Author + information
- Received January 28, 2015
- Accepted March 3, 2015
- Published online April 21, 2015.
- Christopher B. Fordyce, MD, MSc∗∗ (, )
- Matthew T. Roe, MD, MHS∗,
- Tariq Ahmad, MD, MPH∗,
- Peter Libby, MD†,
- Jeffrey S. Borer, MD‡,
- William R. Hiatt, MD§,
- Michael R. Bristow, MD, PhD§,
- Milton Packer, MD‖,
- Scott M. Wasserman, MD¶,
- Ned Braunstein, MD#,
- Bertram Pitt, MD∗∗,
- David L. DeMets, PhD††,
- Katharine Cooper-Arnold, MPH‡‡,
- Paul W. Armstrong, MD§§,
- Scott D. Berkowitz, MD‖‖,
- Rob Scott, MD‖,
- Jayne Prats, PhD¶¶,
- Zorina S. Galis, PhD‡‡,
- Norman Stockbridge, MD, PhD##,
- Eric D. Peterson, MD, MPH∗ and
- Robert M. Califf, MD∗
- ∗Duke Clinical Research Institute, Durham, North Carolina
- †Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
- ‡State University of New York Downstate Medical Center, Brooklyn, New York
- §University of Colorado School of Medicine, Aurora, Colorado
- ‖Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas
- ¶Amgen, Inc., Thousand Oaks, California
- #Regeneron Pharmaceuticals, Tarrytown, New York
- ∗∗University of Michigan School of Medicine, Ann Arbor, Michigan
- ††University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
- ‡‡National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
- §§Canadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada
- ‖‖Bayer HealthCare Pharmaceuticals, Whippany, New Jersey
- ¶¶The Medicines Company, Parsippany, New Jersey
- ##Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland
- ↵∗Reprint requests and correspondence:
Dr. Christopher B. Fordyce, Duke Clinical Research Institute, 2400 Pratt Street, Durham, North Carolina 27705.
Despite the global burden of cardiovascular disease, investment in cardiovascular drug development has stagnated over the past 2 decades, with relative underinvestment compared with other therapeutic areas. The reasons for this trend are multifactorial, but of primary concern is the high cost of conducting cardiovascular outcome trials in the current regulatory environment that demands a direct assessment of risks and benefits, using clinically-evident cardiovascular endpoints. To work toward consensus on improving the environment for cardiovascular drug development, stakeholders from academia, industry, regulatory bodies, and government agencies convened for a think tank meeting in July 2014 in Washington, DC. This paper summarizes the proceedings of the meeting and aims to delineate the current adverse trends in cardiovascular drug development, understand the key issues that underlie these trends within the context of a recognized need for a rigorous regulatory review process, and provide potential solutions to the problems identified.
Despite significant improvements in cardiovascular mortality over the last several decades, cardiovascular disease remains the leading cause of death both in the United States and the rest of the world (1–3). Heart disease and stroke will result in an estimated 24 million deaths/year worldwide by 2030, and will continue to represent the dominant cause of death among the most prevalent chronic diseases (4–6) (Figure 1). Furthermore, mortality and morbidity due to cardiovascular events continue to climb globally as a result of rising cardiovascular disease rates in low-income countries, resulting in increasing disparities in outcomes as a function of wealth and education (7). The burden of cardiovascular disease clearly remains both a major public health concern and growing global challenge.
Notwithstanding this increase in cardiovascular disease prevalence worldwide, investment in cardiovascular drug development has stagnated over the past 2 decades, with relative underinvestment compared with other therapeutic areas (8–13). This alarming trend appears to reflect the business strategy in the pharmaceutical industry of maximizing return on investment (ROI) by focusing on areas currently felt to be most lucrative (8,9). As discussed in the following text, the reasons for these trends are multifactorial. However, a particularly important factor is the high cost of conducting cardiovascular outcome trials in the current regulatory environment that demands a direct assessment of risks and benefits using clinically-evident cardiovascular endpoints for approval rather than biomarkers or putative surrogates. These realities suggest that although the cardiovascular disease burden continues to grow and innovative scientific discoveries continue to occur, investors have concerns regarding what they describe as regulatory uncertainty and high development costs, leading to negative effects on ROI for novel cardiovascular therapies.
To work toward consensus on improving the environment for cardiovascular drug development, stakeholders from academia, industry, and government convened in July 2014 in Washington, DC. This paper summarizes the proceedings of this “think tank” meeting, the specific aims of which were to:
1. Delineate the current adverse trends in cardiovascular drug development;
2. Understand the key issues that underlie these trends within the context of a rigorous regulatory review process that is a key aspect of drug development; and
3. Provide potential solutions to the problems identified.
Current Trends in Cardiovascular Drug Development
Between 2000 and 2009, U.S. Food and Drug Administration (FDA) approvals for new cardiovascular drug therapies declined by approximately 33% compared with the prior decade (11). During the discussions, FDA representatives reported parallel adverse trends in investigational new drug applications to the Division of Cardiovascular and Renal Drugs for new molecular entities (NMEs) seeking approval for marketing (with no change in investigational new drugs and a relative decline in new marketing applications), including NMEs for cardiovascular disease, from 1991 to 2013 (personal communication, N. Stockbridge, December 6, 2014) (Figure 2). Parallel analyses that evaluated regulatory approvals for cardiovascular therapies demonstrated a similar temporal decline, but showed that approvals in several other therapeutic areas, including oncology, rose substantially during the same time frame (11).
