STATEMENT OF WILLIAM S. APPLE, PH. D., EXECUTIVE DIRECTOR, AMERICAN PHARMACEUTICAL ASSOCIATION; ACCOMPANIED BY EDWARD G. FELDMANN, PH. D., DIRECTOR, SCIENTIFIC DIVISION

Dr. APPLE. Thank you, Mr. Chairman. I am a registered pharmacist in the State of Wisconsin.

Prior to coming to the American Pharmaceutical Association in 1958, I served on the faculty of the University of Wisconsin School of Pharmacy. In addition to my present duties I also serve now as president of the American Council on Pharmaceutical Education, which is the accrediting agency of the colleges of pharmacy in the United States. I also serve as vice president of the National Health Council and in a number of other activities related to health of the public.

Mr. FOUNTAIN. You may proceed with your statement.
Dr. APPLE. Thank you, Mr. Chairman.

The American Pharmaceutical Association is the national professional society that represents pharmacists in all facets of professional practice. APhA has no financial, business, or commercial interest in any pharmaceutical product, manufacturer, wholesaler, or pharmacy; its sole interest is promoting the highest standards of public health through the practice of pharmacy.

Individual members of our association are engaged in every phase of pharmaceutical activity; that is, from the discovery of a new drug to the dispensing of it for a patient. The American Pharmaceutical Association commends Chairman Fountain and the members of the House Intergovernmental Relations Subcommittee for recognizing the uncertainties about the safety of new drugs created by recent articles in both the scientific and lay press. The practitioners of our profession who form the final link in the physician-patient-pharn.. cist relationship inform us that a "drug safety uncertainty" syndrome is developing among sick people who require prescribed medication to get well or remain alive.

Patients are asking pharmacists to assure them that the drugs which have been prescribed for them are 100 percent "safe." This represents a marked change from a few decades ago when the public sought assurance from the pharmacist that a drug was 100 percent "effective." Because so much has been accomplished in so little time, we Americans have come to expect the impossible miracle from our scientists, our industries, and professional practitioners in every field, but especially in the field of medicine and pharmacy.

I have in my hand an unlabeled bottle containing tablets of a wellknown drug. In our library at 2215 Constitution Avenue we have scores of scientific books and hundreds of scientific periodicals which contain information about the relative safety and efficacy of this drug. The experts concerned with pharmacological activity say this drug will produce gastric hemorrhage. One research reports a gastric hemorrhage after taking only two tablets of this drug. In addition to capillary damage, hemorrhages have been observed in the kidneys, brain, liver, and mucous membranes. It has been reported that one tablet of this drug may provoke a serious attack in asthma patients. According to the scientific literature, this drug may produce general symptoms of dizziness, deafness, perspiration, nausea, diarrhea, and

tachycardia. In large doses it has been observed to produce cardiac insufficiency, shock, coma, and necrosis of the liver. The drug can damage the acoustic and optic nerves to the extent of causing complete deafness and blindness.

On March 25, 1964, one manufacturing firm is marking the observance of its production of the 300 billionth tablet of this drug. What is this drug? It is acetylsalicylic acid or aspirin. It can legally be obtained without a prescription order, and without question is the most widely used drug in the world today.

Since aspirin was first isolated in 1853, we have learned much about its side effects as well as its beneficial actions. We continue today, and will in the future, to study the pharmacology of aspirin. This is our scientific and professional responsibility.

The question might well be asked if acetylsalicylic acid had first been discovered yesterday, what scientific evidence would the Food and Drug Administration require, and how long would FDA take to approve a new drug application for aspirin? Obviously an answer to this question can be found in the food and drug laws passed by Congress and the implementing regulations promulgated by the Secretary of Health, Education, and Welfare, and the Food and Drug Commissioner. In the final analysis we must look to the public servants charged with the responsibility of making certain interpretative decisions.

