Comments on Chapter Clinical Trials

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1 General comments on this chapter: Comments on Chapter Clinical Trials All in all, I thought this was a good chapter. The committee is also to be congratulated for expanding the document to include guidelines for Aboriginal and qualitative research. These are much appreciated by REB s who have been feeling around in the dark for some years on these issues. There is variability in the quality of chapters and some may require major streamlining (in particular, chapters 1, 8, 10, 11, 12 and 13). The revised document contains a great deal that is very good. However, Chapter 11, like much of the rest of the document, reads more like a guide or manual for how to put together a trial rather than a document that provides the moral underpinnings for research involving humans. Therapeutic Misconceptions is addressed in Chapter 11 and is a good start here as far as it goes in relation to clinical trials. However, this topic has relevance for all practicing health professionals who pursue research and is an issue that health-related REBs deal with, particularly when such professionals are novice researchers. We recommend that therapeutic misconceptions be addressed in the broader terms of implications for the clinician as researcher and moved forward in the document to a more general chapter. Article # Issue Raised 11.1 Lines Does this really need to be said? Should not rather the ethical concerns described in the application be converted to articles? In particular, should not REBs be advised to reject phase 4 marketing studies (lines )? 11.1 Phase Descriptions- As I read through the ethical concerns with each phase, many of those concerns apply regardless of the phase, things like safety, recruitment, conflicts of interest, informed consent, etc. My suggestion would be to list the ethical concerns generally in all phases then within each phase discuss the specific ones. For example, With phase 1, to ensure safety rules are in place, participants knowing it is "first time in humans" or limited use in humans, it is a safety trial not focused on efficacy. As you move through the phases, use of placebos or comparators, etc. and of course with the importance of valid data collection for phase IV trials b/c these trials provide the broad safety profile La rémunération des participants aux essais cliniques de phase I pose un problème considérable dans le contexte du Code civil qui prévoit le versement d une indemnité compensatoire différente d une «rémunération souvent élevée» (lignes 5192 et 5193) Line 4259 Query I thought that Phase 1 trials were on very ill patients? 11.1 A. The definitions of clinical trial phases are informative but the ethical issues for all phases are safety, undue coercion for enrollment, and potential conflicts of 1

2 2 interest. The phase of the study may change the degree of risk (and the risk benefit ratio) but it doesn t alter the ethical issues. Article 11.1 should emphasize the magnitude (and specific knowledge) of the risk at different phases rather than any special ethical issues that different phases of research may raise 11.1 Clarity is needed regarding the use of placebo controls in Phase I/II studies. Article 11.1, application (line 4292) reads: Phase II and III clinical trials, unlike combined Phase I/II clinical trials often include a placebo control to help detect and quantify... Suggested worded may be: A placebo is rarely used in Phase I/II clinical trials given their specific purpose however if a placebo control is used then Section G The issue of conflict of interest is raised mostly with respect to Phase III clinical trials (Article 11.1 application, line 4308). Conflict of interest is concerning and may be present (or be perceived by a reasonable observer to be present) in other phases as well. Could the discussion about conflict of interest reference all clinical trial phases? 11.1 In discussion of inducement, the draft conflates compensation (which is defined as payment for expenses incurred, such as lost wages or parking fees and does not include additional fees) with payment (which refers to additional fees on top of compensation and is directly aimed, perhaps inappropriately, at inducement). We urge the TCPS to replace compensate with pay at lines 731 and Definitions of the various stages of clinical trials are unhelpful in that they neither promote understanding of how underlying principles are specified for various trial stages, nor reflect the diversity of research practice encompassed by each trial phase. Moreover, the definition of clinical trial provided in the opening is taken from the Health Canada Food and Drug Act, and hence is inappropriately narrow and at cross purposes with commentary that follows. The purposes of human protections, any definition should accommodate (a) the range of interventions tested (e.g. devices, biologics, procedures, surgery, psychotherapy, alternative medicines, preventive interventions); (b) the diversity of goals for a clinical trial (e.g. evaluate cost advantages, subjective patient outcomes), and (c) that as above, design rather than intent should determine whether a particular activity counts as a clinical trial Lines Describes in detail phases that are common to drug trials. There is no mention that device testing is not described as phases or any mention of the categorization that is used in device testing i.e. classes I-IV 11.1 Section B Phases of Clinical Trials: lines are not clear on whether all Phase I trials must receive ethics review. If a study is in Phase II is there any requirement that Phase I was reviewed? Do all products require a Phase I study before they are approved for Phase II? 11.1 Section H Analysis and Dissemination of the Data and Results of Clinical Trials. Article is applicable to other chapters of the Policy and its principles should therefore be made more explicit in Chapter Section H: we suggest that the following be added at line 4687: Such policies should require that researchers and sponsors jointly provide the knowledge sharing plan at the time of the initial request for the ethics approval : Quel sens veut-on donner ici au terme «sécurité»? : Clinical trial phases: Good discussion Please note that studies with marketed product in new indications are considered to be phase III studies. (See lines ) 11.1 Reference 4 on the phases of clinical trials is an NIH reference. It would be more appropriate to reference ICH E8, which has been adopted by Health Canada Reference 4 on the phases of clinical trials is an NIH reference. It would be more appropriate to reference ICH E8, which has been adopted by Health Canada.

3 11.1 Line 4264 This Application indicates that healthy participants who take part in Phase I studies should not accept risks they would otherwise refuse, because of the compensation to be received. Although it is a concept to strive for, in reality, healthy volunteers do take part in Phase I studies because of the reimbursement. Indeed, there is even a sub culture of human guinea pigs with its own network for exchanging information regarding studies among potential participants from the point of view of the paid participant. The TCPS may say that the participants should only be reimbursed to cover personal expenses, time and inconvenience. However, the compensation is often based on the type and the number of procedures plus the amount of time necessary. Recommendation: 28. There should be emphasis/guidance given in the Application on recruitment methods that avoid and manage coercion through reimbursement Section A 11.1 General Please note that there may be studies with regulated products that do not meet the definition of a clinical trial (see C in the regulations) and, hence, are not subject to division 5 regulations. These include many phase IV studies where the purpose of the study is not to evaluate safety and efficacy of the product. This is explained in the Regulatory Impact Assessment Statement of the Division 5 regulations. Examples of studies that do not meet the definition of a clinical trial include effectiveness studies, quality of life studies, observational studies, non-interventional studies, compliance studies, cost effectiveness studies, outcomes research studies, population health studies. (See line 4223, ) One of --- is comprised on hospital based contract negotiators at hospitals. These individuals review and negotiate clinical trial agreements on behalf of these academic hospitals and they interact frequently with the clinical researchers who conduct research under the auspices of these hospitals. Our comments on this Chapter are from this Working Group. To us, Chapter 11 appears to make the assumption that all investigators in a multi-site trial should have the obligations of a lead investigator in a multi-site trial. However, many multi-site trials are not set up with all the investigators having equal knowledge and responsibility to disseminate results. Nor should the investigator who recruits three participants out of one hundred necessarily have the same access to multi-site data and responsibility to publish as the investigator who recruits thirty participants or who is the lead in analyzing the data We suggest that the chapter, and specifically Article 11.11, be revised to clarify that sponsor obligations remain with the sponsor and those researchers and institutions at the multiple site have responsibilities that are in line with the role(s) they are playing in the trial. Please find specific suggestions, questions and comments below: D. Focus on Placebo trials. The distinction that phase 1 studies don t have placebos is inaccurate and should be removed. To keep this error in the document may be counterproductive to demonstrating the safety of a product. Indeed, a phase 1 study may be the best place to put a placebo if one wants to get accurate attributable rates of adverse events (safety is the primary outcome for phase 1 studies). The optimal design of a phase 1 vaccine study might include both a placebo and an established vaccine. The ethics of a placebo when an effective therapy is available essentially relates to the risk at which that places the participant. The document also implies that placebo trials should be rejected unless well justified, implying that an REB should have as its default a rejection of a 3

