4

Creating a New Business Model for Clinical Trials

Costs of clinical trials have been rising in the United States (DeVol et al., 2011). The workshop’s third session, “Aligning Cultural and Financial Incentives,” explored opportunities for developing a new business model for clinical trials based on the seamless integration of technological advances and research activities to realize increased efficiencies and reduced costs. Individual speakers also proposed greater harmonization of regulatory responsibilities and administrative processes. If such changes take place on a large scale, clinical trials could become more affordable and attractive to organizations, clinicians, and the public.

TRANSFORMING THE ECONOMICS OF CLINICAL TRIALS1

While the technology for gathering clinical data for research has evolved over time, the business model supporting this technology clearly has not evolved with each stage of technology transformation.
Judith Kramer, Duke University Medical Center; and
Kevin Schulman, Duke University Medical Center

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1 This section is based on the presentations and Discussion Paper by Judith Kramer, Associate Professor of Medicine, Duke University Medical Center, and Executive Director, Clinical Trials Transformation Initiative (CTTI), Duke Translational Medicine Institute; and Kevin Schulman, Professor of Medicine, Duke University Medical Center, and Gregory Mario and Jeremy Mario Professor of Business Administration, Fuqua School of Business. (See Appendix F for the Discussion Paper “Transforming the Economics of Clinical Trials.”)



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4 Creating a New Business Model for Clinical Trials Costs of clinical trials have been rising in the United States (DeVol et al., 2011). The workshop’s third session, “Aligning Cultural and Finan - cial Incentives,” explored opportunities for developing a new business model for clinical trials based on the seamless integration of technologi - cal advances and research activities to realize increased efficiencies and reduced costs. Individual speakers also proposed greater harmoniza- tion of regulatory responsibilities and administrative processes. If such changes take place on a large scale, clinical trials could become more affordable and attractive to organizations, clinicians, and the public. TRANSFORMING THE ECONOMICS OF CLINICAL TRIALS1 While the technology for gathering clinical data for research has evolved over time, the business model supporting this technology clearly has not evolved with each stage of technology transformation. —Judith Kramer, Duke University Medical Center; and Kevin Schulman, Duke University Medical Center 1 This section is based on the presentations and Discussion Paper by Judith Kramer, Associate Professor of Medicine, Duke University Medical Center, and Executive Director, Clinical Trials Transformation Initiative (CTTI), Duke Translational Medicine Institute; and Kevin Schulman, Professor of Medicine, Duke University Medical Center, and Gregory Mario and Jeremy Mario Professor of Business Administration, Fuqua School of Business. (See Appendix F for the Discussion Paper “Transforming the Economics of Clinical Trials.”) 43

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44 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE Advances in IT combined with business model transformation could combine to form a critical step in achieving transformation of the CTE through lower cost, faster, and better data quality of clinical trials according to a background paper prepared by Judith Kramer, Associate Professor of Medicine, Duke University Medical Center, and Executive Director, Clinical Trials Transformation Initiative (CTTI), Duke Trans - lational Medicine Institute; and Kevin Schulman, Professor of Medi- cine, Duke University Medical Center, and Gregory and Jeremy Mario Professor of Business Administration, Fuqua School of Business. (See “Transforming the Economics of Clinical Trials” in Appendix F.) The entities involved in the conduct of clinical trials have not followed the cost-reduction trajectory of other technology-intensive industries and thus have not attained a business transformation sufficient to reap the economic benefits of technologic change. Instead, rapidly rising costs of U.S. clinical trials contribute to cost increases in developing innovative health products. For example, the estimated cost of developing one new drug has been suggested to range from $500 million to $2 billion (Adams and Brantner, 2006). The resulting high cost of conducting clinical trials constricts the pipeline for new drug development, limits the accretion of knowledge about drugs that are produced, deters a focus on innovation and improvements in trial design and conduct, and impedes the investi - gation of important public health inquiries. Increasing costs stem in part from obstacles that exist within regulatory pathways or stem from administrative inefficiencies, including increas- ingly complex clinical trial protocols, abundant requirements issued by various levels of government and different governments and not harmo- nized to ensure consistency, and excessively risk-averse interpretations of regulations by trial sponsors. An example of the last is 100 percent source documentation of all clinical trial data even though regulators—both FDA and the European Medicines Agency (EMA)—do not require it. Some new structures, such as CROs, have arisen to help trial sponsors operate in the complex research environment. CROs are focused on efficiently conduct- ing clinical trials according to current standards and client expectations and do not have as their mandate a goal of advancing innovation in clini- cal trial design and performance. According to some observers, CROs may improve efficiency for trial sponsors, but their business practices may also contribute to the current cost structure of clinical research. According to the authors, new information technologies conceivably could alter the conduct of clinical trials. For instance, electronic data capture (EDC)—using a computerized system to gather clinical data in a clinical trial—has the potential to reduce total costs, prevent errors, and conserve the time expended by physicians, nurses, and data coordinators by replacing multiple paper entries on patients’ clinical progress with