Are they to be guided by the criterion that Congress and the public holds them responsible to be infallibly correct? I don't think that the chairman or the members of the subcommittee would expect such performance of even our most qualified authorities. It seems to us that in the final anlysis the decision must be based on the criterion: Do the possible benefits outweigh the possible risks involved?

In individual patients, the answer may be decidedly negative as well as positive. The American Pharmactutical Association believes that the beneft-to-risk ratio should be applied to the total patient universe in considering the release of a new drug. APhA contends that even a drug which is judged to have a negative benefit-to-risk ratio should be available to help a physician save the life of a single patient.

APhA is concerned that the hysteria of the moment about drug safety could develop into an unwritten protocol of indecision and delay. If the Food and Drug Administration were to never again approve new drug application, injuries or even deaths would still result in individual cases from the drugs which are now available. The Food and Drug Administration, the medical and pharmacy professions, and the pharmaceutical industry have a responsibility to work incessantly and cooperatively for the most positive benefit-to-risk ratio. APhA recognizes that the Congress has a responsibility to assure the public that this kind of effort and cooperative climate exists.

Earlier I cited some of the possible side effects of aspirin. It will continue to be employed as one of our most useful analgesics and antipyretics until the scientific literature reports an accumulated experience that reveals another drug which has an even better benefit-to-risk ratio. Even then, this other drug will not replace aspirin until it can be made available more economically.

On February 5, 1963, President Kennedy told Congress:

I propose a national mental health program to assist in the inauguration of a wholly new emphasis and approach to care for the mentally ill. This approach

relies primarily upon the new knowledge and new drugs acquired and developed in recent years which make it possible for most of the mentally ill to be suc cessfully and quickly treated in their own communities and returned to a useful place in society.

Congress promptly attacked the problem and enacted Public Law 88-164. The value of drugs in treating certain mental illness is now being demonstrated. On March 6, 1964, the Public Health Service issued a release outlining new evidence of marked efficacy of drugs in the treatment of schizophrenia. The phenothiazine family of drugs and more particularly chlorpromazine, fluphenazine and thioridazine were mentioned.

I would like to tell you something about the side effects of chlorpromazine, which the National Institute of Mental Health comprehensive study reported as "the oldest and most reliable drug of this type." In the interest of conserving the time of the committee, I refer you to the package insert which accompanies every package of Thorazine, the Smith Kline & French brand of chlorpromazine (exhibit 1). We have excerpted the insert sections dealing with the side effects and precautions for the use of this drug in psychiatry.

EXHIBIT 1-PRESCRIBING INFORMATION, THORAZINE, BRAND OF CHLORPROMAZINE

TRANQUILIZKE POTENTIATOR—ANTIEMETIC

Thorazine (chlorpromazine, SK&F) is a potent tranquilizer, potentiator and antiemetic with a distinctive sedating effect. Its value and versatility in general medicine, surgery, obstetrics, and psychiatry has been established by use in over 18 million patients.

INDICATIONS IN PSYCHIATRY

For control of agitation, anxiety, tension, confusion, and related symptoms seen in neuroses and such psychotic conditions as schizophrenia, manic-depres sive states (manic phase), severe personality disorders, involutional psychoses, degenerative states *••

Side effects and cautions

Drowsiness is usually mild to moderate and disappears after the first or second week. If troublesome, lower dosage or administer small amounts of dextro amphetamine.

Other side effects: Occasional dry mouth, nasal congestion, constipation, miosis and, very rarely, mydriasis. Mild fever (90° F.) may occur after large I.M. doses. Increases in appetite and weight sometimes occur.

Jaundice: Overall incidence has been low, regardless of indication or dosage. Most investigators conclude it is a sensitivity reaction. Few cases occur in less than one week or after six. Symptoms resemble obstructive jaundice, are without parenchymal damage, and are usually promptly reversible on withdrawal of the medication.

