Oncology Rounds

Oncology Rounds

Protecting Patients or Stifling Research? The Swing of the Research Pendulum

October 2011

Jack Holland MD FRCP FRCP(C)

Oct 2011J Holland OCREB

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Protecting the patient

Stifling Research

The Research Ethics Pendulum

Themes to be explored over the next 45 minutes or so….

• Advancement in science is a good thing…. ▫ for the man in the street▫ for our institutions▫ for business▫ for Ontario, for all of Canada

• Losing the ethical compass may be deadly!• The Research Ethics Board can be your ally• The Research Ethics Board can be a royal pain

in the ass!• Working together - for the man in the street,

the institution, for business, for Ontario, for Canada


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The Impact of ResearchAAHRPP, Fall 2005

• 83% of adults believe it is either “essential” or “very important” that prescription drugs and new treatments be tested in humans

• Each year, several million Americans participate in clinical trials

• Currently, there are more than 41,000 active industry-and government-sponsored clinical trials

PARTICIPATION IN ETHICALLY SOUND RESEARCH IS IN THE BEST INTEREST OF THE PUBLIC

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……. and in 2011, it’s getting more and more exciting• Targeted drug therapy

▫Sloane Kettering is testing 40 mutations in 7 genes in all patients with lung or colon cancer

▫Inhibition of mutated, activated BRAF in metastatic melanoma

• Pharmacogenomics and drug/patient specificity

• “Point of Care Testing”▫“SPARTAN” – in 45 minutes - 25 genes

regulating CYP2C19, influencing projected response to clopidogrel

• High Impact Clinical Trials Program at OICR▫Translational research; team building


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….. and it’s getting more and more complex


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The Complexity of Modern Genetics

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The research maze………

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Clinical Research: Process, Policy, Procedures

PRINCIPAL INVESTIGATOR

STUDY MANAGEMENT OVERSIGHT DISSEMINATIONAPPROVALSSCIENCE

CLINICAL RESEARCHIntegrated

Research Services

VP research

Clinical DepartmentResearch Directors

Peer ScientificReviews

Grants

Contracts

Division / DeptClinical ServicesClinical Program

HEALTH CANADA( &/or FDA )

RESEARCHETHICS BOARD

PatientsPatient Care policySafe Location

Education

Study Audit& Monitoring

Clinical ResearchSite (Nursing, Beds, Exercise Lab)

Staff Education

Template SOPs

Study Budgets

Data Management & Biostatistics

Health Care Team:- Clinical Practice- Rounds

Research SubjectsPatients:- Individual Results- Summary Results

Colleagues:- Conferences- Peer review journals

Public:- Advocacy Groups- Granting Agencies- Media

Medical AdvisoryCommittee

ClinicalDepartments

Study Design (Sponsor; PI)



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…and it’s getting worse, capturing the attention of our provincial governments across the country


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NCIC CTG Data: Average Time (Days) for First Centre Activation 1995-2009

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Ontario Data: Proportion New Treatment Cases Enrolled on Clinical Trials

% N

ew

Can

cer

Tre

atm

en

t C

ases

En

rolled

on

Tri

als

8.9% 11.2% 11.9% 12.4% 9.0% 8.5%

OICR Infrastructure Funding

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Ontario Data: Actual Number of Patients Enrolled on Trials 2004-2009

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Annual Average # of ‘Activated’ CDN Centres per Trial

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Summary Trial Activation Trends•In Institutions, increasing times to trial

activation and first patient enrolled (data not shown)

•Up to 50% of all centres opening a trial never enrol a patient (NCIC CTG data)

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Ontario’s Clinical Trials Enterprise• April 30, 2010 - Ontario Government

▫ $161 million Life Sciences Commercialization Strategy. ▫ provides $17 million for three clinical trials related initiatives,

including

“A New province-wide coordinating infrastructure to streamline administrative processes and ethics reviews across multiple clinical trial sites in order to increase the speed of patient recruitment.”

• November 2010 - key stakeholders group established by the Ministry of Research and Innovation (MRI)

▫ BIOTECanada (National Biotechnology Industry Group)▫ CAHO (Council of Ontario Academic Hospitals of Ontario)▫ COFM (Council of Ontario Faculties of Medicine)▫ MEDEC (Canada’s Medical Technology Companies)▫ OCUR (Ontario Council on University Research)▫ Rx&D (Canada’s Research-based Pharmaceutical Companies)

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Clinical Trials and the Economy• In 2008, global clinical trials market, estimated at

$50 billion; estimated to grow by 10% per year• Canada’s market share 4.1% ($2.05 billion)

▫ But, 12% drop in the average annual growth rate of clinical trials activity in Canada between 2002 and 2007 (Clinicaltrials.gov)

▫ transfer of clinical trial work to low-cost economies ▫ decreasing competitiveness in Canada compared to the U.S. and

Western Europe.

