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THE REFORM PARTY
Dissenting Report on 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.
During its initial phase - studying the effectiveness of Canada's National AIDS Strategy - the Sub-Committee heard that one of the most significant concerns for people with AIDS is the issue of access to experimental drugs. The impetus for reviewing it, as acknowledged by the Sub-Committee, came from the HIV/AIDS community and the activism which has become associated with it although other people with life-threatening illnesses have also become interested in reform of this system.(1)

(1) "The emergence of AIDS and the establishment of treatment activist groups that operate in a coordinated 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" (p. 14).

The normal process of drug development, testing, evaluation and approval can take 5 to 10 years, although, in an increasing number of cases, this process is becoming shorter, as illustrated by the approval of 3TC in under five months. Nonetheless the demand is growing for access to drugs by those who are "catastrophically ill" prior to the complete testing and approval of the drugs for use by the general public.

In Canada, there are a number of mechanisms by which people who are catastrophically ill can obtain an investigational drug; "compassionate access" programs (authorized by Health Canada and provided by pharmaceutical companies) are only one alternative. Other alternatives include:

Compassionate access, however, has increasingly been promoted as the most ethical alternative for the greatest number of people as it "provides the greatest hope of obtaining an experimental therapy" (p. 5).

In order to develop an effective compassionate access system, however, there are at least five areas that deserve scrutiny, and more thoroughly than has yet been done: Responsibility, Risks, Rights, Representation and the Regulatory process.

I. RESPONSIBILITY

In order to properly evaluate compassionate access, it is necessary to determine who the stakeholders are and what the nature of their responsibility should be in the compassionate access process. There are five primary stakeholders: those who are critically ill and are, therefore, seeking the compassionate access, the pharmaceutical companies which test and develop the drugs, the government, Canadians in general, who benefit at different times in their lives from the development of drugs, and physicians.

Responsibility has to be taken in several different areas, but those of primary concern are financial and legal questions.

1. Financial Responsibility

The question exists whether compassionate access programs should require patients to pay a fee for the drugs, and thus share some of the financial responsibility. In the present process, the pharmaceutical companies bear the greatest financial responsibility. The Sub-Committee appears to have accepted the idea that it is unethical for those wanting to use compassionate access programs to be required to pay anything for the opportunity. At the same time, its recommendations focus on increasing the availability of compassionate access. To do this, it recommends additional expectations of the pharmaceutical companies without including provisions guaranteeing the fiscal security of these manufacturers.(2)

(2) Recommendations 1, 2 and 4 (pp. 16 and 19).

However, if pharmaceutical companies cannot bear the weight of the financial responsibility placed upon them, they will become increasingly inefficient.

Discussion also revolved around the nature of the government's financial commitment. It was not evident, however, that the government was prepared to invest any sizable amounts of new funds into compassionate access. Its primary role was defined as regulator and enforcer of the proposed regulations governing compassionate access. In this vein, most of those who wanted the liberalization of compassionate access believed that the only way to do this would be to put more pressure on the pharmaceutical companies to make the provision, therefore, requiring greater government involvement in the system, to ensure that the companies honoured their new obligations.

Compassionate access can also impose a great cost on the general public, a cost which needs to be evaluated against the proposed benefits. In terms of cost, the Sub-Committee heard from one physician that "the expenditure of money and other resources on unproven therapies has the potential to deprive other patients from truly beneficial, approved for sale, but expensive treatments."(3)

(3) National Round Table on Compassionate Access to Experimental Therapies, Library of Parliament, p. 7.

Also, "it was argued that the public is subsidizing the drug research and development costs of the pharmaceutical industry."(4) If compassionate access programs cut further into the profits of the pharmaceutical companies, these additional costs will also be passed down to consumers.

(4) Ibid.

The physician also pays a significant cost for compassionate access programs. This cost is likely to increase if compassionate access is expanded. This cost is measured in the time taken to ensure that patients are making "true informed consent," as well as the follow-up of patients in terms of surveillance and record keeping: "a huge amount of data collection and paper work [already] must be carried out by primary care physicians on behalf of pharmaceutical companies in order to comply with Health Canada regulations." This time, noted the physicians, " . . . 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." (p. 10)

"Physicians made it very clear at the round table that this issue must be resolved before efforts are put into effect to liberalize compassionate access."(5) The Sub-Committee did not resolve this situation; nor has it made a formal recommendation for such a resolution.

(5) Ibid., p. 8.

Recommendation 1: The assignment of fiscal responsibility in the compassionate access process must be more carefully assessed, and the assessment must include a thorough economic evaluation by representatives of all the stakeholder groups (e.g. including groups such as the CMA and provincial health authorities):

2. Legal Responsibility

The matter of legal responsibility was raised by the Sub-Committee's report, but it was never resolved. The Sub-Committee chose to proceed with its recommendations for change without making any specific recommendations for assigning legal obligations.

