Download STRENGTHEN YOUR PRODUCT VALUE STORY ONE PHASE AT

STRENGTHEN YOUR PRODUCT VALUE
STORY ONE PHASE AT A TIME:
A roadmap for gathering the evidence that regulators and payers want
BY MANU SEHGAL, VICE PRESIDENT PAREXEL® INTERNATIONAL
One in ten new drug applications (NDAs) submitted
to the FDA fail to gain approval, according to the Tufts
Center for the Study of Drug Development (TCSDD).
While that may not seem high, these failures occur at
the end of a process that TCSDD estimates takes more
than a decade and costs up to $2.5 billion.
Clearly, regulatory risk is not always eliminated as
products advance. Of course, neither is commercial
risk. Many drugs approved by regulators fail to win
reimbursement from payers. According to the UK’s
National Institute of Health and Care Excellence (NICE)
website, of 382 appraisals conducted by NICE between
2000 and 2016, only 61 percent were recommended
for reimbursement. The top reasons (in descending
order) NICE gave were: non-robust economics;
uncertain clinical benefits; inappropriate trial design,
comparators, or patient populations; price, and safety
concerns.
How can a product license application land on the desk
of FDA reviewers after years of development only to
be rejected for insufficient safety, efficacy or quality
(i.e. CMC data)? Why, after all the sponsors work, does
NICE deem almost two-fifths of products economically
unconvincing, clinically questionable, or questionably
tested?
One problem is that the traditional approach to building
an evidence platform is fractured and sequential:
regulatory teams seek to meet regulatory goals in
each phase; commercial teams work on access
considerations, usually waiting until a product is near
launch before they begin their work in earnest. The endgame scramble that results when these two trajectories
meet at the end of a lengthy development process
impairs the product value story.
Rarely is there a plan to integrate clinical and
commercial perspectives at the various stages of a
product’s journey, so that regulators and payers alike
can find the value evidence they seek.
Your phase-dependent evidence plan
The solution is to staple clinical development and
evidence generation together at the wrist. Developers
should generate data to support the value story at each
stage, from Phase I through post-authorization.
Integrating all forms of value-generation activities
at all phases of development requires detailed
planning (Figure 1). A sound plan combines regulatory
and reimbursement objectives, and pairs primary
research, such as randomized clinical trials (RCTs),
with secondary healthcare data assets (HDAs) such as
patient registries, health insurance claims data, and
medical literature reviews.
PHASE I: SAFETY AND SURVEYING THE
LANDSCAPE
Although the primary goal of first-in-human trials is
safety, companies should begin to leverage other types
of data at this early stage. In the event a compound does
not advance past Phase I, landscape assessment data
about a therapeutic area or pharmaceutical class can
be re-purposed for other assets in the portfolio, saving
time and money.
Evidence planning for every asset should include phasedependent primary and secondary research protocols to
ensure optimal utilization of the two approaches while
saving costs.
In Phase I, the primary goals of clinical trials include:
•E
stablishing safety in humans (often healthy
volunteers)
• Determining dose escalation and tolerability
• Determining treatment duration
• Selecting outcomes/endpoints for subsequent testing.
