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COMPASSIONATE ACCESS TO INVESTIGATIONAL THERAPIES

INTRODUCTION

The House of Commons Sub-Committee on HIV/AIDS was established by the Standing Committee on Health in November 1994, and directed specifically:

To study the spread of HIV and the prevention, treatment and support of persons infected or affected by HIV/AIDS, with special attention being given to the role of poverty and discrimination on the aforementioned matters.
The first action taken by the Sub-Committee was to study the effectiveness of Canada's National AIDS Strategy. Sub-Committee members reviewed the epidemiology of HIV/AIDS in Canada and throughout the world, and conducted an in-depth examination of the specific components of the National AIDS Strategy: leadership, co-ordination and partnership, the budget for the Strategy, community action, education and prevention, care, treatment and support, and research. Hearings were held from December 1994 through May 1995, and A Study of the National AIDS Strategy: Report of the Sub-Committee on HIV/AIDS was presented to Parliament on 6 December 1995. The report contained 23 recommendations aimed at strengthening the response of the federal government to the AIDS epidemic.

During its examination of the National AIDS Strategy, the Sub-Committee heard that one of the most immediate and pressing concerns of people with AIDS and, indeed, of anyone with a life-threatening illness, is the issue of access to experimental drugs. The normal process of drug development, testing, evaluation and approval can take five to ten years; time that people with a terminal condition simply do not have. In Canada, there are a number of mechanisms by which people who are catastrophically ill can obtain an investigational drug; for example, by participation in clinical trials (human testing of an experimental treatment) or by means of compassionate access programs authorized by Health Canada and provided by pharmaceutical companies. Compassionate access programs, although greatly appreciated, are often limited in extent or fraught by financial, legal and ethical considerations.

The Sub-Committee decided to address the issue of compassionate access to experimental drugs by hosting a series of National Round Tables. At the opening Round Table on 6 December 1995, Bernard Patry, then Chairman of the Sub-Committee, stated that: "our purpose is to delve into these complicated issues, identify the constraints and propose solutions that will result in a more liberalized form of compassionate access that is acceptable to all those concerned."(1) At this session, the human face of catastrophic illness was presented when the Sub-Committee heard from advocacy groups and the victims of cancer, amyotrophic lateral sclerosis, multiple sclerosis and AIDS. In addition, primary-care physicians, nurses and representatives of Canada's pharmaceutical industry attended this Round Table. At the second Round Table, Canada's drug regulatory process and the Special Drugs Access Program were examined with emphasis on how these activities could be improved to facilitate compassionate access. The ethical and legal considerations surrounding expanded access were discussed at the third Round Table by Canadian experts in the fields of bioethics and medical law. At the fourth session, the issue of responsibility (government leadership, financial responsibility, and the responsibilities of physicians, patients, insurance companies and pharmaceutical manufacturers) was addressed. The final Round Table, on 1 May 1996, was attended by national organizations: the Canadian Cancer Society, Canadian AIDS Society, Canadian Haemophilia Society, Canadian HIV Trails Network, National Council on Bioethics in Human Research, AIDS Action Now!, Pharmaceutical Manufacturers Association of Canada, and Health Canada. These national groups reviewed the proceedings of the previous sessions, attempted to clarify unresolved issues, establish common ground and provide the Sub-Committee with suggestions and recommendations for action.

(1) House of Commons, Minutes of Proceedings and Evidence of the Sub-Committee on HIV/AIDS of the Standing Committee on Health, Meeting No. 19, 6 December 1995, p. 2 (hereafter cited as meeting number, date and page number; e.g. Meeting No. 21, 6 December 1995, p. 2).

During this study on compassionate access to experimental therapies, Health Canada generously provided the Sub-Committee with a tour of the Drugs Directorate, a seminar on new drug development and regulation in Canada, and documentation on the Emergency Drug Release Program and its proposed replacement program, the Special Access Program. This rather large volume of information has been summarized. Details of new drug development and regulation in Canada are provided in Appendix I; while a concise review of the Emergency Drug Release Program and the Special Access Program appear in Appendix II.

CATASTROPHIC RIGHTS

The concept of catastrophic rights holds that: "a catastrophically-ill patient has the right to be free from any paternalistic interference in electing, in consultation with his physician, any therapy whatsoever that does not cause direct harm to others."(2) This concept is rooted in the principle of freedom. According to Roman Law: "Freedom from which we get the description of men as free, is a man's natural capacity of doing what he pleases unless he is prevented by force or law . . ."(3) Through the ages this principle has undergone little change. The Declaration of the Rights of Man and the Citizen, 1789, proclaimed "Liberty consists in the freedom to do everything which injures no one else;"(4) and, according to John Stuart Mill, ". . . the only purpose for which power can be rightfully exercised over any member of a civilized community, against his will, is to prevent harm to others."(5) Accordingly, autonomy and the ability to try to save one's own life are a fundamental freedom of ancient lineage.

(2) J. Dixon, Catastrophic Rights, Experimental Drugs & AIDS, New Star Books Ltd., Vancouver, 1990, 131 p.

(3) R.W. Lee, The Elements of Roman Law: with a Translation of the Institute of Justinian, Sweet and Maxwell Ltd., London, 4th edition, 1956, p. 57.

(4) M. Viorst, The Great Documents of Western Civilization, Chilton Books, Philadelphia, 1965, p. 190.

(5) J.S. Mill, "On Liberty," Great Books of the Western World, R.M. Hutchins, ed., William Benton, Publisher, Chicago, Vol. 43, 1952, p. 271.

The catastrophic right to try to save one's own life is, unfortunately, neither straight forward nor simple in its application for this is a "positive" right, meaning that its fulfilment requires the participation of others. Derek Jones, Director, National Council on Bioethics in Human Research (NCBHR), explained: "A positive right means a right to be provided with some good. A negative right means a right to be free from interference."(6) When a terminally-ill individual refuses therapy or heroic efforts to prolong life, he or she is exercising a negative right. In our society, we support the individual's right to refuse treatment; abiding by this wish requires nothing of us, except perhaps the provision of palliative care until the end. In contrast, a positive catastrophic right to drugs imposes a corresponding duty on those who have drugs or on those who manufacture drugs to supply these therapies; but this may not always be possible. According to Derek Jones there:

[. . .] is the tendency of both ethics and law to grant fuller recognition of negative rights than positive rights. [. . .] Secondly, even if the modern social contract between citizens includes rights to treatment, it is clear that such rights are not absolute. A patient's right to health care does not imply that he or she has the right to be supplied with all treatments.(7)

(6) Meeting No. 21, 13 December 1995, p. 19.

(7) Ibid.

To date, Canadian public policy and law have chosen to facilitate access to unapproved therapies rather than impose legal requirements. The Department of National Health and Welfare Act specifies that "[t]he powers, duties and functions of the Minister extend to and include all matters relating to the promotion or preservation of the health, social security and social welfare of the people of Canada over which Parliament has jurisdiction." Within the context of this mandate, it can be argued that the government has an obligation to catastrophically-ill Canadians to do all that is reasonable to promote and preserve their health.

The Food and Drugs Act provides the authority to "prohibit the sale of drugs that are manufactured under unsanitary conditions or that are adulterated; to prohibit the false or misleading advertising, labelling, packaging, processing or sale of drugs; and to prohibit the sale of drugs that do not comply with prescribed or professed standards."(8) In short, the Act attempts to safeguard the health of Canadians by prohibiting the sale of drugs of unproven safety and efficacy. As such, the Act would disallow an individual's catastrophic right to an unproven therapy were it not for sections C.08.010 and C.08.011 of the Act's regulations. These provisions establish the conditions for the Emergency Drug Release Program (EDRP); whereby, the Health Protection Branch (HPB) of Health Canada may authorize a pharmaceutical manufacturer to sell a drug, not approved for sale in Canada, to a physician for the emergency treatment of a specific patient. The program covers two therapeutic categories: investigational drugs and drugs approved in foreign countries. When the EDRP was established in 1966, it was largely used for this latter function; however, since the emergence of the AIDS epidemic approximately 15 years ago, the focus of the EDRP has shifted to the point where the authorization of experimental drugs for people who are catastrophically ill is the program's major function. While catastrophic rights do not have the force of legal recognition in Canada, the government's action to facilitate the provision of unapproved medications "implicitly recognizes that critically-ill persons should be allowed to take much greater risks than would otherwise be acceptable."(9)

(8) E. Somers, et al., "Drug Regulation - The Canadian Approach," Regulatory Toxicology and Pharmacology, Vol. 12, 1990, p. 216.
(9) Parliamentary Ad Hoc Committee on AIDS, Confronting a Crisis, June 1990, p. 30-37.

