Abstract
Background
All Canadian provinces have developed drug plans that pay part or all of the cost of prescription drugs for various segments of the population [1] and that incorporate a formulary that lists which drugs are covered.
In order to have their drugs considered for listing in most publicly funded formularies, companies need to file a submission with the Common Drug Review (CDR). The CDR provides advice to all of the provincial drug plans (except the one operated by the province of Quebec) the three territorial and six federal drug plans about the clinical efficacy and cost-effectiveness of a drug against other drug therapies so that public funds are optimally used. CDR bases its recommendation about listing on its assessment of the clinical and economic value of the product and then makes a recommendation to the participating drug plans about listing, taking into consideration the medication’s effectiveness, safety and cost-effectiveness compared to existing therapies [2]. CDR recommendations are not binding on any of the participating drug plans, which are free to make their own funding decisions [3]. Although manufacturers can resubmit an application to CDR if the original application is rejected, the organization does not undertake a re-examination of its recommendation following the identification of new safety concerns around a product.
In Ontario, the manufacturer makes a submission to obtain listing for a product on the Ontario Drug Benefit Formulary (hereafter ODB Formulary) that includes summaries of the clinical evidence compiled for the purposes of having the product approved by Health Canada [4]. This submission is then evaluated by the Committee to Evaluate Drugs (CED), an independent expert advisory committee that includes patient representatives, whose members are appointed by the Ministry of Health and Long-Term Care. The CED considers the clinical value of the drug, its cost effectiveness and the recommendation from the CDR and makes a recommendation to the Executive Officer (EO) of the Ontario Public Drug Programs about whether the drug should be considered for public funding, and the conditions under which the product should be funded [5].
Reading the reports from the CED makes it clear that it considers the balance between the clinical value of a drug and its safety profile in making its decision [6]. The final decision about listing is made by the EO on the basis of the following factors: recommendation from the CED; advice from other advisory bodies, e.g., Citizen’s Council; patient and societal impact, public interest; product listing agreements with manufacturers; drug program budgets; and other factors, e.g., government priorities [7].
The recognition of new safety concerns about a drug may alter its benefit to harm ratio and therefore, may affect whether or not it should continue to be listed on provincial drug formularies or whether its listing status should be changed. Provincial drug plan officials are conscious of the role of safety in the decision-making process. In interviews with informants from across Canada, one noted that a drug does not “get on our drug benefit list unless we’ve reviewed it and said relative to the other products that are available, it offers price advantages, therapeutic advantages and safe[ty] advantages.” Another echoed this position, saying that if safety issues were identified they may affect the way that a drug islisted [8].
The clinical evidence that the Ontario and other provincial plans use is almost exclusively based on premarket clinical trials that typically study only a narrow range of patients with a specific condition, who are taking the drug for only short periods of time. Further, these trials are primarily designed to show efficacy [9]. Therefore, in making their decisions, plans are relying on the relatively limited knowledge about the overall benefit to harm ratio of new drugs available early in their lifecycle [10]. Many safety issues related to drugs are only identified after they have been approved by Health Canada; drugs have almost a 25% risk of acquiring a serious safety warning from Health Canada over their lifecycle [11]. If new safety information appears after a positive listing decision has been made, one provincial drug plan official said “it’s very difficult to pull back on those decisions” although according to another provincial official it may happen if the safety issue is serious [8].
There is no publicly available information about whether or not the Ontario Public Drug Programs re-evaluates the listing status of drugs as a result of safety warnings. The purpose of this paper is two-fold: first, to investigate whether listings on the ODB Formulary are changed after single source drugs,i.e., patented drugs available from a single manufacturer, have received a serious safety warning and second, to determine whether information about the re-evaluation is publicly communicated.