FIGURE 1. ALIGNING REGULATORY AND REIMBURSEMENT OBJECTIVES IN A SINGLE
EVIDENCE PLAN: PHASE BY PHASE
REGULATORY OBJECTIVES
Disease epidemiology,
treatment paradigm,
and defining standard
of care
Phase II
Phase I
Value proposition
development
encompassing disease
area and treatment
landscape assessment
including disease
epidemiology,
treatment paradigm,
unmet need, defining
standard of care
Broader landscape
Assessment for
selection of
appropriate patient
reported outcomes in
clinical trials
Optimization of clinical
trial endpoints,
benchmarking efficacy
and safety, and other
trial design
parameters
Phase III
Comparative
effectiveness
research for clinical
efficacy and
safety of the molecule
and comparators
Quantification of
comparative
effectiveness for
value story
demonstration per
HTA requirements
Cost-benefit value
story development
based on the
economic evidence
to form part of
cost-effectiveness
assessment
Phase IV
Focused positioning
of the product
addressing safety
regulations and
informing benefit/risk
evaluations
Value maintenance
Adherence rates
Therapy line expansion
PLAN
Preclinical
Outcome selection,
dose selection,
Duration of follow-up
Supporting PASS
design,
supporting Medical
information needs,
Risk management
planning
EVIDENCE
Toxicology profile
Pharmacological
class assessment
Pharmacokinetic
evidence
Trial design
Sample size
Justify comparators
Duration of follow-up
Adverse events
Withdrawal rate
Specific sub-groups
Trial design
Sample size
Justify comparators
Duration of follow-up
Adverse events
Withdrawal rate
MULTI-ASSEST
EVIDENCE PLANNING
Specific sub-group based
on histology type
Specific sub-group based
on mutation status
LEADS TO
Specific sub-group based
on receptor status
Customization of
comparator list
Customization of other
products in same
treatment class
REIMBURSEMENT OBJECTIVES
At the same time, secondary research should help to
develop the value proposition and guide the overall
evidence generation plan. A landscape assessment of
the target disease area and treatment paradigm should
cover:
•D
isease epidemiology (establishing incidence/
prevalence rates by geography)
• Disease burden, especially unmet needs
• Current standard of care (SOC), benchmark safety
• Pharmacological class
Secondary research, if used effectively and validated,
can offer high-quality intelligence about market needs
and a product’s potential early in the development
journey.
For example, recently a PAREXEL client with a
rheumatoid arthritis (RA) biologic drug candidate
wanted to understand the current key efficacy
parameters for the disease, as well as the association
between cognitive impairment (CI) and RA, to choose
the best scoring instrument for measuring cognitive
outcomes in Phase II and III clinical trials.
We conducted a literature review of published RCTs,
single arm studies and evidence published from
registeries to summarize: 1) the effectiveness of current
biologics in treating RA; 2) the association between
CI and RA; and 3) the scientific validity and clinical
relevance of various instruments, such as the MiniMental State Exam (MMSE) score and other cognitive
battery scores, that could be used to assess cognition in
an RA trial. Using that information, our client selected
the most suitable instrument for future studies.
In Phase I, secondary research can inform the design
of prospective studies and help companies estimate
the probability of success for a given molecule, leading
to more informed go/no go decisions and pipeline
prioritization.
PHASE II: SHOULD THIS MOLECULE
ADVANCE TO PHASE III?
A primary goal of Phase II evidence collection is to
ensure that investment in a given molecule is warranted
before advancing to Phase III. Will the molecule address
the needs of regulators, payers, and patients? For drugs
that do, the sponsors’s central challenge is to learn
enough to design and conduct the best possible trials
for regulatory approval and beyond (i.e. reimbursement).
In the “learning-confirming” continuum of drug
development, Phase II trials are designed to:
• Establish safety in the target patient population
• Provide proof of concept for a drug’s mechanism of
action
• Select and justify sample sizes, and identify
comparators, determine duration of follow-up,
study adverse events and withdrawal rates, etc., for
confirmatory trials
• Capture preliminary efficacy signals that can inform
go/no go decisions
In Phase II, evidence plans must include secondary
research to broaden and deepen the landscape
assessment. For example, data from national patient
registries can break out regional, national, and local
disparities in disease incidence and prevalence, while
country- and/or region-specific claims data can reveal
differences in the current SOC for a given condition.
Interviewing local affiliates can also be a rich source of
data on geographic variation in healthcare delivery.
Phase II is also when developers select appropriate
patient-reported outcomes (PROs) for clinical trials.
PROs are self-reported, and are often measured by
responses to a questionnaire; they are increasingly
used to provide evidence of value, especially for
oncology drugs.
