Hillel Bocian, MD/MBA Danny Nguyen, Pharm.D/MBA

Patient-Centered Research Management Group

Background: The Current State of Clinical Trials and Comparative Effectiveness Research Current health systems do not have the capacity or infrastructure to sustainably support clinical trials. Additionally, the number of clinical trial investigators is decreasing, and young physicians are not become clinical investigators at a sufficient rate. The ones that do participate usually do so only once. This owes to misaligned financial incentives, as well as to frustrating barriers in the implementation of clinical research (from IRB approval). A large percentage of clinical trial studies are not completed, often because of an inability to recruit sufficient patients (i.e. 40% of National Cancer Institute trials that reach Phase III fail for this reason). There is low awareness among patients with chronic conditions of the existence of clinical trials. When patients are made aware of clinical trials, their skepticism and lack of understanding of the process disincentivizes their participation (despite the fact that most patients who participate in clinical trials report positive experiences). Furthermore, most community doctors are not aware of ongoing clinical trials, and do not know how to plug their patients into this system. A large impediment to the regular conducting of clinical trials within the healthcare delivery system is the lack of an infrastructure for sequential and simultaneous clinical trials in these hospitals. The current, grant-funded research model has been described as a “cottage industry,” because there is no sustainable, replicable infrastructure for clinical trials (protocol development, recruiting of patients, recruiting of faculty, IRB approval, and so forth). However, with the proper financial incentives and corporate supervision, we submit that this is a fixable problem. Even when studies are adequately powered, poor study design and an inefficient system for disseminating information render the studies useless in terms of effecting change in clinical practice. In other words, systems for translating the research into evidence-based practice are lacking. Industry, government, patients, and physicians are silo’d from each other. As such, there are tremendous inefficiencies in the information infrastructure, in the drug development process, in the refinement of clinical processes, Research-and-development process of pharmaceuticals is not patient-centered. This has led to a number of consequences. It is a wide consensus that investigator-initiated research has failed in regards to generating comparative effectiveness studies. The growth of patient advocacy groups, the institution of PCORI, demand for increased transparency of costs, the impending expansion of insurance coverage and range of plan options, and so forth, all have increased the role of patient decision-making.

Initiatives such as PCORI were largely created because medical research was taking too long to become translated into widespread practice, or studies that had been translated into practice ended up rendering guidelines that were not beneficial to certain sub-groups of patients. This is largely because the studies weren't well-designed, as they did not properly represent the range of comorbidities, ages, or socio-demographic factors.

Clinical trial research does not sufficiently incorporate the diversity of the patient population. Specifically, differences in how patients with dissimilar socioeconomic backgrounds, genetic profiles, environmental influences, co-morbidities, medication lists, and personalities are not well-reflected in clinical trials. Clinical trials fit a specific mold of study: randomized, highly-controlled studies on patients with few or no co-morbidities. This presents several problems. First of all, the efficacy and side effect profile of a drug in one patient will be different from that in another patient for purely pharmacogenetic reasons. For instance, the side effect profiles of Avandia and Vioxx were not well-understood until they were overprescribed for patients. Neither hormone-replacement therapy for women with heart disease and autologous bone marrow transplantation were demonstrated to have clinical utility above less-risky alternatives, and often came at the expense of adverse outcomes and poorly-controlled costs. Second, patients have different priorities and intentions with regards to their medical care. These study design of clinical trials are frequently flawed with respect to comparison groups, the study time frame, patient selection, and selection of surrogate markers/endpoints. In summary, current clinical trials practices are not adequate for determining treatment regimens for complex and diverse patient populations, and are not conduits for the implementation of personalized medicine. Very few phase III trials for chronic conditions include patient-centered outcome measurement. The artificial conditions under which they are conducted do not reflect actual clinical practices. These concerns have spurred innovation of systemic structures that will enable comparative effectiveness research to take place reliably and with meaningful applications.

