NCEHR Listserv for August 2003

 

TOPICS

1. Accreditation

2. Clinical Equipoise, Pros and Cons

3. Conflict of Interest, REB Independence and Governance

4. ICH GCP Force of Law?

5. Must Consent Forms be Witnessed?

6. NCEHR Communique Volume 12

7. OHRP Criticizes IRBs

8. Ontario Cancer Care REB Job and Call for Members

9. REB Approval on Informed Consent Form

10. Combining IRBs

11. Sponsor IRB-REB Relationships

 

 

Files to Download

Trial Design and Patient Safety: The Debate Continues

Ontario Cancer Research Ethics Board Coordinator Posting

Ontario Cancer Center REB Newsletter

PRE Call for Public Consultation - Changes to the TCPS

CAPITAL DISTRICT HEALTH AUTHORITY
RESEARCH ETHICS BOARD POLICY ANALYSIS
Governance, Accountability and Conflict of Interest

 

1. Accreditation

From: "Laurel Evans" <levans@mcmaster.ca>
To: "Ethics List" <ethics@lists.ncehr-cnerh.org>
Subject: [Ethics] Accreditation
Date: Tuesday, August 26, 2003 2:17 PM

Speaking of governance, is anyone out there in the know about the status
of the accrediation initiative? If so, could you bring us / me
up-to-date on where it stands and who is involved? Frances? Thanks.

From: "Clark, Elisabeth" <clarke@muhchem.mcgill.ca>

Shafik, Laurel and All --
It is indeed perplexing that we in the stakeholder community, wishing to
support an accreditation process are reduced to wonder out loud about so
central an issue that has been so long pending.

One development in the Accreditation dossier important enough to repeat on
this List was the release of the "Royal College of Physicians and Surgeons
of Canada (RCPSC) Task Force on Clinical Research" final report that makes
the case for action, and presents options.

<http://rcpsc.medical.org/english/about/publicpolicy/index.php3>

Through a series of eight recommendations, the task force proposes pathways
to address the lack of needed organizational, educational and regulatory
frameworks in clinical research.

hommage to the original poster ... elisabeth


From: "Jack Corman (IRB Services)" <jcorman@irbservices.com>
Thanks to Michael for taking the time to be so active on the listserve, and
for raising provocative and important issues and thoughtful discussion. On
the private REB question, I am familiar with the reference cited, published
by the Hastings Center, a private organization I might add. I respectfully
submit that the methodology (survey) was seriously flawed and provided no
basis for any conclusions or assertions by the authors about the performance
of private REBs. Since institutions like Stanford and Harvard are private
and not state institutions, a priori, the term private REB or IRB must also
apply to their research ethics boards.

I believe that Francis Rolleston is right when he notes the apprehension of
bias in this area. If one looks at the Alberta College of Physicians website
information about their Research Ethics Review Committee, it states that
their committee was established

³... on the concern that many physicians who did not hold academic
appointments, but undertook research involving human participants, did not
have reasonable access to the Province¹s academic research ethics boards for
review of the scientific and ethical validity of their research projects.
Physicians therefore had to rely on privately operated research ethics
boards to undertake this review.² (my boldface).

The simple fact that ethics review was being undertaken by private ethical
review services (the largest by far being Western IRB, which as has been
noted came to Johns Hopkins rescue and is accredited by AAHRPP) was deemed
by persons influential with the College as sufficient reason for it to take
this extraordinary step. If that is not bias, what is.

In my opinion at least, there is an urgent need for sunshine in both areas.
Clearly, many public institutions are not adequately funding their research
ethics offices/research ethics boards, notwithstanding the very large sums
of money that are paid to the institution by industry for clinical trials
they conduct. Just speaking as a citizen, this is a travesty, and must be
corrected. Fro the non-hospital affiliated (private) REBs, there is a need
for greater transparency so that the ethics community and public at large
can have confidence that those REBs are in fact properly constituted, take
their responsibilities seriously and manage the conflict of interest
properly. So we come to accreditation.

Accreditation is no guarantee that any accredited REB will be perfect.
Further, accreditation of REBs alone is not sufficient, viz. US
accreditation of Human Subject Protection Programs, of which the REB is a
critical but hardly the only component. However, it is an essential step in
establishing and enforcing criteria for the review, conduct and oversight of
human subject research that will enhance public confidence in the system, no
matter whether private or public. A level playing field, to borrow a
phrase, is all that I ask.

What should accreditation, in general, involve? In my view, there are three
broad areas for REBs to prove themselves before they should qualify to be
accredited. All 3 are interwoven, but deserve to be mentioned individually.

1. Independence: Clinical Trial Regulations require the REB to be
unaffiliated with the sponsor. This by itself is not enough. The REB must
have a structure, membership and procedures to safeguard its independence
from either financial or other conflicts of interest of either the
organization or the membership, and from institutional pressures that may be
brought to bear on it or any of its members in any way. Further, it must be
adequately funded to carry out its mandate, such funding to be independent
of affirmative or negative decisions respecting research projects it
reviews.

2. Competence: ICH GCP E6 1.31: ³Institutional Review Board (IRB:) An
independent body constituted of medical, scientific and non-scientific
members whose responsibility it is to ensure the protection of the rights,
safety and well-being of subjects involved in a trial.² FDA 21CFR 56107: IRB
Membership: The IRB shall be sufficiently qualifiedŠto promote respect for
its advice and counsel in safeguarding the rights and welfare of human
subjectsŠ² I believe that this requirement means that the REB must be
constituted to include persons who adequately understand the complexities of
the research it reviews to be able to review the research in a meaningful
way. Simply constituting a board with members that superficially meet the
TCPS or Clin. Trial regulations is not enough.

3. Compliance: At the end of the day, any accreditation system requires an
inspection be carried out to verify whether or not there is compliance with
requisite criteria. Three such criteria are proposed, as follows.

> * Given that our society is based on the rule of law, the first criterion must
> be to determine whether or not the organization complies with broad legal and
> regulatory requirements in the jurisdiction in which it operates.
> * The next criterion would be compliance with governing principles that are
> not full force of law, such as the Tri-Council Policy Statement, GCP
> Guidelines, and any ethics codes imposed by a particular discipline to which
> the institution/researcher is meant to adhere.
> * The third criterion would be to determine whether the organization has
> adequate policies and procedures to describe how it operates and to show
> ostensible compliance to the first two criteria, followed by checking to see
> whether the REB can demonstrate adherence to those SOPS in its day-to-day
> work.

Who should accredit? Many would say that the Government should establish an
accrediting body. We know that the Royal College, NCEHR and CAREB are some
other potential accreditation entities, as might be the CSA or other similar
body. Everyone seems to be waiting for the Government to come up with a
governance scheme first, and so we wait, the more impatient among us might
say like for Godot. On the other hand, perhaps we need to take a leaf from
the US. Two independent, private accrediting entities accepted by the
Office for Human Research Protections (OHRP) are now in operation, AAHRPP
and Partnership for Human Research Protection Inc. (formerly NCQA).

My vote would be not to wait for an umbrella governance scheme to be fully
realized, but for Health Canada and the Royal College to empower NCEHR to go
forward with a Canadian Human Research Protection Programme accreditation
division, funded by HC, CIHR (or the Tri-Council) and the RCPSC, plus
reasonable user fees and perhaps a grant from RX & D. Perhaps Industry
Canada, which has a stake in fostering innovation, might also provide funds.
The point is that action sooner than later is more than just desirable, it¹s
overdue.

Jack Corman
President/Secretary

IRB Services
14845-6 Yonge Street
Suite 328
Aurora, ON, L4G 1H6
CANADA.
Phone: (905) 727-7989 ext. 25
Fax: (905) 727-7990
Email: jcorman@irbservices.com

Hello, This is my first real contribution to this list serve, so I am going
to ramble a bit giving you some background.

I am a Compliance Specialist for a Clinical/ Drug Development CRO. I have
been monitoring this list serve more as an educational tool rather than
anything else, and I would like to give an alternate or an interim
suggestion to REB accreditation, which may take literally years to
accomplish.

Until 3 years ago, I was primarily a GLP ( nonclinical ) auditor. I am
familiar with ethics from an animal welfare standpoint.(i.e, Testing
facilities should all have animal welfare committees and have procedures on
its conduct, etc..per CCAC.) I am still learning about the Clinical Ethics
side of things which , obviously, is an integral part of any clinical
trial. I realize this list serve is made up of ethics boards from GCP
clinical research and non-GCP research but I am commenting from a GCP
regulated research side of things.

