Population Health Research Institute

McMaster University/Hamilton Health Sciences
David Braley Cardiac, Vascular and Stroke Research Institute 237 Barton Street East Hamilton, Ontario Canada L8L 2X2 www.phri.ca

June 30, 2010 Dr. Mary Parks FDA mary.parks@fda.hhs.gov

Salim Yusuf, MBBS, DPhil, FRCP(UK), FRCPC, FACC, FRSC Telephone: (905) 527-7327 Fax: (905) 297-3781

Re: The urgent need to use reliable methods to assess the true effects of glucose lowering drugs and other therapies on major cardiovascular outcomes.

Dear Dr. Parks, Please excuse me for writing to you and to your committee spontaneously. First, permit me to introduce myself. Second, allow me to indicate my interest in the issue and third, I would like to make a few relevant points that may be valuable to your committee. I am a Professor of Medicine, Executive Director of the Population Health Research Institute at Hamilton Health Sciences and McMaster University in Canada. I have been involved in developing the methodology of both meta-analysis, as well as large, simple, randomized trials since 1976 while I was at Oxford University in England, with Prof Sir Richard Peto and Prof Peter Sleight. Subsequently, from 1984 to 1992, I worked at the National, Heart, Lung and Blood Institute in the clinical trials branch in conjunction with Dr. Curt Furberg and Dr. Larry Friedman, and eventually became the acting Branch Chief of the Clinical Trials Division. I have been the Principal Investigator or chairman of over 60 major trials of several therapies in cardiovascular disease and in diabetes, some of which are now commonly used in clinical practice. I have published extensively on meta-analyses, the misuse and the dangers of using database analyses for the evaluation of therapies, and I have been instrumental in developing a significant part of the methodology that is now widely used for the conduct of large trials. Along with Dr. Hertzel Gerstein, I am the joint Principal Investigator of the TIDE study, which is evaluating two thiazolidinediones (roziglitazone and pioglitazone), as well as vitamin D in high risk diabetes patients. Please note that this is one of several trials in diabetes that we are involved in, and one of over 50 trials that the Population Health Research Institute has been involved with, or is currently conducting. I do not write to you and your committee to express my views on the TIDE study. Instead, I write to you because of my growing concern that the debate in the media, as well as in the literature, is based on poor science. It is essential that any recommendation that your committee and FDA come to is based on ensuring that we continue to support the best scientific methods. Poor methods will lead to unreliable conclusions and we will be left forever with considerable uncertainty. Below, I will list my concerns with the current debate:
Director: Salim Yusuf D.Phil, Associate Directors: Koon Teo MB, PhD, Sonia Anand MD, PhD, Chief Operating Officer: Deidre L. Henne CA, Khursh Ahmed MSc, PhD, Heather M. Arthur RN, PhD, Jackie Bosch MSc, BSc.OT, Susan Chrolavicius RN, BA, Stuart Connolly MD, Beena Cracknell, Catherine Demers MD, MSc, P.J. Devereaux MD, John Eikelboom MBBS, Ernest Fallen MD, Hertzel Gerstein MD, MSc, Jeff Healey MD, MSc, Andre Lamy MD,MHSc, Eva Lonn MD, MSc, Patrick Magloire MD, Kamil Malikov MD, MSc, MBA, Robert Mckelvie MD, PhD, Matthew McQueen MB, ChB, PhD, Shamir Mehta MD, Carlos A. Morillo MD, Katherine Morrison MD, Madhu Natarajan MD, Martin O’Donnell MD, Janice Pogue MSc, Parminder Raina PhD, Arya M. Sharma MD, Tej Sheth MD, Susan Stansbury, Ellison Themeles MSc

Population Health Research Institute
McMaster University/Hamilton Health Sciences
David Braley Cardiac, Vascular and Stroke Research Institute 237 Barton Street East Hamilton, Ontario Canada L8L 2X2 www.phri.ca

