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 of
important public health and clinical questions. A fundamental lesson learnt from 4 decades of conducting RCTs that are the
basis of contemporary treatments in routine clinical practice is that RCTs need to be of sufficient size to produce reliable
results. 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 other
forms of research in Canada and other countries) has been documented by 3 national panels that the MRC and the CIHR
convened over the last 15 years. Most of the substantive issues in these reports have been largely ignored and the funding of
clinical 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 CIHRs
old 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 is
continuing at CIHR and no decisions have yet been made. As I think we discussed previously, in the current environment of
fiscal 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 both
nationally and internationally and many agencies are considering a similar approach. Randomized clinical trials will be
permitted within the Foundation Scheme. However they must be part of a larger program of research (i.e., it cannot be an
application for one project requiring a large sum of money) and we encourage clinician researchers who conduct programmatic
funding to apply to this program.
We, as Canadian leaders in Clinical trials, disagree and are concerned that if these suggestions in Dr. Aubins email
were 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 and
immediate 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; Canada
is 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 the
situation even worse; and
5. There is a need for an immediate increase in support for RCTs, and there is a need for long-term stability in RCT
support.
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 improving
the health of Canadians. This includes basic science research leading to outcomes such as the discovery of insulin and it
includes clinical research of which clinical trials are a vital component. If discoveries from basic science need to be translated
into clinical practice to improve the health of the people of Canada, reliable (and often large) trials are essential. There is
simply no other alternative. CIHR at present does not have a balanced approach by which the flow of discoveries can be
reliably 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, clinical trials of sufficient size to produce reliable results have had the most
direct and immediate impact on the health of people. Large randomized trials are critical for the evaluation of most new and
old therapies, devices, surgical procedures, and healthcare implementation strategies. Studies demonstrate that large clinical
trials have the most profound effect on influencing the actions of health care providers. Therefore it is crucial that Canada has
a balanced approach to funding different forms of research and an appropriate share of the CIHR funds need to be allocated for
the 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 of
quality, not quantity) of studies done in various categories by researchers in several countries. In a report published in Nature,
under the heading of clinical medicine, which includes RCTs, Canada was second only to the US ahead 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. some
commonly used treatments that do more harm than good, which has led to their use declining; and 3. effective knowledge
translation and health services approaches to improving clinical care. The Table below reports a few of the plethora of
Canadian examples. These trials have had profound effects in prolonging and improving the lives of Canadians and citizens
throughout the world and have likely avoided deaths and morbid events in millions of 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 of
Health spent 11% of its overall budgets on RCTs. This means that the US spends nine times as much money per capita on
publicly funded trials as does Canada. Several years ago, the UK recognized the relative paucity of funding for clinical
research, 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. About
20%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 of
biomedical R&D expenditures by country, adjusted for inflation between 2007 and 2012. Globally Canada finished last and
experienced a decrease in inflation-adjusted expenditures going from $6.0 billion in 2007 to $5.3 billion in 2012 (i.e., a
negative 2.6% compound annual growth rate of biomedical R&D expenditures). Canadas decrease in funding occurred in the
public 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 2007
