summary

[Huxley]

1.
Specify the vocabulary
• different concepts are used in this area. A distinction is made between research and experimentation, explanatory and interventionist research, clinical trial, innovative care and experimental treatment:
• these concepts give rise to debates on the meaning of the research.
2.
Recall the methodological principles underlying clinical trials
• the randomized trial with single, double or triple unknown;
• the four phases of the clinical trial.
3.
Present some ethical issues facing the researcher
• various requirements placed on the investigator to accomplish his task while respecting the experimental subjects; scientific competence, adequate resources, concern for the welfare of research subjects, respect for protocol and attention to voluntary consent;
• particular issues:
- innovative care;
- the use of placebo:
- the participation of patients in non-therapeutic trials;
- consent in the case of a combined phase 1 and 2 trial;
- payment for research subjects:
- conflicts of interest.

1
A "human science research council " may want to know the frequency of a disease, the course of the condition or its distribution in the population. The methodology it will use then falls within the description. If he wants to know the mechanisms of the disease, the drugs that can prevent or cure it, the surgical techniques that improve the effectiveness of an intervention, he must use another type of methodology, that which is calls for experimental research. To use Claude Bernard's language, the researcher who aims for therapeutic efficacy must become an experimenter:

This is why experimentation, or the art of obtaining rigorous and well-defined experiments, is the practical and in a way executive basis of the experimental method applied to medicine. [...] Experimentation is unquestionably more difficult in medicine than in any other science; but, by that very fact, it was never in any more necessary and more indispensable (Bernard, 1952, 35).

2
What Claude Bernard undertook in his time is at the heart of what interventionist clinical research is. What is it exactly? The first part of the chapter will be devoted to specifying the terms. The second part will address the methodological principles underlying clinical trials. Finally, the third part will discuss a certain number of ethical problems raised by interventionist clinical research.

Vocabulary question
3
In the previous pages, the words research and experimentation have been used without specifying their specificity. In everyday and medical parlance, they have roughly the same meaning. Claude Bernard's text shows that each of the concepts can have a specific connotation. After clarifying the distinction between the two terms, we will then present other expressions necessary for understanding the ethical issues specific to this chapter.

4
In their essay on the distinction between therapeutic research and non-therapeutic experimentation, Simon Verdun-Jones and David Weisstub note that research is frequently used interchangeably with experimentation. And they add that their review of writings in medicine leads them to conclude that there is a general imprecision in the use of the terms. Sometimes the word research has a broad meaning, while experimentation has a precise meaning, that of a research method. At other times, particularly in the biomedical field, the word searchhas different meanings. On the one hand, it retains its general sense of study with a view to increasing knowledge and, on the other hand, it encompasses studies that aim to assess the safety and usefulness of a medical product, a process or intervention. He then identifies with experimentation (Verdun-Jones and Weisstub, 1998, 92).

5
Due to the vagueness of the terms, Verdun-Jones and Weisstub choose to use them interchangeably. It is true that, in the biomedical field, the two terms indicate "an activity which seeks to verify a hypothesis, to allow conclusions to be drawn and, therefore, to develop or contribute to generalizable knowledge" (The National Commission , 1982, 235). The term experimentation has a more limited meaning, however, as argued, following the Belmont report, the Law Reform Commission of Canada in its working paper entitled Biomedical experimentation on humans:

To experiment, in the broadest sense of the term, is to seek to increase knowledge through systematic recourse to experience. Experimentation is therefore a technique, a process enabling certain facts to be verified by creating conditions conducive to their realization (Reform Commission, 1989, 4).

6
The interventionist clinical research discussed in this chapter can be compared to experimentation. When you think of this type of research, pharmaceutical trials immediately come to mind. They are not the only ones, however. This is the case with clinical trials of medical devices or surgical procedures. The qualifier interventionist was used by Feinstein in 1974 as opposed to explanatory (Feinstein, 1974, 316-334). Interventionist research aims to change the clinical condition of the patient to improve his health and delay death. Pharmaceutical trials are the most common, however, to the point that Good Clinical Practice: Consolidated Guidelines define the clinical trial as follows:

Any investigation carried out on human subjects with a view to discovering or verifying the clinical and pharmacological effects of a research product or other pharmacodynamic effects related to this product, to identify any adverse reaction to a research product, to to study how a research product is absorbed, distributed, metabolized and excreted, in order to assess its safety or efficacy. The terms “clinical trial” and “clinical study” are synonymous (Health Canada, 1997, 4).