Cardiovascular drug development compared with other therapeutic areas
The application of genomic technologies, as well as systems biology approaches, have collectively identified multiple potential new cardiovascular drug targets, as well as actual molecules with potential cardiovascular applications. Unfortunately, these scientific advances have not stimulated an increase in new cardiovascular drug development. Early-phase research and development appear to have stagnated, with fewer molecules in the cardiovascular research pipeline compared with other therapeutic areas. In an analysis comparing the number of drugs undergoing early-phase development at 2 separate intervals (1990 to 1999 vs. 2000 to 2007), the development of antineoplastic agents grew from 16.55% to 23.43% (+6.88%), whereas the development of cardiovascular agents experienced the strongest contraction of any therapeutic area (–4.57%) (9). Furthermore, the success rate for antineoplastic drug approvals increased during this time interval (10). An analysis of all FDA NMEs from 2000 to 2012 found that oncology drugs had not only the greatest number of NME applications (n = 61), but also the highest rate of first-cycle FDA approvals of all therapeutic classes (72%) (12). In contrast, cardiovascular drugs had significantly fewer NME applications (n = 21) and a much lower rate of first-cycle approvals (32%). The current portfolio of drugs being evaluated in clinical trials reflects these trends, with a steep rise in cancer drugs being tested over the last 2 decades (Figure 3) (13).
Rising drug-development costs and the concept of regulatory uncertainty
Notwithstanding the issues that appear to be impeding cardiovascular drug development, during the last decades, the overall pharmaceutical research and development processes have become less efficient in converting promising therapies into actual approved and marketed agents (Figure 4) (14). In 2005, the average capitalized cost to bring 1 new biopharmaceutical product to market, including the cost of failures, was $1.24 billion (14). These high drug-development costs caused overall research and development spending to exceed $50 billion in the United States in 2008.
The high costs of drug development were considered by meeting participants to include the perceived complexities and obstacles in navigating the regulatory drug approval process. Although the critical role of the FDA and other regulatory agencies to balance the timely approval of effective therapies with the need to protect the public from harmful drugs was discussed and strongly endorsed, the concept of “regulatory uncertainty” appears to be deep-seated in the pharmaceutical industry.
The pathway for drug development is becoming more complex and costly for industry, but given multiple prior instances of drugs receiving regulatory approval that eventually resulted in patient harm through post-market analyses, there is intense government and public scrutiny on the regulatory drug approval process (15). Nonetheless, the reality is that the pharmaceutical industry will always be the dominant funding source for drug discovery—a finding reinforced by recent analyses that found that between 40% to 80% (16,17) of randomized controlled trials published in top-tier medical journals were funded by industry sponsors. Pharmaceutical representatives at the meeting cited regulatory uncertainty as not only a common concern across industries (18,19), but also a key influence on decisions regarding the specific development of innovative cardiovascular drugs given the high cost of regulatory failures during drug discovery. Despite these concerns, the FDA representatives expressed a strong willingness to meet early with industry representatives to discuss plans for a drug-development program to provide guidance and feedback regarding the potential regulatory pathways for a promising therapy before the launch of pivotal registration trials.
Studies in economics and finance have found regulatory uncertainty to be potentially a major source of unpredictable variation in the return on business investment (20). The regulatory state is often perceived as a key component of the “external environment” that pharmaceutical companies must take into account when making capital investments or deciding whether to enter competitive markets (18). Some therapies may follow a known regulatory pathway, which may decrease the time to drug approval. For other therapies, the pathway for regulatory approval has not been defined or has been influenced by prior regulatory decisions for therapies in a similar class, so the timeline for drug approval may be expected to be prolonged or difficult to predict. The FDA also recognizes that although innovative drugs are more difficult and costly to develop, they may also be more difficult to review given the lack of experience with a new therapy or indication (21). Thus, although regulatory uncertainty may be a key factor influencing the trends in cardiovascular drug development, the path forward may involve early, in-depth discussions with industry representatives and regulatory agencies that would be expected to guide decisions about how to structure a development program that addresses an unmet need in clinical practice, but also appears viable within the context of a rigorous but fair regulatory review process.
Regulatory issues associated with the globalization of clinical trials
From a contemporary United States perspective, the globalization of cardiovascular clinical trials has resulted in increased regulatory complexity at both the FDA and European Medicines Agency (EMA) (22). Although recent efforts have been made to standardize regulatory reporting in Europe (23), the EMA remains a decentralized organization, with each European nation still having its own drug agency and regulations. Because cardiovascular drug registration trials typically involve many countries to meet enrollment goals, a large and experienced pool of cardiovascular site investigators is critical to the success of these trials. However, over the past decade, the number of FDA-regulated investigators based outside of the United States has grown by 15% annually, whereas United States–based investigators have declined 5.5% annually over the same interval (24). Nonetheless, studies have shown that the FDA approves drugs faster than the EMA and Health Canada (median: 303, 366, and 352 days, respectively) (25), but enrollment in cardiovascular registration trials has appeared to shift to non-Western countries with perceived greater enrollment potential and lower operational costs. Although difficulty in patient recruitment has contributed to this shift of trial enrollment to non-Western countries (26), the perceived bureaucratic and expensive regulatory environments in Western countries is another strong influence (22).
Although globalization of trial conduct and enrollment could theoretically reduce upfront costs for pivotal registration trials, growing concern exists over the geographical variation in patient selection and results in cardiovascular outcomes trials (27,28). The recent TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial demonstrated clear differences in patient selection for heart failure with preserved ejection fraction amongst patients in Russia and Georgia, which highly confounded the overall trial results (29). Additionally, low enrollment of patients in the United States in pivotal registration trials can also introduce confounding, as was demonstrated in the PLATO (Study of Platelet Inhibition and Patient Outcomes) trial with the antiplatelet agent ticagrelor (30). The treatment results were discordant in the United States compared with other geographic regions, with <10% of the patients enrolled in the United States. Therefore, the globalization of clinical trials appears to contribute to regulatory uncertainty and to complicate the regulatory review process for therapies with pivotal trials that showed geographical differences in patient selection/features as well as treatment results.
