Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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FDA Advisory Committees Meeting on Avandia and a brief discussion of the European Medicines Agency’s (EMA) January 2010 Draft Guidance for T2DM, and ends with a discussion regarding the potential ramifications for future global development of antidiabetic drugs for the treatment of T2DM.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.