ADDERALL XR

Suspension and Re-instatement of NOC in 2005

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Presentation Outline

The facts Background Outcome

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Summary

After being marketed for one year, the Notice of Compliance (NOC) for Adderall XR was suspended by Health Canada on Feb 9, 2005 After a review involving independent experts following a process vaguely described in the Food and Drug Regulations, Adderall XRs NOC was re-instated 6 months later

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Impact on operations

The product was primary focus of one sales force

Impact on the US operations Immediate stop of promotion Impact on patients and physicians Redeployment to second product Other actions

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Background

Adderall XR was first approved for the treatment of ADHD in children 6 and over in Canada in January 2004. The immediate-release formulation of Adderall, available in the US, was never marketed in Canada US Package Insert for Adderall XR was revised in Aug 2004
Based on post-marketing adverse reaction reports of sudden death, serious cardiovascular and cerebro-vascular events with immediaterelease Adderall and Adderall XR Warnings regarding sudden death in relation to drug misuse/abuse and pre-existing structural cardiac abnormalities were added

On review of the same proposed labeling changes and supporting documentation, Health Canada suspended the Adderall XR NOC on Feb 9, 2005
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Health Canadas Reasons for Suspension

20 cases of sudden/cardiac death & 12 cases of cerebro-vascular accident

reported globally for Adderall IR and Adderall XR over 9-year period

Adderall XR is associated with risk of sudden/cardiac death and cerebro-vascular accident Preliminary Health Canada analysis suggested that signal for sudden/cardiac death appears to be higher for Adderall IR/XR compared to other stimulants Reporting rates at or above background rate for sudden/cardiac death Risks cannot be adequately managed through labeling
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NDC process

Shire appealed Health Canadas decision immediately, under C.08.009 of the Food and Drug Regulations Old regulation, not implemented in last 30 years according to Health Canada Involves appointing a New Drug Committee to consider Health Canadas decision and make recommendations to the Minister
Independent 3-member New Drug Committee (NDC) appointed by Shire and Health Canada No guidelines, process or timelines available other than what is in C.08.009

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NDC Review

Month 1:
Request and receipt of Health Canadas reasons for the suspension Establishment of process / timelines:
Meeting with Health Canada to agree on NDC process

Submission of Shires NDC nominee, Health Canada nominated a member, and a third member (the Chairman of the NDC) was selected NDC consisted of:
pediatric cardiologist specialist in pediatric development and behavioral problems, and pharmacoepidemiologist

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NDC Review

Month 2:
Preparation of Shires NDC Briefing Package:
Creation / finalization of five expert reports (cardiology, neurology, pharmacoepidemiology, clinical data summary, benefit/risk)

Health Canada also prepared an extensive Briefing Package for submission to the NDC

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Materials reviewed by NDC

In addition to complete background clinical and postmarketing information:

Comprehensive review of background rate and profile of sudden/cardiac death in general age-matched population Comprehensive review of background rate of stroke in general age-matched population Additional, more comparable, analyses of relative estimated reporting rates of sudden/cardiac death and stroke for Adderall versus other ADHD drugs.
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NDC Review

Months 4-5:
Preparation and submission to NDC of rebuttal to Health Canadas Briefing Package Health Canada also prepared and submitted a rebuttal to Shires Briefing Package Questions from, and answers to, NDC members Meeting with NDC:
Presentations by experts representing Health Canada and Shire

Month 6:
NDC recommendation with suggested reinstatement conditions Health Canada final decision / NOC re-instatement Reintroduction communication:
Press release DHPL
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Conclusions of Health Canada and NDC Re-assessment

The reporting rate for sudden death and stroke in patients taking Adderall (IR and XR) is not greater than the general unexposed population, even when accounting for underreporting of adverse events. There is insufficient evidence to support Health Canadas concern that there is an increased risk of sudden/cardiac death or stroke with Adderall XR compared to other ADHD treatments. Theoretically, there exists a pharmacological potential for all ADHD drugs (stimulant and non-stimulant) to increase the risk of sudden/cardiac death. Adderall XR NOC should be reinstated immediately concurrent with labeling changes previously proposed by Shire

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Recommendation of the NDC & Health Canada

The NDC recommended ;

immediate reinstatement of NOC with labeling changes previously proposed by Shire

Re-instatement conditions proposed:

Dear Healthcare Professional Letter be distributed by Shire Continuing Medical Education be sponsored by Shire regarding the profile and predictors of sudden/cardiac death in the general population

Health Canada adopted the NDC recommendations, and NOC was re-instated on August 26, 2005

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C.08.009
(1) Where the Minister has decided (a) to notify the manufacturer of a new drug for veterinary use that the sale of that drug to qualified investigators is prohibited, or (b) to suspend a notice of compliance issued in respect of a new drug submission or an abbreviated new drug submission or a supplement to either submission, the manufacturer, if dissatisfied with that decision, may require the Minister to provide him with the reasons for the decision. (2) Where the manufacturer has received the reasons for a decision of the Minister pursuant to subsection (1), he may require the Minister to refer that decision to a New Drug Committee and thereupon shall provide the Minister with a statement of the reasons for his dissatisfaction and any information and material upon which he relies in support of those reasons.

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C.08.009 (contd)
(3) Where the Minister has been required to refer a decision to a New Drug Committee pursuant to subsection (2), he shall appoint a member of the New Drug Committee, the dissatisfied manufacturer shall appoint a member of the New Drug Committee and the two members so appointed shall appoint a third member of the New Drug Committee who shall be chairman, or, if they are unable to do so within a reasonable time, the Minister shall appoint a third member of the New Drug Committee who shall be chairman. (4) Any person who is in the full-time employment of the Department or in the full-time employment of the dissatisfied manufacturer shall not be appointed a member of a New Drug Committee. (4.1) A member of a New Drug Committee shall, on appointment, sign an undertaking not to disclose or use any information, material, data, evidence or representations considered pursuant to subsection (6). (5) The Minister shall pay the reasonable fees and costs incurred by the member of the New Drug Committee appointed by the Minister, and the dissatisfied manufacturer shall pay the reasonable fees and costs incurred by the member appointed by the dissatisfied manufacturer, and the Minister and the dissatisfied manufacturer shall each pay half of the reasonable fees and costs incurred by the chairman.

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C.08.009 (contd)
(6) The New Drug Committee formed pursuant to subsection (3) shall consider the reasons for the decision of the Minister, the reasons for the dissatisfaction of the dissatisfied manufacturer and any information or material in support of the reasons of the Minister or the dissatisfied manufacturer and may consider other evidence, material, information or representations. (7) The New Drug Committee formed pursuant to subsection (3) shall report its findings and recommendations to the Minister. (7.1) No member of a New Drug Committee shall disclose or use any information, material, data, evidence or representations considered pursuant to subsection (6). (8) Where the Minister has received the findings and recommendations of a New Drug Committee, he may reconsider the decision to which those findings and recommendations relate.

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