Although it was noted that "the patient always has the right to sue the manufacturer, the physician or the institution where the drug was acquired," (p. 29) the observation that "it appears that compassionate access very seldom results in legal action," appeared to be sufficient rationale for the Sub-Committee to not change the present regulations concerning legal liability. The present situation, it said, "would indicate that the present system of informed consent is working fairly well to indemnify those who provide compassionate access." (p. 30)

Recommendation 2: That the government implement the compassionate access program only when the full legal implications are clear and fully determined.

II. RISKS

The Sub-Committee carefully documented some of the most important risks associated with compassionate access. Notwithstanding these risks, at the beginning of its report (p. 3), the Sub-Committee stressed that access to investigational therapies is a right, one which imposes a duty on others. It noted the view that the present law provides for such a view. Nevertheless, by acknowledging the potential dangers associated with compassionate access, it must be acknowledged that this right should not be assumed indiscriminately.

1. The risk to the drug development process

The greatest risk associated with compassionate access appears to be "its potential to slow the drug regulatory process." (p. 8) The report noted "there was strong concurrence that nothing must interfere with the rapidity of drug development, which brings the best treatment to the most people" (p. 8) (including those who will be catastrophically ill in the future).

The risk to the drug development process associated with compassionate access is at least two-fold - as stated in the Sub-Committee report:

This point is not just academic or theoretical. The Sub-Committee heard testimony providing at least two examples: zalcitabine, which "was slowed because of widespread access early in its development," and "the AZT+ddI versus AZT+ddC comparative trial." This trial took over three years "to attract a sufficient number of volunteers," when experts felt that it could have been completed in only 18 months. (p. 9)

The testimony considered by the Sub-Committee, and included in its report, makes it evident that interference with the drug development process would increase the risk to the stakeholders involved. Pharmaceutical companies face a greater financial and legal risk. Governments may also face financial and legal risks. And those who are critically ill would be at greater risk by having access to investigational therapies at an earlier stage, when their impact on the human body is more unpredictable.

In fact, those who end up bearing the heaviest responsibility for compassionate access will be those who become ill in the future, including those who become catastrophically ill. They will not have access to new drugs to heal them - because those new drugs have not yet been developed.

Other significant risks associated with compassionate access were also raised at the round table meetings.

2. The financial impact on the pharmaceutical industry.

The Sub-Committee noted that even now "the generous provision of compassionate access, particularly in the absence of clinical trials, is a benevolent act that could potentially place a pharmaceutical manufacturer in financial jeopardy." (p. 30)

Irrespective of the lack of specific criticism against the present reputation of the pharmaceutical industry concerning its provision of compassionate access programs, the Sub-Committee made recommendations for change which would increase the burden of responsibility on the pharmaceutical companies.(6)

(6) Recommendations 1, 2 and 4 (pp. 16 and 19).

The Sub-Committee heard that "for the pharmaceutical company, the provision of a compassionate access program can cost millions of dollars." (p. 10) The notion that a government should impose an obligation to provide compassionate access programs irrespective of a company's financial analysis of the value of such a program, and the risk it must undertake, was considered ill-advised.(7)

(7) Ibid.

A proposed solution to this problem, which the Sub-Committee rejected, was to force pharmaceutical companies to provide compassionate access under the threat of having its investigational new drug (IND) submission rejected. (p. 12-14)

One of the concerns expressed about such additional pressure being placed on these manufacturers was that it would encourage these international companies to conduct their trials elsewhere. Due to the reputation Canadian companies have for providing compassionate access programs, this could be counter-productive with the greatest loser being the Canadian public.

3. The risk to the "not yet sick"

The Sub-Committee made it clear that it respected the concerns of those who did not want the critically ill to be side-lined by those who are presently healthy and, therefore, may not be as sensitive as they should be to the needs of the critically ill: "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." (p. 6)

This standard, however, should also be evident from the other side: not permitting the needs of those who are healthy now, but who will likely benefit in the future from today's drug development, to be undermined by an undue emphasis on the critically ill. Preventing drug development due to a pharmaceutical company's refusal to conduct a compassionate access program would do just that. Nonetheless, while not going that far, the Sub-Committee has recommended the development of new guidelines for compassionate access, including "criteria to judge whether a pharmaceutical manufacturer's offer of compassionate access to an investigational therapy is fair and reasonable."(8)

(8) Recommendation 2 (p. 16).

Those who become catastrophically ill in the future would be among those who would be harmfully affected by any impediments to the drug development process, including inappropriate or ill defined criteria which limit the flexibility of the pharmaceutical manufacturers.

4. The legal liability of pharmaceuticals

The Sub-Committee report declared that "today 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." (p. 30) Despite the importance of this observation, it was never answered with a formal recommendation by the Sub-Committee.