4 placebo (rather than a neutral position that requires justification). The application section (lines ) is far too restrictive Make explicit what is meant by undue risk. This is especially critical if our previous recommendation is not accepted. If the guiding principle is to be that clinical trials with placebos can proceed if the patients consent and clinical equipoise is not present as long as the patients are not under undue risk, then undue risk ought to be clearly defined and delineated Lines 4360 to 4367: This section confuses "serious adverse events" with "serious adverse reactions". While researchers must report all serious adverse events (regardless of expectedness or causality) to the sponsor (ICH GCP ), they are required to report only serious unexpected adverse reactions to the REB (ICH GCP 3.3.8c). Sponsors are required to expedite the reporting of serious unexpected adverse reactions to researchers, REBs and regulatory authorities (ICH GCP ) and promptly notify researchers and regulatory authorities of "findings that could affect adversely the safety of subjects, impact the conduct of the trial, or alter the IRB/IEC's approval/favourable opinion to continue the trial" (ICH GCP ). All of this is true regardless of whether the trial is conducted at a single site or at multiple sites (contrary to what's indicated in this paragraph). I'd recommend that you reword the whole paragraph, being very careful to distinguish between adverse events and adverse reactions (see ICH E2A for definitions) Proposition reformulation en français Lorsque des essais cliniques se déroulent dans plusieurs établissements, Santé Canada et les BPC-ICH exigent que toute réaction indésirable, grave, imprévue et subie par un participant de l un des établissements, soit déclarée à l organisme de réglementation, aux chercheurs et aux comités d éthique de la recherche de tous les établissements qui prennent part à la recherche (lignes 5315 à 5319) Effets indésirables : L évaluation des effets indésirables est une problématique qui est souvent soulevée par les CÉR. Nous trouvons l idée de créer un comité indépendant de contrôle des données très intéressante (ligne 5329). D où vient cette idée? Est-ce que cela existe ailleurs? Qui créerait ces comités et en assurerait le suivi et la responsabilité (rémunération, etc.)? N est-ce pas une lourde responsabilité pour les chercheurs ou les établissements? Santé Canada aurait-il un rôle à jouer? 11.2 Proposition clarification au sujet des mécanismes de surveillance et de sécurité lors de situations où il y a manifestation d effets indésirables En outre, dans de nombreux essais cliniques, les chercheurs travaillant dans un établissement n ont pas la possibilité d évaluer dans une perspective plus large les situations où il y a manifestation d effets indésirables de manière à être au fait de la fréquence des événements similaires vécus dans d autres établissements ou d avoir les données épidémiologiques requises pour déterminer si toute réaction indésirable est vraiment inattendue. Il est donc important que des mécanismes soient mis en place pour assurer la sécurité des essais. Dans certains cas, le plan produit par le chercheur pour présenter au CÉR des données sur la sécurité pourrait inclure une partie consacrée à la surveillance des cas d effets indésirables pour l ensemble des établissements où se déroule un essai clinique et ainsi prendre sans délai les décisions qui s imposent. Un autre mécanisme est le Comité indépendant de contrôle des données (CICD) (lignes 5310 à 5330) B. Article Important guidance is not included over the relative roles of the REB and the regulator in carefully evaluating previous laboratory and animal research. What is the role of the regulator in allowing a product to move into humans versus the REB s responsibility to evaluate the nature of the trial and the 4

5 risk? We would argue that the REB does not have the primary responsibility to critically evaluate the validity of pre-clinical information but rather to evaluate the design and nature of the clinical study Abandonment of Clinical Equipoise The chapter on clinical trials in the original version of the TCPS opens by establishing moral foundations on which clinical trials rest. In the new Draft, this language is replaced with a description of clinical trials, and reference to regulatory standards like Health Canada regulations. In our view, the emphasis on regulatory compliance is unnecessary (researchers scarcely need a reminder of this), and detracts from the moral authority of the TCPS as it encourages conflation of regulatory compliance with ethical conduct of research Lines Should the requirement o review the investigator s brochure be mentioned in this section? Should there be mention that the expert evaluation should be independent (at arm s length) of the researchers? 11.2 À l article 11.2, il serait important de préciser ce qui est entendu par l expression «futilité» (ligne 5342) pour qualifier un essai clinique qui devrait être interrompu Scrutiny (161) should be proportionate to risk and is too important to not have a separate heading. Cross-reference to Chapter 2, Article 2.7 and the Appendix (606) and Chapter 11 Article 11.2 (4349) Line and , Articles 11.2 and We are very pleased to see explicit recognition in Article 11.2 that REBs are charged with a responsibility to ensure that research does not pose undue risks to subjects, and that this is reinforced in Article This article also adds an important requirement of review of financial considerations to ensure they do not undermine the scientific value of the research. Please note that there is a difference between severity of an adverse event and the seriousness of an adverse event. (see line 4343). It is likely that this should refer to seriousness of adverse events to be consistent with ICH GCP In line 4365, ICH GCP requires that serious unexpected adverse reactions are reported, not serious unexpected adverse events. In line 4407, it appears to allow annual or semi-annual reporting whereas ICH GCP requires prompt reporting. It would be helpful if a distinction could be made between local events (i.e., those that occurred at the investigator s site) versus external events (i.e., those that occurred elsewhere) Le chapitre 11 sur «Les essais cliniques» (p.137) semble augmenter de beaucoup la demande faite aux comités d éthique de la recherche et élargirait trop le mandat desdits comités d éthique. Par exemple, l art (p. 141) suppose que les CER donnent un avis sur le protocole et sur la validité scientifique de celuici. La demande est ainsi trop grande. Aussi, dans le cas d un projet multicentrique, et si un effet secondaire survenait, l art (p. 143) propose de faire signer une nouvelle fois aux participants tous les formulaires de consentement révisés. Une question se pose alors : la vigilance ne devrait-elle pas davantage revenir aux chercheurs plutôt qu aux comités d éthiques? Monitoring Safety section -, I think it is important to understand who the sponsor is. The pharma sponsored trials, whether single centered in phase 1 or in multicentered, the investigator reports safety problems to REB and sponsor and of course to participants if deemed necessary. It is the investigator actng as sponsor studies that the understanding is needed. An investigator-initiated trial could be single or multi-center but it their responsibility as "sponsor" that requires reporting to REB and Health Canada. 5

