letter to cihr

8/11/2019 Letter to CIHR

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Alain Beaudet, MD, PhD

President

Canadian Institutes of Health Research

160 Elgin Street, 9th floor

Ottawa, Ontario K1A 0W9

June 15, 2014

Dear Dr. Beaudet:We are writing to express our substantial concerns regarding the CIHRs funding of major investigator-led

randomized clinical trials (RCTs) that will seriously jeopardize the ability of Canadian investigators to conduct studies ofimportant public health and clinical questions. A fundamental lesson learnt from 4 decades of conducting RCTsthat are thebasis of contemporary treatments in routine clinical practiceis that RCTs need to be of sufficient size to produce reliableresults. The approaches recently proposed by CIHR will make an already tenuous situation even more critical.

Substantial concerns regarding the CIHRs underfunding of clinical trials (both in absolute and relative terms to otherforms of research in Canada and other countries) has been documented by 3 national panels that the MRC and the CIHRconvened over the last 15 years. Most of the substantive issues in these reports have been largely ignored and the funding ofclinical trials by CIHR has remained poor. With the newly proposed changes in the review and funding of research at CIHR,we are seriously concerned that RCTs will suffer even more.

Throughout the last 2 years several of us have inquired to senior leaders at CIHR as to what will happen to the funding

of large RCTs under CIHRs new funding stucture, and we were informed that discussions were ongoing. Although CIHRsold funding structure is finished and the first round of Foundation Scheme Grants are due to be initiated in less than a month,Canadian trialists have not been informed whether, and how, they will be able to obtain funding for large RCTs.

On May 7, 2014, Dr. Jane Aubin responded to our inquiry stating the following. The discussion on large grants iscontinuing at CIHR and no decisions have yet been made. As I think we discussed previously, in the current environment offiscal restraint, CIHR's Governing Council has suggested that CIHR might have to consider an approach where large grants,including large clinical trials, will only be entertained in a strategic funding envelope, e.g., the trial is one of national priority,and also leverage a significant portion of the money from other partners. There are a number of discussions going on bothnationally and internationally and many agencies are considering a similar approach. Randomized clinical trials will bepermitted within the Foundation Scheme. However they must be part of a larger program of research (i.e., it cannot be anapplication for one project requiring a large sum of money) and we encourage clinician researchers who conduct programmaticfunding to apply to this program.

We, as Canadian leaders in Clinical trials, disagree and are concerned that if these suggestions in Dr. Aubins emailwere to be implemented, this would decimate the field and have substantial negative consequences to scientific progress and

the health of Canadians.In this letter we will make the following five points:1. Of all forms of health research, clinical trials of sufficient size to produce reliable results have the most direct andimmediate impact on the health of Canadians;2. Historically Canada has hit far above its weight in RCTs;3. Other countries have recognized the need for large RCTs and fund such trials at a substantially higher level; Canadais already lagging far behind other countries in governmental support for RCTs;4. We now have a crisis in the support of Canadian Trials and trialists, and the proposed changes would make thesituation even worse; and5. There is a need for an immediate increase in support for RCTs, and there is a need for long-term stability in RCTsupport.

1. Clinical trials of sufficient size to produce reliable results have the most direct and immediate impact on the health of

Canadians

Canada has had a long history of success in medical research. All forms of medical research contribute to improvingthe health of Canadians. This includes basic science research leading to outcomes such as the discovery of insulin and itincludes clinical research of which clinical trials are a vital component. If discoveries from basic science need to be translatedinto clinical practice to improve the health of the people of Canada, reliable (and often large) trials are essential. There issimply no other alternative. CIHR at present does nothave a balanced approach by which the flow of discoveries can bereliably evaluated at the most critical interface (i.e., in humans). We believe there is value in all forms of health research;however, of all the forms of health research, cli ni cal tr ial s of suf fi cient size to produce reli able resul ts have had the mostdir ect and immediate impact on the health of people. Large randomized trials are critical for the evaluation of most new andold therapies, devices, surgical procedures, and healthcare implementation strategies. Studies demonstrate that large clinicaltrials have the most profound effect on influencing the actions of health care providers. Therefore it is crucial that Canada has


