Patient 1: Did you hear the latest? There’s a cure for MS!
Patient 2: What? Really?
Patient 1: Yes, a doctor in Italy opened the blood vessels in the necks of MS patients and now they are cured.
Patient 2: Wow! Do they do that here?
Patient 1: I don’t know, but I am calling my doctor today to get this procedure done before my MS gets any worse.
Patient 2: Me too!
(An imaginary dialogue between two MS patients)

The “liberation therapy,” which was developed by Italian physician Paolo Zamboni and was profiled on CTV’s W5 in November 2009, lit a red-hot fire in the multiple sclerosis (MS) community. Doctors were bombarded with questions. MS patients soon learned that the procedure was not covered in Canada.

Quickly thereafter, the provinces were pressured to fund the procedure. Some provinces responded by announcing they would conduct clinical trials to determine the procedure’s safety and effectiveness.

Instead of waiting for provincial funding decisions, some patients travelled to countries where physicians would do the procedure immediately. In some cases the procedure appeared miraculous and the patients seemed cured. In others the patient did well for a while, but, when back at home in Canada, developed complications.

As time went by, several patients claimed that their Canadian physicians would not treat their complications because the doctors here had not been involved in the therapy. One patient died following the procedure. The Quebec College of Physicians went so far as to advise MS patients not to seek the treatment outside Canada.

All through this frenzy, Zamboni was advocating more trials to see if the procedure he had developed was safe and effective. Who was listening?

It has been said that people make decisions based on what they know. Yet, it is often the law of unintended consequences and what they don’t know that get them into trouble.

Health Canada (the regulator) reviews a drug to make sure it works and is safe for a specific condition. In regulatory terms, the specific condition is referred to as an “indication.” If all is well, Health Canada will issue a notice of compliance for the drug for that indication. If a drug is used for a purpose other than that indication, the drug is being used “off-label.”

Perhaps we can use an example from the cardiovascular world to illustrate. High blood pressure (hypertension) can often lead to angina (chest pain due to ischemic heart disease). There are many approved drugs to treat hypertension, and some of these same drugs are also used to treat angina. But not all drugs approved for hypertension are approved for the indication to treat angina, often with good reasons.

The prescribing of drugs off-label can be controversial. This article presents the issues from the perspectives of various stakeholders and reveals the complexity of off-label use.

When it comes to the off-label issue, there are many perspectives and there is no shortage of opinions. Often, different stakeholders will even use the same evidence to present opposing views.

Health Canada (the regulator) reviews a drug to make sure it works and is safe for a specific condition. In regulatory terms, the specific condition is referred to as an “indication.” If all is well, Health Canada will issue a notice of compliance for the drug for that indication. If a drug is used for a purpose other than that indication, the drug is being used “off-label.”

This article, for example, may appear to the reader to be full of contradictions. We propose, however, that the statements here are contradictions not in facts, but in how various stakeholder perspectives apply to facts.

  • Patients: Sick patients say they just want something that will work and is safe. They tend to put their faith in their healer because they cannot be expected to understand the full complexity of issues surrounding approved and off-label use. However, how many patients truly understand the risk they are taking when using a drug off-label? If there are serious adverse effects, what then?
  • Regulators: Drug safety regulators say that the “risk-to-benefit” equation is not known without a full regulatory assessment. However, Health Canada’s power to regulate off-label use is, perhaps surprisingly, more limited than many may think.
  • Payers: Public and private payers interested in cost containment say that the use of drugs off-label leads to unnecessary costs. Yet payers regularly reimburse for drugs used off-label.

When a drug is prescribed off-label, who is responsible for what? Even if we forget responsibility for a moment, who has the complete prescribing picture?

Do physicians know the actual labels associated with the drugs that they commonly prescribe? For that matter, does the patient know that the drug is being prescribed off-label?