ACCESS TO UNAPPROVED DRUGS

There are four ways by which drugs not available for sale in Canada may be obtained; however, only the last two mechanisms are considered to be compassionate.

For the catastrophically-ill person, compassionate access provides the greatest hope of obtaining an experimental therapy. Access, however, is totally at the prerogative of the pharmaceutical manufacturer. Even when the EDRP grants authorization for release of a drug, the manufacturer is neither compelled to release the drug nor obligated to justify its decision. However, the most common reasons for denying or delaying compassionate access are: the agent may be very expensive to produce, compassionate access programs can be very expensive to manage, focusing resources on compassionate access may starve research and development of other drugs; manufacturers have a fiduciary duty to its shareholders and must behave responsibly and minimize the risk of financial loss; there is an insufficient supply beyond that needed for the clinical trial; concerns of liability because the safety of the agent has not yet been proven to the satisfaction of the manufacturer; or it may be feared that compassionate access will slow drug approval, in that it may slow the recruitment of volunteers for a trial, lead to a higher drop-out rate, or compromise the quality of data.

At the Round Table, representatives of the Pharmaceutical Manufacturers Association of Canada (PMAC) stated that it was believed that all PMAC-member companies endeavour to have compassionate-use programs in place and that it was certainly the norm rather than the exception. According to William Milligan, all companies manufacturing HIV/AIDS drugs have provided compassionate access to the extent that production allows, including the protease inhibitors saquinavir, ritonavir and indinavir, which are in short supply. Michael Levy pointed out that approximately 2,900 people living with HIV/AIDS had access to 3TC. Most of these patients were treated through the compassionate access program while others received the drug through clinical trials.(11)

(11) Meeting No. 19, 6 December 1995, p. 50-51.

THE CASE FOR COMPASSIONATE ACCESS

Strong and eloquent arguments were made to justify the compassionate release of investigational drugs. Susan Conrad, a sufferer of amyotrophic lateral sclerosis, told the Sub-Committee that the current drug development and evaluation system meets the needs of the general population, but it fails to address the needs of the terminally ill. For those who are not catastrophically ill, it is an unacceptable risk to take an experimental therapy which might provide benefit; but, which might also have no effect, or worse cause serious illness or death. In contrast, this is not an unacceptable risk for individuals who are facing certain death, for there is the chance the provision of an experimental drug might provide relief, delay disease progression and perhaps even offer a cure. Susan Conrad argued that catastrophic illness does not render "people incapable of rationally considering benefits and risks" and "people who are ill are no more or less likely to behave irrationally than people who are not ill." Further, "we live in a country where mentally capable adults have the legal right to make fundamental choices affecting their own lives." She asked: "Is it acceptable to sacrifice the needs of people who are seriously ill for the benefit of hypothetical future sick people?" The challenge given to the Sub-Committee was to determine if it is possible to protect the drug research system and the needs of the general public without sacrificing people who are already ill.(12)

(12) Ibid., p. 8-12.

There are many advantages to be gained by early access to experimental drugs. Of greatest importance, it provides the possibility of maintaining or improving the quality of life, alleviating pain, restoring health and saving life. Ken Logue, a Toronto primary care physician with a large HIV/AIDS case load, stated that, for many physicians treating people with HIV/AIDS, a majority of their patients are taking an experimental therapy and this forms a standard of care in these practices.(13) By empowering patients, that is by providing them with the opportunity to decide over their own health, compassionate access may contribute to an improvement in clinical health status.

13 Ibid., p. 30-33.

Physicians expressed the opinion that the first right of the patient is access to a knowledgeable physician who can identify the patient's needs, who can communicate and recommend treatment options in a timely and useful manner and who can provide proven therapies of known effect and benefit. However, in the case of the catastrophically ill, after all standard therapy has been exhausted, compassionate access still allows the physician something to offer the patient. Whether an experimental drug is effective or not, compassionate access provides the patient with hope, which in turn improves the patient's mental perspective. Bill Cameron, an Ottawa primary care physician and clinical trials investigator, told the Sub-Committee:

Cooperation between players [. . .] can provide hope to the desperately ill through providing promising, if unproven, treatments in advance of licensure in a compassionate manner. This is more than passing a drowning man a straw at which to grasp. Not only does it offer hope to the afflicted, but the act of compassion offers comfort. Those three things - comfort, hope and real help - are all the rights and needs of the desperately ill.(14)

(14) Meeting No. 20, 7 December 1995, p. 8.

Clinical trials also benefit when the investigational drug is provided compassionately. Experience has shown that people will enter clinical trials if that is the only place a drug is available. In some clinical trials, the experimental drug must be tested against a placebo and only half of the volunteers will actually receive the drug. In this situation there are only two possibilities available to the catastrophically-ill individual: stay out of the trial with the certainty of death, or enter the trial with the hope of getting the drug and achieving some benefit. There are a number of negative elements at play here. When one's life is at stake, it cannot be said that the choice to enter the trial was either free or voluntary. The catastrophically-ill person is grasping at a life-line, but that life-line comes with conditions. There is, therefore, the possibility of an imbalance in power, of feelings of coercion and exploitation of the person's predicament. When any of these elements are present, a very strong argument can be made that the clinical trial is not being conducted in an ethical fashion. On the other hand, if the trial has an open compassionate arm, then the individual can make a truly free and uncoerced choice.

In clinical trials where a drug to combat a life-threatening condition is tested against a placebo and where no open compassionate arm is provided, experience has shown that the resulting data may be compromised. When such a trial is the sole source of an experimental drug, many catastrophically-ill people will volunteer but, quite understandably, their primary purpose is "to try to preserve their lives."(15) Dierdre MacLean, a clinical trials counsellor at the Community AIDS Treatment Information Exchange, told the Sub-Committee: "[i]n the real world [. . .] there is no effective, long-term, highly tolerable treatment for HIV infection, and we must recognize that people enter trials seeking treatment."(16) In the clinical trials that tested the effectiveness of AZT against a placebo, some trial participants collected, mixed and then shared the drug in the hope that all collaborators would get the drug 50% of the time. Some had the drug tested and dropped out of the trial when they found out they were receiving the placebo. When an investigational drug is available compassionately, only those individuals who are committed to the trial for altruistic reasons will be enrolled and as a result the quality of trial data will not be compromised.

(15) Meeting No. 3, 1 May 1996, p. 8.
(16) Meeting No. 20, 7 December 1995, p. 12-13.

The third manner by which compassionate access can benefit clinical trials has already been mentioned. In trials with an open arm, the people receiving compassionate access are monitored within a controlled setting and this gathered information, showing a greater number of patient-days safely seen on a medication, may be used in support of a new drug submission (NDS). It is important to note, however, that compassionate access received outside of the controlled structure of a clinical trial, that is to say, by means of the EDRP and dispensed through a physician, does not provide pharmaceutical manufacturers with data of sufficient quality to support a NDS.(17) Further, Christos Tsoukas, Director, Immune Deficiency Treatment Centre, Montreal General Hospital, stated: "emergency release of drugs outside of a defined protocol usually provides little to no information for the individual or his physician."(18)

(17) Ibid., p. 26.
(18) Meeting No. 19, 6 December 1995, p. 38-43.

Compassionate access programs may also benefit pharmaceutical manufacturers. By providing compassionate access, pharmaceutical companies behave as good corporate citizens garnering a positive image and good public relations with the affected community. This action may promote steady sales and profits for the company. Christos Tsoukas described how compassionate access helps a manufacturer establish a market for its product:

In fact, the compassionate release of drugs that have good therapeutic potential provides a mechanism to make physicians familiar with these medications prior to their licensing. Once licensed, the marketing of these drugs becomes simple because the user-physician group has been identified and has become familiar with the clinical use of the medication. It can thus be argued that it is economically important in the long term for a drug company to have an early compassionate release program.(19)

(19) Ibid.

