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5
Evolving Paradigms
Important Points Highlighted by Individual Speakers
· The mobilization of patient communities can spur research and
lead to the creation of new and more effective therapies.
· Increased collaboration both within FDA and between FDA
and other stakeholders has hastened the approval of new drugs
and diagnostics.
· The blending of pre- and postmarket environments could com-
bine considerations of safety and efficacy with considerations
of clinical effectiveness.
The fourth session of the workshop featured case studies of organiza-
tions and initiatives that have furthered genomic-based approaches to drug
discovery and development. A prominent theme of these case studies was
the importance of collaboration in building the relationships necessary for
timely advances. Collaborations can exist both within an organization,
such as within FDA, or among organizations. They also can remain within
a single sector or span sectors. As is discussed further in the next chapter,
collaborative work will be essential to the creation of new paradigms in
drug discovery and development.
37
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38 GENOME-BASED THERAPEUTICS
FOUNDATIONS AND DRUG DEVELOPMENT: AN EXAMPLE
The Multiple Myeloma Research Foundation (MMRF), which was
founded in 1998, is the largest private funder of multiple myeloma research,
raising over $190 million to date. It funds research around the world, builds
community among people affected by multiple myeloma, and partners
with the Multiple Myeloma Research Consortium (MMRC), which sup-
ports research in 16 institutions to determine which drugs can move from
preclinical testing into Phase I and Phase II development and which was
founded in 2004. Walter Capone of the MMRF and the MMRC described
the organizations and the vision behind their approach.
Multiple myeloma is the second most common blood cancer, affecting
64,000 people in the United States and causing more than 10,000 deaths
annually. It occurs largely among older adults, often African American, and
predominantly male. In 1998 the average survival period with the disease
was 3 years and no drugs were in the pipeline. Today, the average survival
period is 7 years, 4 drugs for the disease have been approved, and 9 drugs
are in Phase III trials.
MMRF's success has been based on increasingly complex collabora-
tive models to drive drug development. By developing strategic plans and
building community, MMRC has accelerated trials and built a tissue bank
that includes more than 3,500 samples. Through the Multiple Myeloma
Genomics Initiative, more than 80 of these samples have been sequenced
and are available through an open-access portal, with plans to sequence 250
samples by the end of 2012. More than 1,000 researchers have accessed
the data, and more are expected in the future. Interestingly, while expected
mutations were found through the genomic analysis, 4 percent of patients
also had activating BRAF mutations, compelling the foundation to examine
the use of vemurafenib for treatment of multiple myeloma.
This effort in turn has supported the Multiple Myeloma Personalized
Medicine Initiative, which seeks to more fully characterize the range of
disease subtypes to enable the development of targeted therapies and poten-
tially curative approaches for patients. Spread across 50 centers and includ-
ing industry partners, the project combines a 1,000-patient longitudinal
study with a companion genomics study that will comprehensively assess the
molecular profiles of patient's tumors throughout disease progression and be
correlated to clinical interventions, including treatment regimens. The study
design allows 3 years for enrollment and includes 5 years of follow-up, and
data will be open access with no intellectual property restrictions.
The MMRF is continuing to expand its programs as the network
of stakeholders in the field grows more complex. Today, not just aca-
demia, industry, and patients are involved but also regulators, physicians,
payers, and diagnostic and platform companies. By working with clinicians,
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EVOLVING PARADIGMS 39
researchers, and a dedicated validation and basic science team, MMRC
has increased the success rate of new drugs in Phase I to between 35 and
40 percent, well above the 10 percent success rate in the pharmaceutical
industry as a whole. It has partnered with industry to open 37 trials with
20 novel agents, has sped the time to the opening of trials by 60 percent,
has reduced the time between Phase I and Phase II trial development and
completion by a third through common agreements and dispensing with
contracting, and has increased enrollment by 14 percent. MMRC also has
expanded its clinical reach well beyond its 16 sites and it has launched an
early-access program for the drugs that have gone into the last stages of
regulatory review.
The Multiple Myeloma Personalized Medicine Initiative also has taken
a collaborative approach. Linking research, clinical, and community activi-
ties, it is a multi-year observational study with tissue banking and matching
as well as in-depth sequencing work. Information generated by the study
is openly available for researchers to identify new targets and biomarkers
and to connect researchers with the patient community. The study is putting
information in clinicians' and patients' hands, Capone said. "Combining
clinical and genomic data in a single platform [will] compel and initiate
scientific discoveries that are not possible today."
