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Using Evidence to Support Value-Based
Decision-Making: Understanding Challenges
to Manufacturer Communications
May 2015
Prepared by:
Nikita Jeswani, Jay Jackson
Corinna Sorenson, Gillian Woollett
Tanisha Carino
Avalere Health LLC
Funding support from the Pharmaceutical Research and Manufacturers of America.
Avalere maintained full editorial control in the development of this content.
Using Evidence to Support Value-Based Decision-Making: Understanding Challenges to Manufacturer Communications
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INTRODUCTION
Continued concern over rising health expenditures,1 as well as growing interest in alternative
payment models as one solution, have sharpened the focus on demonstrating the clinical
and economic value of healthcare items and services. Simultaneously, providers and payers
are being held accountable for achieving better outcomes at lower costs, which has led to
extensive experimentation with new payment and delivery models such as Accountable Care
Organizations and bundled payment. This trend is reinforced by the recent enactment of the
Medicare Access and Children’s Health Insurance Program (CHIP) Reauthorization Act and
by the Department of Health and Human Services’ (HHS) announcement to tie 85 percent of
all traditional Medicare payments to value by 2016 and 90 percent by 2018.2,3 As a result of
growing budget pressures and ever-limited resources, payers and risk-bearing providers are
increasingly expected to make tradeoffs based on evidence of value,4,5,6 including information
on the effectiveness, costs, and risks of new or existing therapies, sometimes in comparison
to standard or usual treatment for a particular condition. In addition, over the last several
years, stakeholders have progressively expressed interest in, and the need for, evidence
that reflects use of interventions in actual clinical practice and that adequately captures the
patient perspective. These data can take the form of healthcare economic information,i, 7, 8
comparative effectiveness research (CER),ii,9 and real-world evidence (RWE),iii, 10 which are
somewhat interrelated.
A number of public and private organizations have played central roles in producing and
supporting the generation of these types of evidence. For example, the U.S. Food and
Drug Administration’s (FDA) Sentinel program, Agency for Healthcare Research and Quality
(AHRQ), and the Patient-Centered Outcomes Research Institute (PCORI) have been pivotal
sources of comparative information, especially in recent years. Private sector organizations,
such as Cochrane Collaboration, ECRI Institute, Blue Cross Blue Shield Association’s
Technology Evaluation Center (TEC), Institute for Clinical and Economic Review (ICER), and
Hayes, Inc., have also been actively engaged in developing these data and supporting
development of new information technology systems and platforms to aid their collection,
analysis, and dissemination. With increasing accountability, payers and providers—who often
have access to robust, internally generated data sets (e.g., claims, electronic health records)—
are beginning to assess and analyze such information to make conclusions about the value
of services and treatments.
i
Healthcare economic information evaluates health resource use and cost associated with treatments. It can be used to compare cost-effectiveness between therapies.
ii
CER entails research evaluating and comparing health outcomes and the clinical effectiveness, risks, and benefits of two or more medical treatments.
iii
RWE is defined as data about the use, benefits, or risks of interventions from sources other than randomized controlled trials.
Using Evidence to Support Value-Based Decision-Making: Understanding Challenges to Manufacturer Communications
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In addition to these organizations and stakeholders, biopharmaceutical manufacturers
play an important role in developing and communicating evidence, given their deep
knowledge of their products. A number of U.S. laws and FDA regulations govern
manufacturer communications about drugs, biologics, and devices, requiring that clinical
claims, for example, be required to meet the “substantial evidence” standard (typically
two well-controlled trials),11 be consistent with the FDA-approved labeling, and provide
fair balance. Meanwhile, Section 114 of the FDA Modernization Act (FDAMA 114) allows
healthcare economic information that “directly relates” to an approved indication and is
based on “competent and reliable scientific evidence” to be proactively provided to formulary
committees or “similar entities.”12 However, interpretation of the statute, particularly around
permissible evidence and possible audiences for communication, has varied dramatically
across industry. As a result, manufacturers have exercised such permissions on a limited
basis. Similarly, a lack of clarity exists around how manufacturers can communicate evidence
generated through CER and RWE, given their relation to economic information and their
recent introduction and emphasis within the U.S. healthcare landscape. In sum, opportunities
for payers and risk-bearing providers to use the full breadth of available evidence when
making decisions are being hindered and perhaps even forgone.
