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The American Pharmaceutical Association believes that the problem before us has been sufficiently discussed. Now is the time for us to start devoting our full capacity to positive and cooperative action.

EXHIBIT 5 THE EDITOR COMMENTS: FOR A SOPHISTICATED PUBLIO

[Journal of Pharmaceutical Sciences, February 1963) |

The pharmaceutical industry can be rightly proud of the extensive steps it takes in testing new drugs to assess their degree of safety or lack of toxicity. While much of this information or testing has been required under the new drug requirements of the Federal law, nevertheless, many firms have generally exceeded the minimum testing required in order to provide as much assurance as possible that a particular drug is adequately safe for use in the treatment of a particular illness.

Unfortunately, however, on the basis of the above experimentation many pharmaceutical firms will refer to their drugs as "safe" in promotion campaigns to physicians, pharmacists, and even to the public. In our opinion, this is most unfortunate and ill-advised, since no drug is completely "safe" and without some possible risk associated with its use or misuse.

Other industries, such as the automobile manufacturers and the electrical appliance producers, have long ago recognized that under certain conditions their products might result in injury to the public using them. This realistic attitude has been reflected in their advertising which rarely, if ever, refers to the safety or complete lack of hazard in using their products.

Why is it, then, that the pharmaceutical industry feels that its products must be held out as being completely safe before those products will gain acceptance and use by the health professions or the public? It appears to us that the pharmaceutical industry might well consider directing more of its advertising and promotion resources toward education of the public to the fact that any drug-like everything else we use in everyday life of necessity has a degree of fundamental hazard connected with it. The sooner that this basic fact is brought home to all those using drugs, the sooner we will have a sophisticated public utilizing the benefits of drugs with a proper realization of the cautions which must be exercised and the potential dangers which cannot be completely divorced from any drug therapy.

EDWARD G. FELDMANN.

Mr. Chairman and members of the subcommittee, the American Pharmaceutical Association appreciates this opportunity to comment on the serious subject of drug safety.

Dr. Feldmann and I will be glad to attempt to answer any questions the subcommittee may have..

Thank you.

Mr. FOUNTAIN. Thank you, Dr. Apple, for your very thoughtprovoking statement. I suspect the American consumer of medicine is probably closer to his pharmacist than he is to his doctor in many instances where prescription drugs are not involved. I expect the pharmacists are called upon for information and advice about drugs probably more often then anyone else. What kind of advice they give or refuse to give I am not in a position to say. I think we all are sometimes prone when in a drugstore, and in pain to ask what is good for this condition rather than take the time to visit a doctor. The organization which you represent is composed of a very valuable group of professional men insofar as I am concerned, and I believe insofar as the consuming public is concerned.

I presume that your statement before the Senate Subcommittee on Reorganization and International Organizations will be available in their printed record!

Dr. APPLE. Yes sir.

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Mr. FOUNTAIN. In that case it will not be necessary to include it in this record. We will examine the other exhibits accompanying your statement and include at appropriate points in the printed hearings those which might be helpful in our study.

You have stated that one researcher reports gastric hemorrhage after taking only two tablets of aspirin. Was there a clear causal relationship established in that particular case, to your knowledge!

Dr. APPLE. Mr. Chairman, I merely quoted to you from the printed text of a book on side effects of drugs by one of the noted authorities. I did this to emphasize the fact that the public does not fully appreciate that every time they ingest a foreign substance there is a hazard involved.

I think that one of the serious things that we need to do now is to educate the public that in the use of drugs they must be cautious, and that they must report promptly to their physicians any side effects they observe.

The individual patient needs to be educated when and how to do this if the information about adverse drug reactions which was previously discussed by witnesses is going to be available to both the FDA and the medical profession.

In this connection, at every hospital where there is a pharmacy and therapeutics committee and the pharmacist serves as secretary of this committee, he actually collects this information. As Dr. Hussey indicated, the hospital is only one end of the spectrum.

Our next task is to collect this information from a much larger source; from the general practitioners and the patients they treat. This is where the community pharmacist, the health practitioner that most people come in contact with, can play a very useful role.