In the same manner, by mobilizing the multiple myeloma community
through a dedicated online portal, the MMRF aims to accelerate and
enable personalized therapies. Key features of the online community include
groups based on common molecular profiles, the ability to connect with
similar patients, a health metrics tracker, tools to help manage the disease,
access to educational materials and data, live Web discussions, and clinical
trial recruitment tools.
Finally, this approach does not apply just to myeloma, Capone said.
It offers a way of bringing information together worldwide from multiple
organizations into a common platform that can drive progress for many
different diseases. The foremost challenge, Capone said, is collecting and
tracking large numbers of patients who have a particular disease or prob-
lem. Even in the case of multiple myeloma, only a few thousand patients
are being followed. "What if all the patients who were afflicted with a
disease were able to become part of and contribute to the community that's
going to drive toward a cure ultimately, and in the process be fully engaged
in advocating for their own care by having and understanding the latest
advances in the field?"
GENOMICS AND REGULATORY SCIENCE
The mandate of FDA is to protect and promote public health, noted
Michael Pacanowski of the FDA's Center for Drug Evaluation and Research
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40 GENOME-BASED THERAPEUTICS
(CDER). However, a tension often exists between protection and promo-
tion, between risk aversion and innovation, and between regulation and
flexibility while still ensuring that safe and effective drugs are brought to
market. However, personalized medicine is changing old ways of thinking
about these issues and FDA has been on the leading edge of these changes,
Pacanowski said.
Genomic-based drug development creates both promise and challenges.
Of the approximately 30 drug approvals in 2011, Pacanowski said, at least
a dozen had some type of genomic information included in their clinical
development, ranging from dosing based on drug metabolism to explor-
atory analyses for known biomarkers to co-developed drugs. He noted
that several recent drug approvals exhibited features that are likely to
become increasingly prominent in the future. For example, the a pprovals
of ivacaftor and crizotinib were very fast, taking just 3 months rather than
the more common 6 to 10 months. The approval of ivacaftor also took
advantage of partnerships with the Cystic Fibrosis Foundation, which
greatly helped in bringing the drug to market quickly.
Drug regulation has been described as the progressive reduction of
uncertainty, Pacanowski observed. While genomics may alter the current
paradigm, it will not change the need to satisfy the same evidentiary stan-
dards that currently exist. In that respect, the advantage of genomic-based
drug development is not that it requires fewer data, but that it often has the
potential for a higher probability of success. Drug development will shift
toward a "quick win, fast fail" model, Pacanowski predicted.
One early way in which CDER has stimulated innovation in the
genomic sciences is through the Voluntary Exploratory Data Submission
program. This program allowed companies to share data informally with-
out regulatory consequences; to obtain feedback on trial designs, method-
ologies, and data interpretation; to gain insights into evolving regulatory
practices; to provide experience to facilitate policy development; to discuss
data elements used to streamline new drug applications; to educate FDA
scientists on emerging data and innovative approaches; and to forge part-
nerships among scientists from different sectors. The agency also prepared
guidance on genomic data submissions, which helped companies navigate
the drug application process, and established a Biomarker Qualification
Program, which promoted the development of biomarkers that are broadly
applicable to multiple drug developers. Furthermore, recent negotiations
over the Prescription Drug User Fee Act have created the potential for fund-
ing to enhance the agency's biomarker and genomic teams.
Internal changes at FDA have spurred these advances. Since 2008,
CDER and the Center for Devices and Radiological Health (CDRH) have
greatly increased their communication and have harmonized their pro-
cedures. In addition, new guidances have been issued on such topics as
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EVOLVING PARADIGMS 41
developing companion diagnostics and early-stage and clinical pharmaco
genomic studies. Currently under development is guidance on enrichment
strategies when using selected populations.
Partnerships have been and will continue to be critical at FDA, as
emphasized in its most recent strategic plan, Pacanowski said (FDA, 2011).
Areas where this is particularly true include the effective development of
qualified tools and surrogate biomarkers, creating a drug safety research
infrastructure, and carrying out comparative effectiveness research. Such
partnerships can take many forms, including industrial consortia, aca-
demic collaborations, government-catalyzed partnerships, or contracts with
payers to do postmarketing research. Pacanowski noted that developing
partnerships with clinical practice societies will be of importance to the
agency because these groups will play a large role in determining what is
considered standard of care for personalized medicine.
In the past, precompetitive collaborations have been an elusive goal,
but barriers are being overcome to establish such partnerships. Successful
examples include the international Serious Adverse Event Consortium and
the Predictive Safety Testing Consortium from C-Path. "It is possible to put
together these partnerships and have effective outputs," Pacanowski said.