To better understand these apparent regulatory uncertainties and resulting barriers faced by
industry, Avalere Health surveyed pharmaceutical manufacturers to ascertain the extent of
current challenges to communicating healthcare economic information, CER, and RWE. This
issue brief highlights our key findings, with a particular focus on how rules and regulations
have shaped the dialogue about value between manufacturers and key decision-makers.
Using Evidence to Support Value-Based Decision-Making: Understanding Challenges to Manufacturer Communications
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APPROACH
Between January 17 and February 14, 2014, Avalere Health surveyed 14 representatives of
small, medium, and large global biopharmaceutical manufacturers to determine the extent
and nature of barriers they have encountered or perceived when considering or attempting to
proactively communicate evidence to formulary committees, payers, and similar entities. We
also aimed to assess whether these potential hurdles vary across different types of evidence
(e.g., CER vs. RWE). To more specifically explore the impact of FDAMA 114 on the ability of
manufacturers to develop and share information about the economic value of their products,
Avalere conducted follow-up semi-structured interviews with representatives of five of the
manufacturers.
We received a total of 15 survey responses, representing 14 manufacturers. The sample
included a mix of U.S. and global, and small and large manufacturers. Individual survey
respondents represented a diverse range of senior job functions and divisions/teams within
each organization (see Figure 1). While the individual respondents may have been associated
with a single division, the respondents were asked to consult with other groups within their
organization in order to generate a company-wide perspective. Following the surveys and
interviews, we collated the data into a repository using Excel and reviewed the information for
key trends regarding manufacturer perspectives on evidence communication.
A key limitation of the survey is that respondents represent only one stakeholder group. There
is a need for additional research that assesses the perspective of payers, providers, patients,
and policymakers—those who are ultimately using evidence in decision-making. It will be
important to understand the extent to which economic, comparative, and real-world data
generated by manufacturers is in demand and whether there are any concerns about the
quality and validity of such information. These perspectives would enable a more complete
understanding of the evidence communication landscape.
Figure 1: Respondents by Division/Team
Regulatory 7%
Medical Affairs
13%
Legal 33%
N=15
Government
Affairs/Policy 20%
Outcomes
Research 27%
Using Evidence to Support Value-Based Decision-Making: Understanding Challenges to Manufacturer Communications
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RESULTS
Responses from the surveys and follow-up interviews highlighted a number of key challenges
and barriers that manufacturers face with regard to the communication of economic and
related information. One respondent noted that health economic, comparative, and realworld information that is “needed in the marketplace often involves comparisons with
other therapies”; however, in most situations, this type of evidence may not always be
supported by the two randomized controlled trials (RCT) typically required of manufacturers
to demonstrate substantial evidence of a drug’s effectiveness for marketing authorization.
Additionally, manufacturers noted that when designing studies, they are limited both by their
own product label and those of similar alternative therapies, since by some interpretations,
both medicines would need to be “directly relate[d]” to the FDA-approved indication being
studied. This raises additional uncertainty regarding the extent to which comparative research
can be conducted on available treatments—information that is increasingly required to
determine value.13,14 The manufacturers queried observed that these issues hinder not
only their ability to respond to evidence demands of healthcare decision-makers, such as
formulary committees, payers, and other healthcare professionals, but create a disincentive
to invest in and further develop this important type of data. In fact, 86 percent of the
manufacturers indicated that FDA’s current regulations and interpretation of the law hinders
the generation and communication of economic information, and 93 percent mentioned such
issues with regard to comparative data (see Figure 2). When asked about their main concerns,
manufacturers cited lack of clarity and guidance around the appropriate application of FDAMA
114, which could expose them to FDA enforcement action such as warning letters.
Figure 2: Impact of Lack of Guidance on Development and Dissemination of Economic
and Comparative Information
Has lack of guidance from FDA inhibited your
organization’s dissemination or development of
healthcare economic information?
No 14%
Has lack of guidance from FDA inhibited your
organization’s dissemination or development
of CER?