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a balanced approach to funding different forms of research and an appropriate share of the CIHR funds need to be allocated forthe support of RCTs of sufficient size so that the results will impact human health.2. Historically Canada has hit far above its weight in RCTs

Canadian scientists who conduct RCTs are world-class. Previous reports have documented the impact (in terms ofquality, not quantity) of studies done in various categories by researchers in several countries. In a report published inNature,under the heading of clinical medicine, which includes RCTs, Canada was second only to theUSahead of England,France, Germany, Australia, and Japan. Canadian-led trials that received peer-reviewed funding have provided the evidence

for: 1. numerous interventions that reduce disability and untimely deaths, which has led to their widespread use; 2. somecommonly used treatments that do more harm than good, which has led to their use declining; and 3. effective knowledgetranslation and health services approaches to improving clinical care. The Table below reports a few of the plethora ofCanadian examples. These trials have had profound effects in prolonging and improving the lives of Canadians and citizensthroughout the world and have likely avoided deaths and morbid events in millionsof individuals.3. Other countries recognize the need for RCTs, and many have increased support. Canada is already lagging far

behind many countries in governmental support for RCTs

CIHR allocated only 3.3% of its overall budget to clinical trials in 2009/10, whereas the US National Institutes ofHealth spent 11% of its overall budgets on RCTs. This means that the US spends ninetimes as much money per capita onpublicly funded trials as does Canada. Several years ago, the UK recognized the relative paucity of funding for clinicalresearch, particularly clinical trials. This realization led to the creation of the National Institute for Health Research (NIHR),with an annual budget of about 1 billion for 2010/11, to complement a similar allocation for basic science research. About20%25% of the NIHR budget (i.e., about 250 million pounds per year or about $400 million Canadian per year) is devoted to

supporting and conducting RCTs and supporting related centres and investigators.A recent study published in the New England Journal of Medicine reported the compound annual growth rate ofbiomedical R&D expenditures by country, adjusted for inflation between 2007 and 2012. Globally Canada finished last andexperienced a decrease in inflation-adjusted expenditures going from $6.0 billion in 2007 to $5.3 billion in 2012 (i.e., anegative 2.6% compound annual growth rate of biomedical R&D expenditures). Canadas decrease in funding occurred in thepublic sector (i.e., a decrease from $4.0 billion in 2007 to $3.3 billion in 2012) not private industry (i.e., $2.0 billion in 2007and $2.0 billion in 2012). In contrast, during the same time period Australia experienced a positive 6.9% compound annualgrowth rate of biomedical R&D expenditure occurring in both the public sector (i.e., $3.3 billion in 2007 to $4.7 billion in2012) and private industry (i.e., $1.1 billion in 2007 to $1.4 billion in 2012). Moreover, the Australian government has justannounced in its 2014-2015 budget the establishment of a $20 billion Medical Research Future Fund. This new funding willessentially double the governments investment in medical research and will add $1 billion in new medical research fundingannually. A substantial part of this is targeted at clinical research, including clinical trials. Funding for clinical trials has beenincreasing substantially in the last 2 decades in Australia and is now in excess of $140 million per year.

4. We now have a crisisin the support of Canadian trials and trialists and the proposed changes would make it worse

CIHR support of clinical trials is already suboptimal. The new funding structure at CIHR has a maximum fundinglimit of $750,000 annually for Project Scheme Grants. Many important large RCTs require $1-2 million annually during therecruitment phase of a trial, thus making such RCTs ineligible for Project Scheme funding. The new Foundation Scheme has amaximum funding limit of $1.5 million annually; however, the Foundation Scheme is explicitly designed to fund a researchprogram and not a single study. Many large clinical trials require $5-8 million in funding. These sums of money wouldconsume the majority of funding available through a Foundation Grant, leaving little funding to support the other studiesrequired for a competitive Foundation Scheme Grant. Moreover, the economic modeling for the new funding structure aims tohave 45% of CIHRs Open Funding Grants Budget go to the Foundation Scheme; however, the Foundation Scheme needs tofund approximately 750 researchers through active grants at steady-state. The economic modelling to ensure this number offunded researchers means that only a few researchers in Canada can obtain $1 Million in annual funding. The most recentmodelling we have seen suggests only 15-20 researchers across all pillarsof research could obtain $1 Million in annualfunding. It is likely that no more than 2 or 3 clinical trialists will obtain this level of funding. Therefore, the new fundingschemes at CIHR have essentially eliminated the funding mechanism for large RCTs. We are unaware of any other form of

