Public Citizen | Publications – Risks of Accutane

Risks of Accutane

HRG Publication #1537

Comments of

Larry D. Sasich, Pharm.D., M.P.H, FASHP

Public Citizen’s Health Research Group

Before

The FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee meeting on isotretinoin (Accutane)

September 18, 2000

Public Citizen’s apprehension over the safety of Accutane began shortly after its approval in May 1982, when we petitioned the Food and Drug Administration (FDA) to take immediate action to warn patients and physicians about the serious adverse effects associated with the use of this drug in September 1983.⁽¹⁾ The thrust of our petition was a request for a boxed warning on the possibility of birth defects, spontaneous abortions, pseudotumor cerebri, impaired vision, and regional ileitis (Chrohn’s Disease) caused by Accutane. In addition, we asked for the mandatory distribution by pharmacists of labeling written for patients, then called Patient Package Inserts, explaining the risks of this drug in non-technical language.

A final rule that became effective on June 1, 1999 gave the FDA the authority to require patient labeling, now known as Medication Guides, for drugs that present a serious risk to the public’s health.⁽²⁾ Accutane is a drug that clearly meets this standard.

An Accutane Medication Guide would inform patients not only about the risk of birth defects and the other adverse effects mentioned above, but also of the possibility of depression, psychosis, and suicidal ideation; erratic bone growth and premature closure of the growth plates; inflammation of the pancreas; elevations of particular blood fats (triglycerides); hearing impairment; decreased night vision and corneal opacities; anaphylactic and other allergic reactions; and drug interactions all now in the drug’s professional product labeling.⁽³⁾

On April 26, 1988 the FDA’s Dermatologic Drugs Advisory Committee recommended, without specifying a method, that the prescribing of Accutane be restricted. Shortly thereafter, we again petitioned the FDA on May 17, 1988 to limit the prescribing of the drug to board-certified or board-eligible dermatologists. Dermatologists would have been required to register with the FDA and be assigned a prescriber number. To prevent the “off-label” use of Accutane, dermatologists would have been required to certify by affidavit that they had read and would follow the regulations and the drug’s approved labeling. Pharmacists would have been prohibited from knowingly filling prescriptions from physicians who were not dermatologists and registered with the FDA. Both physicians and pharmacists would have been subject to criminal penalties for violating the regulations. A copy of our 1988 petition is attached to these comments for reference.

We believe that the legal theory outlined in our 1988 petition shows that the FDA then had the authority to require the restrictions outlined above and that this theory is as sound today as it was 12 years ago. In fact, since our 1988 petition there have been several recent examples of the “creative” use of the Food, Drug and Cosmetic Act to place limitations on the use of certain drugs in a manner consistent with our petition.

1. To reduce the chance of potentially life-threatening agranulocytosis the original labeling for the atypical antipsychotic drug clozapine (Clozaril), required ” a baseline white blood cell (WBC) and differential count before initiation of treatment and a WBC count every week throughout treatment” and that “The distribution of Clozaril is contingent upon performance of the required blood tests.”⁽⁴⁾ Clozapine was approved on September 26, 1989.

2. The approved labeling for thalidomide (Thalomid), a drug cleared for marketing on July 16, 1998, requires that only prescribers and pharmacists registered with the System for Thalidomide Education and Prescribing Safety (STEPS) program are allowed to prescribe and dispense the drug. Also, “patients must be advised of, agree to, and comply with the requirements of the (STEPS) program in order to receive product.”⁽⁵⁾ Thalidomide and Accutane are drugs that may have similar risks in causing birth defects.

3. The use of trovafloxacin (Trovan), a fluoroquinolone antibiotic approved in 1997, was restricted to hospital or long-term nursing care facilities on June 9, 1999 after reports of serious liver injury.⁽⁶⁾

4. The labeling for the anti-arrhythmic agent dofetilide (Tikosyn), approved on October 1, 1999, states it is ” available only to hospitals and prescribers who have received appropriate TIKOSYN dosing and treatment initiation education.”⁽⁷⁾

In addition to requiring a Medication Guide for Accutane and the restriction of the drug’s prescribing to FDA-registered dermatologists and its labeled use, the FDA must require a postmarketing study to determine if these interventions will have met the agency’s goals as stated in the questions to this committee: no patients beginning the drug if they are pregnant and no pregnancies occurring while on Accutane treatment. This study protocol should be approved by the FDA’s Office of Postmarketing Drug Risk Assessment (OPDRA). At a minimum, the study should last one year and include evaluation of the requirements that only a limited supply of Accutane is provided to women and that the drug is not provided without proof of a negative pregnancy test. The precedent for this latter requirement is the clozaril “no blood, no drug” policy mentioned above.