For example, in 2013, the lung cancer drug, Xalkori
(crizotinib), won the second highest benefit rating
possible from IQWiG (the German agency responsible
for assessing the quality and efficiency of medical
treatments) even though it showed no advantage in
overall survivial (OS, the regulatory/RCT gold standard
of efficacy). The PRO measures used convinced German
evaluators that the drug’s impact on morbidities in the
target patient group was “considerable.” Quality of life
(QoL) metrics showed significant improvements not only
in patient well-being, but also in symptoms such as
coughing and pain, illustrating that a disease-specific
and standardized QoL instrument tracking common
symptoms could be used as a powerful secondary
endpoint.
Other ways secondary research can contribute in
Phase II include optimizing Phase III trial endpoints
based on efficacy and safety benchmarks found
in literature reviews, evaluating which trial design
parameters may provide cost effectiveness data based
on a review of previous submissions (both successful
and unsuccessful), and defining the exact threshold
for clinical differentiation versus Phase III comparator
drugs.
PHASE III: CONFIRMING THE VALUE
PROPOSITION
If Phase II trials have been conducted properly, Phase
III trials should have a high probability of success.
They should be designed to produce data that clear
regulatory and reimbursement evidence thresholds for
safety, clinical benefits, and medical value. Phase III
(aka pivotal) trials:
• Confirm efficacy of the molecule in the target
population (including sub-groups)
• Confirm appropriateness/performance of chosen
comparators
• Characterize safety profile: adverse events,
withdrawal rates (including sub-groups)
• Confirm duration of follow-up (clinical relevance, etc.)
• Have large enough sample sizes to produce
statistically valid data
In Phase III, secondary research can strengthen the
value proposition by filling in the cost-benefit ratio of a
product based on economic evidence (such as health
care utilization statistics) and quantifying product
value and cost effectiveness for Health Technology
Assessment (HTA) agencies. HDAs can often fill
evidence gaps, as well.
POST-AUTHORIZATION: DATA-DRIVEN
MAINTENANCE OF THE VALUE STORY
A PHASE-DEPENDENT EVIDENCE PLAN
CAN CUT COSTS AND MITIGATE RISK
Many of the clinical trials conducted post-authorization
are mandated by regulatory agencies. Challenges in this
phase often involve:
Addressing evidence generation in a phase-specific
manner provides mutually reinforcing benefits: trials
contribute to the value argument and the value data
inform the design of the trials. In this way, utilizing
the best available secondary research to inform
primary research can reduce the risk of regulatory and
reimbursement rejections.
• Optimizing post-authorization safety study (PASS)
protocols for both mandated and non-mandated
trials, and aligning those protocols with a risk
management plan (RMP).
• Satisfying medical information needs
• Devising an RMP that meets pharmacovigilance
requirements globally
In today’s healthcare market, evidence of a product’s
value is demanded long after it has been approved
by regulators, and reimbursed by payers. Evidence
planning continues to support activities postauthorization. Secondary research helps to generate
long-term safety and compliance evidence that
maintains and defends a product’s value story.
For example, recently, a PAREXEL client needed an RMP
for a biosimilar per EMA requirements. We conducted
an SLR using specific safety terms to gather the latest
published evidence for the new molecule. Our client
used this data to construct an RMP for submission.
Because the searches we conducted were systematic,
they were reproducible, and could be repeated when
the RMP needed updating. Similarly, we recently utilized
meta-analysis techniques to demonstrate the safety of
a client’s oral contraceptive in order to respond to EMA
concerns about post-authorization adverse events.
A phase-dependent approach has potential to cut
costs by avoiding investing in riskier assets, utilizing
secondary evidence for multiple assets (thereby using
resources more efficiently) , and creating payer value
while simultaneously meeting regulatory requirements.
The best way to plan evidence generation for the value
story is from the beginning. But if you didn’t do that
already, the sooner you start the better.
Addressing evidence
generation in a phase-specific
manner provides mutually
reinforcing benefits: trials
contribute to the value
argument and the value data
inform the design of the trials.
PAREXEL® ACCESS
POSITIONING YOUR PRODUCTS
FOR MARKET SUCCESS.
For more information, please contact:
Elizabeth Thomae +1-720-935-4089
To find out more visit:
www.PAREXEL.com/Access