 357, 371)

Dated: May 22, 1964.

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

[F.R. Doc. 64–5311; Filed May 27, 1964; 8:45 a.m.]

Mr. LARRICK. This recital of recent events, Mr. Chairman, I submit, does show much has been done, both by the Congress and by the FDA, to provide better public protection in the use of drugs.

This also serves to illustrate the legislation and regulations merely reflect the growing needs of our society.

Neither the legislative nor the executive branches of the Government can successfully impose requirements upon drug research and use that are significantly in advance of the requirements the public, including the scientific community, consider proper. Nor may they fail to provide for the controls the public, including the scientific commu

nity recognizes as desirable and necessary. Our Nation would no more have accepted new drug safety provisions in 1906 than it would permit the abandonment of new drug effectiveness requirements in 1964.

Every time a physician prescribes a drug for his patient, even one generally assumed to be relatively innocuous, he realizes that this drug administered to this patient at this particular time may cause a serious adverse effect. There is no such thing as absolute safety in drugs. There are some drugs that are less liable to cause harmful reaction than others, but people die every year from drugs generally regarded as innocuous. The problem was well stated by Dr. Torald Sollman, a world-famous, distinguished pharmacologist, about 10 years ago, when he said:

It is necessary still to emphasize that the administration of potent drugs involves a "calculated risk" where the presumptive benefit is balanced against the possibility of toxic effects and idiosyncrasies; but to calculate wisely it is necessary to know, as accurately as possible, what the risk may be in kind, degree, and frequency; and the special conditions which may increase or decrease the chance of injury.

With the older drugs, considerable data are generally available; but when a new drug is introduced they can often be learned only by experience. If the incidence is small, the injury may not become apparent for some time; or one of the earliest cases may happen to be one of the exceptions, and so bring a valuable drug into disrepute, perhaps depriving the public of an exceptionally valuable remedy.

This is a matter that has not been well understood by the general public. There has been so much publicity about the miracle drugs and about the marvelous cures that are possible today that the average individual untrained in medicine is inclined to believe that a new pill or a new injection should offer the answer to all medical problems. Far from it. With today's tremendous array of drugs, it is even more important than ever for the physician to exercise extreme care in choosing the medication he administers to his patients. We might wonder how the doctor can find it possible to keep abreast of all of the new developments. We are requiring that each new drug, including drug samples, be accompanied by a package insert or pamphlet which gives a sound summary of the facts about what the drug is, what it may be expected to do, what its side effects are likely to be, and what limitations attend its use.

The package insert must describe the disease conditions in which the drug should not be employed and give other warnings needed by the physician for proper use of the new product. This accompanying material must give a fair picture of the good and the bad to be expected from a new drug. We have required that all direct mailing pieces and such sources of drug information as "Physicians Desk Reference" provide a full disclosure of the good and bad of the drug. And we are requiring that all prescription drug advertising provide in fair balance a brief summary of this essential information. Thus the average physician has at his fingertips a vast storehouse of valuable information contained in these pieces of labeling. Many doctors have commended us for the obvious care that has been taken in our consideration of the package inserts.

With all of the information before him, a physician must decide whether for his patient the potential benefits from the use of a drug justify the risk involved in administering it.

Mr. FOUNTAIN. May I interrupt you, Mr. Larrick, to say that I suspect a problem arising for the doctors is in finding time to read and study this material before they make the decision.

Mr. LARRICK. Very true, Mr. Chairman.

Mr. FOUNTAIN. And it is extremely important that they be familiar with it.

Mr. LARRICK. It is extremely important, particularly when you realize a very large percentage of the drugs the doctor uses today were not available when more than two-thirds of the doctors graduated from medical school, because they have been developed so recently. Mr. FOUNTAIN. Thank you.

Mr. LARRICK. It is good medical practice to administer penicillin to a patient with no previous history of penicillin sensitivity who is suffering from a raging infection caused by microorganisms susceptible to this antibiotic. But occasionally, within minutes after a doctor administers an injection of penicillin, the patient gasps for breathshows signs of distress and dies almost immediately from a reaction known as anaphylactic shock.

We would not be justified in taking penicllin off the market because of these infrequent reactions. The reason is that many more lives are saved each year because of the good penicillin does than are lost because of the anaphylactic reactions.

If I had typhoid fever or a member of my family had typhoid fever, I would want the attending physician to prescribe chloramphenicol. This is the only drug available today that offers outstanding promise of cure of this disease. Without it 1 victim out of 10 will die. With it, only one or two per hundred will die. There are also certain other conditions in which this antibiotic is the drug of choice. Every year some people who have received chloramphenicol appear to recover and then in the next few weeks become listless, tired, generally worn out, and later die because the chloramphenicol has destroyed their blood-forming mechanism. They suffer from a condition known as aplastic anemia. They do not manufacture enough blood cells to maintain life.

We have reviewed the facts on chloramphenicol repeatedly and extensively. We have consulted outstanding physicians skilled in the use of antibiotics. On two occasions we have consulted panels of medical experts convened at our request by the National Research Council. The decision every time has been and still is that the lives saved by chloramphenicol, properly used, far exceed the lives that are lost because of the drug. We would not be justified in removing chloramphenicol from the market; we do require very extensive warnings in the labeling of the drug to remind physicians of the hazard.

I submit for the record further details about this drug, chloramphenicol.

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

(The above-mentioned material follows:)

CHLORAMPHENICOL

(Chloromycetin)

This antibiotic was first certified in 1949.

Beginning in 1950 reports appeared that aplastic anemia had been observed following its use.