The era of patient-centered medical care has arrived. Patients must be engaged in the orientation of the research, the research process itself (identification of outcomes and selection of comparators), and how the research findings are used to inform clinical practice. Specifically, they should be involved in framing the research questions, the usability criteria (the thresholds at which research findings will alter clinical decision-making), and in the subsequent changes that are made to clinical practice. Few We argue that comparative effectiveness research is necessary not only for currently-existing drugs and regimens, but also for development of new drugs and regimens. Collaboration of the pharmaceutical industry with the care delivery system will allow for patients and patient advocates to be involved in the decisions of which drugs to build and how they should be targeted towards patient sub-populations.

Patient criteria may involve lifestyle factors that involve their social lives, romantic lives, professional lives, and their overall happiness. Patient prioritization of outcomes (i.e. objective measures vs. lifestyle impacts) will help evaluate the drug from multiple angles. This will benefit both patients and pharmaceutical companies: patients will be able to select drugs based on the benefits important to them, and pharmaceutical companies will still be able to market drugs that were less selective based on, say, biomarkers, but more effective with respect to patient identifiers. Patient-determined risk factors, which may not have occurred to researchers in isolation, may prove to be better proxies of the effectiveness of a medication regimen. For instance, in determining quality-of-life in the context of heart failure, a medication regimen can be determined largely by asking the patient about being out-of-breath after a certain number of blocks (rather than merely examining ejection fraction or BNP levels). Comparative effectiveness research has failed for a number of reasons: misaligned financial incentives, equivocality and ambiguity of study results, and limited clinical utility (from the perspective of both the providers and the patients) FDA restrictions on comparative effectiveness research initiatives by the pharmaceutical companies. Part of what is impairing the dissemination of comparative effectiveness research is that the current way that clinical trials are being performed by the drug companies cannot be taken to constitute “substantial clinical experience,” because a randomized clinical trial (rather than an observational study, for instance) does not truly reflect clinical practice. Manufacturers must tread carefully when speaking about emerging benefits with providers, and the potential legal repercussions (resulting from the FDA’s narrowly-defined language) disincentivize pharmaceutical company initiation of or participation in comparative effectiveness research efforts.

Overall Description of Idea We propose a novel structure called a Patient-Centered Research Management Group (PCRMG). The PCRMG is a hybrid between a healthcare delivery system, a Contract Research Organization (CRO) and a Site Management Organization (SMO) that will specialize in comparative effectiveness research. Key to the design of this special entity will be its emphasis on incorporating patient input and involvement in the study design. The hospital and its providers will act as the “matching system” that links the patients with the researchers (who are, in this case, the pharmaceutical company). Each stakeholder in the structure will provide numerous advantages in the realms of cost control and clinical utility. Most importantly, the structure will provide a streamlined system for conducting studies that are truly representative of clinical practice (rather than being highly selected trials), as these studies would have broad selection criteria from the patient population and would take into account patient preferences The PCRMG adapts the concept presented by Janet Woodcock for a “national clinical research infrastructure,” but enables the structure to conduct comparative effectiveness research with high patient involvement, and to do this via a collaborative initiative with

pharmaceutical companies. Our structure is designed to increase patient involvement in drug development and in treatment protocols, allowing patients to influence drug development, the contexts in which the drug is prescribed, and how the drug is combined with other treatments. The PCRMG would take on some CRO duties, such as clinical trial study design and management. It would also conduct the later “front-end” stages of the clinical trials that are performed by SMO’s (recruiting patients, training investigators, tabulating data, and so forth). Essentially, the pharmaceutical company would be moving downward in the value chain, i.e. vertically-integrating with the care delivery system. In our design a pharmaceutical company will contract with a healthcare system (for instance, an inpatient hospital, or a non-profit outpatient clinic in an HMO) to fund and design comparative effectiveness research trials. Importantly, patient input will be incorporated at all levels of study design. Patients, patient advocates, providers, payers, and the pharmaceutical company will collaborate in roundtable settings, with an external moderator, to develop the following for each study.