Public Citizen believes that Accutane is a beneficial drug when it is used for its approved indication: severe recalcitrant nodular acne. However, if the combination of a Medication Guide and the prescribing and dispensing restrictions mentioned above cannot be shown in a postmarketing study to meet the FDA’s no-pregnancy goals after one year, the drug should be immediately removed from the market.

Continuing Medical Education programs, professional product labeling changes, and optional patient information brochures have been the Pavlovian responses to drug safety issues by manufacturers and the FDA for years. It is time to admit that this is a failed paradigm and recognize that rigorously enforced regulation may be the only way to ensure that patients are informed and that drugs are prescribed appropriately.

Where industry interests have been at stake, the FDA has been innovative in interpreting the Food, Drug and Cosmetic Act to get drugs such as clozapine, thalidomide and dofetilide on the market. It is time for the agency use the same creativity to protect the public’s safety.

We hope that it will not be necessary to return to this committee in the future to discuss how to reduce Accutane’s risks to patients.

 

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1. Wolfe SM, LaCheen C. Citizen’s petition to add warnings to the professional product labeling of isotretinoin (Accutane). Public Citizen’s Health Research Group, September 8, 1983.

2. Department of Health and Human Services, Food and Drug Administration. Prescription Drug Product Labeling; Medication Guide Requirements Final Rule. Federal Register December 1, 1998, Volume 63, Number 230, pages 66377 to 66400.

3. Professional Product Labeling for Accutane (isotretinoin) accessed at www.rocheusa.com/products/accutane/pi.html on September 16, 2000.

4. Physicians’ Desk Reference 45^th ed. Professional Product Labeling for Clozaril (clozapine).Montvale NJ: Medical Economics Company, Inc., 1991.

5. Physicians’ Desk Reference 54^th ed. Professional Product Labeling for Thalomid (thalidomide).Montvale NJ: Medical Economics Company, Inc., 2000.

6. Food and Drug Administration Public Health Advisory for Trovan (trovafloxacin/alatrofloxacin mesylate) June 9, 1999.

7. Professional Product Labeling for dofetilide (Tikosyn) accessed at www.tikosyn.com on September 16, 2000.

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Attachment

HRG publication #ll25 ACCUTANE

May 17, 1988

BEFORE THE

COMMISSIONER OF THE FOOD AND DRUG ADMINISTRATION AND THE

SECRETARY OF THE DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

Petition of Public Citizen 

to Declare Accutane an Imminent

Hazard and to Immediately Approve

Limitations on its Distribution 

Public Citizen hereby petitions the Commissioner of the Food and Drug Administration (“FDA”) and the Secretary of the Department of Health and Human Services (“HHS”) to invoke the imminent hazard provisions of the Federal Food, Drug and Cosmetic Act (“FDC Act”), in order to immediately limit the prescribing of Accutane to dermatologists who have agreed in advance to follow the approved indications for the drug. We also petition the agency to impose certain other limitations on prescribing the drug.

As we discuss in more detail below, 62 Accutane-induced birth defects have been reported in this country and the FDA estimates that the actual number is about ten times that amount, in excess of 600 serious birth defects. These figures are a stark contrast to the three birth defects that have been reported in all of Europe, where regulatory authorities have placed much more stringent restrictions on the distribution of the drug. In light of obvious seriousness and the enormous proportions of this crisis, we urge FDA and HHS to act immediately to limit the distribution of Accutane, consistent with the April 26, 1988 recommendation of the agency’s Dermatologic Drugs Advisory Committee.

