joint committee must have the final say in case of a dispute. This was brought out in my answers to the questions you addressed to me.

Now I would like to ask you a question on a matter which your bill does not make clear. If the compulsory licensing section becomes law, under what names are the drugs to be sold? For example, if companies A through M obtain a license to sell company X's wonder drug, do they all market it only under the public name or is the poor physician now faced with 13 new nonproprietary names, further to confuse his addled brain?

I am

Again, with thanks for allowing me to speak my piece, and with respect,

Sincerely yours,

LSG/lr

encl.: as above

Louis S. Goodman, M. D.
Professor and Chairman
Department of Pharmacology

Within twenty-four hours of my testimony before the Kefauver Subcommittee dealing with Senate Bill 1552, Dr. Austin Smith of the Pharmaceutical Manufacturers Association challenged my statement concerning shortcomings in toxicity tests performed by drug houses. Because of this challenge and because of some ambiguity in interpretation of my brief remarks in the UPI dispatch on this point, I thought it desirable to describe this aspect of drug testing more fully. Here are the facts.

(1) At present, the Food and Drug Administration has essentially no jurisdiction over experimental drugs until a new drug application is filed. This leaves the decision as to the nature and extent of animal toxicity tests performed prior to human testing up to the drug house (or other proponent of the drug) and, to a lesser degree, to the clinical investigator who is to put the drug into man.

(2) The variation between drug houses in preclinical toxicity testing is tremendous. I have been approached to start human testing of a drug with the only information available being the amount of drug required to kill 50 per cent of mice receiving the drug in one intravenous dose. In contrast, it is not infrequent to have a firm supply toxicity information on a proposed drug which runs to many pages in length. The toxicity tests recommended by such experts as Dr. Lehman of the Food and Drug Administration in this country, and Drs. Paget and Spinks of the Imperial Chemical Industries, Ltd., in England, are not infrequently lacking in the toxicity data sent to us by pharmaceutical firms.

(3) Although enough acute animal toxicity data may be available
to justify short-term experiments in man, there are often unavailable
at the start of human testing adequate chronic toxicity data in
animals. This leads to chronic toxicity tests being performed in
man first, since for many disease states the repeated use of the
drug must be investigated. Clinicians who are impressed by the
effect of one or two doses of a new drug will often start chronic

administration of the drug, even when the drug has not been cleared for such prolonged human trials by the drug houses supplying the agent. This phenomenon is well known to the industry.

(4) It is, according to FDA officials, a not uncommon occurrence for new drug applications to be filed with extensive clinical data included, but without adequate supporting animal toxicity data being simultaneously available. In fact, it has been made a matter of public record that drugs have been cleared for sale on the market with chronic toxicity tests still pending.

It is easy to understand why drug houses are reluctant to spend the considerable time and money involved in routine toxicity testing unless the drug shows "promise," i.e., until the first human tests are encouraging. It is also, for reasons described above, easy to understand why human testing can "get ahead" of animal testing. In my opinion, therefore, a minimal amount of toxicity testing should be required by law before a drug ever gets put into man.

There are, I suspect, other reasons for inadequate animal toxicity tests besides those mentioned above. Drug houses vary greatly in the caliber of their staffs. Some have excellent pharmacologists, toxicologists, and pathologists, whereas others are deficient in these regards. Therefore on occasion it is likely that poor judgment and ineptitude also enter the picture, instead of (or in addition to) pressures for speed and economy.

Are

The very existence of the broad discrepancies in toxicity testing described above testify to a troublesome state of affairs. the drug houses who perform extensive toxicity tests before ever going to man merely overcautious conservatives? I think not. Predicting human toxicity is by no means a simple matter, but it is preferable to take all reasonable steps to escape untoward reactions in man that could be predicted from animal work. Somewhere between the extreme care and effort suggested by some pathologists and the inadequacies of the worst of the preclinical evaluation now being done in this country lies a reasonable middle ground which should be standard for all drugs.

I should like to make some constructive suggestions to the Pharmaceutical Manufacturers Association, and to the subcommittee now holding hearings on Senate Bill 1552. First, let a survey be made of member firms of the PMA to determine their current policy on toxicity testing. (I would suggest that each firm supply not only summary letters from high ranking officials, but the earliest complete pharmacology brochure on each drug issued for early clinical tests during the past year.) Next, let a check be made on how

often chronic human testing is performed before chronic animal tests are completed. Third, let some of the most knowledgeable and experienced toxicologists and pathologists available, in the industry and in the FDA, be canvassed for advice as to what minimal toxicity testing should be. Fourth, let the FDA be asked to summarize the inadequacies in toxicity testing observed in new drug applications filed during the past year. The above will accumulate facts needed for measures which will standardize toxicity testing. Such standardized toxicity testing will not only improve the pharmaceutical industry's preparation for human testing, but may also serve to restrain individual investigators or scientists or quacks outside of the drug industry who introduce new compounds into normal humans or patients without any toxicity testing at all.

Dr. Smith cannot be blamed for not being aware of some of these problems in view of his personal lack of experience with animal toxicity testing and early clinical trials, but it is distressing that his denial was issued in such haste as to preclude an attempt to check on the basis for my remarks. It is also strange that the UPI story on my statement was made after a check on its meaning with members of the Kefauver Committee and with representatives of the American Medical Association, but not with the original source. The result was a more confused account than would have resulted from even a quick telephone call to the author of the statement. It is also unfortunate that this coverage of my statement stressed a few bits of my testimony rather than the tenor of the entire statement, which was praised both by Senator Kefauver and by Senator Hruska as a frank and balanced appraisal.

There is growing concern in many quarters over all aspects of human experimentation and it would behoove all concerned to improve those procedures which might prevent disaster in patients receiving experimental drugs. Where patient safety is concerned, there is no room for compromise. I am sure that the academic world would welcome the Pharmaceutical Manufacturers Association in a cooperative effort to solve these serious problems; we look forward to some tangible evidence of good faith along these lines.

Sincerely,

I Lasagn

Louis Lasagna, M.D.

Division of Clinical Pharmacology

LL:rk