6 11.3 L article 11.3 propose l adoption d un plan de surveillance en vertu duquel des données sur la sécurité sont transmises aux CÉR. De telles données sont actuellement transmises aux CÉR, alors que ces derniers ignorent ce qu il faut en faire. Cette proposition devrait être révisée C. Article 11.3: safety monitoring. There is lack of clarity and distinction between the sponsor s role and the investigator s role to the REB. This confusion of responsibilities could lead to lack of appropriate safety monitoring and reporting. It should be specified that the sponsor has the responsibility of providing all safety information to the investigator who has the responsibility to provide it to the REB : Monitoring safety and reporting adverse events: Consider adding a reference to the recent FDA document regarding reporting of adverse events ) Page 125, lines : where possible, REBs should be provided with individual adverse event reports, accompanied by an evaluation, by the sponsor, of their relevance and significance to the trial. Comment: Most REBs do not have the background knowledge needed to make decisions about individual non-local SAE reports. What is the anticipated outcome if a sponsor provides the REB with an individual SAE report and an evaluation? The investigator and the sponsor must take the responsibility to make the REBs aware of concerning and unexpected SAEs. Having all individual SAEs reported to the REB when they are unable to appropriately assess the SAES just increases the workload for everyone involved without any benefit to the individual participants. DSMB reports and SAEs reports incorporated to a revised Investigators Brochure would probably be of much more value to the REB REB Comment: This is the current policy of Articles 11.3 and 11.4 and their applications concerning Data Safety Monitoring Boards (DSMB) are very important but there is some confusion about the various references to DSMBs (Sponsor s DSMB and an institution appointed DSMB) and their roles. Under what circumstances should a REB require an independent sponsor DSMB (which has access to reports from all participating sites) and when is an institution appointed DSMB desirable? What if both are involved in a specific clinical trial and the institution appointed DSMB has concerns that are not shared by the independent DSMB? 11.4 Line , Article This article imposes on REBs a responsibility to monitor safety reports and take appropriate steps in response to them. With respect to serious adverse events, there are severe problems with the current situation. The discussion of safety reports should highlight the imperative need for some national system of review for reports regarding multi-site trials Give Data Safety Monitoring Boards (DSMBs) the responsibility to end a trial if clinical equipoise is significantly disturbed between the treatment arms. Article 11.4 of the new draft mandates DSMBs to stop the trial for safety, futility, or efficacy. Adding clinical equipoise here as a condition clarifies the concepts of futility and efficacy and indicates an appreciation of the ethical/ obligations of the investigators to their subjects : Review of safety reports: This section is too broad and merits changes. There is still the expectation that all SAEs must be reported to the REB and the current document does not change the status quo. There is no clear model offered and more guidance is needed. Perhaps only the local SAEs should be reported 6

7 to the REB Serious Adverse Events reports: There is still the expectation that SAEs must be reported to the REB. This has been a serious concern regarding workload and benefit of such reports being sent to REBs. Further guidance is required and a possible alternative model put forth ) Page 126, lines : Some kinds of standard or recognized treatments (for example, surgery, chemotherapy or radiation therapy) themselves pose substantial risks. An REB may approve a study that involves such high-risk therapies if there are no other reasonable alternative therapies available to patientparticipants and if the research-attributable risk is no greater, or only minimally greater, than that to which participants would routinely be exposed. Such risks may be regarded as within the range of minimal risk for these patient-participants since they are inherent in the treatment that patients undergo as a part of their everyday life. Comment: A clarification may be helpful to state that although these studies may be considered to have minimal risk they should still be reviewed by the full REB board and not considered a delegated review Proposition inclure le médecin traitant du participant car beaucoup d essais cliniques dans les cliniques médicales (projets en santé publique) ou dans les centres hospitaliers universitaires (CHU) se font à partir d une pré-sélection établie par cet acteur. Les chercheurs devraient aussi communiquer toute information nouvelle aux anciens participants à la recherche et, le cas échéant, au médecin traitant lorsque cette information est pertinente au bien-être de ces individus (lignes 5444 à 5445) Line replace "REB" with "researchers" as it is the researcher's obligation to disclose info to the REB, sponsor, Data safety monitoring board, participant. This former issue (of publishing our findings), needs, I think, to be made quite clear throughout all study designs (i.e., not only for clinical trials). But, again, by what mechanism if Journals are not interested after some attempts for researchers to publish findings that are not especially impressive to them, one way or another? Would a register of all research, maintained by some government agency, be a good idea? The registry could include minimal information about the hypothesis, design, population and analytical methods, findings and conclusions (perhaps as a 150-word (max) abstract) with PI contact information. Again, what about research not funded by any of the Tri-Councils? How would one require that privately funded research also be included in such a register? It was not clear to me just how the TCPS expects researchers to behave in the dissemination of their findings particularly in relation to being open with the media, at conferences, and with the scientific literature. Some spelling out of limits (or not) would be helpful F. Line 4462, the obligation of the REB is to require that the investigator disclose any new information both to the REB and to the participant. In this section (and others), it is important to be very clear that the investigator stands in relation to the sponsor, the REB and the participant and has obligations to each of these parties. The safety of the participant trumps all of these responsibilities For Article 11.6 application ( line 4508), suggests revising to the following sentence: When sponsors refuse to report new and significant information 7