Methods
A list of all new active substances (NAS, a molecule never previously marketed in any form in Canada) approved between January 1, 2002 and March 31, 2012 was compiled from the annual reports of the Therapeutic Products Directorate (TPD) and the Biologics and Genetic Therapies Directorate (BGTD) – available by directly contacting the directorates at <
Safety warnings and drug withdrawals for the period January 1, 2002 to September 30, 2013 were identified through advisories for health professionals on the MedEffect Canada web site <http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/index-eng.php>. For each safety advisory or notice of withdrawal of a product, the date and reason was recorded. All serious safety advisories, defined a priori as those using bolded black print or boxed warnings, were included except for those dealing with the withdrawal of a specific batch or lot number due to manufacturing problems or those issued because of misuse of a drug (e.g., an unapproved use) or medication errors (e.g., a warning about remembering to remove a transdermal patch before applying a second one).
Drugs listed on the ODB Formulary were determined by a manual search of editions 38 to 42 of the formulary (published on January 30, 2003, September 27, 2005, April 2, 2007, June 27, 2008 and November 28, 2013), available on-line at http://www.health.gov.on.ca/en/pro/programs/drugs/edition_42.aspx. The date when a drug was listed on the ODB Formulary was taken as the date of publication of the first issue of the ODB Formulary in which the drug appeared. Only drugs that were listed before the safety warning was issued were included. If there was more than one safety warning for the drug, then the drug was still included provided that it was listed before the last safety warning. In addition, the type of listing was recorded: General Benefit, i.e., there are no conditions on use, Limited Use, i.e., the product is only reimbursed under specific clinical criteria/conditions for use, Exceptional Access Program (EAP) for drugs that are not normally funded but may be covered where no listed alternative is available.
If a drug was listed in one edition of the ODB Formulary and not in the next edition or the listing was changed, then two web sites were searched to determine the reason for the change: the web site that records recommendations from the CED and decisions by the EO http://www.health.gov.on.ca/en/pro/programs/drugs/ced_rec_table.aspx (decisions starting from July 2007) and from the web site that contains Communiqués from the EO http://www.health.gov.on.ca/en/pro/programs/drugs/opdp_eo/eo_communiq.aspx (communiqués from April 2006). If drugs were initially listed as Limited Use then the criteria for payment were compared before and after the safety warning was issued to see if they had been modified.
The degree of therapeutic innovation may influence whether a safety warning will lead to a change in listing status. The CED may be reluctant to change the status of a product that offers a significant therapeutic advance. Therapeutic innovation was determined from the annual reports of the Patented Medicine Prices Review Board (PMPRB) available on-line from 2003 to 2012 at <http://www.pmprb-cepmb.gc.ca/english/View.asp?x=91>and for previous years by directly contacting the PMPRB at <
Results
From January 1, 2002 to March 31, 2012 a total of 263 NAS were approved by the TPD or the BGTD of which 42 subsequently acquired one or more serious safety warnings and 26 of these were listed on the ODB Formulary. Eleven of the 26 were not analyzed for the following reasons: one product (efalizumab/Raptiva) that was listed was subsequently removed from the market for safety reasons, four (adalimumab/Humira, cinacalcet/Sensipar, natalizumab/Tysabri and tenofovir/Viread) were listed after the final safety warning and no listing dates were available for six drugs with EAP status. Table 1 lists the remaining 15 products that were analyzed.
Eleven of the 12 products that were initially listed for either General Benefit or Limited Use continued to be listed in the edition of the ODB Formulary published subsequent to their safety warning, with their listing status unchanged. According to a Communiqué from the EO, aliskiren/Rasilez initially listed for General Benefit was delisted from the Formulary as of December 21, 2012 because of preliminary data from the ALTITUDE study that showed that it was unlikely to benefit the patients participating in the clinical trial and could potentially lead to harm [12]. The criteria for use for the five Limited Use drugs did not change as a result of the safety warning. The initial conditions under which funding for the three EAP drugs was considered were not available and therefore it could not be determined if they had changed as a result of the safety warning.
Discussion
The Ontario Public Drug Programs did reconsider the listing of one drug after a new serious safety warning was released by Health Canada. It is likely that this decision was made after an internal review and did not involve the CED because the delisting of aliskiren was reported in a Communiqué from the EO and not in a document from the CED. Whether officials reconsidered the listing of any of the other 14 drugs is unknown because no information was made publicly available about any other re-evaluation.
