Hillel Bocian, MD/MBA Danny Nguyen, Pharm.D/MBA Patient-Centered Research Management GroupBackground: The Current State of Clinical Trials and Comparative EffectivenessResearchCurrent health systems do not have the capacity or infrastructure to sustainably supportclinical trials. Additionally, the number of clinical trial investigators is decreasing, andyoung physicians are not become clinical investigators at a sufficient rate. The onesthat do participate usually do so only once. This owes to misaligned financialincentives, 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, oftenbecause of an inability to recruit sufficient patients (i.e. 40% of National Cancer Institutetrials that reach Phase III fail for this reason). There is low awareness among patientswith chronic conditions of the existence of clinical trials. When patients are made awareof clinical trials, their skepticism and lack of understanding of the process disincentivizestheir participation (despite the fact that most patients who participate in clinical trialsreport positive experiences). Furthermore, most community doctors are not aware ofongoing 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 healthcaredelivery system is the lack of an infrastructure for sequential and simultaneous clinicaltrials in these hospitals. The current, grant-funded research model has been describedas a “cottage industry,” because there is no sustainable, replicable infrastructure forclinical trials (protocol development, recruiting of patients, recruiting of faculty, IRBapproval, and so forth). However, with the proper financial incentives and corporatesupervision, we submit that this is a fixable problem.Even when studies are adequately powered, poor study design and an inefficientsystem for disseminating information render the studies useless in terms of effectingchange in clinical practice. In other words, systems for translating the research intoevidence-based practice are lacking. Industry, government, patients, and physiciansare silo’d from each other. As such, there are tremendous inefficiencies in theinformation infrastructure, in the drug development process, in the refinement of clinicalprocesses, Research-and-development process of pharmaceuticals is not patient-centered. Thishas led to a number of consequences. It is a wide consensus that investigator-initiatedresearch has failed in regards to generating comparative effectiveness studies. Thegrowth of patient advocacy groups, the institution of PCORI, demand for increasedtransparency of costs, the impending expansion of insurance coverage and range ofplan options, and so forth, all have increased the role of patient decision-making.
Initiatives such as PCORI were largely created because medical research was takingtoo long to become translated into widespread practice, or studies that had beentranslated into practice ended up rendering guidelines that were not beneficial to certainsub-groups of patients. This is largely because the studies werent well-designed, asthey did not properly represent the range of comorbidities, ages, or socio-demographicfactors.Clinical trial research does not sufficiently incorporate the diversity of the patientpopulation. Specifically, differences in how patients with dissimilar socioeconomicbackgrounds, genetic profiles, environmental influences, co-morbidities, medicationlists, and personalities are not well-reflected in clinical trials. Clinical trials fit a specificmold 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 effectprofile of a drug in one patient will be different from that in another patient for purelypharmacogenetic reasons. For instance, the side effect profiles of Avandia and Vioxxwere not well-understood until they were overprescribed for patients. Neither hormone-replacement therapy for women with heart disease and autologous bone marrowtransplantation 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 medicalcare. These study design of clinical trials are frequently flawed with respect tocomparison groups, the study time frame, patient selection, and selection of surrogatemarkers/endpoints. In summary, current clinical trials practices are not adequate fordetermining treatment regimens for complex and diverse patient populations, and arenot conduits for the implementation of personalized medicine. Very few phase III trialsfor chronic conditions include patient-centered outcome measurement. The artificialconditions under which they are conducted do not reflect actual clinical practices.These concerns have spurred innovation of systemic structures that will enablecomparative effectiveness research to take place reliably and with meaningfulapplications.The era of patient-centered medical care has arrived. Patients must be engaged in theorientation of the research, the research process itself (identification of outcomes andselection of comparators), and how the research findings are used to inform clinicalpractice. Specifically, they should be involved in framing the research questions, theusability criteria (the thresholds at which research findings will alter clinical decision-making), and in the subsequent changes that are made to clinical practice. FewWe 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 forpatients and patient advocates to be involved in the decisions of which drugs to buildand 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 multipleangles. This will benefit both patients and pharmaceutical companies: patients will beable to select drugs based on the benefits important to them, and pharmaceuticalcompanies 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 riskfactors, which may not have occurred to researchers in isolation, may prove to be betterproxies of the effectiveness of a medication regimen. For instance, in determiningquality-of-life in the context of heart failure, a medication regimen can be determinedlargely 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: misalignedfinancial 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 pharmaceuticalcompanies. Part of what is impairing the dissemination of comparative effectivenessresearch is that the current way that clinical trials are being performed by the drugcompanies cannot be taken to constitute “substantial clinical experience,” because arandomized clinical trial (rather than an observational study, for instance) does not trulyreflect clinical practice. Manufacturers must tread carefully when speaking aboutemerging benefits with providers, and the potential legal repercussions (resulting fromthe FDA’s narrowly-defined language) disincentivize pharmaceutical company initiationof or participation in comparative effectiveness research efforts.Overall Description of IdeaWe propose a novel structure called a Patient-Centered Research Management Group(PCRMG). The PCRMG is a hybrid between a healthcare delivery system, a ContractResearch Organization (CRO) and a Site Management Organization (SMO) that willspecialize in comparative effectiveness research. Key to the design of this specialentity will be its emphasis on incorporating patient input and involvement in the studydesign. The hospital and its providers will act as the “matching system” that links thepatients with the researchers (who are, in this case, the pharmaceutical company).Each stakeholder in the structure will provide numerous advantages in the realms ofcost control and clinical utility. Most importantly, the structure will provide a streamlinedsystem for conducting studies that are truly representative of clinical practice (ratherthan being highly selected trials), as these studies would have broad selection criteriafrom the patient population and would take into account patient preferencesThe PCRMG adapts the concept presented by Janet Woodcock for a “national clinicalresearch infrastructure,” but enables the structure to conduct comparative effectivenessresearch with high patient involvement, and to do this via a collaborative initiative with