8 that is relevant to the welfare of participants, then researchers and/or REBs have a duty to do so so that there is more flexibility. We suggest the following wording: When researchers and/or REBs have a reasonably held belief that there is new and significant information relevant to the welfare of participants that the sponsors refuse Line Sharing new information with former participants should also be done in a timely manner Line Sharing information with the REB and other appropriate regulatory or advisory bodies should also be done in a timely manner Section D - Article 11.6 (lines ) could be enhanced as follows: Researchers should also share new information, including unexpected harms, with former participants. The following could be added: There should be a way to make such unexpected harms publicly available Section D: we suggest to add as well as to the potentially ongoing research elsewhere and the general public at the end of line 4505, after and informed choices. Also, to edit lines 4505 to 4507 as follows If so, reasonable steps should be taken to inform such participants, as well as to publicly disclose the information, in a meaningful and timely manner et 5453 : Ces lignes soulèvent quelques questions, la première étant celle du risque minimal qui, de l avis, devrait être développée. Dans les essais cliniques, le risque minimal pour un patient serait l écart entre le risque posé par l intervention thérapeutique qu il reçoit et celui induit par le protocole de recherche sur l essai d un nouveau médicament dans lequel il participe. Ces lignes devraient également mentionner la responsabilité du chercheur de remettre au CÉR la liste des organismes de réglementation ou d organes consultatifs concernés par son projet, et celle d expliquer comment il compte rejoindre les patients impliqués dans son protocole de recherche dans les meilleurs délais. Le chercheur doit également conserver de façon sécuritaire et sur une longue période les renseignements nominatifs les concernant et 5493 : Lorsqu un promoteur refuse de faire un rapport sur de l information nouvelle et pertinente pour le bien-être des participants, il revient au chercheur la responsabilité première d informer le CÉR du refus du promoteur d informer les participants The academic freedom case of Nancy Olivieri alerted to us of the outrageous efforts by drug companies to prevent the release of negative results, even if public health is at risk. The following recommendation comes from the Report of the Committee of Inquiry on the Case Involving Dr. Nancy Olivieri, the Hospital for Sick Children, the University of Toronto, and Apotex Inc. 12. It is worth re-emphasizing. Recommendation #22: All contracts, protocols, and investigator agreements for industrial sponsorship of clinical trials should expressly provide that the clinical investigators shall not be prevented by the sponsor (or anyone) from informing participants in the study, members of the research group, other physicians administering the treatment, research ethics boards, regulatory agencies, and the scientific community, of risks to participants that the investigators identify during the research. 12Thompson J, Baird P, Downie J. Report of the Commission of Inquiry on the Case Involving Dr. Nancy Olivieri, the Hospital for Sick Children, the University of Toronto, and Apotex Inc. Ottawa: Canadian Association of University Teachers; ) Page 127, line 4462: Section D describes the obligations of REBs to ensure that any new information 8

9 Suggestion: We would suggest that the words and researchers after REBs be added to this sentence to clarify that it is the responsibility of both the REB and researcher to inform participants of new information ) Page 128, line 4508: When sponsors refuse to report new and significant information that is relevant to the welfare of the participants Comment: It may appear less accusatory to change When sponsors to If sponsors as it would be very rare for sponsors not to report relevant safety information REB Comment: This is the current policy of 11.7 Lines Traditional physician-patient relationship Recommendation: Clarify and nuance the role of clinicians in research. The comment that physicians conducting research act outside the traditional physician-patient relationship is vague. Physicians have a deontological code that may take precedence even when they act also as researchers In the section discussing the ethical issues involved in clinical trials (chapter 11, 2008), the authors have removed all mention of the principle of clinical equipoise. In the old 2005 version of the TCPS, clinical equipoise was held as a clear moral foundation on which clinical trials could be ethically performed (Section 7A, 2005). It is possible that it was removed to avoid dismissing trials that do not pose undue risk to subjects while not being in clinical equipoise; examples of this kind have incorrectly construed that clinical equipoise is overly protective of subjects. However, this sentiment neglects the investigators obligation to fulfill justice and beneficence for his or her subjects, which can be interpreted as obliging the investigator to follow clinical equipoise. In addition, the Helsinki Declarations latest draft is stricter in its exceptions to its prohibition of placebo control trials. Therefore, our recommendations will be in a spirit of respecting investigators ethical responsibilities to their subjects in clinical trials and fine-tuning the restrictions on clinical trials to balance scientific inquiry with trial subject safety. Recommendations Article 11.7 of the new draft successfully clarifies the risk of therapeutic misconception in patients. This risk is common in research that occurs in the context of care. The old draft (Section 1C.C1, 2005) failed to make clear the implications that an insufficient communication of the study s design can have on a subjects free and informed consent. The new draft fixes this deficiency by explicitly referring to the concept of therapeutic misconception and citing its negative consequences : Therapeutic misconception: This is a new section and an important addition. 9

10 11.7 Lines Should health care professionals responsible for the participant s care also not be involved in the informed consent process (as with recruitment) due to potential for conflict of interest and therapeutic misconception? 11.7 Certaines difficultés rencontrées dans le passé dans le cadre d essais cliniques pourraient être mentionnées à l article Le texte devrait souligner les obligations éthiques des différents acteurs. Mentionnons, entre autres, l obligation d expliquer aux participants la différence entre un essai clinique et les soins habituels, ainsi que les répercussions attendues de leurs choix H. The section on clinical trials (chapter 11) contains several improvements over the previous Tricouncil. The draft s unambiguous requirement that clinical trials be prospectively registered, regardless of phase, is a major improvement over the previous version; we strongly applaud the language contained in this provision. Another is the draft s language on therapeutic misconception.1 1 though we note that the wording of the section on Therapeutic Misconception could be improved. For example, it is not necessarily therapeutic misconception that patient-participants assume they have been invited to participate because their physician believes it would contribute to their welfare. (4520-2). If a study is in clinical equipoise, the study should contribute to welfare, as should any study whose direct benefits exceed risk. What is at stake here is that subjects might fail to appreciate that trials serve external ends, and involve design features that can frustrate certain therapeutic goals and expectations Accès au contrat par le CÉR : Au Québec, le Ministère exige que les CÉR aient accès aux parties pertinentes du contrat (ligne 5660) Financial Conflicts - This section does refer back to chapter 7 but I think conflict discussion needs to expand beyond financial (ex. academic conflicts) : Il aurait été utile d aborder la question de la compensation des participants et des assurances que les promoteurs privés devraient prendre afin de couvrir les préjudices que pourraient subir les participants. Les clauses de compensation sont de plus en plus limitatives de responsabilité. Or, c est un principe qui ne tient pas la route en éthique. Les Standards contiennent la clause suivante concernant la limitation ou l exclusion de responsabilité : «Suivant l'article 1474 du Code civil du Québec, une personne «ne peut aucunement exclure ou limiter sa responsabilité pour le préjudice corporel ou moral causé à autrui». Par ailleurs, et indépendamment de l article 1474, aucune clause de limitation ou d'exclusion de responsabilité du chercheur, du promoteur, de l'établissement ou de toute autre personne n'est acceptable sur le plan de l éthique. Ce genre de clause doit être prohibé, car il induit en erreur le sujet de recherche. Conséquemment, une telle clause ne doit jamais apparaître dans un formulaire de consentement. La section du formulaire de consentement qui porte sur la responsabilité du chercheur, du promoteur, de l'établissement ou de toute autre personne doit rappeler au sujet qu il conserve tous ses droits dans l éventualité d un préjudice corporel, moral, matériel, financier ou autre. Un passage de cette 1 Supra, note 4, p

