Real-World Clinical Testing Challenges

The drive for personalized medicine and greater patient involvement in treatment decisions is spurring initiatives to generate more informative data on the effects and risks associated with drugs and medical products. The Food and Drug Administration (FDA) seeks to facilitate informed self-treatment with a proposal for expanding access to more over-the-counter (OTC) drugs with "conditions for safe use." Government support for comparative effectiveness research (CER) is attracting great interest from researchers, payers, and pharmaceutical companies looking to identify optimal treatment for a broad range of medical problems. The clamor for more information on drug use and effects in such "real world" situations is shaping clinical trial design and research operations.

Jill Wechsler

Expanding OTCs

FDA officials propose to make more nonprescription drugs available to patients, including treatments for chronic conditions such as high blood pressure and cholesterol, based on demonstrations that consumers can select and use medicines appropriately without going to a doctor. The aim of this "new paradigm," as described by agency officials at a two-day public hearing in March, is to improve public health by making it easier for patients to obtain medicines and to adhere to recommended treatment with the assistance of innovative health information systems and pharmacy services that support self-treatment.

Such a change would require a lengthy FDA rule-making process and most likely authorizing legislation. It also would involve further development of label comprehension studies and actual use trials for documenting that the medicine can be used safely and appropriately based on the approved "drugs facts box" label, plus supporting information and services. Merck failed several times to gain OTC status for its anti-cholesterol drug Mevacor (lovastatin), largely because its studies did not convince FDA that consumers could determine if a cholesterol drug was right for them just by reading the product label.

To move forward, regulators and sponsors need to validate methods for testing the efficacy of patient self-selection programs and devise appropriate exclusivity arrangements or other incentives for manufacturers to invest in and test innovative information and patient monitoring systems. Research firms and IT vendors are promoting new ways to evaluate and ensure compliance with self-diagnostic tools and to coordinate collaboration on OTC oversight programs with physicians, payers, and patients. Despite numerous regulatory, scientific, and political challenges, FDA leaders appear optimistic that innovative studies and IT systems not only can enhance medication use, but also help identify drug-drug interactions and improve pharmacovigilance tracking.

CER challenges

The Patient Centered Outcomes Research Institute (PCORI) is poised to distribute some $120 million in coming months—and nearly $400 million in 2013—to fund research on effective patient treatment strategies and CER study methods. The expectation is that the resulting data will help patients and providers make more informed decisions about treatment options, and save money in the process by curbing inappropriate care. Pharma companies already are providing more comparative and outcomes analysis to formulary committees, insurers, and payers to bolster claims of product value, in addition to efficacy and safety, and the new program should further document real-world effectiveness for certain medical treatments.

PCORI has spent the last year getting organized, hammering out definitions for PCORI and CER, and seeking advice from all corners of the healthcare and research community. Last month it finalized priorities for its research agenda with an eye to awarding initial grants this fall. About $35 million will support studies that compare prevention, diagnosis, and treatment options to identify medical products and practices with superior patient outcomes. Another $18 million will support methodological research for improving the quality and usefulness of clinical data and develop standards for less traditional research methods, such as patient registries, observational studies, and meta-analyses.

The emphasis on "patient-centeredness" is generating new approaches for assessing individual and sub-group response to treatment during drug development. Payers and patient advocates emphasized at a PCORI stakeholder "dialogue" in February that CER must use rigorous science and research methods. A key factor in evaluating grant applications, the PCORI plan states, is how well the research uses "optimal methodological and analytic approaches to address patient-centered evidence."

The importance of considering heterogeneity, or different treatment effects across patients, was the theme of a March CER conference sponsored by the Drug Information Association and the National Pharmaceutical Council (NPC). The impact of heterogeneity in designing clinical studies "cannot be ignored," said Sheldon Greenfield, Professor of Medicine at the University of California, Irvine. He noted that data on co-morbidities, patient biology, and other characteristics likely to affect response should be assessed before a trial starts and not "tag it on at the end."

Marc Berger, Executive Vice President of OPTUMInsight, a provider of healthcare technology solutions; information; analytics; and consulting services, similarly advised pharma companies to embrace CER during development if they want to present a "value story" to payers. Peter Neumann, Professor of Medicine at Tufts Medical Center, emphasized the importance of choosing the right comparators, outcomes, and subgroups to study; analyzing which health and payment systems are better than others; and using real-world data. Sponsors noted the need to evaluate hypotheses for subgroup response, potential biomarkers, and patient-reported outcomes early enough to obtain appropriate comparative information from Phase III studies.

All these developments are prompting pharmaceutical companies to address CER earlier in the drug development process, to engage stakeholders in clinical trial design activities, and to explore innovative approaches for generating evidence, said Eleanor Perfetto, Senior Director for Reimbursement and Regulatory Affairs at Pfizer, at a CER summit last month sponsored by ExLPharma. And timing is important, she emphasized: moving too early can lead to selecting incorrect patient populations and comparators; too late can mean insufficient data to support coverage negotiations for product launch.

This shift towards a more patient-centric approach, moreover, is prompting sponsors to focus R&D on unmet medical needs and to target indications and subgroups with the highest potential return on investment. While subgroup analysis can prevent one-size-fits-all coverage decisions that often reject new technology, sponsors fear that CER studies will require thousands of patients to explore all possible outcomes and issues on various agendas.

An over-arching concern is that the cost of sponsoring extensive CER studies will curb biopharmaceutical innovation. While more efficient study designs could reduce research costs, clinical trials with multiple subgroups, active comparators, and long-term endpoints will make research more expensive, pointed out NPC Research Director Jennifer Graff at the ExLPharma meeting. Such investment may be justified if more complex studies support broader indications and higher prices for medicines found effective with certain patients. And additional payoffs could come from using innovative research methods that increase the probability of success for a clinical trial, facilitate FDA approval of a new product, and lay the basis for additional indications in the future.

To reduce costs and risks, pharma companies are forming partnerships with health plans and pharmacy benefit managers that can provide valuable patient healthcare data. A Pfizer-Medco partnership, Perfetto noted, aims to utilize genomic and phenotypic data to design studies that match patients to treatments most likely to provide benefit. Similar collaborations are evaluating a range of real-world treatment strategies for analyzing patient subgroups and specific diseases.

These and other research initiatives highlight the importance of PCORI's role in setting standards for CER research methods and in coordinating CER activities to avoid redundancies. Dissemination of CER results also is critical to ensure that clinicians incorporate research findings into practice. PCORI will support communications activities by the Agency for Healthcare Research and Quality (AHRQ), which have expanded in recent years. An AHRQ symposium in June will discuss further how research methods can shape the results of randomized clinical trials and observational studies.

An issue sure to arise is the concern voiced by pharma companies that FDA regulations constrain them from commenting on CER findings that touch on unapproved uses of a medical product, while the government, academics, payers, and insurers are free to disseminate and discuss all aspects of outcomes and comparative studies. At an NPC conference in February on "Asymmetry in the Ability to Communicate CER Findings," Robert Temple, Deputy Director for Clinical Science of FDA's Center for Drug Evaluation and Research, emphasized that industry is free to rebut clinical findings that they find objectionable, so long as they present factual and objective information—and avoid promoting off-label uses. Pharma companies want a more level playing field as CER becomes more important for shaping coverage decisions, but insurers and payers remain concerned that industry will use CER for promotional purposes. These issues will prompt even closer scrutiny of comparative studies to ensure they avoid bias and promote better care.

Jill Wechsler is the Washington Editor of Applied Clinical Trials, (301) 656-4634 jwechsler@advanstar.com