Mr. FOUNTAIN. Then I gather that your statement concerning some of the side effects of aspirin is essentially a quotation designed to demonstrate a point, which I think you have made very well. As a matter of fact you have made it so well that I am going to slow up on taking aspirin. However, I would assume that the purpose of what you have said was not to indicate the incidence of these side effectswhether there have been one, two, three, or more cases-but merely to show that these can happen.

Dr. APPLE. That is right, sir.

Mr. FOUNTAIN. And have happened.

Dr. APPLE. That is right. But, as I have indicated, it is still the best analgesic and antipyretic that anyone can obtain without prescription.

Mr. FOUNTAIN. Some people might read this and become alarmed, taking it out of context.

Dr. GOLDBERG. Do you mean it is still the best despite what we see on TV and read in the ads about competing products!

Dr. APPLE. No comment.

Mr. FOUNTAIN. Mr. Gray.

Mr. GRAY. Along the same lines, would you then say that most of these reactions you have listed would normally be considered, in view of their incidence, as idiosyncracies rather than common reactions to aspirin!

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Dr. APPLE. My testimony did not attempt to relate the incidence involved which is a very important factor in our overall considerations. But to the asthmatic who suffers a reaction, it becomes a very serious matter. This is what I think the public must recognize. There is a possibility of indiscriminate use of drugs. Just because they are available does not mean that they are safe.

Mr. FOUNTAIN. Of course, a lot depends on the extent to which they are used.

Dr.APPLE. That is right, sir.

Mr. FOUNTAIN. In other words, if a person does not exercise any discretion at all, he can commit suicide by taking an overdose of any number of available drugs.

Dr. APPLE. Yes, sir.

Mr. FOUNTAIN. You quote Dr. Feldmann here and I would like little elaboration on that quote. You said he commented editorially over a year ago

any drug, like everything else used in everyday life, of necessity has a degree of fundamental hazard connected with it.

Dr. Feldmann, would you like to elaborate a little further on that quote!

Dr. FELDMANN. I think taken in context where it originally appeared, the point was made that any item which we use, whether it is an automobile, electrical appliance, whatever it happens to be, if it is misused, if it is improperly used, it can result in untoward reactions. This does not argue against its being available or being used under the proper set of conditions. The same is true of drugs. The public, the physicians, have to be aware of the limitations, the possible hazards which may be associated with these valuable items.

Mr. FOUNTAIN. Dr. Apple, you made a statement similar to one which Mr. Larrick, Dr. Hussey, and, I believe, others have made. You said:

Do the possible benefits outweigh the possible risks involved?

In other words, you believe the benefits-to-risk ratio should be applied. Would you elaborate on that statement? I believe it does need some elaboration.

Dr. APPLE. Mr. Chairman, I think the best way I can elaborate on that particular thing is to relate a personal experience.

Many years ago, at the University of Wisconsin, I found a citation in the literature about an agent that would oxidize alcohol at a much faster rate than the body normally does. It led my scientific curiosity to experiment with the development of a drug, with the assistance and cooperation of a number of colleagues. We finally reached the point where we had undertaken clinical investigation in a very limited way with the assistance of pharmacologists at the University of Wisconsin Hospital. As a result, we were convinced that that drug was as safe as sodium chloride or plain table salt. Yet when we attempted to get a new drug application for it, and this goes back to the early fifties, we did not succeed. We thought the drug would have made a very excellent sobriety agent-yet we did not demonstrate to the Food and Drug Administration the efficacy to the degree that was required by them at that time. We didn't demonstrate the safety to FDA's satisfaction. Because this was basically an experiment with us and an

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educational experience, we dropped it at that point. But it did open the door for many of us to recognize the general relationship between benefit and risk that always exists.

I said that I would not be reluctant to give my approval, if it need be for my daughter to take a drug which had a negative benefit-to-risk ratio. In other words, the risks would be much greater than the expected benefits. But if we had exhausted all other drugs at that point and the situation was hopeless, I would be willing to approve the use of an investigational drug which perhaps only represents 1 chance in 10. I think that, basically, when drugs do not have at least a certain judged positive benefit-to-risk ratio they should be kept in the investigational stage. But when it is established that a drug has a very high benefit-to-risk incidence during clinical testing which has been done prior to its release, then I think the drug should be made available.

