Although we have witnessed historic lows in the rate of growth of healthcare spending, the implementation of the Affordable Care Act and secular trends have created fundamentally new dynamics in how providers, clinicians, and patients are exposed to the cost of care.  New payment and delivery models being tested by the Center for Medicare & Medicaid Innovation are shifting the financial risk for managing population health to providers and clinicians.  In addition, state health insurance exchanges are poised to introduce new insurance products targeted to meet the needs of price-sensitive consumers.  In Silver Plans, designed to have lower premiums, the out-of-pocket payments for brand named pharmaceuticals could be $70 per prescription.

At the same time, specialty pharmaceuticals are the fastest growing sector in healthcare.  ExpressScript’s Drug Trend Report estimates 22 percent growth in spending for specialty products in 2014.  These dynamics have resulted in heightened demand for evidence on the safety, effectiveness and value of pharmaceuticals by health plans, clinicians, and patients.  Further, these decision-makers desire real-world evidence demonstrating durable patient benefits and cost savings from use of pharmaceuticals.

Simple enough.  Clear demands to an industry with billions invested in research.  What’s the problem?  TrustThe current level of trust in biopharmaceutical and medical products industry-funded research and credibility of industry-sponsored study results is extremely low.  Some of this is a result of highly publicized fines and corporate integrity agreements (CIAs) levied for off-label marketing, inappropriate financial arrangements with providers/researchers, and lack of transparency about trial results.  The resulting loss of trust in industry and its research weakens the role of a key player in meeting the demands for more evidence.

So what are options to correct this? Already, regulators are calling for greater transparency in clinical trial data. The European Medicines Agency is moving to require disclosure of full clinical study reports and controlled access to raw clinical trial data for all newly approved drugsThe FDA is soliciting feedback from stakeholders on the process of opening up access to select de-identified data from marketing applications for drugs and medical devices to researchersPhRMA and its European counterpart EFPIA have just publicly announced their commitment to trial disclosure and a process to make patient-level data available to legitimate independent researchers at appropriate times after regulatory approval, while protecting intellectual property and patient privacy.

In addition, there have been recent examples of emerging models for allowing for independent validation of industry research.  AllTrials, a project led by the UK charitable trust Sense About Science and the medical journal BMJ, was established to campaign for registering all clinical trials, disclosing trial results and clinical study reports, and providing access to patient-level clinical trial data. GSK has been a first-mover in signing on to AllTrials and is registering and publishing its trials, making its clinical study reports public, and providing access to individual patient-level data to researchers who submit a protocol for approval to an independent panel of experts.

Another model which may help to regain public trust in industry research is the Yale Open Data Access (YODA) Project, in which companies may provide complete patient-level clinical trial datasets for examination by independent research groups.  Amidst questions of device safety and potential investigator bias, Medtronic voluntarily provided a grant and patient-level trial data to Yale for two independent analyses of Infuse®, its recombinant human bone morphogenetic protein-2 (rhBMP-2) product. 

Increased transparency in clinical trial data and models for independent reanalyses are intriguing solutions that begin to address the loss of public trust in industry-sponsored research.  However, they are in the early stages of implementation. The management of research access and the impact of multiple analyses which may generate conflicting results on patient trust remain to be seen. There is still a need for clear standards for methods of analysis, replication, validation and communication.

In addition, these solutions do not adequately address the need for real-world evidence that is not generated in the context of a clinical trial; nor do they leverage the investments that have been made by institutions and health systems to capture data on patient care and conduct research within their own four walls. Multi-stakeholder partnerships between industry, health plans, health systems, and patients should be encouraged to ensure that research is funded and conducted in a manner that leads to credible and meaningful evidence for decisionmakers.

Policies to Support Trusted Research Partnerships

Trust is an essential component for developing and sustaining multi-stakeholder partnerships to develop, study, and manage innovative healthcare products and services. Three key policy areas should be addressed to establish and ensure trust among partners and the public for the fruits of these partnerships. First, data access and ownership issues should protect patients’ privacy while ensuring that research is not hindered by data-sharing limitations resulting from excessive fear of liability and lack of incentives.  Second, trust in financial arrangements between industry and providers, payers, and other decisionmakers can be supported by financial transparency policies that disclose payments but also provide context and a framework to promote appropriate industry funding for research. Third, ensuring that industry communications have a solid evidence base is critical to restoring trust.

