Author + information
- Received August 14, 2017
- Revision received October 12, 2017
- Accepted October 16, 2017
- Published online November 27, 2017.
- Faiez Zannad, MD, PhDa,b,c,∗ (, )
- Maria de los Angeles Alonso Garcia, MDd,e,
- Jeffrey S. Borer, MDf,
- Wendy Gattis Stough, PharmDg,
- Thomas Clutton-Brock, MDh,
- Yves Rosenberg, MD, MPHi and
- Milton Packer, MDj
- aINSERM, Centre d’Investigations Cliniques-1433, CHRU Nancy, Université de Lorraine, Nancy, France
- bINSERM U1116, CHRU Nancy, Université de Lorraine, Nancy, France
- cF-CRIN INI-CRCT, Nancy, France
- dImperial College NHS Trust, London, United Kingdom
- eScientific Advice Working Party, European Medicines Agency, London, United Kingdom
- fHoward Gilman Institute, State University of New York Downstate Medical Center, Brooklyn, New York
- gCollege of Pharmacy and Health Sciences, Campbell University, Buies Creek, North Carolina
- hInstitute of Clinical Sciences, University of Birmingham, Birmingham, United Kingdom
- iNational Heart, Lung, and Blood Institute, Bethesda, Maryland
- jBaylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas
- ↵∗Address for correspondence:
Dr. Faiez Zannad, CIC INSERM, Institut Lorrain du Coeur et des Vaisseaux, CHU 54500, Vandœuvre-lès-Nancy, France.
Regulators and payers have contrasting priorities that can lead to divergent decisions and delays in patient access to new treatments. Those involved in coverage decisions have not routinely been integrated in the drug development process. Theoretically, inclusion of payer representatives early in development could help discern discordance among stakeholder priorities; facilitate cooperation to align objectives; foster agreement on the evidence required for approval and reimbursement; improve transparency, accountability, and consistency of payer decision making; and ideally, minimize delays in patient access to new therapies. However, early participation by payers may not provide these expected benefits if payers’ decision-making processes are not evidence based or cannot be reliably predicted. This paper describes current interactions among regulatory agencies, payers, sponsors, and investigators and proposes collaboration among all stakeholders earlier in the development process. The premise that a priori discussions might facilitate the delivery of advances in cardiovascular care is a hypothesis worth testing.
In both the United States and Europe, the average time from initial filing to regulatory approval for new cardiovascular drugs is 6 to 7 years (1,2). Yet, timelines for payer reimbursement decisions, termed the “fourth hurdle” (3,4), may further delay patient access to new treatments by months (5) to years (2), or indefinitely if coverage is denied, high levels of coinsurance are transferred to patients, or repetitive administrative documentation is required. Although these concerns affect many parts of the world, this paper focuses on considerations relevant to the United States and the European Union (EU).
Regulators are responsible for ensuring the safety, efficacy, and quality of drug, biologic, or device therapeutics for an intended use in a specified population. Generally, a single body of scientific evidence derived from active or placebo-controlled large randomized trials forms the basis of regulatory decision making for new cardiovascular treatments. However, payer or health technology assessment (HTA) organizations have a different purview; they determine whether “an intervention offers useful, appropriate and affordable benefits for patients in a particular healthcare system” (6), and they focus heavily on whether the treatment provides value for money in relation to current therapies (Table 1) (7–10). This is particularly true as new high-cost specialty pharmaceuticals enter the market (11). Contrasting priorities can lead to delays between regulatory approval and payer reimbursement. When available evidence is deemed convincing for regulatory approval but not for reimbursement (12), patient access to new treatments is hindered. Payers have not, in general, been systematically engaged in the development process pre-approval, but their engagement may enable value-based information to be generated pre-approval, potentially minimizing delays in patient access post-approval. In this document, we consider involvement of payers in pre-approval drug development, focusing on therapies that offer a demonstrable advance over existing care but do not reach the public in a timely manner because of reimbursement barriers. We will not discuss “me-too” drugs with marginal or uncertain incremental benefits. Differentiation between these scenarios is essential in identifying true advances with potential to reduce morbidity and mortality.
