FDA may consider a formal rulemaking on the use of restricted distribution programs.

An advance notice of proposed rulemaking would "at least get the issue on the table, to get the ideas out," Deputy Chief Counsel Michael Landa suggested during a Drug Information Association risk management workshop in Washington, D.C., May 16.

Given that FDA's legal authority to impose restricted distribution may not be "crystal-clear" - and that only a relatively small number of drugs have limited distribution - a formal rulemaking may be "premature," Landa said. However, "some type of forum in which people begin to discuss these issues to me would make a lot of sense."

Landa suggested that FDA could ask: "When does it make sense for the agency to request [restricted distribution]? When does it make sense for a company to come forward? What types of criteria might one want to see in deciding for the agency whether to request it or for a company whether to come forward?"

"I think in many parts of the law, you have case-by-case solutions to problems and then out of those solutions grows some general sense of how you ought to proceed, so you can set down guidance or a regulation for the future," Landa said.

FDA's recent emphasis on risk management is raising concern among provider groups that the agency will increasingly rely on restricted distribution programs that may exclude groups of pharmacies, hospitals or physicians. During a May 22 public workshop on risk management, representatives from several provider organizations aired those concerns (see ¹ [A#00640210004]).

The increased use of restricted distribution programs is prompting renewed discussion of whether FDA has the legal authority to impose them.

FDA feels that it is warranted in imposing "additional restrictions" - such as consent forms, prescriber qualification requirements, dispensing restrictions and mandatory patient/physician registries - in circumstances when conventional tools have failed, Landa noted.

The agency's premise is that the legal requirement to assure safety necessitates a balancing of benefits and risks such that a drug is "safe under the conditions of use approved by FDA," he explained.

FDA asserted its authority to impose limited distribution programs under the 1992 accelerated approval ("Subpart H") regulations.

The sections of the regulation addressing use of surrogate markers as the basis for approval were incorporated into the "Fast Track" provisions (Sec. 112) of the 1997 FDA Modernization Act.

However, Sec. 112 does not explicitly authorize FDA to impose limited distribution.

During an April 17 Food & Drug Law Institute "Point/Counterpoint" session, Office of Medical Policy Director Robert Temple, MD, was asked whether the agency has the legal authority to impose limited distribution, and whether it should.

"I believe we have the authority to impose such systems," Temple said. "We obviously thought when we imposed Subpart H that we had that authority." If "it ever turned out that a court said we didn't, I would say we should," Temple added. "To me it just fits with the whole idea of how a drug is going to be used."

Covington & Burling partner Peter Barton Hutt offered an opposing view. The restricted distribution portion of Subpart H is "completely unnecessary," Hutt said. Sponsors of products with unique risks that require limited distribution have every incentive to create those programs voluntarily, he said.

However, "once FDA arrogates that authority, as it did under Subpart H, that has no limit. It has no end. It is used simply as a protection for the FDA employees to say that they have done everything possible that they can do to prevent a problem from arising" (² Also see "FDA Debates The “Slowdown”: Temple Sees No Sign Of Excess Caution" - Pink Sheet, 22 April, 2002., p. 28).

A legal challenge to FDA's authority to impose distribution restrictions would likely be grounded in a 1974 court ruling on methadone distribution (APhA v. Weinberger).

FDA still needs to "come to grips with" the 1974 decision, Covington & Burling partner Bruce Kuhlik declared during the DIA conference.

The decision invalidated a risk management program for the narcotic methadone, stating that "nowhere is FDA empowered to approve an NDA upon condition that the drug be distributed only through specified channels."

The agency addressed the ruling in issuing the final Subpart H regulations in 1992. "There is no legal support for the theory that FDA may only approve sponsors' drugs without restriction because physicians or pharmacists may wish to prescribe or dispense drugs in a certain way," the agency contended.

Landa noted that FDA's position is that the methadone decision is "limited to controlled substances...for recreational, narcotic purposes."

Kuhlik pointed to a 1972 statement on off-label use, where FDA stressed that "after a drug is shipped in interstate commerce and comes to rest in the pharmacy...the pharmacist's dispensing of the drug, the physician's prescribing it, the patient's use of it are outside of FDA's authority."

Kuhlik advised FDA to "proceed cautiously." The agency's programs "in the risk management area, at least things on the cutting edge [like] the distribution restrictions...need to be done by consensus. They need to be done with the cooperation and consent of the pharmaceutical company and with the input of everybody else," he said.

Kuhlik is involved in one issue that could raise the question of FDA's authority to require distribution restrictions for generic drugs. He drafted a citizen petition against incorporating generics into Roche's risk management program for Accutane (isotretinoin). Mylan has a generic version of the acne drug pending (³ Also see "Accutane Generics Need Separate Risk Management Programs, Roche Says" - Pink Sheet, 18 February, 2002., p. 24).

Landa acknowledged that FDA may be exposed to litigation if it ever finds itself unable to resolve a distribution issue with a sponsor. "Then the agency is going to have to ask itself, 'What do we do, do we refuse to approve?'" Landa said. "There will be litigation over that."

However, working through case-by-case agreements with sponsors also has pitfalls, Landa noted. For example, he asked how the agency would handle a situation where five companies in a class agree to a restricted program, but the sixth does not. In addition, FDA would not be sure how to proceed in a case where the innovator agrees to a voluntary program, but a potential generic does not, Landa said. "We have to think about that."

Kuhlik added that FDA has to be careful in negotiating the gray area between voluntary agreements and coercion. "It can't be a complete answer that if a company agrees to it to get a drug approved, it's voluntary and therefore unobjectionable," he declared.

Patton Boggs Partner Daniel Kracov suggested that coercion may also be an issue from the patient perspective. "Is it coercion to require a patient to sign an informed consent form...[or] to make them sign on to a registry?" he asked.

Kracov suggested that "in these risk management programs there should always be a provision to allow patients to opt out. Granted, they may have to sign some sort of form saying they recognize that they are giving something up, perhaps, in terms of safety."

Limited distribution programs may make companies more vulnerable to product liability claims by eroding the "learned intermediary" defense, Kracov added.

"If you're requiring the learned intermediary to undergo special training, make them sign 10 forms, make the patients sign four forms, and sign off on a registry and so forth, is...that physician an intermediary anymore at all?" he asked. "Or...is the pharmaceutical company taking responsibility for patient care by essentially instituting a framework for the taking of a treatment of that patient?"

FDA will also have to resolve potential conflicts between its regulations and state law, Kracov said.

"We're going to find as we go down the road of increasingly systemic, top-down risk management, is that there are going to be conflicts with these rules - conflicts in which FDA says that a certain practitioner is not qualified to prescribe a certain drug, whereas in that state, in fact, he has satisfied all the requirements."

Congress may have to step in to resolve such dilemmas, Kracov suggested. "Congress has shown itself to be capable of addressing the need for prescription-plus authority in the context of clinical devices," he noted. "Maybe that's, in the end, something that ultimately Congress will be required to do here."

FDA Restricted Distribution Rulemaking May Clarify Regulatory Issues

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