pharmaceutical companies. Our structure is designed to increase patient involvementin drug development and in treatment protocols, allowing patients to influence drugdevelopment, the contexts in which the drug is prescribed, and how the drug iscombined with other treatments. The PCRMG would take on some CRO duties, such asclinical 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, traininginvestigators, tabulating data, and so forth). Essentially, the pharmaceutical companywould be moving downward in the value chain, i.e. vertically-integrating with the caredelivery system.In our design a pharmaceutical company will contract with a healthcare system (forinstance, an inpatient hospital, or a non-profit outpatient clinic in an HMO) to fund anddesign comparative effectiveness research trials. Importantly, patient input will beincorporated at all levels of study design. Patients, patient advocates, providers,payers, and the pharmaceutical company will collaborate in roundtable settings, with anexternal 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 medicineNote that this WOULD NOT REPLACE standard clinical trials to test the safety of themedication in animals and in highly-controlled human trials. However, the structurewould add value in: 1) phase IV/V (monitoring long-term effects) 2) extending the clinicaltrial into further phases that test it in specific subpopulations, with other medications,with comorbidities, with different patient preferences and 3) guiding drug developmentbefore 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 reimbursementsCare centers will be able to use the collaborative data infrastructure to access data fromand collaborate with other care centers. Multi-center data will be aggregated throughregistries. Academic health centers that participate will benefit from regulatory freedomemerging from a centralized IRB process, allowing for swifter and more cost-effectiveimplementation 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 ofmedications 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 utilitycould 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 CompanyInvolvementThe life sciences industry is considered a “stakeholder” in PCORI. The PharmaceuticalResearch and Manufacturers of America (PhRMA) has come out in support ofcomparative effectiveness research, citing the increased transparency and clinical utilitythat will result. In fact, pharmaceutical executives have portended that CER will be thedifferentiating factor between companies that succeed and companies that do not.However, the literature we surveyed, for the most part, does not emphasize thepharmaceutical company as an important stakeholder, and does not venture to describepotential roles that the pharmaceutical companies could have in patient-centeredmedical care. Mention of pharmaceutical companies is likely to trigger knee-jerkreactions that frame the company as a biased source that does not have the patient’sbest interests in mind. They are, as such, excluded de facto from the possibility of
involvement in patient-centered comparative effectiveness research, and seem to berelegated to the role of the entity that manufactures and ships the drugs that willultimately be evaluated in comparative effectiveness trials. On a broad level, it is almostunconscionable to think that the pharmaceutical company, which makes decisions onwhat drugs to manufacture, funds and houses research-and-development, determinesdrug 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 beharnessed to benefit patients in innovative manners. Among these core competenciesis marketing to patients, an ability that will be key to patient recruitment and patientengagement in the planning and design of studies.Development of a comparative effectiveness structure that incorporates thepharmaceutical industry will allow for the development of personalized medicine. Forinstance, patient input on research will spur drug companies to assess the clinical utilityof their medications based on market segment factors: elderly patients may prioritizefactors such as mobility, while younger patients may prioritize factors such as sexualfunctioning and work performance. These efforts will permit superior risk-stratification ofpatients, with corresponding targeting efforts driven by the pharmaceutical companythat allow patients to achieve optimal life-quality and achieve their personal outcomecriteria. These efforts will manifest as the pharmaceutical company positioning itsproducts.The criteria and methodology being developed for comparative effectiveness researchshould also be used in much earlier stages: i.e. they should not just be to investigatedrugs that have already undergone clinical trials, but should also be used prospectivelyin development of novel treatments or care bundles. If patients are included from thebeginning in the study design, the credibility and viability of the results will be evenstronger.Key steps*Targeting underserved populations:In order to optimally represent underserved populations, it would be best to pilot thissystem in an academic medical setting. First, academic medical settings are most likelyto serve patients who have several medical and mental co-morbidities, polypharmacy,low income, and low literacy. Second, academic medical centers are highly likely to bestaffed by providers who are aware of the comparative effectiveness research that hasbeen 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 abidingby the looser Section 114 standard, rather than the more-confining FDA standard ofcommunication. In a more ideal scenario, PCORI would influence the FDA to adjust itslanguage in order to accommodate comparative effectiveness research. There is acrucial asymmetry: payers are allowed to make reimbursement decisions with muchlooser standards (with respect to the type of research they are relying on) thanpharmaceutical companies are allowed to use in their communications with physicians.These payers are not accountable to use “competent and reliable” evidence, as Section114 states.
PCORI should lobby the FDA to loosen its regulation of how the manufacturer cancommunicate with the provider. The “competent and reliable” evidence standard shouldbe adopted in favor of the “substantial evidence” standard. Currently, “substantialevidence” is limited to two randomized clinical trials and/or information in FDA-approvedlabeling. This does not confer sufficient real-world benefits, as these pieces ofinformation do not reflect the “real world.” Congress has attempted to loosen thestandard to “competent and reliable” evidence, under Section 114 of the FDAModernization Act of 1997, in order to broaden the evidence that manufacturers cancommunicate to providers as including “tests, analysis, research, studies or otherevidence based on the expertise of professionals in the relevant area…conducted andevaluated in an objective manner by persons qualified to do so, using proceduresgenerally 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
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