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The American Journal of Managed Care September 2017
Guideline Concordance of New Statin Prescriptions: Who Got a Statin?
Thomas Cascino, MD; Marzieh Vali, MS, BS; Rita Redberg, MD, MSc; Dawn M. Bravata, MD; John Boscardin, PhD; Elnaz Eilkhani, MPH; and Salomeh Keyhani, MD, MPH
Provider-Owned Insurers
David H. Howard, PhD, and Erin Trish, PhD
The Effect of Narrow Network Plans on Out-of-Pocket Cost
Emily Meredith Gillen, PhD; Kristen Hassmiller Lich, PhD; Laurel Clayton Trantham, PhD; Morris Weinberger, PhD; Pam Silberman, JD, DrPh; and Mark Holmes, PhD
In-Gap Discounts in Medicare Part D and Specialty Drug Use
Jeah Jung, PhD; Wendy Yi Xu, PhD; and Chelim Cheong, PhD
Racial and Ethnic Differences in Hip Fracture Outcomes in Men
Lucy H. Liu, MD, MPH; Malini Chandra, MS, MBA; Joel R. Gonzalez, MPH, MPP; and Joan C. Lo, MD
Integrating Behavioral Health Under an ACO Global Budget: Barriers and Progress in Oregon
Jason Kroening-Roché, MD, MPH; Jennifer D. Hall, MPH; David C. Cameron, BA; Ruth Rowland, MA; and Deborah J. Cohen, PhD
Evaluation of a Packaging Approach to Improve Cholesterol Medication Adherence
Hayden B. Bosworth, PhD; Jamie N. Brown, PharmD, BCPS; Susanne Danus, BS; Linda L. Sanders, MPH; Felicia McCant, MSSW; Leah L. Zullig, PhD; and Maren K. Olsen, PhD
Treatment Barriers Among Younger and Older Socioeconomically Disadvantaged Smokers
Patrick J. Hammett, MA; Steven S. Fu, MD, MSCE; Diana J. Burgess, PhD; David Nelson, PhD; Barbara Clothier, MS, MA; Jessie E. Saul, PhD; John A. Nyman, PhD; Rachel Widome, PhD, MHS; and Anne M. Joseph, MD, MPH
Against the Current: Back-Transfer as a Mechanism for Rural Regionalization
Leah F. Nelson, MD, MS; Karisa K. Harland, PhD, MPH; Dan M. Shane, PhD; Azeemuddin Ahmed, MD, MBA; and Nicholas M. Mohr, MD, MS
Currently Reading
Association Between FDA Black Box Warnings and Medicare Formulary Coverage Changes
Sanket S. Dhruva, MD, MHS; Pinar Karaca-Mandic, PhD; Nilay D. Shah, PhD; Daniel L. Shaw, BA; and Joseph S. Ross, MD, MHS

Association Between FDA Black Box Warnings and Medicare Formulary Coverage Changes

Sanket S. Dhruva, MD, MHS; Pinar Karaca-Mandic, PhD; Nilay D. Shah, PhD; Daniel L. Shaw, BA; and Joseph S. Ross, MD, MHS
Medicare formularies were inconsistent in increasing restrictiveness to drugs that received FDA black box warnings for death and/or cardiovascular risk with safer available drug alternatives.
Objectives: To assess whether Medicare formularies restrict access to drugs receiving new FDA black box warnings for which safer drug alternatives are available.

Study Design: A retrospective analysis using Medicare Prescription Drug Plan Formulary files to determine formulary changes for drugs receiving FDA black box warnings between 2007 and 2013.

Methods: We identified all FDA-approved medications available in tablet or capsule formulation that received a black box warning between 2007 and 2013 related to death and/or cardiovascular risk. We then determined formulary coverage of these drugs pre-black box warning, 1 year after, and 2 years after. For each formulary, we identified formulary restrictiveness, defined as: unrestrictive coverage (no prior authorization or step therapy), restrictive coverage (prior authorization or step therapy required), or no coverage.

Results: Nine drugs with at least 1 FDA-approved safer drug alternative received 10 new black box warnings for death and/or cardiovascular risk between 2007 and 2013. In response to FDA black box warnings, overall formulary restrictiveness increased for 40% (n = 4) of drugs at 1 year, and for 50% (n = 5) at 2 years. However, for the majority of drugs (n = 7),  most formularies remained unrestrictive 2 years after a new black box warning.
Conclusions: Medicare formularies became more restrictive for half of the drugs that recently received new FDA black box warnings for death and/or cardiovascular risk and for which safer drug alternatives are available. However, a substantial proportion of formularies remained unrestrictive, suggesting inconsistent responses to new safety information to curtail the use of these medications.