11 section du formulaire de consentement doit contenir le paragraphe suivant ou un paragraphe similaire adapté au type de la recherche visée: Si vous deviez subir quelque préjudice que ce soit par suite de l administration d un médicament ou de toute autre procédure reliée à l étude, vous recevrez tous les soins et services requis par votre état de santé, sans frais de votre part. En acceptant de participer à cette étude, vous ne renoncez à aucun de vos droits ni ne libérez les chercheurs (le cas échéant : les organismes, les entreprises) ou les institutions concernées de leurs responsabilités légales et professionnelles 1.» 11.8 Line 4550 Change FINANCIAL CONFLICTING INTERESTS, or even better would be CONFLICTING FINANCIAL INTERESTS 11.8 I wonder about the whole question of "the moral integrity" of the researcher in addition to the need for "scientific integrity"? Guidance on this aspect would be most helpful to keep "health research house" in order The addition of article 11.8 is welcome At whom is the document aimed? There are references throughout the document to the responsibilities and expectations of REBs and their role in research governance. Sometimes the language lacks sufficient inclusion of the researchers and the systemic players who support and drive research. The document ought to include greater emphasis on the fiduciary responsibility of all the players and stakeholders in research, and not just the role of REB review. I recognize that this is consistent with the spirit of the document as emphasized in the introduction etc; however, some sections mention the REB without indicating the responsibilities of the researchers in a given topic (eg pg 130 lines ) : Inappropriate incentives: This is a new section. Examples and guidance are required Lines The wording of this section does not specifically state that the REB should do the review but rather that the REB should ensure that the study budget is reviewed. If the former is intended, it should be explicitly stated. What follows in the application (lines ) is wording that implies that it is the REB s role to review the budgets Lines repetition of ensure On page 130, in line 4577, consider clarifying the term finder s fees Budget des essais cliniques (lignes 5566 et suivantes) : Soulignons qu un groupe de travail créé par le Ministère examine présentement les questions reliées à l examen des contrats et du budget par les CÉR et les établissements A related concern with respect to Clinical Trial Budgets in Article 11.9 of the Draft TCPS, is the disclosure to REBs of the kinds and amounts of payments and other budgetary details. Such disclosure to the REB should be clearly mandatory in order to control for potential conflicts of interest, and any inducements paid to the researchers or institutions for the recruitment of subjects should be disclosed to the research participants or subjects as well. Unequal distribution of benefits and rewards versus risks is an ongoing concern for Aboriginal Communities and research participants when they contemplate partnering or participating 11

12 in research; these concerns should be comprehensively addressed in the Draft TCPS through these and similar transparency requirements On page 130, in line 4577, consider clarifying the term finder s fees Par ailleurs, l article 11.9 (p.148), relativement au budget des essais cliniques, suppose que les CER fassent un état financier des budgets afin de s assurer que les médecins ne perçoivent aucun avantage financier de la recherche. Cette mesure n encouragerait pas les médecins à faire de la recherche ) Page 130, line : Research ethics boards should ensure that clinical trial budgets are reviewed to ensure that conflicts of interest are identified and appropriately managed. Comment: This section implies that the REB is responsible for reviewing the budget, however in many instances the institution reviews the budget. As previously mentioned, often the institution is in the best position to determine if the amount of money being provided by a sponsor for a trial is appropriate given the procedures to be performed in the trial. Many institutions already have the mechanisms/committees in place for this role. Having said that,we absolutely agree that all conflicts of interests and payments to the participants must be declared to and reviewed by the REB L article concernant les essais contrôlés nécessitant l administration de placebos constitue un recul inattendu par rapport au texte en vigueur. En effet, le texte de l article est très permissif et hautement sujet à interprétation. Par ailleurs la description des situations où l emploi d un contrôle par placebo est acceptable est abrégée et introduit des clauses jusque là inexistantes qui permettent l utilisation d un placebo si «les patients estiment que leur réaction aux traitements efficaces reconnus ( ) ne répond pas à leurs attentes», ou s ils «ont précédemment refusé les traitements efficaces reconnus». On notera que, tandis que la barre est abaissée pour le placebo, elle est relevée pour le traitement standard ou «couramment dispensé» (EPTC, art 7.4) qui doit maintenant être conforme à la norme d un traitement efficace reconnu. Même le Rapport final du comité de travail national sur les placebos portant sur l'utilisation appropriée des placebos dans les essais cliniques au Canada (Juillet 2004) ne laissait pas présager un tel assouplissement des règles portant sur l utilisation du placebo. Ces changements profonds nous paraissent avoir été adoptés sans une consultation appropriée. Nous ne voyons pas pourquoi on n a pas conservé le libellé de l article 7.4 du texte en vigueur A concern arises when comparing provisions pertaining to Clinical Trials in Chapter 7 of the Current TCPS with the provisions in Chapter 11 of the Draft TCPS. The role of clinical equipoise has been lessened in the Draft TCPS, with a larger role for placebo-controlled studies. Clinical Equipoise requires that a new therapy or intervention be tested against an established effective therapy, whereas placebo-controlled studies would withhold such treatment from the control group. This increased trend towards placebo controls rather than clinical equipoise opens the door to interpret established effective therapy narrowly and therefore to withhold treatment that may have some merit from research subjects randomly assigned to control groups. In many cases, this can do harm to vulnerable research subjects, for instance, in the addiction or substance abuse context, where established therapy that may have some efficacy is withheld to those randomly assigned to control groups. Some of the individuals in the control group may suffer further harm from the addiction, even harm to an embryo or fetus as some participants could be in the early stages of pregnancy at the time. Such potential resultant harm could have a chance of being ameliorated if clinical equipoise were the standard. The explanatory comments for Article in the Draft TCPS go even further stating if there are no established effective 12

13 therapies for the population leaving the door open to exclude established therapies that have some efficacy but which have not been specifically tested on the Aboriginal peoples of Canada. Such a state of affairs should raise a red flag for all concerned about protecting research subjects from over-zealous withholding of treatment through the vehicle of enhanced use of placebo studies. Aboriginal participants in control groups could be particularly vulnerable, as explained Line 4626 Change Is there a more common word than refractory? On page 131, in line 4625, consider adding at the end of the line (this constitutes clinical equipoise) In our opinion, clinical equipoise establishes a normative standard for assessing risk and value for clinical trials, and remains the best heuristic device for REBs and others to determine whether it is ethical to enroll a research participant into a trial. Removal of specific reference to clinical equipoise leads to several problems with current language. For example, reference to undue risk in Article 11.2 is difficult to implement without the standard provided by equipoise ( competent medical care ). The application provision 1, under Placebo (line 4624) specifies the condition of doubt within the community of treating physicians. Equipoise would better specify this doubt must be located within the community of expert practitioners rather than parochial practice Tighten the limitations on the exceptions in which placebo is acceptable as a treatment arm. This should involve stipulating the level of risk that is acceptable, the seriousness of conditions that patients may have in such trials, and the scientific justification for such trials (for example, if valid scientific results can be obtained with an active comparator trial arm instead of placebo, then placebo control should be forbidden). With the changes made to the drafts placebo control section (Section 7.4, 2005; Section 11.10, 2008), the condition which a patient may have for a trial to be allowed to have a placebo control arm need no longer be minor, and the new draft does not stipulate the level of risk of suffering or harm that is acceptable. Therefore, studies that involve patients with major conditions and substantial but not undue risk for which the patient has refused treatment can be carried out Article clarifies the exception in which placebo controls are acceptable in which the treatment to be compared to a placebo is an add-on to standard treatment Item (b) of article states that placebo controls are acceptable if their use is scientifically and methodologically sound. We recommend replacing sound with necessary I am strongly supportive of the wording of the section on Placebo Controlled Studies (4591) I. The section on placebo-controlled trials sends conflicting messages (chapter 11). On the one hand, we are pleased that the language between lines 4617 and 4638 is substantially consistent with the recommendations of the National Placebo Initiative (NPI). On the other hand, language in the paragraph beginning 4592, including statements like placebo-controlled studies have long been the gold-standard design exaggerate the methodological merits of using placebo controls and are inconsistent with NPI s findings (see: NPI final report, pages 14-24) Further, the requirement that participants be well-informed when placebo use requires withdrawal or withholding of therapy could be interpreted as 13

