Accutane prescribers must register with Roche to receive "qualification stickers" under the company's updated pregnancy prevention program.

Pharmacists should only dispense Accutane (isotretinoin) for prescriptions displaying the stickers, FDA said in an Oct. 31 "Talk Paper." The stickers are intended to certify that the physician has taken the pregnancy prevention steps required in revised Accutane labeling.

"All prescriptions for Accutane should have the special yellow sticker attached to the prescriber's regular prescription form," FDA said. The sticker "will indicate to the pharmacist that the patient is 'qualified' according to the new package insert, which means that the female patient has had negative pregnancy tests...as well as education and counseling about pregnancy prevention."

Roche's SMART (System to Manage Accutane Teratogenicity) program, developed in consultation with FDA, is intended to strengthen the existing Pregnancy Prevention Program. Revised Accutane labeling and SMART program materials will be sent to dermatologists and primary care physicians as well as 56,000 pharmacies on Jan. 2.

At that time, the Accutane sales force of 108 reps will begin detailing physicians on the revised risk management plan.

Roche expects there will be a window of at least a month between the mailing of program materials and when pharmacists will stop filling scripts without qualification stickers. Roche is currently negotiating the exact timeframe with FDA.

Physicians can register to prescribe Accutane by reviewing the company's "Guide to Best Practices" and signing a "Letter of Understanding" that certifies their knowledge of the measures to minimize fetal exposures to the acne drug. Upon receipt of the signed letter, Roche will send the prescriber the yellow, self-adhesive Accutane qualification stickers.

Under the SMART program, documentation of two negative pregnancy tests will be required before an initial prescription can be issued.

Patients will have to return to the physician each month to receive a new "qualified" script. "For each month of therapy, they must have a negative pregnancy test result before receiving their next prescription, regardless of whether they are sexually active," FDA said.

The revised risk management program is the latest experiment by FDA and industry with novel risk management tools to try to minimize inappropriate use of pharmaceuticals.

The Pharmaceutical Research & Manufacturers of America and FDA formed a joint working group on risk management in April (¹ Also see "IMS Risk Management Tool Targets "High Risk" MDs: CERTs Conference" - Pink Sheet, 21 May, 2001., p. 28).

The importance of the risk management effort to industry was highlighted by several PhRMA members in recent statements to the financial community suggesting that the development of appropriate risk management tools will reverse the recent trend toward longer FDA review times (² [A#00630440012], p. 15).

If the SMART program proves effective, FDA may have a precedent to use in future cases where the agency believes strict adherence to labeling is critical to the risk/benefit ratio for a product.

Roche has cleared one hurdle with the new program: winning the support of retail pharmacy groups.

The program relies on pharmacists to refuse to fill prescriptions that do not have the physician-certification sticker.

In addition, "pharmacists will dispense a maximum one-month supply of Accutane, fill prescriptions within seven days from the date of 'qualification,' and provide a Medication Guide for patients with each script," FDA said. "Requests for refills (i.e., more Accutane without a new prescription) and phoned-in prescriptions will not be filled."

Roche discussed the program with the National Association of Chain Drug Stores, the National Community Pharmacists Association and the Healthcare Distribution Management Association.

NACDS said it worked with Roche on developing the program and is pleased with its final form. The association noted that it was involved in conversations with Roche and FDA in which it was explicitly determined that the patient (and not the pharmacist) is responsible for obtaining a sticker for the prescription.

NACDS plans to inform its members of the program through its internal newsletter. The association also praised Roche's pharmacy educational materials, including a step-by-step guide to dispensing Accutane.

Pharmacy groups appear to see an opportunity in FDA's efforts to strengthen risk management techniques. American Pharmaceutical Association CEO John Gans suggested during a recent meeting that manufacturers should support pharmacy reimbursement as a tool to enhance risk management (³ Also see "U.S. Rx Trends Showing Impact Of Fewer Drug Approvals, IMS Data Suggest" - Pink Sheet, 22 October, 2001., p. 8).

An independent audit of pharmacies will be conducted by Delta Marketing Dynamics about one year after the SMART program's initiation to assess use of the Accutane qualification stickers by prescribers.

Roche will also use results from a survey conducted by the Slone Epidemiology Unit of the Boston University School of Public Health to measure the effectiveness of the SMART program.

The SMART program was developed in response to the recommendations of FDA's Dermatologic and Ophthalmic Drugs Advisory Committee.

In September 2000, the committed voted in favor of a risk management program that would require confirmation of negative pregnancy tests prior to dispensing Accutane. The panel also recommended complete participation of patients and physicians in a registry, to track pregnancy exposures (⁴ Also see "Pregnancy Test Should Be Required For Accutane Rx, FDA Cmte. Urges" - Pink Sheet, 25 September, 2000., p. 19).

The revisions to Accutane labeling will represent the second time Roche has updated Accutane labeling requirements in about a year. In January, Roche and FDA agreed to a mandatory medication guide/informed consent form to alert patients to the teratogenicity of Accutane as well as the potential psychiatric side effects of the drug (⁵ Also see "Roche Accutane Consent Form Requires Disclosure Of Mental Health History" - Pink Sheet, 29 January, 2001., p. 13).

Labeling was previously updated, in May 2000, to state that physicians "must" ensure that female patients have two negative pregnancy tests prior to therapy and that they discuss the need for using two forms of contraception simultaneously. Labeling says patients also "must" be instructed to join the Slone Accutane survey and view a video about contraception.

Accutane has become a leading example of FDA's concerns about "labeling fatigue," the fear that multiple labeling changes are of decreasing benefit in altering prescriber behavior. Since approval in 1982, Accutane has had 16 labeling changes, Roche said (⁶ Also see "FDA To Study "Labeling Fatigue": Do Serial Changes Influence Prescribing?" - Pink Sheet, 25 September, 2000., p. 21).

Accutane's safety profile has attracted Congressional interest, particularly as it relates to a potential relationship between Accutane and suicidal ideation or other psychiatric events.

The House Government Reform Committee held a hearing on the topic in December. The hearing was held partly in response to a request from Rep. Bart Stupak (D-Mich.), whose son committed suicide while on the acne therapy.

Roche responded to a "request for information" on "the science behind Accutane" from the Energy & Commerce/Oversight Subcommittee, which the company believed was a prelude to a follow-up hearing (⁷ Also see "Accutane Psychiatric Safety Trial Planned: Roche Prepares For Hearings" - Pink Sheet, 20 August, 2001., p. 20).

However, it appears that the new Congressional priorities following the Sept. 11 terrorist attacks have put Accutane hearing plans on hold.

Roche's proposed protocol for a prospective study to evaluate the potential link between isotretinoin and psychiatric effects is under review at FDA, the company said.

Stupak continues to indicate interest in drug safety issues in general. He sponsored language in the committee version of the pediatric exclusivity reauthorization bill to require all pharmacy-dispensed drugs to include a toll-free number in labeling for patients to report adverse events to FDA (see ⁸ Also see "Pediatric Bill Toll-Free Adverse Event Hotline Is Of Concern To Pharmacy" - Pink Sheet, 5 November, 2001.).

The black box warning in Accutane labeling already contains toll-free numbers for Roche Medical Services and FDA's MedWatch program.

Accutane will lose its patent exclusivity on Feb. 7, 2002. Mylan expects to launch generic isotretinoin at that time (⁹ Also see "Mylan Nebivolol Hypertension Drug Patent Protection Expected Through 2015" - Pink Sheet, 16 April, 2001., p. 9). Roche has an "approvable" once-daily formulation of the drug pending at FDA.

Roche Accutane Prescriber Registry Added To Pregnancy Prevention Program

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