Anyways, to get to my point. As an interim, and if there is a desire to do
so, REBs could seek out auditors ( independent of any research being
conducted at their facility) to come to their facilities and conduct an
independent audit. That way your board would know where your weaknesses are
before the FDA or HPFB comes into the facility and starts looking around.
I know this sounds like a pitch, but I am just providing another means to
an end which is your facility having a certain level of confidence that the
quality systems are in place to withstand a sponsor or a regulatory audit.

This is not a comment endorsed by my organization or any professional
society I am involved in, it is strictly my opinion.

Janine Johnson, B.Sc., RQAP-GLP
Compliance Specialist
Cato Research Canada
(514) 856-2286 extension 259

From Michael Goodyear:

That's OK Jack, that's what we 'academics' do - ask provocative but important questions, and generally be a thorn in some people's sides - of course it cost at least one early bioethicist his life courtesy of hemlock, but we digress.

I think we can accept that there is heterogeneity in both 'institutional' and 'private' organisations. Defining one's terms ab initio is usually a useful maoeuvre.

Did I miss something about the Hastings Centre? I agree it is a private organisation. However my understanding is that it is also non-profit and derives its income from endowments, contract work and charitable donations. I am not aware of any potential conflict of interest in terms of its funding, but I have not seen audited financial staements either.

Your point is well taken about 'private' universities. So we have establishedthat 'private' may not necessarily be a useful label.

I will let somebody from Alberta answer the question about the rationale for the ACPS REB. however i did not actually read into their raison d'etre anything pejorative. I actually took 'had to rely on' as a statement of fact. perhaps what is more important is 'did it work' for these physicians, or were they having problems getting research reviewed. This is a relevant question vecause other provinces are looking at similar schemes.

On the Western IRB issue, as you say they are accredited, and it is interesting that at present only four IRBs have been - two institutional and two non-institutional. The reason for this is unknown, and to me seems rather disappointing for the effort that AAHRPP has exerted. An additional safeguard in the US is FDA auditing of IRBs. sincei have had some dealings with WIRB, I have looked into their organisation and talked both to their officials and to Health Canada. Some of our physicians have opted to go outside of our REB and go with organisations like WIRB. I therefore had to establish that their standards were comparable, and at present we are experimenting with a collaborative project. This is not 'out-sourcing' but research carried out by our physicians in their own private off-campus offices.

Support for REBs is a sensitive issue. Every survey that I have looked at to date finds it inadequate. Then there is the potential for conflict of interest if the institution is funding the REB - does this make the REB independent and autonomous? (I am distinguishing this from arms length administrative support - some institutions have longer arms than others). Or should REBs be self-supporting? In which case all REBs would be 'private'.

I do not think that anyone would aregue with transparency, but i am not sure that everyone would go so far as to have REB meetings open to the public as has been advocated.

Which of course brings us to the need for accreditation to create a level playing field. (I see you thought of that term independently Jack). Whose standards should we use? Hands up who thinks they could pass the AAHRPP criteria today?

Independence. I can see I had better put out my latest version of the governance document on the list (hopefully final for now since it has been submitted to the institution). From which you will see we very much support Item 1.

Competence. As soon as you start to look carefully at regulations and guidance around REB composition, the definitions appear very loose. Not helpful except in terms of principle So how about accreditation/certification of REB members? I am not sure that they all realise it yet, but I am going to start asking for NIH certification - yes I know we need a Canadian equivalent - to ensure a minimum core competency.

Compliance. I think that implies auditing. The Force of Law is an interesting topic that we have debated before. Just what what laws do govern REBs in Canada? None? Having your funding yanked by one of the Councils would be a powerful incentive - but have they ever done that based on REB behaviour? Does the PRE even have any idea of what REBs are doing or not doing in this country? Codes of ethics? I sort of get the feeling that the Royal College might be inching in that direction - but many of our REB members are not felows of the College.

Who should bell the Cat? That has generated a lot of paper but no action. I am sure you all submitted your ideas to PRE - whose mandate apparently prevents them from doing it (but is it immutable?). You could go with an existing organisation, but since we are not getting very far you could consider everyone putting in to fund a body just for that. AAHRPP was an initiative of AAU and AAMC (see my Governance document). My understanding is that PHRPP (we are an acronym driven bunch aren't we) was an initiative of JCAHO and NCQA. Why two accreditation organisations? I must confess I forgot to include PHRPP in my document - thanks for reminding me Jack. However you have to buy their standards and i do not think they have actually accredited anyone yet. Will either of them work in Canada?

My vote would also be not to wait for a Government initiative.


Dr Michael D E Goodyear FRACP FRCPC FACP

2. Clinical Equipoise, Pros and Cons

From: "Michael Goodyear" <michael.Goodyear@cdha.nshealth.ca>
I would also recommend the editorial by Gregory Kaebnick on page 2 of the same issue of the Hastings Centre Report, as well as Charles' own commentary on page 3.

If some of the arguments seem familiar it is because FG Miller also had a Sounding Board article "The Therapeutic Orientation to Clinical Trials" published in the NEJM on April 3rd (page 1383). Which should in itself be read in the context of the related articles in the same issue, in particular Grunberg and Cefalu (The Integral Role of Clinical Research in Clinical Care) on page 1386.

I think comments on the above should be copied to the list, so here's my first reaction:

My feeling is that just as in equivalence trials, the equipoise needs to be defined in terms of how much difference can be tolerated. Nobody really wants to do a trial to prove that drug A is exactly the same as drug B, which would of course require a sample size of infinity. It comes down to what one live with, so that sample sizes are calculated on the basis that, for example, drug A is not inferior to drug B by 5% in terms of efficacy, with 95% confidence.

Similarly in ethical equipoise, it is not necessary to establish the concept a priori that the two treatments are identical. Investigator and subject can probably live with a prior probability that there is not more than a 5% difference. The greater the a priori estimate of the difference, the greater the level of discomfort, unless there is some other overwhelming counterbalance. Again, for example - are subjects able to take the chance of receiving a treatment that is 7% inferior, if there is a good chance that the side effects are considerably less.

In my own research practice I am comforted to some extent that the prior probability gets rejected a significant number of times, that any small differences in perceived equivalence are likely to have a high degree of associated error.

From: charles.weijer@dal.ca 08/01/03 02:56PM >>>
Hi all --

There is an ongoing and important debate on the relationship between the
ethics of clinical practice and the ethics of clinical research. In the
May/June 2003 issue of Hastings Center Report, Miller and Brody argue that
the concept of clinical equipoise wrongly conflates the ethics of practice
with the ethics of research. Accordingly they recommend that clinical
equipoise be abandoned. For those who haven't read this provocative article,
I would recommend it. The reference is: Miller FG, Brody H. A critique of
clinical equipoise: therapeutic misconception in the ethics of clinical
trials. Hastings Center Report 2003; 33(3): 19-28.

A colleague and I have written a detailed explication of the relationship
between Bejamin Freedman's notion of clinical equipoise and Charles Fried's
concept of equipoise. The article takes seriously the criticism that
clinical equipoise seem to leave little room for the judgement of individual
clinicians, and suggests that Fried's equipoise and Freedman's clinical
equipoise may be complementary concepts. In doing so the article provides a
detailed explanation of why the ethics of clinical practice and clinical
research are inseparable. The reference is: Miller PB, Weijer C.
Rehabilitating equipoise. Kennedy Institute of Ethics Journal 2003; 13:
93-118.

Comments on or off list regarding the debate would be appreciated.

If anyone would like an electronic reprint of our KIEJ piece, just drop me a
line at charles.weijer@dal.ca (please be sure not to send requests to the
list).

Thanks, Charles. http://bioethics.dal.ca

3. Conflict of Interest, REB Independence and Governance

 

On Behalf Of Michael Goodyear
To: ethics@lists.ncehr-cnerh.org
Cc: mcdonald@ethics.ubc.ca
Subject: [Ethics] Conflict of Interest, REB Independance and Governance


Earlier in the year, Deborah van Oosten at Brock University attempted to
tabulate reporting lines and other administrative items dealing with the
relationship between REBs and their institutions. I am not sure what lay
behind that or what was was done with the information.

In the resulting table 11 responses are listed (including Brock, and us).

Since the position of REBs in relation to their institution can be extremely
important in terms of perceived institutional conflict of interest, this
requires more careful examination.

It would seem that the key issues are reporting lines, accountability,
appointments and funding of REBs, as well as an analysis of the potential
for undue influence on the the chairs or members of the REB, and means of
recourse.