CONCERNS SURROUNDING COMPASSIONATE ACCESS

Round Table participants identified a number of problems associated with compassionate access; however, its potential to slow the drug regulatory process was probably the greatest concern. There was strong concurrence that nothing must interfere with the rapidity of drug development, which brings the best treatment to the most people, and is therefore of paramount importance. The availability of compassionate access may lead to high drop-out rates from trials in progress or it may slow or limit recruitment to controlled trials. Too few participants in a trial statistically compromises the validity of results. Bill Cameron stated that evaluation of the drug zalcitabine was slowed because of widespread access early in its development.(20) Further, Robert Voigt, a Vancouver physician, suggested that the AZT+ddI versus AZT+ddC comparative trial could have been completed in 18 months; however, compassionate access slowed recruitment to such an extent that it took three years to attract a sufficient number of volunteers. Not only did this slow the achievement of knowledge, but some volunteers were on drugs for three years without any evidence of a superior arm.(21) There was considerable agreement that if compassionate access is to occur in parallel to clinical trials then creative solutions must be developed to protect the drug development process; but, it was also stressed that greater flexibility within the drug regulatory process is required in order to respond to the urgent need for drugs to treat immediately life-threatening conditions.

(20) Meeting No. 20, 7 December 1995, p. 9.
(21) Meeting No. 22, 14 December 1995, p. 13.

The media may often prematurely stamp a new drug as "promising" or as a "research breakthrough;" in spite of the fact that there is absolutely no evidence that it is in fact superior to standard therapy. On this point, Robert Voigt stated:

Patients largely make decisions on which drugs to take on emotional grounds, and the new drug around the corner, which will always be the new cure, is always more appealing than the randomized trial they might get onto.(22)

(22) Ibid.

Arn Schilder, Vice-Chair, B.C. People with AIDS, described the current situation of switching between drugs as "drug of the month."(23) The result is that treatments of known benefit and risk are displaced in favour of the unknown benefits and risks of the experimental medication. Unless the patient is failing on standard therapy, this type of compassionate access poses a large risk. In addition, because little is yet known about the effect of multiple drug exposures, it will be increasingly difficult in the future to recruit volunteers who meet trial inclusion criteria. Chaotic and futile selection of drugs today may disqualify a person for a drug and potential benefit tomorrow. There is also the concern that an unknown drug could diminish the effect of a prescribed drug, cause an antagonistic reaction, or cause a drug potentiation (artificially raise blood levels of a drug to the possible point of toxicity).(24)

(23) Meeting No. 22, 14 December 1995, p. 28.
(24) Meeting No. 19, 6 December 1995, p. 38-43.

Christos Tsoukas described some of the problems that can occur when access to an experimental drug precedes a sound understanding of optimum dosage levels. Too much drug may be toxic and cause painful side-effects or, alternatively, low doses in the case of HIV may not suppress the virus and facilitate the appearance of drug-resistant strains. These resistant strains could also be cross resistant to drugs in the same class, including drugs that the patient has not taken yet. This involves both private and societal costs, given the potential for an increase in drug-resistant strains that may be transmitted sexually.(25)

(25) Ibid.

Compassionate access has a number of negative consequences for physicians. A large amount of time is spent discussing new compounds offered under compassionate release, their risks and benefits, to ensure that patients are making true informed consent. The follow-up of patients requires time and effort in terms of surveillance and record keeping. Robert Voigt stated that the administrative load in his practice was so severe that he had to close his office one day a week to attend to paperwork.

I'm alarmed at the increasing amount of data collection being done on behalf of pharmaceutical companies in order to comply with the regulations for the emergency drug release program that is being carried out by primary care physicians. Along with the work of treating patients' medical problems, there is an ever-increasing amount of paperwork involved with the compassionate access protocols.
In the past, physicians would access drugs through compassionate release programs only once or twice a year at most. For physicians caring for people with HIV, it's a daily practice. This is becoming a significant burden and has reached the point where the time spent filling out forms for compassionate access is equal to the time spent caring for individual's medical needs.(26)

(26) Meeting No. 22, 14 December 1995, p. 12.

This time is not covered under provincial health care reimbursement schemes. For physicians who have a large caseload of people with HIV/AIDS, this situation results in decreased income. Representatives of the HIV/AIDS community expressed the concern that physicians will become increasingly less willing to provide compassionate access and will actually avoid accepting people with HIV/AIDS as patients.

For the pharmaceutical industry, the provision of a compassionate access program (creation of an infrastructure to administer the program, drug cost, distribution cost, provision of case records, and data collection) can cost millions of dollars. These costs would not be a major concern to pharmaceutical manufacturers if there was any guarantee that the drug being distributed compassionately would ultimately receive marketing approval. As William Milligan (PMAC) told the Sub-Committee, this is not always the case:

The Pharmaceutical Research Manufacturers of America New Medicines Report, in its 1995 survey, has reported that there are currently over 110 medicines being developed for use in HIV and AIDS, and over 200 cancer medications being developed. Many of these investigational drugs will eventually be approved for treatment, and a great many will not be approved for treatment for a variety of safety and ethical reasons. This raises additional concerns and risks about providing products that may never be approved to physicians and patients, [. . .] If you provide a product through a compassionate release program, there are no guarantees that you're ever going to see the product approved or reimbursed in Canada.(27)

(27) Meeting No. 3, 1 May 1996, p. 17.

CONSENSUS ON THE NEED FOR COMPASSIONATE ACCESS

From the briefs, presentations and five days of Round Table discussions, its appears that the provision of compassionate access to investigational therapies can and does have an impact on the drug development and evaluation process in Canada. In spite of this impact, however, not a single Round Table participant suggested that compassionate access programs should be curtailed in any fashion or that attempts to further liberalize the process should be avoided. Quite to the contrary, participants asserted that what was needed were new and creative ways of doing things: new mechanisms of providing compassionate access that impinge less upon drug testing; greater flexibility in drug evaluation and approval so that the needs and rights of the catastrophically ill are not sacrificed for the presently healthy population; and a political will to do something.

PROPOSED MECHANISMS TO COMPEL OR ENCOURAGE COMPASSIONATE ACCESS TO INVESTIGATIONAL THERAPIES

A number of suggestions were made by Round Table participants on how compassionate access might be encouraged or, alternatively, made mandatory through amendments to existing legislation. In particular, it was suggested that more liberalized access to investigational drugs might be achieved if a statement of intention with respect to compassionate access to an experimental agent was included as an integral part of an investigational new drug (IND) submission.

A. Investigational New Drug Submissions

The pharmokinetic potential of a drug is first assessed in animals or in vitro tests. If it appears that an agent is not highly toxic and may be effective against a human disease, it is ready to enter the clinical trials phase of testing in humans. At this point, the pharmaceutical company develops a clinical trials plan ( a protocol) that outlines the scientific procedure that will be applied for human testing of the drug. These protocols must comply with national and international ethical standards that have been established for experiments involving human test subjects. If a pharmaceutical company conducts clinical trials outside of Canada, the Drugs Directorate, HPB, has no involvement. If, on the other hand, a pharmaceutical company proposes to conduct clinical trials in Canada, then it must act in accordance with the Food and Drugs Act which states that no clinical research may be conducted without the permission of the HPB, Health Canada.

As of 1 November 1995, a two-phase system of interaction with the pharmaceutical industry was established, consisting of a pre-IND phase and an IND submission and review stage. The pre-IND phase requires the company to submit an information package, which is a brief summary of the data and development plans the company has for the drug in question. This may be followed by meetings between the company and HPB to identify and resolve any problems before the company embarks upon its IND submission. This pre-IND stage benefits the company in that problems are identified "up front" prior to the investment of money and energy. Finally, HPB reviews the IND submission. If objections to the IND are raised then the company must amend its clinical trials protocol before approval will be granted. Alternatively, the company could withdraw its submission and attempt to conduct its clinical trials in another country.