The Global CardioVascular Clinical Trialists (CVCT) Forum is an opportunity for cardiovascular clinical trialists, clinicians, biostatisticians, European and United States regulators, government and industry sponsors, and patient representatives to convene and discuss relevant challenges facing cardiovascular clinical research. Concerns about the misalignment between regulatory approval and reimbursement decisions were raised during the annual meeting, December 1 to 3, 2016, in Washington, DC, and it was a specific topic of discussion during the CVCT Workshop, December 4 to 5, 2016, in Washington, DC. This paper summarizes the issues that were brought forth and proposes actions to address obstacles and hasten the delivery of effective, safe, and affordable treatments to patients with cardiovascular disease.
Overview of Current Systems and Complexities
Medical coverage in the United States is complex (13), in large part because multiple public and private payers operate within the health care system. The U.S. Centers for Medicare and Medicaid Services (CMS) provide medical and hospital coverage for approximately 57 million individuals over 65 years of age (Medicare); 41.5 million of these receive prescription drug coverage through the Medicare Part D benefit administered by Medicare-approved private insurers (14). Medicaid provides coverage for approximately 74 million eligible low-income individuals (15). Private insurers provide coverage for an additional 174.5 million people (16).
There is substantial variation in reimbursement practices among the various payers in the United States (17,18). In addition, reimbursement decision making is not transparent among the broad group of payers. Although it is appealing to think that payers’ needs could be addressed if they were involved in the design and execution of pre-approval clinical trials, it is not clear that payers (especially private payers) are able to describe their requirements or specify formal criteria early in development. As neither the benefits nor the price of a new treatment have been determined at this point in time, payers who rely on value or outcome-based pricing approaches may not be able to define their response in advance of a new approval (17,19). Nonetheless, efforts to actively involve payers in the process of evidence generation could improve post-approval communications, as outlined in a recent Food and Drug Administration (FDA) guidance document (20).
The process for reimbursement decisions in the European Union is more streamlined than in the United States, owing to the predominance of single-payer systems and the ability of national organizations to negotiate pricing (21). Nevertheless, post-approval evaluations by HTA bodies (a minimum of 1 per country, often more) and individual member state reimbursement negotiations can be lengthy (2,22). The breadth of HTA coverage across countries and even within regions of a country can vary greatly (23), and HTA decisions are not transparent (24,25).
Formal efforts to integrate reimbursement policy and regulatory perspectives during pre-approval development are not a new concept in Europe. The European Medicines Agency (EMA) developed a pilot program to facilitate parallel pre-licensing scientific advice between regulators and HTA bodies in 2010 (26). The process for simultaneous feedback was derived to help manufacturers understand the evidentiary needs of both regulators and HTA bodies to plan for optimal data collection to satisfy both agencies.
Fundamental differences exist between the EU and the United States in terms of the overall structure and composition of health care budgets. The EU has shifted from a tax to social insurance as the dominant contribution mechanism. Funds are pooled and health care services are purchased centrally, which results in a contractual relation between the health insurance fund and the provider. The EU has moved toward strategic purchasing of services to match limited resources with health needs in an effort to expand population coverage. In the United States, there are additional complexities including federal programs regulated by the CMS and the U.S. Department of Veterans Affairs; Medicaid, which is regulated and allocated via state agencies; and private payers, including new models in which the payer and health care delivery systems share both risks and savings.
Case 1: Sacubitril-valsartan
In the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor–Neprilysin Inhibitor Angiotensin-Converting–Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, sacubitril-valsartan (when compared with enalapril) reduced the risk of cardiovascular death or heart failure hospitalization by 20% among patients with New York Heart Association functional class II to IV heart failure and a reduced left ventricular ejection fraction (27). The drug was reviewed under the FDA’s priority review program and was given a fast track designation; it was approved on July 7, 2015 (28). Although superior to enalapril, the cost of sacubitril-valsartan was ∼$4,500 per year compared with a generic angiotensin-converting enzyme inhibitor (29,30); this additional expense motivated payers to take steps to discourage adoption of the drug. Difficulties with patient access and burdensome insurer hurdles for coverage were noted by heart failure specialists years after regulatory approval (29,30). Insurers routinely denied first requests for approval, forcing practitioners to make repeated efforts for preauthorization; payers frequently had eligibility criteria that differed meaningfully from the FDA approved use of the drug; high patient copays were burdensome to patients. These obstacles occurred, even though the drug was significantly discounted and despite evidence from several cost-effectiveness analyses that sacubitril-valsartan delivered reasonable clinical value for its cost (31–33).