In 1951, New and Non-official Remedies, a publication of the American Medical Association, reported blood changes caused by the use of the drug.

On June 28, 1952, an editorial in the Journal of the American Medical Association referred to additional reports of the effect of the drug on blood and bone marrow. The Food and Drug Administration discontinued the certification of chloramphenicol and referred the question to the National Research Council for a recommendation as to the future of the drug.

In August 1952, the ad hoc committee made its recommendations, and they were immediately made effective by the Food and Drug Administration. The label was required to bear a statement: "Warning: Blood dyscrasias may be associated with intermittent or prolonged use. It is essential that adequate blood studies be made."

The official brochure was required to bear a warning at the top of the circular as follows: "Certain blood dyscrasias (aplastic anemia, thrombocytopenia purpura, granulocytopenia, and pancytopenia) have been associated with the administration of chloramphenicol. It is essential that adequate blood studies be made when prolonged or intermittent administration of this drug is required. Chloramphenicol should not be used indiscriminately or for minor infections."

The use of the drug dropped sharply after this warning, but by the middle of 1960, its use had greatly increased. The Journal of the American Medical Association again issued a warning against indiscriminate use.

On November 28, 1960, the Food and Drug Administration again requested the national Research Council to review the status of chloramphenicol and to make recommendations both on proposals for improving the labeling and on the question whether the use of chloramphenicol should be discontinued entirely or restricted to hospitalized patients only.

On January 11, 1961, the ad hoc committee made its recommendations. The hospital restriction was not approved, but the modifications of the labeling were. The committee's report was accepted and announced in a press release on January 22, 1961, and the regulations providing for the relabeling of this drug were issued on February 3, 1961.

Under these revised regulations, the label on the bottle and on its package is required to bear the statement, "Warning: Blood dyscrasias may be associated with the use of chloramphenicol. It is essential that adequate blood studies be made (see enclosed warnings and precautions)."

Packages were required to bear an insert, and to begin with the following statements which were to be underscored or italicized:

(a) "Warning-Serious and even fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenia) are known to occur after the administration of chloramphenicol. Blood dyscrasias have occurred after both short-term and prolonged therapy with this drug. Bearing in mind the possibility that such reactions may occur, chloramphenicol should be used only for serious infections caused by organisms that are susceptible to its antibacterial effects. Chloramphenicol should not be used when other less potentially dangerous agents will be effective; or in the treatment of trivial infections such as colds, influenza, or viral infections of the throat; or as a prophylactic agent.”

(b) "Precautions-It is essential that adequate blood studies be made during treatment with the drug. While blood studies may detect early peripheral blood changes, such as leukopenia or granulocytopenia, before they become irreversible, such studies cannot be relied upon to detect bone marrow depression prior to development of aplastic anemia."

This order was made effective on the date of its publication in the Federal Register, February 10, 1961, but it stated:

"However, to facilitate the orderly transition from the labeling heretofore used to the new labeling the Commissioner will, for a period of 30 days, certify chloramphenicol preparations bearing the packaging labels adopted on the basis of the recommendations of the NRC in 1952, upon a showing that the firm requesting certification has disseminated to all practitioners licensed by law to administer the drugs, a brochure containing the new warnings."

The mailing of the complete new warnings to physicians was made promptly. Everything certified since March 10, 1961, has had the insert and the new label warning.

Mr. LARRICK. Someone in our society must make decisions with regard to the safety and effectiveness of new drugs. This someone, of

course, is the Food and Drug Administration. We have this responsibility-and a very grave one it is-by law.

The decisionmaking process can conveniently be regarded as a three-step operation, and I may say this is directly responsive to some of the things in your letter that you were good enough to send me in advance:

Step 1. Determine the benefit to be derived from the drug;

Step 2. Determine the risk; and

Step 3. Weigh the benefit against the risk and decide whether it is. in the public interest to approve the drug for marketing or to withdraw approval if the product is already on the market.

Let us consider each step in greater detail.

THE BENEFIT

The 1938 new drug section of the law did not require a manufacturer to prove that his new drug would yield the benefits claimed on its label. It spoke only of safety. Thus, many of the Government's decisions allowing drugs to be marketed had to be made without access to the full facts a physician would want in deciding whether to use the product. We had to operate with one hand tied behind our back. Of course the question of benefit was an integral part of the safety question in dealing with a product to be used in a life-threatening disease such as pneumonia or in dealing with a drug presenting grave risks. We required information about effectiveness for such drugs in order to reach a decision about safety.

But many fairly innocuous new drugs offered for ailments that were not life-threatening were presented to us for evaluation without evidence that they would do what the label claimed. We had no power in such case to require submission of efficacy data. The old law required us to decide whether the drug could be marketed on the basis of less than the whole truth.

One way the Kefauver-Harris amendments of 1962 strengthened the new drug section was by requiring a new drug to be proved effective as well as safe before we could approve it for commercial distribution.

So today, consideration of the benefit of a drug is always an integral part of the decisionmaking process. In the absence of evidence that a drug will do what its label claims, we may decline to approve it, even though it can be administered without harm to man.

Before a drug is marketed, properly conducted clinical trials can show what benefit may be expected from it. After it has been marketed, its use in medical practice, when properly reported and evaluated, can provide further evidence on the question of effectiveness. Also, after October 10, 1964, we may withdraw approval of a new drug application if "there is a lack of substantial evidence that the drug will have the effect it purports or is represented to have" (from sec. 505 (e) of the Food, Drug, and Cosmetic Act).

THE RISK

Dramatic advances in medical science and in administration make it possible to assess the risk associated with a drug more accurately than ever before. So the safety judgments we make today are better than