Transcript Slide 1

New Medicines:
too early/too late?
Thomas Lönngren
EMEA
Sweden, 3 July 2009
The drug regulator’s walk on the tightrope
Protect public health …
… against negative
consequences
from unsafe or
ineffective
medicines
When in doubt, be
negative, “we need
more information”
… against negative
consequences from
failing to meet unmet
medical need
Worry about falsepositive decision
Worry about falsenegative decision
“Type-1 error”
What are the
consequences?
When in doubt, be
positive, “it might be
a patient's only hope”
Are the (dis-)
no penalty
for
error”
incentives balanced “Type-2
right to influence
being
What are the
regulators’
negative!
consequences?
behaviour?
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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Benefit-Risk balance is key
Risks
Benefits
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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, …
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– “early approval”
Conditional Approval (New)
•
•
•
Scope
– Orphan drugs, emergency threats, serious and lifethreatening 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
Phase III
MAA
Phase II
Marketing
Phase I
Renewal
Drug
discovery
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…
Warning,
DHPC
MA
Level of
understanding
of
benefitrisk
Withdrawal
backlash
PhV, other
sources
PhV
Drug
Development
Phase
Time →
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Example
Evolution of Remicade (EU): Efficacy
1999 2000 2001
2002 2003
2004 2005 2006
2007
2008
13 Aug
Initial
Marketing
Authorisatio
n
17 May
Change:
Restriction of
the Crohn’s
disease
indication
(USR)
8 June
Change:
Treatment of
MTX naïve
patients with
early RA
(II-45)
28 Feb
Extension of
Indication:
Ulcerative
Colitis
(II-65)
30 May
Extension of
Indication:
Paediatric Crohn’s
disease
(II-75)
4 July
Change:
Use alone of in
combination
with MTX in
Psoriatic
Arthritis
(II-73)
30 Oct
Change:
Patients who did not
respond to therapy
regardless of
HLA-B27 status in
Ankylosing
Spondylitis
(II-95)
8 April
Change:
Update on
colectomy,
hospitalisations
and surgeries
in patients with
Ulcerative
Colitis
(II-107)
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)
15 May
Extension of
Indication:
Ankylosing
spondylitis
(II-24)
20 Oct
Change:
Long term
treatment in
CD
(II-32)
24 Sept
Extension of
Indication:
Psoriatic
Arthritis
(II-46)
29 Sept
Extension of
Indication:
Plaque
Psoriasis
(II-61)
1 Sept
Extension of
Indication:
From 3rd to
2nd line in
Crohn’s
disease
(II-69)
30 Nov
Change:
Improvement
of physical function
and reduction of
rate of progression
of structural
damage in Psoriatic
Arthritis
(II-100)
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Example
Evolution of Remicade (EU): Safety - 1
2000
2001
2002
2003
2004
Severe Infections
TB education
CHF DDL
General DHPC
DHPC Hepatotoxicity
German “death
scare”
TB DHPC
PSUR interstitial
pneumonitis/fibrosis
Serum sickness,
pericardial effusion
Malignancies
TB/infections
Alert card
CD: 2nd to 3rd line
therapy
PSUR 9 Heart failure
FDA panel lymphoma
PSUR 6 & 7 vasculitis
DHPC Lymphoma
SP commitment to
PSUR 5 myelitis,
CD and RA Registry anaemia, hepato
cellular damage
PSUR 3
pancytopenia
Alcoholic hepatitis
listeriosis
(study stopped)
Dinv Letter
haematologcal AE
Dinv Letter
Transaminases
PSUR 8
agranulocytosis
pancreatitis
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Example
Evolution of Remicade (EU): Safety - 2
2005
2006
2007
2008
2009
Pneumonia
Opportunistic
infections
& Pneumocystis
jiroveci
Pneumonia
Reactivation of HBV
(update), new onset
psoriasis and
pustular
(palmar/plantar)
psoriasis
Peripheral
demyelinating
diseases
Hepatosplenic T-cell
lymphoma in patients
with ulcerative colitis
Delayed
hypersensitivity
Hepatotoxicity
Malignancies in
COPD patients
Hepatosplenic T-cell
lymphoma in
Tuberculosis (update)
paediatric/young adult & skin and toxic
CD patients
epidermal necrolysis,
SJS and erythema
Malignancies (Update) multiforme
Infusion reactions,
Intersticial lung
antibodies & infections disease
in juvenile idiopathic
arthritis (no indication)
Tuberculosis (update, Invasive fungal
including
infections (update)
extrapulmunary
disease
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Example
RAPTIVA
B/R: the starting point…
– 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)
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Example
RAPTIVA
B/R: the post-authorisation
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
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Example
RAPTIVA
B/R: the post-authorisation
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
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Example
RAPTIVA
B/R: the post-authorisation
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 MA
MA subsequently withdrawn (at request of MAH) in June 2009
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Strengthening the system
• Better science
– Biomarkers to personalized medicines
• Examples…
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PROTECT
Pharmacoepidemiological Research on Outcomes of
Therapeutics by a European Consortium
… improving the methodology of safety monitoring
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
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throughout the lifecycle of the product
Focus on adverse reaction reporting
and 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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Post-Authorisation Safety Studies
• Capacity building – ENCePP
• European network for centers in
pharmaepidemiology and pharmacovigelance
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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
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