7
The fact that these various terms are often used equivalently testifies to the complexity of medicine. Indeed, if the doctor seeks the best treatment for his patient and, thus, prefers to use a treatment which has been proven, he will also perform "acts which deviate from the ordinary, from the usually defined practice" ( Delfosse, 2000, 9). Medicine is made up of innovative care. These can be of various kinds. Sometimes, it will be an experiment in the rigorous sense of the term, at other times it could be a care process which is “extraordinary” insofar as it deviates both from the therapeutic ordinary and from the objective of knowledge. scientific (Delfosse, 2000, 9). It is in this context that the distinction between clinical trial or experimentation and innovative care has emerged. The former must be scientifically safe and described according to a clear protocol that has been approved by a research ethics board; the latter are performed when "a clinician deviates significantly from a standard or common practice" (The National Commission, 1982, 235). These are medical procedures performed in the interest of a specific patient and the results of which are uncertain. Here, unlike the clinical trial, the objective is not to test a hypothesis or acquire new knowledge. Therapeutic innovation, also known as the latter are performed when "a clinician deviates significantly from a standard or common practice" (The National Commission, 1982, 235). These are medical procedures performed in the interest of a specific patient and the results of which are uncertain. Here, unlike the clinical trial, the objective is not to test a hypothesis or acquire new knowledge. Therapeutic innovation, also known as the latter are performed when "a clinician deviates significantly from a standard or common practice" (The National Commission, 1982, 235). These are medical procedures performed in the interest of a specific patient and the results of which are uncertain. Here, unlike the clinical trial, the objective is not to test a hypothesis or acquire new knowledge. Therapeutic innovation, also known asexperimental treatment, "designates a treatment in the true sense of the word, an act performed for the direct and immediate benefit of the person who receives it but which, from a scientific point of view, has not yet been fully proven" (Commission for the reform of law, 1989, 5). The Declaration of Helsinkitalks about unproven methods (World Medical Association, 2000, s. 32). So would be a procedure which is already known for another disease, but which has never been used in such a situation. Some will also speak of compassionate or faint hope treatment to describe this kind of care (Jecker & Schneiderman, 1993; Daniels & Sabin, 1998). In such a case, should the doctor submit a request to the hospital ethics committee? Opinions are divided on this subject; the question will be addressed in the third part of the chapter.

8
Why do interventionist clinical trials pose special questions that need to be addressed in a special chapter? The main reason is that these clinical studies are largely performed during treatment. Much of the drugs that will be tested will be in people who are sick and in whom the trial could prove beneficial. Isn't research then therapeutic? Despite the truth in the expression "therapeutic research", it is hardly used any more, at least in America. For the Law Reform Commission of Canada, the main reason that leads it to refuse the expression is the risk of misleading a research subject who believes he is participating in research which would be of immediate benefit to him (Commission de réform du law, 1989, 6). To avoid difficulties, the expressionclinical research replaces that of therapeutic research, which amounts to recognizing that such practices can be both therapeutic and non-therapeutic for the individual patient / subject (Verdun-Jones and Weisstub, 1998, 99). This situation poses particular ethical problems for the researcher which will be addressed in the third part of the chapter.

SOME DEFINITIONS
Qualified Investigator: the person who is responsible to the sponsor for the conduct of the clinical trial at a clinical trial location, who is authorized to provide health care under the laws of the province where that location is trial is located (Minister of Health, 2001, c.05.001).
Multicenter trial: clinical trial performed according to a single protocol at several different locations and, therefore, by more than one investigator (Health Canada, 1997, 8).
Investigator: person responsible for carrying out the clinical trial at the trial site. If the trial is performed by a team, the investigator acts as the team leader and may be called the “principal investigator” (Health Canada, 1997, 7).
Sponsor: person, company, institution or organization responsible for implementing, managing or funding a clinical trial (Health Canada, 1997, 10).

The methodological principles underlying clinical trials
9
The methodological principles which will now be discussed are not of an ethical nature but have been gradually developed to promote results of the highest quality. Some of these principles are general enough to be widely applicable in any clinical trial, while others relate specifically to pharmaceutical research. Due to their relevance, these principles have implications for the ethical review of a protocol. Indeed, if they are not implemented, an ethics committee will be entitled to worry about the scientific value of the project and the relevance of inviting research subjects to participate in the experiment. The quality of the scientific methodology is an ethical requirement since the results of research will enable patients to be better served.

The controlled trial
10
The objective of a randomized or controlled trial is to determine the effectiveness and safety of alternative treatments. Two groups of participants will be compared: the experimental group which is treated with the research product and the control group which receives a known treatment or a placebo. The aim is to minimize the possibilities that the results of the study may be distorted. The allocation of treatment is produced at random.