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45 CREATING A NEW BUSINESS MODEL FOR CLINICAL TRIALS onsite, electronic entry. EHRs could also reduce recruitment and site- screening costs and, furthermore, could enable direct-to-patient research, limiting the involvement of physician intermediaries. Pfizer recently initi- ated the nation’s first clinical trial, in support of an IND application, that recruits participants over the Internet (Mansell, 2011). Smart phones are another technology that can improve communication within research programs and facilitate recruitment of participants in trials. However, research entities continue to rely on legacy systems, such as freestanding site-specific monitoring mechanisms and IRBs, rather than having these functions centralized among all or most sites involved in the same trial. So long as research organizations persist in overlaying the old business model atop the new technologies, many potential efficiencies will not be realized. A broad approach to ensure the business model for clinical trials keeps pace with technology and information needs and capabilities could be based on a research agenda that examines how research is conducted today. This research would point the way forward in terms of identifying potential issues, and pathways, to reach business transformation of clini- cal trials. The research agenda would be reassessed every 2 to 5 years to ensure that business and regulatory mechanisms keep pace with techno- logic advances and other changes in the economic, scientific, and health care environment surrounding the CTE. Suggested pathways and oppor- tunities for moving research business models forward would therefore reflect findings that emanate from a forward-looking research agenda that considers the seamless integration of technology into research. Also, har- monization of regulations among multiple agencies, including different levels of government in the United States and different countries (includ - ing the European Union), could reduce the cost of monitoring trials. Regulatory relief also could come in the form of the establishment of safe harbors for business process innovation—to allow sponsors to follow certain promising pathways before regulations have been developed and finalized. Furthermore, enhanced clinical research education of health professionals could equip practitioners to contribute to strategic efforts to develop new ways to streamline clinical trials into clinical practice. Orga - nizations that play a role in clinical research could reorient themselves toward economic efficiency, shed “sunk costs” such as legacy systems that no longer are needed, avoid overly cumbersome mechanisms for applying regulatory controls, and embrace new information technologies. Possible strategies mentioned during the presentation of the Discussion Paper and discussion with the workshop audience for resolving economic inefficiencies in clinical trials are summarized in Box 4-1. Feasible new business models could emerge to replace the highly labor-intensive and regulation-laden clinical trials system that predomi -

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46 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE BOX 4-1a Selected Potential Strategies for Avoiding Unnecessary Costs in Clinical Trials The following actions suggested by Kramer and Schulman and individual work- shop participants could facilitate the creation of new business models for clinical research that integrate technologic advances: • evelop a national research agenda, based partly on “research-on- esearch” D r findings, to guide business transformation based on the next generation of technology; • armonize regulations issued by different agencies and governments; H • ove away from excessively risk-averse interpretations of regulations by M r esearch organizations; • nhance clinical research education of health professionals, so they can help E design more efficient and meaningful research programs; • pply new information technologies, such as web-based clinical trials and A smart phones, in place of outmoded mechanisms; • se EDC and EHRs to apply clinical data to research, replacing paper-based U legacy systems; • econsider costly regulatory controls, such as the Health Insurance Portability R and Accountability Act (HIPAA) regulations applied to clinical research, and provide safe harbors for business process innovation; • ngage in more strategic planning and consider new organizational structures E for entities conducting clinical trials; and • ocus compliance monitoring and other oversight on areas of greatest risk, and F introduce expedited review and flexibility as appropriate. a The information in this box is based on the presentations of Kramer and Schulman (2011) and Discussion Paper by Judith Kramer, Associate Professor of Medicine, Duke University Medical Center, and Executive Director, CTTI, Duke Translational Medicine Institute; and Kevin Schulman, Professor of Medicine, Duke University Medical Center, and Gregory Mario and Jeremy Mario Professor of Business Administration, Fuqua School of Business (see Appen- dix F for the Discussion Paper “Transforming the Economics of Clinical Trials”); and discussions with the workshop audience. nates today. The adoption of new business models could be facilitated by the engagement of all sectors in the conceptualization of business transformation.2 The uptake of new clinical trial business models could increase return on investment and introduce greater predictability and efficiency as a consistent attribute of the CTE. 2 For example, currently, the CTTI, a collaboration between Duke University and FDA, is undertaking to combine the perspectives of more than 50 stakeholder organizations to develop new approaches and begin to point the way toward a new model for clinical trials.

