102 ND CONGRESS

2d Session

HOUSE OF REPRESENTATIVES Report 102-1064

IS THE FDA PROTECTING CONSUMERS FROM DANGEROUS OFF-LABEL USES OF MEDICAL DRUGS AND DEVICES?

NOVEMBER 19, 1992.-Committed to the Committee of the Whole House on the State of the Union and ordered to be printed.

Mr. CONYERS, from the Committee on Government Operations, submitted the following FORTIETH REPORT together with SEPARATE AND ADDITIONAL VIEWS BASED ON A STUDY BY THE HUMAN RESOURCES AND INTERGOVERNMENTAL RELATIONS SUBCOMMITTEE

On October 1, 1992, the Committee on Government Operations approved and adopted a report entitled "Is the FDA Protecting Consumers From Dangerous Off-Label Uses of Medical Drugs and Devices." The chairman was directed to transmit a copy to the Speaker of the House.

I. INTRODUCTION

Under the House of Representatives Rule X, 2(b)(2), the Committee on Government Operations is authorized to "review and study, on a continuing basis, the operation of Government activities at all levels with a view to determining their economy and efficiency." The committee has assigned this responsibility, as it pertains to the Department of Health and Human Services, to the Human Resources and Intergovernmental Relations Subcommittee.

Pursuant to its authority, the subcommittee conducted an oversight investigation of the Federal role in regulating the "off-label" use of medical devices and drugs. The primary emphasis of the investigation was on the policies and activities of the Food and Drug Administration [FDA].

Under the Food, Drug, and Cosmetic Act, manufacturers may promote a drug or device for uses that the FDA has determined are safe and effective. "Off-label" uses are those that the FDA has not determined to be safe or effective, either because the manufacturer did not submit an application requesting approval for such uses, or because the FDA did not approve an application that was submitted in support for such uses. Promotion for off-label uses is considered misbranding, and is therefore illegal under section 502(a), 502(f)(1) and 505. 1

The investigation focused on three products that are widely used for cosmetic purposes for which the manufacturers have not provided data on safety or effectiveness. Retin A is approved for acne, but is now primarily used for wrinkles and precancerous skin conditions; it has not been proven safe or effective for either, but has been promoted for both. Silicone injections have been considered not safe or effective for humans for more than 20 years, but continue to be used for breast augmentation, and more recently, for wrinkles, scars, and lip augmentation. The silicone liquid that is used for injections is easily available because it is approved for other uses, such as lubricating syringes. Collagen injections are approved for improving the appearance of wrinkles and scars, but not for the lip enlargements that are currently popular.2

On June 11, 1991, the subcommittee conducted a hearing on the potential dangers of the off-label uses of Retin A, liquid silicone, and injectable bovine collagen. This hearing included testimony of FDA officials including the FDA Commissioner, Dr. David A. Kessler, as well as his Chief of Staff, Joseph Levitt; Ms. Ann Witt, Acting Director, Division of Drug Marketing, Advertising and Communication, Center for Drug Evaluation and Research; Mr. Kenneth Feather, Branch Chief, Drug Advertising Regulation; Mr. Robert Sheridan, Director, Office of Device Evaluation,' Center for Devices and Radiological Health; Mr. Joseph Arcarese, Director, Office of Training and Assistance; Ms. Margaret Jane Porter, assistant general counsel; and Dr. Nirmal Mishra; Division of Surgical and Rehabilitation Devices. Other witnesses included Dr. George Lundberg, editor of the Journal of the American Medical Association; Dr. Lawrence Solomon, head of the department of dermatology at the University of Illinois College of Medicine; Dr. Robert Katz, clinical assistant professor of dermatology at the Georgetown University School of Medicine; Dr., Marc Lappe professor of health policy and ethics at the University of Illinois College of Medicine; Dr. Richard Beauchamp, a medical epidemiologist for the Bureau of Disease Control and Epidemiology of the Texas Department of Health; Ms. Nancy Meader of Saunderstown, RI; Ms. Jane King of Plainville, MA; and Ms. Laurie Lehman of Palo Alto, CA.

II. BACKGROUND

A. RETIN A

Retin A (topical retinoic acid, also called tretinoin) is a cream with an active ingredient derived from vitamin A, which is made by Ortho Pharmaceuticals, a subsidiary of Johnson & Johnson. In 1971, Retin A was approved by the FDA for the treatment of acne, but it is currently more widely used for photoaging. Photoaging has been compared to the premature aging of skin caused by exposure to the sun. Symptoms include wrinkles, aging spots, and precancerous skin conditions as well as malignant neoplastic growths.

Retin A was considered an effective anti-acne cream when the number of prescriptions suddenly more than doubled, from 209,000 to 467,000, between December 1987 to February 1988.3 This dramatic increase was apparently a result of its widespread off-label use for wrinkles and related symptoms of photoaging, following a January 22, 1988, press conference. The press conference, funded by Johnson & Johnson, publicized an article and editorial that was about to be published in the Journal of the American Medical Association [JAMA], praising the effectiveness of Retin A as a treatment for wrinkles. The increase was attributed to this unapproved use, since other acne medications did not experience a similar increase in sales at that time. According to an FDA analysis, the increase was primarily due to a "notable change" in the number of prescriptions for women aged 40 and older . 4

The sudden popularity of Retin A continued; between 1987 and the end of 1988, sales almost quadrupled from $33.5 million to $115 million. 5 The JAMA article that was discussed at the press conference, entitled "Topical Tretinoin Improves Photodamaged Skin: A Doubleblind Vehicle-Controlled Study," described 30 patients who applied Retin A (tretinoin) to one forearm and a cream with all the other ingredients except tretinoin on the other . 6 They reported that, after 16 weeks, 'All 30 patients who completed the study showed statistically significant, improvement in photoaging on the tretinoin-treated forearms, but not on the [other] forearms. Fourteen of the 15 patients who received tretinoin to the face had improvement in photoaging, whereas none of the vehicle-treated patients' faces improved."

The accompanying JAMA editorial by Dr. Barbara Gilchtest, a professor at Boston University, entitled "At Last! A Medical Treatment for Skin Aging," described the study as "strong evidence that the wrinkling, sallowness, roughness, and mottled pigmentation characteristic of habitually exposed skin of middle-aged and elderly Caucasians can be improved within a four-month period by daily topical application" of Retin A . 7

Dr. John Voorhees, an author of the JAMA article and professor at the University of Michigan, praised Retin A at the press conference, and he and Dr. Gilchrest appeared on TV networks on morning news shows, evening news shows, and talk shows." They were also interviewed for major newspapers and magazines. It was not disclosed that they had major financial ties to Ortho Pharmaceuticals, either in JAMA or in the mass media, until Money magazine published an investigative story in 1989.9 Although JAMA had at the time a policy requiring authors to disclose their financial relationships to a product when they submitted their articles for publication, no financial information was disclosed by the journal."10

According to Dr. George Lundberg, the editor of JAMA, the journal's disclosure policies were strengthened in October 1989, and he testified that if the articles had been submitted after that date: The authors would have to disclose any financial interests that they had in relation to the industry or the product to us in writing. All authors must now sign a form saying they have disclosed, and we have a list of the things that they must disclose. And then we decide whether or not to disclose this on to the reader; usually, we do. If it is substantial, we always do. If it is trivial, well, we don't bother with it, because we think it is an editorial judgment as to what the reader needs to know. But, presumably, we would have had this information disclosed to us fully. I can't promise that, because it's still the good will and correctness of the author, although they sign an attestation which we keep in a file. I think, by and large, authors are honest with this at this time. . . . We would then, with those articles in 1988, have disclosed to the reader any such financial ties that were there, as we now do. 11

At the same time that JAMA strengthened their financial disclosure policies for authors, the New England Journal of Medicine initiated a policy that prohibited the publication of editorials written by individuals with financial ties to the product being described. Under that policy, Dr. Gilchrest's editorial would not have been accepted for publication because of her consulting and grantee, relationships with Johnson & Johnson. In addition to the physicians who published the research results, other physicians also served as paid spokespersons for the product. For example, Dr. Albert Kligman was widely quoted about the benefits of Retin A, and was usually described as the inventor of Retin A and a professor of dermatology at the University of Pennsylvania. The fact that he received royalties for each Retin A tube that was sold was not mentioned. In addition, Dr. Lynne Drake participated in the press conference and was available for interviews; her credentials were described in detail in her press biography, including her membership on the Board of Directors of the American Academy of Dermatology, and her positions as president of the National Women's Dermatology Society, and a former Robert Wood Johnson Health Policy Fellow who worked for Senator Robert Dole. 13 However, the biography distributed to press neglected to mention that her activities on behalf of Retin A were paid by the company.

B. SILICONE INJECTIONS

Silicone injections were first used to enlarge healthy breasts in Japanese women in the late 1940's. 14 The practice spread to the United States, primarily in California; Las Vegas, NV; and Texas. However, there were obvious problems of silicone migrating to other parts of the body, and attempts to improve success by mixing the silicone with "scarring agents" to keep it in place resulted in other problems, including silicone extruding through the breast. Systemic illnesses were also attributed to silicone injections, and several deaths were reported, one as recently as 1981.',' In some cases, surgical removal of the breasts was necessary. 16 By the 1960's, it had become clear that injections were dangerous, and silicone gel implants became the preferred treatment.

The FDA did not regulate the use of injectable silicone until 1965, when Dow Corning Corp. applied for a Notice of Claimed Investigational exemption for a New Drug [IND].17 This IND was for clinical trials for facial augmentation, not breast augmentation. The research continued from 1965 through the mid-1970's, except for an 18-month period.

In 1967, Dow Corning Corp., the manufacturer of liquid silicone, was indicted for distributing liquid silicone in interstate commerce for human use, in violation of FDA law.18

However, silicone injections continued, and problems continued to be reported. For example, in 1973 physicians reported- the migration of silicone from the breasts to the abdominal wall in a 22-year-old woman who had received injections by a plastic surgeon 2 years earlier. 19 According, to Dr. Norman Anderson, a professor of surgery at Johns Hopkins Medical School and former chairman of the FDA General and Plastic Surgery Advisory Panel, "Efforts by the physician community and the FDA caused a halt in liquid silicone injections into the breast. No ethical physician would do that today." 20 However, according to Dr. Robert Katz, clinical assistant professor of dermatology at Georgetown Medical School, silicone injections in the face are openly discussed in lectures by dermatologists, and the dangers are not widely known.21

In 1975, Dow filed a new drug application [NDA], requesting approval for the sale of liquid silicone for use in treating facial "soft tissue contour defects" such as wrinkles, acne scars, and more severe disorders such as facial atrophy.22 Although serious problems resulting from liquid silicone had been reported in medical journals, Dow Corning claimed that these complications were due to impure or adulterated silicone, improper injection technique or inappropriate selection of site, use of an excessive volume of silicone oil, poor patient selection criteria, or use in the mammary gland . 23 They also claimed that to the best of their knowledge, no proven cases of complications involving their medical grade liquid silicone 350 dymasyl had been demonstrated.24

The FDA did not approve Dow Corning's application' to market liquid injectable silicone for several reasons. Lifetime animal studies are required for approval, but the company's 2-year rat study had been discredited because not all the animals were accounted for.25 Moreover, the data from the clinical trials were considered incomplete because the investigators failed to provide data on at least 1,519 patients who failed to complete treatment; FDA reviewers pointed out that the number of patients whose treatment was not completed and who were not evaluated as par he study may have been as high as 1,986. 26 In addition, there was evidence from animal studies conducted by two independent laboratories that the silicone could cause birth defects, whether injected or applied to the skin." As a result of these problems, the FDA's Bureau of Drugs concluded in 1976 that liquid silicone-would not be approved, and that any future clinical testing should be limited-to major cosmetic defects, instead of wrinkles and small scars, and not include pregnant women. 28

The Medical Device Amendments of 1976 resulted in the regulation of injectable silicone as a medical device instead of a drug. The investigational use of injectable silicone has been restricted since 1976, by Investigational Device Exemption [IDE] regulations. 29 Since they had failed to obtain FDA approval for the sale of their product, Dow Corning sought FDA approval to continue research that could be used to obtain approval in the future. In 1978, Dow Corning received FDA approval to sponsor a 3-year clinical study, with at least a 7-year followup, to evaluate the safety and effectiveness of liquid silicone for the most severe facial deformities." An example of a severe deformity is progressive facial atrophy caused by Romberg disease, a disease characterized by the degeneration of skin, nerves, muscles, and sometimes cartilage and bone, usually on one side of the face. 31 The onset of Romberg disease is during the first 20 years of life; although the disease is painless, it can be emotionally devastating. The Dow study was approved for the treatment of 300 people, although only 128 patients were treated.