RANDOMIZATION A
systematic, statistically balanced but unbiased method of allocating subjects among various experimental groups to obtain statistically valid results.
Health and Welfare Canada, 1989, 21

11
Such controlled trials are done without the knowledge of the subject. The method can be single, double or triple unknown. In the first case (single blind or single blind), the subject ignores the treatment that will be administered to him. In the second scenario (double-blind or double-blind), the subject and the researcher are both unaware of the treatment that will be administered. Some documents also speak of the triple unknown method, the terminology not seeming well fixed in this regard. Thus, the guidelines of the Medicines Directorate of Health Canada, published in 1989 and 1992, use the expression of triple unknown to describe the method that Good Clinical Practicesdescribe as a double-blind trial. These controlled clinical trials are mostly conducted as a result of extensive laboratory animal studies.

Clinical research
Good Clinical Practices
Triple unknown method The subject, the researcher and the experimental specialist do not know the treatment that will be administered to the subject.

Test without the knowledge of the subject Procedure in which one or more participants are kept in the dark about the treatment administered. Usually, a double-blind trial means that subjects, investigators, monitors and in some cases data analysts ignore the treatment being administered.

Health and Welfare Canada 1989, 22
Health Canada, 1997, 3

The phases of the clinical trial
12
Clinical trials in humans have four distinct phases. Phase 1 trials consist of an evaluation of the product in usually healthy volunteers. The trial period is usually quite short and the experimental conditions particularly rigorous. The doses given are initially tiny and then gradually increased. Investigators want to assess the toxicity of a new molecule and arrive at the most suitable doses for humans. Phase 1 takes place under the supervision of a clinical researcher. As it uses healthy volunteers and these are paid by the sponsors of the trial products, it usually takes place in the sponsor's clinical departments.

13
The private nature of trials, in the context of the development of a host of new drugs, is not without raising ethical questions “relating to the choice and recruitment of subjects, the process and the value of free consent and informed, to the composition of REBs and the appropriateness of their protocols (where they exist), and to the duties of federal regulatory bodies ” (Policy Statement, 1998, 7.2). An ethics committee unrelated to the sponsor must continuously evaluate and monitor any phase 1 clinical trial (Minister of Health, 2001, c.05.010; Health Canada, 1997, 14 ; Policy statement,1998, 7.2). In Quebec, under article 21 of the Civil Code, regardless of the place where the research is carried out, establishment, doctor's office or private laboratory, a committee appointed by the Minister of Health and Social Services must assess a phase 1 research project involving minors and incapacitated adults. If the sponsor's or investigator's establishment does not have such a committee, it must contact the central research ethics committee created for this purpose (Ministry of Health and Social Services, 1998, 13) .

14
A growing number of phase 1 clinical trials are being performed in teaching hospitals, at the request of sponsors. One of the reasons is that in certain circumstances these trials must involve people with illnesses. One immediately thinks of AIDS patients and terminally ill cancer patients for whom no conventional treatment has been shown to be effective. In fact, in such situations, researchers have already entered phase 2, the first two phases combining.

15
Phase clinical trials %aim to "confirm the efficacy of the product, assess its therapeutic interest, assess the relationship between the risks and the benefits associated with its administration and seek the best dose and the best mode of administration according to the desired effect ”(Delfosse, 1993, 56). To do this, the methodology of controlled trials can be used. A small number of patients receive the product, and their reaction to treatment is carefully analyzed. Due to the selected participants, phase 2 calls for rigorous medical surveillance. The RECs of university hospitals are therefore directly involved in the evaluation and monitoring of these trials. If the product administered to the selected group does not show any benefit, clinical experience stops and the first trials must resume.

16
The primary goal of the phase 3 trial is to analyze the pharmacological efficacy of new drugs.

PHASE 3
• Study the medium-term tolerance and the variability of efficacy in order to assess the relationship between the benefits and the disadvantages (adverse effects and cost).
• Look for a series of knowledge that will be useful to the prescriber:
- treatment monitoring conditions;
- characteristics of the patients which require an adjustment of the dosage;
- duration of treatment ;
- modalities of stopping it;
- profile of the responder patient;
- interactions with other drugs;
- maximum catch conditions.
Delfosse , 1993, 57

17
The number of patients selected must be high, hence the interest of multicenter trials. Because of the objectives sought, the trials are long-term and take place both in university hospitals and in private clinics. Indeed, it is a question of reproducing, as much as possible, the conditions of use of the future drug when it is on sale. Randomization is used as a method, comparing the new product with another already existing but judged less effective or with a placebo in the event that it does not exist on the market. One of the most controversial issues regarding phases 2 and 3 relates to the use of placebos "intended to detect and quantify the acute toxicity and efficacy of investigational drugs" (Policy Statement, 1998, 7.3).

18
Once phase 3 has been completed, if the sponsor is satisfied with the results of the analyzes of the new product, it submits a comprehensive dossier to the Drugs Directorate of Health Canada for approval. At this point, there is still a lot of unknowns about how well the drug actually works. The first three phases are carried out in a controlled environment, while once approval is given by Health Canada, the new product takes on its own life. In vivo studiesare then required. This is phase 4 or surveillance studies. They aim to better understand the adverse reactions and effectiveness over a long period of time. It also includes morbidity / mortality and other studies of an epidemiological nature aimed at confirming the validity of the initial approval.