Aplicable Guides and Reports
GCP (1.31) defines an IRB (or IEC 1.27) as an independent body. TCPS (1.2)
requires that institutions 'ensure that REBs have the appropriate financial
and administrative independence to fulfill their primary duties'. OHRP
(Chapter I, Institutional responsibilities) states that 'it is vital that
IRB members, department heads, and other officials with responsibility for
oversight of research have open and ready access to the highest levels of
authority within the institution.'

Overall the issue seems to have created more interest south of the border
than north (eg DHHS 2001, AAU 2001, NBAC 2001, NHRPAC 2001, AAMC 2002).

The DHHS considers that broad representation of members from outside the
institution is the most effective solution but comments that the IRB must be
positioned with respect to the administrative structure to allow it to
function in an autonomous manner. NHRPAC appears to support this. AAU deals
more with the institution's own financial investments. The AAMC report also
addresses the administrative aspects of REB (IRB) governance. It refers to
several proposals to create "firewalls" around Academic Affairs (eg GAO
2001). However the task force's mandate was specifically financial interest.
The NBAC report covers a wide range of topics. In addressing Conflict of
Interest, it acknowledges in addition 'subtle and pervasive' conflict as
being more difficult to manage.

Clearly there are more pervasive forms of influence than the obvious
financial ones.

The NBAC also carried out a number of specific studies (Volume II), two of
which (Fletcher, McCarthy) dealt with the role of the OPRR in relation to
its parent institution, the NIH. NBAC pointed to the GAO report of 1996
which indicated an inherent conflict in that the director of NIH was
responsible for both the success of the intramural programme and for
enforcement of HRS protection through OPRR. Tuskagee was the most flagrant
example of NIH-PHS failing. NBAC referred to 'institutional blindness' and
felt that the mission and interests of the Institute and the OPPR were in
fundamental conflict. It recommended transfer of the office to DHHS, which
was duly executed as the reincarnated OHRP. In interviews with the
respective sides it was clear that the research administration depicted OPRR
as an impediment to research. In justifying both the elevation and
relocation of OPRR, NBAC pointed to many other institutional conflicts such
as the Atomic Energy Commission that was bo!
th promoting and regulating nuclear power.

A third paper (Peckman) specifically looked at the role of local IRBs. In
the section dealing with the IRB within the institution, the two were
depicted as inherently in conflict. Bell et al surveyed reporting lines and
found that only 7% of IRBs reported to a level higher than a Vice President
or Provost. Yet many commentators had seriously questioned whether an
individual such as a VP Research who is directly responsible for research
funding can also oversee a body who independently reviews research.
Ironically the OPRR itself recommended elevation of the IRB 'to a higher
level within the institutional hierarchy'.

In Canada the seminal work is the Law Commission of Canada report entitled
'The Governance of Health Research Involving Human Subjects (McDonald 2000).
In addressing independance, McDonald stresses the vested interests dominate
governance of research and that the Canadian situation is even more
vulnerable than its US counterpart. He lends weight to the OIG
recommendation 'for insulating IRBs from conflicts that can compromise their
mission in protecting human subjects' and recommends the need for insulation
as being even greater in Canada. Specifically McDonald states that "it is
crucial for substantive reasons and for the sake of of appearances that REBs
not report to or be appointed by offices of research". (OIG
recommendations had included 'does not report directly to the part of the
institution responsible for bringing in research funds...and has recourse
should it be subject to any pressure'

Specifically the report stresses the situation in Quebec, where it is stated
that REBs are 'independent from both hospitals' research centres and the
scientific review boards...They are attached to the hospitals' Boards of
Directors which also appoint their members'. It is worth noting that in
Quebec many of the principles of REB conduct and governance are enshrined in
the Ministère de la santé et des services sociaux du Quebec action plan
(1998)

Amongst sources quoted by McDonald are Edgar and Rothman ' Does it make
sense to give the leadership of an institution, which by its very nature
cannot survive without funds and fame brought in by clinical research, the
reponsibility of appointing the membership of a monitoring committee'.

It is within this framework that we need to consider the recent announcement
that the current executive be replaced with a nominee of the heads of the
clinical departments.

REFERENCES

AAU: http://www.aau.edu/research/COI.01.pdf
AAMC: http://www.aamc.org/members/coitf/2002coireport.pdf
NBAC: http://www.georgetown.edu/research/nrcbl/nbac/human/overvol1.pdf
http://www.georgetown.edu/research/nrcbl/nbac/human/overvol2.pdf
NHRPAC: http://ohrp.osophs.dhhs.gov/nhrpac/documents/aug01a.pdf
DHHS: http://ohrp.osophs.dhhs.gov/humansubjects/finreltn/finguid.htm

Bell: http://ohrp.osophs.dhhs.gov/hsp_report/hsp_final_rpt.pdf
McDonald: http://www.lcc.gc.ca/en/themes/gr/hrish/macdonald/macdonald.pdf

OIG: Office of the Inspector-General, Institutional Review Boards: A Time
for Reform (Department of Health and
Human Services (U.S.), June 1998) at 17.
http://oig.hhs.gov/oei/reports/oei-01-97-00193.pdf

H. Edgar & D.J. Rothman, The Institutional Review Board and Beyond: Future
Challenges to the Ethics of
Human Experimentation (1995) 73/4 The Milbank Quarterly 489 at 490.

 

I'd like to comment not to approve or disapprove but rather to shift from "conflict of interest" to the primary objective of a REB review. The idea being not to overlook possible "problems" (such as eventual "conflict" of interest) that may "appear" (and not necessarily "exist"- this is an important distinction that may however, in my view, lead to dismissal of "otherwise perceived ethical" protocoles or reviewers; I must say I'm not at ease with that direct implication from "perceived conflict of interest" to "rejection/unethical" - and I'll come back another time) but rather to come back to the essence of having a REB review.

I see the REB member role as making sure human dignity is preserved along a three layer set: human subjects; investigators; society. I see "protection of human subjects" as a way of keeping "humanity" * and therefore "dignity" * in the realm of research (quantitative or qualitative). I see "protection of human subjects" as another way of saying "protection of human dignity" whether those humans are "research subjects" or "investigators" or "REB members", they are all participants of our Humanity with this inherent quality that we recognise as "dignity", therefore deserving respect and to be protected. I intentionally used "human subject" in a wide sense, and not only for what we (in ethics of research) call "human subjects" (sometimes "research participants"...)

When the"subject line" of this e-mail is in fact "Conflict of Interest, REB Independance and Governance, why shifting to human dignity? Because, I feel "conflicts of interest" are only an epiphenomenon of "forgetting human dignity". Although, I recognise there is a wider concern with conflict of interest issues that root in reality, I strongly hope we'll not fall in the trap of seing (appearance!) them everywhere... It would only be too easy to cease from reviewing protocoles for the sole reason that REB members reviewing protocoles are "attached" to the same institution they are reviewing protocoles for. The Canadian system is a peer reviewed system and as such it brings forward that idea of trust in a constructive dialogue in between reviewed projects instigators (investigators, funding sources, research institutions) and "ethics promotors" (projects reviewers (REBs), normative texts (laws, guidelines, etc.) and national overviewed committees (if/when they exist...)).

In a perhaps idealist way but nevertheless what I consider to be a solid anchor, I'll borrow Francis Rolleston's "convergeance of interest" expression and make "Human dignity" its focus point in the sphere of ethics of research.

These are only quickly written thoughts that I'm developing aside (in french, I must admit).
I feel ethics of research is a beautiful field as it conveys for responsability and development for what is "just" in view of our Humanity.

I wish you all a good week-end,

Marie Buy

From: "Francis Rolleston" <frolleston@sympatico.ca>
May I add my voice to those of Luc Simon and Hal Weinberg? The accusation
of conflict of interest is too often used to trump all other arguments. It
is always possible to find potential conflicts of interest, leading to the
kinds of adversarial environment to which Hal alludes. I agree with him
that this is often more destructive than constructive.

I much prefer the concept of convergence of interest, in which people who
approach things from perhaps different points of view seek to identify where
their long-term objectives converge. Of course, this can lead to a downward
spiral to the lowest standards. But that is not the only potential outcome.