Only one of the 15 drugs offered a significant new therapeutic advance, but they were all subsequently recognized as less safe than was thought when the listing decision was originally made. These results raise the possibility that the government is continuing to pay for some drugs that would have been rejected or placed in a more restricted listing category had the new safety concerns been initially known.
Although the ODB Formulary primarily serves as a list to let physicians and other prescribers know what products will be publicly covered, it also is intended to act as a guide to prescribing as can be seen by the “therapeutic notes” regarding appropriate and cost-effective use of prescription drugs that are available for some drugs. In addition there are notes that accompany Limited Use products, e.g., some of the information for dabigatran (Pradaxa): “Documented stable renal function is defined as creatinine clearance or estimated glomerular filtration rate maintained for at least 3 months … At risk patients with atrial fibrillation are defined as those with a CHADS2 score of greater than or equal to 1” [13]. Formulary status influences prescribing decisions [14, 15] and previous research shows that delisting drugs changes prescribing behaviour [16, 17]. If a reassessment results in a decision to remove a drug from the formulary then that would clearly lead to decreased use.
If drugs are not delisted, the question remains whether an additional statement from Ontario authorities about the safety of a drug would be valuable to doctors beyond the initial communications that they receive from drug companies and/or Health Canada when a problem is first identified. Use of safety information by Canadian doctors is quite variable; about three quarters say that they read the “Dear Doctor” letters from drug companies and Health Canada, while slightly less than half consult the Canadian Adverse Reaction Newsletter and less than a fifth make use of safety advisories on the Health Canada web site [18]. In addition, all of these resources are frequently used by only a small minority of healthcare professionals [18].
Investigations into the effects of safety information from Health Canada on prescribing have shown mixed results; two warnings about the use of desmopressin in children lead to a 30% decrease in prescribing [19], but multiple warnings about the use of atypical antipsychotic agents in patients with dementia only slowed the growth in their use and did not reduce their overall prescription rate [20]. In general, the available international evidence indicates that a single message is not sufficient to change prescribing and that multiple messages are necessary to both increase knowledge and, more importantly, to alter behaviour [21–24]. While additional general communications about drug safety from Ontario formulary officials, such as the one issued about aliskiren, are not a substitute for other measures to increase safety such as detailed information about additional monitoring, laboratory investigations and the avoidance of drug-drug interactions, another message about the safety of a product should be one strategy to help ensure appropriate prescribing.
Decisions about the benefit to harm ratio of drugs involve some element of subjectivity and uncertainty and it is conceivable that even with a newly identified serious safety issue that the judgment will be that a product’s listing should not change, especially if the product offers a major therapeutic benefit. Furthermore, all safety warnings are not equivalent and the number of people who will be affected and the degree of harm they will experience is usually not known when the warning is issued. For example, the warning about varenicline (Champix) that “thorough consideration should be given to the treatment option of nicotine replacement therapy” is not the same as the warning for deferasirox (Exjade) that the drug may cause “renal failure, gastrointestinal hemorrhage, deaths”.
The results of this study that show that the formulary status of the vast majority of drugs does not change following a serious safety warning about them clearly only apply to Ontario. However, they raise the question about how other drug funders, public and private, deal with this issue; a question that should be investigated in other jurisdictions.
Conclusion
It is currently unknown whether the formulary listing status for the large majority of drugs that receive a serious safety warning is re-evaluated in Ontario, but even if it is the results are not communicated to the public or the medical profession.
The Ontario drug program needs to develop and make public a set of criteria to identify when it will re-evaluate the listing status of a drug after Health Canada issues a safety warning. These criteria could include the nature of the safety problem, the possible number of people who may be affected, the availability of alternative treatments and the benefits that the drug offers. The results of a re-evaluation should be made public so that prescribers and patients alike know that ODB Formulary officials still regard the drugs as having a positive benefit to harm ratio and to help doctors in their prescribing decisions.