Facilitate Data Access for Research While Protecting Privacy

Data access to an expanding array of resources — including clinical trials, clinical practice, and claims databases and observational research data (e.g. patient registries) — are critical to conducting research.  The Health Insurance Portability and Accountability Act of 1996 (HIPAA) Privacy regulations were promulgated to ensure patient privacy and govern entities managing health care information. Unfortunately, HIPAA regulations have created unnecessary barriers to the research process, including requirements for complex patient consent forms, multiple separate consent forms for trials and corollary studies, and prohibitions on future unspecified research. These rules have been blamed for increasing research costs, delays or cessation of some studies, and decreased patient participation and population representativeness.

Fortunately, HIPAA rule changes issued this year under the HITECH ACT, ”The Final Rule”, eliminated some of these issues. Study-specific authorizations may now include authorization for future unrelated research as long as a reasonable subject can understand how his/her information may be used. Regulations were also modified to allow one consent form for both “conditioned authorizations” required for study participation and “unconditioned authorizations” for optional research activities, reducing complexity and confusion for patients.

Yet, while these changes were designed to enhance clinical trial participation by patients and investigators and decrease barriers to conducting research, other barriers were erected.  The HITECH Act expanded HIPAA liability for patient information protection to include contractors, subcontractors, and other business associates that process health information; this definition includes pharmaceutical and medical device companies, health information exchanges, electronic prescribing gateways, and many health information technology companies.  Monetary penalties for noncompliance were increased, to a maximum $1.5 million per violation.  In addition, patients who pay cash for a service may request that their provider block transmission of information on that service to the health plan.  The impact on accuracy and completeness of medical records is yet to be seen.

Finally, the new rule added barriers to data reuse and mining by imposing restrictions on the aggregation and resale of data. In general, specific patient authorization is required with limited exceptions. Fully and partially identifiable “limited data sets” can be sold for research purposes, but these transactions must not generate profit.  Completely de-identified data can be shared and business associates can be paid a “reasonable cost-based fee”; however, limitations on profits and fear of liability may decrease the willingness of key stakeholders — particularly provider groups, integrated health systems and electronic health record vendors — to develop the integrated longitudinal data sets needed for the type of real-word evidence desired by decisionmakers. It is important to track the impact of these recent regulatory changes on both patient privacy and research and modify policy as needed.

Provide Context and Clarity for Appropriate Financial Support for Research

One regulation affecting payments for research and other services is Section 6002 of ACA, known as the Physician Payment Sunshine law. As of August 2013, this law requires collection and subsequent public reporting of industry payments to physicians, including payments for research.  The law was designed to support transparency and reduce incentives for undue financial influence, and thus to promote trust in treatment decisions and research integrity. It remains to be seen whether the scrutiny and potential for misinterpretation about industry financial arrangements will impact investigator and institutional participation in scientifically valuable industry- sponsored research.  Clarity around the definition of fair market value, safe harbors for research, and the provision of context for research payments might enhance the climate for industry-sponsored multi-stakeholder research.

Safe harbors for industry contracting for research are another critical area in need of regulatory clarity. The federal Anti-Kickback provisions prohibit improper payments to providers, plans, academic institutions and other health care decisionmakers that could inappropriately impact health care decisions. These same entities are often partners who conduct clinical trials and real-world studies sponsored by pharmaceutical and medical device companies. Because of the broad nature of the Anti-Kickback law, Congress required the development of “safe harbor” provisions that specify payment and business provisions that would not be subject to the statutes. These safe harbors include personal service agreements that are used as the basis for contracting with researchers.

However, inappropriate use of research arrangements may result in criminal and civil investigations.  The 2003 Office of Inspector General (OIG) Compliance Guide for Pharmaceutical Manufactures targeted clinical trial sponsorship, particularly post-market studies and research grants for investigator initiated trials, for scrutiny.  OIG recommended that these studies be managed by non-marketing employees and that payments be only for legitimate, reasonable and necessary services; be of “fair market value”; and not tied or related to product purchases.