14 contradicting the statement that use of placebo controls must not compromise the safety or well-being of participants Dans un souci de clarté, à l article 11.10, les lignes devraient être rédigées sous forme de phrases complètes Section G on Placebo Controlled Studies does not deal with the potential for ethical issues beyond safety. The bullet points under section 11.10(b) do not support a document that aims for participant protection or methodological soundness. Further, it deals with a number of irrelevant methodological issues, and sets up an undefined standard of well being for trial participants. If such a standard is intended, we might also ask why participant well being does not appear in the introductory statement on placebo. Line 4600 only mentions safety, as if this had primacy over efficacy all other considerations Footnote #6 under Applications needs clarification. Only numbers 4. and 5. can be cited as based on recommendations of the NPWC. We understand that this is being misinterpreted by some readers to mean that the entire Chapter reflects the work of the National Placebo Working Committee G. Placebo-Controlled Studies Generally we feel that Chapter 11 should include a new section for Psychotherapeutic research. Unlike drug trials, Psychotherapy research is rarely involved in Phase I, II or sometimes III. This section focuses on placebo comparators as the alternative. However, although Psychotherapy research does use placebo comparators, it also very often uses wait-list controls, which are not discussed in this chapter. Its exclusion from this chapter could be interpreted as saying that we cannot keep participants on a wait-list for treatment as a type of control. Given that this is in fact a common and practical control used in psychotherapy research this should be addressed. Best practices should be stated indicating that a wait-list might be a better control for psychotherapeutic research and that this waitlist group should be offered the treatment after the study. Article This article is unacceptable for psychotherapy research i.e., it is unreasonable to clump together drug and psychotherapy research. Lines : A new therapy or intervention should generally be tested against an established effective therapy. Lines : An active treatment comparator in a clinical trial of a new therapy is generally the appropriate study design when an established effective therapy exists for the population and clinical indication under study. Lines : A placebo comparator is acceptable [when] there are no established effective therapies Testing against established effective therapy is not reasonable, and would be cost prohibitive for psychotherapy research. First, in psychotherapy research there will almost always be an established effective treatment. However, given that power considerations will be similar to those considerations for bio-medical research, and given that there will be no industry backer (i.e., funder), this provision rules out most clinical research on practical grounds because sample sizes to detect the difference between an effective therapy (let s say 35%) with a new therapy (let s say 50% effective) will be prohibitively huge. This is a major problem and we feel that edits to this article are essential. 14

15 11.10 Regarding placebo-controlled studies: there are some studies that are required by regulatory authorities involving placebo controls that would not be approvable given the wording in the second edition. For example, the European Agency for the Evaluation of Medicinal Products, Note for Guidance on Clinical Investigation of Medicinal Products in the Treatment of Depression requires studies of rebound and withdrawal phenomena which require an active treatment run-in period followed by a placebo-controlled phase. Such studies provide important knowledge on rebound and withdrawal that is relevant to physicians treating patients with depression. Such studies would be approvable if the wording was revised (line 4607) from it does not compromise the safety or wellbeing of participants, and to read the risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects and the importance of knowledge that may reasonably be expected to result, and Lignes 5626 à 5629 (Placebo), article b). Il nous semble que les prescriptions de l article constituent un net recul par rapport à la version de Il n est pas acceptable qu une thérapie soit supprimée ou suspendue aux fins de la recherche, à moins que cette thérapie n ait pas été véritablement prouvée comme efficace Lignes 5646 à 5649 (points 4 et 5). Ces deux affirmations mènent à un biais de sélection des participants. Lignes 5647 et 5649, écrire «affection». Pourquoi avoir enlevé l exception contenue à la règle 7.4 b : «il a été démontré que le traitement normalisé ne valait pas mieux que le placebo»? Line 4603 There are a number of conditions listed which must be in place for placebo-controlled studies. However, in the Draft, the use of the word and after the second condition could mislead the reader to think that only one of these conditions is sufficient to run a placebo-controlled trial. All of the conditions should be in place for placebo-controlled trials and this should be clearly stated in the TCPS Recommendation 29. Put the word and after each bullet point Article dealing with Placebo-Controlled Studies requiring administration of a placebo constitutes an unexpected setback in comparison to the original text. The text of the article is indeed ambiguous and highly subject to interpretation. In point, the description of the situations where the use of a placebo as a control is acceptable has been reduced. It also introduces clauses that were until now non existent to allow the use of a placebo, if patients believe that their response to the recognized effective treatment (.) does not meet their expectations, or if they have previously refused the recognized effective treatments. It should be noted that while the bar is set lower for use of the placebo, it is set higher for the standard or commonly available treatment, (TCPS, article 7.4), that presently respect the norms of a recognized effective treatment. Even the Final Report of the National Placebo Working Committee on the Appropriate Use of Placebos in Clinical Trials in Canada (July 2004) did not predict such relaxation of the rules for use of placebos. It seems that these drastic changes were brought without the appropriate consultation and we do not understand why, apart from the potential pressures of the pharmaceutical industry and/or Health Canada, the wording of Article 7.4 in the 1 st edition was not preserved Publication des résultats : La responsabilité de publier les résultats ne devrait pas incomber à l établissement. L Article (lignes 5665 à 5671) impose à l établissement une tâche plus lourde que ce qui est décrit dans l explication de l article (lignes 5709 à 5714). Le CÉR doit s assurer que le contrat ne contient 15

