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SCIENCE & TECHNOLOGY
The Current Regulatory Landscape for Cardiac and
Cardiovascular Safety Assessments—Part II
By Raymond A. Huml, MS, DVM, RAC and
J. Rick Turner, PhD, PGCE, MTOPRA
Last month, in Part I of this two-part series, we
provided an overview of the history of formalized cardiac safety assessment, a brief discussion
of the dedicated study used to investigate a
drug’s propensity to increase the length of the
QT/QTc interval, and an overview of the regulatory history of formalized cardiovascular safety
assessment for antidiabetic drugs for Type 2
Diabetes Mellitus (T2DM).
Part II discusses key aspects of the US Food
and Drug Administration’s (FDA) December
2008 Guidance for Industry Diabetes Mellitus—
Evaluating Cardiovascular Risk in New Antidiabetic
Therapies to Treat Type 2 Diabetes, continues
the discussion in the literature regarding the
cardiovascular safety of Avandia and Actos, provides insights into the July 2010 FDA Advisory
Committees Meeting on Avandia and a brief
discussion of the European Medicines Agency’s
(EMA) January 2010 Draft Guidance for T2DM,
and ends with a discussion regarding the potential ramifications for future global development
of antidiabetic drugs for the treatment of T2DM.
FDA’s December 2008 Guidance for
Industry
The 2008 guidance document1 requires compelling evidence that a new agent to treat T2DM is
not associated with an unacceptable increase in
cardiovascular risk. A three-component model,
involving clinical, regulatory and statistical
science, is employed.2 At the end of an investigational drug’s preapproval clinical development
program, a meta-analysis is to be conducted using
data from essentially all Phase 2 and Phase 3 trials to assess whether the drug is associated with
an unacceptable increase in risk. Compared with
former clinical trials enrolling a smaller number
of subjects that may have been at a lower risk of
cardiac events and of shorter duration conducted
prior to the publication of this document, the
nature of the trials and the nature of the subjects
that will need to be studied are now different.
Larger and longer late Phase 2 trials are called for,
38
February 2011
as are larger and longer Phase 3 trials that include
subjects at high risk for cardiovascular events.
The document provides guidance on suitable cardiovascular safety endpoints. The Major
Adverse Cardiovascular Events (MACE) composite endpoint is certainly acceptable. This
includes nonfatal myocardial infarction, nonfatal
stroke and cardiovascular death. A composite
endpoint can be advantageous when the number
of individual events may be too low for meaningful comparison of those occurring in the test
drug treatment group with those in the comparator treatment group. The guidance also makes
clear that endpoints now require independent
adjudication.
The meta-analysis to be conducted at the end
of the development program assesses the drug’s
MACE liability.3,4 Since the cardiovascular safety
of the test drug is judged against that of a comparator, a risk ratio point estimate and associated
confidence intervals (CIs) are of interest. Primary
interest falls on the upper limit of a two-sided
95% CI placed around the relative risk ratio point
estimate generated by the meta-analysis. Three
scenarios are discussed in the guidance:
1. If the upper limit of this CI is equal to
or greater than 1.8, a drug is deemed
to have an unacceptable risk. In this
case, “an additional single, large safety
trial should be conducted that alone, or
added to other trials, would be able to
satisfy this upper [limit of the CI] before
NDA/BLA submission.”5
2. If the upper limit is equal to or greater
than 1.3 but less than 1.8, and the
overall risk/benefit analysis presented
at submission supports marketing
approval, a subsequent step will generally be necessary. A postmarketing trial
is required to show definitively that
the upper limit of the CI is actually less
than 1.3. Thus, for drugs that are not
deemed to have an unacceptable risk
at this point, later studies must show
that a more comprehensive assessment
yields a risk ratio less than 1.3.
3.
If the upper limit is less than 1.3 and the
overall risk/benefit analysis presented
at submission supports marketing
approval, “a postmarketing cardiovascular trial generally may not be necessary.”6
Continued Discussion in the
Literature of the Cardiovascular
Safety of Avandia and Actos
Since the July 2007 FDA Advisory Committees
meeting, many papers discussing the cardiovascular safety of both Avandia and Actos have
been published, some of which approached the
safety of the two drugs comparatively. However,
a review of this literature reveals that the picture
is still far from clear. Some publications have
reflected the views of the 2007 meta-analysis
cited earlier,7 including an updated meta-analysis published by the same authors in 2010.8
Graham et al9 reported that the prescription of
rosiglitazone, compared with pioglitazone, was
associated with an increased risk of stroke, heart
failure and all-cause mortality, and an increased
risk of the composite of acute myocardial infarction (AMI), stroke, heart failure or all-cause
mortality in patients 65 years or older. Other
publications have reported quite different findings. In a retrospective cohort study, Wertz et al10
directly compared Avandia and Actos and found
no significant differences in their risk of AMI,
acute heart failure or death, findings echoed by
Bilik et al.11
The Wellpoint Study, using an insurance
company database and published in August
2010, appeared to show no difference between
Avandia and Actos regarding key cardiac
adverse events, including heart attack. Although
this study appeared somewhat reassuring from a
cardiac safety standpoint, critics cite several key
shortcomings such as:
1. Average age of patients in the most
recent study was 54, whereas patients
treated under Medicare are typically
over age 65.