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47 CREATING A NEW BUSINESS MODEL FOR CLINICAL TRIALS IDENTIFYING OPPORTUNITIES TO IMPROVE REGULATORY FRAMEWORKS FOR CLINICAL TRIALS3 Regulations are sometimes an excuse and sometimes a huge, real issue. —Kevin Schulman, Duke University Medical Center Regulatory Harmonization Paul Eisenberg, Senior Vice President, Global Regulatory Affairs and Safety, Amgen Inc., discussed regulatory challenges from an industry per- spective, focusing on the need for greater regulatory harmonization (see also Chapter 5). According to Eisenberg, FDA’s IND application process in the United States, while not particularly onerous in any single respect, is overall more cumbersome than corresponding European or other for- eign processes. A selection of problematic processes associated with U.S. regulatory frameworks suggested by Eisenberg includes • the use of form 1572 (which other nations actually discourage) for clinical investigators; • thorough and time-consuming FDA review of the formulation and processes that led to the development of the clinical trial materials used in a study under the IND process. By contrast, in Europe, products developed in accordance with Good Manufacturing Prac- tice (GMP) guidelines are deemed safe, and trial practices that meet Good Clinical Practice (GCP) principles are deemed acceptable. In some countries, a clinical trial can begin with a “clinical trial noti- fication,” or a single IRB approval of the trial protocol; • undeveloped regulatory framework for the co-development of devices and drugs under the IND process in the United States. In the past decade, an increasing number of pharmaceutical products in development have come from large molecules that, by nature, are more complex in their delivery mechanisms to patients. Thus, large-molecule products in development might require syringes or other devices to be developed simultaneously so that individuals can benefit from these novel therapeutics; • the evolving and somewhat confusing mechanism for reporting adverse events experienced by clinical trial participants (including immediate reporting of “serious” and unexpected events experi- enced by participants); 3 This section is based on remarks made by Paul Eisenberg, Senior Vice President, Global Regulatory Affairs and Safety, Amgen Inc., and the Discussion Paper “Developing a Clinical Trials Infrastructure” (see Appendix G).

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48 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE • management of privacy protections under the HIPAA privacy reg- ulations; and • frequent, time-consuming inspections conducted by multiple regu- latory authorities at research sites outside the United States. The United States is not always a regulatory minefield. For example, ethical review—the IRB process—actually tends to be more efficient in the United States than in other countries. Nevertheless, as a consequence of existing regulation-related challenges, Eisenberg said, pharmaceutical research and manufacturing firms that would otherwise prefer to conduct clinical trials at U.S. academic health and science centers may find them - selves drawn instead to foreign venues for research. Given the fact that research is conducted in many countries, oppor- tunities for substantial collaboration and regulatory harmonization exist. One is the potential for a standard international nomenclature—to describe drug reactions, for example. Another opportunity that could be explored is the establishment of a worldwide clinical trial database, similar to ClinicalTrials.gov, but with broader participation from around the world. Joint or coordinated inspections for GCP constitute a third potential opportunity for international harmonization. OPPORTUNITIES FOR ALIGNING CULTURAL AND FINANCIAL INCENTIVES IN CLINICAL TRIALS In a panel discussion, the session chair, panel presenters, Discussion Paper co-authors, and audience members reacted to and built upon the ideas contained in the Discussion Paper. Participants included session chair, Arthur Rubenstein, Professor of Medicine, Division of Endocri - nology, Raymond and Ruth Perelman School of Medicine, University of Pennsylvania; Richard Rudick, Professor of Medicine and Hazel Prior Hostetler Chair of Neurology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University; Christopher Beardmore, CEO, Translational Research Management; and Scott Steele, Director of Research Alliances, University of Rochester. This section provides an integrated summary of their remarks and should not be construed as reflecting consensus or endorsement by the workshop participants, the planning committee, the Forum, or the National Academies. The health care system is adopting widespread transformative prac - tices, such as moving toward employment of physicians by large health care delivery systems (as opposed to individual physicians in private practice), use of performance measures in determining reimbursement, distance health monitoring, and other major changes. But, according to several participants, transformation of the CTE and of the health care