19
These studies are important because they allow a thorough knowledge of the real life of the drug. However, they are difficult to carry out because of the high costs and the need for a real collaboration of all the interested parties: ministries of health, doctors, health establishments, pharmaceutical industry, research laboratories. Each party has to share their information, which is not easy when important financial interests are at stake. One of the difficulties unique to Canada is that the approval of the drug is the responsibility of Health Canada and the studies of Surveillance is more relevant to provinces that pay for drugs used in hospitals or operate drug insurance programs. For the time being,

Ethical issues
20
The search for new drugs is today a huge scientific and financial undertaking. There are multiple interests at stake both in health care and in economic policy. The same goes for the medical device sector. Establishing, in this context, the responsibilities of each other represents a colossal task which goes beyond the project of this book devoted to the ethics of the researcher. But who is this researcher?

21
Is it the specialist who, in his university or industrial laboratory, develops new molecules? Is this the person responsible for performing the clinical study at the trial site and called investigator by Les Bonnes Pratiques Cliniques? Of the person or body responsible for implementing the management or financing of a clinical trial and whom Good Clinical Practice calls a sponsor? For the purposes of this section, the words researcher and investigator will be used as synonyms.

22
First, we will discuss the requirements placed on the investigator to accomplish his task in such a way as to respect human subjects. Then, some issues specific to clinical research will be discussed. Thus, innovative care, the use of placebos, the participation of patients in non-therapeutic research, the integrity of the consent process in the case of a combined phase 1 and 2 trial, the payment of the subjects of research and finally the conflicts of interest which lie in wait for the investigator.

Requirements for the investigator
23
Clinical research is on the increase and the hopes that it arouse are great as well as the risks run, considerable sums of money are committed to it, the university hospitals are playing their reputation there, the doctor-researchers insisting on being associated with it. in one way or another. The physician-researcher whose name appears on the list of signatories of the article published by the New England Journal of Medicine or the Lancet acquires, among his colleagues and his patients, a reputation which is not to be despised in a highly competitive environment. Because of these multiple issues, investigators must have skills that organizations increasingly regulate. When we compare the Nuremberg Codeand the first Helsinki Declaration on Good Clinical Practice, the progress made is considerable. I choose this last document, published in 1997 by Health Canada, because it deals specifically with research on pharmaceutical products for human use. Certain qualifications of the investigator overlap with what has already been presented during the study of the research protocol to be prepared by the researcher. Others are more specific. I would like to highlight five elements of Good Clinical Practices that deserve the attention of the researcher (Health Canada, 1997, 18-28).

High scientific competence
24
The researcher "must have the knowledge, training and experience necessary to perform the test in an appropriate manner", among other things "fully understand the way to use the research products as described in the protocol" .

Adequate resources
25
These mean the capacity:
recruit the required number of appropriate subjects;
complete the test within the established timeframe;
to be able to count on a sufficient number of qualified employees;
to have adequate facilities available;
to properly inform all those involved with the investigation of the protocol and its implications for each and everyone.

Concern for the good of research subjects
26
This is expressed in necessity:
that a doctor, responsible for all decisions of a medical nature, take part in this type of test, either as principal investigator or as secondary;
that a research subject receive appropriate medical care during and after participation in the trial for any therapeutic incident related to the trial;
that any serious therapeutic incident be immediately reported to the sponsor;
that the investigator ask the research subject if he wishes his doctor to be informed of his participation in the trial;
that the investigator inquire into the reasons a participant may have for withdrawing prematurely from the trial. He must, however, act reasonably and respect his silence;
that the investigator informs any participating subject of the discontinuation or interruption of the study and that he ensures that an appropriate treatment or follow-up is provided to him.

Respect of protocol
27
The investigator undertakes to:
perform the trial according to the protocol approved by the sponsor;
do not add any variation, unless it is to eliminate an immediate danger for the subjects participating in the test;
submit any variant or modification to the protocol to the sponsor and to the research ethics committee.
Voluntary consent
The subject of informed consent has been discussed extensively in Chapter 4. It is not opportune to return to it here, except to point out the precise and detailed requirements provided by Good Clinical Practices.

