The department should resist pressure to make all products subject to clinical trials and should stick to its evidence-based roots.

The Health Products and Food Branch of Health Canada is setting out its vision for the future through a new strategic plan. Within this revamp, there appears unfortunately to be a desire to shift the culture of the organization away from one that uses a broad range of evidence to one that relies on a higher level of science for decision-making. The branch now refers to itself more often as a “science-based” organization, perhaps in an effort to show critics in the media that it has become a more rigorous regulator. If Health Canada concedes to this external pressure by changing its traditional pragmatic approach to the use of evidence, companies will face increased costs to support their products’ safety and efficacy, and consumers may face loss of access to well-established health products.

Government is charged with assessing products under the Food and Drugs Act to determine if they are safe and if the claims that are made are not fraudulent. This is the basic mandate of the enabling legislation for Health Canada.

The government has regulations that set the ground rules for satisfying the legislative imperative. These regulations are designed to establish the terms under which the minister shall or may act to grant or revoke market authorization. They also set out the requirements for persons who wish to sell a food, drug, device or cosmetic. The general rule of thumb is that market access for these products is based upon satisfying the minister (department) that a product is safe and not fraudulent.

The guidelines that have been developed over years of consultation are numerous and diverse. They are tied to an overall risk-based policy approach that has been adopted by most, if not all, regulatory agencies around the globe. The practical consequence of a risk-based framework is that it recognizes that lower-risk situations call for proportional application of evidence and oversight.

If the baseline evidentiary standard for all products is to be the same across the board, as some would suggest, then it would have to be argued that only randomized, double-blind clinical trials would suffice for all products under the Food and Drugs Act. But it is absurd to think that the same level of scientific rigour should be applied to a skin moisturizer as would be expected for a new cancer drug. Common sense dictates that the highest standards of evidence must be applied when little or nothing is known about a substance being proposed for sale to Canadians.

It is absurd to think that the same level of scientific rigour should be applied to a skin moisturizer as would be expected for a new cancer drug.

There is a case to be made for permitting the sale of products when the benefits may be very small or supported by weak evidence but when the risk associated with use is even smaller. On the other hand, there are numerous examples where benefits have been well established through very strong studies but the risks outweigh the utility of the product. For example, phenylpropanolamine is a very effective decongestant that may raise blood pressure slightly. It was removed from the market because Health Canada felt the risk outweighed the need for a treatment of a minor illness like nasal congestion. It is also important to remember that these two risk parameters are relative. Simply put, lower-risk products should attract a broader range of evidentiary standards regardless of their classification, and higher-risk products should demand greater rigour.

Many types of studies can be used to assess benefits and risks. For example, systematic reviews, randomized controlled trials, cohort studies and case control studies are all scientific and should have a place in the standards of evidence used by government.

The strengths and weaknesses of a study design should be seen in light of the kind of question the study sets out to answer. Sometimes, observational studies are the only way researchers can explore certain questions. Such studies compare subjects against a larger group in cases where the researchers lack the ability to control key aspects of the experiment.  For example, it would likely be unethical to design a randomized controlled trial deliberately exposing people (especially vulnerable groups such as pregnant women, children and elderly patients) to a potentially harmful situation.

If a health problem is a rare condition, a case control study (which begins by studying the existing cases) may be the most efficient way to identify potential causes of a problem. Or, if little is known about how a problem develops over time, a cohort study in which groups of people with common characteristics are tracked may be the best design.

While the results of observational studies are, by their nature, open to dispute, this does not diminish their value in making regulatory decisions. Health Canada uses observational studies to assess postmarket safety, quality and efficacy, despite the risk of confounding biases. For example, a cohort observational study might find that people who meditated regularly were less prone to heart disease than those who didn’t. But the link may be explained by the fact that people who meditate also exercise more and follow healthier diets. In other words, although a cohort is defined by one common characteristic or exposure to some external influence, they may also share other characteristics that affect the outcome.

Even though randomized clinical trials are still considered by many to be the gold standard for producing reliable evidence, there’s a growing realization that such research is not perfect, and that many questions simply can’t be studied using this approach. Such research is time-consuming and expensive — it may take years before results are available. Also, intervention research is often restricted by how many participants researchers can manage or how long participants can be expected to live in controlled conditions. Such research involves study participants who are randomly assigned to one of two groups, with one group being exposed to the intervention and the other to a placebo.

Media people know that there is a broad range of evidence available using the scientific method, but they also are aware that the gold standard is the randomized clinical trial method. In an effort to make headlines, the media rallies around the idea that everything Health Canada touches should be held to the same high standard. This is unreasonable and not needed in order to make rational decisions on benefits and risks. Experts on evidence-based regulatory decision-making know that clinical trials are the least-used tool for making benefit-risk assessments due to their high cost, ethical considerations, and the need to force such interventions on the public when other types of evidence would provide a satisfactory outcome analysis. For example, it would seem overreaching to demand a clinical trial to allow a bandage to be sold under medical device regulations.

Health Canada should not take the bait. It should stand tall and be clear that it makes use of many types of evidence, and it applies these data to a risk assessment process; it should explain how it manages identified risks in relation to benefits. Regulatory science is more sophisticated than simply saying that if there isn’t clinical trial evidence available, then the decision will be to refuse market access. If we move away from broad-range evidentiary standards toward a less diverse and more rigid application of science, it begs the question as to whether the branch needs the variety of skilled people who have been trained in assessment using the full array of tools to make judgments about the benefits and risks of products.

Health Canada should not take the bait. It should stand tall and be clear that it makes use of many types of evidence.

Health Canada appears to be sending a subtle message that it is moving the goalposts with respect to the level of scientific rigour it intends to use to allow products to have access to the market and to stay on the market. Such an abandonment of the long-standing use of a full range of evidence for regulatory decision-making will not benefit the public and ignores the need to blend the pragmatic with the academic to ensure that the bounds of the enabling legislation are not exceeded by administrative decisions and culture.

If the intent is to impose higher evidence standards on industry while retaining the department’s use of observational studies and reports of individual cases for the purpose of refusing market entry or removal, this creates a double standard that lacks fairness or utility. Continuing to make use of the very types of evidence that it does not permit others to use would belie any notion that the government is a science-based organization. Health Canada would be better served by sticking to being an evidence-based organization and standing up to media criticism about not applying the randomized clinical trial standard to all products under its purview.

Photo: science photo / Shutterstock.com

 


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