Unless reimbursement criteria are specified, most drug plans do not even require that the pharmacist know why the drug is being prescribed. What this means is that if patients are eligible for benefit coverage, the drug will most likely be paid for by their benefit plan.

It is surprisingly common for stakeholders not to have the whole prescribing picture, which of course makes it very difficult to assign responsibility if things go wrong. However, what about when the parties actually know that the drug is being prescribed and reimbursed off-label? What happens then?

According to Randall S. Stafford (2008), in a US study off-label use was found to account for 21 percent of all prescriptions of 160 common drugs, with a wide variation depending on the class of drug. The Canadian Expert Drug Advisory Committee, the advisory group of Health Canada’s Canadian Drug Review, has publicly acknowledged in posted reviews that physicians prescribe drugs off-label.

It is not uncommon for drugs to be used off-label when there are no other choices available. In cancer, oncologists often have to experiment with combinations of drugs to achieve their objectives. When a life is on the line, formal Health Canada approval for an indication is far down the priority checklist.

There is quite a bit of off-label drug use in the pediatric setting as well. Often, trials have not been done for use in children, and as a result, pediatricians use their experience to adjust doses to achieve desired effects.

But what are the issues when there are alternatives available that have been thoroughly tested? What questions need to be considered when making a decision to use or not to use, to fund or not to fund a treatment off-label? Marketing drugs off-label involves promoting them for uses other than those that have been approved, a practice that involves big money — and big headlines.

In September 2009, New York-based Pfizer struck the largest off-label drug promotion settlement to date, agreeing to pay $2.3 billion for unauthorized marketing of its painkiller Bextra, which had been recalled, and three other drugs. Associate Attorney General Tom Perrelli was quoted in a Bloomberg News story as saying, “When a drug is marketed or promoted for non-authorized, so-called off-label uses, any use not approved by the FDA [Food and Drug Administration] — as was the case here — public health may be at risk.”

In September 2010, Novartis agreed to pay a total of total of $422.5 million to settle criminal and civil charges of improperly marketing its epilepsy drug Trileptal.

Drug payers are also taking action against off-label promotion because they claim it leads to unauthorized use and unnecessary cost. AstraZeneca announced in April 2010 that it would pay $218 million to state Medicaid programs in the United States as part of a settlement with the Department of Justice. Medicaid programs provide drug assistance to people on social assistance.

Before it can be legally prescribed and sold in Canada, a drug must be approved by Health Canada. If a pharmaceutical company actively promotes a drug off-label, Health Canada can prosecute that company. However, Health Canada’s regulatory powers are limited when it comes to controlling the use of a drug off-label. There is a significant difference between promotion and use.

Health Canada does not get involved in the day-to-day practice of medicine, nor does it interfere with how the provinces manage their reimbursement programs. This does not mean that Health Canada turns a blind eye to off-label use of drugs.

It is not uncommon for drugs to be used off-label when there are no other choices available. In cancer, oncologists often have to experiment with combinations of drugs to achieve their objectives. When a life is on the line, formal Health Canada approval for an indication is far down the priority checklist.

Health Canada does conduct periodic safety reviews to look for signals that a drug may be causing adverse events harmful to patients. The Canada Vigilance Adverse Reaction Online Database is also used to collect information to help monitor drug safety.

If Health Canada sees a problem, it will act. However, it may not see all the signals, as not all adverse events are reported.

Health Canada requires that pharmaceutical companies conduct clinical studies to gather efficacy and safety data for a particular indication. Payers also need and want proof that the drug will work and be safe for the indication(s) before they will pay, so similar research is also submitted to public and private drug plans.

If a drug is being used off-label for a condition, but has not been rigorously tested for that condition, several important unanswered questions remain, including:

  • What is the optimal dose and duration of therapy?
  • What are the guidelines for the preparation of the drug, if that is  necessary?
  • How do the adverse events of the drug that is being prescribed off-label compare with the adverse events of other drugs that are approved for that condition?