We propose that patients would be involved in:

-preliminary stages of drug development

-evaluation of medication regimens -study and expansion of off-label uses -movement towards personalized medicine

Note that this WOULD NOT REPLACE standard clinical trials to test the safety of the medication in animals and in highly-controlled human trials. However, the structure would add value in: 1) phase IV/V (monitoring long-term effects) 2) extending the clinical trial into further phases that test it in specific subpopulations, with other medications, with comorbidities, with different patient preferences and 3) guiding drug development before phase I even takes place. This structure would provide advantages in the following areas:

-Exploration of off-label usage of medications

-Targeting of medicines based on a patient’s unique genomic profile, unique Preferences, patient preferences -Information sharing between healthcare networks via registries. The pharmaceutical company would provide the crucial link for registries, data transmissibility (i.e. standardized data

-defrayed cost of clinical trial implementation => speedier drug development -Increased transparency of drug price-setting, formulary determination, and reimbursements

Care centers will be able to use the collaborative data infrastructure to access data from and collaborate with other care centers. Multi-center data will be aggregated through registries. Academic health centers that participate will benefit from regulatory freedom emerging from a centralized IRB process, allowing for swifter and more cost-effective implementation of translational research. The patient will benefit in several ways: access to novel treatments, highly-personalized treatments, lower out-of-pocket-costs, and an empowered voice in the treatment process. Another unique element would be the funding and financing mechanism of medications in the PCRMG. The assessment of which drugs to place on the formulary, and where on the formulary they should be placed, would be much more closely-correlated to their respective clinical utilities (and the ease with which that clinical utility could be measured) under our system. .

*Coverage with evidence development, and other “conditional covering” mechanisms *Risk-sharing agreements (for example, the pharmaceutical company would give a rebate to the hospital for improved outcomes in patients that are compliant with the drug regimen, or pharmaceutical companies subsidize the treatment of adverse events that their medications were supposed to prevent). Not only do the pharmaceutical companies benefit from risk-sharing, but the patients and physicians benefit too because there are incentives for encouraging patient compliance with medication.

The Case for Pharmaceutical Company Involvement The life sciences industry is considered a “stakeholder” in PCORI. The Pharmaceutical Research and Manufacturers of America (PhRMA) has come out in support of comparative effectiveness research, citing the increased transparency and clinical utility that will result. In fact, pharmaceutical executives have portended that CER will be the differentiating factor between companies that succeed and companies that do not. However, the literature we surveyed, for the most part, does not emphasize the pharmaceutical company as an important stakeholder, and does not venture to describe potential roles that the pharmaceutical companies could have in patient-centered medical care. Mention of pharmaceutical companies is likely to trigger knee-jerk reactions that frame the company as a biased source that does not have the patient’s best interests in mind. They are, as such, excluded de facto from the possibility of

involvement in patient-centered comparative effectiveness research, and seem to be relegated to the role of the entity that manufactures and ships the drugs that will ultimately be evaluated in comparative effectiveness trials. On a broad level, it is almost unconscionable to think that the pharmaceutical company, which makes decisions on what drugs to manufacture, funds and houses research-and-development, determines drug safety, and sets prices would not be included in a patient-centered model. Our model allows the industry to act as both a manufacturer and a service organization. The core competencies of private sector drug and device manufacturers can be harnessed to benefit patients in innovative manners. Among these core competencies is marketing to patients, an ability that will be key to patient recruitment and patient engagement in the planning and design of studies. Development of a comparative effectiveness structure that incorporates the pharmaceutical industry will allow for the development of personalized medicine. For instance, patient input on research will spur drug companies to assess the clinical utility of their medications based on market segment factors: elderly patients may prioritize factors such as mobility, while younger patients may prioritize factors such as sexual functioning and work performance. These efforts will permit superior risk-stratification of patients, with corresponding targeting efforts driven by the pharmaceutical company that allow patients to achieve optimal life-quality and achieve their personal outcome criteria. These efforts will manifest as the pharmaceutical company positioning its products.