• Provincial and federal governments are looking closely at ways of providing industry with a streamlined approach to ethics review and contracting for multi-centred clinical trials

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Ontario’s Clinical Trials Enterprise• Phase 1: Proof of Concept

▫designate REB “nodes” to undertake province-wide ethics review

▫establish a set standards acceptable across all sites

• Phase 2: Development of an online application and data management system

• Phase 3: Establishment of a centralized office (“Clinical Trials Ontario”) for linkage and coordination

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Phase 1: Project Management • Creation of a Project Management Office (PMO)

▫ to support planning and implementation▫ to liaise with project sponsors in alignment with local,

provincial and national initiatives ▫ to hold the funding for the entire project▫ to provide project updates to stakeholders and project sponsors,

including detailed costing at the end of each phase of the project

• Creation of an Oversight Committee

▫ to provide day to day direction/governance to the PMO; engage the broader Stakeholder Committee for input on substantive decisions required in Phase 1

two research hospital representatives from the Stakeholder Committee

two university representatives from the Stakeholder Committee two industry representatives chosen by Rx&D.

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Phase 1: Selection of Phase I Nodes

Region Site

Hamilton Hamilton Health Sciences Centre

Kingston Queen’s University

London University of Western Ontario

Northern Ontario Thunder bay Regional health Sciences Centre

Ottawa Ottawa Hospital Research Institute

Toronto St Michael’s HospitalSunnybrook Health Sciences CentreUniversity Health Network

Following a number of defined primary and secondary criteria the following sites/nodes were identified:

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Alberta• Research Ethics Reciprocity Agreement signed

February 2011

• 6 REBs which are legislated under the Health Information Act

• Agreement applies only to multi-jurisdictional research, does not obviate the need for local ethics review

• Still need to implement and develop common SOPs, applications, guidelines and an IT infrastructure to support

• Of the 3000 active studies in the University of Alberta REB database what % are multi-jurisdictional?

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Saskatchewan

• 5 REBs with ministerial approval, 4 have agreed to share in the harmonization process

• Bottom up approach with limited reciprocity

• Applications and Consent forms have been harmonized

• 6 REBs which are legislated under the Health Information Act

• Trust-building exercise

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The clinical contractEthical review

Villains?


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Brains Buildings

Buck$ More Buck$

Brilliance

REB

Success Factors in the Research Enterprise


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Why is REB approval a big deal?

Are REBs doing a good job?


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Two questions for you to consider

It’s all about developing a culture of ethical integrity


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“You do as you’re told, we pay you as we please. You work like a slave, we punish you at random.

That, in a nutshell, is our corporate culture”

Developing a Culture of Personal Ethical Integrity


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Mandate of the REB

To protect the rights, safety and well-being of any patient or healthy volunteer who participates in research at…….

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Foundations of Research Ethics Historical precedent Recent disasters - screw ups!! The importance of maintaining “trust”

with the public It’s just the right thing to do

You should agree The institution should agree

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Joseph Mengele & The Eva Kor Story

• Eva Kor, living testament to the absolute requirement for informed consent of subjects in medical experimentation


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More Recent Disasters


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Hospital for Sick Children 2007

CLINICAL TRIALS GONE WRONG – THE TEGENERO STORY AND CRISIS COMMUNICATIONS

February 2007

• Only six years after being spun out of the University of Würzburg, TeGenero AG had a US$19 million war chest thanks to venture capitalists and a promising new drug about to enter human trials - AG TGN1412

• Less than five months after the catastrophic failure of its trial, the company was bankrupt.


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WHAT HAPPENED?

• In the early hours of the morning of March 15th

six men were rushed to a London hospital after being dosed with the experimental drug – TGN 1412.

• During the course of the first day, shortly after the dosing was complete, a trial participant complained of a headache, fever and pain. He took his shirt off, saying he felt like he was burning.

• His fellow trial participants followed suit shortly thereafter. All the test subjects who got the real drug (two got a placebo) ended up in an intensive care unit.