On the other hand, just because the data don’t exist doesn’t mean that an off-label prescription is not the best choice. Patients respond differently. It just means the data have not been gathered and published — yet.

Ultimately, the decision to take a drug in an off-label situation may have less to do with clinical information, and more to do with other factors:

  • the physician’s experience;
  • whether a drug is reimbursed;
  • the patient’s personal or financial situation;
  • the patient’s own willingness to take the risk (if he or she knows the risk); and/or
  • the patient’s motivation to heal

With respect to prescribing off-label drugs, robust clinical data may take a back seat to the physician’s judgment and experience.

Drug commercialization is resource intensive and risky. It takes hundreds of millions of dollars of research and development to bring a drug to market. Medical practice is always advancing and there is no guarantee that the drug being developed will be accepted by regulators or by the medical market.
The patent laws and regulations encourage innovation and ensure that drug developers have the opportunity to get a fair return on their investment. Pharmaceutical companies necessarily assess the products in their pipeline based on not only patient outcome but also commercial success.

Sometimes, the estimated return on investment does not justify further formal study of what a drug can deliver. Filing a supplemental new drug submission with Health Canada for a new indication carries significant cost and can take time. If the patent on the drug will expire in the near term, there is no incentive for the pharmaceutical company to undertake this process.

Patient safety is often mentioned in off-label drug cases. Indeed, it is the issue that gets highlighted the most when patients suffer harm from therapy.

Some groups have proposed that off-label drug prescribing may be acceptable as long as the patient provides informed consent. But what is truly informed consent? Most patients do not understand the complexities surrounding drug trials and evaluations. Can they really provide informed consent when it comes to disease or condition and treatment, or do they just trust their doctors to provide the best care and do no harm?

Health Canada reviews drugs to determine if they are efficacious (will/and work) safe (won’t harm), and also works to ensure high quality control so that Canadians can count on getting the same quality of response every time they take the medication. Here the federal Food and Drugs Act applies. When it comes to off-label drug prescribing, Health Canada does not endorse it. Yet the government’s own legislation does not provide enough legislative power to control off-label drug use.

Health Canada is currently undergoing a process of regulatory reform to address these limitations. Bill C-51 was introduced in 2008 to amend the Food and Drugs Act, but the bill died when that session of Parliament ended. Part of the Bill was designed to further define what the role of Health Canada should be in the postmarket world. Agencies such as the Drug Safety and Effectiveness Network were born with this in mind.

Regulatory reform continues to be under active study at Health Canada.

However, updated legislation has not yet been brought forward.

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We know that patients take medications and other treatments regardless of whether they have been tested or authorized for their condition. Highly motivated patients want to heal — and will pay out of pocket and assume the risk for therapies if they perceive a benefit. For proof, just look at the growth in the alternative health industry.

Drugs being used off-label may indeed help some patients. However, how are patients who have adverse reactions managed without clear pharmacovigilance data and no risk management plan? Indeed, who would be responsible for such a risk management plan?

Even if a motivated patient decides to assume the risk of taking a drug off-label by providing consent, there is no clear and accepted process on how to obtain such consent in a way that fully protects the patient.

Is there a danger of creating a “two tiered” patient protection standard? Patients treated with drugs off-label may not receive the same level of institutional protection as patients who are treated with drugs that have received relevant Health Canada approval.

This is complicated by the reimbursement equation. If a reimbursement agency funds drugs for conditions for which they have not been fully tested, does that agency influence patient care? Does that make the agency partly responsible for the patient? On the other hand, if drug plans make more drugs available for reimbursement, does the potentially improved outcome outweigh the potential increased risk? How would one know without doing the evaluation?

Pharmaceutical companies market their products to physicians, to pharmacists and sometimes to consumers directly. Marketing and promotional practices are highly regulated and require a specialized skill set that varies regionally.

