by Louis-Nicolas Fortin and Thérèse Leroux
Centre de recherche en droit public
Université de Montréal
(October 15, 1996)

This is an abridged version of a working document prepared for the National Council on Ethics in Human Research by Louis-Nicolas Fortin, Lawyer, Researcher, and Thérèse Leroux, Biochemist and Lawyer, Researcher, and Professor, Centre de recherche en droit public, Faculté de droit, Université de Montréal. This document does not necessarily reflect the opinions of the NCEHR regarding this subject. We invite you to submit your comments on this subject.

The application of ethical principles to the field of research involving human subjects has given rise to the creation of various control mechanisms such as ethics committees introduced to provide protection for research subjects. The publication of guidelines issued by the Medical Research Council of Canada (MRC)¹ prompted institutions participating in research to set up ethics committees. No federal legislation requires that such structures be established.

This normative framework results in some degree of disparity in ethics committees and the way they apply ethical principles.² Consequently, it seems important to determine the extent to which the ethics review performed by ethics committees should be monitored, and what would be the best approach to take. In 1992, the National Council on Ethics in Human Research (NCEHR) instituted a procedure for visiting ethics committees.³ Is such a mechanism sufficient, or are other measures needed to ensure protection for research subjects in Canada?

By presenting the mechanisms developed in other countries and the approach taken by the Canadian Council on Animal Care (CCAC), we will first identify a number of different options. We will continue with a description of the current situation and current thoughts on the subject in Canada and in Quebec, including certain constitutional considerations. We will then suggest various models of ethics review monitoring mechanisms. Lastly, we will indicate some advantages and disadvantages of each of these models.

FOR MONITORING ETHICS COMMITTEES

With a view to benefiting from the experience of those who already have a well established monitoring mechanism, we will look at the current situation in (A) other countries, and in (B) Canada, where animal protection committees are subject to formal monitoring by the Canadian Council on Animal Care (CCAC).

A) OTHER COUNTRIES

A review of the measures for monitoring ethics committees in other countries yields a wide variety of models from the absence of any agency with monitoring authority,⁴ to very stringent monitoring mechanisms,⁵ and, in between, some general measures for revoking accreditation.⁶ In examining the situation which prevails in the United States (1) as well as in France (2), two very interesting models are illustrated.

Section 1 – United States

In the United States, there are rigorous standards governing the research ethics committees known as Institutional Review Boards (IRBs),⁷ the purpose of which is to protect the rights and welfare of human subjects taking part in experiments regulated by the Food and Drug Administration (FDA) or experiments that support applications for research (NID) or notice of compliance (NOC) (marketing permits) for products regulated by the FDA.⁸ In this regard, an administrative review and monitoring mechanism is provided for to ensure compliance with the regulatory provisions respecting the committee’s organization and personnel,⁹ its functions and operations,¹⁰ its activities and its records.¹¹ If, during an FDA inspection, the investigator observes that the committee is not complying with the standards, the investigator will present a summary of observations to a representative of the committee involved. The FDA may subsequently send a letter describing the non-compliance to the committee and to the parent institution. The FDA requires that the committee or institution respond within a specified time and describe the corrective actions that will be taken. The FDA may schedule a reinspection to confirm that the corrections have been made.

Until the institution proves that the situation has been remedied, the FDA may apply certain sanctions.¹² Thus, the FDA may withhold approval of any new studies that are conducted at the institution or reviewed by the ethics committee; direct that no new subjects be added to ongoing studies; terminate ongoing studies when doing so would not endanger the subjects; or, when non-compliance with the standards creates a significant threat to the rights and welfare of the subjects, notify the State and Federal agencies concerned and other parties with a direct interest in the FDA’s activities.