1. Small meta-analyses are not reliable: The meta-analysis by Nissen et al published in the New England Journal of Medicine (2007; 356(24): 2457-71) has created considerable interest in the issue of whether rosiglitazone has adverse effects on cardiovascular outcomes. However, this metaanalysis is based on very few events, other meta-analyses have not confirmed the conclusions, and most notably there is no justification as to why this meta-analysis focused solely on rosiglitazone, but was not based on all thiazolidinediones. In particular, most meta-analyses that have been conducted in the literature (such as beta-blockers in myocardial infarction or heart failure, ACEinhibitors in the same conditions, thrombolysis, cholesterol lowering agents, etc) have always been based on examining a class of drugs as a whole, unless there was specific reasons to believe that specific drugs in a class markedly differed from other drugs. In the case of the glitazones, there is no compelling evidence that one glitazone differs materially from the other on major clinical outcomes. Indeed, an AHRQ commissioned systematic TZD drug class review concluded that data were “not sufficient to determine the comparative effectiveness of pioglitazone and rosiglitazone on microvascular or macrovascular complications of diabetes as there are no head- to-head data and indirect data are sparse” (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=tzd). Thus, the most relevant analysis would be a meta-analysis involving ALL the trials of glitazones versus placebo. Such information is available to the FDA, and I would urge you to use such an approach based on the TOTALITY of all data, in preference to a meta-analysis done on a single agent within a class. Such an approach would avoid the potential data-dependent emphasis on one or another agent that leads to “selection” biases. As explained in an article that Janice Pogue and I wrote some 12 years back on overcoming the limitations of meta-analysis (Lancet 1998; 351(9095):47-52), meta-analyses based on small numbers of events can be substantially misleading. Practical examples of these come from our own experience where we have been misled by meta-analyses of trials based on scant data. This includes a meta-analysis of magnesium in acute MI, where we observed a 50% reduction in mortality (p<0.001) (Teo et al BMJ 1991; 303(6816): 1499-503). Instead of relying on this as conclusive evidence, despite the extreme statistical significance, we conducted a large prospective study (the ISIS-4 study on about 60,000 people, Lancet 1995; 345(8951): 669-85), which demonstrated absolutely no benefit from magnesium, but instead, a trend towards harm. Therefore, even directionally reliable information cannot be obtained from meta-analysis based on scant data. This instance is not isolated. Similar misleading information has come from a meta-analysis of beta-blockers of small trials in avoiding peri-operative cardiovascular events. The apparent benefit claimed by this meta-analysis was contradicted by the large POISE study that we conducted (Lancet 2008; 371(9627): 1839-47). Conversely, suggestions of harm with calcium channel blockers that were based on small trials were shown to be wrong by large prospective trials that demonstrated benefit. Therefore, small meta-analysis, at best, can provide a hypothesis that needs to be tested in prospective well-designed large trials.

Director: Salim Yusuf D.Phil, Associate Directors: Koon Teo MB, PhD, Sonia Anand MD, PhD, Chief Operating Officer: Deidre L. Henne CA, Khursh Ahmed MSc, PhD, Heather M. Arthur RN, PhD, Jackie Bosch MSc, BSc.OT, Susan Chrolavicius RN, BA, Stuart Connolly MD, Beena Cracknell, Catherine Demers MD, MSc, P.J. Devereaux MD, John Eikelboom MBBS, Ernest Fallen MD, Hertzel Gerstein MD, MSc, Jeff Healey MD, MSc, Andre Lamy MD,MHSc, Eva Lonn MD, MSc, Patrick Magloire MD, Kamil Malikov MD, MSc, MBA, Robert Mckelvie MD, PhD, Matthew McQueen MB, ChB, PhD, Shamir Mehta MD, Carlos A. Morillo MD, Katherine Morrison MD, Madhu Natarajan MD, Martin O’Donnell MD, Janice Pogue MSc, Parminder Raina PhD, Arya M. Sharma MD, Tej Sheth MD, Susan Stansbury, Ellison Themeles MSc

Population Health Research Institute
McMaster University/Hamilton Health Sciences
David Braley Cardiac, Vascular and Stroke Research Institute 237 Barton Street East Hamilton, Ontario Canada L8L 2X2 www.phri.ca

2. Observational analysis of databases can be extremely misleading in evaluating therapies: Some 20 years ago, I along with Drs. Curt Furberg, Kent Bailey and Janet Wittes, published an article in Circulation titled “Digitalis: a new controversy about an old drug. The pitfalls of inappropriate methods” (Circulation 1986; 73(1): 14-8). At that time, five database analyses claimed an increased mortality with digitalis and yet when a large prospective trial was conducted it showed a neutral effect on mortality, but an important reduction in hospitalizations for heart failure, which was clinically relevant. We know of many other instances where database analyses are misleading. This includes the recent story of hormone replacement therapy, where several analyses of observational studies suggested substantial reduction in cardiovascular events. However, the large Women’s Health Initiative trial on hormone replacement therapy indicated substantial harm. Similar misleading results have been obtained with other therapies as well. Again, these two examples (digitalis and HRT) indicate that database analyses can lead to even directionally incorrect answers. Therefore, irrespective of their results, observational analyses cannot generally be used for anything other than the generation of hypotheses which in turn need to be tested in large clinical trials. An exception to this would be the occurrence of rare outcomes such as thrombocytopenia or aplastic anemia, or when large relative risks (in excess of 4 or 5) are observed. 3. Reliable results can only be obtained by large long-term trials that accrue over 1000 and ideally several thousand events: The need for large trials to evaluate therapies reliably is well known (Stat Med 1984; 3(4): 409-22). It is unfortunate that until recently very few large (e.g. over 10,000 people) and long term trials (e.g. over 5 yrs of exposure) in the field of diabetes have been conducted. Unless trials are both large and prolonged, at best only uncommon early side effects will be detected, as any intervention that is expected to reduce major vascular events through an impact on atherosclerosis needs prolonged treatment of several thousands of individuals for a few years for the real effects of the treatment to emerge. Thus any conclusion based on relatively few patients followed for less than a year or two could well be misleading. A year or two ago, the FDA took the very progressive step of demanding large studies of all new antidiabetic agents. However, this leaves us with the dilemma of not knowing what the true long term effects of most currently used glucose lowering agents on major, vascular and other events. This includes metformin, the sulfonylureas, and insulin. Fortunately, at least for insulin and many of the new agents, large trials are underway. Until such large and long term trials have been completed, it would be impossible for us to obtain reliable information about any of the agents. The same holds true for the thiazolidinediones.