The FDA has never approved studies of injectable silicone for any other research involving soft tissue augmentation, or for general use. 32 Nevertheless, doctors have continued to treat patients using silicone injections, and since the 1970's liquid silicone has become increasingly popular for facial treatments, including wrinkles, scars, and lip enlargement. The FDA was aware of this illegal activity, and in March 1979, published an article warning that, "Despite its popularity, Most liquid silicone surgery practices are condemned by both the FDA and the American Medical Association . 33 The article described the "serious and sometimes fatal complications" as including "swelling, discoloration, cyst formation, and migration of silicone particles to the brain, lungs, or heart."

The FDA has made several efforts to publicize the dangers of silicone injections. For example, in January 1983 an FDA official wrote to the editor of Cosmopolitan magazine to complain about a November 1982 article describing the benefits of silicone facial injections for "wrinkles, deep expression lines, [and] scars from acne or chicken pox." 34

1. Published research on silicone injections

For many years, there have been articles in medical journals describing the dangers of silicone injections.For example, in 1978 an article in Plastic and Reconstructive Surgery described "five patients who had severe complications after the injection of liquid silicone for facial augmentation." 35

These patients included one man and four women, whose injections resulted in severe pain, inflammation, swelling, and/or Cushing's syndrome. At least four of the patients received medical grade silicone.An article published in a dermatology journal in 1989 described leg ulcers that a woman experienced 23 years after receiving injections of silicone to improve the shape of her legs.36 Although there was a long lag time for the ulcers, 10 years after the injections she had pain and a progressive purple discoloration on both calves. The injected silicone was of unknown purity.

A case report published in 1990 described a 46-year-old Korean woman who had silicone injections to augment the bridge of her nose in 1964, at the age of 22, while living in Korea." Six years later, she developed pain beneath the left eye, which progressed for 8 years until a nodule appeared. Between 1979-82, she had seven operations in the United States to try to remove all the silicone. There was extensive inflammation and fibrosis. The woman's face was horribly deformed and many reconstructive surgeries were necessary, including eye socket reconstruction. Again, the injected silicone was of unknown purity.

C. COLLAGEN INJECTIONS

Collagen is a protein that is found throughout the human body. Since 1981, injectable Collagen made from cow skin has been marketed by the Collagen Corp. for cosmetic use under the names Zyderm I and II and Zyplast. 38 In the early 1980's, consumers were sometimes told about collagen injections when they wrote to the FDA requesting information about silicone injections for wrinkles and scars.39 When consumers asked about silicone injections, which were not legal, the FDA responded by explaining that silicone injections were not approved for wrinkles and scars, and implied that the person making the inquiry should consider collagen injections instead. Collagen injections are approved for "soft tissue augmentation," treating wrinkles, acne scars, and other facial problems. Most patients are women, but approximately 20% percent are men. However, after the actress Barbara Hershey had collagen injections in her lips for her role in the movie "Beaches," a fad was born: Pouty lips. 40 Lip injections are not approved by the FDA because there are muscles in the lips that could be damaged, and because they are not aimed at treating contour deformities; Collagen Corp. has never submitted a supplementary application to the FDA proving the safety or effectiveness of the procedure.

The cosmetic effects of collagen injections are temporary, usually lasting a few months. Although the company advertises that the treatment lasts 3-12 months, those results are mainly based on research on the treatment of scars; research on wrinkles indicates that it may be effective for only 2-4 months.41

Prior to receiving injections in the face, prospective patients receive a small test dose of collagen in the arm, to determine whether they are allergic to the drug. If the area of the test forms a red lump, no treatment is given. However, between 1-6 percent "pass" their test, but nevertheless have an allergic reaction to the treatment that can be very unattractive and can last up to 3 years. 42 This is a known and admitted risk; for example, the company claims that only 1.3 percent have adverse reactions to Zyderm I, usually "localized swelling and erythema." 43

III. FINDINGS AND CONCLUSIONS

A. SERIOUS SCIENTIFIC QUESTIONS REMAIN ABOUT THE SAFETY AND EFFECTIVENESS OF RETIN A FOR WRINKLES

There is general agreement that Retin A sometimes makes the skin appear more youthful; the controversy is how well and why Retin A works. The initial claims that the cream makes skin more healthy have been attacked by scientists who believe it may have the opposite effect. According to Dr. Robert Katz, clinical assistant professor of dermatology at Georgetown University, some physicians believe that Retin A makes the skin look less wrinkled by irritating it. In his subcommittee testimony, he described a recent study published in the British Journal of Dermatology, which found no difference in skin thickening and increased blood supply when Retin A was compared to abrasive soap.44

In the British study, 12 patients were treated with Retin A (.05 percent) and abrasive soap on their forearms for 8 weeks. The authors state that the changes in the skin produced by Retin A that are considered "to indicate a specific antiphotoaging effect" were also achieved by the abrasive soap. In their evaluation of the biological changes that could influence appearance, the authors claimed that "there was an even greater increase in total skin thickness" of the skin treated with-the abrasive soap, and an increase in the skin blood flow that was not found in the skin treated with Retin A. They concluded that the abrasive soap "can have similar and even more dramatic effects on the parameters chosen to judge the antiphotoaging effects" of Retin A. Their findings therefore support the testimony that the apparent benefits of Retin A on appearance may be due to the irritation caused by the product, rather than healing or other beneficial physiological effects.

Similarly, Dr. Lawrence Solomon, head of the department of dermatology at the University of Illinois Medical School, testified that, "There is a direct tie between the irritation the drug produces and the swelling which temporarily causes wrinkles to 'disappear.' If the harmful effect is that which makes you look better, one might just as well slap oneself silly and achieve the same results." 45

Both Dr. Katz and Dr. Solomon testified that the physicians who evaluated the "improvement in fine wrinkles" of the patients who were treated with Retin A may have been biased, because they could have determined which patients were receiving the Retin A and which were treated with placebo.

Clinical research is supposed to be "double-blind," which means that neither the patients nor the health professionals evaluating them know whether they are receiving the experimental treatment or a placebo. Double-blind studies are conducted to minimize the bias that can occur when researchers want to prove that a treatment is effective.16 Dr. Katz and Dr. Solomon testified that the published studies were not double-blind because most of the subjects using Retin A suffered from skin irritation, compared to virtually none of the placebo group, making it obvious who was using Retin A. Foe example, in the original study published in JAMA in 1988, 92 percent of the patients experienced skin irritation. 47

This irritation would make it obvious that the patients were being treated with Retin A, and since the physicians who were treating them had financial relationships with the company that makes Retin A, their judgement of whether the wrinkles "improved" could have been biased,whether intentionally or unintentionally.

This point was clarified by Dr. Katz in his testimony: [A]nybody, any physician or any layperson, who thinks about a fine wrinkle realizes how subjective that is. In the original study, almost all patients recognized slight im-provement of fine wrinkles [including the patients who were treated with placebo]. This is very, very subjective, and the only way that [the results are] believable is if you have a control group. The authors claimed to have a control group, but this was clearly not the case, because the control[group] was clearly recognizable from the- Retin A cream [group] because of Retin A's irritancy. 48

One essential component of the promotion of Retin A for wrinkles was the "before-and after" photographs that were made available in published articles and in media interviews. The sometimes dramatic changes portrayed as resulting from Retin A seemed conclusive proof that the drug was effective. However, there is evidence that at least some of the "before and after" photos were misleading. An analysis conducted by the deputy chief of the Time/ Life Photo Lab concluded that changes in lighting and camera angles could have affected the appearance of wrinkles, making the drug seem more effective than it really is." 49

If Retin A is ineffective for wrinkles, that means that millions of dollars are being wasted on its use. However, in addition to the question of effectiveness, Retin A poses safety questions as well. Retin A is known to cause skin to become more sensitive to sun light, so that patients are warned that they must use a sunscreen whenever they are outdoors. In some cases, if patients are not adequately warned or not sufficiently careful, severe, painful sunburn can result, causing blisters or even long-term skin damage.50

For example, Ms. Nancy Meader of Saunderstown, RI, testified that she was given a prescription by a physician's assistant who did not describe the correct way to use it.51 She applied it thickly around her eyes; after 4 days of use, she had a severe sunburn-type condition around her eyes, which caused wrinkles and leathery skin for several years. To this day, she must take extensive precautions before going outside in the sun.

In addition to questions of whether Retin A is potentially dangerous because it makes the skin more sensitive to sunlight, there is research evidence that Retin A may present a risk of birth defects, since it is molecularly similar to Accutane, an acne medication which has been linked to serious birth defects. A letter published in the New England Journal of Medicine in 1989 reported that the intake of a major ingredient of Retin A, 13-cis-retinoic acid, during pregnancy "results in high placental and embryonic concentrations of all-trans-retinoic acid," a known cause of birth defects. 52

In 1989, an NIH Consensus Conference concluded that, "There is no available information regarding long-term positive or negative effects of Retin A and similar compounds for treating sun-induced wrinkles," 53

Ortho Pharmaceuticals has never applied for FDA approval for Retin A for the treatment of wrinkles. Instead, the company appears to be focusing its efforts on gaining FDA approval for a slightly different product, an emollient cream called Renova, with the same active ingredient. However, a New Drug Approval [NDA] application for Renova was withdrawn by the company in March 1991 in response to the FDA's criticisms about the quality of the product and concerns about systemic absorption resulting from chronic use. 54 Nevertheless, even after the application was withdrawn, some physicians with ties to the company continued to praise the effectiveness of Retin A and Renova, and publicly claim that they were being reviewed by the FDA and would soon be approved. 55

At the time of the hearing, the Renova application had been withdrawn, but it was resubmitted later in 1991. On April 9, 1992, the FDA advisory panel recommended that it be approved with labeling specifying that it can improve the appearance of mottled pigmentation, roughness of the skin, and fine wrinkling; the panel rejected the claim of evidence that it "heals" or "treats" sun damaged skin.56 The studies submitted by the company all compared Renova to a nonirritating cream; the results showed that many patients receiving the placebo cream also rated their wrinkles and skin texture as improved. The British study compared Retin A to an abrasive soap was not discussed at the advisory panel meeting.

B. THE SAFETY AND EFFECTIVENESS OF RETIN A FOR PRECANCEROUS SKIN CONDITIONS HAS NOT BEEN ESTABLISHED

The use of Retin A for precancerous skin conditions such as actinic keratosis is even more controversial than its use for wrinkles. There is some research evidence that it may improve the appearance of skin lesions, but there is also contradictory evidence that retinoids such as Retin A may be harmful for precancerous skin conditions. Because of these contradictory findings, the NIH Consensus Conference expressed concern about "the conflicting data presented at the conference suggesting that retinoids may inhibit or induce skin tumors in animals exposed to ultraviolet radiation. 57

In 1987, Johnson & Johnson funded 10 researchers to study the effectiveness of Retin A for actinic keratosis, a precancerous condition. According to researchers involved with this study, at least some of the researchers found that Retin A was not effective. The data from the 10 studies were given to Johnson & Johnson, where officials promised to statistically analyze them. The results have never been published or made public, and to date, the company has refused to provide them to the subcommittee. 58 Despite claims of effectiveness made by Dr. Kligman, the inventor of Retin A, and despite years of research funding on the topic, Ortho has never applied for FDA approval of Retin A or Renova for skin cancers or precancerous skin conditions.