health research that is essentially being eliminated with the new funding structure at CIHR.Dr. Aubin also indicated that CIHR is considering funding of large clinical trials only, in a strategic funding

envelope, e.g., the trial is one of national priority, and also leverage a significant portion of the money from other partners.This approach would result in only commercially oriented trials obtaining funding. As a result, health care costs will go up, asall new PROVEN therapies will be expensive interventions. This will not only increase the costs to the provinces and limitaccess to healthcare overall, it will also single out disadvantaged groups (e.g., poor), who often do not have access to expensivetherapies, and will take the focus of research away from interventions that might help these groups. We need more, not fewer,clinical trials funded in Canada. Although we support leveraging money when possible, many trials of national importance tothe health of Canadians will not be able to leverage money. We agree with Dr. Aubins comment regarding the need for aseparate dedicated funding envelope for large RCTs, which would be separate from the funding for smaller RCTs. Thesesmaller trials could be funded via the Foundation or the Project Schemes.


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Elizabeth Asztalos (Neonatology, University of Toronto)

Rebecca Auer (General Surgeon, University of Ottawa)

Alan Barkun (Gastroenterology, McGill University)

Brendan Barrett (Nephrology, Memorial University)

Jon Barrett (Obstetrics and Gynecology, University of Toronto)

Robert Beanlands (Cardiology, University of Ottawa)

Mohit Bhandari (Orthopedic Surgery, McMaster University)

David Birnie (Cardiology, University of Ottawa)

Penny Brasher (Statistician, University of British Colombia)

Rodney Breau (Surgery, University of Ottawa)

Jan Brozek (General Medicine and Allergy, McMaster University)

Dianne Bryant (Trialist, University of Western Ontario)

Jason Busse (Pain Medicine, McMaster University) -

Bill Cameron (Infectious Disease and Respirology, University of Ottawa)

Larry Chambers (Trialists, Epidemiologist, University of Ottawa)

Mark Clemons (Oncology, University of Ottawa)

Stuart Connolly (Cardiology, McMaster University)

Deborah Cook (Intensive Care, McMaster University)

Curtis Cooper (Infectious Disease, University of Ottawa)

Shelagh Coutts (Neurology, University of Calgary)

Jafna Cox (Cardiology, Dalhousie University)

Gilles Dagenais (Cardiology, University of Laval)


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Janet Dancey (Oncology, Queens University)

Andrew Day (Statistics, Queens University)

Andrew Demchuk (Neurology, University of Calgary)

Marc Deyell (Cardiology, University of British Columbia)

Bindi Dhesy (Oncology, McMaster University)

Paul Dorian (Cardiology, University of Toronto)

John Eikelboom (Thrombosis and Transfusion Medicine, McMaster University)

Elisabeth Eisenhauer (Oncology, Queens University)

Derek Exner (Cardiology, University of Calgary)

Justin Ezekowitz (Cardiology, University of Alberta)

Paul Farand (Cardiologist, University of Sherbrooke)

Michael Farkough (Cardiology, University of Toronto)

Dean Ferguson (Trialist, University of Ottawa)

Mark Fitzgerald (Respirology, University of British Columbia)

Guy Fradet (Cardiothoracic Surgery, University of British Colombia)

Stephen Fremes (Cardiac Surgery, University of Toronto)

Martin Gardner (Cardiology, Dalhousie University)

Amit Garg (Nephrology, University of Western Ontario)

Hertzel Gerstein (Endocrinology, McMaster University)

Jagbir Gill (Nephrology, University of British Columbia)

John Gill (Nephrology, University of British Colombia)

Ian Gilron (Pain Medicine, Queens University)


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Shaun Goodman (Cardiology, University of Toronto)