B. Evidence of Demonstrated Good Faith

As a means of encouragement, Susan Conrad suggested that one "option would be to require evidence of a demonstrated good faith effort to provide the option of compassionate access as a prerequisite to filing a formal licensing petition."(28) This evidence of demonstrated good faith could be required at the pre-IND submission stage and be included in the company's initial information package to the Drugs Directorate. Such a requirement would necessitate action on the part of the pharmaceutical company in that the manufacturer would have to address the advantages and disadvantages of compassionate access for a specific drug, and the action of examining this issue might encourage a policy decision in favour of expanded access.

(28) Meeting No. 19, 6 December 1995, p. 10-11.

C. Linking Compassionate Access to the Approval of IND Submissions

As a means of encouraging compassionate access, AIDS Action Now! suggested that the approval of IND submissions be linked to the inclusion of a statement of intention by the pharmaceutical manufacturer with respect to the provision of the investigational drug during clinical trials. Lise Pinault, Co-ordinator, Coalition des organismes communautaires québécois de lutte contre le sida (COCQ-SIDA), described how this mechanism could be put into effect. As part of the IND submission, the statement of intention would indicate:

(29) Ibid., p. 3-5.

Health Canada would then assess the fairness and reasonableness of the statement of intent and would be allowed to require further information (on a confidential basis) from the company, including:

In the event Health Canada is not satisfied because the company has not provided sufficient information or because the company does not intend to provide reasonable compassionate access to its experimental drug, then it should refuse approval of the IND.(30)

(30) Ibid.

In making its decision, Health Canada should take into account all relevant factors including:

If during the course of the clinical trial there is a change in the demand for the experimental agent, Health Canada should request that the company file a revised statement of intention for consideration.(31)

(31) Ibid.

The proposal by AIDS Action Now! and COCQ-SIDA, that approval of an IND submission be linked to a "reasonable and fair" statement of compassionate access intent, appears to be a logical means of encouraging pharmaceutical manufacturers to start thinking about the provision of compassionate access programs early in the planning stage of clinical trials.

D. The Ethical Imperative for Linking Statements of Compassionate Access Intent to IND Approval

The Medical Research Council (MRC), in its Guidelines on Research Involving Human Subjects, 1987, has stated: "[i]n the face of an evolution of ethical values and the recognition of cases of abuse, public policy has developed ethical codes to protect subjects of research." MRC goes on to explain that these ethical codes are framed in guidelines rather than legislation, because "[g]uidelines can accommodate more easily than law the shifting social evaluations that affect research [. . .]"(32)

(32) Medical Research Council of Canada, Guidelines on Research Involving Human Subjects, 1987, Ministry of Supply and Services Canada, Ottawa, 1987, 65 p.

The Sub-Committee finds itself at a juncture of shifting societal values and expectations with respect to the conduct of clinical trials that test experimental therapies to combat life-threatening conditions in human populations that are terminally ill. Previously, it was socially and ethically acceptable to run double-blind clinical trials that tested, for example, a new cancer drug against a placebo in a population of terminally-ill cancer patients. The emergence of AIDS and the establishment of treatment activist groups, that operate in a co-ordinated and united fashion to fight for their right to the best medical treatment possible, has changed the expectations and demands of not only people with HIV, but all people who are facing a catastrophic illness.

As noted earlier in this report, when participation in a clinical trial constitutes the sole means by which a person may attempt to save their life, then the trial is potentially tainted by an imbalance of power, feelings of coercion, and possible exploitation of the person's predicament. Indeed, MRC's Guidelines on Research Involving Human Subjects, 1987, plus its proposed replacement document the Code of Conduct for Research Involving Humans, give substance to the claim that such trials are unethical. On the issue of consent, the MRC Guidelines state:

The cardinal principle of research on human subjects is that, to the extent that it is possible, a subject's involvement should be informed and voluntary [. . .]
The invitation to a prospective research subject must be made in a way that allows the individual freedom of choice. Sufficient time to reflect is important. It need scarcely be said that undue influence must not be employed [. . .]
The law recognizes unequal relationships as inherently suspect. In such relationships, the law presumes that any agreement between a weaker and stronger party, from which the stronger party gains unusual advantage, is tainted.(33)

(33) Medical Research Council of Canada (1987).

In 1994, the MRC, the Natural Sciences and Engineering Research Council and the Social Sciences and Humanities Research Council formed a tri-council working group to develop common guidelines for the ethical conduct of research involving human subjects. The result of this work, the Code of Conduct for Research Involving Humans, is expected to replace the MRC Guidelines early in 1997. If anything, the new Code describes even more explicitly the conditions that would render the conduct of a clinical trial unethical. The Code embraces the principle of justice as described in the International Ethical Guidelines for Biomedical Research Involving Human Subjects, 1993, which in part states:

"Vulnerability" refers to a substantial incapacity to protect one's own interest owing to such impediments as lack of capability to give informed consent, lack of alternative means of obtaining medical care or other expensive necessities, [. . .] special provisions must be made for the protection of the rights and welfare of vulnerable people.(34)

(34) Tri-Council Working Group, Code of Conduct for Research Involving Humans, Ministry of Supply and Services Canada, Ottawa, March 1996, section 2, p. 3.

Article 12.1 of the Code sets the principle that "[r]esearch that exploits any person or group is unacceptable;"(35) and on the issue of "free and informed consent" the Code states:

(35) Ibid., section 12, p. 1.

Free consent is uncoerced consent. While coercion usually involves force or the threat of force, there can be coercive offers of benefits, especially where the benefits are essential to the well-being of the subject. For instance, this occurs where essential medical services are made conditional on research participation [. . .] As a general rule, the greater the imbalance of power between research population and the researcher or the institution sponsoring or permitting such research, the more care should be taken in making sure consent is genuinely free and uncoerced [. . .](36)

(36) Ibid., section 2, p. 8.

Based on the MRC Guidelines and the Code of Conduct for Research Involving Humans, it could be concluded that any clinical trial testing an investigational therapy to treat a life-threatening illness (37) in a terminally-ill population, in the absence of either a compassionate access program to that therapy or a fair and reasonable explanation why such a program cannot be offered, is unethical; and as such, the Health Protection Branch should not approve the investigational new drug submission related to that clinical trial.

(37) This concept of a life-threatening illness includes all opportunistic infections that might result in the premature death of a patient due to the weakened and susceptible condition caused by any primary life-threatening illness such as cancer, emphysema, heart disease, HIV disease, etc.

To determine if the protocol of a clinical trial is ethical in nature, it will be necessary for HPB to require the inclusion, in pre-IND submissions and IND submissions, of a statement of the pharmaceutical manufacturer's intention for the compassionate provision of the investigational therapy.

Recommendation No. 1

The Sub-Committee recommends that the Governor in Council make whatever changes are necessary to the regulations of the Food and Drugs Act in order to require that pre-investigational new drug submissions and investigational new drug submissions include a statement of the pharmaceutical manufacturer's intention with respect to the compassionate provision of the investigational agent(s).

The Sub-Committee recognizes that there will be situations that preclude the immediate ability of a pharmaceutical manufacturer to provide a compassionate access program; further, situations may change, such that a drug not available at the beginning of a clinical trial phase may be available later, or a compassionate access program may be expanded as the manufacturer is able to scale-up production. Further demand for the therapy may also change depending upon trial results that show a therapy to be more or less toxic, more or less effective. Accordingly, there must be flexibility built into the decision-making process that determines whether the level of compassionate access offered by a company is or is not fair and reasonable. To ensure that decision-making does not appear to be arbitrary, it will be necessary for stakeholders to agree upon a set of criteria against which the fairness and reasonableness of an offer of compassionate access is judged.

Recommendation No. 2

The Sub-Committee recommends that Health Canada, in co-operation with representatives of the Pharmaceutical Manufacturers Association of Canada and treatment activist groups, develop compassionate access guidelines. These guidelines are to include, but not necessarily be limited to, criteria to judge whether a pharmaceutical manufacturer's offer of compassionate access to an investigational therapy is fair and reasonable; and provisions to accommodate the flexible nature of consumer demand and the availability of an investigational therapy. These guidelines should be developed in all due haste and be available for decision-making purposes no later than 1 June 1997.

