1. 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.

2. 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.

3. 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

4. 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

5. -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

6. 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.

7. *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.

8. 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

9. 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.