The Sub-Committee appeared satisfied with the status quo, arguing that "informed consent" appears to be working sufficiently today. Testimony at the round table, however, disputed this assumption, saying that it was not a sufficient standard for the future. As the Sub-Committee noted, "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." (p. 29) Nevertheless, the Sub-Committee made no recommendations to address the need for increased protection for manufacturers imposed on them by the Sub-Committee's recommendations.

5. The legal liability of the government

Also, no recommendations were made to about the nature of the government's (and hence the tax payers') liability, despite the evidence submitted to the Sub-Committee about the precarious position in which the government could find itself. "Mario Simard [legal counsel for Health Canada] felt that government liability would change in the event legislation was enacted to compel pharmaceutical companies to distribute an investigational drug. . . . 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." (p.30)

The shortsightedness of the Sub-Committee is of greater concern in light of the trend in civil litigation in Canada today. Claims in several sectors of society have risen markedly in the last few years. The Globe and Mail(9) reported six months ago that the cost of municipal claims has risen 530 percent in the past 15 years at Frank Cowan Co., the largest public insurer in Ontario.

(9) May 9, 1996.

Also in Ontario, the pending caseload for civil suits rose from 15,128 cases to 21,497 between 1990/91 and 1994/95.(10)

(10) Ontario, Ministry of the Attorney General, Court Statistics Annual Report 1994/95, p. 9.

The growth in the number of lawyers in Canada since 1985 is also seen as an indication of a greater volume of court activity throughout the country. The number has risen from 45,000 to 63,000 between 1985 and 1995.(11)

(11) Federation of Law Societies of Canada.

Recommendation 3: That the appropriate role of the government in the development process be clearly delineated prior to saddling it (and therefore the taxpayer) with added risks, including legal liability, in the realm of compassionate access.

6. The risk to the catastrophically ill (p. 4-5)

Due to their vulnerability, they are that much more anxious than others to do what they can to alleviate their pain and extend their lives. As a result, as the Sub-Committee heard, many of them have a tendency to make decisions about drug use based primarily on "emotional grounds."(12)

(12) National Round Table on Compassionate Access to Experimental Therapies, Library of Parliament, p. 7.

At least four different problems were identified in this respect. Firstly, the catastrophically ill can jump from drug to drug anxiously looking for the one that will help. Due to the lack of scientific knowledge about multiple drug exposures "chaotic and futile selection of drugs today may disqualify a person for a drug and potential benefit tomorrow." Additionally, multiple drug exposure could increase the level of toxicity in the person's body.

The second problem was identified with the "failure to comply with dosage requirements. Too high a dose could be toxic, and too low a dose may not be sufficient to suppress the virus. The third problem is that although the catastrophically ill "may feel they have nothing to lose and they are willing to take the risk, a bad situation can often be made significantly worse."

The fourth concern is that new drugs with unknown potential are seen as more appealing than present treatment, so with the media's influence "often prematurely stamp[ing] a new drug as `promising' or a `breakthrough in AIDS research,'" the critically ill could be motivated to make a decision that is more destructive than beneficial.

Despite the rights attributed to the catastrophically ill, there seems to be some justification - for their sake - to review and maintain responsible guidelines including limits of their access to investigational therapies if access is deemed likely to put them at greater risk.

Recommendation 4: More input is needed from a cross-section of health care professionals to determine their continued role in aiding the catastrophically ill in making these crucial decisions about the use of compassionate access programs.

None of the risk factors cited by the Sub-Committee were addressed in a meaningful way. Nevertheless the Sub-Committee proceeded with its policy recommendations to liberalize the system on the basis that the critically ill have an increased chance of receiving treatment that can ease their pain and slow down the development of their illness, if not possibly heal them, sooner than if they waited for the process to proceed further. The potential benefits were deemed sufficient to offset the increased risk to the catastrophically ill.

Some people also theorized that the increased access to investigational therapies could improve the process for the financial benefit of the pharmaceutical companies and the health benefit of those who will become ill at a later date. This suggestion, however, was challenged by those who argued that without a controlled arm in the study, the data was meaningless. A summary of the round table submissions noted that "mandatory reporting of adverse drug reactions, outside of controlled trials, was one of the most contentious issues discussed at the round table and the question remains unresolved."(13)

(13) Ibid., p. 9.

Recommendation 5: The risks noted are serious enough that they must be discussed directly and openly by all stakeholders prior to any decision to proceed with changes to the compassionate access system.

III. RIGHTS

The Sub-Committee accepted the premise of "catastrophic rights" - 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." (p. 3) This right appeared to take precedence over the rights of other stakeholders in the compassionate access process, including the rights of those who will be catastrophically ill in the future.