In the United States, pharmaceutical advertising is overseen by a number of self-governing bodies including the FDA’s Division of Drug Marketing, Advertising, and Communications (DDMAC), the National Advertising Division, and the National Advertising Review Board.

United States drug makers must submit final direct-to-consumer ad materials to the DDMAC when the product is first introduced. Submitting draft materials is voluntary. In Canada, drug marketers are required to submit draft materials to the Pharmaceutical Advertising Advisory Board (PAAB) to obtain preclearance of materials.

The Canadian system appears to have been set up to address problems before rather than after the fact. Is this one of the reasons that we have not seen the same level of off-label drug legal action and fines in Canada as in the US?

In Canada, section 9 (1) of the Food and Drugs Act governs marketing practices. Advertising a drug off-label is not permitted. The PAAB provides a preclearance review for all advertising and promotional systems within the regulatory framework.

During its preclearance review process, the PAAB reviews over 5,000 pieces of pharmaceutical marketing in Canada per year. When it notices a violation of the code, it takes steps to rectify the problem, up to and including advising Health Canada of a potential violation of the Act.

Pharmaceutical advertising is conducted to increase drug sales. But what is considered advertising? Printed flyers, fact sheets and direct-to-consumer television advertising clearly fall into this category. But what about a press release from a provincial authority that announces it will pay for a drug for an approved indication or off-label use? Is this considered advertising?

One of the many factors in the prescribing decision is the patient’s financial means and whether he or she has coverage. With this in mind, the reimbursement of a drug either for an approved indication or off-label will increase that drug’s sales.

Some will say it is unethical to fund a drug off-label. Others will say it is unethical to deny funding to a patient who needs therapy. Who is right? When it comes to ethics, whose ethics are we talking about?

As a case in point, while drafting this article, we received a press release from Nova Scotia announcing the reimbursement of both Lucentis (approved indication) and Avastin (off-label) for wet age-related macular degeneration (wet AMD). By announcing the increased treatment options for patients in the province with a degenerative eye disease, was the Nova Scotia minister inadvertently breaking a federal law? Not knowingly, at least. As this paper suggests, it’s not what you know that will get you into trouble. It’s what you don’t know. Furthermore, where does informing end and advertising begin?

In Canada, most people have at least some access to either a public or private drug plan. Public drug plans may cover all residents of a province or they may just cover certain groups, such as the elderly and those on social assistance. Drugs go through the Common Drug Review (CDR) process, and they receive a recommendation from the Canadian Expert Drug Advisory Committee (CEDAC) on whether the drug should be listed by the provinces.

CEDAC recommendations are used by public drug plans to decide whether to reimburse a drug, and how it should be reimbursed. CEDAC has never recommended that a drug be funded for off-label use. Further, CEDAC has raised the issue of the off-label use of a drug only five times in its recommendations. Four of the five raised the concern that the drug in question could be used off-label if reimbursed by the public plan. The provinces have never funded a drug that has gone through this process for an off-label condition through their main public drug programs.

When CEDAC reviewed Lucentis for wet AMD, CEDAC noted that Avastin was being used off-label to treat the same condition. Fast-forward to today, when some provinces fund Avastin for wet AMD, not through their regular provincial pharmacare programs, but through special programs administered by hospitals.

Private payers such as insurance companies and large employers are interested in a balance of employee health and productivity, and costeffectiveness. Drug plans are also part of employee compensation.

Generally, there are fewer restrictions in private drug plans than in public drug plans. Many private plans cover any drug requiring a prescription, often with no questions asked. There is significant potential for the off-label use of drugs in these types of plans because there are no constraints.

Some private plan designs require advisers to conduct independent drug reviews. This may lead to prior authorization, a process where it may be difficult to obtain reimbursement for drugs for conditions that are not approved by Health Canada.

On the other hand, some employers will specifically allow reimbursement of a drug off-label on an exception basis if they deem that it is in their or the employee’s interest.