Potential Causes of Relative Underinvestment in Cardiovascular Drug Development
Few incentives to promote cardiovascular drug development
Cardiovascular drug development currently suffers from a lack of “push-pull” incentives relative to other fields, particularly oncology, which tends to dominate contemporary drug development. “Push” funding policies aim to incentivize the pharmaceutical industry by reducing costs during the research and development stages, whereas “pull” mechanisms create incentives for the pharmaceutical industry by creating viable market demand for novel therapies that address unmet clinical needs (31). Push mechanisms may partially offset research and development by underwriting a portion of the costs, whereas pull mechanisms may reward positive trial results for novel therapies.
At the federal funding level, the field of oncology has several push mechanisms that may accelerate the discovery of novel therapies by academic researchers that could potentially be commercialized through academic-industry collaborations. First, the 2013 National Institutes of Health (NIH) budget was approximately $29.3 billion, with $4.8 billion allocated to the National Cancer Institute (NCI), the largest proportion among all institutes and a distinction held by the NCI since at least 1980 (32,33). In comparison, despite the relative proportional increase in the budget of the National Heart, Lung, and Blood Institute (NHLBI) compared with the NCI during this time period (32), the allocation in the 2013 budget to the NHLBI was significantly lower at $2.9 billion (34). Second, the FDA has several special-designation programs designed to expedite and facilitate the authorization and approval of new medications for unmet medical needs. A detailed analysis found that the greatest percentage of applications to each of these programs was for oncology therapies (35). In comparison with oncology drugs, cardiovascular drug applications were far fewer in all programs: orphan (9% vs. 38%), priority review (4% vs. 53%), accelerated approval (8% vs. 32%), and fast track (1% vs. 56%). Finally, as a result of the FDA’s orphan program and the increasing focus of the pharmaceutical industry on novel “first-in-class” therapies, the number of NMEs targeting orphan indications has risen 3-fold over the past 3 decades (36). However, there are few cardiovascular disease conditions that would qualify for orphan drug programs, so the interest for novel therapies has naturally shifted to the oncology field.
Advocacy and fundraising, major push mechanisms, are also dominated by oncology. In 2011, charitable donations raised during the Susan G. Komen Race for the Cure for breast cancer ($258 million) and Movember for prostate cancer ($147 million) were over 7-fold greater than that of the American Heart Association (AHA) Jump Rope for Heart campaign ($54 million) (37). Furthermore, the AHA raised $509 million in 2010, compared with $903 million raised by the American Cancer Society (38). The oncology field has also dominated crowdfunding initiatives—ventures that raise small amounts of money from a large number of people (typically via the Internet). A recent analysis of 97 crowdfunding campaigns aimed at cancer research found that the average amount raised per campaign was $45,629 (average donation: $186), including 5 rare-disease campaigns raising between $17,217 and $248,734 (39). In contrast, few crowdfunding campaigns have involved cardiovascular disease, although a new initiative to fund early-stage products was introduced at the AHA 2014 Scientific Sessions (40). Finally, an example of the consequences of philanthropic discrepancies affecting future drug development is reflected in the number of young investigator awards available for fellows in either subspecialty: the AHA had 0 research grants of at least 1 year in duration for fellows in 2012, the American College of Cardiology had 4, and the American Society of Clinical Oncology had 38 (41).
What drives successful cancer fundraising campaigns? It is possible that certain organizations are better organized to raise funds. However, fear may also explain the documented discrepancy between public perception of disease severity and reality (42). For example, a 2011 survey conducted by the MetLife Foundation found that 41% of responders named cancer as the disease they feared most; only 8% named heart disease, and another 8% feared stroke (43). Surveys of women conducted by the AHA show many believe cancer to be the number 1 cause of death for females, not heart disease, as annual mortality statistics consistently confirm (44). Given that the diagnosis of cancer typically elicits a much greater emotional response than that of cardiovascular disease, the disparities in the breadth and success of fundraising and advocacy campaigns for cancer versus cardiovascular disease likely reflect societal opinions on the “unmet needs” for medical conditions, despite the aforementioned global burden of cardiovascular disease.
Diverting investment away from cardiovascular therapies
Even though the biotechnology sector continues to show interest in drug development, trends for venture capital funding priorities demonstrate a shift away from cardiovascular disease. Between January 2005 and June 2012, acquisitions of venture-backed life science companies with 1 or 2 products in the pipeline remained strong (45). However, companies with oncology and infectious disease products had the greatest acquisitions, with approximately double the money spent compared with acquisitions that focused on cardiovascular disease products. Similarly, biotechnology companies with either an oncology or a neurology focus had the most licensing agreements during the same time period (2005 to 2012)—4-fold higher than the cardiovascular arena. The consensus opinion expressed at the meeting was that although it appears that venture capital investor interest in biotechnology remains strong, the appetite for risk is lower compared with historical trends, so investment firms typically are less interested in cardiovascular drug-development programs given the uncertain ROI for the previously mentioned reasons. Compared with the blockbuster therapies that were previously developed from biotechnology companies, investors are now prepared to accept a lower ROI (i.e., an orphan drug for a defined and small population) in exchange for a lower risk of drug-development failure (46,47). In fact, global sales of oncology drugs in 2013 topped $67 billion, the highest of any class of medications (48). These findings highlight the interest of investment firms in oncology therapies that typically have a clear regulatory pathway and a strong degree of advocacy from patient groups.