FDA has been and will continue to be committed to personalized
medicine and individualized therapeutics, Pacanowski concluded. "It is part
and parcel to rational and sound drug development and will probably be
applied in almost every scenario in the coming decades."
PHARMACY BENEFIT MANAGEMENT
AND PHARMACOGENOMICS
In the current paradigm of drug discovery and development, the pre-
market environment and the postmarket environment are separate and
distinct (Figure 5-1). Companies try to get regulatory approval for a drug
and then hope that patients and providers will use it and that payers will
pay for it. Increasingly, there are examples in which there is regulatory
success but commercial failure, said Felix Frueh of the Medco Research
Institute.
This paradigm will change, Frueh predicted. In the future, the pre market
environment and postmarket environment will be blended (Figure 5-2).
Companies will receive information from payers early in the drug devel-
opment process. Considerations of efficacy and safety will interact with
considerations of not just clinical utility but clinical effectiveness. The logis-
tics of deploying a new therapy will be a factor--including, for example,
off-label uses. The stakeholders in the drug development process will be
confronted with a new set of questions, Frueh said, and it will be necessary
to assess how this new paradigm will influence drug development.
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42 GENOME-BASED THERAPEUTICS
Approval
Assessor Regulators Payers
body
Evidence · Quality, safety, · Relative efficacy/
focus efficacy effectiveness
· Benefit-risk profile · Cost vs. health benefit
· Budget impact
Studies/ · Emphasis on RCT, · Active-controlled RCT
Data most often · Observational studies
placebo-controlled · Cost-effectiveness/utility
analyses
· Budget impact analyses
FIGURE 5-1In the current paradigm of drug discovery and development, the
Figure
approval of a drug rigidly separates 5-1.eps
the domains of regulators and payers.
NOTE: RCT, randomized control trial.
SOURCE: Adapted from Eichler et al., 2010.
These changes will affect regulators and payers as much as they will
industry and government, Frueh said. Today, regulators are increasingly
interested in comparative data and outcomes research. The demand for
more safety data cannot be met entirely by randomized controlled trials, so
regulators in the United States and Europe have set up sentinel networks to
assess postmarket data. Reimbursement bodies are calling for value-based
pricing that is tied to the demonstration of comparative effectiveness in the
real world. In Germany, for example, the Federal Joint Committee requires
drug makers to demonstrate greater efficacy for a new compound before
they can charge more.
Strategic partnerships are also emerging to generate and access post-
market data. Pfizer, for example, has teamed with Medco to use large
patient databases to perform both retrospective and prospective research on
personalized therapies. In this way clinical trials can be designed to answer
not only regulatory questions but questions that are relevant for the payer,
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EVOLVING PARADIGMS 43
Approval
Assessor Regulators
body
Payers
Dedicated relative efficacy/
effectiveness assessment?
Evidence · Quality, safety, · Cost vs. health benefit
focus efficacy · Budget impact
· Benefit-risk profile
· Relative efficacy/effectiveness
· Emphasis on RCT, · Cost-effectiveness/utility
Studies/
most often analyses
Data
placebo-controlled · Budget impact analysis
· Active-controlled RCT
· Adaptive Phase III-IV trials
· Observational studies
· Meta-analysis
FIGURE 5-2In the future, the responsibilities of regulators and payers could
overlap, resulting in a dynamicFigure
interplay between evidence generation and drug
5-2.eps
approval.
NOTE: RCT, randomized control trial.
SOURCE: Adapted from Eichler et al., 2010.
such as whether the right clinical endpoint has been selected. Similarly,
questions of comparative effectiveness can be addressed, such as whether
an older drug (for example, clopidogrel) that is about to go off patent is
safer and more effective than a new and more expensive drug (for example,
prasugrel) for people with particular genetic backgrounds. While not the
primary concern of payers, economic questions also take on significance in
these analyses, Frueh said. All of this information can also be important
for drug developers who need to make decisions about whether and how
to proceed with the development of a particular compound. Companies
could utilize a personalized medicine methodology to identify an unmet
medical need, for example. Developers could approach payers early about
creating programs to identify patients who are unlikely to benefit from a
drug already on the market but could benefit from a newly developed drug.
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44 GENOME-BASED THERAPEUTICS
Frueh concluded with several provocative thoughts emphasizing the
role of payers:
· Comparative-effectiveness evaluations will become increasingly
required by payers because of the need to demonstrate that a new
treatment is better than the standard of care.