Particularly in an area such as this, in which so many well informed and
caring people are dedicated to doing "what is right" for the people of
Canada, I believe that the organizational structures of institutions can
readily be arranged so that the highest goals of ethics are achieved. This
is why I much prefer to define the role of the REB as being to help ensure
the highest standards of research, which is a much more complex task than
simply to protect the subjects of research. As a research subject, I am
not sure that I want to be protected. What I want is excellence in
research, which cannot be achieved without excellence in ethics. As an REB
member and Chair, I see myself as very much an agent of the publicly funded
institutions that established the REBs (Ottawa Hospital and NRC
respectively), sitting on the REB to help them serve Canadians. In this
context, we believe that the REB policies that we are now developing at NRC
must be approved by the top authorities at NRC who, because NRC is a
research institution, are necessarily research oriented, but also directly
responsible to Government for all aspects of the operations of the Council.

The premise of local REB review is that of encouraging a high level of
awareness and responsible action in the institution as a whole, an essential
educational and standard setting process that would be seriously jeopardized
by externalizing it in the name of addressing one perception of conflict of
interest.

Francis Rolleston

From: "Michael Goodyear" <michael.Goodyear@cdha.nshealth.ca>
Actually I think that it is a little more complex than that.

I think there are two related themes here. The first relates to how institutions including REBs deal with Conflict of Interest. One is to avoid it, the other to ensure that it is declared. While obvious associations and financial interests are relatively easy to deal with, it is the more subtle pressures that are much more difficult. The only true independance would be a completely separate board with no association administrateively or personal with the institution whose research is being reviewed. It might even come to this. As with Caesar's wife, it is often more important that we not only be above suspicion but be seen to be above suspicion. hence the need for transparent independance.

The second relates to the more general relationship of the research community and its regulation. As the Royal College of Physicians and Surgeons (one of the candidates for an accrediting body) recently observed, research ethics needs to be imbedded in the consciousness of all researchers and to sense that is a 'self-regulating' community (as opposed tot he US federally mandated model). I agree that we need to work hard to change the existing ethos, and avoid the idea of divergent goals for the researcher and the REB, we should all have the same objects and goals in mind.


Dr Michael D E Goodyear FRACP FRCPC FACP

From: "Michael Goodyear" <michael.Goodyear@cdha.nshealth.ca>
Tom,

Professor Michael McDonald of the McDonald Commission also sent me his support. Nevertheless I have received official notice of termination from the CEO. Interestingly cc to Padmos, but not the Board.

I hear on the grapevine you may be in line for the next DMAC chair, are you sure you will have time for the REB? You are always welcome in any capacity, at least so long as I am in the steering position.

Again these are complex issues, and while nobody would disagree with the sentiments, it is the implementation that remains challenging.

First I think that 'accusation' mayu be problematic, it is the 'appearance' of conflict and influence that we are seeking to insulate the REB from. Sadly an adversarial atmosphere is what we often find. Thus I find myself facing accusations sent to the administration by departmental heads over 'significant delays in approval' which were in fact due to poorly prepared submissions and long delays in response to our requests.

Ideally the goals of the research community and the REB should not only converge but be congruent. Clearly acheiving the highest standards as Francis states, folds into itself protection of human subjects. Perhaps respect would be a better word.

Many people like Francis, particularly those who have also been subjects, have questioned the concept of 'protection', and there has been a concern that protectionism and parentalism converge. Hence the importance of listening to the subjects we strive to 'protect'. To Francis' rhetorical question as to whether the subject wishes to be protected, I will reply - 'of course'. That is, the subject expects that the research reflects concensus, that the risk benefit ratio is not extreme, and that they are being dealt with honestly. Again maybe 'protection' does not adequately convey the expectations.

I think Francis' last point is crucial, that the REB should be a local catalyst and promote awareness. For those of us who are concerned that this is not happening, I would suggest that a more formal training programme to acheive core competence is required. Catalysis per se is not good enough. This is the basis for proposals to make the REB or IRB a more respected entity in the institution (to serve on which would be considered an honour, not a chore).


Dr Michael D E Goodyear FRACP FRCPC FACP

From: "Michael Goodyear" <michael.Goodyear@cdha.nshealth.ca>
Which makes me wonder how many institutions with REBs have formal COI written policies?

Dr Michael D E Goodyear FRACP FRCPC FACP

From: "Sally Gray" <sgray@wlu.ca>
Hi

Laurier has a conflict of interest policy
(http://www.wlu.ca/~wwwsecr/policy/8-1.shtml); the ethics policy states
that REB members will be bound by the university's policy.

Sally

From: "Michael Goodyear" <michael.Goodyear@cdha.nshealth.ca>
I believe that modern thinking about COI is that the potential is inevitable whereever decisions are made, and that recognising this and identifying it is crucial to management. COI arises from circumstances and does not reflect on the character of the individuals concerned. Failure to recognise this and fear of being labelled leads to failure to disclose and worsens the situation.

If we can return to the original theme, I have witnessed and continue to witness REBs being placed under intolerable pressure by their institutions and by individuals within those institutions who are in a position of influence. It is for these reasons that somwe of us are arguing that the REB should be isolated untill in a utopic world, the goals of all concerned are perfectly congruent.

Appearance of course is a key word as stated here. It is vital that all decisions made are defensible.

Dr Michael D E Goodyear FRACP FRCPC FACP

From: "Michael Goodyear" <michael.Goodyear@cdha.nshealth.ca>
OK here is ours. Strictly speaking it is university not hospital but most REB members have university appointments.

http://www.senate.dal.ca/policy.cfm?policy=PA&type=P


Dr Michael D E Goodyear FRACP FRCPC FACP

From: "Michael Goodyear" <michael.Goodyear@cdha.nshealth.ca>
This topic was aired on the list a while ago. While there has been a lot of of discussion in Canada with regards to Governance, as in an over-arching governance nationally, there has been relatively little on the internal governance structures within institutions.

To that end I have compiled a resource. Those of you who are older and wiser will no doubt see many errors and omissions and if you pass them on I will incorporate them.

 

4. ICH GCP Force of Law?

From: "Michael Goodyear" <michael.Goodyear@cdha.nshealth.ca>
I would be more optimistic that we can provide some guidance that brings all these elements together rather than change one to suit the other. In my discussion with Health Canada the dominant argument is that since GCP is an 'international' agreement it is important that we are in compliance with it, or there is little point in doing trials here.

Dr Michael D E Goodyear FRACP FRCPC FACP

From: "Vanderwel, Marianne" <marianne.vanderwel@pfizer.com>
Hello everyone,

I am a little behind on reading the listserv emails and have just made up to
this one. I thought you might be interested to know that I reanalysed the
differences between TCPS and GCPs and the clinical trial regulations. This
analysis was sent to the Panel on Research Ethics in response to their call
for comments. I have attached it for those of you who are interested in the
excruciating details.

While I understand the reluctance to change the TCPS, I would like to point
out that changing ICH GCPs is an even more monumental task since it involves
regulators and industry from Europe, US and Japan. I am optimistically
confident that TCPS can be updated to be consistent with Health Canada
requirements for clinical trials involving drugs.

Also, in the new guidance for clinical trial sponsors, the foreword contains
an interesting description of what a guidance document is about. "Guidance
documents are administrative instruments not having force of law and, as
such, allow for flexibility in approach. Alternate approaches to the
principles and practices described in this document may be acceptable
provided they are supported by adequate scientific justification. Alternate
approaches should be discussed in advance with the relevant program area to
avoid the possible finding that applicable statutory or regulatory
requirements have not been met".

Gotta go now, I think I have over 90 more emails to read in this listserv
alone ...

Marianne


-----Original Message-----
From: Francis Rolleston [mailto:frolleston@sympatico.ca]
Preparing a report of the differences would be a useful step toward
harmonized policies, but not an end in itself. Perhaps the goal should be
revised Health Canada policies that state what will be required in Canada,
but prepared with sensitivity to the various statements that influence us.

Perhaps also listserv participants (not subjects in this case!) might
identify areas of significant disagreement on this listserv, so that people
can propose options or consensus as to what we in Canada think is the best
resolution.

In 1999-2000, we tried at MRC/CIHR to identify the procedural differences
between TCPS and ICH GCP. Marianne Vanderwel's analysis was by far the best
contribution to this.

Francis Rolleston

-----Original Message-----
From: ethics-admin@lists.ncehr-cnerh.org
[mailto:ethics-admin@lists.ncehr-cnerh.org]On Behalf Of Jack Corman
Sent: July 24, 2003 12:55 PM
To: NCEHR
Subject: Re: [Ethics] ich gcp force of law?

Good idea, Michael. Especially the regulations and the TCPS, since they need
to be compatible. Otherwise, there may be times when researchers face
Hobson's choice, i.e. either break the law or violate the TCPS. Not a
tenable situation.