and $2.0 billion in 2012). In contrast, during the same time period Australia experienced a positive 6.9% compound annual
growth rate of biomedical R&D expenditure occurring in both the public sector (i.e., $3.3 billion in 2007 to $4.7 billion in
2012) and private industry (i.e., $1.1 billion in 2007 to $1.4 billion in 2012). Moreover, the Australian government has just
announced in its 2014-2015 budget the establishment of a $20 billion Medical Research Future Fund. This new funding will
essentially double the governments investment in medical research and will add $1 billion in new medical research funding
annually. A substantial part of this is targeted at clinical research, including clinical trials. Funding for clinical trials has been
increasing substantially in the last 2 decades in Australia and is now in excess of $140 million per year.
4. We now have a crisis in 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 funding
limit of $750,000 annually for Project Scheme Grants. Many important large RCTs require $1-2 million annually during the
recruitment phase of a trial, thus making such RCTs ineligible for Project Scheme funding. The new Foundation Scheme has a
maximum funding limit of $1.5 million annually; however, the Foundation Scheme is explicitly designed to fund a research
program and not a single study. Many large clinical trials require $5-8 million in funding. These sums of money would
consume the majority of funding available through a Foundation Grant, leaving little funding to support the other studies
required for a competitive Foundation Scheme Grant. Moreover, the economic modeling for the new funding structure aims to
have 45% of CIHRs Open Funding Grants Budget go to the Foundation Scheme; however, the Foundation Scheme needs to
fund approximately 750 researchers through active grants at steady-state. The economic modelling to ensure this number of
funded researchers means that only a few researchers in Canada can obtain $1 Million in annual funding. The most recent
modelling we have seen suggests only 15-20 researchers across all pillars of research could obtain $1 Million in annual
funding. It is likely that no more than 2 or 3 clinical trialists will obtain this level of funding. Therefore, the new funding
schemes 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, as
all new PROVEN therapies will be expensive interventions. This will not only increase the costs to the provinces and limit
access to healthcare overall, it will also single out disadvantaged groups (e.g., poor), who often do not have access to expensive
therapies, 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 to
the health of Canadians will not be able to leverage money. We agree with Dr. Aubins comment regarding the need for a
separate dedicated funding envelope for large RCTs, which would be separate from the funding for smaller RCTs. These
smaller trials could be funded via the Foundation or the Project Schemes.
5. There is a need for an immediate injection of RCT support, and there is a need for long-term stability in RCT
support.
We are calling on CIHR to do the following:
1. immediately increase funding for RCTs from 3.3% to 5% of the total budget immediately and to 10% within 3
years (these recommendations have been made repeatedly for the last 15 years), and we are willing to work with
CIHR to make the case for this long-term increase in funding;
2. create a separate dedicated funding envelope for large RCTs;
3. inform Canadian researchers before June 22, 2014 if they will be able to subsequently compete for large RCT
grants while holding a Foundation Scheme Grant;
3. ensure that CIHR not require matching funding for at least a substantial proportion of future large clinical trials;
4. establish that for the majority of funded trials that the peer review community should decide which trials are of
national priority; and
5. begin a dialogue with Canadian clinical researchers regarding the creation of a new model to enable support of
human research in Canada. Such dialogue could consider a) 2 vice-presidents (one for basic science and one for the
pillars 2, 3, and 4); b) 3-4 vice-presidents to cover the 4 pillars; c) a new branch of CIHR dedicated to human applied
research; or d) a new agency for human applied research, as has been done in the UK.
We respectfully request that you as the Chair of the Governing Council of CIHR find urgent solutions to these issues.
We look forward to receiving your response. We request you to circulate this letter to all members of the Governing Council
and that these concerns are fully discussed by them. Several of us would be pleased to meet with you to discuss solutions and
ways forward, if you think this would help.