Case 2: Proprotein convertase subtilisin/kexin type 9 inhibitors
Despite treatment with high-intensity statins, many patients fail to achieve low-density lipoprotein cholesterol goals (34). Proprotein convertase subtilisin/kexin type 9 inhibitors reduce low-density lipoprotein cholesterol levels substantially when added to optimal statin therapy (35,36); regulatory approval was based on this effect. Recently, the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial showed that evolocumab reduced the risk of major adverse cardiovascular events by 15%, when compared with placebo in patients with clinically evident atherosclerotic disease on optimal lipid-lowering therapy (37). Many payers regarded this effect to reduce the risk of major adverse cardiovascular events as being modest, given the cost of these drugs ($14,000 to $15,000 per year) (38); high rates of coverage denial have been reported (39,40).
Case 3: Canakinumab and anacetrapib
In June 2017, 2 pharmaceutical companies (Novartis and Merck) notified the public that large-scale trials with novel drugs appeared to reduce the risk of major adverse cardiovascular events in high-risk patients with established coronary artery disease (41,42). One trial (CANTOS [Canakinumab Antiinflammatory Thrombosis Outcome Study]) evaluated the effects of canakinumab (43), an interleukin 1 beta antagonist, which is already approved for use for rare autoimmune conditions. Compared with placebo, canakinumab 150 mg reduced the risk of the primary endpoint of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death (hazard ratio: 0.85; 95% confidence interval: 0.74 to 0.98; p = 0.021) (43). The other trial (REVEAL [Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification]) evaluated anacetrapib (44), which inhibits cholesteryl ester transfer protein. Anacetrapib reduced the risk of a first major coronary event (coronary death, myocardial infarction, or coronary revascularization) compared with placebo (rate ratio: 0.91; 95% confidence interval: 0.85 to 0.97; p = 0.004) (44). As speculated before the full study results were published, the effects of these 2 drugs were modest (45). The cost of canakinumab could be as high as $64,000 per year; anacetrapib is also expected to be priced at premium levels. Likely because of these realities, Merck has announced that it will seek further guidance before making a decision to submit the dossier supporting anacetrapib for regulatory approval (41,46).
Potential Benefits of Earlier Payer Collaboration
Earlier and predictable patient access to effective new cardiovascular therapies is the primary goal underpinning proposals to collaboratively engage regulatory and payer representatives in pre-approval drug development decisions. The first step is to share perspectives among stakeholders, including patients, as the various stakeholders are likely to have different requirements or have different interpretations of the evidence. Payers understandably place a greater emphasis on evidence related to cost effectiveness, whereas such evidence may be less important to regulators or investigators (Table 1). The oncology literature suggests that payers and patients hold different priorities as to which high-cost therapies should be funded, with economic considerations prioritized by payers (8). In an evaluation of HTA body decision making for hypothetical new medicines, higher levels of incremental cost effectiveness, higher number of quality adjusted life years, less uncertainty around cost effectiveness, and improved survival were significant factors in decision making (9). Acceptable levels of cost effectiveness were twice as high for therapies impacting survival, as compared with those only influencing health-related quality of life (9).
Differences in regulator and payer priorities always exist because of the contrasts in their fundamental purpose. However, by identifying discordant perspectives early in the process, it is possible that early stakeholder collaboration might be helpful before the initiation of pivotal clinical trials. Ideally, drug development programs could be designed to meet the evidentiary needs of all parties; a specific threshold of evidence could be identified a priori that (if satisfied) could minimize delays in reimbursement. Some progress has already been made. For instance, early collaboration has led to payers’ direct financial support of the conduct of clinical trials; currently, coverage can be provided while new evidence is being generated (the CMS Coverage with Evidence Development [CED]). However, the CMS CED only applies to items and services provided under Medicare Parts A and B and not to self-administered drugs covered under Medicare Part D (47). Our framework envisions a broader level of communication, collaboration and strategic alignment at an early stage of drug or device development.