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“The death of 18-year-old Jesse Gelsinger in a gene-transfer trial led to the discovery by the National Institutes of Health (NIH) of many hundreds of unreported adverse events among volunteers enrolled in gene-transfer

experiments”

Contd. Sept 14th 2000Oct 2011

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Background*

• 18 year old volunteer (for corrective gene study) • Jesse Gelsinger died during study

• The complaint alleged that:

▫ The University was to receive ownership stake in the sponsor company

▫ The University and various physicians associated with research had substantial financial and equity interests with respect to research products

• The extent of financial interests were not disclosed to Gelsinger in the informed consent process

• Case settled for an undisclosed amount

* Gelsinger v. Trustees of the University of Pennsylvania- http://www.skrplaw.com/links/healthcare2.html

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“To put it simply, if we cannot guarantee sound research in general — and patients' safety in particular —

public support for gene therapy and other potentially lifesaving treatments will evaporate. Volunteers will not show up, and the generous stream of Government research dollars……..may shrink. So clinical researchers and the institutions that support them must, without exception, maintain the public's confidence in our work, our competence, and most important, our ethics”.

Donna Shalala

US Deptof Health

and Human Services

Sept 14th 2000

(on the death of 18 yr old

Jesse Gelsinger)

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Suspensions of Federally Supported Research

Date Institution

March ‘99 Veterans’ Affairs Los Angeles

May ‘99 Duke University

August ‘99 University of Illinois Chicago

Jan 2000 Virginia Commonwealth University

June 2001 University of Oklahoma

July 2002 John Hopkins Medical Institutions

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What if, 2011 UHN??; Ottawa Hosp Res Institute???

National Post

February 2004

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National Post

February 2004

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Death of Ryan Lucio

Children’s HospitalOf Eastern Ontario

September 2003

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Brains Buildings

Buck$ More Buck$

Brilliance

REB

Success Factors in the Research Enterprise


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Brains Buildings

Buck$ More Buck$

Brilliance

REB

Vulnerability of the Research Enterprise

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So, are we doing a good job?

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Research Ethics Boards

‘A sad indictment of the whole system of review is the adversarial relationship that now seems to exist between frustrated, overburdened researchers and frustrated, overburdened research ethics

committees’

Lancet Oncology May 2004

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Do IRBs Protect Human Research Participants?

Christine Grady, RN, PhD

JAMA. 2010;304(10):1122-1123.

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Institutional review boards are described as dysfunctional, in crisis, and " . . . more concerned with protecting the institution than research participants.“

Researchers, institutions, and some IRB members complain about burden and "mission creep“ — the excessive paperwork, inflexible interpretation of regulatory requirements, attention to inconsequential details, and expanding obligations of IRBs that seem to have little to do with protection of research participants.

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Grady, C. JAMA. 2010;304(10):1122-1123


Excessive or "hyper" regulation is seen as seriously affecting or stifling research productivity without adding meaningful protections for participants.

"IRBs have disrupted student careers, set back tenure clocks, and blunted the essence of many intellectual traditions. Facing demands that spiral to the level of sheer impracticality, faculty and students . . . face a stark choice: to conduct innovative research in their fields or to meet the requirements of their IRB."

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The Paradoxical Problem with Multiple-IRB Review

• There is little evidence that having multiple IRBs review a single study has led to the ethical improvement of protocols of consent forms

• On the contrary this practice seems to pose a significant risk of diminishing the ethical integrity of the study

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Menikoff, J Director, Office for Human Research Protection

NEJM Oct 2010Gasp……say it ain’t so!

And more……!

“It should be recognized that the problem with multiple- IRB review relates not merely to wasted time and effort but also to less-than-optimal protection of people who volunteer to participate in research

This recognition should add urgency to our efforts to solve this problem”.

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Reforming the Regulations Governing Research with Human Subjects

Ezekiel J. Emanuel, M.D., Ph.D., and Jerry Menikoff, M.D., J.D.

Sounding Board

N Eng J Med July 2011


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Protecting the patient

Stifling Research

The Research Ethics Pendulum

Conclusions• There is a growing perception, nationally and

internationally, that the process of ethics review may be a major contributing factor to the documented reduction in the progress of clinical research, particularly research involving multicentre clinical trials.

• Canadian REBs could assume a leadership role in bringing about meaningful change to the process of ethics review; this would be beneficial to

▫ the health of the population at large▫ our institutions and the community they serve ▫ the Ontario and Canadian economy

• The search for opportunities for improvement in REB functioning should be a priority

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Moving forward………


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Balance: Getting it right!

The Solution

Do we need to re-think the functioningof the Research Ethics Board?

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European Union

Restricts each participating country to a “single opinion” representing the ethics review for that country, “notwithstanding the number of Ethics Committees” involved

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the UK experience

• In 2001, the UK government created the National Cancer

Research Network (NCRN):

▫ to support high quality cancer clinical studies within the National Health Service

▫ to improve the speed, quality, and integration of research leading

▫ to improve patient care.

