FDA is proposing four levels of risk management programs for prescription drugs and biologics in a "Risk Management Programs" draft ¹ concept paper released March 6.

Risk management programs should "be broadly characterized into one of several 'levels' to reflect how much the tools used in the RMP diverge from conventional prescribing, dispensing, and use," the concept paper states.

The first level would include only changes to the package insert. The concept paper notes, however, that all relabeling does not necessarily constitute a risk management program.

"Submissions to FDA to revise the [package insert] for adverse events would not automatically lead to an RMP being proposed."

"For most products, risk management planning will be handled by the information contained in" labeling, the agency noted.

The second level would also include education and outreach to health professionals and patients.

Education and outreach efforts include health care professional letters, training programs, continuing medical education, public notices, patient package inserts and medication guides, FDA noted.

Risk management programs categorized at Level 3 would include all of the elements of the first two levels, as well as "systems which guide the circumstances for practitioners and/or patients to prescribe, dispense, or receive a product."

Examples of those systems include patient agreements and informed consent; certification programs for practitioners; enrollment of physicians, pharmacies, and patients in a safety program; limitations on supply or refills of product; specialized product packaging; and specialized systems, records or stickers that attest that safety measures have been satisfied.

Restricted access systems would apply to products at Level 4, where "access to the product requires adherence to specific program elements," such as prescribing only by registered physicians, dispensing only by registered pharmacies or practitioners, or dispensing only to patients with documentation of safe use conditions, such as lab results.

FDA's risk management initiative was spurred in part by a loss of confidence by agency officials in the effectiveness of serial labeling changes in reducing drug risk. The higher-level tiers outlined in the preliminary "toolkit" suggest next steps that could be taken if relabeling appears ineffective.

Given the program evaluation requirements outlined in the draft concept paper, even a relabeling could be a significant undertaking for a company.

The impact of each risk management plan will be measured as part of the program, assessing the tools themselves and the overall effectiveness in achieving the program goals. The evaluations should include "sources of potential measurement error or bias."

At least two different evaluation methods should be used for key components of the program, such as hospitalization data and death certificate surveillance.

If patient outcomes cannot be measured directly, closely related measures should be used, including surrogates of health outcomes such as co-prescribing of contraindicated medications. The draft paper also recommends "process measures that reflect desirable safety behaviors," such as performance of recommended laboratory monitoring, and "assessments of comprehension," such as provider, pharmacist, or patient surveys.

The concept paper also urges pilot testing of programs.

FDA simultaneously released two other draft concept papers - "Premarketing Risk Assessment" and "Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment" (see ² Also see "Pharmacoepidemiologic Studies Should Estimate AE Background Rates – FDA" - Pink Sheet, 10 March, 2003.).

The concept papers are part of FDA's effort to develop guidance on risk management, as mandated in the 2002 reauthorization of the user fee program.

FDA plans to hold a ³ public meeting to discuss the concept papers on April 9-11 in Washington, D.C. The agency will devote one day of discussion to each concept paper. FDA expects to finalize the three guidances by fall 2004.

FDA Risk Management Plan: Four Levels, From Labeling To Restricted Access

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