Transparency and accountability of payer decision making may also be introduced through the process of defining evidentiary requirements for reimbursement before regulatory approval. Although it is understood that payers place a high priority on cost effectiveness, the quality of these analyses depends on the underlying assumptions, models, and methodology used. Value frameworks also can be specific to certain audiences, but less relevant for others (48). Adopting robust scientific standards for cost effectiveness (49) or other analyses used in reimbursement decision making may achieve greater transparency and broader acceptance of reimbursement decisions. In fragmented systems with multiple payers (e.g., in the United States), transparency (Table 2) (49,50) across a broad payer group could reduce variation in reimbursement decisions among different payer organizations or justify differences in coverage where appropriate. Payer decisions might appropriately differ because of differences in the patient population (e.g., CMS may deny coverage to a therapy that shows benefit primarily in a younger population). Across different countries, HTA recommendations may be influenced by differences in societal definitions of value and willingness to pay, geographical variations in the evidence base (e.g., subgroup-by-treatment interactions), disagreements on whether a comparator represents standard of care in a specific country, or concerns about generalizability if a country was poorly represented in the evidence base (51). Given these possibilities, it might be difficult to converge upon a single standard; however, even if alignment were not achieved, communications aimed at enhancing transparency is likely to build trust among physicians, payers, and patients.
Mechanisms for Integrating Payers During Pre-Approval Therapeutic Development
Some pharmaceutical companies already engage key payers and HTA bodies before and during drug development, but experience indicates that payers can provide advice that is inconsistent, of variable quality, and nonbinding, making such interactions (as they currently take place) of questionable value. However, if these deficiencies could be addressed, early engagement might be more meaningful. Yet, in the United States, it is difficult to understand how a priori agreements could be binding, as there is no single agency that oversees health care reimbursement and the perspectives of payers may change rapidly over short periods of time.
Nonetheless, it is encouraging that steps are being taken to promote earlier interaction among regulators and payers in North America, Europe, and other parts of the world (52,53). The U.S. FDA has a mechanism to permit overlapping FDA and CMS review of innovative medical devices through the Expedited Access Pathway (54). This process allows both FDA and CMS to concurrently review data about a medical device while maintaining their separate evidentiary requirements. By engaging both agencies during the planning phase, manufacturers have an opportunity to incorporate FDA and CMS perspectives into a single pivotal clinical trial. However, the degree to which this program will encourage clinical development programs to design trials to satisfy approval and reimbursement requirements is uncertain. Sponsors might be reluctant to take risks that would undermine the likelihood of CMS coverage or they may limit data collection to meet CMS requirements at the exclusion of a broader population (55). The benefits (if any) of this approach need ongoing evaluation, as experience with the program accumulates (56). This joint FDA-CMS program is currently limited to medical devices and has not yet been extended to drugs.
Interestingly, the FDA issued a notice in February 2016 to organizations that make medical device coverage recommendations, which invited them to participate in pre-submission meetings and provide input on payer evidentiary needs (57). Seven organizations (listed on the FDA website) responded to the federal register notice at the time of this writing (58), but the extent to which collaborations have prospectively informed clinical trial design is not yet known. The MaRS Excellence in Clinical Innovation Technology Evaluation program is another initiative that connects product developers with researchers to produce evidence needed to establish product value and also facilitates discussions with health systems to ensure adoption if supported by study results (59). The lessons learned from these experiences will help to refine processes for interaction and opportunities for broader integration.
The success of the parallel scientific advice EMA-HTA pilot project has led to the development of a best practice guidance for parallel regulatory-HTA scientific advice (60). Additional steps have been taken in Europe to advance progress toward wider adoption of early interaction between regulators and HTA bodies within the framework of the European Network for Health Technology Assessment Joint Actions. Alignment between reimbursement pathways and regulatory approval has often been discussed in the context of adaptive licensing (61,62), but efforts to achieve alignment should be considered regardless of the regulatory pathway. European countries employ a variety of instruments to tackle uncertainty arising from lack of information about budget impact, cost effectiveness, use in real life, and access. This uncertainty can be addressed in 2 ways: 1) granting reimbursement for a limited period during which additional evidence on the drug effectiveness is collected; or 2) limiting utilization (i.e., to patient subgroups likely to benefit) so that cost effectiveness is improved (7). The approach of reimbursement while collecting evidence also raises the possibility that a therapy could be determined to be ineffective based on additional evidence, and thus approval or reimbursement could be revoked. Better alignment of regulatory and payer decision making pre-approval might also ensure better coordination of post-approval decisions, and avoid situations where regulatory approval has been withdrawn but reimbursement continued (63). The tremendous resource allocation needed for updating data on efficacy and safety and revoking either regulatory or reimbursement approvals should not be underestimated. Additionally, post-approval evidence is sometimes generated from nonrandomized studies, and these data may be of insufficient quality to support decision making.