No*
7%
N=14
N=14
Yes 86%
Yes 93%
*One respondent unsure
Using Evidence to Support Value-Based Decision-Making: Understanding Challenges to Manufacturer Communications
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Figure 3: Lack of Clarity of What “Directly Relates” to an Approved Indication
FDAMA114 allows the dissemination of economic information that “directly relates” to an FDA-approved
indication. Has your organization faced uncertainties as to the appropriateness of proactively disseminating
the following types of economic information?
100
N=14
86%
79%
79%
71%
75
57%
50
43%
21%
25
0
Downstream
implications
Alternate
setting
Alternate
dose
Subgroup
analyses
Costeffectiveness
analyses
Alternate
duration of
use
Other
Other: patient registries; real-world utilization patterns that are the standard of care even if off-label; comparative analyses
A similar level of uncertainty relates to FDA’s interpretation of the phrase in FDAMA 114,
“directly relate[d]” to an FDA-approved indication. Specifically, 86 percent of the manufacturers
indicated doubt regarding whether data on the downstream economic implications of a drug,
based on the treatment’s impact on health outcomes (e.g., cost savings from a reduction in
cardiovascular problems due to an approved diabetes drug), “directly relates” to an approved
indication (see Figure 3). Furthermore, 79 percent of survey respondents noted lack of clarity
regarding use of evidence that extrapolates the findings of a study that was either conducted
in a different care setting or if utilization of the drug extends beyond the dosing regimen
denoted on the package insert.
Over the last several years, those responsible for making decisions about the “selection of
drugs for managed care or other similar organizations”15 have proliferated beyond formulary
committees to such an extent that determining what represents a “similar entity” is challenging.
While manufacturers vary in their interpretation about what types of entities can be defined
as a “similar entity,” the majority indicated they would like to be able to communicate with
the full range entities involved in making decisions and recommendations regarding the use
of medicines, including drug compendia and clinical pathway developers, as well as provider
entities, particularly those operating within risk-based payment models.
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A significant issue that further confounds the challenges manufacturers face in
communicating economic and other information is that other entities—regulators, payers,
physicians, and patients—uphold varying evidentiary standards,16 which complicates efficient
evidence generation and reduces confidence that such information will be considered
sufficient in different contexts (see Table 1). At the same time, other communicators of
evidence outside of industry are not held to such standards, which raises concerns about the
quality and accuracy of such information making its way to the healthcare community.
This variation gives rise to questions about what types and amounts of evidence are required
to substantiate value throughout the lifecycle of a drug. Respondents expressed greatest
confidence in generating and communicating evidence about their medicines when the data
are derived from randomized controlled clinical trials. Nevertheless, most maintained that
data obtained under a number of different study methods may be appropriate to substantiate
an economic or comparative claim, so long as robust methods are used to ensure that
any resulting claims are adequately substantiated.vi These methods may include adequate
and well-controlled studies, but will also include meta-analyses or systematic reviews,
observational study designs, and economic modeling techniques.
Table 1: Varying Evidentiary Standards Across FDA and Other Governmental Agencies17
Standard
Role
Agency
“Substantial evidence”18
Approval of new drugs and
biological
U.S. Food and Drug
Administration
“Substantial clinical experience”19
Regulation of prescription drug
advertising and dissemination of
product information, including
post-market safety evidence
U.S. Food and Drug
Administration
“Competent and reliable scientific
evidence”20, iv, 21
Regulation of healthcare
economic claims
U.S. Food and Drug
Administration
“Reasonable and necessary”22
Average decision-making at
national and local levels
Centers for Medicare
& Medicaid Services
“Competent and reliable scientific
evidence”23, 24, 25
Substantiation to support claims
Federal Trade
Commissionv
iv The majority of manufacturers identified uncertainty regarding “competent and reliable” scientific evidence as their principal concern, which is consistent with the findings of other research on this topic.
v
Several respondents agreed that the FTC’s definition could be appropriate for FDA’s regulation of healthcare economic claims under FDAMA 114.
vi Many manufacturers considered generally accepted good research practice criteria, such as those developed by third parties. Among the standards that were named were those maintained by the International Society for Pharmacoeconomics and Outcomes Research (ISPOR), the National Institute for Health and Care Excellence (NICE), PCORI, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).