There is no conclusive evidence that pre-existing liver disease makes patients more susceptible to jaundice. Alcoholics with cirrhosis have been successfully treated with Thorazine (chlorpromazine, SK&F) without complications. Nevertheless, the medication should be used cautiously in patients with liver disease. If fever with grippe-like symptoms occurs, test for increased bilirubin or for bile in urine. If tests are positive, stop treatment.

Liver function tests of jaundice induced by the drug may mimic extra-hepatic obstruction; withhold exploratory laparotomy until extrahepatic obstruction is confirmed.

Agranulocytosis, though rare, has been reported. Observe patients regularly for sudden appearance of sore throat or other signs of infection. If white blood counts and differential smears indicate cellular depression, stop treatment and start antibiotic and other suitable therapy.

Most cases have occurred between the 4th and 10th weeks of therapy; patients should be watched closely during that period.

Moderate suppression of white blood cells is not an indication for stopping treatment unless accompanied by other symptoms.

Potentiation: Thorazine (chlorpromazine, SK&F) prolongs and intensifies the action of C.N.S. depressants such as anesthetics, barbiturates, and narcotics. It is best to stop such depressants before starting treatment. Later these agents may be reinstated at low doses and increased as needed. About 4 to the usual dosage of such agents is required. Note: This agent does not potentiate the anticonvulsant action of barbiturates. Thus dosage of anticonvulsants, including barbiturates, should not be reduced if Thorazine (chlorpromazine, SK&F) is started. Instead, start at low doses and increase, if necessary.

Hypotensive Effects: Postural hypotension, simple tachycardia, momentary fainting and dizziness may occur after the first injection; occasionally after subsequent injections; rarely, after the first oral dose. Usually recovery is spontaneous and symptoms disappear within 2 to 2 hours. Occasionally, these effects may be more severe and prolonged, producing a shock-like condition.

To minimize hypotension, keep patient prone and observe for at least 1⁄2 hour after initial injection. To control hypotension, place patient in head-low position with legs raised. If a vasoconstrictor is required, "Levophed" and "NeoSynephrine" are the most suitable. Other pressor agents, including epinephrine, should not be used as they may cause a paradoxical further lowering of blood pressure.

Antiemetic Effect: Thorazine (chlorpromazine, SK&F) may mask signs of overdosage of toxic drugs and may obscure conditions such as intestinal obstruction and brain tumor.

Dermatological Reactions of a mild urticarial type (suggesting allergic origin) or photosensitivity are seen. Avoid undue exposure to sun. More severe reac tions, including exfoliative dermatitis, have been reported occasionally.

Neuromuscular (Extrapyramidal) Reactions closely resembling parkinsonism occurred in a few patients on high psychiatric doses. Such symptoms are reversible and usually disappear shortly after dosage is decreased, the drug temporarily withdrawn, or concomitant administration of an anti-parkinsonism agent (see PDR). In severe cases suitable supportive measures such as maintaining a clear airway and adequate hydration should be used. When therapy is reinstituted, it should be at a lower dosage.

Lactation and Moderate Breast Engorgement may occur in females on large doses. This transitory condition disappears on lowering dosage or stopping drug.

NOTE.-It is generally recognized that in pregnant patients all medications should be used cautiously, especially in the first trimester.

Contraindications

Comatose states or presence of large amounts of C.N.S. depressants (alcohol, barbiturates, narcotics, etc.).

Overdosage

One of three clinical pictures may be seen:

1. Extreme somnolence: patient can usually be roused with prodding, but if permitted will fall asleep. General condition is usually satisfactoryskin, though pale, is warm and dry. Slight blood pressure, respiratory and pulse changes may occur but are not problems.

2. Mild to moderate drop in blood pressure (whether conscious or unconscious). Skin is markedly grey but warm and dry. Nail beds are pink. Respiration is slow and regular. Pulse is strong but rate slightly increased. 3. Severe hypotension, possibly accompanied by weakness, cyanosis, perspiration, rapid thready pulse and respiratory depression. Treatment is essentially symptomatic and supportive. Early gastric lavage and intestinal purges may help. Centrally acting emetics will not help i cause of the antiemetic effect of Thorazine (chlorpromazine, SK&F). Give hot coffee or tea.