Alternatively, a comparison between the TCPS, Clinical Trial Regulations,
Declaration of Helsinki and Human Subject Research Codes of Conduct in
various regions might be a project for NCEHR to undertake. Maybe Health
Canada's Ethics Division would see merit in the idea and fund NCEHR to
conduct the review and issue a report.

Jack Corman

From: "Michael Goodyear" <michael.Goodyear@cdha.nshealth.ca>


A suitable task for PRE might include examining all the inconsistencies
betwee F and D Act, Helsinki, TCPS and GCP.

Dr Michael D E Goodyear FRACP FRCPC FACP

Assistant Professor, Division of Medical Oncology, Department of Medicine,
Dalhousie University
Executive Chair, Research Ethics Board, Capital District Health Authority
http://development/capitalhealth/research/researchEthics/index.html

>>> jcorman@irbservices.com 07/24/03 11:57AM >>>
The US also adopted ICH GCP when they were published in the Federal Register
in 1997. The HC official Elisabeth contacted may/may not have been fully
aware that Justice refused to sign off on the ICH GCP E6 because there were
certain elements in conflict with the Food & Drug Act. That's why ICH GCP
remains a guideline.

As the government works out a new Food & Drug Act, there will undoubtedly be
changes that affect GCP. It may be at that time that ICH GCP will in fact
become law of the land; perhaps that is what the official meant. Until then,
it's not.

However, not withstanding their status as guidelines, it seems more than
sensible that we adhere to them. The regulations require that clinical
trials be conducted according to GCP. If you don't follow ICH GCP, what
will you follow? If the Inspectorate pays you a visit, to what GCP will you
be able to show adherence if not ICH?

As to silence on Ryan, interesting contrast vs. Olivieri. There is no Apotex
to finger in this one.

Jack Corman

on 7/24/03 8:56 AM, Michael Goodyear at michael.Goodyear@cdha.nshealth.ca
wrote:
...or this just the Canadian way of life - we live with guidelines, while
below the parallel they have 'common' rules?
(And what did ever happen to the Ryan issue - never known such silence on
this list)

Dr Michael D E Goodyear FRACP FRCPC FACP


>>> clarke@muhchem.mcgill.ca 07/23/03 07:36PM >>>
At 17:29 7/23/2003 -0400, Jack Corman wrote:
"Neither country officially has adopted ICH GCP in its regulations, and,
hence, ICH GCP still officially has only guideline status on either side of
the border."

Jack, i changed the thread ...

Now i used to agree with you about the ICH GCP and its force of law in
Canada, and tpursued the question, here online and with HC staff. I don't
feel i received a clear answer.

It did always strike me as curious that Canada, as an observer to the ICH
process had adopted the guideline, before the parties to the agreement, US,
Japan, EU and the Pharma Manufacturing Ass. in their domains adopted it as
law.

One HC staff informed that in our "Regulations" at C.05.010 "good clinical
practices" appears in lower case and does not indicate the title of the ICH
GCP document. I was assured that this was a "detail" would be corrected in
the future (whatever that means) and that "GCP is the law".

In the forward of the ICH CGP document we read "The Good Clinical
Practices: Consolidated Guideline" supersedes the Drugs Directorate's 1989
guideline ... so guidelines again ... is the problem a lack of a framework
to enforce international standards as law?

Since the ICH primarily sets the rules for the manufacturing and conduct of
clinical research leading to new drug registration, and does not exist to
call the shots for REBs, are the rules being applied selectively?

Does ICH GCP carry the force of law in Canada? Will this question fade
with summer vacation as it seems did discussion of circumstances
surrounding the on-study death of Ryan at CHEO? There are lessons to be
learned. We deal in serious matters

Elisabeth Clark
Research Ethics Officer/Human Protections Administrator
McGill University Health Center

5. Must Consent Forms be Witnessed?

From: "Michael Goodyear" <michael.Goodyear@cdha.nshealth.ca>

>From which I think we can proceed as follows:

There is no requirement for the signature to be witnessed under normal conditions of a competent literate non-vulnerable individual participating in the consent process in a language in which they are fluent.

Some institutions may override this by local policy. Some sponsors may feel similarly.

Investigators are free to include a witness line on a consent form but it would be prudent to also identify the witness. Both investigators and witnesses should be aware of the limitations of liability protection and the possible burden of added liability. Probably the greater the risks of the research and the greater the probability of incomplete comprehension of the research, the more prudent it would be to have an impartial witness to the consent process.

Dr Michael D E Goodyear FRACP FRCPC FACP

From: "Michael Goodyear" <michael.Goodyear@cdha.nshealth.ca>
I am inclined to agree that it is the concept of the consent form as a contract that has created so many problems for us, to say nothing of the language employed.

Conset is a contract only in the social sense, of which the form is but a small part. An additional signature might be considered an institutional safeguard.

Can we have a legal opinion on this?

Dr Michael D E Goodyear FRACP FRCPC FACP

From: "Francis Rolleston" <frolleston@sympatico.ca>
I think that the idea of a witness is dangerous territory, and should not be
used.

To re-phrase what Howard and Michael have already covered, I understand that
legally the witness to a signature certifies that the person actually signed
the document, nothing more. The suggestion that a witness might attest to
the process of information transfer and its quality starts to get pretty
heavy. Questions would arise as to the impartiality of the witness, for
example.

But to me the most important issue is the nature of the consent form itself.
Is it a contract? If so, by whom and to whom? My answer to those questions
is that a consent form represents a contract by the research team to the
subject, but that it must never be seen as a contract by the subject to the
research team. To witness the subject's signature implies that the subject
has entered into a contract. And I do not like anything that implies such a
conclusion.

So the REBs with which I am involved routinely remove the witness line and
replace it by the signature of the person who discussed the consent with the
subject, perhaps with a suitable sentence as to what the signature means.

However, one protocol that I am currently considering has caused me to
question whether this should always be the case. It is for a Phase 1 trial,
in which normal healthy volunteers are to be paid for an extensive
commitment of time, abstinence from a bunch of things, adherence to quite a
defined protocol, to be in a place at certain times for sampling etc. In
that case, an element of contractual obligations by the subject is present.

From: "Laurel Evans" <levans@mcmaster.ca>
A contract in law consists of : An offer (by party A), an acceptance
(by Party B), and the exchange of some consideration (monetary or
otherwise). In the research context, the researcher offers to conduct
research, the participant agrees to participate, in exchange for ...?
The participant hopes that he or she will receive someting of value, but
they haven't agreed to participate only on the premise that they will
get some benefit. I haven't researched the issue, however, I don't
think that a court would view a consent document as a contract. A
consent document is written evidence of an agreement / understanding
relating to the conduct of the research, and would be used for that
purpose in any law suit arising out of the research. In my opinion, a
consent document in and of itself does not create legally binding
obligations on one party to the other, i.e. you can't sue the
participant for failing to live up to the terms of the document per se,
nor can the participant sue the researcher/institution for failing to
live up to the terms of the consent document/or failing to conduct the
research. You can, however, sue the researcher for damages arising not
out of the conduct of the research. In my opinion, any action arising
out of a research project would be brought in the form of a "tort"
action for negligence, rather than a "contract" action for "breach of
the consent form". The consent form would be evidence of how the
parties understood the research was going to be conducted, and the risks
that were being agreed to. The fact that there is a witness or an
additional signature would not change the nature of the relationship,
between the parties.


F rom: "Francis Rolleston" <frolleston@sympatico.ca>
I accept the legalities as set out by Laurel. But that seems to be less
important than the perception of the subject about the document, and the
meanings of the signatures, which the subject needs to understand in a non
threatening environment, without legal advice. So the clarification of
contract law, for which I am grateful, does not change my view of the
inappropriateness of a witness to the subject’s signature.

Francis Rolleston
500 Denbury Avenue
Ottawa, ON

 

From: "Michael Goodyear" <michael.Goodyear@cdha.nshealth.ca>
At least under ICH GCP there is no requirement for a witness (4.8.8) unless the subject (or their legal representative) cannot read (4.8.9), in which case the witness must be present for the entire discussion, and is presumed therefore to be attesting to the process:

. By signing the consent form, the witness attests that the information in the
consent form and any other written information was accurately explained to, and
apparently understood by, the subject or the subject's legally acceptable
representative, and that informed consent was freely given by the subject or the
subject's legally acceptable representative.