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49 CREATING A NEW BUSINESS MODEL FOR CLINICAL TRIALS system are proceeding on different tracks, even within institutions, such as AHSSs. Cultural and Other Barriers Workshop participants mentioned several possible cultural, eco- nomic, and regulatory barriers impeding transformation of the CTE into new business models. It was suggested by one workshop participant that older researchers are often less comfortable with new information technologies than younger researchers, which might hinder their involve- ment in the latest clinical trials. Another barrier is that regulatory and legal concerns make some people fearful of attempting innovations that could create liability problems for their institution. Some workshop par- ticipants noted that the public is not highly informed about science and research, and that there may be a casual attitude that is shared by political leaders and even clinical practitioners. In the current health care system, academic medicine is largely separate from community practice, and community practitioners may not view their job function as involving research. Rudick noted that clinical research and clinical investigators cannot function, let alone thrive, when they operate separately from the health care system. He stressed the need to integrate clinical trials, and more broadly clinical research, into the U.S. health care system in order to realize a truly transformed CTE. It was noted that although the pluralistic U.S. health care system has several advantages over a monolithic system, such as avoiding some wasteful expenditures for large systems before they are piloted on a small scale, the fragmentation makes it difficult to achieve change quickly and universally. Cultural change also could be spurred by new regulatory approaches. For example, it was noted that establishment of an opt-out mechanism, where people are presumed to approve use of their patient records for research purposes unless they specify otherwise, could facili - tate the secondary use of patient data for research purposes and promote the expectation of public participation in research. Reimbursement and Economic Incentives It is of signal importance for third-party payers to cover the costs of participation in clinical trials. Patients in trials can incur costs greater than patients in routine health care. Also, rational budgeting of clinical trials by sponsors is impossible without knowing which expenses are research administrative costs, to be paid by sponsors, and which are routine care costs, which may be required to be paid by insurers or patients. Some states already require payers to cover the routine medical care costs of

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50 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE patient participation in clinical trials. Section 10103(c) of the Patient Pro - tection and Affordable Care Act requires coverage of routine patient care costs associated with clinical trials, with no discrimination against clinical trial participants, by the beginning of 2014. An additional dimension of the reimbursement landscape is the frag - mented nature of the U.S. health care system, including the existence of many payers. This fragmentation makes it difficult both to clarify which payer is responsible for covering the costs of a clinical trial and to have consistent and universal transformation of the business models for clinical trials. However, one participant noted that, because each payer makes its own coverage and payment decisions, an opportunity exists for providers to develop an innovative payment approach through negotiation with an individual payer (akin to a payer-specific demonstration program). Beardmore noted the feeling of some community oncologists that they are marginalized in discussions of cancer care policy and reimbursement reform despite the expectation that they will enthusiastically support and implement the programs and policies being developed (Kolodziej, 2011). He also noted that with respect to reimbursement, many large payers are moving toward value-based insurance design, in which payers link reimbursement levels to evidence on health outcomes to reduce waste (IOM, 2007; Kapowich, 2010). One workshop participant suggested that this move indicates that cultural change about the value of research and evidence could ideally be partnered with a change in payment systems to demand (or “pull,” as opposed to “push”) more knowledge about treatments. In addition to adequate compensation for patients and healthy vol- unteers participating in research, Eisenberg noted that insufficient com- pensation for clinical investigators is a problem that contributes to low levels of participation in and leadership of trials in the United States. Rudick also noted that there currently is no effective financing mechanism in place for clinical investigators in academic medicine, resulting in an unstable and unattractive career path. Informatics EDC, directed by a neutral entity operating via a system of cloud com- puting, can connect individual systems used by health care systems and research organizations. This interoperable approach could obviate the need for one unified data system. Alternatively, a central data repository could be established, with universally retrievable information about the capacity of research sites, the credentials of investigators, protection of human subjects, training, and other topics, thereby eliminating the need for the laborious and wasteful gathering of information to support each new trial.