• Clinical trial participation among cancer patients in the UK doubled since 2001, rising to 14%.

• National Clinical Research Co-ordinating Centre created to expand the work of NCRN to other disease states▫ initial Government investment of 14 million pounds▫ centralization of contracts▫ centralization of ethics review

• In 5 years, trial participation equivalent to that of the US NIH

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Office for Human Research Protections (OHRP)

• to have sponsors require the use of a central IRB as a condition for participating in a study.▫ nothing in the existing U.S. regulations would prevent

them from doing so

• OHRP be given the authority to take action against IRBs — as distinct from the institutions conducting the research — for noncompliance with regulations

▫ with the intent of providing assurance to individual institutions that they would not be blamed if an outside IRB were responsible for violations.

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Canada: Proposals for ChangeHébert and SaginurCMAJ March 2009

•Harmonization of institutional standards across the country▫common forms would reduce the bureaucratic

burden for multicentre trials. ▫institutions and ethics committees would

work together to review trials and share findings.

▫established benchmarks would ensure timeliness and quality of reviews

▫a national education program would support REB members and health researchers

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Personal thoughts…….

• In Canada there is no system of accreditation to bring consistency to the process of research ethics review

• Movement towards centralized processes of ethics review is taking place, but slowly, and typically within provinces or within research-specific disciplines▫ Newfoundland and Quebec▫ OCREB▫ Common system of electronic data capture, ethics

review, processing and communication UBC; Alberta; OCREB

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Meanwhile…………..

• For as long as the system of multi-REB review persists (the status quo for the most part)

▫ REBs should seriously re-examine their primary mission

▫ REBs should seriously re-evaluate how they function in establishing priorities in streamling work-flow processes in reducing redundancy in communicating - with each other and with the research

community in education

both internal (the REB membership and its staff) and external ( the greater research community and the public)

in bullding and sustaining a “culture of ethical integrity” for the institutions they serve

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Conclusions: REBs should……..

• consider ways in which to enhance ethics review across multiple sites through collaboration and avoidance of duplication : locally, provincially, nationally▫ reciprocal agreements; Board of Record (BOR) agreements▫ common forms; accepted templates; common electronic

formats• provide value for research participants and for the

entire research enterprise• be valued and respected for the knowledge, judgment

and dedication represented by their members• include some of the institution’s best people in their

field• be viewed as an excellent educational resource for

aspiring researchers, learners

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REBs should……..• constantly re-evaluate their processes in carrying out

their primary function of “protecting the rights, safety and well-being of any patient or healthy volunteer who participates in research conducted by a member of the staff of the institution”

• be receptive to constructive criticism and open to change

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On a positive note……


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Collaborative Initiatives: 1

•An common consent form for cancer trials, acceptable to:

▫Ontario Cancer Research Ethics Board▫National Cancer Insitute of Canada

Clinical Trials Group (NCIC-CTG)▫BC Cancer Agency


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•Potential for reciprocity agreements between ▫Ontario (Ontario Cancer Research Ethics

Board)▫Alberta▫British Columbia (BC Cancer Agency)

Facilitated by a common electronic submission/data entry/communication platform


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•Potential Role of Sponsor in Initial Application

▫Initial provincial application from the SPONSOR

“upstream” provincial approval

relatively rapid approval for lead centre

approval of additional centers within 2 weeks or less.

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Overall Conclusions• In Canada the appetite for streamlining the process of

research ethics review is strengthening, province by province

• The principal motivation appears to be largely economic▫ to enhance Canada’s competitivness in global clinical trials

• There is “buy-in” from Government, the major institutions, industry and from ethics boards

• Harmonization of ethics review thus far is best developed in cancer clinical trials

• The major barriers indentified thus far include:▫ Lack of a common platform of communication betweeen major

research centres within and between provinces▫ Lack of a national accreditation process for ethics boards to

facilitate the development of reciprocity agreements betweeen major research centres within and between provinces

▫ Lack of a unifying federal “agenda” regarding funding and infrastructure


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Themes explored over the next 45 minutes or so….

• Advancement in science is a good thing…. ▫ for the man in the street▫ for our institutions▫ for business▫ for Ontario, for all of Canada

• Losing the ethical compass may be deadly!• The Research Ethics Board can be your ally• The Research Ethics Board can be a royal pain

in the ass!• Working together - for the man in the street,

the institution, for business, for Ontario, for Canada


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Jack Holland MD FRCP FRCP(C)

Chair: Ontario Cancer Research Ethics Board

Chair: Oncology Research Ethics Board,University Health Network, Toronto

[email protected]@uhnresearch.ca


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