28
Each of the five points mentioned here testifies to the importance given to the qualifications of the researcher, both on a strictly scientific level and in terms of respect for research subjects. The researcher's responsibility extends as much to his research as to the people to whom he asks for help by submitting to an experiment. Due to the nature of the Good Clinical Practices document ,it is possible that this one does not succeed in clearly highlighting the fundamental and preliminary requirement of the five mentioned: medical research must remain inseparable from the strictly medical work which consists in serving the patients for whom the doctor-researchers remain responsible. It is in this context of therapeutic concern that the English expression clinical equipoise (Freedman, 1987) was born and that the Policy Statement translates as “principle of clinical equilibrium” (Policy Statement,1998, 1.6). The concept which is taking on great importance today means that a trial can only begin if there is real uncertainty within the medical community as to the value of the products to be compared and if the study is constructed in such a way as to nullify the gap of uncertainty among experts and to build consensus on the best treatment to offer to patients. Otherwise, why use patients? Clinical judgment once again reminds us of the meaning of interventionist clinical research: to serve the sick.

Specific issues
Innovative treatments
29
On several occasions, we have addressed the issue of innovative care, without however taking a position on them. Should the physician submit to the REB a treatment that deviates considerably from the norm and that he does not consider as research but rather as a “last chance” treatment? The question has given rise to various responses. At first glance, the answer seems negative, such an approach corresponding perfectly to the most traditional medical practice. As Marie-Luce Delfosse notes, this act “is ultimately identified with the therapeutic relationship” (Delfosse, 2000, 9). Further reflection leads to broadening the answer. It seems to me essential that the doctor carry out a consultation before undertaking a therapeutic action which deviates considerably from the accepted norm. Who to consult? It makes sense that he must consult his colleagues, the care team and, of course, the sick person or his relatives. Should he consult an ethics committee? If so, a research ethics committee or a clinical ethics committee?

30
The opinion of a hospital ethics committee could prove to be a welcome initiative. This committee's task is to help inform difficult medical decisions. His concern leads him to prioritize the interests of the patient. The diversity of committee members favors a broad perspective. As it is a treatment, the proposed medical act would benefit from being evaluated by this ethics committee. Other reasons justify the intervention of the research ethics committee. The first stems from the context of experimental medicine, which has seen a proliferation of therapeutic innovations, hence the need to evaluate them rigorously. This ethical requirement is all the stronger as several innovations, when they are subjected to rigorous control studies, have no advantage over conventional treatments (Roy, 1998, 582). Second, various documents that address the issue of innovative therapy recommend consultation with the research ethics board. This choice is explained by the fact that the question of innovative care is, at least in part, inseparable from the debates on experimentation carried out more than twenty years ago now.

31
Some physicians argued, among other things, that they were not subject to the standards of research ethics if they were doing therapeutic research. This context helps to understand the REB's choice to study this type of care. This is how the Belmont Report expresses it :

Any such new protocol should be formally researched from the outset to ensure that it is safe and effective. Medical practice committees therefore have the responsibility, for example, of insisting that a major innovation be incorporated into a formal research project (The National Commission, 1982, 235-236).

32
The Declaration of Helsinki of October 2000 goes in the same direction as the Belmont Report (World Medical Association, 2000, art. 32).

33
The Civil Code of Quebec addresses the issue of innovative care in the third paragraph of article 21: “The care that the ethics committee considers to be innovative care that is required by the state of health of the patient does not constitute an experiment. person who submits to it. It is up to the CER to determine the status of the planned activity. If this is judged to be a therapeutic innovation rather than a research activity, the REB does not have to approve it (Patenaude and Cabanac, 2000, 92). In this sense, the hospital ethics committee could be called upon to evaluate it like any other therapeutic act. The choice made by the Civil Code is interesting in that it tries to reconcile the two perspectives that prevail today in innovative care, namely that of therapy and that of research.

Use of placebos
34
The use of placebos is hotly debated in both clinical practice and research (Weijer & Anderson, 2001). It has been a subject of controversy in recent discussions surrounding the revision of the Declaration of Helsinki (Nicholson, 2001, 8). A "round table-search for consensus", organized in May 1998 by the National Council for Ethics in Human Research (CNERH), clearly highlighted the different antagonisms. Advocates of placebo argued that this type of trial is necessary to protect patients from potentially dangerous or ineffective treatments. It provides scientific data of the highest quality. Using active or standardized treatments as a control treatment may expose more patients to potentially dangerous or ineffective treatments. For the second school of thought, a placebo could not be used if there are already truly effective interventions or treatments. Three reasons were presented. It is unethical to deprive patients of clearly effective treatment for research purposes. To this ethical claim is added the argument that the use of placebos is not necessary to obtain good scientific results. Finally, third reason, research protocols providing for the use of placebos cannot provide the information that is most important for patients and physicians,

35
At the end of the May 1998 meeting, the participants who brought together specialists from government, academia and the private sector drafted the wording of the article that would become rule 7.4 of the Tri-Council Policy Statement:

In general, the administration of placebos in a clinical trial is unacceptable when there are interventions or treatments routinely provided to specific populations of subjects (Policy Statement, 1998, 7-4).

