Report of the Adderall XR New Drug Committee

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Preamble

At the request of Health Canada (HC) and Shire BioChem Inc (Shire) the "Adderall XR New Drug Committee" (NDC) was formed. The members of the committee are Dr. Mitchell Levine (chair) a pharmaco-epidemiologist, Dr. Robert Gow a pediatric cardiologist and Dr. Sarah Shea a consultant physician in pediatric developmental and behavioural problems. The committee was asked to provide recommendations to the Minister of Health relating to the decision to suspend the Notice of Compliance (NOC) for Adderall XR, a drug formulation of long acting amphetamine salts used in the management of Attention Deficit Hyperactivity Disorders (ADHD). To address this goal the committee relied upon an extensive review of the materials provided to the committee members by HC and Shire, presentations and discussions that took place on July 19, 2005 among HC, Shire and the committee, and information provided by HC and Shire at the NDC's request after that meeting.

The principle issue of concern that the NDC was asked to address involved an assessment of the risk of sudden/cardiac death and/or stroke in patients receiving Adderall XR. The committee indicated at the outset that issues of safety and effectiveness pertaining to Adderall XR would be assessed in comparison to alternate drug therapies available for treating ADHD. That is, any incremental benefits or risks associated with Adderall XR in comparison to no drug therapy (or placebo) would not be evaluated.

It was apparent to the NDC that the fundamental basis for the disagreement between HC and Shire regarding the risks associated with Adderall XR was that each party had used different data sets for their analysis of risk, which had resulted in subsequent divergent inferences being drawn from those data. A critical task for the NDC was to evaluate the different analyses and determine which was more likely to reflect an accurate representation of relative risk for Adderall XR compared to other treatments currently available.

It is not the intention of this report to describe in detail the data presented by the two parties. Rather, this report will highlight the features of the analyses that could affect either the internal or external validity of the results obtained from the different analyses. This report of the committee's findings and recommendations will attempt to address from a comparative perspective (i.e., Adderall XR versus alternate drug therapies) the questions jointly posed by HC and Shire to the NDC.

Findings

HC suspended the NOC for Adderall XR on February 9, 2005 due to concerns generated by case reports of sudden/cardiac death and/or stroke in individuals receiving Adderall. In light of HC's responsibility to ensure that risks from drug therapies are minimized and given that alternate therapies were immediately available for Canadian patients with ADHD, the withdrawal of Adderall XR from the market would appear to have been an appropriate action at the time, based upon the precautionary principle held by HC.

The initial analysis suggested a higher event rate for sudden/cardiac death and/or stroke amongst Adderall users compared to alternate drug therapies for ADHD. In addition there did not appear to be an adequate solution to mitigate this perceived increase in risk, as many of the events that were reported had occurred in patients without any identifiable risk factors. As well, the option of lowering the dose was not supported by any data that would indicate that there would be a reduction in risk and a preservation of efficacy.

Since case reports cannot confirm or refute a suspected association between a drug and an adverse effect more sophisticated analyses are required. For rare events such as sudden/cardiac death, data from previously conducted RCTs would be insufficient, and the analysis would also require comparisons with active therapies not placebo. Non-experimental designs such as cohort and case-control studies would be the next best alternative. Neither HC nor Shire has conducted these types of studies. The type of analyses that have been conducted to date resemble a hybrid of ecological studies, cohort studies and case reports, as exposure status and outcome status are not distinctly linked for all individuals and outcome status is not known for all persons. As a consequence, this would be considered a relatively weak methodology for assessing risk. In the analyses conducted by HC and Shire, the number of case reports identified for a particular drug (with sufficient causality assessment) were divided by an estimate of the exposed population, generating a reporting rate ratio. A comparison of reporting rate ratios was made between Adderall XR and alternate therapies, which was represented by a relative risk.

In the initial HC analyses there would appear to be some important limitations that would affect the internal validity of the calculated relative risk. The time period used for identifying cases and determining the exposed population was very different between Adderall XR (1996-2004) and the alternate therapies (1976-2004). There were also some differences in how the denominators were calculated. In epidemiological studies it is imperative that the two cohorts (defined by their exposure status) have similar opportunities for the outcome of interest, which in this analysis is the generation of a case report. Due to differences in how the denominators were determined, a similar opportunity for case reporting could not be assured in the analysis and thus the results may be biased. A full explanation of the sources for bias and confounding in the HC analysis is beyond the scope of this report.