In support of this petition, we hereby incorporate the Public Citizen Health Research Group’s April 26, 1988 testimony to the Dermatologic Drugs Advisory Committee and its September 13, 1984 petition of the FDA requesting a change in Accutane’s label.^l

A. FACTUAL BACKGROUND

The material facts that support this petition are that, despite a change in the drug’s labeling in 1985, physicians have continued to over-prescribe Accutane, leading to at least several hundred avoidable birth defects.²

1. Birth Defects Caused by Accutane.

As mentioned above, 62 severe birth defects caused by Accutane have been reported to the FDA. At the April 26, 1988 Dermatologic Drugs Advisory Committee Meeting, FDA officials estimated that between 3,876 and 21,100 American women have become pregnant while on the drug. It has also been estimated these women have had spontaneous abortions at close to three times the rate of spontaneous abortions in the general population,³ and the agency estimates that roughly 60% of pregnant women who have used Accutane have chosen to obtain abortions. Thus, according to the FDA’s estimates, approximately 600-5,400 women who have taken the drug have given birth to a child and 25% of these children, or roughly 600, have severe birth defects caused by Accutane. We recognize that these numbers are only estimates, but it seems very likely that there have been several hundred birth defects caused by Accutane.

As many witnesses testified at the Advisory Committee Hearing, regardless of how many birth defects have occurred since the change in Accutane’s labeling, the number is significant and unacceptable. Therefore, the FDA should immediately take steps that will ensure, to the greatest extent possible, that the birth defects cause by Accutane be reduced to the lowest possible number.

There is one other general point that needs emphasis. It is sometimes argued that the FDA’s principal role should be limited to informing doctors and consumers about the risks of drugs and that the agency should let doctors and consumers make their own decisions. In the case of Accutane, however, that argument has absolutely no relevance because the ultimate victim will be an unborn fetus who cannot give consent. This factor provides additional support for our position that the FDA employ all of its regulatory authority to ensure that injuries from the drug are minimized.

Usually, this will mean that the product should be removed from the market. However, we recognize that Accutane is valuable for the treatment of severe and non-responsive recalcitrant cystic acne, a condition that can be disfiguring. Therefore, we are supporting a one-year trial period during which distribution of the drug would be limited in accordance with the conditions outlined below. If prescribing of the drug to women of childbearing age is not reduced significantly and if the number of birth defects is not reduced to a rate comparable to those found in those European countries that restrict the distribution of Accutane, then we believe that the drug should be removed from the market. However, we believe that limiting the distribution and prescribing of the product will reduce the number of birth defects to at or near zero as has apparently been accomplished in European countries.

2. Physicians Have Over-Prescribed Accutane, Leading to Unnecessary Birth Defects.

Since 1982, the only indication for which Accutane has been approved is “severe recalcitrant cystic acne.” While the drug has been contraindicated for pregnant women since it was first approved, in 1985 the labeling was significantly strengthened to include a bold, prominent boxed warning stating that “Accutane must not be used by females who are pregnant or intend to become pregnant while undergoing treatment” because of the risk of “major fetal abnormalities,” and that women put on the drug should first be given a pregnancy test. In addition, since 1985, Hoffmann-La Roche (“Roche”), the manufacturer of the product, has distributed patient package inserts (“PPIs”) to pharmacies. While we believe that the labeling and the PPIs should be strengthened even further, experience to date indicates that such requirements are not likely to provide a sufficient incentive to physicians to abide by the indications of the drug, which is essential to reducing birth defects and pregnancy exposures to the lowest possible level.

The FDA’s own research provides strong support for our claim. In the United States there are currently about 400,000500,000 cases cystic acne, but only about 70,000 females have this condition. Since the disease is spread out over a several year period and since only a fraction of the women who have the disease are not responsive to other therapies, less than 5,000 females a year may appropriately be medicated with this drug, according to the FDA. Yet, according to Roche’s own estimates, about 560,000 women have been treated with Accutane since 1982, and approximately 287,000 since the drug’s labeling was changed in 1985. This is approximately 100,000 cases per year or twenty times the number of women who actually should be using the drug.

The data suggests that there are two distinct problems with respect to the prescribing of Accutane. The first is that physicians are not taking sufficient precautions to ensure that women treated with Accutane do not become pregnant. Second, the impact of this failure on the part of physicians is magnified by the general tendency of doctors to prescribe Accutane for minor acne and other conditions which have not been approved by the FDA and which are not justified in light of the extraordinary risks of this drug. Any plan to adequately regulate Accutane must address both these problems.