36
How to interpret such a rule? This must be interpreted from the principle of clinical equilibrium. If the latter is present at the start of the trial, it becomes acceptable to use a placebo in a number of cases referred to in the Policy Statement.

CONDITIONS OF USE OF A PLACEBO
1. Around the standardized treatment:
* no standardized treatment exists;
* it is not better than the placebo;
* it is called into question by serious evidence;
* a population of patients is refractory to it.
2. Around costs and supply;
effective treatment cannot be offered to subjects due to cost and supply reasons. In this context, for reasons of equity, however, such trials could not be conducted if effective treatment was offered to the rich, but poor or uninsured subjects were deprived of it.
Policy statement, 1998, 7.4-7.5

37
An article from May 2000, published in JAMA, presents some real-life cases that may inform rule 7.4 of the Policy Statement.The authors say that ten years ago a new class of antiemetics, antiserotinins, was developed. To assess this, the investigators conducted randomized, placebo-controlled trials with cancer patients receiving standard antiemetic chemotherapy, placebo, or antiserotinins. It is clear that the dominant therapies of the day were effective, although imperfect. In this context, new products were desired, but the use of placebo was not indicated, since there was a recognized treatment which even served as a control. The use of placebo was all the less indicated since comparative studies between two active treatments are carried out regularly in therapeutic trials (Emanuel, 2000, 2708-2709).

38
In the context of globalization, the question of the use of placebo raises specific questions which have given rise to important debates at the international level. In 1998, Marcia Angell, then editor of the New England Journal of Medicine, signed an editorial strongly condemning an ongoing clinical trial in Africa in HIV pregnant women. The aim was to test a new drug that acts as a barrier to the transmission of seropositivity from mother to fetus. This was a placebo-controlled trial. The New England Journal reviewwas to say that the use of placebo was unacceptable here since a standardized treatment already existed, AZT. It was therefore necessary to compare two active substances. She maintained that there were two weights, two measures, this experiment not meeting the minimum standards of developed countries (Angel, 1998). Contrary to the editor-in-chief, the proponents of the trial replied that discussions had taken place at WHO, in the medical and political circles of the countries concerned, and that the placebo trial had been found to be the only option possible. Indeed, African countries do not have access to AZT due to the costs of this drug. If the new product were to prove effective, patients in those countries could benefit from it.

39
In this debate, there was a double interpretation of an article of the Declaration of Helsinkiof 1996: "During any clinical study - with or without a control group - the patient should benefit from the best diagnostic and therapeutic means available" (Delfosse, 1993, 304). This article was at the heart of the discussions that took place during the revision of the Declaration. Some argued that the article should be interpreted taking into account the local context: researchers should consider the diagnostic and therapeutic methods available in the area. The others retorted that we must consider all existing diagnostic and therapeutic means. Otherwise, the risk would be too great that investigators and promoters would take advantage of this to carry out their research in disadvantaged areas and in developing countries. Policy Statement:

It is possible to administer a placebo, as a controlled treatment in a clinical trial if it is not possible to offer subjects an effective treatment for reasons of cost or supply (this argument can only be made when basic conditions of justice characterize the health care system in question - for example, a trial requiring the administration of placebos cannot be permitted when an effective, but expensive treatment is offered to wealthier subjects, but not to poorer or uninsured subjects) (Policy Statement, 1998, 7.5).

40
An example of research in a developing country that is inappropriate in a developed country is the Rhesus rotavirus tetravalent (rr-tv) vaccine. This vaccine which prevents diarrhea was approved in the United States after quite regular clinical trials. Shortly after its market launch, it was withdrawn due to significant side effects in 1 in 1,000 cases (intussusception). Should we, however, continue clinical trials in developing countries? Ezekiel and his colleagues answer in the affirmative. Indeed, despite oral rehydration, 600,000 children in developing countries die each year from rotavirus diarrhea. It would be acceptable to continue clinical trials in these countries if the vaccine could achieve a sufficient degree of protection against diarrhea with a low incidence of complications for these children. For each case of intussusception, 50 child deaths are avoided. Since there are no other prevention methods here, the placebo trial would be acceptable (Ezekiel, 2000, 2709-2710). The basic ethical criteria already mentioned should guide researchers: relevance of the study, validity, balance of risks and benefits and equity in the choice of populations.