Michelle Graham (Cardiology, University of Alberta)

Jeremy Grimshaw (Health Care TrialsU of Ottawa)

Gordon Guyatt (General Internal Medicine, McMaster University)

Vladimir Hachinski (Neurology, University of Western Ontario)

Stewart Harris (Endocrinology, University of Western Ontario)

Jeff Healey (Cardiology, McMaster University)

Brenda Hemmelgarn (Nephrology, University of Calgary)

Michael Hill (Neurology, University of Calgary)

Anne Holbrook (General Medicine, McMaster University)DLS

Irene Hramiak (Endocrinology, University of Western Ontario)

Eileen Hutton (Midwifery, McMaster University)

Michael Jacka (Anesthesiology, University of Alberta)

Sanjit Jolly (Cardiology, McMaster University)

Charlotte Jones (Endocrinology, University of British Colombia)

Janusz Kaczorowski (Epidemiology, University of Montreal)

Paul J. Karanicolas (Hepatobiliary Surgery, University of Toronto)

Greg Knoll (Nephrology, University of Ottawa)

Andrew Krahn (Cardiology, University of British Colombia)

Lyne Lalonde (Pharmacy, University of Montreal) -


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Andre Lamy (Cardiac Surgery, McMaster University)

Scott Lear (Epidemiologist, Trialist, Simon Fraser University)

Agnes Lee (Thrombosis, University of British Columbia)

Douglas Lee (Cardiology, University of Toronto)

Lawrence Leiter (Endocrinology, University of Toronto)

Evan Lockwood (Cardiology, University of Alberta)

Charmaine Lok (NephrologyUniversity of Toronto)

Laurent Macle (Cardiology, University of Montreal)

Stuart MacLeod (Paediatrics, University of British Columbia)

Sumit Majumdar (Internal Medicine, University of Alberta)

John Mancini (Cardiology, University of British Colombia)

Braden Manns (Nephrology, University of Calgary)

Guillaume Martel (Surgery, University of Ottawa)

Finlay McAlister (General Internal Medicine, University of Alberta)

Sarah McDonald (Obstetrics, McMaster University)

Shamir Mehta (Cardiology, McMaster University)

Ralph Meyer (Oncologist, McMaster University)

Michael McGillion (School of Nursing, McMaster University)

Paul Moayyedi (Gastroenterology, McMaster University)

David Moher (Trialist, University of Ottawa)

Carlos Morillo (Cardiology, McMaster University)


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Robby Nieuwlaat (Trialist, Epidemiologist, McMaster University)

Paul Novak (Cardiology, University of British Columbia)

Paul OByrne (Respirology, McMaster University)

Alexandra Papaioannou (Geriatrics, McMaster University)

Joel Parlow (Anesthesiology, Queens University)

Janice Pogue (Statistics, McMaster University)

Tim Ramsay (Statistics, University of Ottawa)

Robin Roberts (Trialist, Statistics, McMaster University)

Robert Roberts (Cardiology, Genetics, University of Ottawa)

Roopinder Sandhu (Cardiology, University of Alberta)

Martin Schechter (Population Health, University of British Columbia)

Holger Schunemann (General Internal Medicine, McMaster University) -

J.D. Schwalm (Cardiology, McMaster University)

Colette Seifer (Cardiology, University of Manitoba)

Stan Shapiro (Statistics, McGill University)

Robert Sheldon (Cardiology, University of Calgary)

Chris Simpson (Cardiology, Queens University)

Robert Sindelar (Pharmaceutical Sciences, University of British Columbia)

Samuel Siu (Cardiology, University of Western Ontario)

Eric Smith(Neurology, University of Calgary)

Sadeesh Srinathan (Thoracic Surgeon, University of Manitoba)


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David Spence (Neurology, Pharmacology, University of Western Ontario)

Sharon Straus (Geriatrics, University of Toronto) -

Wayne Taylor (Statistics, Trialist, DataFax Hamilton)

Monica Taljaard (Epidemiologist, University of Ottawa)

JC Tardiff (Cardiology, University of Montreal)

Koon Teo (Cardiology, McMaster University)