2. The Wellpoint Study was based on
claims data from 2001 to 2005, before
any health warnings related to the drug
had emerged, whereas the updated
(2010) Nissen and Wolski Study
reviewed data from 2006 and 2009,
when physicians may have been more
selective in choosing patients to receive
the drug.12
July 2010 FDA Advisory Committees
Meeting on Avandia
In July 2010, the Endocrinologic and Metabolic
Drugs Advisory Committee and the Drug Safety
and Risk Management Advisory Committee met
again, primarily to focus on the cardiovascular
safety of Avandia. Compared with the 2007 joint
meeting, this meeting had a longer and more
complex list of predetermined questions to be
voted upon by members of the committees.13-16
Most notably, while 12 members voted in favor
of removing rosiglitazone from the market, 20
members voted against it. Of these 20 members,
10 voted for additional warnings and restrictions
on the use of the drug and seven voted for additional warnings.
In concordance with the overall recommendation of the Advisory Committees’ members,
FDA did not withdraw rosiglitazone from the
US market, but it did require the drug’s sponsor to submit a Risk Evaluation and Mitigation
Strategy (REMS) within 60 days of the agency’s
announcement of its decision on 23 September
2010. The REMS is a tool available to FDA to
mitigate overall risk, making the drug available
to certain patients under circumstances for which
the treatment risk/benefit profile is acceptable, while not allowing the drug’s use in other
patients for whom the risk/benefit profile is
likely to be unfavorable.
EMA’s January 2010 Draft Guidance
The directives in the FDA and EMA guidance
documents concerning cardiovascular safety
assessment during clinical development of a new
antidiabetic drug are qualitatively comparable,
with one salient difference: the lack of explicit
values for CI upper bounds in the EMA document. It discusses “point and interval estimates”
and an “unacceptable lack of precision”17 (presumably referring to confidence intervals that
are judged too wide), but appears to leave EMA
regulators more discretionary latitude than do
the explicit thresholds of regulatory concern
adopted by FDA.18
Regulatory Focus
41
Potential Ramifications for Future
Global Development of Antidiabetic
Drugs for T2DM
Cardiac safety remains a key concern across all
geographies, especially in countries that have
adopted ICH guidance, but may have large
ramifications for emerging markets that have not
yet adopted ICH guidelines, such as India and
China, which are playing a greater role in global
drug development.
The raising of the regulatory bar for the
development of antidiabetic drugs for T2DM
by the FDA and EMA documents is a potential
concern to some in the drug development community. If cardiovascular outcomes studies are
required, additional capital and operational costs
and delays in time to market could be considerable, so considerable, in fact, that some companies
will no longer be able to pursue development of
these drugs for a disease that is increasingly prevalent globally. As Caveney and Turner observed,
“Regulators, policy makers, and industry leaders will need to be vigilant and work together to
ensure that the new regulatory guidance does not
stifle the development of antidiabetic agents.”19
Summary
•
•
Key industry guidance for issues related
to cardiac safety of drugs for non-proarrthymic conditionshave been adopted
by all key ICH geographies including
Canada, the US, the EU and Japan
FDA and EMA requirements for T2DM
drugs add significant additional cost and
time to development of any potential
newT2DM therapy, thereby raising the
bar high enough to potentially limit further development in this therapeutic area.
References
1.
Guidance for Industry Diabetes Mellitus—Evaluating
Cardiovascular Risk in New Antidiabetic Therapies to Treat Type
2 Diabetes. FDA website. http://www.fda.gov/downloads/
Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM071627.pdf. Accessed 17 January 2011.
2.
Turner JR. “Integrated cardiovascular safety: Employing
a three-component risk exclusion model in the assessment of investigational drugs.” Applied Clinical Trials.
June 2010;76-79.
3.
Caveney E, Turner JR. Understanding the FDA Guidance
on Assessing Cardiovascular Risks for new Antidiabetic
Therapies. 2010 Quintiles White Paper, available by contacting Dr. Turner at [email protected].
4.
Turner JR, Caveney E. European Medicines Agency
Guideline on Assessing Cardiovascular Risks of New
Antidiabetic Therapies: Comparison with FDA Guidance. 2010
Quintiles White Paper, available by contacting Dr. Turner
at [email protected].
5.
Op cit 1.
6.
Ibid.
Nissen SE, Wolski K. “Effect of rosiglitazone on the risk
7.
of myocardial infarction and death from cardiovascular
causes.” N Engl J Med. 2007;356:2457-2471.
8.