Using Evidence to Support Value-Based Decision-Making: Understanding Challenges to Manufacturer Communications
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When asked about potential solutions for many of these issues, particularly about providing
additional guidance to interpret and apply FDAMA 114, 86 percent of respondents indicated
that additional guidance would be helpful and that it would spur more investment in
economic, CER, and RWE studies (see Figure 4). If FDA were to publish additional guidance
or if regulations were to be revised, manufacturers highlighted a number of areas where
further clarification and direction are needed, including the role and acceptance of different
study designs, such as registry and database studies (see Figure 5), as well as input on
how to incorporate the patient perspective in evaluating the value of medicines. Other
topics potentially ripe for further stakeholder discussion include: (1) how to address external
validity and generalizability of studies; (2) methods to identify appropriate partners for data
generation; and (3) means of educating decision-makers on evaluating the quality of CER
and RWE studies.
It should be noted that some manufacturers indicated concern that further FDA guidance or
regulation in this space would result in standards even more restrictive than present, which
would further chill the development and communication of economic and other information
about medicines by manufacturers.
Figure 4: Impact of Appropriate Guidance and Clarification on Investment in and
Communication of Economic Information
With appropriate guidance and clarification, my organization would invest in more studies and research to
support the development of healthcare economic information
Disagree 7%
Neutral 7%
N=14
Strongly Disagree
50%
Agree 36%
Using Evidence to Support Value-Based Decision-Making: Understanding Challenges to Manufacturer Communications
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Figure 5: Types of Evidence that Should Be Addressed in Guidance
If FDA were to issue guidance on the communication of clinical CER, which types of studies would your
organization like to see addressed?
93%
93%
100
N=14
86%
86%
86%
71%
75
50
29%
25
0
Registry
studies
Database
studies
Metaanalyses/
systematic
review
Randomized
controlled
trials
Prospective
cohort
studies
Simulation/
modeling
Other
Other: Pragmatic studies; comparator arms not in package insert; retrospective studies; interventional studies; subpopulation analyses;
studies that include soft endpoints such as patient preference, burden of illness, cost of care, and quality of life; budget impact models
Using Evidence to Support Value-Based Decision-Making: Understanding Challenges to Manufacturer Communications
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DISCUSSION
Although FDA, payers, and industry alike have recognized the potential value of healthcare
economic information, CER, and RWE to inform decision-making, a lack of FDA guidance
or regulations interpreting FDAMA 114 has limited the flow of information from evidence
generators to evidence users. In particular, the survey and subsequent interviews indicate
that more clarity and guidance regarding which types of studies are permissible and how
FDA and other key decision-makers intend to enforce or otherwise influence proactive
communication of this evidence is required in order for manufacturers to actively participate
in the dialogue on the value of medicines. While this is the majority view, there is also an
opposing perspective that FDA guidance is simply not needed or needs to be approached
with caution so that it does not result in an overly conservative interpretation of FDAMA 114.
A key challenge remains: There is a lack of consistency regarding what evidence is (or could
be) considered in decision-making, what constitutes sound research methodology, and how
such information can be effectively communicated to key stakeholders. Part of the solution
to these issues is trying to reach some level of consensus on how “value” is defined and
what evidence standards are needed to support it.26 The inconsistency in existing standards
(and variations in regulatory restrictions and enforcement actions for non-industry entities vs.
industry) sends different messages to healthcare professionals, who must make decisions
based on different types of evidence and are ultimately accountable for delivering value.
The manufacturers queried in our study noted that they would support greater stakeholder
collaboration on development and adoption of appropriate evidence standards and “good
communication principles,” in order to strengthen the credibility of different types of evidence
and their dissemination. Manufacturer-generated evidence that adheres to such standards,
in conjunction with information generated by other stakeholders, can improve the overall
evidence base from which regulatory, coverage, and treatment decisions are made. In turn,
this can support the achievement of value targets as set in current payment and delivery
mechanisms and, in the future, HHS’ goals for 2016 and 2018.