Patient participation in non-therapeutic trials
41
Interventionist clinical research has therapeutic objectives. However, sometimes a patient is selected for the sole purpose of scientific research. This is the case of a clinical study aimed at verifying the side effects of a particular product (Commission de reform du droit, 1989, 5). A patient could also become the subject of a clinical trial that contains therapeutic and non-therapeutic elements. This is the case of a protocol in which the tested product aims to prevent or cure a disease, but in which certain components do not directly serve the patient but increase knowledge. For the International Ethical Guidelines for Biomedical Research Involving Human Beingsof CIOMS, the research protocols contain elements that are neither diagnostic, nor prophylactic, nor therapeutic for the subject-patient. This is the case with the prescription of a placebo and the administration of tests which go beyond strict medical needs (CIOMS, 1993, 11). These non-therapeutic elements may have drawbacks or be a source of discomfort which do not benefit the patient in any way (Verdun-Jones, 1998, 99-100).

42
How should a researcher, if he gives priority to his patient, behave towards the latter? He will first have to determine for himself whether the protocol is primarily intended for treatment or for increasing knowledge. A remark by Verdun-Jones and Weisstub is enlightening in this regard:

The presence of an excessive number of incidental operations, which the therapeutic objective does not really require, tends to indicate that an experiment is more related to the process of scientific study than to the treatment of patients and that it is should be considered to be primarily non-therapeutic in nature (Verdun-Jones, 1998, 103).

43
Secondly, the researcher must clearly indicate to the patient, and without evasiveness, the direction of his research. It will then be up to the latter to determine his choice. If he does not have a clear idea of ​​the type of research in which he is invited to participate, the patient will tend, especially if the disease is severe, to respond positively to the request, believing that they have a chance of recovery. The patient is thus misled and his consent is not informed.

Consent in the case of a combined phase 1 and 2 trial
44
The combined phase 1 and 2 clinical trials are absolutely necessary: ​​they target extremely serious diseases for which the therapeutic arsenal remains largely inadequate. Let us think here of AIDS. The situation of the patients with whom the studies take place is often desperate. In such cases, two particular concerns should inspire the investigator. On the one hand, the latter must attach great importance to "the integrity of the free and informed consent process" (Policy statement,1998, 7.2). Indeed, due to the condition of patients whose disease can be very advanced, subjects, families and even researchers are desperate to try to save a life. There is a risk of misjudging the reasonable advantages and disadvantages of research. Hence the need to properly structure the voluntary consent process. On the other hand, this misperception "also influences the clarity and importance of shutdown or withdrawal procedures". The researcher's collaboration with the research ethics board, as suggested by the Policy Statement, can prove fruitful for the investigator who will find in the REB an instrument that helps him to broaden his gaze (Statement of policy, 1998, 7.2).

Payment for research subjects
45
Researchers cannot conduct their clinical trials without recruiting subjects. How to encourage them to participate? Is paying them acceptable? Despite intense debates that have continued for years, it is recognized that healthy Phase 1 volunteers, for example, are paid for their collaboration. At the other end of the spectrum, the reverse is also clear: patients participating in chemotherapy studies are not. The publicity made to find volunteers suffering from asthma or the human immunodeficiency virus clearly shows that these patients are paid for their participation (Dickert and Grady, 1999, 198).

46
What are the usual arguments used to oppose the payment of research subjects? Research subjects would lose the freedom necessary for voluntary consent; money would be the motive for participating rather than understanding the project. To this first reason, there is a second: the economically weak populations would engage more in these experiments, which leads them to bear too heavy a share of the risks and burdens of research. These two reasons are especially valid for phase 1; for the other phases, the opponents also mention that the researcher-doctor transforms his therapeutic relationship into a commercial relationship and places his patient in greater dependence. Finally, participation in a clinical research project brings benefits to the patient.

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These arguments have never succeeded in convincing the entire scientific and political community. Far from harming the understanding of the project, it could be, it is pointed out, that paying a patient enables him to better distinguish care from research, particularly in the context where the patient pays for his care. In such a situation, the patient is no longer doing the doctor a favor, which also reduces the feeling of dependency and vulnerability. For many patients, participation brings nothing. On the contrary, they run certain risks and the tests required in addition to the treatments may bring them more disadvantages than benefits. So why, in a case where no benefit can result from the research, pay a healthy volunteer and not a patient?

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The debate is lively. What approach should a researcher take? The researcher who is particularly sensitive to the equality of all the subjects involved in a trial might decide to favor a method which reimburses each one of his real costs, including a loss of salary (Medical Research Council, 1987, 25). The researcher could be more sensitive to the various disadvantages to which the research subjects are subjected and decide to use a salary approach. Participating in research is unskilled work but involves risks. Participants could be paid according to the model of the unskilled but lifelong essential workforce of the company (Dickert and Grady, 1999, 199-200). Whatever model is chosen, it seems necessary to develop a policy which achieves consensus in the whole of society on this subject. In this way, justice with regard to research subjects and the need for researchers to recruit subjects will be respected.