Sincerely:

(in alphabetic order)


John Cairns P.J. Devereaux Jack Hirsh


Dave Sackett Salim Yusuf




Co-signatories (in alphabetical order)

Shawn Aaron (Respirologist, University of Ottawa)

Rick Adachi (Rheumatology, McMaster University)

Shabbir Alibhai (Geriatrics, University of Toronto)

Todd Anderson (Cardiology, University of Calgary)

Paul Armstrong (Cardiology, University of Alberta)

Malcolm Arnold (Cardiology, University of Western Ontario)

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)

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)

Shaun Goodman (Cardiology, University of Toronto)

Michelle Graham (Cardiology, University of Alberta)

Jeremy Grimshaw (Health Care Trials U 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) -

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 (Nephrology University 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)



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)
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)

George Wyse (Cardiology, University of Calgary)

Karen Yeates (Nephrology, Queens University)

Bernie Zinman (Endocrinologist, University of Toronto)








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 RCT
funded by MRC in 1970)
Aspirin reduced major stroke and death among patients with
threatened 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 Carotid
Endarterectomy Trial (NASCET)
Showed that carotid endarterectomy reduced the 2-year risk of stroke
or death by 60% in patients with severe stenosis, and significantly
improved risk in patients with moderate stenosis. This became and
remains the global standard of care.
Post-term Induction Trial Labor induction reduced the risk of caesarian section compared to
antenatal monitoring in post-term pregnancies, became and remains
global standard of care.
Prevention of gastrointestinal
bleeding in mechanically
ventilated patients trial
Ranitidine was superior to sucralfate in preventing gastrointestinal
bleeding in patients requiring mechanical ventilation, results
impacted care globally.
HOPE An angiotensin -converting enzyme inhibitor (ramipril) reduced the
risk of death, myocardial infarction, and stroke in patients with
atherosclerosis, became and remains global standard of care.
Alberta Nocturnal Dialysis trial For people with end-stage kidney failure, frequent home nocturnal
hemodialysis improves quality of life, and markers of cardiovascular
health in comparison to intermittent, thrice weekly dialysis, without
increasing 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 their
criminal activity and social isolation than conventional treatments.
NCIC Clinical Trials Group
Trial CE.3 (Brain Cancer)
This RCT developed in collaboration with European partners
evaluated a radiosensitizing/adjuvant approach to treatment in
glioblastoma and was the first study in 3 decades to; identify an
intervention that significantly improved survival. This treatment is
now used around the world as the standard of care in glioblastoma
treatment
TRANSFER Acute Myocardial
Infarction (AMI)
A strategy of immediate transfer to another hospital with early
coronary angiography (with revascularization where appropriate)
strategy reduced the risk of the composite of death, reinfarction,
recurrent ischemia, new or worsening congestive heart failure, or
cardiogenic shock among higher-risk patients with ST-segment
myocardial. This has influenced care in Canada and globally.
Resynchronization-Defibrillation
for Ambulatory Heart Failure
(RAFT) Trial
Among patients with mild to moderate heart failure who are
receiving an implantable cardioverter-defibrillator (ICD) the addition
of cardiac-resynchronization therapy (CRT) reduces the risk of
mortality and hospital admission for heart failure. International
guidelines now recommend this intervention and patients throughout
Canada and around the global benefit from this intervention.
Diabetes Control and
Complications Trial (DCCT)
This Canadian and American trial showed that tight glycemic control
reduces eye, kidney, nerve, and cardiovascular outcomes in type 1
diabetes and has changed the way that type 1 diabetes is treated in
Canada and globally.
NCIC Clinical Trials Group
Trial BR.10 (Lung cancer)
This trial evaluated the use of [post-operative adjuvant
chemotherapy in patients with resected non-small cell lung cancer
and demonstrated a 15% absolute improvement in 5 year survival
rates in the treated group. Subsequent Ontario population level data
have shown not only has adjuvant chemotherapy been adopted into
practice, but that there is evidence of improvement in survival at the
population level in the era following adoption of this intervention.
Commonly used treatments that were shown to do more harm than good or to consume
unnecessary resources
EC/IC Bypass Study Extracranialintracranial arterial bypass surgery increased the risk of
stroke compared to medical therapy in patients with symptomatic
cerebral arterial disease, these results led to the discontinuation of
this surgery.
Transfusion requirements in
critical care Trial
A less expensive, conservative transfusion policy is as good as or
better than a more expensive liberal policy in saving the lives of
patients with critical illnesses, these results have influenced
guidelines and clinical care globally.
POISE Trial A commonly used intervention (a beta-blocker) given to patients
having noncardiac surgery was shown to increase the risk of stroke
and mortality compared to placebo, these results have influenced
guidelines and clinical care globally.
Duration of radiation treatment in
breast cancer
Among women with invasive breast cancer who had undergone
breast-conserving surgery and in whom resection margins are clear
and axillary lymph nodes are negative a hypofractionated 3-week
schedule of whole-breast irradiation is as effective as a 5-week
schedule (the prior standard of care). These results have impacted
guidelines and the care of Canadian women suffering from breast
cancer and in the process established greater capacity in the system
to deliver timely radiation therapy to women with breast cancer.
Diabetic Intervention with
Vitamins in Diabetic Nephropathy
trial (DIVINe)
Showed that high-dose B vitamins that lowered homocysteine were
harmful in patients with diabetic nephropathy, accelerating decline
of renal function and doubling cardiovascular events among patients
with GFR<50.
Effective knowledge translation and health services approaches to improving clinical care
Burlington Trial of the Nurse
Practitioner
Demonstrated that Canadian Nurse-Practitioners could provide high-
quality care for 80% of primary care complaints at great financial
savings, these results were crucial for the development of Nurse-
Practitioner programs.
Quarite Trial Education and audit was demonstrated to be effective in reducing
maternal mortality in Sub-Saharan Africa, these results are
influencing care in Africa.
CHAP Trial A cluster trial among Ontarian towns demonstrating that linkage
between pharmacy-measured blood pressures and general
practitioners reduced hospitalizations and treatment costs for
cardiovascular disease.
Note most of these trials have little commercial interest but have substantial human impact.
Action to Control Cardiovascular
Risk in Diabetes (ACCORD)
Trial
A Canadian led trial that showed that intensive glycemic control
increases the risk of cardiovascular death in some people with
established type 2 diabetes and has modified Canadian guidelines
and the care of these individuals.