However there are legal liabilities attached to such signatures. Here is the pertinent Canadian regulation (TCPS 2.4(e)):

"In some circumstances, witnessing the signatures on the consent form may be felt to be appropriate. In law, the role of a witness is only to attest that the person actually signed the form; a witness is not responsible for certifying such factors as the signature being obtained under defined conditions or that the signers were competent. However, a court might subsequently seek the opinions of the witness on such issues."

This is in contradistinction to the requirement for the person conducting the discussion.


While an investigator may derive some comfort from asking a witness to sign, they may be deriving a false sense of security. Furthermore they must be clear as to what the witness is actually attesting to, and make the witness aware of their liabilities.

It would seem that there are a number of levels of engagement of the witness.
(a) Witnessing the signature as bona fide
(b) Witnessing the consent process
(c) Witnessing and attesting to the process

With increasing engagement comes increased liability. Indeed the more liability the more the witness becomes a subject, and as in some cases of reduced capacity may need a separate consent of their own.

As to actual comprehension of consent, some have divided this into steps and required a signature to each. This certainly discourages rash decision making.
Eg:
(a) I have understood to my satisfaction the information regarding participation in the research project
(c) All my questions have been answered to my satisfaction
(b) I agree to participate as a subject

But as Howard says, what does this mean? In a well cited British cancer trial, participants were given the conset form and asked to return in a week and to answer a questionnaire as to their understanding of the study. The intent had been to only register comprehending patients. The results were predictably disastrous.

In an earlier contribution (rejected -sorry Jon) I asked what does "fully informed" mean, since this was a frequent sponsor justification for "growing" consent forms. To be "fully informed" approaches infinity in terms of knowledge transfer and is therefore both facile and futile.

However some sort of feedback is worth exploring outside of emergency situations.


6. NCEHR Communique Volume 12

From: "Blake, Andrea" <ablake@ncehr-cnerh.org>
NCEHR Communiqué is now available on the NCEHR website
http://ncehr-cnerh.org under Communiqué.

 

7. OHRP Criticizes IRBs

From: "Michael Goodyear" <michael.Goodyear@cdha.nshealth.ca>
I think anyone who has not read this should do so. Is it relevant to us? Not at the moment. Might it become so? Very likely.

It comes on the tail of an era of unprecedented shut downs of IRBs due to poor performance. What is relevant in the US today often becomes reality sooner or later here, and some sort of umbrella oversight/accreditation of REBs in Canada seems inevitable.

Note in particular the comments about upgrading professionalism. Anyone who thinks running research ethics is a volunteer job is sadly mistaken, and any institution that considers downgrading the time commitments for its RWEB chairs does so at its peril, if that is not too strong a term, but it has happened.

The place of REBs in scientific review is another world of debate again. It remains largely unresolved in our institution although I favour obtaining prior peer review.

This is also relevant in the current debate over local vs central REB review. You will have noted the move in ontario towards some sort of central review of cancer trials.

http://www.cancercare.on.ca/collaborativeprojects/ocreb.html

http://www.ocrn.on.ca/ethics_Home.htm

The source of the OHRP report is:
http://ohrp.osophs.dhhs.gov/detrm_letrs/YR03/jul2003.htm

where it is listed as July 3rd ARDS network

Dr Michael D E Goodyear FRACP FRCPC FACP

 

8. Ontario Cancer Care REB Job and Call for Members

From: "Susan Hoddinott" <hoddinott@uwo.ca>
To: "CAURA Listerver" <caura-net@listserv.uoguelph.ca>; "NCEHR Listerver" <ethics@lists.ncehr-cnerh.org>
Subject: [Ethics] Ontario Cancer REB Coordinator Position
Date: Thursday, August 07, 2003 2:27 PM

Attached please find a job posting for the Coordinatior position at the
new Ontario Cancer Research Ethics Board
All questions and applications should be send to
Mr. Sid Stacey, Executive Director, OCREB
Address: OCRN, 149 College Street, Suite 501, TORONTO, ON, M5T 1P5
Fax: 416-977-7446
Email: sid.stacey@ocrn.on.ca

From: "Blake, Andrea" <ablake@ncehr-cnerh.org>
To: "List Serv (E-mail)" <ethics@lists.ncehr-cnerh.org>
Subject: [Ethics] FW: Ontario Cancer Research Ethics Board - Newsletter & Call for Members
Date: Monday, August 11, 2003 9:21 AM


Hello,
For your information, please find attached the first issue of the
Ontario Cancer Research Ethics Board Newsletter and a Call for Members.
Please feel free to post or forward to interested individuals in your
organization. Thank you.

<<OCREB-Newsletter6.pdf>> <<Call.for.members.doc>>

Sid Stacey, MHSc, FACHE, CHE
Executive Director, Ontario Cancer Research Ethics Board
Ontario Cancer Research Network (OCRN)
149 College Street, Suite 501
Toronto, ON M5T 1P5

tel 416 977-7599 x242
fax 416 977-7446
email: sid.stacey@ocrn.on.ca
www.ocrn.on.ca

9. REB Approval on Informed Consent Form

From: "Michael Goodyear" <michael.Goodyear@cdha.nshealth.ca>
A pharmaceutical firm is insisting that we include words to the effect that the REB has reviewed and approved this protocol in the consent form.

We disagree. in reply they tell us that we are non-GCP compliant because article 4.8.5 mandates this. With all due respect it says nothing of the sort. We are also told we have to it because it is the company SOP. We do not see the relevance of this either.

4.8.5 The investigator, or a person designated by the investigator, should fully
inform the subject or, if the subject is unable to provide informed consent, the
subject's legally acceptable representative, of all pertinent aspects of the trial
including the written information given approval/favorable opinion by the
IRB/IEC.

In fact one of our major sponsors (NCIC) specifically forbids such language:

3. Reference to approval by the REB, NCI or Cooperative Group may be misleading to the patient.

Is anyone else having this problem?

Dr Michael D E Goodyear FRACP FRCPC FACP

From: "Judith Abbott" <judith.abbott@ualberta.ca>
We do not allow such wording in informed consent documents; our committee considers it to be coercive. So far no sponsor has insisted that the wording go back in.

And I agree with Michael that this is not mandated in GCP.

Judith Abbott

rom: "Susan Hoddinott" <hoddinott@uwo.ca>
We do not allow statements that say this research has been reviewed and
approved by the REB. To-date this stand has not caused any problems with
sponsors.

Susan

From: "Alex Quitazol" <aquitazol@allied-research.com>
I do not see which part of the quoted ICH-GCP article the REB is not
complying with. Maybe the sponsor should examine the article a little bit
more closely and realize that, in fact, the article cited pertains to
investigators' responsibility to provide all relevant aspects of the trial
to subjects, including any written info that has been approved by the REB
for distrribution to potential subjects.

Secondly, the sponsor's SOP is their SOP (the REBs have their own set to
follow) and does not automatically apply to any party that they engage
business with, unless explicitly stated in any other documents.


Alex Quitazol, B.Sc.,CCRP

From: "Francis Rolleston" <frolleston@sympatico.ca>
Both REBs on which I sit do want a statement about REB review, if only to
permit identification of the REB Chair as a contact point for any questions
or concerns.

This looks like another issue on which a degree of consensus should be
reached. I personally do not see much weight to extra pressure to consent
from a statement that the REB has approved the project. I see it more as a
statement of comfort that there is actually such a thing as an REB that is
trying to work in such an area. But I recognize the other side of the
argument. Interesting

Francis Rolleston

From: "Dale Quest" <questd@duke.usask.ca>
Few that brush know much of how or why the Dental Association is constituted,
but maybe take some comfort in seeing its logo on their tube of Crest. I
suppose Notice of Ethical Reviews have responded, "Please delete the statement
regarding ethical and regulatory approval. The approval process is not intended
to reassure subjects. Such approvals are required for all clinical trials, but
may be incorrectly interpreted by subjects as an endorsement", in part because
some time back the REB took a stance based on principle, and it was then
expedient to remain consistent on recurring matters like that. Particularly in
years back and often still, research subjects seem unclear about what a
research ethics board is or what it does. If a statement regarding ethical and
regulatory approval (That is an endorsement, right?) might be construed by
potential subjects to be a message of reassurance, is it ethically appropriate
to leave a statement open to that interpretation?

From: <David.Miller4@med.va.gov>
Interesting issue where two competing liberties may bump into each other and
where neither party is required to play in the same sandbox.