Therefore, we believe that Roche’s proposals for patient package inserts, stronger warnings and written informed consent will be inadequate to eliminate all the avoidable birth defects. In addition to making these requirements mandatory, it is also essential that the FDA limit the distribution of the drug to dermatologists who would be required to prescribe the drug in accordance with the indications and conditions approved by the FDA.B. Action Requested.

We request the Commissioner of the FDA and the Secretary of HHS to employ the imminent hazard provision of section 505(e) of the Food, Drug and Cosmetic Act, 21 U.S.C. § 355(e), to revoke the agency’s current approval of the new drug application (NDA) for Accutane and to simultaneously approve a NDA for Accutane with the conditions described below.

We also request that the Commissioner issue regulations to accompany the modified NDA to ensure that pharmacists and physicians comply with the new limitations that we are requesting be placed on Accutane. Violation of these regulations should be made subject to the criminal penalties contained in section 303 of the FDC Act, 21 U.S.C. § 333.

1. Only Dermatologists Should be Permitted to Prescribe Accutane. If Roche is to be permitted to market Accutane, then the FDA must limit the drug’s distribution, as recommended by the Dermatologic Drugs Advisory Committee. We favor permitting only dermatologists who have registered with the FDA to prescribe the drug.

There are approximately 7,000 dermatologists in the United States so that a regulation that limited the prescribing of Accutane to this specialty would make it feasible for the FDA to protect patients adequately. In addition, dermatologists are better able to ensure that other therapies have been attempted before prescribing Accutane, which should be used only if it has been determined that no other treatment is effective.

We request the FDA to modify the NDA for Accutane so that Roche is prohibited from promoting Accutane to physicians who are not board certified or board eligible dermatologists. Since the modified NDA would only apply to Roche, however, we also request FDA to use its general rulemaking authority, 21 U.S.C. § 371(a), to issue regulations prohibiting physicians other than dermatologists from prescribing Accutane and prohibiting pharmacists from knowingly filling prescriptions from physicians who are not dermatologists.⁴

2.Dermatoloqists Should Be Prohibited From Prescribinq Accutane for Unapproved Indications. The regulations should also prohibit dermatologists from prescribing Accutane outside its approved indications and require them to take the precautions outlined in our testimony. Specifically, the regulation should state that dermatologists may prescribe the drug only for severe recalcitrant cystic acne and only where other specified therapies have not been successful.

3.Patients Should be Given Written Informed Consent. It is also critical that physicians prescribing Accutane be required to obtain informed consent from female patients and a written agreement from the patient that she will use contraception or other measures to avoid pregnancy. At a minimum, the consent form should identify the estimated risk of severe birth defects to children born to women who become pregnant while on Accutane (which we understand to be 20-25%) and should contain a photograph of an affected infant. If the FDA adopts this approach, which should be made mandatory through regulations, we will provide other suggestions as to the content of the informed consent form.

4. Other Restrictions. We also urge the agency to modify the NDA and adopt regulations imposing the additional restrictions discussed in the comments that we submitted to the Dermatologic Drugs Advisory Committee. While Roche has agreed to undertake many of these changes voluntarily, it is critical that they be made mandatory so that the public receives the maximum possible protection against exposure to Accutane by women during pregnancy. The additional restrictions include (1) important changes in the drug’s labeling, (2) mandatory PPIs, (3) lowering the initial dose for the drug, and (4) photographs of affected infants on any promotions materials which contain photographs of a patient with acne. C. Statement of Grounds. The HHS and the FDA have authority to adopt the measures urged in this petition under the provisions of the FDC Act that give the agencies the authority to limit the conditions under which a new drug may be marketed and to adopt regulations in furtherance of the purposes of the FDC Act. 21 U.S.C. §§ 355, 701(a). The Secretary may suspend approval of the NDA prior to a hearing where there is an “imminent hazard to public health,” as we believe is plainly the case here. 21 U.S.C. § 355(e). Under section 505 of the FDC Act, 21 U.S.C. § 355, the Commissioner must reject the NDA or withdraw it if upon the basis of the information submitted to him as part of the application, or upon the basis of any other information before him with respect to such drug, he has insufficient information to determine whether such drug is safe for use under such conditions.

