The drug regulator’s walk on the tightrope Protect public health … … against negative consequences from unsafe or ineffective medicines … against negative consequences from failing to meet unmet medical need When in doubt, be negative, “we need more information” Worry about false-positive decision “Type-1 error” When in doubt, be positive, “it might be a patient's only hope” Worry about false-negative decision “Type-2 error” What are the consequences? What are the consequences? no penalty for being negative! Are the (dis-) incentives balanced right to influence regulators’ behaviour?
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or put another way…..
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Benefit Risk Evaluation Definition: Risk benefit evaluation The process by which the benefits and risks of a medicine are assessed and balanced, and to ensure that the adverse consequences of a medicine do not exceed the benefits within the population treated
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Risks Benefits Benefit-Risk balance is key
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Type of Approval Normal Comprehensive data to assess risk-benefit balance Exceptional circumstances Comprehensive data can normally never be provided because Indication too rare Contrary to medical ethics State of scientific knowledge Conditional Approval (NEW) Comprehensive clinical data not yet available but… benefit-risk balance positive, … “early approval”
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Conditional Approval (New) Scope Orphan drugs, emergency threats, serious and life-threatening diseases Requirements Positive benefit-risk balance It is likely that comprehensive data can be provided Unmet medical needs will be fulfilled Immediate availability outweigh risks Authorisation valid for 1 year (renewable) Keypoint: level of certainty reduced but benefit risk is still judged positive
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Benefit Risk Balance Different perspectives: Company - public health Regulator - public health Doctor - individual’s health Patient - individual’s health
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Benefit Risk Balance The target diseases is key to the balance: Self limiting – common cold Chronic progressive - diabetes Intermittent – multiple sclerosis Morbidity - suffering Mortality - death
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Benefit Risk Balance Population being treated: Young vs. old Ethnic differences
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Benefit Risk Balance Purpose of intervention: Prevention - vaccines Treatment – cancer txs Diagnosis – contrast media
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Benefit Risk – a Continuous Process Drug discovery Phase I Phase II Phase III MAA Marketing Renewal Reclassification …. where the outcome may differ….
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Benefit Risk – Ever Changing New data New alternatives New disease
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From one-off licensing… Level of under-standing of benefit-risk Time → MA Warning, DHPC Withdrawal backlash Drug Development Phase PhV PhV, other sources
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Example Evolution of Remicade (EU): Efficacy 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 13 Aug Initial Marketing Authorisation 27 June Extension of Indication: Adult Rheumatoid Arthritis (II-01) 29 Jan Change: Reduction in rate of progression of joint damage in RA (II-04) 17 May Change: Restriction of the Crohn’s disease indication (USR) 15 May Extension of Indication: Ankylosing spondylitis (II-24) 20 Oct Change: Long term treatment in CD (II-32) 8 June Change: Treatment of MTX naïve patients with early RA (II-45) 24 Sept Extension of Indication: Psoriatic Arthritis (II-46) 29 Sept Extension of Indication: Plaque Psoriasis (II-61) 28 Feb Extension of Indication: Ulcerative Colitis (II-65) 4 July Change: Use alone of in combination with MTX in Psoriatic Arthritis (II-73) 1 Sept Extension of Indication: From 3rd to 2nd line in Crohn’s disease (II-69) 30 May Extension of Indication: Paediatric Crohn’s disease (II-75) 30 Oct Change: Patients who did not respond to therapy regardless of HLA-B27 status in Ankylosing Spondylitis (II-95) 30 Nov Change: Improvement of physical function and reduction of rate of progression of structural damage in Psoriatic Arthritis (II-100) 8 April Change: Update on colectomy, hospitalisations and surgeries in patients with Ulcerative Colitis (II-107)
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Example Evolution of Remicade (EU): Safety - 1 2000 2001 2002 2003 2004 Severe Infections German “death scare” TB/infections Alert card TB education TB DHPC CD: 2nd to 3rd line therapy SP commitment to CD and RA Registry PSUR 3 pancytopenia listeriosis CHF DDL PSUR interstitial pneumonitis/fibrosis FDA panel lymphoma PSUR 5 myelitis, anaemia, hepato cellular damage Alcoholic hepatitis (study stopped) General DHPC Serum sickness, pericardial effusion PSUR 6 & 7 vasculitis Dinv Letter haematologcal AE Dinv Letter Transaminases PSUR 8 agranulocytosis pancreatitis DHPC Hepatotoxicity Malignancies PSUR 9 Heart failure DHPC Lymphoma
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Example Evolution of Remicade (EU): Safety - 2 2005 2006 2007 2008 2009 Pneumonia Delayed hypersensitivity Hepatotoxicity Malignancies in COPD patients Opportunistic infections & Pneumocystis jiroveci Pneumonia Hepatosplenic T-cell lymphoma in paediatric/young adult CD patients Malignancies (Update) Infusion reactions, antibodies & infections in juvenile idiopathic arthritis (no indication) Reactivation of HBV (update), new onset psoriasis and pustular (palmar/plantar) psoriasis Tuberculosis (update) & skin and toxic epidermal necrolysis, SJS and erythema multiforme Intersticial lung disease Peripheral demyelinating diseases Tuberculosis (update, including extrapulmunary disease Hepatosplenic T-cell lymphoma in patients with ulcerative colitis Invasive fungal infections (update)
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Authorised in EU in September 2004 to treat adults with moderate to severe plaque psoriasis who have failed to respond or cannot take other systemic treatments (2nd line therapy). BENEFITS – efficacy in a ‘high-need’ group of patients, i.e. those with moderate to severe disease that do not have treatment alternatives SAFETY – most frequent side effects: flu-like symptoms – limited data available for long-term therapy CONCLUSIONS: BENEFITS outweigh RISKS (in this restricted group of patients) Example RAPTIVA B/R: the starting point…
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September 2008 – January 2009 Three cases of progressive multifocal leukoencephalopaty (PML) identified PML: Rare brain infection caused by a virus Virus commonly found in the general population but only leads to PML if the immune system has been weakened Usually leads to severe disability or death Raptiva no longer only therapeutic option for these high-need patients other products had meanwhile been approved for use in moderate to severe psoriasis Example RAPTIVA B/R: the post-authorisation
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