On one hand, wording that implies an "endorsement" of the protocol ("....the
REB of your local institution reviewed and encourages your participation in
this study...") is clearly wrong and needs to be avoided at all costs. If
the REB feels the sponsor is requiring a statement which is inappropriate,
then don't allow the study to be conducted at the institution and find
another sponsor.

On the other hand, the funds to conduct the trial are those of the sponsor.
If an "appropriate" statement can be crafted which does not imply
endorsement, the REB might consider it, but if not then go somewhere else to
run the study.

The practical concern for subject protection is that the sponsor will
mandate use an inappropriate statement and then shop around for a local
board who will approve the wording simply to get the funds. More of a
likelihood in clinical trials.

This being said, I am unaware of any empirical examination of this
particular question (i.e., potential subject perception of REB review
statements).

From: "Cam McDermaid" <cmcdermaid@cmcc.ca>

Thanks David.

I sometimes feel that we are discussing how many teeth a horse has.

I appreciate the concerns that an "endorsement" may be construed from
a statement in the consent form. Countering that, does a potential
participant have the right to know if a study has undergone review
and been approved and should they be explicitly told? That a sponsor
wants it in is a poor second to what the intent of the statement is
in the consent process and the risks and benefits of including it.

Engaging in tooth counting; it may be sufficient to state that the
work has been reviewed, rather than use the word "approved". We don't
include such statements, but simply have a line identifying the REB
contact for information about rights of participants.

Cheers

Cam

From: "Michael Goodyear" <michael.Goodyear@cdha.nshealth.ca>
Hmmmm....

This is looking more complex than first impressions might have indicated. My first reaction was that we have a standard consent form for good reasons, one of which is to make the reviewers task easier. I am reluctant, without good reason, to keep adorning it for each individual company. In the past we gave in only to then have the changes we had made rejected the next time around. Our overall philosophy has been to try and simplify and shorten consent forms, not keep adding to them. The danger being that the key elements get lost in the forest.

We are not completely unreasonable. This week a company suddenly decided to object to our Research Related injury clause which reads, in part, "If you become ill or injured as a direct result of participating in this study...". They claimed that if a subject slipped on the floor, they could claim compensation. They insisted on changing this to "If you become ill or injured as a direct result of the study drug...". We accepted that for that particular trial, at the same time considering it more of a company liability issue than anything to do with consenting to take part in a research study, and with an extremely low probability of being put to the test - indded we would prefer such things get put into the contract).

Initially we did not have any strong feelings on this issue other than the above and noting that NCIC did not want it in as potentially misleading. Most people who have responded to date appear to agree. Some find it coercive.

There is of course, unfortunately, a fundamental lack of empirical research on many if not most of these issues. Now the issue has been recast as as one of competing liberties, and therefore fertile ground for ethical analysis. There is I think no argument on explicit endorsement. The question as to how any such statement about Research Ethics Boards might be interpreted by subjects is of interest and I suspect could apply to many statements in Informed Consent Forms (ICF). We are often told that subjects must be "fully informed" by sponsors seeking ICF adornment. What does that mean? I am reminded of a patient who wanted us to hand over all the information available on a drug. Since the drug has been on the market for about 30 years, and is still being actively investigated, the total information content would fill a library stack. If a ICF says it has been approved by the REB does that imply the rest have not? Francis feels or at least represents REBs that feel that the REB chair should be available to patients. Who does that? I got told to remove that many years ago, and have never seen it since. What would they ask? We use the patient representatives. I should ask them if they ever get called. For that matter the PI's name is there under information. In a trial with many co-investigators, does the PI ever get called?

So we come to the question of who dictates the format of ICFs. the REB or the sponsor. In my experience most of these issues go away if we stand firm, or as indicated here, sometimes a compromise is drafted which meets the spirit. Sponsors need investigator sites. However shopping and playing off REBs should be a matter of concern.

Frankly I doubt that the statement would influence most potential participants one way or the other - it is just more words in a form which in itself is only a part of the process of consent. By all means write a pamplet on "What is a clinical trial?" which includes information about the role of REBs and give it to all potential participants to ponder on. There are already a number of such documents out there.

The good thing is that we get to tal (and think) about the issues.

10. Combining IRBs

From: "Michael Goodyear" <michael.Goodyear@cdha.nshealth.ca>
This was not a trend that I would have predicted in the US. Institutions like Johns Hopkins used WIRB as an emergency measure when their own IRB was shut down.

However now academic institutions are out-sourcing their ethics reviews and contracting their institutional boards. You will note that they claim to have 'stramlined' reviews and saved costs.

However their is a body of literature that would suggest that private 'for profit' IRBs do not perform at the same level as institutional IRBs. These claims coud start a worrying trend. On the other hand they are a challenge for existing IRBs.

The other argument goes that it is essential to have a local IRB/REB to interface with the institution and research community. Otherwise the process becomes mechanical and 'efficient' with no consideration of local requirements or conditions.

Dr Michael D E Goodyear FRACP FRCPC FACP

 

From: "Tom Ekers" <tekers@cmxres.com>
Michael,

I have very much enjoyed your contributions to the list server over the past months. You have raised some interesting and thoughtful issues.

I however must take exception to your implied suggestions that private central ethics boards do not perform effectively here in Canada. There are a number of private boards who are very supportive of certification in order to address just those issues that arose at many of the US instiutional boards. Interestingly in a recent discussion with a senior TPD individual ( and they get first hand evidence of the effectiveness of a number of board activities), it was stated that the most effective boards were in fact the private boards. I am concerned that many institutional boards in this country, primairly in the community hospital setting, do not do an effective job as their organizations are thin and their comitment to SOPs is questionable for ethics reviews. I believe most of the large academic boards have come a long way to resolving issues that needed addresssing.

Rather than suggesting the private boards are not effective I would suggest we all work towards an effective certification program that ensures any work done by boards in this country is up to international standards. I might also suggest that the members of the listserver consider that private boards came about because as the clincial research activity moved into the community (now estimated at 60%) the instituional boards were unable and unwilling to provide services to these sites. Now that private boards do an effective job at meeting those needs it is interesting that institutions now feel that it is their right to assume these responsibilities and are using politics to try to overcome what they could not do in the first place.

Tom Ekers
From: "Jack Corman" <irbs@interlog.com>
I had hoped to avoid this discussion, but I guess it was inevitable that the
baseless public assertion of inferiority of private ethics boards would be
made; it cannot go unchallenged, for at least the reason that not all
private REBs, nor all hospital REBs for that matter, can be lumped
together. Perhaps the same assertion of inferiority of private vs. hospital
labs should be levelled at clinical laboratories such as MDS and Canadian
Medical Laboratories. Or perhaps someone should assert that, let¹s say, if
some of the university-based contributors to this discussion group establish
private medical or legal practices, they would somehow abandon their ethical
and moral compasses because they would then be private practitioners.

The preponderance of the evidence clearly shows that those trusted most by
the public violate that trust time and time again; for example, just check
the FDA warning letters and institutional suspensions over the years. Check
any research ethics curriculum, including NCEHR¹s own REB 101, and
inevitably the examples of outrageous conduct towards research subjects are
in state-sponsored research conducted by some of the most famous
investigators in some of the world¹s best known institutions. The Annals of
Internal Medicine publication this spring on trends in litigation shows the
same. Let¹s not deceive ourselves that we are much better in Canada.
We¹re just lucky that Canadians don¹t go running to their lawyers as much as
Americans do.

Wasn¹t it Dalhousie¹s Jocelyn Downie that this spring claimed on Canadian
public airwaves that the REB system is an accident waiting to happen,
essentially because they continue to be over-worked and under-resourced? How
can that be when public institutions receive thousands of dollars in REB
fees from sponsors (just like private REBs), not to mention millions of
dollars from industry for the conduct of research their REBs approve?

I call for an independent public inquiry led by the auditor general into
publicly administered research. Jocelyn Downey is either right or wrong.
We the public who trust in you demand to know which it is. Let the inquiry
include independent REBs. Let¹s see where the inquiry leads. Rx & D
monitors and auditors already know. It¹s high time the facts came out.

From: "Francis Rolleston" <frolleston@sympatico.ca>
It is all too easy to label people or organizations. Racial profiling is
one result. Stigmatization of the mentally ill is another. And there are
many others.

Labelling allows us to categorize individuals because they belong to certain
groups, and hence allow us to say that we, who do not include ourselves in
the label, are necessarily better than they, who we can conveniently so
label. I have a real difficulty in reconciling that with principles of
ethics.