Commercial viability over efficacy or safety as a driver of cardiovascular drug-development failure
In addition to a lack of push incentives, a lack of pull incentives currently hinders cardiovascular drug development due mainly to industry concerns regarding ROIs. A recent analysis demonstrated that cardiovascular drug failures following pivotal registration trials most often result from a lack of commercial viability rather than from efficacy or safety issues (10) (Figure 5). Failure from commercial viability for cardiovascular therapies occurred for several reasons, including cases where expected future costs rise or expected revenues fall (perhaps due to increased competition or that testing suggests the target profile should be narrowed) to the point where the project is no longer perceived to be financially viable, or when pharmaceutical firms abandon a development program for strategic reasons (J.A. DiMasi, personal communication, December 9, 2014). For cardiovascular therapies, physicians, payers, and regulatory agencies demand large trials that are adequately powered to show a difference in clinical outcomes for approval. In general, and apart from some conditions such as heart failure, the progression of cardiovascular disease to “hard” natural history outcomes is relatively prolonged compared with the more rapid accumulations of such outcomes in oncology. Therefore, cardiovascular outcomes trials require large sample sizes and must continue for many years to accumulate enough endpoints to be adequately powered. Additionally, new cardiovascular medications must be tested on a background of a multitude of guideline-recommended therapies that comprise the “standard of care.” Because patients selected for most cardiovascular outcomes trials on background medical therapy have relatively low event rates, trials have become larger, prolonged, and costlier with each new therapeutic modality (49).
Necessity of measuring validated clinical outcomes over surrogate endpoints
The use of putative surrogate endpoints to bring potentially beneficial treatments to patients many years before the availability of clinical outcomes at relatively lower cost appeals to investors, scientists, and patients who hope to seek access to beneficial therapies (50). Yet, such shortcuts can have several well-documented unintended consequences, demanding direct measures of clinical outcomes that matter to patients. In cardiovascular medicine, both blood pressure and low-density lipoprotein levels have served as surrogates of important clinical outcomes under specific circumstances, but only after validation in multiple randomized clinical trials involving tens of thousands of patients (51,52). Success of the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), which demonstrated that low-density lipoprotein lowering with a combination of ezetimibe and simvastatin versus simvastatin alone resulted in improved long-term clinical outcomes, provides further impetus for the development of novel agents, including PCSK9 inhibitors (53). Yet, alpha-adrenergic blockers lower blood pressure but appear to be inferior in reducing cardiovascular events compared with other blood pressure-lowering treatments (54). Torcetrapib and long-acting niacin increased high-density lipoprotein cholesterol considerably, but provided no cardiovascular outcome benefits in multiple large trials and, conversely, were associated with significant harm due to off-target drug effects (55,56). Other cardiovascular clinical trials have exposed harms after showing positive results with surrogate outcomes, including morbidity from the utilization of inotropes in cardiogenic shock despite improved hemodynamic parameters or death associated with the use of class IC antiarrhythmic agents despite successful suppression of premature ventricular contractions post-myocardial infarction (57–59).
Intermediate endpoints, such as progression-free survival (PFS), are more commonly used in oncology. The use of PFS among all systemic-therapy randomized controlled trials of breast, colorectal, and non–small-cell lung cancers published in the Journal of Clinical Oncology increased from 0% (1975 to 1984) to 26% more recently (2005 to 2009), whereas 23% of new FDA drug approval indications from 2005 to 2007 were on the basis of trials with PFS as the primary endpoint (60–62). Therefore, there has not only been a clear increase in the use of intermediate endpoints over time, but the prevalence of intermediate endpoint use has been consistent across studies. Justification for the use of PFS as a valid outcome for drug approval relates to the extended patient follow-up and to being confounded by causes of mortality unrelated to cancer. Furthermore, as novel therapies demonstrate effectiveness along the treatment continuum for cancers such as breast and colorectal, survival may be influenced by the use of such therapies when trials have been completed (63,64). However, the use of PFS as a primary endpoint in many randomized controlled trials of advanced solid tumors, including breast cancer, has not been on the basis of evidence of its surrogacy for either overall survival or quality of life (60,65). Despite approving many therapies on the basis of PFS, the FDA has long acknowledged that tumor responses may not necessarily equate with clinical benefit, because nonresponding patients may benefit from a delay in tumor progression and tumors may recur more aggressively if they regress quickly in some cases (66,67). Taken together, despite their appeal to make trials more efficient, putative surrogate endpoints do not fully predict the true balance of risk and benefit of interventions. This failure usually is a result of incomplete coupling between the biomarker of interest and the array of clinical outcomes and the unknown and unintended pharmacological actions of an intervention that are independent of the disease process (68).
Notwithstanding the different types of outcomes that meet the thresholds for approval in cardiovascular disease versus cancer, the quality of clinical trial evidence used for recent approvals of novel therapeutic agents varies widely across indications. An analysis of the pivotal clinical trial evidence required for FDA approval between 2005 and 2012 is striking: cardiovascular disease, diabetes mellitus, and hyperlipidemia trials were larger than those in other therapeutic areas (median sample size = 651 subjects), were of longer duration (median = 24 weeks), were mostly randomized (98.6%), were typically conducted in a double-blind fashion (93.2%), and almost uniformly used a placebo or an active control in the comparator arm (97.2%) (Table 1) (69). In contrast, trials used to support cancer drug approvals were small (median sample size = 266 subjects), were of shorter duration (median = 18.5 weeks), were less frequently randomized (47.3%), were less frequently conducted in a double-blind manner (27.3%), and less than one-half used a placebo or active control in the comparator arm (47.3%). The consensus at the meeting was that cardiovascular medicine must continue to rely on proven clinical outcomes in the new era of drug development, especially in light of the previously-mentioned failures of putative surrogate endpoints (54–59).