In addition there were many concerns and conditions expressed by stakeholders at the round table which were acknowledged by the Sub-Committee. But these concerns were not resolved or addressed through meaningful recommendations that would predicate any changes to the present process.

This sentiment was evident despite the concern expressed by at least one advocate for the catastrophically ill - Neill Iscoe of the Canadian Cancer Society, who, despite his primary concern for the well-being of cancer victims, did not deem it ethical to dismiss the well-being of others for their sake: "society believes in the right to self-determination," he said, "but does not believe this right permits one person to exercise that right to the disadvantage or detriment of another individual. Specifically, it was felt that compassionate access, while necessary, should not be allowed to impede rapid drug development." (p. 19-20)

The Sub-Committee expressed this commitment to catastrophic rights even though it acknowledged that "catastrophic rights do not have the force of legal recognition in Canada." (p. 4)

Recommendation 6: That the government define the meaning and intent of the application of the term "catastrophic rights" in its policies.

The preferential treatment which the Sub-Committee has given to those who are presently catastrophically ill was, in fact, established in the original purpose for the investigation: "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." (p. 6)

Unfortunately, among those who are potentially harmed by this preferential treatment are individuals who will become catastrophically ill in the future. The Sub-Committee sympathetically cited a participant at the round table who asked, "Is it acceptable to sacrifice the needs of people who are seriously ill for the benefit of hypothetically future sick people?" (p. 6) This being said, it is not hypothetical that people will be sick in the future - and some of those individuals will be catastrophically ill.

If the drug development system is slowed due to an excessive burden being placed upon it for the exclusive sake of those who are catastrophically ill today, the ramifications for those who are catastrophically ill in the future could be the lack of effective treatment that would otherwise be available to them.

It becomes clear that, despite the Sub-Committee's discussion about new ethical priorities which are demanding changes to compassionate access, no ethical conclusion can be reached on this issue if a balance is not established between the rights of all the stakeholders.

IV. REPRESENTATION

The majority of witnesses were from groups representing HIV/AIDS victims. Others were also represented, including those with cancer and MS.

Other stakeholders were also included in the round table discussions, including representatives of the pharmaceutical industry, physicians and the government.

Most witnesses were advocating for greater liberalization of compassionate access.

Nobody appeared to specifically represent Canadians - the "hypothetically future sick people."

Recommendation 7: That witnesses to this review, and more generally to all committee work, should be chosen to reflect all aspects of the question, including all stakeholder groups and all points of view.

V. REGULATORY PROCESS

1. Some of the primary demands highlighted by advocates for more compassionate access related directly to the government's regulatory role in the current process.

The criticism was targeted at:

Good science and research requires a minimal amount of time. That being said, comparing the length of the normal approval process in Canada with other countries such as the US, and noting the speed in which some drugs can be approved when put on a "fast-track," indicates the possibility of improvement in this area.

2. Testimony was given at the round table that the Drugs Directorate has streamlined the approval process. "Their average 17 month evaluation period is now considered to be quite good. Also, their 180-day accelerated review process ("fast-track") . . . is very fast," (p. 26) it reported.

At the same time, the US Food and Drug Administration (FDA) "has introduced an accelerated conditional approval process for drugs for life-threatening illnesses which has resulted in approvals in 90 days or less." (p. 26)

Recommendation 8: That as long as the caliber of the science and research used in the drug approval process is not compromised, the Directorate should continue to look for ways to improve the speed and efficiency of its approval process.

Recommendation 9: That in nations where the caliber of science and research is comparable to that of Canada, the government should consider how drug development may be expedited through recognition of the work done in those countries. Therefore, with the qualification that specific protection is guaranteed to Canadian sovereignty, we support in principle the Sub-Committee's Recommendation No. 7, which calls the government to "study the future direction of drug regulation in Canada." (p. 29)

3. Another serious problem over government involvement relates to the role of provincial governments: "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." (p. 31)

Recommendation 10: That this problem needs to be addressed, therefore, we agree in principle with the Sub-Committee's Recommendation No. 8. (p. 32).

4. Other problems with government involvement include the time taken to evaluate drugs.

CONCLUSION

In view of the evidence presented to the round table on compassionate access to investigational therapies, it appears that there are many questions to be answered and problems to address before making potentially problematic changes to the present compassionate access system.

Yet this is the mandate which was accepted by the Sub-Committee on HIV/AIDS. The then Chairman of the Committee, Dr. Bernard Patry, 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."

Operating with the premise that changes must be made as soon as possible, imposed pressure on the Sub-Committee to proceed at an accelerated pace that appears to have prevented it from taking all the legitimate issues into consideration before making its recommendations to revise the compassionate access process.

Recommendation 11: That we affirm the value of compassionate access programs. Changes to compassionate access should be made only as the potential problems surrounding the issues of responsibility, risk, rights, representation and the regulatory process are fully assessed and resolved.

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