Despite the warnings of the NIH Consensus Conference, the media continues to publish stories of Retin A's use for wrinkles and precancerous skin conditions. For example, in 1990 USA Today ran a prominent story quoting Dr. Kligman's presentation praising Retin A at a scientific conference, stating that it showed great promise in the treatment of skin cancers and that new uses for the product "are rapidly multiplying." 59 Dr. Kligman discovered Retin A, holds the patent, had received approximately $190,000 from Retin A sales as of early 1989, and receives funding from Ortho. His financial ties to Retin A were not mentioned in the article. 60

C. FOR MORE THAN 3 YEARS, FDA'S ATTEMPTS TO STOP THE PROMOTI0N OF RETIN A FOR OFF-LABEL USES WERE UNSUCCESSFUL

The 1988 press conference on Retin A resulted in enormous press coverage featuring physicians enthusiastically describing the benefits of Retin A. Although most of the promotion of Retin A was conducted by university faculty members rather than company employees, many of these researchers received funds from Johnson & Johnson. For example, Dr. John Voorhees of the University of Michigan had received four grants predating his January 1988 Retin A article in JAMA, totalling $253,120; he received $689,750 in 1988-89. In addition, he received 24 honoraria and 23 reimbursements for travel from 1987-89, and these also increased after his JAMA article. 61 University faculty acted essentially as paid spokespersons, promoting a drug for an unapproved use. The manufacturer did not pay these researchers directly; in many cases, the money was paid to a third party, such as a university or public relations firm, which then paid the researcher. 62 So, for example, Johnson & Johnson gave grants to Boston University Medical School and to a public relations firm, who then gave money to individual faculty members who praised the drug at professional meetings or in "educational materials." If they were asked if they received funds from the drug company, they said no, and when the company was asked for a list of investigators who received funds from them, those names were excluded.Similarly, when the FDA criticized the company for their promotional activities, the company claimed that the researchers were acting independently, and that their promotional activities were not under the control of the company. For example, in a January 1990 letter to the FDA, a company official stated that, "Ortho has not participated in or directly or indirectly provided funding for any 'public discussions of Retin A and its use in the treatment of photoaging or wrinkling.' " 63

A careful evaluation of various articles and videotapes indicate that the company frequently paid the bills for professional activities that promoted the off-label use of Retin A. For example, Johnson & Johnson paid for several videotapes about Retin A that were sent to physicians. Retin A videotapes dated 1986 credit Boston University for preparing the tape and Ortho Pharmaceuticals for funding; however, more recent tapes gave credit to Boston University but did not mention either Johnson & Johnson or Ortho, even though they provided the funds to Boston University. 64

At the subcommittee hearing, Dr. Robert Katz, a dermatologist in private practice in Rockville, MD, and an assistant clinical professor at Georgetown Medical School, described the effectiveness of the 1988 press conference. His office received 30 phone calls inquiring about Retin A for wrinkles the next day." He also had a large number of patients who asked for Retin A when they came in for other treatments. These requests are particularly noteworthy because Dr. Katz consistently refused to prescribe Retin A for wrinkles.

The dermatologists who testified at the hearing expressed their clear concerns about the role of physicians as paid spokesmen for a product that they are supposed to be objectively evaluating. For example, Dr. Solomon testified:

I have no objection to academics being inventors of drugs; they should be. They should benefit society. However, it becomes somewhat suspect when they are the only investigators of a drug. It becomes totally suspect when they are giving press-conferences, when they are showing up on various talk shows, doing a tour, like an author of a book does a tour-that becomes very suspect.

To publish in a respected journal, such as the JAMA, is appropriate. To give lectures to your colleagues at appropriate meetings is fine. There comes a point where even that should stop and let somebody else put in their word as to whether or not the substance is safe and effective. When you go beyond that, it is promotion. 66

After the 1988 press conference, the FDA began to express their concerns about promotional activities to the company. According to an internal FDA memo, the FDA met with Ortho representatives on February 4, 1988, to "advise caution regarding the release of preliminary data on Retin A" for photoaging.67 This warning was first made 1 month after the press conference that resulted in major media coverage. However, the FDA did not request documents from Ortho until August 31, 1989. Chairman Weiss wrote to the FDA in November 1989 to request information about the FDA's activities; the FDA again made inquiries to Ortho in December 1989. 68

David Banks, Assistant to the Director of FDA's Division of Drug Advertising and Labeling, met with Ortho representatives in February 1990 and expressed concern that recent promotions for a dispensing cap for Retin A failed to indicate that the drug was for use with acne. 69 Banks expressed FDA's view that this omission could be perceived as an advertisement for use for sun-damaged skin, especially given the company's previous promotional activities. According to his memo, "They responded by stating that they had failed to notice this omission . . . and would prevent such actions by the firm in the future." Three days later, Banks was assured that Ortho would insert the words "for acne" in each promotion.In February 1990, the University of Pennsylvania student newspaper reported that, as part of a university lawsuit against Johnson & Johnson, company lawyers had filed a 1983 memorandum describing a plan to "launch" the use of Retin A for wrinkles without FDA approval.70 The memorandum, filed as part of almost 1,000 pages of documents, described a 1983 meeting between Dr. George Thorne of Johnson & Johnson and Dr. Albert Kligman, the University of Pennsylvania faculty member who discovered Retin A. According to the memo, Dr. Kligman advocated an Ortho-supported scientific/educational effort to promote Retin A for photoaging. He stated that it could sell well without advertising and this would be a good idea because the NDA submission that would be necessary to legally promote Retin A for photoaging "would be lengthy, complicated, and likely to fail." 71 [Emphasis added.]

This memo clearly contradicted the company's previous claims of the researchers were independent of the company. On March 6, 1990, FDA's Acting Director of Drug Advertising and Labeling, Ken Feather, sent a memorandum to FDA's Director of the Office of Drug Standards, summarizing concerns about the illegal promotion of Retin A for photoaging. 72 Feather cited the 1983 Thorne memorandum as evidence of the company's intentional promotional activities on behalf of the use of Retin A for photoaging.

According to the FDA, by early 1986 Ortho had started a "massive" campaign that:

. . . vigorously and specifically encouraged administration of Retin A for a wide range of unapproved indications related to photoaging. The campaign vigorously and repeatedly encouraged physicians to administer the drug for these unapproved indications via physician seminars and physician-directed sole-sponsored publications, and Dr. Kligman appeared repeatedly and enthusiastically in these programs. 73

Dr. Kligman played a major role, advocating the use of Retin A for photoaging through physician seminars and nonpeer reviewed publications that were "devoted predominantly to discussions of unapproved uses of Retin A." Ortho paid for many of these publications and medical symposia. In addition, the memorandum described Ortho public relations efforts directed at consumers; physicians compensated by Ortho made media appearances on behalf of Retin A for unapproved uses. According to the FDA, these physicians usually did not disclose their financial relationships with Ortho.

On April 24, 1990, Carl Peck, Director of the FDA's Center for Drug Evaluation and Research (of the Office of Compliance), sent a memorandum to Joseph Levitt, the FDA Commissioner's Chief of Staff, recommending that the FDA should "move expeditiously" to followup on "convincing evidence" of impropriety.74 Four months later on August 20, Peck recommended further investigation because of Ortho's "intent to defraud or mislead." Based on the 1983 meeting between Thorne and Kligman, the August FDA memo specifies that "there appears to have been a conspiratorial effort on the part of Ortho employees and individuals receiving payment . . . to further the public's acceptance of this unapproved therapeutic treatment as safe and effective."

Johnson & Johnson has publicly acknowledged that the case has been referred to the Justice Department for investigation. 75 This request was sent to the Justice Department on December 4,1990. 76 Although this FDA investigation predated the appointment of Dr. David Kessler as the new FDA Commissioner, Dr. Kessler had expressed his concerns about the FDA's need to better regulate prescription drug advertising in an article that was written and accepted for publication prior to his appointment at the FDA. The article, published in November 1991 in JAMA, included the example of Johnson & Johnson's promotion of Retin A as, "One of the most interesting cases in the area of press relations," focusing on the improper use of a university faculty member as a spokesman at the 1988 press conference. 77

In the article, Dr. Kessler criticized the company's sponsorship of a video news release" and stated that if there is a discussion of a study that supports an unapproved use, that discussion "is per se a violation of existing FDA regulations" if it takes place at a promotional event, including a company-sponsored scientific seminar. Although he conceded in the article that "the regulatory fine line between scientific exchange and promotion is extremely fine," in his testimony before the subcommittee 7 months later, he stated:

Physicians may not, under the guise of scientific exchange, involve themselves in the manufacturer's promotion of unapproved uses. In no uncertain terms let me say to the medical community, that we will subject not only the manufacturers, but all those involved in the manufacturer's promotion, to the full force of the law. 78 [Emphasis in the original.]

D. AT LEAST ONE SENIOR COMPANY OFFICIAL BELIEVES THAT THE COMPANY DOES NOT NEED TO COMPLY WITH THE LAW THAT FORBIDS THE PROMOTION OF RETIN A FOR OFF-LABEL USES

At an October 1990 symposium sponsored by the Drug Information Association, a Johnson & Johnson official from their Office of the General Counsel, Peter Bewley, stated that the current FDA prohibition against the promotion of a drug for off-label uses is unconstitutional and unethical. 79 He argued that it is the company's duty to make information available about possible new uses of a drug to the broadest possible audience, in order to give the maximum number of people the opportunity to benefit from the drug. He argued that any drug that has been already approved for one use is probably safe and therefore should be available. 80

This position ignores the fact that even if the usually short-term use of Retin A for acne for teenagers is safe, there is no safety information about the prolonged use of Retin A among the elderly. Older skin absorbs differently than younger skin, and Retin A's use for wrinkles is considered indefinite, since it is used at least twice a week, and its effects are lost when the patient stops using it. The use of Retin A by women in their 30's or early 40's may also be problematic if those women become pregnant; as previously noted, there is concern that the impact on the fetus may be similar to that for Accutane, another retinoid used for the treatment of acne. Finally, as previously noted, there is contradictory evidence about the safety of retinoids for precancerous skin conditions.

E. FDA-APPROVED STUDIES ON LIQUID SILICONE WERE POORLY CONDUCTED AND PUT PATIENTS AT RISK WITHOUT THEIR KNOWLEDGE OR CONSENT

When Dow Corning applied for FDA approval to conduct studies on the use of liquid injectable silicone for facial defects in the mid 1960's, it was well established that silicone injections to the breast were extremely dangerous. It was therefore obvious that the studies of silicone facial treatments needed to be carefully monitored, since the risks were unknown. However, the FDA's own reviews of the Dow Corning studies indicate that the studies were poorly conducted and - poorly monitored.

According to Dr. Marc Lappe, professor of health policy and ethics at the University of Illinois College of Medicine at Chicago, "Patients were generally not told that the material being injected was 'experimental' in nature; that all of it could not be removed once injected; and that adverse reactions, including granulomas and death, had been reported in some patients." 81 Dr. Lappe cited articles published in the medical literature in the 1970's that specified that patients should be told that the injections were irrevocable. In addition, the subcommittee heard testimony and received letters from patients who were completely unaware of the potential dangers of silicone injections, including a woman who received injections when she was only 14 years old. 82 Subcommittee staff interviewed plastic surgeons from several cities, who confirmed that silicone injections could cause facial deformities and described the total removal of silicone injected in the face as "impossible." 83 Dr. Lappe also pointed out that animal studies should always be conducted prior to exposing human patients, to help determine if a treatment is likely to be unsafe.

However, animal studies conducted by Dow Corning indicated that pure silicone could cause chronic inflammatory response. 84 Although these studies were completed as early as 1966, the company did not make this information publicly available. 85

Dr. Lappe testified that the ethical conduct of clinical trials requires that after animal studies indicate that a product appears to be safe, studies should be conducted on a small number of patients. 86 If those results are favorable, only then should a large number of human patients be exposed to an experimental product. However, the original Dow Corning study included thousands of human patients, without first making adequate tests on animals or a small number of humans.

The FDA should have responded to these major shortcomings by refusing to approve Dow Corning's proposed study in 1965; however, the FDA approved the study proposal, and the study was conducted for the next 10 years. In addition to these major problems, the FDA had serious reservations that the study itself was conducted in a thoroughly unscientific manner. An FDA review of the Dow Corning report on their FDA-approved studies conducted from 1965-1975 expressed strong concerns that at least 1,500 women who were treated under the rubric of the study were not medically evaluated and thus not included in the report of the study results. 87 No data were available on the outcome of their treatment. Since all patients receiving treatment were required to be included in the study, this was a very serious violation of the agreement between Dow Corning and the FDA for conducting the study.

The physicians participating in the Dow study reported that most of their patients were improved as a result of treatment. The FDA Medical Officer's review of the application stated that, "Adverse reactions which were evaluated by the investigators included erythema [redness], edema, ecchymosis [ruptured blood vessels], pigmentation loss, or pain. While all of these reactions were seen in the majority of patients treated, most were not of a severe or lasting nature." 88 The Medical Officer stated that Dow Corning only reported one "unsatisfactory result," in which injections caused tender red nodules within and beneath the skin. However, the Medical Officer also mentioned one case where the silicone "started to migrate" and two cases where injections resulted in swelling or palpable nodes in the region of the injection.