If the committee or institution fails to take the necessary steps to remedy the situation, the Commissioner of Food and Drugs must determine whether the non-compliance justifies the disqualification of the committee or the institution. Following a hearing, the Commissioner renders a decision which determines the outcome of the ongoing protocols.¹³ The Commissioner’s determination is disclosed to the public.¹⁴ It is important to note that, according to the regulations, disqualification does not preclude any other remedy authorized by the law, and that the FDA may, at any time, through the Department of Justice, institute judicial proceedings or any other regulatory action, or refer pertinent matters to any other agency for action.¹⁵

The FDA will not approve an application for a permit for research that is to be under the review of a disqualified committee or conducted at a disqualified institution. It will also refuse a notice of compliance (marketing permit) application based on such research. However, the committee or institution involved may make a written submission for reinstatement, explaining the corrective actions taken and providing methods of assuring future compliance with the rules. The Commissioner may then reinstate the committee or institution and shall provide notification of reinstatement to all persons who received notice of the disqualification.¹⁶

Section 2 – France

In 1988, French legislators set out a number of ethical guidelines on research involving humans into France’s public health code, the Code de la santé publique.¹⁷ The minister responsible for Health is required to accredit one or more advisory committees in each region for the protection of individuals participating in biomedical research.¹⁸ Any research project with human subjects must be submitted to such a committee,¹⁹ which shall express an opinion on the validity of the research.²⁰ Any negative opinion shall be communicated to the minister responsible for Health.

Specifically, the composition of the advisory committee for the protection of individuals participating in biomedical research, as well as the conditions affecting its accreditation, funding, operation and the appointment of its members are specified by an order-in-council.²¹ In addition, the application for accreditation presented by the chair of the committee to the minister responsible for Health must include the committee’s by-laws, its principal address, and its anticipated operating requirements, particularly in terms of staff, as well as its members’ names and qualifications. The committee is accredited by a ministerial order published in the country’s official gazette, the Journal officiel de la République française. As a part of its responsibilities, the committee must report annually on its activities.²² It should be noted that the minister responsible for Health has the power to revoke the accreditation of a committee.²³ However, there is no system in place for evaluating the committee or revoking accreditation.

While the description of the method of monitoring and ultimately controlling the advisory committees’ performance is laconic, the minister responsible for Health possesses the power to impose sanctions. It should be noted, however, that no explicit reference is made to the national advisory committee on ethics in the life and health sciences, the Comité consultatif national d’éthique pour les sciences de la vie et de la santé.²⁴ The monitoring of the regional advisory committees is outside its jurisdiction.

B) CANADA

The Canadian Council on Animal Care (CCAC)²⁵ has developed a system to monitor its local committees which is worth looking into. While the systems established in the United States and in France are determined by legislation, this is not the case with the CCAC. The CCAC assessment program focuses on the care and use of animals and the effectiveness of institutional Animal Care Committees. These committees must ensure that animals are used in an ethical manner and that the CCAC guidelines²⁶ are complied with. No research may begin until a local committee has evaluated and approved the protocol.

The assessment program provides for periodic assessment visits conducted by "assessment panels." These panels include scientists (generally three) appointed by the CCAC and having experience in and special knowledge of the care and use of animals in research. Each panel will also include a member from the Canadian Federation of Humane Societies or another animal welfare group. The CCAC’s Director or Associate Director of Assessments will be an ex-officio member of the panel. All panel members volunteer their services.

Prior to any assessment visit, the institution must send information to the CCAC on (1) the administration, (2) the staff responsible for animal care, (3) the area and layout of premises allocated to animal housing and use, (4) the species and number of animals used, (5) the actual use of the animals, and (6) the research projects and educational activities examined by the local committee. This will enable the panel to better plan its visit.

In general, the visit begins with a meeting with the members of the local committee and the chief administrator of the institution. The institution’s animal care program is assessed and any changes made following the recommendations from the last assessment are analyzed. Following the initial meeting, the panel visits all the areas where animals are kept or where experiments are conducted. At this time, a number of researchers are asked questions and specific procedures are observed. The panel members are generally accompanied by a member of the local committee and a representative of the institution’s administration.

When the site visit is completed, another meeting is held with the chief administrator of the institution and all members of the local committee, at which time the panel gives an overview of the most important observations and recommendations, which will be presented later in a detailed report.

If the panel has significant or serious concerns regarding any aspect of the care or use of the animals, it may direct that the situation be remedied immediately.

Following this visit, the panel prepares a report which includes the panel’s recommendations. If a member of the panel is not satisfied with the report’s conclusions, he or she may submit a dissenting report. The report is sent to the CCAC members and is then sent to the chief administrator of the institution. The content of the report is confidential, but may be used by the institution as it sees fit. If it is to be distributed to the general public, the CCAC must be notified in advance.