These safe harbors are unclear and subject to varying interpretation among stakeholders.  Several companies have been investigated by the Department of Justice, the OIG, and several states for alleged use of clinical trial funds to pay physicians to prescribe off- label, or have been fined for research related violations. Clearly, the move to ensure that research payments are for legitimate purposes is designed to enhance trust. However, to reduce their risk of liability, some pharmaceutical companies require that almost every research project, large or small, go through independent review by outside auditors — an expensive solution that delays and limits studies as well as increases costs.  Some independent delivery systems and Accountable Care Organizations (ACOs) are so concerned about possible violations that they avoid any industry support for research – including support for research fellows.

There is a need to develop a comprehensive, consistent approach to measuring fair market value and to create a framework which encourages industry funding of scientifically valid research for plans, providers and academic institutions.

Promote Communication of Credible, Scientific information Among Key Stakeholders

Effective use of research results requires information exchange among health care stakeholders.  An array of stakeholders develop, use and communicate clinical trial and real-world evidence about device and drugs.   These actors include payers, professional societies developing practice guidelines, government agencies, technology assessors and academic detailers which are not regulated by FDA.  The need for real-time decisions based on robust clinical evidence necessitates revisiting the current framework to allow for appropriate industry participation in information exchange with these decision-makers.

Pharmaceutical and medical device company communications are regulated by the FDA under the Federal Food Drug and Cosmetic Act (FFDCA).  This framework was designed to ensure that physicians and patients could trust that communications from industry were based on valid evidence.  Traditionally, industry communications about evidence from clinical trials and real-world observational studies must meet the standard of “substantial evidence” and must be limited to “on label” communications between industry and other healthcare providers. The FDA’s substantial evidence standard has generally meant adequate and well-controlled clinical trials. Exemptions provide for off-label discussions in response to unsolicited medical requests from individual health care practitioners and for limited distribution of peer-reviewed publications.

Recent court cases such as US vs. Caronia challenge FDA’s enforcement of restrictions on off-label communication by industry. In this instance, the US Court of Appeals for the 2nd Circuit vacated criminal conviction of a sales representative for off-label use, citing First Amendment protections and stating that truthful speech does not constitute misbranding. However, the implications of this case for other cases of misbranding are unclear. The position of the FDA to restrict “promotional speech” to evidence supported by clinical trials does not seem to have changed.

An additional “safe harbor” provides for communication of economic information. In 1997, in recognition of the increasing importance of payer and formulary decisionmakers and the demand for health care economic information, Congress passed the Food and Drug Administration Modernization Act (FDAMA) including Section 114. This allows industry to provide formulary authorities with economic data directly related to an approved indication as long as it meets the definition of “competent and reliable scientific evidence.”  Economic data may come from clinical trials or real-world studies.

FDA has not generally cited industry for violations of Section 114 nor referenced it in warning letters about industry economic communications. It is unclear whether this reflects adequacy of the harbor, lack of use of the provision by industry due to its ambiguity, or lack of enforcement by FDA. Public statements by the FDA indicate its view that while Section 114 allows economic data to be based on competent and reliable information, all clinical components of economic analysis must be based on the “substantial evidence” standard of two controlled trials; this severely limits communication of standard economic cost-effectiveness or cost/QUALY analyses.

Outside the “unsolicited request,” or formulary decisionmakers context, the FDA has generally rejected commercial speech based on observational data; warning letters regarding industry communications about work productivity and social functioning reinforce this position. There have been calls for an expansion and clarification of FDAMA 114 to allow it to be used for real-world evidence. The current regulatory framework creates a disincentive for industry to conduct collaborative real-world studies because of restrictions on proactive communication of results with key decision-makers and limits on bi-directional discussion, particularly of observational data, in a manner which could support a balanced use of information on product impact. Also, the lack of standards for conducting and communicating real-world evidence among other stakeholders — payers, plans, professional societies, etc — is likely to foster conflicting results and distrust among patients.

In summary, there is a need to restore trust in industry-sponsored research and to support innovative efficient models for trials and studies of real-world effectiveness. Policy changes are needed to support data access for research, to provide transparency with context and safe harbors for industry funding of research, and to create frameworks for scientific exchange of real-world evidence among industry and key health care decisionmakers.  These changes could help foster trust, support incentives for continued innovation, and promote the diffusion of information that is needed to more effectively manage a future of scarce resources.+