In the United States and around the world, the list of potential defendants in legal cases about off-label use is growing. Who is responsible? Again, this is an area where there are more questions than answers.

Physicians have traditionally held liability insurance coverage. However, would their insurance companies pay if a physician was successfully sued for the administration of a drug for an off-label condition? Would that answer change if a provincial drug plan, a hospital or a special program reimbursed that drug? What if the physician’s decision was influenced by a structured decision guideline set up by his or her organization?

In the case of drug companies, US pharmaceutical executives can be prosecuted for violations of the federal Food, Drug, and Cosmetic Act. The ability to prosecute hasn’t been widely used for drug industry cases in the past two decades, but with the increased attention on off-label prescribing, some say that could change. Executives would face fines as high as $100,000 and one year in jail. The FDA can also bar individuals from working in the drug industry.

As access to off-label prescriptions increases, potential liability isn’t far behind. Could governments be sued? How about claims departments in insurance companies? What about those who sit on advisory committees?

Some will say it is unethical to fund a drug off-label. Others will say it is unethical to deny funding to a patient who needs therapy. Who is right? When it comes to ethics, whose ethics are we talking about?

Would a recommendation to fund a drug off-label threaten the standards in place at the CDR? If yes, how would this change the standards that have been developed over time at CDR? What other standards would be at risk?

As for the physician, is it ethical for a physician to prescribe a drug for an off-label indication if a proven alternative is available? Or is it unethical for a prescriber to ignore off-label use of a drug if he or she thinks that doing so is in the best interest of the patient?

Some organizations are facing this issue head-on. In April 2009, the Eastern Health regional health authority network in Newfoundland launched a pilot program introducing a “decision map,” which addresses the many requests it receives for off-label and off-formulary drugs. Individual requests were handled by a multidisciplinary committee that responded to the evidence, ethics and equity of the request using a series of structured steps covering the drug’s approval status, evidence available, current and future financial costs and whether the case is exceptional.

Eastern Health confirmed that benefit-to-risk ratio is a large factor in the decision, and that supportive evidence is essential. It also reports that while the decision map did not make decisions easier, it did introduce structure and support around the issue.

However, does the presence of a defined process now expose Eastern Health to additional risk for trying to do “the right thing”? Think of the issues discussed. What is the network’s exposure to risk in this issue before and after the process?

One can act in a righteous manner and say that one should allow, or not allow, drugs to be reimbursed off-label. What we have discovered is that many opinions can be justified depending on one’s perspective.

There are times when treatment options are limited and off-label use provides patients with potential help for their condition. However, there are also times when approved treatment options exist, but an alternative product that does not have the desired indication is prescribed and reimbursed solely because it is less expensive.

We all want it “better, cheaper and faster.” Technology is advancing quickly, and that has raised our expectations in other areas.

To be clear, we are not saying that all off-label reimbursement is bad. Indeed, if reimbursement were restricted to approved indications only, the health of Canadians would suffer. However, if the driving factor for prescribing and reimbursement is cost alone, a number of questions arise. For example:

  • Is it just about the money or do clinical standards really matter?
  • Does the benefit of a less expensive drug outweigh the potential of increased patient risk? How can we answer this question without a  full assessment?
  • If drugs are readily reimbursed with little clinical data, will pharmaceutical companies bother to do major trials to establish the safety and efficacy of a drug for new indications in the future? What are the consequences for drug development?
  • Is Eastern Health on the right track? What kind of system will give us the answers we need?

Regardless of whether it is appropriate to prescribe and reimburse products off-label, there are no easy answers. We think it is time to have a more inclusive dialogue that will allow more perspectives to be heard and understood.

Yes, times are changing, and what we don’t know just might get us into trouble.

Photo: Shutterstock

George Wyatt
George Wyatt is the managing director of Wyatt Health Management, a leading pharmaceutical reimbursement consultancy.
Karen M. Black
Karen M. Black is a senior communication consultant with Wyatt Health Management.

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