E. Compelling Compassionate Access

The foregoing recommendations will assist in the provision of compassionate access in those instances where a pharmaceutical company is conducting clinical trials in Canada; however, they will have no effect when clinical trials are conducted outside of Canada. AIDS Action Now! addressed this issue and proposed two possible actions by government:

There are many more studies going on in the United States, and often they don't come to Canada at all in clinical trials [. . .] The ultimate powers you have there are to revoke the patent or take away the marketing rights for another product that the company sells in Canada.(38)

(38) Meeting No. 6, 28 March 1995, p. 51.

The Sub-Committee has considered these two possibilities and found them to be unworkable. Details of this consideration are provided in Appendix III.

The Sub-Committee feels that other options should be pursed; most specifically, the avenues of co-operation and reciprocal partnerships. During the Round Table sessions, the Sub-Committee heard a number of reasons why pharmaceutical companies should be expected to provide compassionate access to Canadian patients. Arn Schilder (B.C. People with AIDS) stated:

Our position is that people living with HIV and AIDS contribute [. . .] a profound investment in the pharmaceutical industry through their participation. Without the collaboration of the consumer group, the pharmaceutical company would be unable to effectively carry out their research. If somebody is catastrophically ill, they should have access to any therapy they believe could benefit them, free of charge.(39)

(39) Meeting No. 21, 13 December 1995, p. 14.

Derek Jones (NCBHR) provided another point of view:

Drug research involves a further partnership with the Canadian government and public. Drug companies take advantage of the favourable tax and financial climate paid for by the taxpayer.
Reciprocity and equity suggest that companies be made to understand that open label supply of experimental drugs in conformity with the policy and ethics is part of doing business in Canada.(40)

(40) Ibid., p. 20.

It could be argued that this obligation is really only operative when the pharmaceutical manufacturer is conducting clinical trials in Canada. Does the manufacturer have a similar obligation even when the company is not conducting trials in Canada? A statement by Donald Zarowny of the Canadian HIV Trials Network, would indicate that this is indeed the case:

The pharmaceutical industry is an essential partner in the health care process. Its role is to develop new drugs and distribute them. Companies make money doing this and return some of it to the drug discovery and development process. We acknowledge their role in our society by providing the inventor of the drug with a period of protection by issuing patents. Since we accord them a defined role and specific benefits, I believe it is ethical to expect them to participate in the resolution of the issues around compassionate access.(41)

(41) Ibid., p. 27.

The generous provision of compassionate access, particularly in the absence of clinical trails, is a benevolent act that could potentially place a pharmaceutical manufacturer in financial jeopardy. If, for example, a manufacturer is providing an experimental therapy free of charge to all 1,000 people in a country suffering a rare form of cancer, then what motivation is there for the drug regulatory agency of that country to provide a timely evaluation of the drug when it is already readily available? Accordingly, just as a co-operative test population, patent protection and a favourable tax and investment climate obligates a pharmaceutical manufacturer to provide compassionate access, it can be argued that the provision of compassionate access, particularly when done in the absence of clinical trials, should encourage the government to conduct a speedy evaluation of the drug in question.

Recommendation No. 3

When a pharmaceutical manufacturer, in the absence of a clinical trial in Canada, establishes a compassionate access program to provide Canadian patients with an experimental therapy, the Sub-Committee recommends that the Drugs Directorate of Health Canada conduct the evaluation of the new drug submission for that therapy as expeditiously as possible.

F. Reciprocal Requirement to Justify a Refusal for Compassionate Access

Susan Conrad suggested that another mechanism that could be used to encourage pharmaceutical manufacturers to provide compassionate access to investigational therapies would be to amend Section C.08.010 of the Food and Drugs Act to make pharmaceutical companies accountable to the federal government for a refusal of compassionate access. In the instance where a pharmaceutical company wishes to sell a new experimental drug to qualified investigators but this transaction is prohibited by Health Canada, Section C.08.009 of the Food and Drug Act regulations provides the pharmaceutical company with the right to require the Minister to provide the manufacturer with the reasons for the decision; further, this section also allows the manufacturer to require the Minister to refer this matter to a newly appointed New Drug Committee.

The following Section, C.08.010, sets out the regulations for the operation of the EDRP. Specifically, it allows the Drugs Directorate to authorize the release of a drug, not approved for sale in Canada, by a pharmaceutical company for the emergency treatment of a patient. Although the sale of the drug may have Health Canada authorization, the pharmaceutical company is not required to comply and it is under no legal obligation to provide an explanation to Health Canada, the patient or physician for its refusal. Susan Conrad argued that "[i]t should not constitute undue hardship to ask that manufacturers be required to meet the same onus as the federal government in the context of justifying a refusal to consider the option of compassionate access."(42) Accordingly, section C.08.010 could be amended to contain provisions similar to those in section C.08.009, except in this case the regulations would provide Health Canada the authority to require pharmaceutical manufacturers to account for a refusal to provide compassionate access.

(42) Meeting No. 19, 6 December 1995, p. 10.

Recommendation No. 4

The Sub-Committee recommends that the Governor in Council amend the regulations of the Food and Drugs Act that pertain to the Emergency Drug Release Program to give Health Canada the authority to require pharmaceutical manufacturers to account for a refusal to provide compassionate access to a therapy not approved for sale in Canada.

ETHICAL aspects

A. Overarching Considerations

The five National Round Table sessions were characterized by a high level of agreement. Indeed, there was no stated disagreement to the concept of a catastrophic right. It was pointed out, however, that this right is only operational when the physician agrees with the choice of therapy; that is to say, an individual's right to an unmarketed therapy does not override the physician's equal right "to do no harm." This ethical obligation, to do no harm, goes to the heart of the question of when it becomes appropriate to consider an unproven therapy as a possible candidate for compassionate access. Although a few participants held that there should be no risk limitations on access to experimental drugs, the majority opinion held that release of a therapy should only be considered when "an acceptable balance between efficacy and toxicity" has been demonstrated.(43) Further, it was firmly held that the rights of those with catastrophic illness have defined limits. On this point, Neill Iscoe of the Canadian Cancer Society, stated that "society believes in the right to self-determination but does not believe this right permits one person to exercise that right to the disadvantage or detriment of another individual."(44) Specifically, it was felt that compassionate access, while necessary, should not be allowed to impede rapid drug development.

(43) Meeting No. 21, 13 December 1995, p. 15.
(44) Ibid., p. 21.

It was argued that when we recognize that someone has a catastrophic right to drugs, such recognition imposes corresponding duties on those who have drugs or manufacture them. "The pharmaceutical industry has the moral obligation on humanitarian grounds to respond by providing access to an experimental drug."(45) There was also support for the position that, as long as a sufficient supply of drug is available, then it should be supplied free. Within the context of clinical trials and open label compassionate access programs, where data is collected and used in support of a drug licensing application, there was no question that the therapeutic agent should be provided free. It was also strongly held that compassionate access through the EDRP should also be free. Neill Iscoe told the Sub-Committee that the Canadian Cancer Society "does not believe people should be charged for therapies that have not received a notice of compliance."(46)

(45) Ibid., p. 14.
(46) Ibid., p. 21.

B. Who Should Receive Compassionate Access?

One possible definition for catastrophic illness is that it is a medical condition that has ceased to respond in a positive manner to standard therapy and irreversible physical deterioration can be expected to ensue. Individuals in this state are recognized as having the right to compassionate access. Disease is a continuum, however, and there are many people who have a terminal condition but are not catastrophically ill. People may live for ten or more years after being infected with HIV, and they are considered to have developed AIDS only after their CD4 count has dropped to below 50 and/or they have had one or more AIDS-defining opportunistic infections. Similarly, there are many relatively healthy people with cancer who know they are progressing toward death. Time is of the essence for these people, and they too want access to drugs that may be the "magic bullet" for their condition. During the five Round Table sessions, a general eligibility hierarchy for compassionate access became apparent with priority being given to the catastrophically ill, followed by those with a terminal condition who:

The compassionate provision of drugs to this last group of individuals is the crux of the compassionate access problem. The success of rapid, scientifically-rigorous clinical trials depends upon the co-operation of candidates that meet inclusion criteria; however, if they feel coerced, they make poor test subjects. This problem has started to become less of a concern in clinical trials testing anti-HIV agents, because there are now a number of approved drugs that are used as standard therapy against HIV. Increasingly, in these trials the new experimental anti-HIV agent is tested against standard therapy, not a placebo. Accordingly, a potential candidate, who has not failed standard therapy, would not necessarily improve his/her situation by opting for compassionate access to the unknown therapy. In spite of logic, there is a strong lure for the new exciting, "promising" drug.

