that he felt would clarify the discrepancy.

him to forward whatever he had in this regard.

I told

He then asked if we had any other actions in the process that the firm was not aware of. I told him there were none.

Redward Steibet

Edward G. Selbert
Compliance Officer

oc: HFD-322

cc: HFD-302 (G. Koustenis)

00: Alb. R.P.

cc: CHI

cc: NYK HFR 21 (info)

EGS: ap

Following an inspection of April 17 thru 21, 1975, covering the veterinary product Neoprontosil, Brand of Azosulfamide, its labeling was forwarded to our Bureau of Veterinary Medicine for review and evaluation. We have just received the Bureau's comments regarding the product and wish to pass them on to you at this time.

As labeled the product is a prescription drug, and its labeling should bear the prescription legend. The term, "large animals" appearing on the reverse side of the insert, should be deleted and replaced solely with the specific species, i.e., horses.

Since the product is a prescription drug, we consider it, as labeled, to be in violation of 502 (f) (1) of the Food, Drug and Cosmetic Act. Please advise this office, within 30 days of receipt of this letter, of the steps you have taken to bring the product into compliance.

Very truly yours,

bc:Alb. R.P. bc:HFV-220 EGS: ap

Edward G. Seibert
Compliance Officer
Buffalo District

DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE HA-228

Acting Associate Director

for New Drug Evaluation

Director

Scientific Investigations Staff

SEP 29 1975

AF 5-07 FILE

Worcester County Rehabilitiation and Detention Center IRC

I have reviewed this material and agree with you that Winthrop should
receive a reprimand. Additionally, I believe, Dr. Bachrach, the clinical
Investigator, Should also be reprimanded. Accordingly, I have drawn
up two additional letters and revised the letter to Mr. Weinstein.

There is another matter about this that concerns me. The protocol, sub-
mitted on February 21, 1975, would certainly lead one to believe that all
three dose levels, 1.e. 100 mg b.i.d., 250 mg b.1.d., and 500 mg b.i.d.
would be started simulaaneously and each dose level would be administered
to five subjects with two serving as controls. The medical officer's
evaluation states, "the designaand the details of the proposed investi-
gation, including the clinical and laboratory safeguards, and the dosage,
are satisfactory." The supervisory medical officer, Dr, John Winkler, took
exception to the medical officer's review noting that pharmacology con-
currence would be needed for expansion from a single dose tolerance study
to the outlined multiple dose study. It was initially the opinion of
the pharmacologist that the data would only support the proposed 100 mg
b.i.d. dosage though a later opinion was that 200 mg b.i.d. might also be
supported.

The company was notified by phone on March 5 to discontinue the higher
doses until safety of the lowest dose had been established. The company
Indicated that the study was already underway, but that they would drop the
higher doses. The report of the study indicates that on the second day
of medication, 3 subjects on 500 mg developed cramps and soft stools.
Additionally, 2 of 7 subjects ultimately receiving 100 mg/day had similar
complaints. The reviewing medical officer felt that stopping the two
higher doses was apparently undue caution because in a memo of March 24, 1975,
he states, "it is a general practive in clinical pharmacology that if a
given dose of drug does not cause prohibitive clinical adverse reactions
the next step would be to try multiple doses of this drug." He apparantaty
did not take into consideration that repeated doses of a drug may be
more toxic than a single dose and, therefore, subacute toxicity studies
must be approached in a cautious step-like fashion starting at a dose well
below the lowest dose in animals not causing toxicity in subacute animal
studies.

Thus if we are to criticize the company the investigatork and the review committee with poor judgement, should we not also bring the matter to the attention of the medical officer in question. At the same time, I believe the supervisory medical officer should be commended for his prompt intervention in this matter.

In the interim, Mr. Weinstein's letter has been located and is submitted herewith.

Reference is made to your Notice of Claimed Investigational Exemption for a New Drug for WIN 34,384, IND 10,694.

We call your attention to the recent phase I tolerance study conducted by Dr. Samuel Bachrach at the Worcester County Rehabilitation and Detention Center. The protocol involved 3 groups of 7 subjects each, simultaneously started on doses of 100 mg b.i.d., 250 mg b.i.d., and 500 mg b.i.d., respectively. We recognized that neither the animal studies nor the single dose human study reported in this IND IND supported the safety of the high doses of this regimen. in subsequent telephone Contacts between or. John winkler of our Division of Surgical and Dental Drug Products, and your representative, Dr. J. Short, the study was modified as per your submission of June 26, 1975. Further, we find that your protocol design was highly unusual. As you are aware, it is desirable to perform rising dose tolerance studies sequentially so that the safety of the lower dose is established before proceeding to the next higher dose.

Unfortunately, we have encountered other examples in which phase I studies were apparently designed to secure safety information promptly, but at the same time placed the subjects at unnecessary risk. Such Studies had led to concern with regard to the use of prisoners as Subjects in investigational drug trials. Therefore, it is incumbent upon the sponsors of drug research in this country to be especially Vigilant in the design of proper phase i protocols.

If you have further comments or if we have not fully understood the mechanics or intent of the protocol in question, please let us know.

Sincerely yours,

Carl M. Leventhal, M.D.
Deputy Director

Bureau of Drugs