“Misclassification” of cardiovascular disease: implications for drug discovery
Traditionally, cardiovascular drug development has focused on systemic therapies centering on large populations, such as hypertension and heart failure. However, these conditions result from multiple heterogeneous influences and pathways and have several potential therapeutic biological targets. Relatively few new drug targets for cardiovascular disease exist that can be completely separated from potential overlap with existing targets, because there are often multiple effective drugs in any given class (i.e., statins, antiplatelet agents, novel anticoagulants), which often renders distinction from existing therapies difficult. This setting presents considerable challenges to the development of new therapies. Yet, recent scientific advances, including harnessing genetic and systems biology approaches, promise to yield many novel drug targets in the multiple pathways involved in cardiovascular diseases such as thrombosis, myocardial relaxation and strain, lipid metabolism, and atherosclerosis. The traditional “lumping” of heterogeneous disease—on the basis of taxonomy established by the International Classification of Diseases that seldom incorporated rapidly-emerging molecular data, incidental patient characteristics, or socio-environmental influences on disease (70)—should give way to a subclassification on the basis of biological signatures that better represents the underlying pathophysiology and permits more precise targeting of treatments (71). This approach mimics the now well-established strategy of targeted therapies in oncology (receptor level) and infectious diseases (organism level) and provides enticing drug targets. As opposed to cancers, common cardiovascular diseases do not arise from single gene mutations, but rather reflect interactions of risk factors with multiple genes that each contribute a small portion of risk. This complexity currently furnishes fewer appealing biological targets in cardiovascular medicine than in cancers (9). Nonetheless, in a recent industry survey, most large pharmaceutical companies (14 of 16) have still expressed an interest in partnering regarding cardiovascular disease (44).
Strategies to Advance Cardiovascular Drug Development
Reduce operating costs of clinical trials
Well-intentioned efforts to minimize the risk of harm or undesirable outcomes in patients enrolled in clinical trials have introduced numerous inefficiencies in the conduct of trials, particularly in pivotal registration trials that result in rigorous regulatory review (72). Meeting participants uniformly agreed that reducing the amount of extraneous data collected for a cardiovascular clinical trial offers an important cost savings opportunity. The typical clinical trial in 2012 involved 13 endpoints, had 169 case report form pages, and required study volunteers to make 11 visits over an average of 175 days (49). To advance discussions about reducing the amount of extraneous data collected for a large cardiovascular outcomes trial, the participants recommended that pharmaceutical industry sponsors meet early with key stakeholders (regulators, academic collaborators) to omit collection of unessential data and to simplify case report forms. Furthermore, there was a clear recommendation from FDA representatives to the pharmaceutical industry to meet with the FDA to gain a commitment early during the drug-development process to limit the amount of data to be collected. Academic collaborators should be encouraged to support the scientific legitimacy of this approach, with the goal of emphasizing quality by design (discussed in the following text). Adopting FDA guidance with respect to centralized monitoring practices and risk-based monitoring is a strategy that should continue to ensure subject protection and overall study quality while increasing efficiency (73). Other strategies to reduce costs include the use of centralized institutional review boards (74,75) and improving the system of reporting and interpreting unexpected serious adverse events through decreasing the review of uninterpretable case reports (76). The Clinical Trials Transformation Initiative (CTTI)—a public-private partnership founded by the FDA and Duke University to identify barriers to the conduct of large, simple trials—has recognized other important impediments to clinical research involving regulatory bodies, sponsor-imposed delays, academic impediments, and health system and clinical practice site impediments (72). Finally, harnessing the massive National Patient-Centered Clinical Research Network (PCORnet) program to centralize and organize clinical data will not only augment our understanding of risk and outcomes for people with specific diseases, but should also provide answers that are vital to patients more quickly, efficiently, and at a lower cost than previously possible (77).
Increase focus on practical, streamlined trials
Despite a temptation to use surrogate endpoints to decrease sample sizes and shorten the duration of clinical trials (ostensibly to reduce the likelihood of drug-development failures), it was agreed that we must continue to promote large, pragmatic trials to measure clinical outcomes when evaluating new cardiovascular therapies. Larger trials also help resolve conflicting data. After post-approval analyses of data from small, randomized trials suggested that use of nesiritide was associated with a rate of worsening renal function and death, the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) demonstrated the safety of nesiritide but demonstrated no efficacy benefits with this agent (78). Finally, if conducted properly, large, simple trials can prove to be successful despite high rates of background, guidelines-recommended therapies that are known to improve outcomes when used widely. A prime example of the contemporary success of a novel agent studied in a large trial is PARADIGM-HF (Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACEI [Angiotensin-Converting–Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial), which compared LCZ696 versus enalapril in heart failure with reduced ejection fraction (79). This trial was stopped early due to efficacy in the LCZ696 arm. Finally, integrating quality by design principles during the planning of large, simple trials is a key ingredient for trial streamlining. CTTI promotes quality by design with the goal that clinical trials will be more streamlined, fit for purpose, and quality driven (80). Trials with adequate sample sizes to assess benefits and risks using cardiovascular events should, therefore, remain the reference standard for cardiovascular drug development.
Leverage phase II trials to inform phase III trials
Many participants in the meeting felt that the research and development community could more effectively leverage data collected from phase II trials to better plan for phase III trials. Although there is a need to use phase II trial data to predict phase III outcomes and to adequately design phase III trials for regulatory approval, it is equally important to use the data gathered to understand the impact of a novel therapy on biology and disease pathways to plan future development. Phase II studies should, thus, focus on informing and refining important variables such as dosing, population pharmacokinetic modeling, side effects, and the treatment effect on biomarkers before commencing pivotal phase III registration trials. In fact, biomarkers are most appropriately used in phase II trials to screen for promising new therapies through evaluation of biological activity (68). Embedding adaptive design (AD) within a single clinical trial may furnish a novel strategy as well. This approach allows a review of accumulating information during a trial that may suggest modification of trial characteristics, thus addressing uncertainty about choices made during planning (81). AD allows pre-specified updates to the maximum sample size, study duration, treatment group allocation, dosing, number of treatment arms, or study endpoints. AD could translate into more efficient therapy development by reducing trial size. In turn, this could lead to more viable studies, with less risk for sponsors. However, although some academic and industry representatives may be eager to use AD strategies, regulators have been rightfully cautious to accept all AD trials for approval due to the broad spectrum of potentially problematic adaptations involved (81,82).