Round Table participants put forward a few ideas on how, in the presence of a compassionate access program, greater participation in clinical trials might be achieved. John Ruedy, Faculty of Medicine, Dalhousie University, suggested that it would be possible to "devise a quota of compassionate release related to enrolment so that there is a limit to the number of compassionate releases until enrolment is full in the trial."(47) It was also pointed out that, with the exception of clinical trials related to HIV, it is common practice to pay test participants an honorarium that covers expenses, such as travel and child care. Given that a large number of HIV-positive people are surviving on social assistance, the offer of some level of remuneration might encourage participation in clinical trials. A few Round Table participants suggested that greater co-operation might be achieved if the experimental drug was supplied free of charge to everyone but those who qualified for clinical trials. Others felt this suggestion was unethical. On this issue Neill Iscoe stated:

(47) Ibid., p. 25.

[. . .] the idea of charging patients choosing not to enter the trial [. . .] raises the spectre of two classes of patients: those with the means to buy the drug and those who do not. In the context of people made vulnerable by life-threatening illness, this distinction is particularly odious and, at a minimum, highly coercive to those less affluent, forcing them to consider participating in a trial, [is] a less than truly voluntary process.(48)

(48) Meeting No. 3, 1 May 1996, p. 3.

C. National Ethical Standards and the Functioning of Autonomous Research Ethics Boards

The National Council on Bioethics in Human Research (NCBHR) was established in 1988. Although NCBHR carries out a number of functions, its principal responsibility is implementation of MRC's Guidelines on Research Involving Human Subjects, 1987; and it does so by providing information and advice on national research ethics issues to the 125, or so, research ethics boards (REBs) at hospitals and research institutions across Canada.

At the Round Table, it was emphasized that there is a clear distinction between treatment and research; compassionate access to an investigational drug being a treatment issue, while participation in a clinical trial is research. NCBHR pointed out that local REBs may strictly limit their examination of a clinical trial to whether the protocol meets the ethical standards set by national and international agencies for the ethical treatment of human research subjects. This opinion was echoed by Michael Levy, PMAC, who stated that REBs "are often loath to adjudicate on the ethics of open-labelled trials or compassionate access [. . .]"(49)

(49) Meeting No. 21, 13 December 1995, p. 32.

PMAC representatives, physicians and clinicians expressed the concern that the action of autonomous REBs, making case-by-case ethical determinations based on their interpretation of MRC's Guidelines, has the potential of creating ethical environments that may differ from region to region. This problem is exacerbated by the fact that there have been no Canadian directives that regulate the professional composition of REBs. PMAC representatives asserted that if we rely on the REBs to provide a check and balance in the system, then it is important to ensure that there is some consistency across the country. William Milligan asserted that "[t]he government must clearly define the composition and mandate of REBs and establish a mandate for the NCBHR [. . .]"(50)

(50) Meeting No. 3, 1 May 1996, p. 16.

This concern, however, may have been largely remedied by the recent release of the tri-council Code of Conduct for Research Involving Humans. As previously mentioned, the Code is the proposed replacement document for the MRC Guidelines. Unlike the Guidelines, which are more open to interpretation, the Code is a detailed document that provides principles, descriptions of responsibilities, prescriptive procedures, and it specifically states national standards for ethical research. Of particular relevance to this study, "[t]he Code defines quite rigorously [. . .] the minimum standards for the composition and operating procedures of REBs."(51) Stemming from the many demands by Round Table participants for a more harmonized approach to research ethics in Canada, the Sub-Committee feels that the NCBHR mandate needs to be strengthened.

(51) Tri-Council Working Group, March 1996, p. ix.

Recommendation No. 5

The Sub-Committee recommends that Health Canada review and strengthen the mandate of the National Council on Bioethics in Human Research to clearly establish the objective of promoting harmonized national standards of ethics in research involving humans.

D. Informed Consent Forms

For a clinical trial to be conducted in an ethical manner, the researchers conducting the trial must first fully inform the research subjects about all aspects of the trial. Both the MRC Guidelines and the Code give prescriptive details on how this information is to be presented. While the presentation of information does not appear to be a problem, considerable discontent was expressed by physicians, patients and treatment activists about the chaotic array of poor quality informed consent forms. Patients and physicians want standardized informed consent forms that are written in simple language; however, the final content of these forms is decided upon by individual REBs. It would appear this problem was largely due to the fact that no individual or agency in authority had ever taken responsibility for the development and dissemination of a standard informed consent form for use in clinical trials in Canada. The Sub-Committee is pleased to note that the Tri-Council Working Group has published, as Appendix D of the Code of Conduct for Research Involving Humans, two sample consent forms; one for competent research subjects and the other for third party authorization. These forms have been designed specifically for use in clinical trials; however, it should be expected that they will also become used in open-label clinical trials and when patients obtain an investigational therapy through the EDRP.

THE ROLE OF HEALTH CANADA IN MAKING NEW THERAPIES AVAILABLE

Representatives from the Drugs Directorate of Health Canada described in detail the operation of the EDRP, the Special Access Program (SAP) which is proposed to replace the EDRP, how drugs are developed in Canada and the Canadian drug regulatory process. This information appears in appendices I and II.

A. Special Access Program

Health Canada found that there are a number of problems with the EDRP and they wish to replace it with the SAP. In August 1995, the proposed plan was distributed to stakeholders for comment. Health Canada officials stated that the National Round Table discussions and comments would be taken into consideration in developing the final program.

The SAP has a number of advantages. It would remove government from emergency situations where its presence could slow access to a needed therapy. For the manufacturer, patient and physician, and particularly for the Drugs Directorate, this proposed program should be less labour and time intensive. Since the manufacturer would be required to prepare a drug information package for approval by Health Canada, better and more accurate information should be available for decision-making by government and for risk-benefit decisions by patient and physician. Round Table participants identified a number of problems with the proposed SAP and suggestions were made to strengthen the program.

PMAC believes that the proposed program is a significant improvement for both industry and the Drugs Directorate, in that significant steps have been taken to streamline the process; however, Michael Levy asserted that the recording and reporting requirements will be onerous for industry, and there is a need to clearly delineate responsibilities among physicians, industry and the Drugs Directorate. The SAP does not provide a provision for the right of a manufacturer to refuse compassionate access on appropriate grounds such as safety reasons, lack of information and lack of drug availability.(52) Sophia Fourie stated that it is essential that the SAP be recognized solely as a legal vehicle for making an unmarketed drug available, and that this action must not be construed as an official approval or sanctioning of the drug in question.(53) It was suggested that SAP guidelines provide clear definitions of such key terms as "emergency" and "suspected serious adverse event," as well as clarification of auditing procedures and record keeping. PMAC felt that, when compassionate access is requested through the SAP, safety aspects must be considered in the context of doing no harm and having certain expectations of what the drug can actually do in life-threatening diseases. Finally, PMAC pointed out that the provision of compassionate access is a large expense for drug manufacturers and, accordingly, it would be appropriate for the SAP to address the issue of manufacturers charging for a drug.(54)

(52) Meeting No. 20, 7 December 1995, p. 13-14.
(53) Ibid.
(54) Ibid.

Physicians noted that the SAP, like the EDRP, mandates the reporting of drug safety data, but it has no provisions or suggestions for how the huge administrative work load it causes will be alleviated. The Sub-Committee heard that for primary care physicians with a large practice of patients receiving experimental drugs, the action of obtaining these therapies through the EDRP causes an immense and unmanageable administrative paper load, physicians are not paid for this burden, it acts as a disincentive to treat people with HIV/AIDS, and the submitted data is of questionable quality for the purpose of giving weight to a new drug licensing application. Indeed, on behalf of PMAC, Michael Levy stated: "[w]e strongly disagree that the data gathered is valuable to the manufacturer in seeking a speedy approval for new therapies." According to Jacques Bouchard, the Drugs Directorate only requires the reporting of significant adverse drug effects.

