OBJECTIVES:  The Breakthrough Therapy Designation provides an expedited Food and Drug Administration (FDA) review pathway for novel pharmaceuticals that treat serious or life-threatening disease and show preliminary clinical evidence of substantial improvement over existing therapies. The aim of this research is to determine whether that clinical data is sufficient for US payer coverage and reimbursement. METHODS: We compared characteristics of all novel pharmaceuticals approved with and without a breakthrough therapy designation using publicly available information provided by Drugs@FDA. Benefits documents and coverage policies were extracted from the 20 largest US private insurance companies. Coverage status and prior authorization criteria were then compared to FDA approval. RESULTS: Between 11/1/2013 and 12/31/2015, FDA CDER approved 90 novel pharmaceuticals; 22 new molecular entities/new biological products that received Breakthrough Therapy Designation and 68 novel pharmaceuticals that did not receive Breakthrough Therapy Designation. We identified 684 coverage policies issued by private payers for the included new drugs. Almost no payers denied access to any of the included novel drugs; 96.78% of all coverage policies provided at least some degree of patient access. Breakthrough therapies were universally covered by all payers. Private payer coverage of breakthrough therapies was equivalent to the corresponding FDA label in 79.17% of cases, more restrictive in 8.33%, less restrictive in 10.19%, and varied in 2.31%. All ‘less restrictive’ or ‘varied’ breakthrough therapies were cancer drugs. Breakthrough therapies were significantly more likely to be equivalent to corresponding FDA approval than other novel pharmaceuticals (79.17% vs. 56.4%). Novel pharmaceuticals that did not receive breakthrough therapy designation were significantly more likely to have additional restrictions applied. CONCLUSIONS:  Although the Breakthrough Therapy Designation leads to faster regulatory approval, payer coverage remains a significant hurdle for drug manufacturers as they bring novel pharmaceuticals to market. For patients, coverage inconsistencies can mean variable access to breakthrough therapies.