16 pas de clause de restriction indue de la publication des résultats, afin de laisser la liberté nécessaire au chercheur et non à l établissement. Cela nous semble une responsabilité trop lourde et nouvelle Results Section - my biggest beef is the length of time it takes for participants to receive their results after the trial is completed. The reference in this section of 'in a timely manner" needs to be more specified. I know this is a tough timeline to define but consideration into acceptable timelines need to be explored. There are protocol amendments that can extend the study that can delay results for years L article aborde le contenu des contrats de recherche. Une approche qui fait intervenir les CÉR isolément est condamnée à l échec en raison de l expertise insuffisante des CÉR à ce propos et de la grande variabilité prévisible dans les approches des CÉR Line 4714 Concept As before, here I think of demands for data access/sharing for re-analysis and/or re-interpretation E. Line 4665 in a timely manner is one of the most abused terms in industry sponsored clinical trials. More guidance should be provided that encourages results of interest to be returned to participants; this is particularly important for industry-sponsored clinical trials I would suggest that a third requirement should added which is that separate institutional contract review committees make available full information to the REB including the original contract and other matters specified in the conflict of interest chapter Finally, Article application (line 4678) Contracts should also ensure that researchers have the necessary access to trial data... may not be explicit enough about the trial data. Perhaps Contracts should also ensure that researchers have necessary access to all original trial data. Would be better, as it presumes we are referring to non-manipulated data (e.g., in table form) Chapter 6 deals almost exclusively with procedural issues. Where do we find the criteria that REBs should use to judge the ethical acceptability of a proposal? In addition to provisions for informed consent, confidentiality, minimization of risk and inclusivity, should not REBs consider the social worth of the proposed research (cf. lines , but that deals with research after the fact, whereas social worth should be considered beforehand, for the very same reasons)? Finalement, le Sous-comité estime que l article est imprécis. Des expressions telles que «limitation indue à la publication» (ligne 5672), «politiques écrites raisonnables» (lignes ) ou encore «restriction [ ] qui limite de façon excessive le contenu de l information scientifique pouvant être diffusé» (lignes ) mériteraient d être définies, possiblement au moyen d exemples. En outre, il serait approprié de rappeler les limites du mandat des CÉR et de préciser qu un ensemble d organismes de régulation devrait également participer à ce type de surveillance Section H: we suggest that policies requiring that clinical trial research contracts be examined (line 4691 to line 4708) also ask for sources of funding, institutional affiliations and that conflicts of interest be declared in the publication et 5689 : La diffusion publique des résultats de la recherche devrait se faire le plus tôt possible, plutôt qu en temps utile Ethics of knowledge translation and publication issues should address potential risks associated with certain findings Researchers ought to be reminded to take special care in the planning and publishing of research findings. This does not advocate censorship, rather it suggests that researchers understand that their findings may produce adverse responses to individuals and communities, and can cause real harm, embarrassment, shock, stigma and prejudice. As a result care ought to be given to the way information is shared, including fair advance notice to a person or 16

17 community in question, and even choosing not to publish widely certain kind of findings Enfin, l art (p.150) statue sur l analyse et la diffusion des données et des résultats des essais cliniques. Les établissements et les comités d éthique devraient prendre les mesures nécessaires pour permettre la diffusion des résultats. Or, les chercheurs sont parfois liés à un contrat avec les entreprises pharmaceutiques relativement à la diffusion de leurs résultats. Aussi, demander aux CER de prendre des mesures adéquates afin de permettre la diffusion des résultats est une entreprise complexe, et qui en outre dépasse le mandat des CER. Mais les membres du comité s entendent sur le fait qu il faut encourager la diffusion des résultats, mais qu il n est pas envisageable de prendre des mesures particulières pour ce faire Lines : All results must be published or disseminated Lines : Negative results must be disseminated We understand that this provision is intended to prevent sponsors/funders from suppressing negative results. However, there are some issues for psychotherapeutic research. First, there is no distinction made between negative and null results so they may be clumped together. We oppose any requirement to publish null results. If a new therapy has a negative effect than yes perhaps this should be disseminated at least to the research community however, if a new therapy is simply not effective then there is no need to publish that result. Researchers will not comply and they should not be forced to do so. Perhaps Health Canada can provide a forum for this issue? Lines , 4708: Researcher access to data Access to data implied by this policy will not be upheld by industry. They even control how data are presented. We need reassurance that psychotherapeutic research will not be held to standards that will not be met in pharmacological and bio-medical research Lines : Clinical trial registration Does the requirement of registering with Clinical Trial databases extend to psychotherapy research? ) Page 132, line : REBs should require the satisfactory amendment or removal of any confidentiality clauses or publication restrictions that unduly limit either the. Comment: This section should be clarified to state that contracts and agreements would be negotiated by the institution. The REB reviews any restrictions on publication rights in the submission and should require the removal of any unethical clauses prior to sign off by the institution and PI REB Comment: This is the current policy of State that all clinical trials should be registered with a recognized and easily web-accessible public registry. Is this already the norm? If not, this might impose a heavy burden on the research community, and should define what information needs to be accessible Clinical Trial Registration: I think the addition of registration into this document is positive, however; elaborating on this point would be helpful. There needs to be clear guidelines from regulatory bodies (including Health Canada, TCPS and REBs) for clinical trials conducted in Canada. What is the TCPS position on other clinical trial registries: What is the TCPS position on clinical trials that are NOT funded by CIHR (industry 17

18 sponsored, international trials with Canadian sites, etc.)? Who's responsibility is it to register the clinical trial (Sponsor, Investigator/QI, CRO)? How does the REB know if a trial has been registered? What are the ramifications of registering an industry-sponsored clinical trial (in terms of protecting the confidentiality of proprietary information)? What about industry-sponsor trials that are conducted for internal R&D (where the company has no interest in publishing results: bioavailability studies, comparator product studies)? What about Phase IV trials that do not require government approval (Health Canada CTAs)? I noted in the clinical trials chapter the requirement to register all new trials. Does this apply to industry-funded trials also and, if so, by what mechanism would this be implemented and enforced? I understand this is to more ensure that the results of trials, whether neutral, positive or negative, should be made public Lines , Article We agree that clinical trials should be registered in an accessible public registry. The discussion of this Article should clarify what trials need to be registered Inclusion of the section on clinical trial registration is a very good addition Clinical Trial Registration: we suggest the following restructuring of the section, which includes moving up the text in the Application paragraph: Clinical trial registries are one way to help ensure that negative trial results are widely available. These, in addition to editorial policies, ethical policies reforms, and revised national and institutional ethics policies contribute to a multi-faceted approach to combating non-disclosure, publication bias, and the suppression of data in clinical research. They permit web-based access to information about ongoing clinical trials so that anyone may have information about trials and their results. Article All clinical trials should be registered with a recognized and freely web-accessible public registry before recruitment of the first research participant. Application. REBs must ensure that every clinical trial is registered before recruitment of the first trial participant in one of WHO or ICMJE acknowledged registries. Researchers should provide the REB with a number assigned to trial upon the registration, print-out of the trial information on the Registry s website and/or a link to it Enfin, à la lecture des lignes 5772 et 5773, pense que la consignation dans un registre public reconnu et facilement accessible des résultats de recherche devrait également concerner les recherches autres que cliniques Trial registration: Would it not be helpful to require that registration information should be made available to REBs for all approved trials? Article requires all clinical trials to be registered with a recognized and easily web-accessible public registry. There is no international consensus on this requirement and many believe that only clinical trials with patients require registration. Indeed, it is not required under US regulations to register bioequivalence or bioavailability studies involving marketing products used in normal health volunteers (e.g. studies to generic products). FDA recognizes that these studies do not contribute new knowledge about the products and do not need to be registered ) Page 134, line : All clinical trials should be registered with a recognized and easily web-accessible public registry. Comment: This section could be clarified. Is this section implying that all research studies should be registered? Currently it is not mandatory to register all research studies. 18