Mr. FOUNTAIN. Dr. Goldberg.

Dr. GOLDBERG. Dr. Apple, your statement, on page 3, relates to what you said a moment ago with respect to a negative benefit-to-risk ratio. You said specifically:

PHS contends that even a drug which is judged to have a negative benefit-torisk ratio should be available if it will help a physician save the life of single patient.

Dr. APPLE. I did.

Dr. GOLDBERG. Did you mean available on the market or available in the investigational drug stage?

Dr. APPLE. Available in the investigational drug stage.

Dr. GOLDBERG. Which would not make it widely available since the number of physicians who would be encompassed in an approved plan for investigation under the Drug Amendments of 1962 would probably be quite limited.

Dr. APPLE. The food and drug laws now very carefully regulate who can handle investigational drugs. If a physician believes that one of these drugs might be the last possible recourse for saving his patient's life, it behooves him to confer with a colleague who has the authority to use the investigational drug.

What I am saying is that the drug should be available when practitioners, who are qualified to handle it, in their best judgment believe there is an opportunity to attempt to save a patient's life and learn more about that drug.

Dr. GOLDBERG. Then you do not mean to suggest that every physician should have that same discretion and have the drug available to him?

Dr. APPLE. I certainly don't. The food and drug regulations now very carefully prescribe who is qualified to handle investigational drugs.

Dr. GOLDBERG. I wondered about that point because your statement, as it appears, seemed to be at variance with what Commissioner Larrick testified to yesterday. With respect to the availability of dangerous drugs that have a low benefit-to-risk ratio, he stated that other factors must be considered in deciding whether they should be made available to the individual practitioner.

You do agree with that!

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Dr. APPLE. I do, except that I hope we don't become overly cautious in the administration of these procedures.

Dr. GOLDBERG. I can understand it when you talk of making available a dangerous drug which offers one hope of saving a person who would otherwise die. That is an extreme case. But the example you used in your testimony-had your daughter been a schizophrenic you would be willing to use a dangerous drug-that is not a question of saving life, at least in the absolute sense.

Would you make the drug available in that situation to the individual practitioner at his discretion?

Dr. FELDMANN. If I may comment here, the benefit may not necessarily be a case of life or death but the risk does not necessarily have to be a case of life or death either. The risk involved is not necessarily a fatal one.

Mr. FOUNTAIN. If I were about to be given a drug and someone told me that there is 50 percent chance that you will die and 50 percent you will live, I am inclined to think I would depend on nature and the Lord. Dr. FELDMANN. I think, as Dr. Apple pointed out in his testimony with phenothiazines, some of the side effects that were noted there were of a rather mild nature in the PHS study. There is another point we should bear in mind; that is, there is an extreme degree of biological variation. We are aware, for instance, only a small percentage of the population may be allergic to a certain drug, chemical, everyday substance such as poison ivy, strawberries. Similar individuals can vary considerably as to their degree of response, favorable. response, to a given drug. In other words, just as the variation, adverse variation can vary and can represent a small part of the total population, the fact that one or two people out of a hundred develop a certain side effect to a drug does not mean that the other people in that sampling would also develop those side effects no matter how much of that drug they took.

Mr. FOUNTAIN. Then the use of that formula, benefit-to-risk ratio, depends, to a large extent upon what the benefits are and what the risks are.

Dr. FELDMANN. That is true.

Mr. FOUNTAIN. The kinds of benefits and the kinds of risks.

Dr. APPLE. Mr. Chairman, that ratio will vary depending on the environment in which the drug is actually consumed. For example, there will be a spectrum of benefits, and there will be a spectrum of risks. We feel, of course, that a hospitalized patient obviously, with constant medical attention and supervision in the use of the drug, may actually experience a much smaller risk ratio than the patient at home, without that medical attention and supervision, consuming the same drug.

Mr. FOUNTAIN. You stated also that you

have informed the Food and Drug Administration that the more than 100,000 active practitioners of pharmacy who dispense 800 million prescription orders annually represent an undeveloped source of information about adverse drug reactions.

Then you go into a discussion of what your profession, and the American Society of Hospital Pharmacists, did in cooperating with the FDA pilot project.

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