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51 CREATING A NEW BUSINESS MODEL FOR CLINICAL TRIALS Many informatics products now are legacy-driven. An AHSS that has invested in separate systems for billing and research does not have incentives to replace both systems with a new, integrated product. Dif - ferent academic institutions have their own systems, and little interoper- ability exists. While federal regulators, health care providers, and the IT industry focus primarily on the “meaningful use”4 of EHRs, according to a workshop participant they are not sufficiently investing in connectivity and the use of EHRs in the health care setting for clinical trials. Conse - quently, the records of patients who receive care from different providers, health systems, or academic institutions are all incomplete. It was sug - gested by one workshop participant to start increasing efficiency and interoperability by merging information for compliance systems such as financial disclosure forms. Billing, scheduling, and other processes also could be combined. International Competition Many participants noted that the United States will have to invest more heavily to remain competitive in the field of clinical research and to achieve more effective and value-driven health care. While other countries are increasing their commitment to medical research, in recent decades U.S. health policy concerns have been concentrated on cost containment. Clinical research has not been central to the discussion, even though research could lead to a significant reduction in expenditures for medically unnecessary procedures, which contribute to an estimated $750 billion to $765 billion of excess in annual U.S. health expenditures (IOM, 2010b). Workshop participants expressed differing views about the best way to meet the challenge of globalization in clinical trials. One view was that it may make sense to let other countries undertake industry-driven studies, of the type regulated by FDA, while the United States moves into quality improvement and clinical effectiveness research as an area of growth. A contrasting view was that, to the extent clinical trials are mov - ing offshore due to excessive U.S. research costs, this is a loss to the United States. In this view, research should be conducted in the United States if the results are to be applied to U.S. populations specifically. Another 4 The HITECH Act, part of the American Recovery and Reinvestment Act of 2009, allowed CMS to provide financial incentives to health providers for the adoption and “meaningful use” of certified EHR technology. Meaningful use entails three components: (1) the use of certified EHR technology in a meaningful manner, such as e-prescribing; (2) the use of certified EHR technology for electronic exchange of health information to improve quality of health care; and (3) the use of certified EHR technology to submit clinical quality and other measures. For more information, visit https://www.cms.gov/EHRIncentivePrograms/30_Meaningful_Use. asp (accessed March 28, 2012).

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52 ENVISIONING A TRANSFORMED CLINICAL TRIALS ENTERPRISE type of viewpoint offered at the workshop identified spillover benefits to conducting clinical trials in the United States. Trials are educational opportunities because knowledge of, or participation in, clinical trials facilitates dialogue among clinicians about developing medical evidence for new treatments or comparing products or interventions already in use. Clinical trials are also a source of jobs. And finally, clinical trials can result in improved clinical care for trial participants. Building Consortia to Create Conditions for Change When the U.S. semiconductor industry faced strong pressure from Japanese competition and other forces, a Semiconductor Manufacturing Technology consortium (SEMATECH) was formed to create elements of a single manufacturing infrastructure, supported with the pooling of funds and public–private partnerships. The consortium concept may be appli - cable to the challenges facing the CTE, according to Steele. The creation of consortia could enhance the current clinical trials infrastructure. Already the Biomarkers Consortium, managed by the Foundation for the NIH (FNIH), is developing common adaptive trial designs. The CTSAs and academic medical centers share training programs, improve common understanding about regulatory requirements, improve informatics, develop model clinical trial agreements, and achieve other infrastructure enhancements across the CTSA institutions. The consortia model also could help overcome cultural barriers to CTE transformation, by resolving problems in leadership and governance. For example, Steele suggested that a consortium could be developed to revamp the weighty IRB struc- ture as currently used in clinical research. Interagency coordination also can be improved through coordinating councils with multiagency input.