Despite the company's claim that patients were satisfied, the FDA Medical Officer concluded that the company's lack of long-term safety information was unacceptable, given that the study had been conducted for 10 years. In addition, the lack of information about a large number of patients made it impossible to determine whether the product was usually safe.At the subcommittee hearing in 1991, then-director of the FDA's Office of Device Evaluation, Robert Sheridan, testified that as a result of the shortcomings of the first Dow Corning injectable silicone study, the second study, initiated in 1978, was controlled "very carefully," " However, when the final report for the Dow Corning study was submitted to the FDA in August 1990, the criticisms of FDA reviewers indicate that it too was poorly conductedand not adequately monitored. 90 The FDA review described the study as an "Uncontrolled, unblinded clinical trial." 91

The FDA determined that the study protocol was violated in many ways; for example, one-third of the patients apparently did not have the severity of facial deformities that was required to participate in the study. FDA's review of the photographic slides indicate that "before" photographs were submitted but "after" photos were often missing or not conclusive because of changes in lighting and other problems. The assessment of outcome was a subjective rating, with no objective measures; moreover, these ratings were missing for 19 percent of the patients. 92 Perhaps most important, half of the patients were followed for less than 4 years; all patients were supposed to be followed for at least 7 years. 93

In this last study, Dow Corning reported that 2 of the 128 patients (1.6 percent) had severe tissue breakdown. This meant that their skin died, requiring skin grafts. The monitor concluded that 4 percent of the patients had severe complications; 7 percent had a fair outcome and 3 percent had a poor outcome. 94 This level of complications was considered acceptable by the manufacturer, but unacceptable by the FDA, considering the short followup time and the relatively modest benefits of the treatment.

F. FOR MORE THAN 15 YEARS AFTER FDA DETERMINED THAT LIQUID INJECTABLE SILICONE WAS NOT SAFE, FDA FAILED TO EXERCISE ITS AUTHORITY TO REGULATE THE PRODUCT

In the mid-1970's, the FDA refused Dow Corning's efforts to have liquid injectable silicone approved for general use, because of reports of problems and the company's lack of objective safety data. However, just as the FDA did not carefully monitor the use of silicone injections by "investigators" participating in the Dow Corning studies, the FDA also failed to respond to the increasingly widespread use of silicone injections by other physicians, Silicone injections were increasingly discussed in women's magazines during the 1980's and early 1990'S.95 The FDA was aware of the articles, since they frequently resulted in letters to the FDA asking about the availability of the product.96

Moreover, the FDA published an article about the risks of liquid silicone in the FDA Consumer in 1979, and in 1983 an official wrote to the editor of Cosmopolitan magazine criticizing an article describing the benefits of silicone injections. 97 However, the FDA did virtually nothing else to protect consumers or to criticize either clinicians or manufacturers.

Despite their inaction, FDA officials were concerned about the dangers of silicone injections and knew that the agency was responsible for regulating the product. The ambivalence of the FDA, reflecting their acknowledgement of their responsibility and their

reluctance to "interfere" with the practice of medicine, is clearly articulated in a May 1, 1981, letter. In that letter, the Associate Director for Compliance wrote that the Federal Food, Drug, and Cosmetic Act:

. . . does not authorize the FDA to regulate or to interfere with the practice of medicine. .

. Moreover, the FDA has historically refrained from attempting to interfere in the doctor/patient relationship. In general, the FDA has not objected to physicians using an approved new drug for unapproved use, when, in the physician's judgment, the drug may provide benefit to a particular person's condition.

However, if a new drug that is the subject of an "IND" is shipped in interstate commerce and the manufacturer, his agent, or any other person directly or indirectly suggests to the physician doing the investigational studies, or to the patient to whom the investigational new drug is to be administered, that the drug may properly be used for other than an investigational use approved under the "IND," such action constitutes a direct violation of the Act. Use of an investigational new drug by any person other than a sponsor and/or investigator . . . also constitutes a violation of the Act.98

The FDA official described their authorized activities as including, but not being limited to, "restricting the channel of distribution, or withdrawal of approval in the case of 'approved new drugs'; revoking the IND in the case of an investigational 'new drug' and invoking statutory 'sanctions' such as seizure and/or injection when appropriate." She also wrote that physicians cannot legally inject silicone for soft tissue augmentation unless the physician is a sponsor and/or an investigator. However, sanctions "would, of course, depend upon the resources available to FDA, the hazard involved, and the particular circumstances in a given case." 99

During the 1970's and 1980's, the FDA agents followed up on accusations of misuse of silicone injections. For example, in 1984, the FDA interviewed Dr. Richard Aronsohn of Los Angeles, who admitted that he injected liquid silicone in patients, but claimed that he had purchased his supply in 1962, when its sale was still legal. 100 According to the FDA memorandum of the meeting, Dr. Aronsohn told the FDA investigator that he could legally inject mud in his patients if he wanted to. Dr. Aronsohn refused to tell the investigator how much silicone was in his possession or to show him his supply. He also stated that since he was not an investigator in the Dow Corning study, he did not need to report his patients' results.

In 1985, Walter Gundaker, Director of the FDA's Office of Compliance, Center for Devices and Radiologic Health, wrote to the Director of the Office of Enforcement about their plans to "pursue the recommended Grand Jury Investigation of 'Dr. Robert Russell"' who was selling liquid silicone to physicians. However, according to a July 24, 1984, memorandum, the FDA investigators had been " unable to locate, contact or even confirm the actual existence of a Dr. Robert Russell." 101

The FDA also investigated Dr. Norman Orentreich of New York City, who was originally included in the Dow Corning study (IND) that had been approved by the FDA, and then dropped because his use of silicone for minor facial defects was not an approved use for the Dow Corning Investigational Device Evaluation [IDE] approved in 1978. 102 According to the Dow Corning report in their 1976 New Drug Application [NDA], Dr. Orentreich had treated hundreds of patients that he did not include in his research records. 103 Dr. Orentreich has been quoted in numerous magazine articles as a prominent dermatologist who has injected thousands of women with silicone for wrinkles and other cosmetic purposes. 104 In addition to speaking publicly about his practice, Dr. Orentreich has published articles in medical journals about the results of his injections. 105

The FDA investigated Dr. Orentreich from the late 1970's until the mid 1980's. In November 1983, FDA officials wrote to Dr. Orentreich, warning him that he should not administer silicone without an IDE approved by the FDA; Dr. Orentreich's attorneys responded by claiming that the FDA had no jurisdiction since the doctor manufactured his own silicone, and there was, therefore, no interstate commerce. 106 The doctor used industrial grade silicone, which he could purchase legally, and then "purified" it using a filter and sterilization. 117 The investigation was reported in the New York Times on July 19, l984. In that article, Dr. Orentreich's lawyers again claimed he was not under FDA jurisdiction, and the doctor himself was quoted as saying, "Who is the FDA? A few technicians and one or two doctors?" 108 In a July 24, 1984, memorandum, the FDA District Director from Brooklyn described an ongoing investigation of Orentreich, warning, "So that you will be aware, we have reason to believe that Mrs. Nancy Reagan has been treated by Dr. Orentreich." 109

Despite that warning, the FDA investigation continued, and on March 5,1985, Walter Gundaker, Director of the Office of Compliance, requested a review of a recommended injunction against Dr. Orentreich. In his memorandum, he warned that preliminary findings from the analysis of the "purified" liquid silicone used by Dr. Orentreich and his colleagues indicated that it contained "the same impurities detected in the untreated industrial silicone." 110

It was at this point, when the evidence against Dr. Orentreich suggested that the product he was injecting might be particularly harmful, that the FDA decisions were elevated from the regional office to higher officials in Rockville, MD. According to a July 30, 1985, memorandum to Walter Gundaker, the FDA decided to place "the Orentreich injunction recommendation in permanent abeyance." 111 Gundaker wrote, "Though violations of the law exist and appear defensible, we agree that it would be imprudent for FDA to single out only one physician for regulatory action when it is well known that the practice of using LIS [liquid injectable silicone] is widespread. We also agree that 'practice of medicine' issues should be addressed by appropriate state authorities."

At a subcommittee hearing on a related topic in December 1990, Chairman Weiss asked FDA officials why silicone injections were allowed to continue across the country. 112 They stated that they could not regulate physicians' use of silicone injections, but only the sale of silicone by manufacturers. They also claimed that they were unaware of specific uses of silicone for unapproved uses. The FDA documents made available to the subcommittee clearly indicate that this is not true.

Finally, 5 months after the subcommittee hearing, in November 1991, the FDA sent warning letters to Dr. Orentreich, Dr. Aronsohn, and other physicians who were openly treating patients with injectable silicone. 113 At approximately the same time, the FDA became aware of a network news investigation following up on the subcommittee hearing.

In February 1992, the FDA announced that Dr. Norman Orentreich, his son David, and his colleague Michael Kalman, had signed consent decrees agreeing to stop injecting liquid silicone. 114 Consent decrees were signed by Dr. Aronsohn and another doctor several months later.

G. PHYSICIANS ARE SOMETIMES UNAWARE OF THE DANGERS OF UNAPPROVED MEDICAL PRODUCTS AND OFF-LABEL USES

The widespread use of liquid silicone is a good example of a product that has been found to be unsafe, but which physicians apparently believe to be safe. In the absence of an information campaign by the FDA or any consumer group, silicone injections have been very publicly discussed, usually in positive terms, in newspapers and magazines, and at medical meetings, for more than 15 years.

Lack of physician concern about off-label uses is not unique to silicone injections. Dr. Robert Katz, a dermatologist in private practice testified that dermatologists were not concerned about the fact that Retin A and liquid silicone were not approved for the treatment of wrinkles, because they are accustomed to prescribing drugs for off-label uses. 115 In addition, if the relatively small number of patients who use any specific medication do not complain about adverse reactions, the physicians may have no way to know that other patients have experienced problems. In order to protect patients, it is necessary to make sure that physicians have access to objective information and have training that enables them to understand what kind of research is needed to ensure safety.

Physicians are not usually trained as researchers, and they may have limited knowledge of what constitutes scientific proof of safety and effectiveness. Dr. Katz and Dr. Lawrence Solomon described how pharmaceutical companies develop friendly relationships with medical students that continue throughout their professional careers. For example, Dr. Solomon testified:

[W]hat bothers me is the pervasive influence these pharmaceutical houses have, almost from the first day that students enter medical school. They are given flashlights and little hammers. They are taken to lunch. They are given a variety of small gifts. The little black bag is a drug company gift, for the most part. Books are given to them. I am concerned that there has to be a balance between the right of free association of any individual, including medical students, and excessive interference. . . . When I see them walking around the corridors with pocket-stuffers, which are always visible, no matter which way they are put in, advertising the latest, most expensive antibiotic or highly expensive antihistamine, it disturbs me a great deal. 116

When representatives from these companies inform doctors that a product is safe and effective, those doctors may not be unduly concerned about the fact that the FDA has not yet approved it. In addition to the influence of pharmaceutical company representatives, physicians are influenced by the articles and presentations of colleagues. In some cases, physicians may not realize that the colleague who is praising a medical product at a scientific conference has a financial relationship with the product's manufacturer. For example, in the case of Retin A, Dr. Lawrence Solomon testified, "I find it deplorable that a good number of our most distinguished colleagues are out there promoting [Retin A] for [wrinkles], no matter what evidence there is to the contrary." 117 A related issue is that crucial safety information about a product may be unavailable to the FDA or the public because it is protected by court orders. In the case of research on silicone, Dow Corning studies that were relevant to the safety of injections, as well as silicone gel breast implants, were unavailable to the public for years until several court documents from a breast implant law suit were inadvertently made available to a reporter in December 1991. 118 Even scientists who had examined the documents as expert witnesses believed that they were not able to describe them to congressional investigators or the public. When the FDA and the public are prevented from learning crucial safety information, it makes it difficult for physicians to make informed choices in the treatment of their patients.

H. COLLAGEN HAS BEEN PROMOTED FOR OFF-LABEL USES

Although the FDA has repeatedly told Collagen Corp. that it is not legal for the company to promote the use of collagen for lip enlargement, this use has been widely promoted by physicians in newspaper and magazines articles. The role of Collagen Corp. in encouraging this widespread, off-label use has not always been clear. In recent years, the FDA has repeatedly warned Collagen Corp. that they must not promote lip enlargement because they have not proven it is safe or effective. At first, the company claimed that it should be considered an approved use; the FDA argued that it was not "soft tissue augmentation" because. there are muscles in the lips. In response, Collagen Corp. claimed that there were no muscles in the lips that could be harmed, a claim that they could not support and soon abandoned. 120 The company then claimed they did not "actively" promote such use, but since doctors came to them for advice on how to use injections for lip enlargement, they continued to train those physicians. 121 They required physicians to sign a "waiver" stating that they understood this was not an approved use. 122 It was not until December 1990 that the president of Collagen Corp. notified the FDA that the company would no longer provide training for lip injections. Collagen Corp. promoted lip injections in other ways as well, sometimes defending the treatment with inaccurate statements. For example, in response to an October 1990 Washington Post article describing such injections as not approved, the president of the corporation wrote a letter to the editor that claimed, "The FDA has not restricted the use of injectable Collagen for lip augmentation." 123

At a Paris fashion show in October 1990, Collagen Corp. launched the "Paris lip," which is created with injections at the border of the lips. FDA initially compromised by saying that as long as the injections are not on the vermilion (the red part), such injections can be considered approved. 124 Therefore, the "Paris lip" injections were widely promoted by the company, even after they stopped providing training for lip injections in December 199O. 125 However, the FDA informed the subcommittee in September 1991 that such injections are not approved unless they correct a "contour deficiency." 126

I. COLLAGEN CORP. HAS FAILED TO REPORT ADVERSE REACTIONS TO THE MEDICAL DEVICE REPORTING [MDR] SYSTEM

Off-label uses of collagen are not the only concern of scientists studying the product. The Texas Department of Health has conducted an investigation to determine whether Collagen injections can cause serious reactions, including immune disorders, whether used as approved or off-label. Texas officials concluded that Collagen Corp. has provided inaccurate data on the safety of their product. They claim the company failed to report hundreds of adverse reactions to the FDA's MDR (Medical Device Reporting) system.