Conflicts of interest
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The behavior of Robert Gallo in the race to discover the AIDS virus, the actions of Roger Poisson falsifying research files and the attitude of the authorities of Sick Children's and the University of Toronto in the Olivieri case have raised awareness the scientific community, government authorities and the public to conflicts of interest that threaten all those involved in clinical research. Looking more closely at these stories, the observer quickly realizes the multiplicity of conflicts of interest that we discover in this sector.

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In the context of this presentation, it is impossible to take stock of the situation regarding conflicts of interest in the field of clinical research. Think of those affecting governments, the pharmaceutical industry, universities, REBs and researchers themselves. The list is long. In accordance with the primary orientation of this book, it will be a question here of the conflicts of interest that threaten researchers. Before presenting some of these conflicts, I will briefly discuss a definition of the terms.

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What is a conflict of interest? A doctor-researcher is bound by several obligations. As a doctor, he must give priority to his patient. As a researcher, the advancement of knowledge is his primary concern. Because this doctor is attached to a hospital which has its own culture and values ​​the quality of its image and its reputation, a first conflict may arise between his responsibilities as a doctor and the expectations of the institution. Because this researcher is attached to a university research center which favors success in research for the promotion of its staff, he may be tempted to overshadow his responsibility as a doctor and thus neglect the priority given to patients. Researcher and doctor, this individual is sometimes divided between his two responsibilities.

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A very interesting way of defining conflict of interest was proposed by DF Thompson in an article in the New England Journal of Medicine in 1993. The author proposes to distinguish between primary interests and secondary interests ( secondary).The former concern the professional responsibilities of the doctor, researcher or professor. This is about patient care, research integrity and student education. The second concern prestige, academic advancement, financial gains, and the advantages of relationships with certain circles of money or power (Thompson, 1993). This approach ties in with a large number of conflicts of interest discussed today. It is close to the experience. However, it seems to me that it does not sufficiently highlight the fact that conflicts also occur within the main interests. Doctors-researchers and professors-researchers are torn between missions that have sometimes become contradictory.

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The context of clinical research practice explains the structural nature of conflicts of interest. The list of places where the researcher may find himself in a conflict of interest is such that these are not accidental: they belong to what clinical research has become.

VARIOUS SOURCES OF CONFLICTS OF INTEREST
1. The researcher has
personal • interests ;
• professionals;
• financial.
2. The scientific community is in search of
• serious knowledge;
• public respectability.
3. The establishment expects productivity from the researcher
;
• a reputation that will be brought to it by good scientific renown;
• financial resources from funding agencies and sponsors.
4. The patient participates in clinical trials in the hope of benefiting from them.
5. The Sponsor agrees to subsidize academic units to conduct research which gives legitimacy to its products.
6. The public whose taxes and donations support the vitality of academic medicine.
According to Huth , 1996, 390

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How can the researcher cope with the various demands made of him? In recent years, several organizations have proposed guidelines for resolving the difficulties posed by conflicts of interest. The main medical journals have taken a common position on the issue. The CMA Journalis very clear in this regard, as can be seen in the guidance given to the authors (CMA, 2001). The aim is to ensure that clinical research produces efficient, safe and inexpensive diagnostic and therapeutic instruments. These guidelines focus on the conflicts of interest that arise from the funding of research by industry; this is undoubtedly a central problem because of the partnerships which are increasingly valued by government and university authorities. In May 2000, Marcia Angel, the editor of the New England Journal of Medicine,wrote, in an article about an antidepressant produced by Bristol-Myers Squibb Laboratories, that “the authors' links [of the article] with the laboratories manufacturing antidepressants were so important that in listing exhaustively in the Journal would have taken up too much space ”(Angell, 2000). The pharmaceutical industry plays a decisive role in the development of innovative active treatments. It provides, according to Thomas Bodenheimer, 70% of funding for clinical drug trials, while the NIHprovide only 30%. In such a context, can researchers be more immune to special interests than other people? To the question, Thomas Bodenheimer replies that when pharmacoeconomic studies of cancer drugs are supported by industry, 5% of them show unfavorable results, whereas the result jumps to 38% if the funding of studies similar comes from other sources (Bodenheimer, 2000).

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The Tri-Council Policy Statement devotes a chapter to the issue of conflict of interest and asks researchers to comply with the following rule:

Researchers and REB members will disclose to REBs any real, apparent or potential conflict of interest. RECs should put in place mechanisms to address and resolve these conflicts (Policy Statement, 1998, 4.1).

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A few years ago, the National Council for Bioethics in Human Research, now known as the National Council for Human Research Ethics, developed a whole reflection on this question and proposed a number of guidance.

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Because of the importance of clinical research today, researchers have a particularly important responsibility: to participate in improving the health of the population in the most rigorous, efficient and equitable manner possible. This is a formidable task for researchers. How to respond well to the expectations that are communicated to them? The function of "human science research council " ethics is to help them to act well in today's context. This remains an extraordinary challenge for our time.