21 U.S.C. § 355(d)(4). The “conditions” referred to are “the conditions prescribed, recommended, or suggested in the proposed labeling” for the drug. 21 U.S.C. § 355(d)(1). Thus, the statute gives the agency the authority both to revoke the current NDA for Accutane, on the ground that without limitations on the drugs’ distribution, Roche cannot carry its burden of proving the drug safe, and to grant an NDA imposing labeling conditions under which the drug may be used. If those conditions are not adequate to ensure the drug’s safety, then under section 701(a), the FDA has authority “to promulgate regulations for the efficient enforcement of [the] Act.” 21 U.S.C. § 371(a). Here, the regulations that we are requesting will clearly promote “the efficient enforcement” of the central provisions of the Act that are designed to protect public health, and therefore section 701(a) gives the agency authority to limit the distribution of Accutane if it chooses to do so.

We understand that some officials at the FDA do not believe that it has authority to adopt the measures we are requesting, particularly the provision limiting prescribing of the drug to dermatologists. It would be both unfortunate and peculiar for the agency to adopt such an “all or nothing” interpretation of the FDC Act which would limit its choices to permitting unrestricted marketing of Accutane or banning its sale.

In fact, for many years, the FDA has asserted that the agency has the authority that we are requesting it to exercise here. This position was officially set out in 1972 in a Federal Register notice, where the FDA stated as follows:

Where the unapproved use of an approved new drug becomes widespread or endangers the public health, the Food and Drug Administration is obligated to investigate it thoroughly and to take whatever action is warranted to protect the public. Several alterative courses of action are available to the Food and Drug Administration under these circumstances, depending upon the specific facts of each case. These actions include: Requiring a change in the labeling to warn against . . . the unapproved use, . . . restrictinq the channel of distribution, or even withdrawing approval of the drug or removing it from the market in extreme cases. When necessary, the Food and Drug Administration will not hesitate to take whatever action of this nature may be required to bring possible harmful use of an approved drug under control.

Legal Status of Approved Labeling for Prescription Drugs; Prescribing for Uses Unapproved by the Food and Drug Administration: Notice of Proposed Rule Making, 37 Fed. Reg. 16503 (August 15, 1972) (emphasis supplied). The agency has never modified this policy statement, and we have been informed by the office of Chief Counsel that it currently represents official FDA policy. The agency’s regulation of clinical investigators of new drugs supports our argument that it has the authority to regulate the circumstances under which physicians can prescribe a drug, where such regulation is necessary to protect patients. Although the statutory provision applicable to investigational new drugs, 21 U.S.C. § 355(i), does not mention regulating clinical investigators, we believe, as apparently does the agency, that the FDA plainly has authority to impose record-keeping and other requirements on clinical investigators and to disqualify investigators who do not comply with the regulatory requirements.

See 21 C.F.R. § 312.70 (1987). Similarly, the agency has implicit authority to impose direct limitations on doctors and pharmacists where such limitations are a necessary prerequisite to finding that a new drug meets the safety requirements in section 505, 21 U.S.C. § 355. Failure to abide by the regulations on the part of the manufacturer, physicians or pharmacists should be made subject to criminal penalties, pursuant to 21 U.S.C. § 331.⁵

Section 301(d) of the FDC Act, 21 U.S.C. § 331(d), prohibits the “introduction or delivery for introduction into interstate commerce of any article in violation of . . . section 505,” the provision applicable to new drugs. We are suggesting that manufacturers, pharmacists and physicians all be required to abide by the FDA regulations that we are proposing for Accutane. There can be little doubt that such regulations could be made applicable to manufacturers, since they are already barred from promoting drugs in any way that is inconsistent with the product’s indications. Similarly, the agency already regulates pharmacists by requiring that they distribute patient package inserts (“PPIs”) for certain drugs, and it could use that authority to prohibit pharmacists from filling prescriptions written by physicians who had not been “certified” by the FDA. The PPI regulations were issued pursuant to the section 505 and the agency’s general rulemaking authority, 21 U.S.C. § 355, 371(a), and they were upheld in Pharmaceutical Manufacturers Association v. Food and Drug Administration, 484 F. Supp. 1179 (D.Del. 1980).

The record before the FDA supports a finding that, without restrictions on physicians of the type that we are requesting, Accutane cannot meet the safety requirements of section 505. Therefore, we believe, section 701(a) gives the FDA the authority to prohibit misprescribing of the drug “for efficient enforcement of the Act.” This may be accomplished by regulations permitting only dermatologists to prescribe Accutane and restricting prescriptions to patients with the FDA-approved indications.