Use novel NIH programs to support early-phase development
Despite pre-clinical testing and selection, many drugs that enter human studies never make it to market because of failure between phases I and III (83). The NIH has initiated new programs in search of an effective approach to actively support early clinical development, hoping to provide a bridge to facilitate successful innovation. Although the majority of NIH funding goes to support nonhuman research, it is also committed to funding applied sciences (84). The newest NIH institute, the National Center for Advancing Translational Sciences, was created in 2010 to accelerate translation of ideas into treatments via different programs, including those that enable repurposing of existing drugs for new indications (85).
The NHLBI has also developed several new approaches to specifically facilitate the translation of basic cardiovascular discoveries into clinical applications. The goal is to continue to develop a variety of programs that create teams of academic investigators and industry partners (86) (Figure 6). The NIH Centers for Accelerated Innovations (NCAIs) aim to identify and advance the development of promising emerging technologies toward new commercial products for the prevention and management of medical conditions affecting the cardiovascular, pulmonary, and hematologic systems. The NCAIs are developing a centralized institutional approach to move basic science discoveries through the early stages of technology development to enable their subsequent commercialization. Inventors, especially those who are new to the product-development process, have access to relevant personal training and mentoring opportunities. The new Vascular Interventions/Innovations and Therapeutic Advances program (87) aims to address the need for new or better therapeutic interventions (drugs or devices) and diagnostic modalities in several medical conditions that have been traditionally neglected by industry. Strategies include: 1) no restrictions on the applicant’s type of institutional affiliation or on geographic location (within the United States); 2) assistance with project management, regulatory issues, and expert industry advice; and 3) opportunities to leverage other existing NIH translational programs. Areas of recent funding include vascular disorders, thrombotic diseases, and pulmonary hypertension. The Small Business Innovation Research funding mechanism provides seed funding to support the development of a broad array of commercial products to detect, diagnose, treat, and prevent disease. Other current programs include the Science Moving Towards Research Translation and Therapy program and the Gene Therapy Research Program (GTRP). These new programs are unproven, but they do represent an effort by the NHLBI to encourage and enable cardiovascular drug research even in the risk-adverse capital environment that currently exists.
Leverage academic experts as an interface between industry and regulatory bodies
Optimal cardiovascular drug development depends on true partnerships amongst academic representatives, regulatory officials, industry scientists, and clinical researchers, as well as practicing clinicians—all of whom represent the needs of patients with cardiovascular disease (Central Illustration). The use of academic clinical trialists is important in the design and conduct of pivotal cardiovascular registration trials where expertise on the cardiovascular disease condition, clinical trial operations, and established relationship with regulatory agencies are integrated attributes that are unique to academic researchers (88). Academic researchers can work with the pharmaceutical industry to help identify and define unmet clinical needs and to translate mechanisms of drug effect into clinical scenarios where the benefits may exceed the risks. Those qualifying as academic researchers are typically university-affiliated, have expertise in the field, and have prior clinical trial experience. Selected academic research organizations, especially in cardiovascular medicine, foster the “science of clinical operations” and stand well-positioned to enact and conduct efficient and streamlined clinical trials. However, academic clinical trials do not have to be affiliated with an academic research organization. Above all, with expertise and understanding of clinical practice, academic researchers can facilitate discussions between the regulatory bodies and the pharmaceutical industry from the perspective of expertise in disease therapeutics and patient-centered clinical care.
Continue to strengthen the science
Many cardiovascular drugs have been developed on the basis of proven biological activity in modifying a biomarker, hoping that the biomarker directly reflects disease outcomes. As discussed previously, many successful therapies have targeted biomarkers (specific lipid fractions and hypertension), resulting in improved clinical outcomes, but the definitive recommendation for therapy occurred only after vigorous testing in the form of multiple clinical trials with thousands of patients and valid clinical endpoints. In this setting, the effect sizes may be modest, and therefore, interventions require large trials to show benefit. At the meeting, there was general agreement that to improve efficiency from a scientific standpoint, development strategy should move away from targeting a directional change in biomarkers to: 1) use biomarkers to form enriched populations and further classify disease; and 2) learn more about the biologic targets and causal mechanisms that drive most cardiovascular diseases.
Using biomarkers to enrich study populations may help refine our definitions of disease and lead to successful drug development. Several examples already exist in the published data. In the COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trial, which demonstrated a 20% reduction in all-cause mortality or hospitalization with treatment with chronic resynchronization therapy (with or without an intracardiac defibrillator), the patient population was enriched by only including those with a QRS interval of ≥120 ms. The investigators widely acknowledge that if this therapy had been applied to the entire heart failure population, it almost certainly would have been negative (89). The JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) primary prevention trial, which demonstrated a reduction of major cardiovascular events with rosuvastatin, enriched an apparently healthy population by including only those with an elevation of an inflammatory marker, C-reactive protein (90). Finally, although the TOPCAT trial of spironolactone in patients with preserved ejection fraction was negative overall, a pre-specified subgroup of patients with elevated brain natriuretic peptide may have benefitted—a finding that must be regarded as exploratory and requires replication (91). Enrichment with biomarkers could help fuel studies to tackle several unmet cardiovascular research needs, including pulmonary hypertension, hypertrophic cardiomyopathy, and congenital heart disease. Therefore, although the use of biomarkers as surrogate endpoints can prove treacherous, they may be useful to enrich populations that may benefit from specific therapies.