Am J Manag Care. 2017;23(9):e310-e315
Takeaway Points
The impact of FDA black box warnings on formulary restrictiveness is not well known. This study investigated whether Medicare formulary coverage changed after oral drugs with safe available drug alternatives received new FDA black box warnings related to death and/or cardiovascular risk. 
  • Some formularies either dropped coverage or began requiring prior authorization to restrict the prescribing of unsafe drugs. 
  • A substantial proportion of formularies made no changes to restrict coverage. 
  • There are opportunities to improve consistency in formulary responses to FDA black box warnings to curtail utilization of drugs with known safety risks and for which safer drug alternatives are available.
The FDA requires that drugs with serious or life-threatening risks have a boxed warning (commonly referred to as a “black box warning” [BBW]) on their label. The BBW is one of the FDA’s strongest actions short of drug recall or withdrawal, and is intended to inform patients and prescribers about serious safety concerns that must be considered in assessing the risks and benefits of a drug or that the FDA allows use of the drug only with restrictions to ensure safe use. However, BBWs have not been consistently associated with reduced prescribing1-3 for several possible reasons. First, prescribers may be unaware that the FDA had issued the warnings.1,4,5 Second, prescribers may think that, despite BBWs, the drugs have a superior benefit/risk ratio to alternative therapies or that the safety concern is not as severe as suggested, and opt to continue prescribing while using strategies to mitigate risk, such as closer patient monitoring.1,4,6-8 Third, BBWs may apply only to limited patient populations, and prescribers may not believe the risk applies more generally.
Another possibility is that BBWs are not taken into account within insurance plan drug formularies. Formularies limit prescribing of unsafe drugs through 2 strategies: formulary exclusion (ie, no coverage) or utilization management (eg, prior authorization or step therapy). One study found no change to state Medicaid plans’ prior authorization requirements following the 2005 BBW for atypical antipsychotic use among the elderly,9 and another found that only 2 state Medicaid programs restricted use after the 2007 BBW for rosiglitazone.10 To better understand the potential role that insurance plan drug formularies may play in restricting the use of potentially unsafe drugs that have safer available alternatives, we characterized changes to Medicare formularies for oral drugs that received new BBWs between 2007 and 2013 for death and/or cardiovascular risk. As these are among the most severe adverse events, we hypothesized that they would have the greatest likelihood of resulting in formulary changes to restrict use. Because each BBW is specific to the drug’s indications and risk, we focused on a limited sample to provide an illustrative summary of formulary changes.

Data Source

We conducted a retrospective analysis of Medicare formularies using data from the CMS Prescription Drug Plan Formulary Files. We obtained data on both standalone prescription drug plans and Medicare Advantage prescription drug plan formularies for Medicare Part D, as of each June and December from 2006 through 2015.

We used the FDA’s MedWatch website to identify all FDA-approved tablet or capsule formulation medications used in an outpatient setting that received BBWs between 2007 and 2013 related to death and/or cardiovascular risk. MedWatch is the agency’s safety information and adverse event reporting program. We examined all BBWs and first excluded those for drugs used in-hospital only or not relevant to Medicare beneficiaries. We also excluded BBWs for combination drugs, since the primary drug would already be included in our sample. Next, we excluded BBWs for cancer, HIV, or immunosuppressants as these are protected classes treating diseases that require specialized pathways of care. We also excluded warnings for a narrow subset of patients and warnings related to drug-drug interactions. Lastly, we limited our study to drugs with at least 1 drug alternative without a BBW approved for use for the same primary condition, based on the US Pharmacopeial Convention Category & Class versions 5.0 and 6.0. When a drug had multiple BBWs, each warning was considered a unique event.
Formulary Restrictiveness

Our main outcome was formulary restrictiveness based on formulary exclusion, step therapy, or prior authorization. For each drug’s lowest available dose, we classified all Medicare formularies as unrestrictive, restrictive, or no coverage at 3 time points: immediately preceding, at least 1 year after, and at least 2 years after the BBW. An unrestrictive formulary covered the drug without prior authorization or step therapy requirements. A restrictive formulary covered the drug but required either prior authorization and/or step therapy. A formulary that did not explicitly provide coverage did not include the drug on its formulary, which means patients are responsible for the entire drug cost except in very rare circumstances.
Statistical Analyses

We used descriptive statistics to characterize the proportion of formularies that were unrestrictive, restrictive, and did not provide coverage for each drug at all 3 time points. We used χ2 or Fischer’s Exact tests to examine differences in formulary restrictiveness for each drug, comparing restrictiveness pre-BBW to restrictiveness at both 1 year and 2 years afterward. All statistical tests were 2-tailed with a type 1 error rate of 0.025 to account for multiple comparisons for each drug.

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