Thus, given that the existing data are scant and unreliable, there is every reason to conduct well designed trials, which are both large and prolonged that could generate reliable data (e.g. TIDE). I would therefore hope that your committee will be supportive of rigorous methodology, the conduct of such trials and the conclusions that arise from it.
Director: Salim Yusuf D.Phil, Associate Directors: Koon Teo MB, PhD, Sonia Anand MD, PhD, Chief Operating Officer: Deidre L. Henne CA, Khursh Ahmed MSc, PhD, Heather M. Arthur RN, PhD, Jackie Bosch MSc, BSc.OT, Susan Chrolavicius RN, BA, Stuart Connolly MD, Beena Cracknell, Catherine Demers MD, MSc, P.J. Devereaux MD, John Eikelboom MBBS, Ernest Fallen MD, Hertzel Gerstein MD, MSc, Jeff Healey MD, MSc, Andre Lamy MD,MHSc, Eva Lonn MD, MSc, Patrick Magloire MD, Kamil Malikov MD, MSc, MBA, Robert Mckelvie MD, PhD, Matthew McQueen MB, ChB, PhD, Shamir Mehta MD, Carlos A. Morillo MD, Katherine Morrison MD, Madhu Natarajan MD, Martin O’Donnell MD, Janice Pogue MSc, Parminder Raina PhD, Arya M. Sharma MD, Tej Sheth MD, Susan Stansbury, Ellison Themeles MSc

Population Health Research Institute
McMaster University/Hamilton Health Sciences
David Braley Cardiac, Vascular and Stroke Research Institute 237 Barton Street East Hamilton, Ontario Canada L8L 2X2 www.phri.ca

As you may well recognize, my views are not isolated, and a large part of the scientific community shares this view. My hope is that good sense and good science will prevail and ultimately allow the conduct of well designed studies so that reliable answers will emerge. Without this, science and our patients will be “losers”, and we will never know whether the treatments that patients are receiving or denied are of any particular value.

I trust these thoughts are of value to you and your committee. If you have any questions, I would be happy to discuss them with you by telephone. At present I do not intend to participate in your two day hearings in Washington, DC on July 13 and 14th.

Best wishes, Yours sincerely,

Salim Yusuf, DPhil, FRCPC, FRSC Professor of Medicine, McMaster University Executive Director, Population Health Research Institute McMaster University, Hamilton Health Sciences Vice President Research, Chief Scientific Officer, Hamilton Health Sciences Heart & Stroke Foundation of Ontario/Marion W. Burke Chair in Cardiovascular Diseases SY:jl

Director: Salim Yusuf D.Phil, Associate Directors: Koon Teo MB, PhD, Sonia Anand MD, PhD, Chief Operating Officer: Deidre L. Henne CA, Khursh Ahmed MSc, PhD, Heather M. Arthur RN, PhD, Jackie Bosch MSc, BSc.OT, Susan Chrolavicius RN, BA, Stuart Connolly MD, Beena Cracknell, Catherine Demers MD, MSc, P.J. Devereaux MD, John Eikelboom MBBS, Ernest Fallen MD, Hertzel Gerstein MD, MSc, Jeff Healey MD, MSc, Andre Lamy MD,MHSc, Eva Lonn MD, MSc, Patrick Magloire MD, Kamil Malikov MD, MSc, MBA, Robert Mckelvie MD, PhD, Matthew McQueen MB, ChB, PhD, Shamir Mehta MD, Carlos A. Morillo MD, Katherine Morrison MD, Madhu Natarajan MD, Martin O’Donnell MD, Janice Pogue MSc, Parminder Raina PhD, Arya M. Sharma MD, Tej Sheth MD, Susan Stansbury, Ellison Themeles MSc