Overall, greater clarity and guidance around evidence generation and communication is
needed in order to fully incentivize investments in studies that can effectively elucidate the
value of interventions and support sound and informed decision-making. Meeting these
aims is important to ensure continued research and innovation in healthcare. The most
recent iteration of the pending 21st Century Cures legislationvii, 27 and pending FDA guidance,
which the Agency has alluded to for imminent release, present key opportunities for multistakeholder dialogue to address current evidence communication challenges and move
toward a vision where high-quality, accurate, and evidence-based information can flow freely
to those accountable for delivering value in healthcare.
vii The draft amends current law (Section 114 of the FDA Modernization Act of 1997) to facilitate the ability of medical product
manufacturers to communicate with payers about the clinical and economic value of their products. Intended to allow greater
communication between payers and manufacturers, the statute has areas of ambiguity that have not been addressed by FDA.
In response, the draft would accomplish several things: (1) Expand the audience from “formulary committees or other similar
entit(ies)” to include payers of any type; (2) Expand the range of healthcare economic information that is communicable by virtue
of being related to the label (i.e., it removes the word “directly” from “directly relates to an [approved] indication”); (3) Allow for the
communication of particular components of an analysis, such as data, assumptions, and methods; (4) Require a conspicuous
statement indicating how information being communicated is different from the label, and (5) Expand the type of information that
can be communicated, allowing for information on “aggregate clinical consequences and costs” (which may be interpreted to mean
systemic benefits of a product, e.g., readmissions reductions). Such amendments would further support comparative studies.
Using Evidence to Support Value-Based Decision-Making: Understanding Challenges to Manufacturer Communications
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REFERENCES
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bill/114th-congress/house-bill/2/text
3 HHS. “Better, Smarter, Healthier: In historic announcement, HHS sets clear goals and timeline for shifting Medicare
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19&keytype2=tf_ipsecsha
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net/research/docs/031913_Dialogue_WhitePaper.pdf
7
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9 Agency for Healthcare Research and Quality. What Is Comparative Effectiveness Research. http://effectivehealthcare.ahrq.gov/
index.cfm/what-is-comparative-effectiveness-research1/
10 Adapted from ISPOR’s definition of RWD. International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Real-World Data. Frequently Used Terminology. Accessed July 18, 2014. http://www.ispor.org/Terminology/Default.asp
11 21 U.S.C. § 355(d)
12 FDCA Section 502(a) [21 U.S.C. § 352(a)]
13 Meltzer M, Pizzi LT, Jutkowitz E. Payer decision-making with limited comparative and cost effectiveness data: the case of new pharmacological treatments for gout. Evid Based Med. 2012 Aug;17(4):105-8. doi: 10.1136/ebmed-2011-100065. Epub 2012 Feb 18.
14 Temple RJ. “Communication of CER Findings. Asymmetry in the Ability to Communicate CER Findings: Ethics and Issues for Informed Decision Making.” Presented at National Pharmaceutical Council, Washington, DC, February 9, 2012.
15 FDCA Section 502(a)
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healthaffairs.org/content/25/5/1363.full?sid=35db6a35-08bc-46f9-83ca-ce05d75ad46d
17 Garrison LP Jr., Neumann PJ, Radensky P, Walcoff SD. A flexible approach to evidentiary standards for comparative effective
ness research. Health Aff (Millwood). 2010;29(10):1812-17.
18 21 U.S.C. § 355(d)
19 21 CFR 202.1(e)(4)(ii)(c)
20 21 U.S.C. § 352(a)(1)
21 Neumann, P. “Health Economics Communication and FDAMA Section 114.” Presentation to Chicago ISPOR Chapter. Tufts Center for the Evaluation of Value and Risk and Health. May 2, 2013.
22 Soc. Sec. Act § 1862(a)(1)(A) (42 U.S.C. § 1395(y)(a)(1)(A)
23 Federal Trade Commission v. Prolong Super Lubricants, Inc. Docket no. C‐3906 (Nov. 22, 1999)
24 FTC v. Iovate Health Sciences, No. 10-CV-587 (W.D.N.Y. 2010).
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26 Avalere Health. Delivering Value in Health care: A Multi-Stakeholder Vision for Innovation. March 2013. http://www.avalerehealth.
net/research/docs/031913_Dialogue_WhitePaper.pdf
27 21st Century Cures. April 28, 2015 Discussion Draft. Sec. 2101
Using Evidence to Support Value-Based Decision-Making: Understanding Challenges to Manufacturer Communications
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Using Evidence to Support Value-Based Decision-Making: Understanding Challenges to Manufacturer Communications
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