For example, Dr. Richard Beauchamp, an epidemiologist at the Texas Department of Health, testified that Collagen Corp. reported only 54 adverse reactions from the more than 6,000 consumer complaints received. 127 The Texas Department of Health concluded that more than 800 systemic reactions, as well as other serious problems, were not reported to the FDA's MDR system. They notified the FDA about that underreporting, and about evidence thatcollagen injections may cause a serious immune disorder called polymyositis/dermatomyositis [PM/DM]. In July 1989,Texas Department health officials contacted the FDA, who then reviewed the company's records of adverse reactions and asked the Center for Disease Control [CDC] for assistance.

In 1990, the FDA reviewed 508 patient files, and concluded that the company failed to report any of the one-third that were serious enough to warrant a report to the MDR. An additional 39 percent of the files had problems that made it impossible to determine whether or not reports should have been filed. The FDA also provided the company with six illustrative examples of cases that should have been reported, including lupus, abscesses, arthritis, and scarring. 128 The company claimed that the examples cited by the FDA were not reportable to the MDR for a variety of reasons: The abscesses and scars were not serious enough to report, and lupus was not reported because the doctor involved did not suggest that the lupus was caused by the collagen. However, this is a classic Catch-22 situation: The company has informed Physicians that collagen does not cause autoimmune disorders, and it is therefore not surprising that the physicians do not report that a case of lupus was caused by the injections.

J. FDA HAS AGREED TO IGNORE SERIOUS ADVERSE REACTIONS, AS WELL AS COSMETIC PROBLEMS THAT LAST LONGER THAN THE POTENTIAL BENEFITS OF COLLAGEN INJECTIONS

After arguing about the underreporting of adverse reactions to the MDR system in the autumn of 1991, FDA officials negotiated a new definition of adverse reactions with Collagen officials. For example, the company agreed to report autoimmune disorders unless the doctor specifically reported that the Collagen "did not or probably did not cause or contribute to the adverse [reaction]." 129

In addition, FDA officials agreed that the company did not need to report scars that lasted less than 6 months or did not yet represent "permanent damage." 130 FDA's compromise on this definition does not seem justified, given that the benefit, which is also cosmetic, frequently lasts only lasts 2-4 months.131

The company agreed to the FDA's requirement that abscesses or infections requiring antibiotic treatment would be considered an adverse reaction requiring reporting, but that abscesses requiring steroid injections, incisions, draining, or topical antibiotics would not. 132 Similarly, pain, redness, or other problems requiring steroids, compresses, or antihistamines would not require an MDR report.

By acquiescing to company pressure to eliminate many negative side effects from the MDR reporting requirements, the FDA has undermined the ability of patients and potential patients to learn about the problems experienced by other consumers. It also makes it more difficult for the FDA to determine the potential risks. Since informed consent depends on accurate information about risks as well as benefits, the FDA has undermined that process by allowing the company to ignore valuable information about adverse reactions.

K. COLLAGEN INJECTIONS MAY CAUSE AUTOIMMUNE DISEASES

Texas Department of Health officials criticized Collagen Corp. for misleading the FDA and the public about the safety of their product, whether for approved or off-label uses. 133 They focused on growing evidence that Collagen injections might cause or trigger autoimmune diseases, particularly two rare, potentially fatal diseases called polymyositis/dermatomyositis [PM/DM]. Their scientific staff determined that at least eight collagen patients had been reported as diagnosed with PM/DM, most within 6 months of their collagen injections. Since PM/DM is such a rare disorder, Texas officials estimated that only 1-2 patients of the 345,000 exposed to collagen would have been expected to contract PM/DM, if the disease was not caused by the collagen.

After the Texas Department of Health contacted the FDA about their concerns in August 1989, the FDA asked the Centers for Disease Control [CDC] for assistance in studying the possible link between collagen and PM/DM. In a March 1990 memorandum, the CDC reviewer described the potential link with autoimmune disease as "an important problem warranting further investigation." 114

According to Dr. Richard Beauchamp, an epidemiologist at the Texas Department of Health, the FDA believed the arguments of Collagen Corp. and therefore denied the possible relationship between collagen and PM/DM, on the basis of faulty assumptions about the number of cases."' In his testimony, he explained that the company assumed that their reported number of cases of immune diseases is the actual number of such cases. Even if the company had accurately reported all the immune reactions reported to them, which the Texas Department of Health and the FDA believe it did not, this would have been unreasonable since it is well known that most adverse reactions are never reported to the companies. For example, a study of adverse reactions to drugs, coauthored by an FDA scientist, concluded that only 18 percent are reported and only 5 percent are reported to the FDA. 136 Therefore, if eight cases of PM/DM were reported as adverse reactions, the estimate would be that the actual number of cases was at least five times as high.

Texas Department of Health officials also criticized Collagen Corp. for overestimating the number of people who received injections; if they overestimated the number of people exposed to collagen, this would make the proportion of patients with immune disorders seem smaller. It is impossible to determine exactly how many people have received collagen injections, because the company counted the number of doses distributed instead of the number of people treated. Since the collagen lasts only a few months, many people receive two or more injections.

Collagen Corp. claims that their estimates of patients took into account the fact that some patients receive more than one dose. However, they calculated the number of patients by assuming that only 25 percent of their patients were repeaters, and that repeaters received half the dosage in their second treatment. This reduced the number by only 12.5 percent. The benefits of collagen injections last for only a few months; if most patients are sufficiently satisfied to seek subsequent treatment, then the estimate of 25 percent repeat customers would cause a gross overestimate of the number of patients who have received collagen injections. This also raises an interesting question from a risk/benefit point of view: If such a small number of patients seek additional treatments, this suggests that the benefits are small, and the potential risks thus become even more important from a regulatory point of view.

The Texas Department of Health also accused the company of underestimating the problems by assuming that all PM/DM cases would be reported among collagen users, even if the PM/DM was diagnosed years after the injections. Their scientists believe that adverse reactions are much more likely to be reported if they occur within 1 year of treatment.137 After the subcommittee hearing, the FDA reconsidered its position regarding the association between collagen and PM/DM. On September 12, 1991, FDA Commissioner Kessler testified that the correlation between collagen and PM/DM was significant at the 91 percent confidence level, which is not as high as the 95 percent confidence level that is considered more conclusive. 138 A few days later, Collagen Corp. announced a labeling change, reflecting "the higher than expected incidence rate of PM/DM." 139 In November 1991, the FDA convened a scientific meeting on the topic, where, "Experts noted that the limitations in the available data make it difficult to be certain about the causal relationship between collagen and PM/DM." 140 The company continues to maintain that collagen does not cause PM/DM, and the FDA has not yet determined whether there is a causal link.

L. FDA HAS MADE REPEATED EFFORTS TO PERSUADE COLLAGEN CORP. TO STOP MISREPRESENTING THE SAFETY OF THEIR PRODUCT

After a February 1991 network television news magazine program on collagen, the FDA issued a Talk Paper stating that the president of Collagen Corp. had misrepresented the safety of the product by falsely claiming there was clear evidence that collagen did not cause autoimmune disorders. 141 The FDA also criticized the company's failure to accurately report all adverse reactions as required by law. Also in February 1991, the FDA ordered a labeling change warning about possible association between collagen injections and serious connective tissue diseases such as rheumatoid arthritis and scleroderma. 142

In February 1991, FDA staff began to discuss the possibility of recommending criminal prosecution of the company, but recommended against it. 143 On May 9, 1991, the San Francisco Compliance Branch recommended seizure of all of Collagen Corp.'s products because of the company's "misbranding." Misbranding referred to the company's failure to report adverse reactions and its promotion of the product for unapproved uses, such as lip enlargement. On August 16, 1991, the FDA announced that the U.S. attorney's office in San Francisco filed a seizure action against injectable collagen products because of the firm's failure "to include a warning on the product's labeling about the possible link between injectable collagen and a broad range of connective tissue diseases. 144 The products' labels were changed in order to resume sales, and then changed again to include stronger warnings about PM/DM.

IV. RECOMMENDATIONS

A. CONGRESS SHOULD GIVE FDA THE STATUTORY AUTHORITY TO OBTAIN ALL INFORMATION NEEDED TO DETERMINE WHETHER RESEARCHERS OR PHYSICIANS ARE RECEIVING MONEY FROM MANUFACTURERS

As a result of information that the manufacturer provided to the subcommittee, the subcommittee was able to determine which physicians and scientists who were extolling the benefits of Retin A had received research grants, honoraria, and consulting fees from the company that makes the product. The FDA did not have access to the same information, because they claim to not have the authority to demand that information from a company or researcher.

There is often a fine line between the sharing of research results and the promotion of a drug. If the FDA is to seriously attempt to enforce the law against the promotion of drugs and devices for off-label uses, they must have the authority to obtain information regarding whether individuals are directly or indirectly paid for their ii sharing of scientific information." The FDA would have this subpoena authority under H.R. 3642, the FDA Enforcement Bill. The committee recommends that Congress pass this legislation.

B. FDA SHOULD ENFORCE PENALTIES FOR THE ILLEGAL PROMOTION OF DRUGS AND MEDICAL DEVICES FOR OFF-LABEL USES

Dr. Lawrence Solomon, head of the department of dermatology at the University of Illinois Medical School, pointed out that sanctions against the illegal promotion of a drug for an off-label use are viewed simply as one of the costs of doing business for some companies, because the benefits of this practice far outweigh the penalties, and the penalties are rarely enforced by the FDA. He testified, "When a drug company earns vast amounts of money from the promotion of a drug, and when the fine for its misuse is tiny, they are going to continue to do it. I mean, it's just good business. It is necessary to make the fine equal to the benefits, and then they will stop doing it. I can't imagine what else would generate a change in behavior from a business." 145

According to the FDA, the usual maximum penalty for the promotion of a drug for an off-label use would be $100,000 for an individual and $200,000 for an organization. However, it is possible to fine a company up to twice the gross gain that resulted from the infraction. 146 Using that formula, the FDA would have the authority to charge fines that exceed the financial benefits of the promotional activity. However, the FDA has not used that authority, and companies believe that they can continue to promote drugs for off-label uses with little risk of substantial penalty.

C. FDA SHOULD REEVALUATE THE SAFETY AND EFFECTIVENESS OF COLLAGEN

In recent years, Congress and the public have strongly urged the FDA to consider making drugs available to AIDS patients, even before those drugs have been conclusively proven effective, because it is widely recognized that such drugs represent the only hope for those patients. The opposite also needs to be considered: For those drugs or devices with limited benefits, such as temporary wrinkle treatments, the FDA needs to more carefully consider the risks.FDA's decision that a facial scar or abscess lasting almost 6 months does not need to be reported to the MDR system-as an adverse reaction seems particularly misguided, given that the cosmetic benefits of the injections are minor and may last half as long.

More importantly, new evidence suggesting a link between collagen use and a life-threatening illness, PM/DM, must be weighed against other new evidence that collagen injections last only 2-4 months in the treatment of wrinkles. When the device was initially approved, research that was primarily based on its use for scars indicated longer-term benefits. As its use for wrinkles has increased, the FDA needs to ensure that patients receive accurate information about risks and benefits. In addition, the FDA should reconsider its approval of this device, as well as its decision to regulate it as a device rather than a drug.

D. RESEARCH OR DEMONSTRATION PROJECTS ARE NEEDED TO INCREASE PHYSICIANS I REPORTING OF ADVERSE REACTIONS TO DRUGS AND DEVICES FOR APPROVED AND FOR OFF-LABEL USES

Collagen is but one of many cases where the subcommittee has found tremendous shortcomings in the adverse reaction reporting system. This must be corrected.

It is a basic flaw in the regulation of drugs and devices that so few physicians report the adverse reactions of their patients to the FDA or manufacturers, either for approved or off-label uses. As computer technology advances, making it possible to make reporting even easier, research is needed to determine how the process can be improved to increase reporting. This could involve developing new incentives for better physician participation, improving the ease of reporting, or eliminating manufacturers as the "middleman" in the reporting process. It may be necessary to fund demonstration projects or other programs aimed at improving the accuracy and timeliness of reporting.