To improve understanding of the causal mechanisms of disease, several novel approaches have been leveraged. A genome-wide association study identified 13 new susceptibility loci for coronary artery disease (92). Of the 13 loci, only 3 were associated with conventional, established cardiac risk factors, and all were found to be of greater significance than PCSK9, which missed the genome-wide significance level by a small margin. This analysis shows that there are many potential nonconventional targets associated with the pathogenesis of coronary artery disease available for mining. Next-generation sequencing found a strong association between titin and dilated cardiomyopathy (93), and the importance of systems biology approaches for drug discovery has now been recognized for over a decade (94). Other strategies include Mendelian randomization, proteomics, and metabolomics. New basic science technologies have helped further our understanding of some of the causal mechanisms of cardiovascular disease and have the potential to stimulate future drug development. Increasing transdisciplinary exchanges of knowledge between the basic and clinical research fields through training and collaborations will enhance efforts to identify new targets, pathologic mechanisms, and drugs to address the unmet need in cardiovascular disease.
Strategies to improve industry-sponsored cardiovascular drug development
The pharmaceutical industry is generally composed of 2 main industry groups: those from the top 15 largest pharmaceutical companies (“Big Pharma”) and other companies considered small to medium-sized enterprises (95). From a drug-development process, this distinction may be important when evaluating research and development strategies. Small to medium-sized enterprises typically focus on the biology and potentially large effect sizes in serious cardiovascular illnesses. As discussed, leveraging human genetics or known human pharmacology will be extremely valuable to identify drug targets with a higher likelihood of success, instead of investing in a multitude of targets and accepting that some will fail. An example of this was the identification of the PCSK9 protein as a compelling target to treat hypercholesterolemia (96,97). The convergence of deoxyribonucleic acid sequencing, computational biology, and statistical methods is uncovering new compelling targets that should lead to the next wave of therapies aimed at reducing cardiovascular morbidity and mortality. In addition, this new paradigm should mitigate investment risk and facilitate the acceleration of high-potential programs. As a corollary, some meeting participants felt that a move toward reduced investment in targets supported only by nonclinical genetics and disease models would be beneficial. Programs with the greatest risk of failure should be reserved for the most grievous illness, novel science, and potential biggest incremental advance for patients. Last, technological advances in small and large molecule generation and manufacturing as well as new insights into biology that allow for different therapeutic modalities have positioned the industry to address cardiovascular disease in ways previously not achievable.
From a “Big Pharma” industry perspective, simple randomized trial design could prove to be key. This pathway emphasizes clinical outcomes over putative surrogate endpoints. Trials must be sufficiently large to detect small but clinically-meaningful differences in mortality and other major outcomes important to both the individual and to society. Priority should be given to suspected unexpected serious adverse reactions and to limiting the recording of less impactful adverse and serious adverse events. Streamlined, risk-based, and remote monitoring would be beneficial. Big firms should continue to strive to improve trial efficiency and emphasize meaningful clinical outcomes.
Promising trial designs to improve drug development
A potential novel strategy to help streamline clinical trials in the future would be to perform a smaller pre-marketing study but agree to a larger post-marketing comparative effectiveness trial. Currently, post-marketing studies cannot be used to support approval and are primarily used to refine the labeling of an approved drug therapy. These are generally studies required of or agreed to by a sponsor that are conducted after the FDA has approved a product for marketing, and they typically serve to gather additional information about a product's safety, efficacy, or optimal use (98). By functioning as a more comprehensive extension of a typical post-marketing study, a “continuum” study design would pre-specify integrated, systematic, monitored data from pooled pre-market randomized and post-market registry (99). Gathering pre- and post-market “real world” safety data might both improve safety assessment and support the assurance of safety in smaller pre-market studies. From an industry perspective, smaller studies resulting in reduction of pre-market cost and time could provide incentive for a serious commitment to complete post-market registries that are larger and more rigorous than current post-market data collections. In 2012, the FDA released its vision for post-market surveillance for medical devices (100). Although this effort specifically covered medical devices, this system could be adapted and implemented as a form of post-market enforcement to study novel drugs. These systems can and should be used to also assess efficacy (101). Furthermore, such post-marketing comparative effectiveness trials could align with 1 of several Patient-Centered Outcomes Research Institute initiatives, including PCORnet (discussed previously), whose goal is to build clinical research into the health care process by creating a national network for conducting clinical outcomes research (102,103). An example of a future clinical trial integrating an industry sponsor, the FDA, and patient-centered outcomes might be a post-marketing comparative effectiveness trial supported by the Patient-Centered Outcomes Research Institute, the data from which are then captured, integrated, and studied using PCORnet.
Conclusions: a Call to End the Hibernation
Despite the growing global burden of cardiovascular disease, metrics indicate that cardiovascular drug development has steadily declined relative to the growth of scientific discovery and the expansion of development in other therapeutic areas. This trend is particularly concerning given the unprecedented effect of cardiovascular drugs on outcomes, particularly in high-income countries (104). Investment in cardiovascular drug development has shifted elsewhere. This trend seems driven primarily by economic factors, including ROI with increased reimbursement and the perceived reduction in investment risk in bringing noncardiovascular drugs to market.
Nevertheless, the science of clinical therapeutics drives the continued requirement for the field of cardiovascular medicine to have large cardiovascular outcomes trials to demonstrate the balance of benefits and harms of potential novel therapies. Fortunately, despite the current perceived hibernation of cardiovascular drug development, most large pharmaceutical firms still have an interest in pursuing novel cardiovascular therapies should the right opportunity exist (45). The key issues and potential solutions are summarized in Table 2. Leveraging academic collaborations and novel governmental programs to identify, derisk, and develop potential therapeutic targets through pre-clinical and early-phase development appears to provide a positive path forward. By strengthening and refining the scientific questions and early-phase discoveries, cardiovascular drug development can rise once again by targeting enriched populations, using novel operational approaches to study design and conduct afforded by advances in the science of clinical trials, and emphasizing the pursuit of unmet clinical needs. Outcomes research and population health are coalescing around streamlining and simplification. As such, the “hibernation period” for cardiovascular drug development could draw to a close by application of the principles recommended in this paper.