Lehana Thabane (Statistics, McMaster University)

Judith Therrien (Cardiologist, McGill University)

George Tomlinson (Biostatistics, University of Toronto)

Marcello Tonelli (Nephrology, University of Alberta)

Jack Tu (Cardiology, University of Toronto)

Ross Tsuyuki (Pharmacy, University of Alberta)

Sander Van Zanten (Gastroenterology, University of Alberta)

Ron Wald (Nephrology, University of Toronto)

Mark Walker (Obstetrics, University of Ottawa)

Michael Walsh (Nephrology, McMaster University)

Garth Warnock (Surgery, University of British Columbia)

Tim Whelan (Radiation Oncology, McMaster University)

Richard Whitlock (Cardiac Surgery, McMaster University)

Steve Whilton (Cardiology, University of Calgary)


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George Wyse (Cardiology, University of Calgary)

Karen Yeates (Nephrology, Queens University)

Bernie Zinman (Endocrinologist, University of Toronto)


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Table: Examples of practice changing Canadian led trials that received peer-reviewed funding

Trial Results

Interventions that reduce disability and untimely deaths

Canadian Aspirin Trial (first RCTfunded by MRC in 1970)

Aspirin reduced major stroke and death among patients withthreatened stroke, became and remains global standard of care.

Aspirin in unstable angina trial Aspirin reduced the risk of myocardial infarction and mortality,became and remains global standard of care.

North American CarotidEndarterectomy Trial (NASCET)

Showed that carotid endarterectomy reduced the 2-year risk of strokeor death by 60% in patients with severe stenosis, and significantlyimproved risk in patients with moderate stenosis. This became andremains the global standard of care.

Post-term Induction Trial Labor induction reduced the risk of caesarian section compared toantenatal monitoring in post-term pregnancies, became and remains

global standard of care.Prevention of gastrointestinalbleeding in mechanicallyventilated patients trial

Ranitidine was superior to sucralfate in preventing gastrointestinalbleeding in patients requiring mechanical ventilation, resultsimpacted care globally.

HOPE An angiotensin -converting enzyme inhibitor (ramipril) reduced therisk of death, myocardial infarction, and stroke in patients withatherosclerosis, became and remains global standard of care.

Alberta Nocturnal Dialysis trial For people with end-stage kidney failure, frequent home nocturnalhemodialysis improves quality of life, and markers of cardiovascularhealth in comparison to intermittent, thrice weekly dialysis, withoutincreasing cost.

North American Opiate

Medication Initiative (NAOMI)

In people with severe heroin addiction, medically prescribed heroin

(diacetylmorphine) was more effective at retaining patients,improving their mental and physical health, and reducing theircriminal activity and social isolation than conventional treatments.

NCIC Clinical Trials GroupTrial CE.3 (Brain Cancer)

This RCT developed in collaboration with European partnersevaluated a radiosensitizing/adjuvant approach to treatment inglioblastoma and was the first study in 3 decades to; identify anintervention that significantly improved survival. This treatment isnow used around the world as the standard of care in glioblastomatreatment

TRANSFER Acute MyocardialInfarction (AMI)

A strategy of immediate transfer to another hospital with earlycoronary angiography (with revascularization where appropriate)strategy reduced the risk of the composite of death, reinfarction,

recurrent ischemia, new or worsening congestive heart failure, orcardiogenic shock among higher-risk patients with ST-segmentmyocardial. This has influenced care in Canada and globally.

Resynchronization-Defibrillationfor Ambulatory Heart Failure(RAFT) Trial

Among patients with mild to moderate heart failure who arereceiving an implantable cardioverter-defibrillator (ICD) the additionof cardiac-resynchronization therapy (CRT) reduces the risk ofmortality and hospital admission for heart failure. Internationalguidelines now recommend this intervention and patients throughoutCanada and around the global benefit from this intervention.

Diabetes Control andComplications Trial (DCCT)

This Canadian and American trial showed that tight glycemic controlreduces eye, kidney, nerve, and cardiovascular outcomes in type 1diabetes and has changed the way that type 1 diabetes is treated inCanada and globally.


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