In response to the CCAC’s report, the institution must, within six months, submit the methods it plans to use to implement the panel’s recommendations. If the CCAC is not satisfied with the report it receives, it may take any measures it deems necessary. For example, the CCAC may bring an institution’s failure to comply to the attention of the Medical Research Council and the Natural Sciences and Engineering Research Council. In March 1985, these two research councils issued a notice to the effect that they reserved the right, jointly or separately, to apply financial or other sanctions.²⁷ While these incentives are rarely used, they are both real and important.

The CCAC considers the response of all research communities that use animals in their protocols very positive, since the institutions generally comply with its recommendations.²⁸

THE CANADIAN SITUATION IN CONTEXT

In order to identify the model that will ensure the best monitoring of Canadian ethics committees, it is essential to review the context in which such monitoring takes place. Therefore, in this second part, we will examine the current situation at the national level (A) and in Quebec (B), while outlining certain constitutional questions (C) which will have to be taken into account in selecting an appropriate model.

A) AT THE NATIONAL LEVEL

At the national level, two items attracted our attention: 1) the advisory site-visit service initiated by the NCEHR; and 2) the draft report prepared by the Tri-Council Working Group, entitled "Code of Conduct for Research Involving Humans".

Section 1 – National Council on Bioethics in Human Research

In 1989, the Medical Research Council of Canada, the Royal College of Physicians and Surgeons of Canada, and Health Canada established the National Council on Ethics in Human Research (NCEHR). In the scope of its mandate,²⁹ NCEHR implemented an advisory site-visit service. Using the voluntary site-visit process, the NCEHR Working Group on Evaluation studied the REBs affiliated with faculties of medicine across Canada.³⁰ Its objectives were: a) to help institutions assess the strengths and weaknesses of their system of ethics review; b) foster dialogue and understanding on the utility and limits of national ethical guidelines in the institutional setting; and c) create a national database on REB practices for the benefit of the national research ethics community. This initiative provided a national portrait of ethics review of research involving human subjects.

Section 2 – The Tri-Council Report

In 1994, the Medical Research Council of Canada, the Social Sciences and Humanities Research Council of Canada, and the Natural Sciences and Engineering Research Council of Canada established a working group to develop new joint policies on research involving human subjects. The working group produced a draft report in March 1996³¹ and a final report in May 1997. From its reading, it can be seen that the authors did not set forth any rule specifically intended to establish an ethics review monitoring mechanism. Instead, they deal with the internal mechanism for appealing an REB decision.³² Consequently, the draft report does not enlighten us as to the opinion of the three Councils where outside monitoring of REBs is concerned.

B) QUEBEC’S SITUATION

We have identified two sources that inform us on the state of research ethics in Quebec:

Section 1 – The Civil Code of Quebec

The coming into force of the new Civil Code of Quebec, in January 1994, brought about a number of important changes in the research field in Quebec. In particular, Article 21 established strict rules in the case of experiments involving human subjects from vulnerable populations, namely minors and persons of full age who are incapable of giving consent. Here, the legislator recognized the existence of ethics committees for the first time in Quebec civil law.

Since that time, a researcher must, before beginning an experiment involving a group of minor persons or incapable persons of full age, obtain approval from the Minister of Health and Social Services.³³ To this end, the researcher submits the research project to an ethics committee, which forwards its opinion on the research project to the Minister of Health and Social Services. The Minister’s approval can only be given upon receipt of a favorable opinion from the ethics committee.

Article 21 of the CCQ provides that the ethics committee empowered to advise the Minister is "an ethics committee of the hospital designated by the Minister or [...] an ethics committee created by him for that purpose." Therefore, the ethics committee must be recognized by the Minister of Health and Social Services. The Minister does not monitor the decision-making process of the ethics committee. When the Minister approves the committee’s opinion, however, he endorses its decision and thus exercises control over the actual decision made by the ethics committee.

The mechanism provided for in Article 21 of the CCQ applies to both research sponsored by granting agencies and research funded by private industry. It deals only with experiments involving subjects who are minor persons or incapable persons of full age. Consequently, the decisions of ethics committees reviewing research protocols that involve only capable human subjects are not subject to control by the Minister.

The absence of any formal or universal mechanism for monitoring the decision-making process of ethics committees at the provincial level in Quebec should therefore be noted. The Committee of Experts on the Evaluation of Control Mechanisms in Clinical Research, chaired by Me Pierre Deschamps, was interested in this subject and shares its thoughts in its final report.