E. FDA SHOULD PURSUE CRIMINAL ACTION AGAINST MANUFACTURERS THAT WILLFULLY VIOLATE THE LAWS REGARDING THE REPORTING OF ADVERSE REACTIONS

Even if physicians improve their reporting of adverse reactions to manufacturers, that will not help consumers unless the manufacturers accurately report adverse reactions to the FDA. The Texas Department of Health investigated Collagen Corp.'s reporting activities and found that most serious adverse reactions were not reported to the FDA under the MDR system. It is unusual for the FDA to receive such assistance from a State Department of Health, but even when the information was provided, the FDA was reluctant to pursue criminal prosecution of the company for their failure to obey the law.

If the FDA is not willing to enforce the law, it will not be surprising if companies do not take those reporting requirements seriously. Enforcement would have an important deterrent effect that would also benefit consumers.

F. FDA SHOULD WORK WITH MEDICAL SCHOOLS TO DEVELOP CURRICULA ON THE IMPORTANCE OF PROVING THE SAFETY AND EFFECTIVENESS OF DRUGS AND DEVICES

In the three examples discussed in this report, it is clear that Physicians were not concerned that they were prescribing drugs or devices for uses that were not approved by the FDA. In fact, expert testimony indicated that, at least among dermatologists, prescribing drugs for off-label uses is so common that it causes virtually no concern.

The FDA does not regulate the practice of medicine, but it could do more to provide information to medical schools and doctors about the importance of data proving the safety and effectiveness of a product or a particular treatment. Training aimed at increasing doctors' understanding of safety data could help balance the pervasive influence of pharmaceutical representatives that was described in hearing testimony.

G. FDA SHOULD ENSURE THAT LABELS PROVIDE SUFFICIENT INFORMATION SO THAT PHYSICIANS CAN PROVIDE INFORMED CONSENT TO PATIENTS ABOUT THE KNOWN OR SUSPECTED RISKS

By law, the FDA is required to ensure that package inserts and other labeling information accurately describe the potential risks of a product for physicians, so that they can provide that information to patients. 147 In reality, however, that information is limited by the data that the manufacturer provides to the FDA, and by pressure from the manufacturer to

make the warnings less frightening to doctors and their patients.In the case of collagen injections, the studies submitted by the, manufacturer to the FDA excluded patients with immune disorders because of concern about the risks. However, the FDA later agreed that the company did not need to include a contraindication to patients with immune disorders, since there was no evidence that those patients were at risk; the FDA determined that a warning was sufficient. This is a classic Catch-22: There is no evidence of risk because there is no research, and the research was not conducted because of concerns about the outcome. In such a case, the FDA has to also consider the lack of evidence indicating that the product is safe.

In this and other situations, the FDA succumbed to pressure from the manufacturer to back down on decisions it had made regarding the labeling for collagen injections. Although manufacturers deserve the opportunity to defend their product, it is equally important that patients' right to informed consent be considered. Particularly when labeling changes are considered, an advisory panel should be convened, and the FDA must be particularly vigilant to minimize the financial conflicts of interest for those participating and those presenting information.

H. CONGRESS SHOULD PASS LEGISLATION CLARIFYING FDA'S AUTHORITY TO REVIEW PROTECTED COURT DOCUMENTS RELATED TO PRODUCTS THAT IT REGULATES

Information related to the safety of silicone was available to Dow Corning for many years, but they did not provide that information to the FDA. Those documents had clear implications for silicone injections, as well as silicone breast implants. These examples clearly indicate that the FDA needs the authority to review all documents related to the safety and effectiveness of products it regulates, even when those documents have been protected by court orders. There is currently controversy about whether the FDA already has such authority; it is therefore appropriate for Congress to pass legislation that clarifies the FDA's authority under such circumstances.However, a related issue is the failure of the FDA to review even those documents it has access to. The subcommittee received copies of hundreds of pages of research documents Dow Corning provided to the FDA that were so illegible that they were impossible to read. 148 Nevertheless, they were stamped "Best copy available" as well as "Confidential." It was obvious that no one at the FDA could have read those documents, and apparently the FDA did not ever require the manufacturer to provide them with better copies.

SEPARATE VIEWS OF HON. CRAIG THOMAS, HON. JON L. KYL, HON. STEVEN SCHIFF, HON. AL McCANDLESS, HON. FRANK HORTON, AND HON. WILLIAM F. CLINGER, JR.

On June 11, 1991, the Human Resources Subcommittee conducted a hearing to discuss the promotion of drugs and devices for off-label uses. Retin A and collagen are two products that have been approved for specific uses. Physicians have used their own discretion to use them for different purposes. The producers of the products have allowed this to occur.The third product under consideration, liquid silicone injections has never been approved for any purpose. Yet its use for voluntary plastic surgery and augmentations has been a part of our culture for more than 30 years. The FDA has correctly turned down applications to approve its use. It is apparent from the testimony that there is more that they can do.

The question before this subcommittee is what role our Federal agencies, particularly the Food and Drug Administration and the Department of Justice, should play in this process. We agree with the general premise that the potential harm to the general public requires this role to become more active than it has been in the past.The findings and recommendations of this report raise some questions that have resulted in the filing of separate views, as opposed to additional or dissenting views. The hearing and report only focused on half the equation, which is not enough to adequately deal with the problem. The subcommittee has no authority to oversee the practice of medicine.Retin A and collagen are approved for specific purposes. That means these items have gone through the application process, animal and human studies, and the regulation of labels. In short, they were proven to be safe and effective for specific uses.

Retin A

Retin A was approved for the treatment of acne. A study published by authors with a financial stake in the company, combined with a media that too often reports the basic headlines of a story while disregarding the details' created a demand for a product that was thought to be a "fountain of youth." Ms. Nancy Meader described the problems she encountered when applying the product to skin around her eyes. She talked of the inflammation, thickening, wrinkling and damage to the skin, and the emotional scarring that accompanied the pain. She heard a story on the national news that was incomplete. She relied upon the instructions of a physician's assistant, and no package insert was included with her purchase. She was failed by the system, but not the FDA-the product was labelled properly, including the fact that the long-term safety and effectiveness has not been established for wrinkles.

Collagen

Of particular concern are the findings and language of the report dealing with the issue of collagen. It is important for the record to accurately reflect the most updated information on this issue.Collagen has been used for off-label purposes, and the Food and Drug Administration did intercede to stop this practice. Collagen Corp. participated actively in these conversations, and the appropriate labeling was determined. The subcommittee report goes beyond the question of off-label use by implying the use of the product-any use-may cause autoimmune disease. References were made to this connection during questioning, and several documents from the Texas Department of Health (TDH) from 1989 to 1991 were included in the record. At one point in these documents, the TDH stated:

Even though our preliminary and subsequent results are both statistically significant, in and of themselves, they are not sufficient to establish a causal link between collagen injections and PM/DM. . . . However, elevated disease rates (even when combined with a plausible hypothesis) are not sufficient to establish causation, and it is necessary to look for other common factors or precipitating events that the PM/DM/Collagen patients may share and to rule out the possible confounders.

In his testimony, Dr. Richard Beauchamp of the Texas Department of Health stated, "It is not unreasonable to believe that there is a possibility that exposure to bovine collages could be producing this disease that we have seen in the treated population." 2 On June 2, 1992, in an oral deposition in the District Court of Travis County, TX, Dr. Beauchamp stated a patient survey had turned up no new cases of PM/DM. He had not done a follow-up report to Collagen Corp. about an individual who had contracted PM/DM and had been exposed to collagen. In that case, he did not feel there was a "causal relationship" because of the "time frame" of the exposure. 3

On October 25, 1991, an advisory panel was convened to discuss the possible link of collagen with autoimmune disorders. Dr. Beauchamp was asked to make a presentation. The panel noted in their November 8, 1991, "Talk Paper" that, "The experts noted that limitations in the available data make it difficult to be certain about the causal relationship between collagen and PM/DM." Ms. Jane King of Plainville, MA, was on the first panel of witnesses to discuss her condition. At no time during her oral or written testimony, nor during subsequent questioning, was it revealed that she was in litigation with the Collagen Corp. This suit was dismissed by the U.S. District Court for Massachusetts on February 11, 1992, on a summary judgement motion in favor of the Corp. Howard Palefsky, the president and C.E.O. of Collagen Corp., notified Chairman Weiss of this decision in a letter dated February 25, 1992. In fact, the Collagen Corp. has won all but one of their liability suits against individuals claiming they developed an autoimmune disorder. 5

It is not the intent of these views to establish or disprove any causal relationship. Scientific experts are continuing their studies. This subcommittee, as well as all committees within Congress, should exert caution when discussing cases under litigation. The Congress is not a department within a law firm, developing research and facts to assist litigants in a court of law. The findings of the majority cannot, and should not, be used in any fashion to argue or justify a position in ongoing civil action.

Recommendations

There is some agreement on the recommendations put forth by the majority. FDA is reevaluating the safety and effectiveness of collagen. FDA should pursue criminal actions against manufacturers that willfully violate the laws regarding the reporting of adverse reactions, and enforce penalties for the illegal promotion of drugs and devices. The recent case of Dow Corning and breast implants indicates that the issue of FDA authority to review protected court documents should be addressed. The FDA already has significant statutory authority to determine whether researchers, physicians, or companies are engaging in further activity. Current efforts in Congress to extend this authority further should be rejected. The current regulation of labels has been strictly enforced, as demonstrated by the correspondence and memorandums between FDA and the Collagen Corp. placed in the hearing report. And the FDA has worked with medical schools in a variety of forums to discuss the legal and ethical considerations involved in these issues.But it is significant to note the responsibility of the medical profession itself. As Dr. Lundberg said in his testimony, the FDA does not regulate the practice of medicine. Thus, the FDA neither approves nor disapproves specific uses of legally marketed drugs by a physician in his or her own practice." 6 In the rush to blame the FDA and the current administration for all the ills of the world, the bottom line is that the practice of medicine comes down to a patient-doctor relationship. Dr. Lundberg stated:

There is so much money to be made that the ethical principles can be overrun to get at the physician-prescriber and even at patients. The social contract that has existed between the physician and patient for centuries, in which the physician must be trusted to do the right thing for the patient, is severely threatened. 7

1 Hearing record at p. 82.

2 Hearing record at p. 62.

3 Partial transcript on file in the minority staff office.

4 On file in the minority staff office.

5 Memorandum on file in minority staff office.

6 Hearing record at p. 97.

7 Ibid., at pp. 97-98.

We have regulated the FDA, giving them the rights and tools to go after violators. The decision of doctors-as well as patients-to disregard labels, instructions, contraindications, and good sense is something that we will never be able to regulate or legislate out of existence. We must continue to find other avenues to stop this problem.

CRAIG THOMAS
JON L. KYL
STEVEN SCHIFF
AL MCCANDLESS
FRANK HORTON
WILLIAM F. CLINGER, Jr

ADDITIONAL VIEWS OF HON.TOM LANTOS AND HON. ROSA L. DELAURO

We approve of the committee's intent in this report to highlight the risks which may result from unapproved uses of drugs and medical devices, and with the subcommittee's attempts to encourage the FDA to respond appropriately to these cases. We have serious reservations, however, about the portions of this report which deal with collagen injections. Bovine injectable collagen is used in the treatment of scarring, age lines and wrinkles. The report indicates that because the product has merely "cosmetic" uses and thus, by implication, no serious or important therapeutic value, it somehow deserves more rigorous review and enforcement by the FDA. We understand that collagen is in fact being developed for significant therapeutic uses in the treatment of urinary stress incontinence and bone grafting. We are concerned that the report's recommendation that the FDA once again reevaluate the safety and efficacy of collagen-in the face of countervailing evidence which is either entirely omitted from the report or mischaracterized in the report-unfairly casts serious doubts on this product. The report, in reference to collagen, does not fully and accurately state the findings of an expert panel convened by the FDA to review the safety and efficacy of this product. The report also focuses in great detail on a Texas Department of Health [TDH] investigation into injectable collagen which was in progress at the time of the subcommittee's hearing on this issue in June 1991, but it omits any information regarding the subsequent findings of the TDH's comprehensive physician-patient survey on collagen that w as ongoing when an official of the TDH testified before the subcommittee and which has now been completed.

We submit these additional views to ensure that the record on these points is clear.