Severe hypotension usually responds to measures described under Hypotensive Effects, column 6. Additional measures include pressure bandages to lower limbs, oxygen and I.V. fluids.

1 "Levopbed" and "Neo-Synephrine" are the trademarks (Reg. U.S. Pat. Off.) of Winthrop Laboratories for its brands of levarterenol and phenylephrine, respectively.

If stimulant is desired, use amphetamine, dextro amphetamine, or caffeine and sodium benzoate.

Avoid stimulants that may cause convulsions (e.g., picrotoxin and pentylenetetrazol).

Obviously the risks involved in using this drug are serious. Again, in the interest of conserving the time of the committee, I refer you to the pertinent PHS release (exhibit 2). The results of the study did indeed reveal side effects, but the findings state that these side effects "generally were mild despite the higher dosages required ***.”

On the "benefit" side, according to the results of the 22-year study, "95 percent of drug-treated schizophrenics improved within 6 weeks" and "75 percent showed marked to moderate improvement." If my 15-year-old daughter had been 1 of the 400 patients in the study, I would have given my consent to the use of any one of the 3 phenothiazine drugs. If she did not respond to these drugs, I would give my consent to the use of any drug which in the considered judgment of the medical practitioners attending her represents even a 1-to-1 benefitto-risk ratio. I think most parents and families would agree that these patients deserve this much of an opportunity to get well.

EXHIBIT 2-PRESS RELEASE FROM USPHS REGARDING DRUGS FOR THE TREATMENT OF SCHIZOPHRENIA

[For release in a.m. papers Mar. 6, 1964]

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE,
PUBLIC HEALTH SERVICE, NATIONAL INSTITUTES OF HEALTH,
NATIONAL INSTITUTE OF MENTAL HEALTH,

Bethesda, Md.

New evidence of marked efficacy of drugs in the treatment of schizophrenia has just been released by Public Health Service and collaborating scientists. The comprehensive study, supported and directed by the National Institute of Mental Health, Bethesda, Md., shows that 95 percent of drug-treated schizophrenics improved within six weeks. Seventy-five percent showed marked to moderate improvement, according to results of the two and a half year study, reported in the current issue of "The Archives of General Psychiatry."

This is the first large-scale study in which acutely ill patients were treated in varying types of psychiatric hospitals. They ranged from small private hospitals to large State institutions. Altogether, the Institute's Psychopharmacology Service Center enlisted nine hopsitals for this Collaborative Study Group. Earlier studies have been limited to hospitals of a single kind.

These results, coupled with the findings from other Institute research, suggest these drugs will be highly effective tools for treating schizophrenics in compre hensive community mental health centers where the emphasis is on rapid and early treatment near the patient's home. The hope is that many of these patients could thus avoid tragic years in institutions.

The investigators explain that their findings make it "more feasible to treat acute psychoses in a variety of clinical settings rather than (solely) in public mental hospitals."

Patients in the study were young schizophrenics averaging 28 years of age, usually suffering either their first psychotic breakdown or first hospitalization, and whom participating clinicians judged to be "markedly ill."

More than 400 patients either were given chlorpromazine, two of the newer phenothiazines (flupheniazine or thioridazine ) or served as controls and received no drugs. The phenothiazine family of drugs was chosen because it contains the tranquilizers with the greatest potency. Chlorpromazine is the oldest and most reliable drug of this type.

Other results of the study were:

1. Nearly half of the improved patients were rated as having no symptoms or only borderline illness at the end of six weeks.

2. The degree of improvement had not leveled off by the end of the study, indicating that improvement probably was continuing, and would have been observed if the project had been longer.