Section 2 – The Deschamps Report

In 1994, Quebec’s Minister of Health and Social Services announced the creation of a Committee of Experts on the Evaluation of Control Mechanisms in Clinical Research. In its final report, the Committee recommends the creation of a permanent structure.³⁴

The structure could be an evaluation board modeled on the Conseil d’évaluation des nouvelles technologies,³⁵ or a standing committee responsible for accrediting the institution in accordance with a regulatory framework and appropriate evaluation and monitoring activities. The Committee rejects the suggestion of assigning such a research ethics evaluation body dependent on a research granting agency, in order to avoid any real or apparent conflict of interest.

The Committee suggests a number of characteristics that the permanent provincial structure should have. First, it should be composed of individuals representing the scientific community and the community at large (research, medicine, nursing, ethics, law, finance, general public). Evaluation activities could be carried out by teams of evaluators (comprising, for example, three individuals such as an active researcher, an administrator, and an ethicist with practical experience in clinical research). These teams would go to a given site to carry out their evaluation, which should be based on predetermined criteria to enable them to determine whether the health institution is fulfilling its responsibilities for reviewing and monitoring research activities. Depending on the Committee, concrete recommendations on the infrastructure and operation of the institution’s ethics review should follow the team’s on-site visit. A certificate of compliance or non-compliance could then be issued. Accreditation, sponsored for a period of 3 to 5 years, would be required for the institution to pursue its research activities.

The Deschamps Report deals with health institutions where clinical research activities take place. Private industry, however, can conduct experiments outside health institutions. The report makes no reference to this situation and therefore does not discuss the authority of such an evaluation structure with respect to the private sector.

C) THE CONSTITUTIONAL ASPECT

An agency aiming to ensure the universality of the monitoring of ethics review of research with human subjects in Canada must be empowered by a competent authority. Sections 91 and 92 of the Constitution Act, 1867³⁶ provide for the distribution of powers between the Federal Parliament and the provincial legislatures. Since the application of biomedical ethics principles to human research is related to the field of public health, the issue of distribution of powers will be examined with reference to this field of activity.

Pursuant to Section 92(7) of the Constitution Act, 1867, the Provinces were given exclusive power over health care services (establishment, maintenance and administration of hospitals, asylums, institutions and hospices). In addition, general power in health matters has historically been considered as being merely of a local or private nature, and is thus assigned to the Provinces by Section 92(16).

Nevertheless, the Federal Parliament is not bereft of all power to legislate in public health matters. For example, it has the general power to make laws for the peace, order and good government of Canada. This power is residuary, which means it is confined to matters that do not come within the classes of subjects assigned exclusively to the Provinces.³⁷ Under the "national dimensions" theory,³⁸ the Federal Parliament may make laws regarding a question which it deems to be national in scope and which meets the criteria established by the Supreme Court³⁹ – that it be unique, specific and indivisible – which clearly distinguish this question from provincial matters. Furthermore, the impact on provincial jurisdiction must be compatible with the distribution of legislative powers effected by the Constitution.

The Federal Parliament may rely also on certain exclusive powers assigned by Section 91 of the Constitution Act, 1867. Thus, it may rely on its legislative competence in criminal matters,⁴⁰ as it has done in the past to control the pharmaceutical field and pass the Food and Drugs Act⁴¹ and the Narcotic Control Act,⁴² for example.

In addition, Parliament’s power to make certain payments to individuals, organizations and governments for purposes in regard to which it does not necessarily have the power to make laws⁴³ has enabled Parliament to establish programs that fall within areas of provincial jurisdictions, such as the Hospital Insurance Program.

As a rule, REBs reviewing research involving human subjects were established by public and private institutions at the provincial level. Although a number of them followed the relevant guidelines of Canadian agencies such as the Medical Research Council of Canada, REBs usually report to provincial institutions. The monitoring of their activities by a Canadian agency therefore raises an important jurisdictional question. Indeed, any corrective actions that may be taken by a monitoring mechanism must be based on a legitimate power. The question will be of greater or lesser urgency depending on the type of action the responsible agency is required to take: its role could vary from one of consultation and recommendation to a more coercive monitoring role. Now is therefore a good time to present the different theoretical models for monitoring ethics review of research involving human subjects.