1. THE REPORT'S RECOMMENDATION THAT THE FDA REEVALUATE THE SAFETY AND EFFECTIVENESS OF COLIAGEN IGNORES THE FINDINGS OF THE SPECIAL FDA PANEL CONVENED IN OCTOBER 1991 FOR THAT PRECISE PURPOSE

The committee report recommends that, "FDA should reconsider its approval of this device because "new evidence suggesting a link between collagen use and life-threatening illness, PM/DM, must be weighed against other new evidence that collagen injections last only 2-4 months in the treatment of wrinkles." This recommendation is unwarranted in view of the fact that the FDA on October 25, 1991, convened a special expert panel meeting to do precisely that-and found that "there is insufficient statistical or biological evidence to support a conclusion that collagen injections cause autoimmune or connective tissue diseases in persons without a history of these diseases." 1 The statement about "new evidence" in the committee report, released 11 months after that panel meeting, ignores the panel's finding and without foundation suggests that there is additional information which the FDA has not considered. The reason for calling an expert panel meeting, such as the one on October 25, 1991, was made clear at the subcommittee's June 11, 1991, hearing. In response to questioning by the subcommittee, Robert Sheridan, Director of the Office of Device Evaluation at the FDA's Center for Devices and Radiological Health, testified about the procedures the FDA would follow if the agency found a statistical link between collagen and autoimmune disease. Sheridan indicated that, in the event that the FDA did revise its conclusions in this regard, the agency would convene a special expert panel to review the available evidence and recommend whether the product should be withdrawn from the market.2 Following the subcommittee hearing, the FDA did revise its conclusions on the issue of the possible link between collagen and autoimmune disease. The FDA's initial examination of this issue, originally conducted in late 1989 and early 1990, concluded that there was no such association: "Based on these estimates and presently available data, there is no evidence even under rather restrictive assumptions to demonstrate that the observed number of potential cases of PM/DM reported represent a statistically significant excess over what would be expected accounting for age, year of implant, sex and race. 3

This conclusion was revised in September 1991, following a meeting of representatives of the FDA, the Texas Department of Health, the National Institutes of Health, and the Centers for Disease Control. As in the procedures outlined by Mr. Sheridan to the subcommittee, the issue of whether an association between collagen and autoimmune disease exists was submitted to an expert panel review, which the FDA convened on October 26, 1991. The panel was composed of eight experts in the field of epidemiology, immunology, laboratory medicine, and connective tissue disorders.4 They found, as noted above, that there was no evidence to support either a statistical or a biological connection. As the panel's chairman noted, however, "Absence of evidence is not evidence of absence," and the expert panel recommended further study of this issue.5

Collagen Corp., 6 the small biomedical company which manufactures bovine injectable Collagen, was subsequently required by the FDA to change its labeling to reflect a stronger degree of possible association, and the company did so in early 1992. The FDA also required the company to submit a protocol for a followup study on this issue, and it did so. These actions respond directly to the subcommittee's concerns that these rare and difficult-to-diagnose diseases are underreported. The committee report, however, mischaracterizes both the nature and conclusion of the panel meeting and the company's subsequent actions. The report mentions the FDA panel meeting in a single, six-line paragraph and misrepresents its conclusions. The panel's actual finding was the following:

The experts noted that there is insufficient statistical or biological evidence to support a conclusion that Collagen injections cause autoimmune or connective tissue diseases in persons without a history of these diseases. 7

The committee report, however, focuses on explanatory comments from the panel's discussion which imply that the panel had insufficient data on which to draw. It is evident that the FDA did not ignore the questions regarding the safety of the product. Indeed the record is clear that-following the subcommittee hearing in June of 1991-the FDA reconsidered the question of the safety and effectiveness of injectable collagen in consultation with the Centers for Disease Control, National Institutes of Health, and the Texas Department of Health. The FDA convened an expert panel to address the question of safety. Yet, citing no new evidence and ignoring the key findings of the expert panel, the report recommends that the FDA should again reevaluate the safety and effectiveness of collagen. We believe that the steps taken by, the FDA following the subcommittee hearing in June 1991 were timely and significant in addressing the questions raised about this product. In light of the fact that no new evidence has been presented since October 1991, we see no need at this time to dismiss the findings of the FDA's expert panel or require another review of this matter. I892.

The report's extensive discussion of the Texas Department of Health's Investigation into the Safety and Efficacy of Collagen is Incomplete Dr. Richard Beauchamp, medical epidemiologist and public health physician at the Bureau of Disease Control and Epidemiology of the Texas Department of Health [TDH], explained in his prepared statement presented at the subcommittee's June 11, 1991, hearing that:

Even though our preliminary and subsequent results are both statistically significant, in and of themselves, they are not sufficient to establish a causal link between collagen injections and PM/DM. . . .Nevertheless, we do feel that the present findings are sufficient to warrant further study. Consequently TDH is undertaking a study of all PM/DM patients diagnosed in Texas since June 1980. We have sent PM/DM case reporting forms to 4,329 dermatologists, plastic surgeons, rheumatologists, internists, ear/nose/throat specialists, and neurologists in Texas.8

This information indicates that the TDH felt it needed additional information in order to establish a definitive link between collagen and autoimmune disease. Fifteen months have elapsed since the subcommittee was notified that the TDH had undertaken this important survey, yet the committee report fails to address its findings. We note that, according to sworn testimony in June of 1992, Dr. Beauchamp related that this survey did not reveal any new cases of PM/DM causally linked to the use of collagen.11 The committee report states that "new evidence suggesting a link between collagen use and a life-threatening illness, PM/DM, must be weighed against other new evidence that collagen injections last only 2-4 months in the treatment of wrinkles." We think that any effort to weigh new evidence must include the latest available evidence. This should be done before reaching the conclusions that the safety and efficacy of collagen should be reevaluated. Regrettably, it was not done in this case.

Tom LANTOS.
ROSA L. DFLAURO.

1. FDA Talk Paper, Nov. 8, 1991, p. 1.

2. Promotion of Drugs and Medical Devices for Unapproved Uses: Hearings Before the Subcommittee on Human Resources and Intergovernmental Relations of the House Committee on Government Operations, 102d Congress, lst Session (1991), p. 228.

3 Food and Drug Administration memorandum from the Director of the Division of Biometric Sciences to the Acting Director of the Office of Compliance, Jan. 3, 1991, P. 1.

4 The members of the panel were the following: Noel R. Rose, M.D., Ph D., chairman, Department of Immunology and Infectious Diseases, Johns Hopkins University School of Hygiene and Public Health; Thomas A. Medsger, M.D., Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine; Paul H. Plotz, M.D., chief, Connective Tissue Disorders, Arthritis and Rheumatism Branch, National Institutes of Health; Michael A. Cremer, M.D., Veterans Administration Medical Center; Sudhir Gupte, MD., chief, Division of Basic and Clinical Immunology, University of California; Mark Hochberg, MD., University of Maryland; Alexander Baumgarten, MD., Ph.D., professor, Laboratory Medicine, Yale Medical School, Yale-New Haven Hospital.

5"Collagen Relationship to Polymyositis/Dermatomyositis," M-D-D-1 Reports (Medical De. vices, Diagnostics and Instrumentation) ("The Gray Sheet"), p. 2 (Oct. 28, 1991).

6 The headquarters of Collagen Corp. is in Palo Alto, CA, and the corporation has facilities in the San Francisco Bay area. Some employees are residents of the IIth congressional district of California, which is currently represented by Congressman Tom Lantos.

7 FDA Talk Paper, Nov. 8,1991, p. 1

8 Promotion of Drugs and medical Devices for Unapproved Uses: Hearings Before the Subcommittee on Human Resources of the House Committee on Government Operations, 102d Congress, 1st Session (1991), p. 82.

9Collagen Corporation v. Texas Department of Health, No. 91-17864, deposition of Richard Beauchamp, M.D. (June 2, 1992), p. 75.

ADDITIONAL VIEWS OF HON. DONALD M. PAYNE

This report presents very troubling findings about FDA's failure to protect consumers from products whose risks may far outweigh their benefits. When a patient buys a product or treatment that is supposed to make them look better, they should not be risking permanent disfigurement or potentially fatal illnesses. In addition, they should not be wasting their money on a product that does not work as advertised.The serious questions that have been raised about the safety and effectiveness of collagen injections are a telling example of the problems that occur when the FDA fails to protect the interests of consumers. It is outrageous that there are no long-term studies of the potential autoimmune risks of this product.In October 1991, an FDA advisory committee concluded that there have been no comprehensive studies of whether collagen injections may cause a potentially fatal autoimmune disease called PM/DM, making it impossible to determine whether or not collagen can cause this disease. The Texas Department of Health continues to report that the three documented cases of PM/DM in Texas are 32 times the expected rate for the 17,000 people who have had collagen injections in that State. The Texas Department of Health notified the subcommittee that their survey, which was sent to 4,239 Texas physicians, was inconclusive because it was answered by only 12 percent of those who received it. Scientists at the Texas Department of Health continue to be concerned that the prevalence of PM/DM among collagen patients in the State may well be even higher than the extraordinarily high rate that has already been documented. It is unfortunate that FDA advisory committee meetings, such as the one that discussed collagen in October 1991, continue to rely almost exclusively on information provided by the company whose product is under review, or their paid consultants. Other researchers are rarely invited to participate, and even more rarely provided travel expenses to cover the cost of such activities. As a result, important research results and clinical findings that are not supportive of the application may be excluded from review by FDA staff or the advisory committee. This is a serious flaw in the current approval system, which makes it especially difficult for the FDA to make unbiased decisions. I sincerely hope that a new administration will restructure the process to make it less biased. It is also unfortunate that the FDA continues to do relatively little to ensure that consumers and physicians have access to information about the risks of the products that the agency regulates. We can expect dangerous off-label uses to continue, such as silicone injections for cosmetic purposes, because the FDA has never disclosed the results of studies it has received. In addition, other important documents about the risks of injectable silicone remain under court seal, and therefore unavailable to the FDA and the public. Again, this is an issue that should be legislatively corrected early in the next Congress.

DONALD M. PAYNE.

References 1 through 148

1 FDA memorandum from Acting Director of Division of Drug Advertising and Labeling to the Director of Office of Drug Standards, May 6, 1990, p. 3; in subcommittee files.

2 Hearing before a subcommittee of the Committee on Government Operations, U.S. House of Representatives, "Promotion of Drugs and Medical Devices for Unapproved Uses," June 11, 1991, hereafter referred to as Hearing.

3Memorandum from Dr. Carlene Baum to FDA Epidemiology Branch, July 25, 1988; in sub-committee files.4 ibid.

5 Vreeland, L.N. (April 1989). The selling of Retin A, Money, pp. 75ff.

6 The "vehicle" refers to the cream which is identical to Retin A, but without the active ingridient, tretinoin. The article was authored by Jonathan-S. Weiss, Charles N. Ellis, John T. Headington, Theresa Tincoff, Ted A. Hamilton, and John J. Voorhees, and published in the Journal of the American Medical Association [JAMA), Jan. 22/29, 1988, vol. 259, No. 4, pp. 527-532.

7 The editorial appeared in the same issue of JAMA, pp. 569-570.

8 Although Jonathan Weiss was the First author of the article, he was a student of Dr. John Voorhees, who had received the grant to study Retin A.

9 Vreeland, L.N. Op. cit,

1O The extent to which the authors disclosed their financial relationships to JAMA has not been publicly reported. Copies of the articles are in subcommittee files.

11 Hearing, testimony of Dr. George Lundberg, editor of JAMA, p. 141.

12 New England Journal of Medicine, Apr. 4, 1991, p 1004

13 The biography distributed to press is in subcommittee files. In addition to the direct funding Dr. Drake received to participate in interviews, the Robert Wood Johnson fellowship that she received is associated with Johnson & Johnson.

14 This brief description of silicone injections is from a Hearing before a subcommittee of the Committee on Government Operations, U.S. House of Representatives, "Is the FDA Protecting Patients From the Dangers of Silicone Breast Implants," 'Dec. 18, 1990, hereafter referred to as Breast Implant Hearing; testimony of Dr. Norman Anderson, associate professor of medicine and surgery, Johns Hopkins School of Medicine, pp. 30-31.

15 In subcommitty

16 Witt, L. (April 1974). what is a woman without breasts? Today's Health, pp. 30ff. The FDA described these problems in a 1982 fact sheet that was published in Hearing, p. 299.

17 This document is in subcommittee files.

18 Producer of silicone is indicted, Washington Post, Aug. 17, 1967; in subcommittee files. A6cording to the article, in addition to the company, the president of Dow Corning, the director of the medical products division in 1964, and the sales manager of the division were also indicted.

19 Delage, C., Shane, J.J., & Johnson, F.B. (1973). Mammary silicone granuloma: Migration of silicone fluid to abdominal wall and i6guinal region, Archives of Dermatology, vol. 108, pp. 104107.