To my mind, there is no necessary difference in degrees of potential for
conflict of interest between an REB that charges for its services and one
that is established by an institution. Both serve the interests of the
organization that established them. To say that, because of organizational
structures, one is necessarily better than another, is labeling individuals
because of perceived characteristics of groups. Note the word ”perceived”;
what is the basis of that perception?

I sit on two institutional REBs; I chair one of them, for which I am paid
under contract. Does that mean that my work is necessarily of less high
quality than of another REB Chair or member who is not paid or otherwise
recognized, for his or her work on an REB? Or is my paid work necessarily
of less quality than my work on the other REB for which I serve as a
volunteer? I hope not, because that would be a direct attack on my
integrity, and that of the organization that has contracted my services.

The issue is, how do REBs perform. At present we have no mechanism for
assessing this. We need such mechanisms. This is why the work now underway
within Health Canada on governance, arising from the reference in the Speech
from the Throne in Sept 2002, is so important.

Please, lets not label, but look to quality of work by individuals, or
individual REBs, and how to assess it.

Francis Rolleston

F rom: "Michael Goodyear" <michael.Goodyear@cdha.nshealth.ca>
Dear Colleagues,

I too had hoped not to see this discussion on the list, at least not in this form. Can we all take a deep breath and a firm hold on our ethical roots? I sincerely hope that we are all motivated by the same guiding principles.

1. Let's go back to where this started, which was an exchange of e-mails on IRB Forum about out-sourcing research ethics reviews to a central organisation, in this case the Western IRB. Since the e-mail I forwarded came from a well known Medical School in the US and claimed that outsourcing had streamlined the process and reduced costs, I thought it might be of interest to some of the members of the NCEHR list.

In editorialising the message, I noted that I was surprised because I thought that the use of central IRBs was confined to research in the community and smaller jurisdictions that did not have the resources to mount adequate in-house review. In doing so I also noted that Western had performed an invaluable service during the crisis at Johns Hopkins.

2. The issues that I thought might be worth us discussing were (a) that of the relative merits of local versus central versus mixed reviews, and (b) the issue of outcomes, which in this case seemed to be based on time (streamlining) and cost. Are these valid performance indicators for REBs?

3. To help the discussion I pointed to 'a body of literature' that claimed there were differences in performance between REBs based on other indicators. This seems to have created some upset. I was not endorsing one view point or another but asking questions about outcomes.

I should have been more precise. I was thinking particularly about an article in IRB:Ethics & Human Research ( Lemmens T, Thompson A. Noninstitutional commercial review boards in North America: a critical appraisal and comparison with IRBs. IRB. 2001 Mar-Apr;23(2):1-12). I may have also wrongly assumed that people were familiar with the article since this paper was funded by NCEHR (and Benjamin Freedman was one of the original grant recipients but died before it was completed). I thought this might provoke some academic debate. The authors are from the Joint Centre at Toronto for anyone who does not know them.

I tried to conclude on a constructive note stating that these observations presented institutional IRBs with a challenge, and stated some of the arguments for the maintenance of local review (even though I have gone on record in describing some of the potential advantages of central review - watch the Ontario cancer initiative).

I apologise to anyone who felt they were being labelled or were the victim of a slur, that was not the intent and would not have been consistent with the culture of our discipline.

4. We all need to realise that there is a wide diversity of backgrounds in people who contribute to and read the NCEHR list. Indeed it is healthy that there should be regular dialogue between us.

5. I agree with Jack that it would be simplistic to assert that all 'private' IRBs should be considered in a single category. I also agree with Jack that there is no obvious pattern to the most egregious deviations from the research ethics ideal in terms of the location of the IRBs involved.

6. Jocelyn would not be alone in terms of predicting the potential for trouble. The major reviews of both the US and Canadian Research Ethics systems have drawn identical conclusions. I am not sure if we have any reliable data on the fees that REBs receive, and how much of that goes to the REB as opposed to Research Administration. Frankly, since I do not pay my REB members, more money is not going to help my problems. The idea of an audit is certainly an interesting gauntlet. However if there are those who believe that the answers are already known, it would be in the public interest to divulge them.

7. It is unfortunate that these issues should be seen as labelling. Francis is correct about the pitfalls of such an approach. Nevertheless to make sense of the world we do categorise and attempt to test hypotheses as to differences between groups.

In fact Francis may be in a better situation than any of us to appreciate any cultural differences between REB structures. Ironically I have been an advocate for paying chairs as opposed to volunteers as part of the need to professionalise research ethics. Indeed in the interests of accountability and disclosure of conflict of interest I will state that the Executive Chair here at Capital Health is considered 0.4FTE, and the department of primary appointment bills the office for the time 'donated'. So like Francis I am 'payed' for my REB work, although it is only a sleight of hand in that it is just a matter of where the money comes from compared to my being 100% clinical and 'volunteering'.

8. I agree with Francis that one of the central issues is measuring performance and the lack of indicators. Actually I think we are the only unit in this institution that is not subject to performance indicators. We do need to measure what we do, and we also need to move forward as a group of committed collaborative individuals who have agreed, for better or worse, to air their problems with their peers.

9. Does this clear the air at all for anyone?

Dr Michael D E Goodyear FRACP FRCPC FACP

 

11. Sponsor IRB-REB Relationships


I can't imagine why a sponsor would need to know what REB would be
responsible for oversight at the development end of a study. We all know
that sponsors select potential investigators based on their qualifications
to conduct the specific research. Surely there cannot be a *black list* of
REBs in existance that would influence investigator selection.

All proponets of clinical research understand that "time to study
initiation" is a priority for sponsors, and we equally understand that the
better studies are defined by submission of complete protocols and
appropriate CFs. I'm of the belief that well-prepared submissions require
little in the way of extensive recommendations for approval and therefore
produce the best turn-around times.

It also seems to be in a sponsor's best interest to assist investigators
with understanding what makes a submission complete making complete their
according to their respective REB's review requirements, i.e. provision of
all printed and recorded material subject to review, sufficient # of copies
ect. This afterall is repetitive procedures.

I wonder to what extent the high turn-over of study personnel within the
biopharm industry, coupled with increasingly outsourced regulatory CRO
operations are responsible for delays imposed on the overall process? We
seem to run into a lot of new or newly re-located CRAs who often appear to
be learning on the job.

To avoid an REB from acting as the institution's "most highly educated,
unpaid editorial committee" (as my Dean used to say) it would seem a simple
matter for sponsors to consistently assure that the proposed model CF is
re-written according to the institution's consent document requirements, in
both official languages, in sufficient time for the *first pass* through
the REB.

Such initiative would go a long way to enhance the review process, and
achieve the type of turn-around times we all wish to see in the partnership
required to bring worthwhile new drugs and medical devices to market.

Elisabeth Clark
Research Ethics Officer/Human Protections Administrator
McGill University Health Center

tel: 514-934-1934 x-34720
fax: 514-843-1486
clarke@muhchem.mcgill.ca


At 10:28 7/29/2003 -0300, Michael wrote:
> I was asked about the appropriateness of the following scenario:
>Sponsor has interested an investigator in a study concept, but
>investigator has not yet seen protocol. Investigator indicates interest.
>Sponsor then asks for Name, Telephone number and Fax number of REB chair
>who will be reviewing study. While Sponsor-Board relationships are
>addressed from time to time it is usually in the context of REBs
>contacting the sponsor after review to try and expeditiously iron out some
>problems. This one is new to me. What do you think?
>
>Assistant Professor, Division of Medical Oncology, Department of Medicine,
>Dalhousie University


At first glance , and indered it was brought to my attention that way, it seemed a Macchiavellian Scheme to exert undue influence. A more benign interpretation would be that the information was needed to complete the CTA.

The blacklist idea is new to me. However as Elizabeth helpfully points out, it could be a good thing if the idea was to provide assistance in preparing submissions. Do they know all our quirks that well?

CTSU are trying to provide centres with the materials for a perfect submission, and I have also come across some industry material "Answers to Questions your IRB might ask".

Surely the last thing sponsors need is for inexperienced investigators/coordinators to send in a doomed submission that will cause endless delays in perfecting. Therefore it would be very much in the sponor's interests to prereview the submission or assist in its preparation.

The downside is that it might divorce the protrocol even further from the investigative team than it sometimes appears now. It is very depressing to me to ask PIs a few simple but well placed questions and realise that they have never read the protocol. Of course that is sometimes obvious from the submission which has very little to do with the protocol to which it is attached. This causes a lot of frustration at our end.

Dr Michael D E Goodyear FRACP FRCPC FACP