VARIOUS INTERVENTION ALTERNATIVES

Following this study of a number of foreign and Canadian ethics review monitoring mechanisms, it is obvious that a variety of models are possible: informal visits (A), visits conducted within a formal framework (B), accreditation or certification (C), or investigation with sanctions (D).

Certain aspects of these four models are nevertheless similar. For example, whatever monitoring agency is used, it must determine the criteria on which its analysis will be based. These criteria must be generally constant from one visit to the next, although adjustments may be required according to the respective contexts of the institutions involved and their ethics committee(s).

Analysis Criteria: Following is a list of criteria that could be used by the monitoring agency:⁴⁴

It is fundamental to the four models to visit the institution where ethics review of research projects involving human beings is conducted. To this end, there are certain similarities concerning the composition of the site visit committee, the pre-visit questionnaire, and how the site visit is conducted.

Composition of Site-visit Committee: The visit to the institution will have to be made by a site-visit committee composed of both ethics specialists and individuals with research experience in fields relevant to the research projects submitted to the ethics committee visited. The members of a site-visit committee must avoid any conflict of interest with the institution visited.

Pre-visit Questionnaire: A questionnaire sent to the ethics committee, to which the committee must respond prior to the site visit, is an initial source of valuable information for the monitoring agency. The agency is able to determine from this which aspects of the institution’s ethics review will need to be examined in greater detail during the visits.

Visit: The visit starts with a meeting with the members of the ethics committee and the responsible officials of the institution who can provide relevant information to the site-visit committee. The latter may consult the minutes of meetings, research records kept by the ethics committee, and other documents useful to the ethics review, as well as any document dealing with the structure of the ethics review system in the institution. It may visit the premises where research is carried out and interview researchers and other members of the research teams. Lastly, the site-visit committee may ask that any additional information it considers necessary for its analysis be forwarded to it at a later date.

We now present the mechanics of each of these models to provide a clearer picture of what is involved in their implementation.

A) INFORMAL VISITS⁴⁵

A mechanism of informal visits with Research Ethics Boards makes it possible to identify the strengths and weaknesses of the review system used by each ethics committee that has accepted the invitation, and to suggest to the committee measures it could take to improve or correct certain situations. The operation of such a monitoring mechanism is based on the sending of a questionnaire, followed by a site visit, and lastly the issuing of a site-visit report.

Frequency of Visits: There is no requirement as to the number or frequency of these visits. The evaluation may be undertaken on the initiative of the monitoring agency or at the request of the ethics committee or its parent institution.

Site-visit Report: Following the site visit, a report is prepared and given to the ethics committee concerned, its parent institution, and the members of the monitoring agency. This report points out any weaknesses observed during the analysis of the institutional ethics review system and presents the recommendations of the site-visit committee.

In addition, the monitoring agency should produce an annual report of its activities, which might include a list of the institutions visited as well as the composition of the site-visit committees. It should also include periodically a general picture of ethics review in Canada.

B) VISITS WITHIN A FORMAL FRAMEWORK⁴⁶

Another mechanism for monitoring ethics review of research involving human subjects might be an evaluation program providing for mandatory visits.

Frequency of Visits: The frequency of these mandatory visits should be predetermined, for example, every two or three years. In addition, special visits would always be possible, either at the request of the ethics committee or its parent institution, or on the initiative of the agency responsible for monitoring ethics review of research.

Visit: Following the visit, the evaluation group gives an overview of its observations to the ethics committee members and the institution’s administrators, stressing the most important recommendations (details of which will appear in a subsequent site-visit report). If points requiring urgent and special attention are raised, the group immediately notifies the committee and the institution’s authorities. The group may direct that action be taken immediately to remedy the situation.

Site-visit Report: The evaluation group may request any information it considers necessary for its analysis and preparation of its evaluation report. This report will present the group’s findings regarding the institution’s compliance with the various evaluation criteria, as well as its recommendations. The group will identify what action the institution will need to take to comply with its recommendations. The report will be forwarded as soon as possible to the members of the monitoring agency, the institution’s administration, and the ethics committee. The content of the site-visit report would normally be considered confidential. However, if the institution wished to make the report public, the monitoring agency could make provisions in this regard.

In general, the monitoring agency gives institutions a brief period (e.g. a few weeks) to correct deficiencies that are considered serious. Within six months of receipt of the site-visit report, the institution must submit to the evaluation group its own report describing the means used to comply with the urgent recommendations and the steps it plans to take to implement the remaining recommendations.