2O Breast Implant Hearing, testimony of Dr. Norman Anderson, associate professor of medicine ELnd surgery, Johns Hopkins School of Medicine, p. 31.

21 Hearing, testimony of Dr. Robert Katz, clinical assistant professor of dermatology at Georgetown University School of Medicine, p. 134.

22 FDA memorandum to the record from Paul F. Tilton, Sept. 10, 1990, p. 1; in Hearing, P. 203.

23 Medical Officer's Review of New Drug Application 17-767, Jan. 12, 1976, p. 2.

24 Ibid., P. 3.

25 Ibid. A 2-year rat study is considered a lifetime study. Other animals have to be studied for longer periods of time to be considered lifetime studies.

26 Midical Officer's Review of New Drug Application 17-767, Jan. 12, 1976, p. 23; in Hearing, P. 199.

27 FDA memorandum to the record from Paul F. Tilton, op. cit., P. 1; in Hearing, P. 203.

28 Ibid.

29 Ibid., p. 204.

3O Dow Corning Corp., Final Clinical Report, Amendment to IDE L002702, Aug. 24, 1990; in subcommittee files.

31 FDA memorandum to the record from Paul F. Tilton, op. cit.; in Hearing, pp. 203-208.

32 According to FDA documents in subcommittee files, an IDE was approved for eye research.

33 Kievan, P. (March 1979). New face lift not all smiles, FDA Consumer, March 1979; in Hearing, p. 297.

34 Letter from Marlene Hoffner, Associate Director for Health Affairs, office of Medidal Devices, FDA, to Helen Gurley Brown, editor of Cosmopolitan, Jan. 31, 1983; in subcommittee files.

35 Pearl, R.M., Laub, D.R., & Kaplan, E.N. (1978)-Complications following silicone injections for augmentation of the contours of the face, Plastic and Reconstructive Surgery, vol. 61, pp.888-891. This is the official journal 6f the American Society of Plastic and Reconstructive Surgeons.

36 Rae, V., Pardo, R.J., Blackwelder, P.L., & Falanga, V. (1989). Leg ulcers following subcutaneous injection of a liquid silicone preparation, Archives of Dermatology, vol. 125, pp. 670-673.

37 Raszewski, R., Guyuron, B., Lash, R.H., McMahon, J.T. & Tuthill, R.J. (1990). A severe fibrotic reaction after cosmetic liquid silicone injection: A case report, Journal of Cranio-Maxillofacial Surgery, vol. 18, pp. 225-228.

38 FDA reviews collagen studies, FDA Consumer, June 1991; in Hearing, p. 305.

39 Copies of these letters are in subcommittee file.

40 Henig, R.M. (Oct. 7, 1990). Lush lips and other vanities, Washington Post, Good Health Magazine, p. -30.

41 The latest revised package insert proposed by Collagen Corp., according to the Texas Department of Health, states that "touch up implantation may be required in 3-12 months in expression lines in the face" or 6-24 months in acne scarring. A study published in Aesthetic Plastic Surgery, 1990, vol. 14, pp. 227-234, states that "in the aging face the majority of patients were ... disappointed with the loss of correction after six months. This was especially true in the 25% of patients . . . who had previous Zyderm II which was short-lived, i.e. two to three months or even less. Although Zyplast lasted longer than Zyderm II in this group (an average average of four months), it still fell short of the patient's expectations.". See Hearing, testimony of Dr. Richard Beauchamp, p. 87.

42 can college injections erase wrinkles safely? Consumer Reports Health Letter, May 1991, pp. 35-36.

43 Erythema is abnormal redness. Package inserts describing these risks are in subcommittee files.

44 Marks, R., Hill, S., & Barton, S.P. (1990). The effects of an abrasive agent on normal skin and on photoaged skin in comparison with topical tretinoin. British Journal of Dermatology, Vol. 123, pp. 457-496; in Hearing, pp. 42-51.

45 Hearing, testimony of Lawrence Solomon, head of the department of dermatology at the University of Illinois cCllege of Medicine, p. 93.

46 The desire to prove that a treatment works can be caused by financial interests in the product or the humanitarian desire to help people; any bias that results may be unintentional.

47 Weiss J.S., et all, op. Cit., p. 134.

49 Vreeland, L. (April 1989). Op. Cit.

50 Hearing, testimony of Nancy Meader, pp. 6-21, 36-37.

51 Hearing, testimony of Nancy Meader, pp. 6-21.

52 Letter from Dr. Joan Kraft, Dr. Heinz Nau, Dr. Edward Lammer, and Dr. Ann Olney, New England Journal of Medicine, July 27, 1989, p. 262; in Hearing, p. 190.

53 Consensus Panel Says: Ban the Tan; Declares Tanning Unhealthy, May 1989 press release, National Institute of Arthritis and Musculoskeletal and Skin Diseases; in Hearing, p. 185.

54 Memorandum from Dr. Murray Lumpkin, Director of the Division of Anti-Infective Drug Products, FDA, to Hugh Cannon, Associate Commissioner for Legislative Affairs, FDA, May 24, 1991; in subcommittee-files.

55 For example, in USA Today on Mar. 31, 1991, Dr. Peter Pochi of Boston University was paraphrased as saying that a new formulation of Retin A "is being reviewed by the Food and Drug Administration and could be approved in the next two years." This article, which does not mention Dr. Pochi's financial ties to -the company, is in subcommittee files.

56 The transcript of the FDA panel meeting is in subcommittee files.

57 Consensus Panel Says: Ban the Tan; Declares Tanning Unhealthy; op. cit., in Hearing, p.185.

58 Documents pertaining to this research are in subcommittee files.

59 Elias M (Aug 9, 1990). Retin A may help keep skin cancer at bay, USA Today, p.1D.

60 Retin A Patent rights suit v. J & J, F-D-C Report, Apr. 29, 1991, p. T&G 2; in subcommittee files.

61 This information is based on documents in subcommittee files, and is described in Hearing, p. 340.

62 Documents describing these arrangements are in subcommittee files.

63 Letter from Russel Hume, executive director of the R.W. Johnson Pharmaceutical Research Institute, to David Banks, Assistant to the Director, Division of Drug Advertising and Labeling, FDA, Jan. 19, 1990; in subcommittee files. A similar discussion with Mr. Hume in February 1988 wasdescribed in a memorandum from FDA officials officials Arthur Yellin and Kenneth Feather, which is also in subcommittee.

64 The videotapes are in subcommitty files.

65 Hearing, Testimony of Dr. Robert Katz, p. 38, 40.

66 Hearing, testimony of Dr. Lawrence Solomon, P. 138.

67 Memorandum dated Mar. 2, 1990, in Hearing, P. 331.

68 Hearing, chronology provided by FDA, p. 331.

69 Feb. 13,1990, and Feb. 16, 1990, memorandums describing this meeting and signed by David Banks are in subcommittee files.

7O Gorelick, R. (Feb. 14,1990). Retin A documents may shed light on government investigation, The Daily Pennsylvanian, p.1, 13,

71 This February 1983 memorandum is in Hearing, pp. 167-168.

72 This memorandum is in subcommittee files.

73 Ibid., p. 2.

74 The documents described in this paragraph are in subcommittee files.

75 Stout, H. (June 12, 1992). U.S. may bring civil charges over Retin A, Wall Street Journal, p. B1.

76 On Sept. 25, 1992, U.S. Department of Justice officials refused a request from subcommittee staff for information on the status of this investigation.

77 Kessler, D.A. & Pines, W.L. (1990). The Federal regulation of prescription drug advertising and promotion, JAMA, vol. 264, No, 18, pp. 2409-2415 reprinted in Hearing, pp. 169-175.

78 Hearing, testimony of Commissioner David A. Kessler pp. 156-157.

79 A brief summery of the speech was published in F-D-C Reports, Nov. 6, 1989, p. T&G 7; in subcommittee files.

80 Although Mr. Bewley stated that his presentation did not reflect the official position of Johnson & Johnson his position in the Office of General Counsel and his speech to an audience filled with FDA officials reflects on the position of the company,

81 Hearing, testimony of Dr. Marc Lapp6, professor of health policy and ethics, University of Illinois at Chicago, p. 58.

82 Hearing of testimony of Laurie Lehman, pp. 22-26

83 Document describing these interviews are in subcommittee files.

84 Hearing, testimony of Marc Lappe p. 57

85 Ibid. Dow Corning silicone studies are in subcommittee files.

86 lbid., p. 58.

87 Medical Officer's Review of New Drug Application 17-767, Jan. 12, 1976, p 23; in Hearing, P. 199.

88 lbid., p. 198.

89 Hearing, testimony of Robert Sheridan, Director of the Office of Device Evaluation, FDA, p. 201.

90 FDA memorandum to the record from Paul F. Tilton, op. cit.; in Hearing, pp. 203-208.

91 Ibid., p. 204.

92 Ibid., P. 205.

93 Ibid., p. 207.

94 Ibid.

95 Sample articles are in subcommittee files.

96 Copies of correspondence are in subcommittee files.

97 This letter is in subcommittee files.

98 Letter to Glenn W. Dorfman from Ann B. Holt, May 1, 1981; in subcommittee files.

99 Ibid., p. 2.

100 Memorandum from Los Angeles District, FDA, to the Director of the Investigations Branch, Sept. 12, 1984; in subcommittee f21

101 Memorandum from FDA District Director, region 11, Brooklyn, July 26, 1984; in subcommittee riles.

102 Memorandum from Pamela Wojtowicz, Division of Compliance Operations, FDA, to Susan Bounds, Freedom of Information Staff, Oct. 31, 1984, p. 2, in subcommittee files.

103 Medical Officer's Review of New Drug Application, Jan. 12, 1976, pp. 4,9

104 See, for example, Griffing, M.F. (November 1982). How I erased deep laugh lines (and got my Madonna smile), "Cosmopolitan," pp. 210-214; and Costikyan, B. (February 1990). Cosmo talks to Norman Orentreich, M.D. Cosmopolitan," pp. 122-4.

105 See, for example, Orentreich, D. & Orentreich, N. (April 1987). Acne scar revision. Advanced Dermatologic Surgery, vol. 5, pp. 359-368.

106 Memorandum from George Gerstenberg, FDA District Director of region II, Brooklyn, to Mervin Shumate, July 26, 1984; in subcommittee files.

107 This process is described in a Mar. 6, 1985, FDA memorandum from Walter Gundaker, Director of the Office of Compliance; in subcommittee files.

108 Blumenthal, R. (July 19, 1991). New York dermatologist is fighting with FDA over silicone injections. New York Times, B5.

109 This memorandum is in Hearing, pp. 192-193.

11O This document is in subcommittee riles.

111 This document is in subcommittee riles.

112 Breast Implant Hearing, pp. 110-115.

113 The warning letter to Dr. Orentreich and his lawyers' response are printed in Hearing, pp. 333-337. Warning letters sent to Dr. Richard Aronsohn of Los Angeles and Dr. Ricardo Samitier-Cardet of Miami are in subcommittee riles.

114 This press release is in Hearing, pp. 338-339.

115 Hearing, testimony of Dr. Robert Katz, p. 134. The subcommittee has obtained a videotape which trains doctors to perform silicone facial injections; the tape was produced in 1990 by McGhan, which sells liquid silicone (Nusil MED-6710). McGhan's 1990 Product Profile information sheet for its silicone fluid states that it "is useful for small tissue augmentations including acne and scar revision." This document is in subcommittee file.

116 Hearing, testimony of Dr. Lawrence Solomon, p 136.

117 Hearing, testimony of Dr. Lawrence Solomon, pp. 137-138. 118 These documents, and articles describing their release to the public, are in subcommittee files.

119 Hearing, testimony of Dr. Marc Lappe, pp. 52-60; and Breast Implant Hearing, testimony of Thomas Talcott, pp. 82-87.

120 Correspondence on this topic, including a June 1, 1989, letter from Collagen Corp., is in subcommittee files.

121 letter from Howard Palefsky, president of Collagen Corp., to Walter Gundaker, Acting Director of the Center for Devices and Radiological Health, FDA, Dec. 12, 1990; in Hearing, pp. 252-253.

122 Ibid

123 Letter to the editor of the Washington Post, Oct. 30, 1990, in Hearing, p. 240.

24 Correspondence between FDA and Collagen Corp. on this topic are in Hearing, pp. 241-253.

125 Letter from Howard Palefsky, op. cit., in Hearing, p. 252.

126 Hearing, FDA response to letter from Chairman Weiss, p. 278.

127 Hearing testimony of Richard Beauchamp, epidemiologist at the Texas Department of Health, p. 73

128 Correspondence regarding the underreporting of adv