We also believe that the agency could enforce such regulations under the criminal penalties in section 303(d), 21 U.S.C. § 331(d). If the FDA required Roche to state in Accutane’s labeling that the drug may be prescribed by a dermatologist, then Roche would be violating section 303(d) if it promoted the drug for use by physicians other than dermatologists. Similarly, a physician who is not a dermatologist who prescribes the drug is aiding and abetting Roche in the “introduction or delivery for introduction into interstate commerce” of a drug “in violation of section 505,” which itself is a violation of section 301(d).

We recognize that the FDA usually relies on the state laws to regulate prescribing of approved drugs by physicians, although it has adopted regulations regarding the use in investigational new drugs by physicians in their medical practice. We do not envision a change in this allocation of responsibilities in the usual case. However, we are advocating that in the unusual case where the facts require that restrictions be placed on the prescribing of drugs, as we believe is clearly the case with respect to Accutane, then the agency should exercise its authority to impose such conditions.⁶

The closest analogy to the action that we are requesting in this petition is the agency’s regulation of methadone. Under its regulations, the FDA has specifically prohibited physicians from using that drug for treatment of narcotic addicts without prior FDA approval. 21 C.F.R. § 291.505(b)(4) (1987). The regulations also prescribe the indications that methadone may be used for, the doses that may be used and, finally, that informed consent be obtained from patients. 21 C.F.R. §§ 291.505 (b)(4), (c)(8),(d)(3)(i), (d)(3)(ii) (1987). While it is true that the agency relies in part on the Public Health Service Act and the Controlled Substances Act as authorities for its regulation of Methadone, these regulations provide a good model for the regulation of Accutane.⁷

D. Environmental Impact.

The requested action will have an insignificant impact on the environment.

In addition, cases decided by the Supreme Court since American Pharmaceutical Association case make it clear that agencies such as the FDA are to be given great deference in interpreting their own regulatory statutes, casting considerable doubt on whether American Pharmaceutical Association is still good law, even as limited to methadone. See, e.q., Young v. Community Nutrition Institute, 476 U.S. 974 (1986), where the Court reversed the D.C. Circuit, which had overturned the FDA’s interpretation of section 406 of the FDC Act and held that the agency’s interpretation of a statute will be upheld if it is “sufficiently rational to preclude a court from substituting its judgment for that of the FDA.” 476 U.S. at 981; see also Chevron U.S.A., Inc. v. Natural Resources Defense Council, Inc., 467 U.S. 837 (1984).

We recognize that the methadone regulation refers to both an investigational and a treatment use. 21 C.F.R. § 291.505. However, the limitations on the drug’s distribution plainly apply to the treatment use, and thus the regulations stand as a precedent for limiting the distribution of a drug such as Accutane.

E. Economic Impact.

The requested action may have a short-term adverse impact on the financial condition of Hoffmann-La Roche. However, in the long-term it will benefit both the manufacturer of Accutane and the physicians who are negligently prescribing it by reducing the incidence of malpractice and product liability lawsuits. Although the economic impact on consumers is trivial in comparison to the avoidable physical injuries and unnecessary abortions caused by Accutane, granting the petition will also have a beneficial economic impact by eliminating the unnecessary medical and other costs associated with children born with severe birth defects and both spontaneous and voluntary abortions.F. Certification.

The undersigned certifies, that, to the best knowledge and belief of the undersigned, this petition includes all information and views on which the petition relies, and that it includes representative data and information known to the petitioner which are unfavorable to the petition.

* * * * * *

We recognize that the FDA has never approved an NDA on the condition that its use be limited to a particular specialty. Similarly, the FDA has invoked the imminent hazard provision of the FDC Act on only one occasion since it was enacted in 1962. We also cannot imagine a stronger case for invoking either authority, given the seriousness and number of adverse reactions caused by Accutane and fact that there is a definable population (males and woman who do not become pregnant) for whom the drug is valuable. Therefore, we believe that it is imperative that both agencies use their full authority to limit the distribution of Accutane.