If the monitoring agency deems this response inadequate, it determines the areas in which the institution fails to comply with the criteria established to meet the requirements of adequate ethics review. The monitoring agency may then bring the institution’s status of non-compliance to the attention of the authority to which it reports. For this monitoring mechanism to be truly effective where granting agencies were involved, the agencies would have to apply economic sanctions to the institution concerned. Another way to ensure compliance with the recommendations of the monitoring agency would be to provide for administrative sanctions against any institution not meeting the requirements of ethics review of research with human subjects in Canada.

C) ACCREDITATION OR CERTIFICATION

We define an accreditation program as an evaluation procedure whereby an ethics committee or an institution is or is not granted a certificate attesting that it meets the predetermined criteria for ethics review of research involving human subjects. The consequences for the status (accredited or non-accredited) of an ethics committee or an institution must be determined in advance. This procedure must be fully transparent.

Frequency of Visits: Accreditation is valid for the same period for each institution (e.g., three years). A site-visit by an accreditation committee must therefore take place during the last year of validity.

Site-visit Report: Following the visit, the accreditation committee meets to prepare a report that includes observations, conclusions and recommendations. This report is submitted to a review panel composed of members of the monitoring agency. The head of the accreditation committee involved will answer all questions raised by the review panel. The review panel accepts, amends or rejects the report. In the first two cases, the report is forwarded to the members of the monitoring agency. If the monitoring agency approves it, a notice will be sent to the institution. In the event the report is rejected, a new accreditation committee will be formed.

The ethics committees or institutions that receive accreditation may continue their operations. Those that have not been accredited have 30 days in which to exercise their right to appeal the decision of the monitoring agency. The decision of the appeal authority must be rendered within a fixed period (e.g., 60 days). When the time allowed for appeal has expired or when a negative decision is confirmed by the appeal authority, the institution no longer has the right to use human research subjects until such time as it proves that it has complied with the recommendations of the accreditation committee.

Institutions or ethics committees that are not accredited may be visited again by the accreditation committee when they forward a briefing document demonstrating that changes have been made since the last visit.

It is advisable to consider whether provisions for partial accreditation would be appropriate. In the event that an institution has several ethics committees, for example, would one committee’s non-compliance lead to full or partial de-accreditation of the institution? It is therefore necessary to determine whether the smallest unit that will be subject to accreditation is the institution or individual ethics committees. In the latter case, the accredited committees within the institution could continue their activities. However, once this question has been decided, the institution or ethics committee subject to accreditation must comply with all the criteria relating to ethics review, since research involving human subjects does not lend itself to partial compliance with these criteria. The accreditation criteria should not be optional.

D) POWER TO INVESTIGATE⁴⁷

This mechanism for evaluating ethics review requires legislation that provides for investigative powers and structures. Thus, inspection visits are mandatory. Under the evaluation program, both the institutions carrying out research with human subjects and their ethics committee(s) are granted recognition of their compliance with ethics review criteria. Also under this program, the consequences of non-compliance are enforced toward the institution or the ethics committee.

Frequency of Visits: The frequency of visits is set out and is the same for every institution (e.g., every two or three years). Special visits are always possible at the request of the institution or ethics committee, or on the initiative of the agency responsible for monitoring ethics review of research.

Composition of Investigating Groups: While the U.S. authorities opted for a mechanism that uses a single inspector, the presence of several people during the investigation may allow a better assessment of the situation. The investigation groups should include, in addition to a member of the monitoring agency, scientists and ethics experts whose names appear on a list approved by the responsible government department. Care will be taken to ensure that the scientific members of the group are selected in accordance with the particular research field of the institution to be visited.

Visit: At the end of the visit, the investigating group gives a summary of its observations to a representative of the committee and a representative of the institution’s administration.

Site-visit Report: Following the report of the investigating group, the monitoring agency sends a document describing in detail the areas in which the ethics committee or the institution does not comply with the ethics review criteria. It directs the ethics committee or the institution to send in, within a given period (e.g., a few weeks), the corrective action that will be taken. The monitoring agency may schedule a second inspection visit and notifies the ethics committee and the institution accordingly. The purpose of this visit is to verify that the necessary corrections have been made and ensure compliance with the ethics review criteria.