The authors would like to thank Drs. Kenneth Kaitin, Joseph DiMasi, and Joshua Cohen from the Tufts Center for the Study of Drug Development as well as Dr. Zubin Eapen from the Duke Clinical Research Institute for their insightful comments during the synthesis of the manuscript. The authors would also like to thank Morgan deBlecourt for her editorial contributions, which were provided as part of her regular duties as an employee of the Duke Clinical Research Institute.
The Cardiovascular Drug Development Think Tank was supported by Amgen, Inc., Bayer HealthCare Pharmaceuticals, Bayer Pharma AG, Bristol-Myers Squibb, Janssen Pharmaceuticals, Regeneron, and The Medicines Company. Dr. Fordyce has received support from the Clinician Investigator Program of the University of British Columbia.
Dr. Roe has received research grants from Eli Lilly & Co., Sanofi-Aventis, Daiichi-Sankyo, Amgen, and Familial Hypercholesterolemia Foundation; has received lecture fees from AstraZeneca and Bristol-Myers Squibb; and has received consulting fees from AstraZeneca, Eli Lilly & Co., Merck & Co., Janssen Pharmaceuticals, Elsevier Publishers, and Amgen.
Dr. Ahmad has served as a consultant to Roche; has received an educational grant from Thoratec Corporation; and has received a grant from the Daland Foundation. Dr. Libby is an unpaid consultant or involved in clinical trials for Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Esperion Therapeutics, Genzyme, GlaxoSmithKline, Kowa Pharmaceuticals, Merck, Novartis, Pfizer, Sanofi-Regeneron, Takeda Pharmaceuticals; is a member of the scientific advisory board for Athera Biotechnologies and Interleukin Genetics; and his laboratory receives research funding from General Electric, GlaxoSmithKline, and Novartis. Dr. Borer has been a paid consultant, clinical trial executive committee member, data and safety monitoring committee chair or member, and clinical events adjudication committee member during the past year for Amgen, Boehringer-Ingelheim, JenaValve, Takeda USA, Celgene, Cleveland Biolabs, Somahlution, Cardiorentis, Celladon, Biotronik, BioMarin, Salix, Novartis, ARMGO, Pfizer, and Laboratoires Servier; and has stock in BioMarin. Dr. Hiatt has received research grants from AstraZeneca and Bayer; and his research organization affiliate of the University of Colorado receives funds from companies including AET Biotech, AstraZeneca, Bayer, Cardioxyl, National Institutes of Health, CSI, GlaxoSmithKline, Janssen, Kyushu University, Merck, Pluristem, Reneuron, and Takeda. Dr. Bristow is an employee, shareholder, and board member of ARCA biopharma. Dr. Packer is a consultant for Actelion, Amgen, CardioKinetix, Cardiorentis, Janssen, Novartis, Pfizer, and St. Jude Medical. Dr. Wasserman is an employee of Amgen, Inc. Dr. Braunstein is an employee of Regeneron Pharmaceuticals and a retired employee of Merck; and owns stock in both Regeneron Pharmaceuticals and Merck. Dr. Pitt is a consultant for Pfizer, Bayer, AstraZeneca, scPharmaceuticals, Relypsa, Aurasense, Da Vinci Therapeutics, Stealth Peptides, and Tricida; has stock options in Relypsa, scPharmaceuticals, Aurasense, Tricida; has a patent pending for site-specific delivery of eplerenone to the myocardium; has served on data monitoring boards of Novartis, Johnson & Johnson, Oxygen Biotherapeutics, and Cytopherx; and has served on the events committee of Juventis. Dr. DeMets is a consultant to the National Institutes of Health, the Food and Drug Administration, and the pharmaceutical and medical device industry on the design, monitoring, and analysis of clinical trials; and receives compensation for serving on several industry-sponsored data and safety monitoring committees, including AstraZeneca, Amgen, Actelion, GlaxoSmithKline, Merck, Sanofi, Boehringer Ingelheim, Teva, and AbbVie. Dr. Armstrong received research grants from Boehringer Ingelheim, Merck Sharp & Dohme in conjunction with Duke Clinical Research Institute (DCRI), GlaxoSmithKiline, Amylin Pharmaceutical, Inc. in conjunction with DCRI, Merck & Co., Inc., Sanofi-aventis Research and Development, and Regado Bioscience; and received consulting fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck & Co., Inc., F. Hoffmann-La Roche Ltd., Axio/Orexigen, Merck, Eli Lilly, and Bayer. Dr. Berkowitz is an employee of Bayer HealthCare. Dr. Scott is an employee of and shareholder of Amgen, Inc. Dr. Prats is an employee of The Medicines Company. Dr. Stockbridge is an employee of the Food and Drug Administration. Dr. Peterson has received research grants from the American College of Cardiology, American Heart Association, Eli Lilly & Co., Janssen Pharmaceutical Products, and the Society of Thoracic Surgeons; and has received consulting fees from AstraZeneca, Bayer AG, Boehringer Ingelheim, Genentech, Janssen Pharmaceutical Products, Merck & Co., and Sanofi-Aventis. Dr. Califf has received research grants from Amylin, Bristol-Myers Squibb, Eli Lilly & Co., Janssen Research and Development LLC, Merck, and Novartis; and received consulting fees from Amgen, Bayer Healthcare, BMEB Services LLC, Medscape LLC/heart.org, Merck, Novartis, Regado NJ, and Roche; and has equity in N30 Pharma and Portola. The views expressed are those of the authors and do not necessarily reflect official National Heart, Lung, and Blood Institute positions. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- adaptive design
- new molecular entity
- progression-free survival
- return on investment
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