New Medicines:too early/too late?

Thomas LönngrenEMEA

Sweden, 3 July 2009

The drug regulator’s walk on the tightropeProtect 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

6Risks 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

Withdrawalbacklash

Drug Development

Phase

PhV

PhV, other sources

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ExampleEvolution of Remicade (EU): Efficacy

1999 2000 2001 2002 2003 2004 2005 2006 2007 200813 AugInitial Marketing Authorisation

27 JuneExtension of Indication:Adult RheumatoidArthritis (II-01)

29 JanChange:Reduction in rate of progression of joint damage in RA (II-04)

17 May Change:Restriction of the Crohn’s disease indication (USR)

15 MayExtension of Indication:Ankylosing spondylitis (II-24)

20 OctChange:Long term treatment in CD(II-32)

8 JuneChange:Treatment of MTX naïve patients with early RA (II-45)

24 SeptExtension of Indication:Psoriatic Arthritis (II-46)

29 SeptExtension of Indication:Plaque Psoriasis (II-61)

28 FebExtension of Indication:Ulcerative Colitis (II-65)

4 JulyChange: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 MayExtension of Indication:Paediatric Crohn’s disease(II-75)

30 Oct Change:Patients who did not respond to therapy regardless ofHLA-B27 status in Ankylosing Spondylitis(II-95)

30 Nov Change:Improvementof 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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ExampleEvolution of Remicade (EU): Safety - 1

2000 2001 2002 2003 2004

Severe Infections

German “deathscare”

TB/infectionsAlert 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 interstitialpneumonitis/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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ExampleEvolution 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-celllymphoma inpaediatric/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)

ExampleRAPTIVA

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

ExampleRAPTIVA

B/R: the post-authorisation

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January 2009 – BENEFITS

• (Modest) efficacy in the treatment of high-need patients in a condition that is disabling and causes social an psychological problems for patients

• BUT the condition is very rarely life-threatening • AND other therapies are now available

– RISKS• PML cases (three confirmed, one suspected)• Other serious side effects such as infections (meningitis, sepsis,

tuberculosis) • INCLUDING some with a fatal outcome

ExampleRAPTIVA

B/R: the post-authorisation

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January 2009– BENEFITS vs RISKS? How to change B/R?

• Difficult to identify patients at risk of PML• Not possible to identify restricted population for whom benefits outweigh the

risk of PML

Further restrictions to PI unlikely to reduce risk!

BENEFITS NO LONGER OUTWEIGH RISKS

SUSPENSION OF MAMA subsequently withdrawn (at request of MAH) in June 2009

ExampleRAPTIVA

B/R: the post-authorisation

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• Better science– Biomarkers to personalized medicines

• Examples…

Strengthening the system

PROTECT

Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium

… improving the methodology of safety monitoring

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How to improve benefit risk assessment

• Enhance methodology of Benefit-Risk assessment• Goals:

– Qualitative Quantitative– Implicit criteria Explicit criteria– Incorporate patients’ valuations of

beneficial/adverse outcomes• Actions:• To revise/structure the current benefit-risk

assessment section of the CHMP assessment report• To further research the methodology of benefit

risk assessment

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Risk Management Plan

Risk Management: a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicinal products, including the assessment of the effectiveness of those interventions

Proactive: Sponsor submits “EU Risk Management Plan” at time of MAA, updated throughout the lifecycle of the product

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Focus on adverse reaction reportingand Eudravigilance

• Eudravigilance = web based data-processing network and management system for electronic exchange, management and scientific evaluation of individual case safety reports (ICSR)

• Current Eudravigilance functionality:– The Industry and all EU Member States and are electronically reporting to

Eudravigilance– All Member States can analyse the data to conduct safety monitoring

(pharmacovigilance)– Compliance with data protection legislation (notified to the DPS in

August 2008)– Pooled data – detects ADRs earlier, detects rare ADRs, compare ADRs

based on how medicines used: better protect health– More than 2 million case reports and 30,000 new reports per month

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• Capacity building – ENCePP• European network for centers in

pharmaepidemiology and pharmacovigelance

Post-Authorisation Safety Studies

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Conclusions

• Regulating medicines:– Difficult judgements

– We have many regulatory and scientific tools to help

– We are investing to strengthen – Benefit risk balance is key