This article has been co-authored by Terri V. Newman, post-graduate fellow in Pharmacoanalytics, Pharmacoeconomics and Outcomes Research, University of Pittsburgh School of Pharmacy; and Natasha Parekh, clinical instructor, University of Pittsburgh School of Medicine, Division of General Internal Medicine; Alvaro San Juan Rodriguez, post-graduate fellow in Pharmacoanalytics, Pharmacoeconomics and Outcomes Research, University of Pittsburgh School of Pharmacy.
In 2015, the FDA approved the PCSK9 inhibitors evolocumab and alirocumab for lowering low-density lipoprotein cholesterol (LDL-C). The approval of these agents was based on clinical trials
that found PCSK9 inhibitors reduced LDL-C levels by around 60%. Based on this LDL-C reduction, PCSK9 inhibitors were predicted to reduce the risk of cardiovascular events by around 36% to 39%. As clinicians, patients, and payers waited for the results of 4 large phase 3 trials powered to assess the efficacy of PCSK9 inhibitors in the prevention of cardiovascular events, these predictions generated high expectations for the potential of this therapeutic class in the treatment of atherosclerotic cardiovascular disease. Some even postulated that, despite their current price of $14,000 per year of treatment, PCSK9 inhibitors could dramatically decrease
the burden of atherosclerotic cardiovascular disease at a price comparable with other lipid lowering therapies because of the cost savings associated with avoiding downstream cardiovascular events .
The results of the FOURIER trial, the first of 4 large clinical trials conducted to assess the efficacy of PCSK9 inhibitors in the prevention of major cardiovascular events, were published
in March 2017. It found that the PCSK9 inhibitor evolocumab reduced the risk of major cardiovascular events, including cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina, and coronary revascularization, by 15%. Evolocumab was further associated with a 27% reduction in the risk of MI, and a 21% reduction in the risk of stroke. The failure of these results to meet the expectations generated by previous predictions was reflected in media and in the stock market, immediately following their publication. While experts suggested that Amgen would have to reconsider the pricing of evolocumab, Amgen announced its willingness to offer innovative contracts payers to remove access barriers to evolocumab. Specifically, Amgen offered
to refund payers the cost of evolocumab for patients who have a MI or a stroke while using the drug.
In a recent research letter in JAMA Internal Medicine
, Hernandez simulated the impact that these contracts would have on the price of evolocumab to demonstrate that they would barely decrease the annual price of evolocumab by 2% to 3%. These refunds would be considerably lower than current discounts offered for evolocumab, which according to Amgen, average
between 30% and 35%. Even after the application of both current discounts and outcomes based refunds, the annual price of evolocumab therapy would be around $9000, which is 2 to 3 times the price at which evolocumab would be cost effective
It is important to consider the clinical value and cost-effectiveness of these drugs in the context of the current LDL-C treatment guidelines. A recent update
to the American College of Cardiology Expert Decision Consensus Pathway made some key changes on the role of non-statin therapies in the management of atherosclerotic cardiovascular disease. One particular change involves the expanded consideration given to PCSK9 inhibitors in the secondary prevention of patients with clinical disease and comorbidities already on a statin. Prior to the guideline update, if this treatment group required the addition of a non-statin therapy for further LDL-C lowering, ezetimibe would be preferred. However, ezetimibe and PCSK9 inhibitors are given equal consideration in the new update.
As clinicians and payers await publication of the results of the ODYSSEY trial scheduled for later this year, the debate on the place of PCSK9 inhibitors in clinical practice will likely continue. It will be particularly important to consider whether clinical guidelines should account for the price and cost-effectiveness of the agents under evaluation when providing recommendations.
In addition to the important implications on the place in therapy of PCSK9 inhibitors, this research letter raises 6 important points for payers to consider while designing outcomes-based contracts:
Payers should require manufacturers to bear an amount of risk that compensates for the administrative costs of implementing these contracts. The refunds proposed by Amgen for evolocumab would translate into an approximate 2.15% price reduction across patients. This small percentage may not be enough impetus for insurers to incur costs related to the administrative efforts needed to implement these contracts.
Payers and manufacturers will also have to negotiate whether patient copayments will also be refunded in addition to the costs borne by the payer. In the latter case, payers and manufacturers will have to share information on the copayments borne by patients, particularly because payers do not have information on the use of copayment cards provided by manufacturers.
An important aspect in the negotiation of these contracts will be outcome selection. Preferably, outcomes should be traceable using claims data, and should capture meaningful endpoints, not surrogate outcomes.
Negotiations for outcomes-based contracts will also have to consider the length of the cost of therapy to be refunded. For example, if a patient was to have a stroke after using evolocumab for 5 years, it is unclear whether the payer would be refunded for the amount that corresponds to the 5 years of therapy or only 1. Additionally, manufacturers will likely establish terms under which patients are required to use the drug for a certain period of time before payers become eligible for refunds. These periods will differ across therapeutic areas and should reflect an adequate time that allows for the drug under negotiation to demonstrate clinical effectiveness. For instance, the outcomes-based contract between Amgen and Harvard Pilgrim for evolocumab requires that patients adhere to the evolocumab regimen for at least 6 months before they qualify for discounts in the event of a MI or a stroke.
In engaging in these contracts, payers will also have to decide whether other drugs in the same therapeutic class will be excluded from the formulary, will still be covered and reimbursed through standard means, or will be managed through other outcomes-based contracts. It is particularly remarkable in the case of Cigna, which has engaged in separate outcomes-based contracts for the 2 PCSK9 inhibitors available.
Finally, payers and manufacturers will also have to debate the role of pharmaceutical benefit managers in these contracts, and whether they will also bear financial risk for the costs of the medications under negotiation.
In summary, in order for outcomes-based pricing agreements to translate into an increased value in pharmaceutical use and spending, their formulation should be carefully designed to account for the peculiarities of the management of pharmaceutical benefits, as well as for the cost-effectiveness of the therapy under evaluation.