The Current Drug Development Paradigm: Responding to US and European Demands for Evidence of Comparative Effectiveness and Relative Effectiveness

Abstract

In the United States (US) and Europe, and indeed, globally, pharmaceutical companies are facing rapidly evolving regulatory and reimbursement evidentiary expectations linked in large part to the clinical and economic realities confronting their respective healthcare systems. Specifically, demands for comparative effectiveness research (CER) and relative effectiveness (RE) evidence have been driven by: (1) health care spending pressures; (2) lack of information to guide the efficient use of new technologies; and (3) consequent political momentum to promote enhanced generation of evidence to inform post-regulatory clinical and coverage decision-making. CER (the term commonly used in the US) and RE (the term commonly used in Europe) both share a focus of producing evidence about how treatments work compared with existing alternatives under circumstances of usual care.

The purpose of this work has been to ascertain how the current drug development paradigm at five global pharmaceutical companies is evolving in response to perceived demands for evidence of comparative effectiveness and relative effectiveness, in particular, from payers and HTA bodies, but also from clinicians and patients. To accomplish this goal, we first undertook a targeted literature review (primarily to provide context and help to identify some themes for the interview programme), followed by a semi-structured interview program with an international sample of 19 senior executives (12 identified as CER experts and seven as RE experts). These executives hold positions in clinical development; health economics and outcomes research (HEOR); medical affairs; and pricing, access and reimbursement (PAR) across five global pharmaceutical companies. Our goal was to develop more detailed information about how these organisations currently conceptualise CER/RE, how they have begun to modify their internal processes to respond accordingly, and what they perceive to be the enablers and barriers for continued adaptation in response to both internal and external factors confronting the pharmaceutical industry.

Both tasks have revealed a number of common emerging themes regarding both CER and RE, and more importantly,how companies are adapting to this new environment which is elevating the importance of information needs of these post-regulatory decision makers. First, the current drug development paradigm has already started to change in response to CER/RE evidence demands from stakeholders. These changes range from inclusion of active comparators in clinical trials, involvement of stakeholders to help define key phase IIb and III study design features, incorporation of PRO measures and earlier planning for phase IV studies. It is also true, however, that some of these changes do not deliver on all the elements of CER/RE, particularly the “under usual circumstances of care” dimension. However, our key informant interviews highlighted the need for industry to improve on current methods for eliciting the patient perspective,as their current conceptualisation of CER/RE tends to be primarily payer-focused.

Second, CER/RE investments are being made at different phases depending on the company. Not surprisingly, however, CER/RE investments currently lag behind the phases of initial evaluations. Such evaluations typically involve project team discussions with representatives from HEOR and PAR. Issues such as the development of initial product profiles and models of expected product effects on clinical outcomes relative to alternative treatments are discussed. If the investigational compound progresses beyond these initial evaluations (including the requisite safety and early efficacy requirements), then typically the project team leader would advocate for the incremental investments to be made in the clinical development program to support CER/RE data collection. The degree to which they focus on this currently in the US as compared to Europe is less, given that the EU has a longer experience of responding to the demands of national HTA/pricing and reimbursement bodies.

Third, a number of barriers have been identified in terms of incorporating CER/RE considerations into companies’ drug development plans. While we spoke to a group of individuals that could be characterised as “early adopters” of CER/RE, they identified a number of existing internal barriers to the successful integration of CER/RE within companies. Barriers included a lack of clear accountability for incorporating CER/RE considerations into development plans, and lack of incentives, as well as the high costs of undertaking such studies. However, some of these costs may be mitigated by increased use of observational studies and electronic health record data. However there will need to be additional investments in the research infrastructure to conduct CER/RE as well as on-going methods development and dialogue to ensure regulatory acceptability for promotion of study results in the US. Another barrier raised was the lack of shared understanding on the development team of the importance of external demands for CER/RE data, together with the lack of confidence amongst scientific staff that today’s experts have sufficient methods or adequate data to generate robust/valid data from CER/RE studies.

Fourth, a number of facilitators to the successful integration of CER/RE were identified, including an internal champion, often a very senior member of the company who could provide leadership and support, the ability to attract and retain top talent to lead the CER/RE research effort, and external pressures and drivers for CER/RE.

Fifth, there was universal agreement on the part of our interviewees that by the year 2020, CER/RE would have a much greater role in influencing the process of drug development as compared to today. However the question remains as to whether the industry’s incremental investments in CER/RE will have the anticipated positive return on investment in terms of reimbursement and market access.