If the data is used to augment a drug approval application, then is this not a research activity and should not the pharmaceutical manufacturer reimburse the physician for his time? Alternatively, if the cause of the problem is an excessive demand for information by Health Canada, then it is essential that new mechanisms be put in place to alleviate the burden.

Finally, it was noted that there is nothing in the SAP to compel or encourage pharmaceutical companies to provide compassionate access; nor is there any provision to require a company to justify its decision. James Kreppner, Board of Directors, Canadian Haemophilia Society, expressed his concerns:

It's one thing to have government go to a drug company and say "Will you make this drug available, because we have someone asking for it," and another thing to have a patient go to a drug company and say "Will you make this drug available because I like it." [. . .] its the EDRP requests that get more serious consideration on the part of drug companies. That shouldn't be surprising, because they know very well that if they refuse it, at least that's something that's noticed by somebody.(55)

(55) Meeting No. 3, 1 May 1996, p. 11.

James Kreppner also pointed out that the SAP, as it now stands, would place the onus for action on the pharmaceutical manufacturer.

With the SAP their easiest response is to say no. If they say no, they don't have to do any further work. If they say yes, then they have to go to Health Canada and provide the information on the drug . . . They have to notify the Drugs Director[ate] within 48 hours.(56)

(56) Ibid.

These sentiments were echoed by Maggie Atkinson, Co-Chair, AIDS Action Now!:

With respect to compassionate access, I think there needs to be an improvement of the EDRP or the SAP system in order to expedite access. [. . .] I think it's important to have the government have some kind of role in there in making the request. Even with EDRP, the companies still. . . ignore individuals.(57)

57 Ibid., p. 13-14.

For Health Canada, the major advantage of the SAP would be the removal of the Drugs Directorate from case-by-case involvement in compassionate access; but for those seeking a drug, this represents decreased leverage with the pharmaceutical manufacturer. It therefore appears that some form of a redress mechanism is needed in the SAP. Officials from the Drugs Directorate stated they would take into account the comments and discussions provided at the National Round Table in their development of the SAP. Accordingly, the Sub-Committee trusts that Health Canada will consider and act upon the concerns expressed by patients, physicians and the pharmaceutical industry as they put together a new program to replace the EDRP.

B. Canadian Drug Regulatory Process

Many times during the National Round Table, it was stated that rapid drug development, within the structure of scientifically-rigorous, controlled clinical trials, should be the primary goal of all those who work to control disease. In addition, it was often stated that Health Canada must adopt measures to speed the regulatory process. Proposed actions to speed the process included: allocate more resources for drug evaluation; work toward harmonized international standards for drug evaluation; greater use of external reviewers; undertake joint reviews with the United States Food and Drug Administration (FDA); institute the United States system of rolling reviews; and consider the institution of a conditional approval system.

The Drugs Directorate informed the Round Table that their process has undergone streamlining and their average 17-month evaluation period is now considered to be quite good. Also, their 180-day accelerated review process ("fast-track") for drugs intended for the treatment of immediately life-threatening and other serious disease is very fast, as evidenced by the approval of 3TC in under five months. It was noted that the Canadian group responsible for drug evaluation is a fraction the size of that at the FDA in the United States. In order for this small group to evaluate a drug in a timely fashion, the Drugs Directorate requires that pharmaceutical manufacturers present their NDS in a format that tends to be unique in the world. PMAC-member companies first prepare a standard NDS submission for the United States, then they must reformat the document and prepare comprehensive, cross-referenced summaries, an exercise that can take up to four months. Once this is done, however, a small number of people can evaluate the submission in a reasonable length of time. The Canadian system therefore has the advantage of efficiency.

Although the speed of Canadian drug evaluation has improved, at the final Round Table session the Sub-Committee heard that our drug evaluation system is again lagging behind that of the United States. In the United States, the FDA has introduced an accelerated conditional approval process for drugs for life-threatening illnesses which has resulted in approvals in 90 days or less; for example, 90 days for saquinavir, 72 days for ritonavir, and only 42 days for crixivan.(58) Meanwhile in Canada, a 180-day fast-track evaluation remains the fastest route to a notice of compliance.

(58) AIDS Action Now!, Brief, 1 May 1996, 5 p.

The concept of conditional approval holds that investigational therapies would receive marketing approval if phase I and II clinical trials had indicated an acceptable degree of safety and efficacy. These drugs would then be prescribed and sold to those people in a life-threatening situation. Post-marketing surveillance would be conducted and marketing approval withdrawn in the event that reported adverse reactions indicated a poor risk-benefit. This system has the obvious disadvantage of increased risk; however, on the positive side, those in a life-threatening situation get the earliest possible access to a drug and the pharmaceutical company is reimbursed for its product. Representatives from the Drugs Directorate stated that they are currently drafting a proposal for a conditional licensing framework, and it should be soon ready for consideration.

The Sub-Committee notes that the Parliamentary Ad Hoc Committee on AIDS recommended that Health Canada develop a Canadian system for the conditional approval of drugs to treat life-threatening illnesses:

The Committee further recommends that, in line with the limited recognition of catastrophic rights that is now implicit in the drug approval process, the Department of National Health and Welfare give consideration to the formal adoption of a system of conditional approvals for drugs designed to treat life-threatening illnesses, after basic safety and efficacy have been established, which would generally permit the prescribing of such drugs by physicians while further evaluations are being conducted.(59)

(59) Parliamentary Ad Hoc Committee on AIDS, Confronting a Crisis, June 1990, p. 30-37.

Recommendation No. 6

The Sub-Committee recommends that Health Canada move with all due haste to put into effect, by no later than 1 June 1997, a conditional approval process for drugs designed to treat life-threatening illnesses.

Canada's slower drug evaluation process causes a number of problems, particularly when the United States approves a drug to fight a life-threatening illness months ahead of Canada. This situation creates two classes of people with HIV/AIDS, those who can afford to travel to the United States and pay $800 to $1,000 a month for a drug such as ritonavir, and the poor, who must wait for both Health Canada to approve the drug, and for their province to add it to the provincial formulary so that the cost will be covered by social assistance. Maggie Atkinson asserts that many poor people die waiting.(60)

(60) AIDS Action Now!, Brief, 1 May 1996, 5 p.

This situation also raises the question of why Canada continues with a national drug evaluation process that appears to do nothing more than duplicate reviews being carried on in other countries. We know people with life-threatening illnesses travel to the United States to legally purchase and import drugs in an effort to save their lives; further, Canadians are not physiologically different from Americans. So what benefit is achieved in Canada by restricting the sale of drugs, evaluated as safe and efficacious and approved in the United States, until Health Canada has also evaluated them? Jacques Bouchard stated that many countries in the world do not carry out their own drug evaluations; rather, they give market approval to a new therapeutic agent after the FDA has evaluated and approved it.(61) Health Canada conducts drug evaluations because it is legally mandated by the Food and Drugs Act; and as Jacques Bouchard pointed out: "[y]ou, as legislators, will have to decide whether Canada is to remain a distinct entity in the area of drug regulation."(62)

(61) Meeting No. 22, 14 December 1995, p. 35.
(62) Ibid.

Repeatedly during the National Round Table, various participants suggested that Canada should be involved in joint reviews with the United States. This proposal is not new; it was discussed in a published Health Canada document,(63) and Denis Gagnon suggested it in his 1992 Review of the Canadian Drug Approval System. Michael O'Shaughnessy, Director, B.C. Centre for Excellence in HIV/AIDS, told the Sub-Committee that he had attended tripartite meetings involving Canada, the United States and Great Britain where the concept of joint reviews was freely discussed and endorsed by Canada; and, Canada did conduct one joint review of the anti-HIV drug ddI with the FDA. Michael O'Shaughnessy asked: "If you say to the United States government and to Great Britain, `This is a good thing to do; we have a model that worked,' then what happened that it never happened again?"(64) Michael Levy, PMAC, discussed the European situation:

(63) E. Somers, et al., "Drug Regulation - The Canadian Approach," Regulatory Toxicology and Pharmacology, Vol. 12, 1990, p. 216.
(64) Meeting No. 22, 14 December 1995, p. 35.

