Association Between FDA Black Box Warnings and Medicare Formulary Coverage Changes

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.
Published Online: September 29, 2017
Sanket S. Dhruva, MD, MHS; Pinar Karaca-Mandic, PhD; Nilay D. Shah, PhD; Daniel L. Shaw, BA; and Joseph S. Ross, MD, MHS
ABSTRACT

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.

METHODS

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.

Sample

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.

RESULTS

Nine medications in a tablet or capsule formulation received a total of 10 new BBWs related to death and/or cardiovascular risk between 2007 and 2013 and had at least 1 drug alternative without a BBW. Four of the 9 drugs (44%) had existing BBWs before the FDA issued BBWs between 2007 and 2013. Seven (70%) of the 10 BBWs were related to death and 5 (50%) to cardiovascular risk (2 related to both cardiovascular risk and death). Two BBWs, those for propylthiouracil and ketoconazole, specifically advised against use of the given medication except in very unique circumstances.

Two years after each of the 10 new BBWs, for 5 (50%) drugs, Medicare formularies became more restrictive, on average, by removing coverage or adding prior authorization requirements. There was no overall increase in step therapy requirements. For 1 (10%) drug, formularies became less restrictive on average and for 4 (40%) drugs there was no overall change in average formulary restrictiveness. When restricting to the 4 drugs with prior BBWs, results were overall similar: Medicare formularies became more restrictive for 2 (50%) drugs at both 1 and 2 years.

Rosiglitazone

Rosiglitazone is approved to improve glycemic control for type 2 diabetes. In August 2007, thiazolidinediones, a medication class that includes rosiglitazone and pioglitazone, received a BBW for congestive heart failure. Prior to this BBW, 78% (n = 255) of formularies provided unrestrictive coverage, 19% (n = 62) provided restrictive coverage, and 3% (n = 10) provided no coverage. There was no significant change in formulary restrictiveness at 1 or 2 years (Figure).

Prior to its strengthened February 2011 BBW for a significantly increased risk of myocardial infarction, 57% (n = 148) of formularies provided unrestrictive coverage, 36% (n = 94) provided restrictive coverage, and 7% (n = 18) provided no coverage. At 1 year, rates were 32%, 36%, and 32%, respectively (P <.001) (Figure), suggesting that formularies had become significantly more restrictive. Changes in restrictiveness were due to fewer formularies providing coverage and covering formularies requiring prior authorization (Table).

Pioglitazone

Pioglitazone is approved to improve glycemic control for type 2 diabetes. Prior to its August 2007 BBW for congestive heart failure, 67% (n = 220) of formularies provided unrestrictive coverage, 19% (n = 62) provided restrictive coverage, and 14% (n = 45) provided no coverage. At 1 year, rates were 73%, 27%, and 0%, respectively (P <.001) (Figure), suggesting that formularies had become significantly less restrictive. Changes in restrictiveness were predominantly due to more formularies providing coverage.

Zyban (buproprion)

Zyban is approved for smoking cessation. Prior to its July 2009 BBW for serious neuropsychiatric events, including suicide, 24% (n = 75) of formularies provided unrestrictive coverage, 5% (n = 11) provided restrictive coverage, and 73% (n = 232) provided no coverage. There was no significant change in formulary restrictiveness at 1 year (Figure). At 2 years, rates were 19%, 0%, and 80%, respectively (P = .006), suggesting that formularies had become significantly more restrictive. Changes in restrictiveness were predominantly due to fewer formularies providing coverage.

Varenicline

Varenicline is approved for smoking cessation. Prior to its July 2009 BBW for serious neuropsychiatric events including suicide, 60% (n = 191) of formularies provided unrestrictive coverage, 21% (n = 68) provided restrictive coverage, and 19% (n = 59) provided no coverage. At 1 year, rates were 51%, 49%, and 0%, respectively (P <.001) (Figure). Changes in restrictiveness were predominantly due to more formularies requiring prior authorization (Table).

Quinine

PDF is available on the last page.
Compendia
Adult ADHD Compendium
COPD Compendium
Dermatology Compendium
Diabetes Compendium
Hematology Compendium
Immuno-oncology Compendium
Lipids Compendium
MACRA Compendium
Neutropenia Compendium
Oncology Compendium
Pain Compendium
Reimbursement Compendium
Rheumatoid Arthritis Compendium
Know Your News
HF Compendium
Managed Care PODCAST