• Increased incentives for survey participation.

The first-year evaluation of SMART found that 127 pregnancies were reported among isotretinoin users in the year before SMART (April 1, 2001, to March 31, 2002) and 120 during SMART’s first year (April 1, 2002, to March 31, 2003) (Avigan and DalPan, 2004; Pitts and Karwoski, 2004; Ackermann Shiff et al., 2006).

The ineffectiveness of SMART led to a more aggressive approach. iPLEDGE, the risk management program instituted in March 2006, drew praise for its comprehensiveness but criticism that the complicated responsibilities for patients, prescribing physicians, and dispensing pharmacists would discourage use. Key components of iPLEDGE are registration of patients and pharmacists, documentation by female patients of child-bearing potential of two forms of contraception and a laboratory-confirmed negative pregnancy test, verification by the pharmacist that the prescription is valid, and distribution of a medication guide.

RiskMAPs are a fairly new development, and an FDA guidance acknowledges the need for evaluation of plan performance (FDA, 2005b). PDUFA III gave ODS/OSE a role in the review and evaluation of risk management plans. The PDUFA III goals call for ODS/OSE participation in pre-NDA meetings and pre-biologic license application meetings to discuss preliminary risk management plans and proposed observational studies and, in the period 2–3 years after approval, to evaluate risk management plans after implementation.

4.4: The committee recommends that CDER assure the performance of timely and scientifically-valid evaluations (whether done internally or by industry sponsors) of Risk Minimization Action Plans (RiskMAPs). This review should include determining whether an individual RiskMAP is effective and overall evaluations of the strategies used and the processes of CDER staff and industry sponsors for planning and implementing RiskMaps. Evaluations should consider burdens and consequences in addition to design and effectiveness.

Risk-Benefit Analyses Throughout the Lifecycle

The regulatory decision to approve a drug requires the determination that the benefits of the drug outweigh the risks associated with it when used for the indication for which the drug is approved. That is, the drug must demonstrate a favorable risk-benefit profile. As a country we have chosen to place a significant degree of decision-making about the availability and potential use of medicines in the hands of a science-based regulatory body.



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