Nissen SE, Wolski K. “Rosiglitazone Revisited: An
Updated Meta-analysis of Risk for Myocardial Infarction
and Cardiovascular Mortality.” Archs of Intern Med. 28
June 2010. [Epublication ahead of print].
9.
Graham DJ, Quellet-Hellstrom R, MaCurdy TW, et al.“Risk
of acute myocardial infarction, stroke, heart failure, and
42
February 2011
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
death in elderly Medicare patients treated with rosiglitazone or pioglitazone.” JAMA. 2010;304:411-418.
Wertz DA, Chang CL, Sarawate CA. “Risk of
Cardiovascular Events and All-Cause Mortality in
Patients Treated With Thiazolidinediones in a ManagedCare Population.” Circulation, Cardiovascular Quality and
Outcomes. 24 August 2010. [Epublication ahead of print].
Bilik D, McEwen LN, Brown MB, et
al.“Thiazolidinediones, cardiovascular disease and cardiovascular mortality: translating research into action for
diabetes (TRIAD).” Pharmacoepidemiology and Drug Safety.
2010; 19:715-721.
WellPoint study. First Word Lite Edition. http://www.
firstwordplus.com/Fws.do?articleid=ABADC2DC93B
F4943BB3580E7925C2223 accessed 26 August 2010. See
also Lane L. Bioworld Today (e-publication); Study: No
difference in risks between GlaxoSmithKline’s Avandia,
Takeda’s Actos from article in Circulation: Cardiovascular
Quality and Outcomes; 24 August 2010.
http://www.fda.gov/downloads/AdvisoryCommittees/
CommitteesMeetingMaterials/Drugs/
EndocrinologicandMetabolicDrugsAdvisoryCommittee/
UCM222622.pdf (Accessed 2 September 2010)
http://www.fda.gov/downloads/AdvisoryCommittees/
CommitteesMeetingMaterials/Drugs/
EndocrinologicandMetabolicDrugsAdvisoryCommittee/
UCM222625.pdf (Accessed 2 September 2010)
http://www.fda.gov/downloads/AdvisoryCommittees/
CommitteesMeetingMaterials/Drugs/
EndocrinologicandMetabolicDrugsAdvisoryCommittee/
UCM222628.pdf. (Accessed 2 September 2010)
http://www.fda.gov/downloads/AdvisoryCommittees/
CommitteesMeetingMaterials/Drugs/
EndocrinologicandMetabolicDrugsAdvisoryCommittee/
UCM222629.pdf. (Accessed 2 September 2010)
Guideline on clinical investigation. EMA website. http://
www.ema.europa.eu/docs/en_GB/document_library/
Scientific_guideline/2010/02/WC500073570.pdf.
Accessed 17 January 2011.
Caveney E, Turner JR. “Regulatory Landscapes for Future
Antidiabetic Drug Development (Part I): FDA Guidance
on Assessment of Cardiovascular Risks.” Journal for
Clinical Studies. January 2010; 34-36.
Ibid.
Bibliography
Salvi V, Karnad DR, Panicker GK, Kothari S. “Update on
1.
the evaluation of a new drug for effects on cardiac repolarization in humans: Issues in early drug development.”
British Journal of Pharmacology. 2010;159:34-48.
2.
Satin LZ, Durham TA, Turner JR. “Assessing a Drug’s
Proarrhythmic Liability: An Overview of Computer
Simulation Modeling, Nonclinical Assays, and the Thorough
QT/QTc Study.” Drug Information Journal, in press.
3.
Talbot J, Waller P. Stephens’ Detection of New Adverse Drug
Reactions, 5th ed. Chichester, UK: John Wiley & Sons. 2004.
Authors
Raymond A. Huml, MS, DVM, RAC, is executive director of
Global Due Diligence for Quintiles Capital Solutions – part of
Quintiles Transnational Corp. He is a frequent contributor to
Regulatory Focus on a variety of subjects and has co-authored
multiple updates for RAPS on the topic of cardiac safety. He was
the recipient of RAPS’ 2004 New Professional Award and is a
frequent speaker at society programs. He was the first individual
author to publish a book through RAPS (Introduction to the Due
Diligence Process; copyright 2010) and can be reached at raymond.
[email protected]. J. Rick Turner, PhD, PGCE, MTOPRA, is
senior scientific director, Cardiac Safety Services, Quintiles, affiliate clinical associate professor, University of Florida College of
Pharmacy, and Senior Fellow, Center for Medicine in the Public
Interest. He specializes in the design and analysis of clinical trials,
with a special interest in the cardiac and cardiovascular safety of
non-cardiac drugs. He has published 65 peer-reviewed papers
and 10 books. He can be contacted at [email protected].
Acknowledgement
The lead author wishes to thank Ross M. Tonkens, MD, FACCP,
a cardiac physician and regular Regulatory Focus contributor
and editor, for his editorial comments and insights into the
field of cardiac safety.