The criteria and methodology being developed for comparative effectiveness research should also be used in much earlier stages: i.e. they should not just be to investigate drugs that have already undergone clinical trials, but should also be used prospectively in development of novel treatments or care bundles. If patients are included from the beginning in the study design, the credibility and viability of the results will be even stronger.

Key steps *Targeting underserved populations: In order to optimally represent underserved populations, it would be best to pilot this system in an academic medical setting. First, academic medical settings are most likely to serve patients who have several medical and mental co-morbidities, polypharmacy, low income, and low literacy. Second, academic medical centers are highly likely to be staffed by providers who are aware of the comparative effectiveness research that has been done and that needs to be done.

*Study and trial designs:

-Emphasis on observational studies and prospective trial designs

-Emphasis on personalization of data-seeking and, correspondingly, personalization of treatment regimen

-Naturalistic and pragmatic “simple” trials that can efficiently test out a new treatment in the context of a typical clinical practice

-Adaptive trials (where the variable and control groups, as well as the treatment, can change in the middle of the trial)

-Cumulative Meta-analysis, made possible by registries.

-Standardized research data sets, with subsequent cumulative meta-analyses

*Patient Portal

-Engage patients, through cost incentives, to tabulate their side effects and mark how they feel on a wellness scale on an online database. -Marketing surveys for the purpose of segmenting patients

*Patient registries: -Implement patient-generated data elements => standardize across PCMRG’s.

- use billing codes for bundled payments (CPT, DRG) and RAF score in order to track patients and correlate with co-morbidities and patient-generated data elements.

*Overcoming FDA barriers: Our system would be possible if the manufacturer was willing to take the risk of abiding by the looser Section 114 standard, rather than the more-confining FDA standard of communication. In a more ideal scenario, PCORI would influence the FDA to adjust its language in order to accommodate comparative effectiveness research. There is a crucial asymmetry: payers are allowed to make reimbursement decisions with much looser standards (with respect to the type of research they are relying on) than pharmaceutical companies are allowed to use in their communications with physicians. These payers are not accountable to use “competent and reliable” evidence, as Section 114 states.

PCORI should lobby the FDA to loosen its regulation of how the manufacturer can communicate with the provider. The “competent and reliable” evidence standard should be adopted in favor of the “substantial evidence” standard. Currently, “substantial evidence” is limited to two randomized clinical trials and/or information in FDA-approved labeling. This does not confer sufficient real-world benefits, as these pieces of information do not reflect the “real world.” Congress has attempted to loosen the standard to “competent and reliable” evidence, under Section 114 of the FDA Modernization Act of 1997, in order to broaden the evidence that manufacturers can communicate to providers as including “tests, analysis, research, studies or other evidence based on the expertise of professionals in the relevant area…conducted and evaluated in an objective manner by persons qualified to do so, using procedures generally accepted by others in the profession to yield accurate and reliable results.” *Patient buy-in:

It must be communicated how participation in design of the comparative effectiveness research, as well as actual participation as a subject in the study, will help them and patients like them. This will require the use of expert facilitators

Sources

Berger, Mark L. “Comparative Effectiveness Research: The View from a Pharmaceutical Company.” Global Health Outcomes, 2012.

Monroe, C. Doublas, “Kaiser Permanente’s Evaluation and Management of Biotech Drugs: Assessing, Measuring, and Affecting Use.” Health Affairs, 2006.

Pearson, Steven D. “How Medicare Could use Comparative Effectiveness Research in Deciding on New Coverage and Reimbursement.” Health Affairs, 2010.

Selker, Harry P. “Industry Influence on Comparative-Effectiveness Research Funded Through Health Care Reform.” New England Journal of Medicine, 2009.

Witty, Andrew, “New Strategies For Innovation in Global Health: A Pharmaceutical Industry Perspective.” Health Affairs, 2011.