19 11.12 Obligation to register clinical trials has been a topic since 2006 when the by the International Committee of Medical Journal Editors (ICMJE) led the international effort to register clinical trials (CT) in publicly accessible registries. This effort has gained acceptance by the research communities, health research regulators and pharmaceutical and biotechnology industries and the criteria for including research is expanding to include a secondary registry of research results. This positive development enable initiatives to study the cause-and-effect of medical interventions with a health outcome, as well create a mechanism for research subjects to learn about their contribution in specific health research. Our federal research funding agencies have invested in the clinical trial registry project, and both Health Canada and the CIHR have been involved in the World Health Organization (WHO) project to develop an International Clinical Trial Registry Platform to link existing registries into a comprehensive network. The WHO, ICMJE and CIHR supported Ottawa Statement agree that prospective public clinical trial registration carries an ethical obligation to enable the flow of information. It is clear that the including a requirement for CT registration in the TCPS 2 nd edition is consistent with this obligation. Section A. Proposition : Je propose de débuter l aperçu avec la phrase de la ligne 5141 afin de mettre en contexte le choix de la définition donnée à l essai clinique. Les essais cliniques consistent habituellement en l essai de médicaments nouveaux ou de médicaments existants pour le traitement de nouvelles applications (ligne 5141). Pour cette raison, nous retenons une définition faisant principalement référence à l essai de médicaments nouveaux ou de médicaments existants pour le traitement de nouvelles applications (ligne 5142 modifiée). Ainsi, un essai clinique est une «[r]echerche sur des sujets humains dont l objet est soit de découvrir ou de vérifier les effets cliniques, pharmacologiques ou pharmacodynamiques d une drogue pour usage humain, soit de déceler les incidents thérapeutiques liés à cette drogue, soit d en étudier l absorption, la distribution, le métabolisme et l élimination ou soit d en établir l innocuité ou l efficacité»1 (ligne 5125). Cependant, les essais cliniques portent aussi sur des instruments médicaux, des produits biologiques, radiopharmaceutiques et géniques et des produits de santé naturels, ainsi que sur des thérapies comportementales et psychologiques. Les lignes directrices présentées dans le chapitre s appliquent aussi, s il y a lieu, aux essais portant sur ces autres thérapies ou interventions (déplacer les lignes 5144 à 5148). Les essais cliniques sont le plus souvent pratiqués en recherche biomédicale et en recherche sur la santé, etc.. (poursuivre avec la ligne 5130). Section A. Proposition : Tenir compte, dans les essais cliniques, de l évaluation des méthodes diagnostiques. Ce type d évaluation se fait, entre autres, dans les recherches portant sur les maladies dégénératives (dont l Alzheimer). Section A. Les essais cliniques sont le plus souvent pratiqués en recherche biomédicale et en recherche sur la santé, mais des travaux de recherche sont aussi menés dans d autres disciplines cliniques connexes, telle la psychologie, pour évaluer des méthodes diagnostiques et des interventions, habituellement en comparant deux ou plusieurs approches (lignes 5130 à 5133). Le Sous-comité croit que dans l introduction du chapitre 11, il serait préférable d ajouter les thérapies mécaniques, ou manuelles, à la liste des pratiques pouvant être évaluées dans le cadre d un essai clinique (lignes ). Il serait également approprié d évoquer, dans cette introduction, la question des conflits 19

20 11.8 d intérêts pouvant avoir une incidence sur la protection des participants lorsque des essais cliniques sont parrainés par l industrie (dont il sera question à l article 11.8 lignes 5556 et 5565). Le Sous-comité observe, par ailleurs, que les enjeux entourant les essais cliniques effectués dans le secteur privé ne sont pas abordés. Bien que l EPTC n ait pas d emprise directe sur de tels essais, il serait néanmoins utile d en souligner les enjeux et possiblement d indiquer que les informations sur la rémunération des chercheurs doivent être incluses aux formulaires de consentements. S agissant de l utilisation du mot «sécurité», qui apparaît à plusieurs reprises dans le chapitre 11, le Sous-comité croit que l enjeu concerne plutôt les «risques pour le bien-être et l intégrité physique» des participants. Si le terme de «sécurité» doit être conservé, il serait sans doute préférable de préciser, dès le départ, ce à quoi il renvoie dans le contexte des essais cliniques. Section A. I have one criticism, which I believe is extremely important. This relates to the first paragraph of Chapter 11: Clinical Trials. The paragraph reads as follows: A clinical trial is "an investigation in respect of a drug for use in humans that involves human subjects and that is intended to discover or verify clinical, pharmacological or pharmacodynamic effects of the drug, identify any adverse events in respect of the drug, study the absorption, distribution, metabolism and excretion of the drug, or ascertain the safety or efficacy of the drug". (lines ). In the context of TCPS, this is a very misleading statement. All types of clinical trials should be included in the first paragraph, going on to describe drug trials as a subset of clinical trials only after the first paragraph. I suggest the following wording for the first paragraph (and incorporating old paragraph 2, lines : A clinical trial is an investigation that involves the application of one or more interventions used in humans, carried out to investigate the clinical, psychological, metabolic or economic outcome of the intervention(s). Interventions may include drugs, surgical procedures, medical devices, biologics, radiopharmaceuticals, genetic therapies, natural health products, behavioural therapies, psychological therapies, health technologies or health management options. Clinical trials are most frequently undertaken in biomedical or health research, although other clinically related disciplines, such as psychology, also conduct research that evaluates interventions. Following this general statement, more specific paragraphs should follow, relating to drugs, other types of clinical trials, plus details about Health Canada regulations. This flow would ensure that "clinical trials" is an inclusive term, and will be applicable to all trialists. I do hope that you will consider revising Chapter 11, section A. 20

Please find attached a revised amendment letter, extending the contract until 31 st December 2011.

Please find attached a revised amendment letter, extending the contract until 31 st December 2011. Sent: 11 May 2011 10:53 Subject: Please find attached a revised amendment letter, extending the contract until 31 st December 2011. I look forward to receiving two signed copies of this letter. Sent: 10

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