Until the situation is remedied, the monitoring agency may apply various sanctions. Thus, when non-compliance with the criteria by the ethics committee or the institution involved represents a significant threat to the human subjects, the monitoring agency may notify the federal and provincial agencies concerned with the nature of the non-compliance; it may ask the granting agencies not to fund any research protocol that comes from the institution involved or falls within the jurisdiction of the ethics committee; it may ask the granting agencies not to accept any changes to current research protocols if they come from the institution involved or fall within the jurisdiction of the ethics committee.

In the event the ethics committee or institution involved does not take the necessary corrective action, the situation must be brought to the attention of an independent board of inquiry. If this board establishes that the situation could lead to eventual disqualification of these entities, a hearing must be held.

At the end of this hearing, the board of inquiry may conclude that the committee or the institution has refused or repeatedly failed to comply with the ethics review criteria, thereby placing the research subjects at risk. In this case, the committee or the institution may lose the qualification they had been granted by the monitoring agency for compliance with the ethics review criteria. The board then delivers its decision with reasons, and establishes the procedure to be followed on current research protocols.

The board of inquiry sends a notice of disqualification to the ethics committee and the institution, and to other interested parties such as granting agencies and researchers. Public distribution may be considered. Disqualification does not preclude recourse to other legal or administrative remedies. In addition, granting agencies should not accept a research protocol involving an institution that has received a notice of disqualification.

Institutions or ethics committees who have received such a notice may ask to be reinstated by the monitoring agency. They must prove to the board of inquiry that they have taken the necessary corrective action to comply with the ethics review criteria.

CRITIQUE OF THE VARIOUS ALTERNATIVES

By presenting these different models, we can see the many options available for monitoring ethics review of research in Canada. However, a number of advantages or disadvantages, strengths or weaknesses, can be identified for each of these models.

The model limited to informal visits fosters the education and training of members of ethical committees; it also encourages recourse to the expertise of the monitoring agency by the research ethics committee when complex situations arise. However, the voluntary nature of the informal visits program makes the universality of its application uncertain, since the institutions and ethics committees are under no obligation to submit to it. At the same time, if the monitoring agency is created by granting agencies, the institutions would be ill advised to refuse this site-visit process if they benefit from the granting programs involved. This model corresponds to the current situation of NCEHR.

The model that involves visits conducted within a formal framework provides assurance of more consistent monitoring of ethics review mechanisms, and at the same time maintains an atmosphere conducive to information exchange. The problem of universality remains. It is therefore essential that all institutions participating in research with human subjects, and not just those that seek funding from granting agencies, be subject to this mechanism. The prestige of the monitoring agency is not necessarily enough.

The CCAC opted for this review mechanism. The granting agencies undertook not to finance research projects from institutions that fail to comply with the animal welfare requirements established by the CCAC. The sanction for non-compliance is not the responsibility of the monitoring agency and involves only the institutions receiving funding from the granting agencies. Nevertheless, the CCAC affirms that the "CCAC’s programs have been well received, and enjoy the support and cooperation of all institutions involved, including private-sector companies and government departments that are not dependent on funds from granting agencies."⁴⁸

The model dealing with the accreditation or certification of institutions offers a stringent and explicit review mechanism. The obtaining of qualification is probably a more acceptable mechanism for institutions than a coercive monitoring system associated with the investigation process. However, both the obligation to submit to the evaluation mechanism and the repercussions of non-compliance with the established rules depend on the authority that initiates the accreditation or certification. Consequently, the repercussions of non-compliance remain uncertain, given Canadian legislation.

The last model presented, that of monitoring by means of investigation, includes a coercive aspect, since it is described in legislation. It may affect the private, public and parapublic sectors simultaneously. However, it means the setting up of a complex administrative structure and a rigorous formalism.

According to the U.S. administrative monitoring mechanism,⁴⁹ the FDA investigator must report any irregularity in the institutional ethics review mechanism with respect to criteria determined by a strict and precise set of rules.⁵⁰ However, the implementation of such a program across Canada would require significant changes in the supervision of ethics review of research involving human subjects. Indeed, the conditions applying to ethics review of protocols in Canada are currently dealt with, in particular, in the Medical Research Council Guidelines and the Directive from the Drugs Directorate of Health Canada.⁵¹ These guidelines do not have the same force as an act or regulation.⁵² Furthermore, the Canadian criteria dealing with ethics review of research involving human subjects are not precise enough to allow an objective evaluation in the event of an investigation. The current status of ethics review standards in Canada therefore does not lend itself to the establishment of an agency that could sanction non-compliance as severely as in the U.S.