[. . .] there's a very recent model in the European Community where each of those countries, which are more similar in size to Canada than the United States, had their own independent review agencies. They were all reviewing the same dossiers, the same huge packages of information, eventually coming up with very similar answers. They agreed that this was inefficient. They set up a joint committee that governs all of the EC states.(65)

(65) Ibid., p. 36.

As was repeatedly stated by PMAC representatives: "The best access to new drugs is speedy and efficient approval." To achieve this objective, some National Round Table participants suggested that more funds be allocated to the Drugs Directorate. The Sub-Committee does not endorse this suggestion as the net result would be more money spent on duplicating a process already accomplished by the FDA. Nor does the Sub-Committee recommend that Canada cease to evaluate the safety and efficacy of new therapies, for as a developed and relatively rich country, the Sub-Committee believes that Canada has an ethical duty to share the costs of drug evaluation. This Sub-Committee did not study Canada's drug regulatory system in the depth necessary to base firm recommendations, but believes the future direction of drug evaluation in Canada is an issue that must be thoroughly examined.

Recommendation No. 7

The Sub-Committee recommends that the Government of Canada study the future direction of drug regulation in Canada. This study should investigate, but not necessarily be limited to, the cost-benefits of the present system, the advisability of phasing out the Canadian system, the efficiency and effectiveness of the new drug evaluation system in the European Community, and the possibility of applying this model to NAFTA partners.

LIABILITY

Under the EDRP, Health Canada may authorize a pharmaceutical company to release an experimental therapy. The EDRP supplies the legal basis for the release of a drug, however, this authorization is not based on any assessment of safety, risk or possible clinical benefit. The government makes no recommendations and accordingly does not carry liability. Indeed, legal counsel for Health Canada, Mario Simard, indicated that there was no known incidence where legal action was ever taken against the government because of authorized compassionate release of an experimental therapy.(66) On the other hand, the Round Table heard that the manufacturer is liable for whatever damage its products might cause, and this is the reason why the decision to release or not release a drug is left to the manufacturer. The patient always has the right to sue the manufacturer, the physician or the institution where the drug was acquired.

(66) Meeting No. 21, 13 December 1995, p. 2-4.

Mario Simard felt that government liability would change in the event legislation was enacted to compel pharmaceutical companies to distribute an investigational drug.(67) For example, it was considered likely that the government would be held liable if a company was compelled to release a drug against its better judgement, and the recipient was harmed. The reverse could also occur; that is, the pharmaceutical company might refuse to release the drug and in the absence of the drug the individual's condition worsens, in which case the government might be held liable for not enforcing an order of release. Mario Simard also stressed that compelling a company to provide a drug under compassionate release would require amending the Food and Drugs Act and that such a requirement would be contrary to the objectives of the Act. The Food and Drugs Act is linked to the criminal power of the federal Parliament and its purpose is to prohibit the sale or marketing of dangerous products and to regulate the distribution of these products.(68)

(67) Ibid., p. 7-8.
(68) Ibid.

PMAC representatives and many physicians and clinicians expressed concerns about being held liable for the possible negative consequences that might arise from compassionate release of an experimental drug. In spite of these concerns, the Round Table was not provided with any evidence of legal action taken against physicians, clinicians or PMAC-member companies. Although the potential undoubtedly exists, it appears that compassionate access very seldom results in legal action. This would indicate that the present system of informed consent is working fairly well to indemnify those who provide compassionate access.

PMAC noted that national and international guidelines for the ethical conduct of research involving human subjects requires the disclosure of potential risks and benefits in order to allow the patient to make an informed decision on exposure to a drug. Today, however, there is greater and greater pressure from physicians and patients to make drugs available before even the most basic information, such as dose levels, is known. Should the government facilitate this shift to earlier release, then the government must explore new options that clearly delineate legal liability. The Round Table was reminded that in exploring new options, the catastrophically ill must not be forgotten for they deserve protection against both potential harm and exaggerated claims.

RESPONSIBILITY

Participants at the Round Table sessions made it clear that they look to government to take leadership in the development and establishment of national guidelines to affect a standard of compassionate access that is equitable to all catastrophically-ill Canadians. Government also has the responsibility of addressing the peripheral issues; for example, liability concerns, the maintenance of a universal health care system that encompasses compassionate access, the scientific rigour of controlled clinical trials, and an efficient and timely drug regulatory system. Susan Conrad, speaking on behalf of the catastrophically ill, stated:

It is the responsibility of the federal government to fight with all the resources at its disposal so that the people living with catastrophic illness have the right to make their own choices, and the information and resources necessary to carry these choices out. [. . .] What is needed is a commitment to assuming responsibility for trying to find a way.(69)

(69) Meeting No. 19, 6 December 1995, p. 12.

It was also suggested by PMAC representatives that the federal government has an important role to play in co-ordinating the passage of a drug from being available compassionately to available by prescription. William Milligan told the Sub-Committee that pharmaceutical manufacturers are under tremendous pressure from patients, physicians and treatment activists to get compassionate access programs up and running; and that the Drugs Directorate is under pressure to move the drug through the evaluation process as quickly as possible. However, once approved, it may take months before the provincial governments add the drug to provincial formularies so that it is available by prescription and can be paid for by drug insurance plans or by social assistance. As an example of this problem, the anti-HIV drug Hivid (ddC) received a notice of compliance in 1993; but, as of 1 May 1996, the province of Nova Scotia still had not added it to its drug formulary. If a pharmaceutical manufacturer has been supplying the drug compassionately, then there is a moral obligation to keep supplying the drug until it can be obtained by prescription. Accordingly, slow action by a province can act as a strong disincentive for future compassionate access programs.

Michael O'Shaughnessy told the Sub-Committee that the B.C. Centre for Excellence in HIV/AIDS distributes free of charge all anti-retroviral drugs used to treat HIV disease in the province to the more than 2,000 individuals enrolled in the drug treatment program. There were about 300 people in British Columbia receiving 3TC under a compassionate release program; however, after the notice of compliance was granted, the manufacturer informed the Centre that it would continue supplying the drug for only another 30 days. This left government officials scrambling to find additional new funds to cover the cost of 3TC. Michael O'Shaughnessy asserted:

[. . .] the potential impact of the introduction of new drugs on provincial drug programs necessitate that we all must find better ways to work together and communicate with each other, since so many of our initiatives are interdependent.(70)

(70) Meeting No. 22, 14 December 1995, p. 12.

The Sub-Committee recognizes that the addition of new drugs to provincial formularies and the operation of mechanisms, where they exist, to assist in drug payments, are matters of exclusive provincial jurisdiction. On the other hand, the smooth transition of a drug from investigational status to prescription status is a concern to all Canadians.

Recommendation No. 8

The Sub-Committee recommends that the federal Minister of Health propose to the Conference of Ministers of Health the establishment of a consultative mechanism to facilitate the timely adoption of new drugs on provincial formularies.

In Canada, it is the responsibility of the pharmaceutical manufacturer, the physician and the clinical investigator, providing experimental drugs to patients either compassionately or in the trials setting, to conduct themselves in accordance with national and international guidelines.

Many physicians are overburdened by the paperwork associated with compassionate access but are not reimbursed for this service. The Sub-Committee is aware of this problem, and is particularly concerned as it may act as a disincentive for physicians to accept patients that require investigational therapies. However, physician salaries fall within provincial jurisdiction; and it is the responsibility of physicians and their professional associations to negotiate with their respective provincial Ministries of Health.

For the pharmaceutical manufacturer there are a number of additional responsibilities; for example, a fiduciary responsibility, and the responsibilities of assuring product quality and the provision of accurate drug information so that patient consent is indeed informed. Sophia Fourie assured the Sub-Committee that the pharmaceutical industry is aware of its ethical responsibility to its consumers:

Manufacturers have shown, through the consistent implementation of early access programs in Canada, that the provision of expanded access is a priority and a recognized responsibility, and that companies have and will continue to shoulder this responsibility.(71)

(71) Ibid., p. 2.

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