We also recognize that certain officials within the FDA have raised questions as to whether the FDA has the authority to limit the prescribing of a drug to a specialty and whether it may require informed consent for an approved drug. However, legal officials at the agency have informed us that the FDA has taken the position that it does have the authority to limit the distribution of drugs. If the FDA rules that it does not have such authority, then we will consider seeking review of that determination in federal court as well as seeking legislation in Congress. In either event, it is imperative that this issue be decided as expeditiously as possible.

Given the nature of the issue before the FDA, we request action on this petition within 30 days, including a final ruling on the agency’s authority to adopt the measures that we have requested. We believe that failure to act on the petition within that period of time would constitute “unreasonable delay” in violation of the Administrative Procedure Act.

William B. Schultz

Public Citizen Litigation Group

Suite 700

2000 P Street, N.W.

Washington, D.C. 20036

(202) 785-3704

ATTORNEY FOR PUBLIC CITIZEN

Lynn Silver, M.D. MPH

Sidney M. Wolfe, M.D., Director

Public Citizen Health Research Group

Suite 700

2000 P Street, N.W.

Washington, D.C. 20036

_________________

¹Public Citizen is a public interest organization with about 60,000 members, some of whom are women of child-bearing age. Unless the Food and Drug Administration (“FDA”) takes prompt action, there is a substantial likelihood that in the future some of these women will use Accutane, even though it is not indicated for them. Therefore, they would unnecessarily be placed at risk of giving birth to a deformed child or of having a spontaneous abortion. We also are filing this petition on behalf of our members who have an interest in clarifying the FDA’s authority to limit the distribution of drugs which pose a serious health hazard because of the substantial likelihood that in the future the exercise of such authority will be needed for drugs that those members will be using.

² Unless otherwise noted, all references to FDA data in this petition are to data presented at the April 26, 1988 Advisory Committee Hearing.

³Dr. Lammer presented Accutane data in his testimony at the April 26, 1988 hearing; for information on the abortion rate in the general population, see Ventura, S, et. al., “Estimates of Pregnancies and Pregnancy Rates for U.S. 1976-85,” American J. of Public Health, Vol. 78, No. 5, pp. 506.

⁴To facilitate enforcement, we urge the FDA to assign prescribing numbers to dermatologists who would be required to register with the agency, and to certify by affidavit that he or she has read and will follow the regulations and is aware that a dermatologist who violates the regulations is subject to criminal penalties. The regulations should prohibit pharmacists from selling Accutane unless the prescription contains the FDA prescribing number.

⁵ The FDA has occasionally used its authority to regulate investigational new drugs, 21 U.S.C. § 355(i), as a means of limiting the distribution of new drugs, even when there are no ongoing investigations of the drugs. For example, although the FDA never approved Thalidomide, for many years it has allowed the drug to be used for treating leprosy under an approved IND application. Similarly, when the agency invoked the imminent hazard provision of the FDC Act to revoke the NDA for phenformin, the oral diabetes drug, it allowed the drug to be made available to a limited number of patients under an approve IND application. we believe that this use of the IND provisions to make drugs which are not being investigated available for treatment is probably illegal and that the better course would be to approve a limited NDA as requested in this petition.

⁶ In F.T.C. v. Simeon Management Corp., 391 F. Supp. 697(N.D. Calif.1975), a district court judge ruled that the FDA does not have the authority under section 505 of the FDC Act, 21 U.S.C. § 355, to regulate the administration of a drug by a physician. However, the court did not consider the issue of whether under section 701(a), 21 U.S.C. § 371(a), the agency would have the authority to issue substantive, binding regulations applicable to physicians, as we are requesting in this petition.

⁷ In American Pharmaceutical Ass’n v. Weinberger, 377 F. Supp. 824 (D.C. Cir. 1974), affirmed, 530 F.2d 1054 (D.C. Cir. 1976) (per curiam), the Court held that the FDA could not limit the distribution of methadone to certain hospital and drug treatment centers, an approach that petitioners are not advocating. While it might be argued that the methadone ease would bar the FDA from limiting the distribution of Accutane to specific physicians, excluding distribution to pharmacies, nothing in that case limits the agency’s ability to mandate that physicians follow the indications for the drug or to require that a physician meet the requirements of a specialty in order to prescribe the drug. In addition, the agency’s attorneys have consistently taken the position that the holding of American Pharmaceutical Association is limited to methadone and that thus the court’s decision does not impair the agency’s ability to limit the distribution of other drugs, such as Accutane.