It is obvious from the present study that it is easier to monitor ethics review of research carried out in universities or hospitals, or of research protocols funded by granting agencies. If monitoring rules are not integrated into legislation, it will be necessary to count on the good faith and cooperation of private industry if these rules are to be applied to the ethics committees of all research institutions in Canada.

To ensure that the ultimate objective of a mechanism for monitoring ethics review of research with human subjects is achieved, it is essential first of all to consider the complexity and flexibility of the structure. Second, the efficiency of the model adopted requires that the coercible ethics committees and the repercussions of the evaluation to which they may be subject be clearly identified.

APPENDIX I

Table of the Strengths and Weaknesses of the Models Presented

21 CFR 56, Subparts A to E

France:

Law No. 88-1138 of 20 December 1988 (J.O. 22 December 1988, p. 16032)

Law No. 90-86 of 23 January 1990 (J.O. 25 January 1990)

Law No. 90-549 of 2 July 1990 (J.O. 5 July 1990)

Code de la santé publique, Livre II bis entitled « Protection des personnes qui se prêtent à des recherches biomédicales ».

Code de la santé publique, Part II, Livre II bis entitled « Protection des personnes qui se prêtent à des recherches biomédicales ».

Canada:

Constitution Act, 1867, 30 & 31 Victoria, ch. 3 (U.K.)

Food and Drugs Act, R.S.C. (1985), ch. F-27

Narcotic Control Act, R.S.C. (1985), ch. N-1

TABLE OF CASE LAW

MacDonald v. Canada (A.G.), [1995] 3 S.C.R. 199

R. v. Crown Zellerbach Canada Ltd., [1988] 1 S.C.R. 401

Reference re Validity of Section 5(a) of the Dairy Industry Act, [1949] S.C.R. 1

BRUN H and TREMBLAY G, Droit constitutionnel (Constitutional Law), 2nd ed., Cowansville, Les éd. Yvon Blais, 1990.

CANADIAN COUNCIL ON ANIMAL CARE, "Guide to the Care and Use of Experimental Animals", Vol. 1, 2nd ed., Ottawa, 1993, 232 pp.

COMITÉ D’EXPERTS SUR L’ÉVALUATION DES MÉCANISMES DE CONTRÔLE EN MATIÈRE DE RECHERCHE CLINIQUE, Rapport sur l’évaluation des mécanismes de contrôle en matière de recherche clinique au Québec (Report on the Evaluation of Control Mechanisms in Clinical Research in Quebec), presented to the Minister of Health and Social Services of Quebec, 1995.

MEDICAL RESEARCH COUNCIL OF CANADA, Guidelines on Research Involving Human Subjects 1987, Ottawa, 67 pp.

MEDICAL RESEARCH COUNCIL OF CANADA, SOCIAL SCIENCES AND HUMANITIES RESEARCH COUNCIL OF CANADA AND NATURAL SCIENCES AND ENGINEERING RESEARCH COUNCIL OF CANADA, "Code of Conduct for Research Involving Humans", Draft Report prepared by the Tri-Council Working Group, March 1996.

NATIONAL COUNCIL ON BIOETHICS IN HUMAN RESEARCH, "Protecting and Promoting the Human Research Subject: A Review of the Function of Research Ethics Boards in Canadian Faculties of Medicine", NCBHR Communiqué 1995; Vol. 6 no. 1, p. 3.

NATIONAL COUNCIL ON BIOETHICS IN HUMAN RESEARCH, NCBHR Brochure, 3rd ed., 1996, 6 pp.

NATIONAL COUNCIL ON BIOETHICS IN HUMAN RESEARCH, "Council News", NCBHR Communiqué 1995; Vol. 6 no. 2, p. 1.

ROYAL COLLEGE OF PHYSICIANS OF LONDON, Guidelines on the practice of ethics committees in medical research involving human subjects, London, 1990.

HEALTH AND WELFARE CANADA, Drugs Directorate, "Guidelines on the Conduct of Clinical Investigations", Ottawa, 1992.