Conclusions and Next Steps
The European Network for Health Technology Assessment and the EMA have made substantial strides toward achieving parallel review and joint advice from HTA bodies and regulators. This experience, as well as experience from the FDA-CMS parallel review pathway, is likely to inform future directions and policies needed to move toward a wider role for parallel payer and regulatory review. There is no easy solution, but collaborative engagement of regulators, payers, HTA bodies, pharmaceutical companies, academic leaders, investigators, patients, physicians, professional organizations, and other health care providers represents an important step to developing a system that reflects the views and needs of all stakeholders (Central Illustration). Regulators and payers differ in their perspectives on medical advances and the weight they place on components of the evidence base. Collaborative discussion is needed to fully understand these views and their drivers. The concept that early interactions might reduce the delay of access to important new treatments is a hypothesis worth testing. Even if such interactions prove to be disappointing in the long term, they will undoubtedly improve the level of understanding and trust.
Drug and device evaluations are enhanced when industry developers, manufacturers, trialists, regulators, payers, health professionals, and patients collaborate to agree on the “burden of proof” and describe at an early stage the potential mechanisms and pathways that would achieve “value-based health care.” This approach ultimately improves timely patient access to new treatments that reduce the burden of disease or prolong life. This strategy goes beyond the usual clinical trial endpoints and the classical evaluation of clinical relevance of combined outcomes versus individual outcomes, the differences between absolute or relative risk reductions versus the clinical weight of an outcome, and the number needed to treat or harm.
“Value-based health care” focuses on outcomes that are relevant to patients, including, but not limited to, clinical outcomes. Therefore, patient representatives and consumer advocacy groups should be involved as essential stakeholders.
A linked or network of evidence approach may be occasionally better suited than a “hierarchy of evidence” approach. Ultimately, the cost value of a net benefit greater than risk of a therapy requires judgments that do not and cannot have a truly objective basis, as the importance of specific benefits will vary with the benefit and with the affected population. Alignment of policies between payers and regulators cannot happen until discussion is initiated, and such discussions will necessarily involve consumers. We believe that international fora that assemble all key stakeholders, such as the CVCT Forum from which the present paper has stemmed, may help advance the steps toward reaching such alignment, with the principles of requisite trial design as the work product of the conferences.
The authors acknowledge the contributions of Dr. Robert Temple, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, who was a discussant at the CVCT Workshop from which this manuscript was based.
This work was generated from discussions during the Thirteenth Global CardioVascular Clinical Trialists (CVCT) Forum held in Washington, DC, in December 2016. The CVCT was organized by the Clinical Investigation Center (CIC) Inserm, CHU, and University of Lorraine, France, and INI-CRCT (F-CRIN), Nancy, France, and funded by an unrestricted educational grant from Association de Recherche et d'Information en Cardiologie (ARISC) a nonprofit educational organization, in Nancy, France. ARISC had no involvement in preparation, review, or approval of the manuscript for publication. Dr. Zannad has received personal fees from Janssen, Bayer, Novartis, Boston Scientific, Resmed, Amgen, CVRx, Quantum Genomics, Takeda, General Electric, Boehringer, Relypsa, ZS Pharma, AstraZeneca, GlaxoSmithKline, Roche Diagnostics, ZS Pharma, and Vifor Fresenius. Dr. Borer has received consulting honoraria from Janssen, BioMarin, Servier, Amgen, ARMGO, and Gilead; has served on the data and safety monitoring board for clinical trials sponsored by Novartis, Pfizer, and GlaxoSmithKline; has served on the cardiac event adjudication committee for clinical trials sponsored by Takeda and AstraZeneca; and owns stock in BioMarin and ARMGO. Dr. Stough has received consulting honoraria from the European Society of Cardiology, Heart Failure Association of the European Society of Cardiology, Heart Failure Society of America, Overcome (Cardiovascular Clinical Trialists and Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists), Celyad, and Respicardia. Dr. Clutton-Brock has served as the chair of the NICE Interventional Procedures Advisory Committee. Dr. Packer has been a consultant for Amgen, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi-Sankyo, Celyad, Relypsa, AstraZeneca, Sanofi, ZS Pharma, and Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- Centers for Medicare and Medicaid Services
- Coverage with Evidence Development
- CardioVascular Clinical Trialists
- European Medicines Agency
- European Union
- Food and Drug Administration
- health technology assessment
- Received August 14, 2017.
- Revision received October 12, 2017.
- Accepted October 16, 2017.
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