· What if payers were to cover a drug only if it actually works?
· Payers will progressively move toward employing coverage with
evidence development.
· Can payers act to encourage patients to participate in clinical trials
or even help in recruitment?
· What if payers were to co-sponsor clinical trials or provide phar-
macy, lab, and outcome data for research?
· Could payers partner with industry to develop more personalized
medicines faster?
Over the next 5 years, Frueh said, the answers to these questions could
reshape relationships in the drug discovery and development system. For
example, if payers across the board were to embrace the coverage-with-
evidence-development paradigm, "that would really change the way that
we'd be looking at drugs and diagnostics."
REPURPOSING OF DRUGS
The NCATS Pharmaceutical Collection (NPC) is a comprehensive
resource of 3,800 approved and investigational medicines that was designed
to facilitate the repurposing of medicines by the scientific community.1
As a recent paper states, the NPC is "a definitive, complete, and non
redundant list of all approved molecular entities as a freely available elec-
tronic resource and a physical collection of small molecules amenable to
high-throughput screening" (Huang et al., 2011).
Christopher Austin of NCATS at NIH demonstrated how the NPC can
be used. Drugs approved in different jurisdictions throughout the world
can be accessed. Searches can look for indication, target, drug name, and
so on. A search on "migraine," for example, returned 14 drugs that are
approved worldwide. Clicking on a particular drug gives the mechanism
of action, known targets, the regulatory status in different countries, and
other information.
To demonstrate the utility of the collection for drug repurposement,
Austin cited a recent example of successfully identifying a drug that could
potentially be used for the treatment of chronic lymphocytic l
eukemia (CLL),
1 The NPC can be accessed at http://tripod.nih.gov/npc.
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EVOLVING PARADIGMS 45
which accounts for about 15,000 new diagnoses per year in the United
States. In partnership with the University of Kansas and the L eukemia &
Lymphoma Society, NCATS screened the NPC collection for effects against
CLL patient cells as well as against cells from normal donors. Some drugs
killed the CLL cells from all patients, while some killed the cells from only
some of the patients. Subsets of these drugs were less effective or ineffec-
tive in killing normal donor cells. One particular drug called Auranofin
was originally approved for the treatment of rheumatoid arthritis in 1984.
Reverse pharmacology revealed the mechanism of action of the drug, and
three clinical trial sites are now active.
The principal lesson Austin drew from this experience is that effec-
tive translation requires collaboration. The partnership benefited by the
marriage of funding sources, expertise, project management, and the early
incorporation of technology transfer agreements which allowed for rapid
movement in establishing the trials. In fact, less than a year passed between
signing the partnership agreement and the dosing of the first patients. "This
is a great example of how, [through] a team effort, we were able to move
forward."
One complication in the repurposing of drugs is that about 90 percent
of the drugs in the pharmaceutical collection are generic. For these drugs,
paying for a registration trial to expand the indication can be a barrier.
In addition, regulatory issues can impede the repurposing of on-patent or
abandoned drugs. For example, one might wish to know if the new indica-
tion is related to the original mechanism of action or if it is related to an
unexpected or unrelated mechanism. Or if the mode of delivery is the same.
To answer such questions, it is typically the case that data are needed from
the firm that originally created the drug.
Public policy changes may be necessary to encourage drug repurpos-
ing. For example, establishing exclusivity could allow the licensing of a
discovery to a for-profit organization to take a drug through registration.
Also, it is never too early to start thinking about reimbursement strategies,
Austin said, because the goal is to get the drug to patients.
A Value Maximization Path, or ValueMaP, is under development
to provide guidance in pursing drug repurposing. This guidance draws
on examples of what has worked in previous projects, such as rational
repurpos ing based on knowledge of disease pathogenesis and drug phar-
macology. In addition, in selected cases computational approaches have
been able to identify promising pathways or patterns (Sirota et al., 2011).
Partnerships need comprehensive and complementary expertise at every
step of the process, Austin said. When the process breaks down, it often
does so in the experimental medicine space, such as in the early clinical
trials. Other problems have arisen when repurposing is based solely on
animal models, when computational approaches are used without experi-
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46 GENOME-BASED THERAPEUTICS
mental testing, and when phenotypic screens are done without a prospective
plan for translating the results to humans.
Repurposing generic drugs provides a tremendous opportunity to
improve human health without great additional costs, Austin concluded.
But new funding paradigms may be necessary to make such drugs available
to patients.
