CATEGORY (USE OF DRUG): Injectable silicone fluid for soft tissue

augmentation.

DOSAGE FORM: 2.0 ml. glass ampules containing 1.5 ml. of Dymasyl.

to the

The value

in water

It remains liquid under all ambient conditions associated with
tissue viability.

While

Safety: Adverse reactions which were evaluated by the investigators included erythema, edema, ecchymosis, pigmentation loss or pain. all of these reactions were seen in the majority of patients treated, most were not of a severe or lasting nature.

The only reaction resulting in an unsatisfactory result (according to sponsor) occurred in a patient in which the drug was used to augment the subcutaneous tissues of the calf of the leg. Three months later the patient developed tender, red nodules within and beneath the skin. These persisted over a period of many months, responded to steroid therapy, but recurred on several occasions. Ultimately the patient underwent surgical removal of as much of the drug as was possible. investigator in this case has recommended that the material not be used in lower extremities. He notes that he has heard of one other such case and treated a third patient (injected elsewhere) with identical symptoms in the thigh region.

The

In two case reports submitted by Dr. Rees mention is made of swelling or palpable nodes in the region of injection. In a case report submitted by Dr. Murray it is stated that some of the injected drug started to migrate and an attempt at aspiration was made.

Evidence of safety over the long-term is not sufficient. This drug has been in investigational use for ten years, and was used for several years prior to the filing of the IND. An evaluation of ten year results should be possible.

RECOMMENDATIONS

The sponsor should be requested to respond to the following:

No case reports have been submitted for any patient treated sub-
sequent to 1972. If no patient has been treated since that date
this should be so stated. If any investigational studies have been
performed since 1972 full reports concerning these studies should
be submitted. If investigations are ongoing the amount of drug
shipped to each investigator should be stated. This should be
stated as the total amount shipped prior to submission of the NDA
as well as the amount per month since submission of the NDA.

Final evaluation forms and/or copies of office or hospital records should be submitted for the patients treated by Dr. Thomas D. Rees and eleven of the patients treated by Dr. Milton T. Edgerton.

In the studies conducted by plastic surgeons it is noted that 624 patients were enrolled in the studies. In various tables the

number accounted for is 616 (Table 12-2

page 01142), 606 (baseline

severity evaluation), 626 (Tak a 12-6 page 1152), etc. Further,
the information in Table 12-2 appears to be similar to that in 12-
6, but the percent of patients said to be evaluated as adequate or
better is not the same in both tables. Clarification with regard
to these seemingly conflicting numbers is requested.

The reporting of overall incidence of reactions (page 01156) is
confusing, particularly the portion which refers to Major Physician
Role. In this regard it is noted that a total of ten subjects
manifested some effect on long-term follow-up. Please identify
these patients so that their case reports may be further reviewed.
It is stated that 129 patients had reactions of a moderate to
severe degree, and these patients should be specifically identified.
With regard to patients who failed to complete therapy it is noted
that 487 of those enrolled in the study by Dr. Norman Orentreich
failed to complete therapy. A more detailed explanation, or follow-
up, of these patients is required. In other statements concerning
patients who failed to complete therapy the number is variously
listed as 1,986, 1,717, 1,519, etc. Clarification is requested.
Also, these should be identified by patient number and investigator.
The patients treated by Dr. Orentreich who did, and did not, complete
therapy should be identified by patient number so that a more
comprehensive review of these patient records may be undertaken.

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ng-term follow-up information should be obtained on as many

ents as possible. This should be particularly true of patients were treated five or more years ago, and those receiving 20 ml. more of drug. Follow-up examinations should include a complete physical examination, clinical evaluation of the results of therapy, photographs, (particularly in cases where earlier photographs are available) liver function studies (alkaline phosphatase, bilirubin, LDE, SCOT, SGPT), SMA 12, and other tests or evaluations as indicated. It should be ascertained whether any patient required further medical therapy as a result of having received Dymasyl.

01293.

rmation, including follow-up, original office or hospital requested for the following patients:

9-011, 8-030, 8-041 8-153, 8-154, 8-055 (cause of
and
autopsy report), 8-065 (cause of death and autopsy
ort)3-010, 8-117.

the age: patients in column 1 of table on page

It is noted that Dr. Franklin L. Ashley is both medical monitor and
investigator. Henceforth he should either cease investigational
work with this drug, or a new medical monitor who is not an investigator
should be chosen.

The package insert will require revision, but final comments will be withheld pending submission of additional data.

This application is not recommended for approval under Section 505 (b) (1) and (6).

Dr. KESSLER. Certainly, anything that goes beyond true research should not be permitted under the IDE. Let me let Mr. Sheridan, who may have some knowledge of that IDE, comment, if he would. Mr. SHERIDAN. Mr. Chairman, we shared the concern in the agency about injectable silicone as far back as the late 1960's and early 1970's. As you know, at that time, we were aware of its use and extended, to the extent that we could, our authority under the statute to define injectable silicone as a drug, because we didn't at that time have strong enforcement authority for medical devices. Consequently, it is now called a transitional product, and the Center for Drugs, the then Bureau of Drugs, required investigational applications for its use.

I am not intimately familiar with all of the details of the very early Dow study, but my recollection is that it was for very broad purposes, for severe facial deformities and for-by the way, the information-some of the general information about this application that I am discussing is available to the public. I can't get into a lot of detail, but I can certainly discuss with you the nature of the study. It was for severe facial deformities. It was also for minor cosmetic corrections.

Mr. WEISS. But our question is, why were clear violations of proper study protocol just simply ignored?

Mr. SHERIDAN. I believe, sir, that-I'm sorry. I am taking too long to answer, but I think I will.

Mr. WEISS. You are.

Mr. SHERIDAN. I think that the extensive use occurred primarily in the cosmetic area. I can't say why at that time regulatory action was not taken. But I can say that in 1978, when Dow reappliedand, again, I believe I am able to talk about this-we issued another investigational license to them under our IDE provisions, and we limited its use, having known about some of the abuses that occurred earlier, to severe facial deformities, and they were limited to 130 or so patients.

So I think that reflected a recognition of some of the shortcomings of the earlier study, and we controlled that one very carefully. Mr. WEISS. I would like Dr. Mishra, who I think is somewhat more familiar with this matter, to respond to the question that I asked as to why the study was not monitored more carefully. Would you, before you sit down, raise your right hand. [Witness sworn.]

Mr. WEISS. Please pull your chair closer to the microphone.

Dr. MISHRA. Mr. Chairman, I would appreciate it if you would repeat the question.

Mr. WEISS. Yes. Between 1968 and 1975, Dow Corning gave FDA several reports on the results of their study of injectable silicone. The reports showed that several investigators of this FDA-approved study injected hundreds of patients who were not part of the study, and this was illegal. One of our witnesses this morning described this Dow Corning study as experimental treatment disguised as research. Yet FDA continued to allow Dow to conduct studies of injectable silicone. Why?

Dr. MISHRA. I have no explanation of that. I was a technical reviewer on this area, but I cannot give an explanation of why no