To address the issue of bias, the NDC requested HC to re-analyze the data using more comparable denominator data for the two groups. The resulting relative risk was 2.2 for Adderall compared to Concerta (methylphenidate) but this was not statistically significant (i.e., the 95% confidence interval includes 1.0). Because of the infrequent event rates in both groups the precision of the relative risk estimate was quite poor, which means that a true increase in risk may have been missed.

The analysis presented by Shire also had important limitations for the inferences that were drawn from those results. There are a number of potential confounders and reporting biases that might have influenced the results. Under reporting is key, as the event rate in the exposed populations is less than one would expect to occur in the absence of drug exposure. If the under reporting is asymmetric for the groups being compared, then biased results will be generated. The Shire data reported a lowered risk for sudden/cardiac death for Adderall than Concerta, but the 95% confidence interval included 1.0 and thus no relative 'beneficial' effect of Adderall has been demonstrated. As Shire was unable to provide any objective evidence that Adderall XR is clinically superior to the alternate treatments, a claim of incremental benefit cannot be used to offset any perceived increase in risk. Nor was there adequate evidence that Adderall XR is particularly beneficial in patients who are refractory to the alternate medications used for ADHD.

Thus the NDC is required to draw conclusions that are based upon analyses that are methodologically weak, results that are not robust and can be easily influenced by nuances in ascertainment procedures, and statistical analyses that lack precision. With these caveats, it is the finding of the NDC that an increased risk of sudden/cardiac death and/or stroke with Adderall XR compared to alternate active treatments has not been proven. It is also recognized, however, by the NDC that such an increase has not been ruled out due to limitations in the data currently available for analysis. Unfortunately a more definitive conclusion about the relative risk of Adderall XR and sudden/cardiac death and/or stroke is not likely to be forthcoming in the near future.

As the focus of this report is a comparative analysis of Adderall XR to alternate drug therapies currently available, the absolute increased risk for any or all therapies compared to placebo (or no therapy) was not addressed. Nevertheless, the committee does recognize that there is a theoretical potential for all stimulant drugs used in the management of ADHD to increase the risk of sudden/cardiac death. Whether this increased risk is similar to the undertaking of exercise or other strenuous activities, or is dependant upon underlying predisposing congenital or acquired cardiac risk factors is uncertain. As well, an event that occurs in an exposed individual can never be separated from the background rate of sudden/cardiac death that occurs in unexposed individuals. There is no clinical test to determine attribution, and as case report rates are smaller than the crude event rates in the total population, the attributable risk percent for Adderall XR or other stimulant drugs cannot be calculated.

Recommendations

In light of the NDC findings that there is insufficient evidence to support the belief that there is an increased risk of sudden/cardiac death with Adderall XR compared to alternate active treatments, but also recognizing that such an increase is biologically plausible and has not been scientifically disproved for Adderall XR as well as for other stimulants, the NDC recommends the following:

1. That the Minister end the suspension of the NOC for Adderall XR (concurrent with #2 below).
2. That Shire revise the product monograph and patient leaflet, in the manner indicated in the November 2004 Notifiable Change, control # 095253.
3. That Shire adopt the actions outlined in the letter sent to the NDC from Bonnie Cockhill, Director of Regulatory and Scientific Affairs, dated July 21, 2005.
4. That the Minister enhance post-marketing surveillance for ALL stimulant drugs used in the management of ADHD.
5. That ALL stimulant drugs prescribed in the management of ADHD should be used with caution in patients who (a) are involved in strenuous exercise or activities, (b) use other stimulants or (c) have a family history of sudden/cardiac death. Although confirmation of an incremental risk for adverse cardiac events arising from treatment with stimulant medications is lacking, even in the absence of this information it may still be prudent for a baseline EKG be obtained prior to implementing drug therapy for patients with one or more of the factors described above.

Respectfully submitted,

Mitchell Levine, MD, MSc, FRCPC, FISPE
Robert Gow, MD, FRCPC
Sarah Shea, MD, FRCPC