Benefit-risk decisions in the licensing of medicines ... · Opt in Treatment decision would be...
Transcript of Benefit-risk decisions in the licensing of medicines ... · Opt in Treatment decision would be...
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Federal Institute for Drugs and Medical Devices | The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)
Benefit-risk decisions in the licensing of medicines Current EU practice and challenges
Harald Enzmann
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Federal Institute for Drugs and Medical Devices | The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)
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• Split responsibilities in the EU
• Present licensing of medicines in the EU • Principles • Limitations
• Future development of benefit risk
decisions in the licensing of medicines
Agenda
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Federal Institute for Drugs and Medical Devices | The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)
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• Split responsibilities in the EU
• Present licensing of medicines in the EU • Principles • Limitations
• Future development of benefit risk
decisions in the licensing of medicines
Agenda
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Innovative Das BfArM ist ein Bundesinstitut im Geschäftsbereich des Bundesministeriums für Gesundheit 4
28 member states
501 mio inhabitants
National authorisations,
MRP, DCP
Generic
44 national authorities
24 official languages
Responsibilities in the EU - Licensing
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Safety Issues Das BfArM ist ein Bundesinstitut im Geschäftsbereich des Bundesministeriums für Gesundheit 5
28 member states
501 mio inhabitants
HTA and payers
Reimbursement & Price Decisions
National or regional decision makers
24 official languages
Responsibilities in the EU – Post Licensing
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Federal Institute for Drugs and Medical Devices | The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)
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• Split responsibilities in the EU
• Present licensing of medicines in the EU • Principles • Limitations
• Future development of the licensing of
medicines
Agenda
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Federal Institute for Drugs and Medical Devices | The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)
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Benefit-Risk Decisions in Licensing Scientific Content in Marketing Authorization Application
• Efficacy: (two pivotal studies) • Superior to placebo or active comparator
• Non-inferior to active comparator
• Safety: (preclinical and clinical) • Safety risk must be outweighed by expected benefits
• Comparison with active comparator important
• NO economics • prize of product, costs of treatment are NOT part of the dossier
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Federal Institute for Drugs and Medical Devices | The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)
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1. Description of Benefits and Risks • Benefits
• Beneficial effects • Beneficial effects, focussed on but not limited to clinical efficacy
• Uncertainty • Impact of supportive data, subgroup differences, assumptions
• Risks • Unfavourable effects
• Adverse drug reactions, drug-drug interactions, toxicity profile, potential for misuse, environmental impact
• Uncertainty • Trial specifics, e.g. limited no. of patients, above average supervision
in trials, non-clinical safety findings Guidance for Assessors: http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004800.pdf
Benefit-Risk Decisions in Licensing Assessment of Marketing Authorization Applications
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Federal Institute for Drugs and Medical Devices | The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)
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• Assign values • Compare the favourable effects among each other • Compare the unfavourable effects among each other
• Assess the benefit-risk balance • “Evaluation of the positive effects in relation to the risks” • Compare and trade-off favourable and unfavourable effects
• Discuss the benefit-risk balance critically • Impact of uncertainties • Values according to perspectives of different stakeholders • Need for further studies
Guidance for Assessors: http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004800.pdf
2. Value Judgments of Benefits and Risks
Benefit-Risk Decisions in Licensing Assessment of Marketing Authorization Applications
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• Cure • Overall survival • Progression / disease free survival
• These endpoints include both efficacy and safety aspects
• Not dependent on patients‘ perception
• CHMP/205/95 Evaluation of anticancer medicinal products in man Rev.4/ Effective June 2013 • Acceptable primary endpoints include cure rate, OS and PFS/DFS. Convincingly demonstrated
favourable effects on survival are, from both a clinical and methodological perspective, the most persuasive outcome of a clinical trial. Prolonged PFS/DFS as such, however, is considered to be of benefit to the patient. … If PFS/DFS is the selected primary endpoint, OS should be reported as a secondary and vice versa.
Objective Description of Benefits Example: Efficacy Endpoints in Oncology
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Federal Institute for Drugs and Medical Devices | The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)
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• What are the AEs – as reported by patients or doctors • How frequent are the AEs - as reported by patients or doctors • How severe* are the AEs – may not reflect patients’ perception
• Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
• Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL**.
• Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL***.
• Grade 4 Life-threatening consequences; urgent intervention indicated.
• Grade 5 Death related to AE.
* Common Terminology Criteria for Adverse Events v4.0 (CTCAE) ** Instrumental Activities of Daily Living ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. *** Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.
Standardized Grading of Risks
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benefit risk
risk
risk benefit
benefit
benefit
risk
Treatment decision für einzelne Patientinnen oder Patienten • Abhängig von objektiven
individuellen Faktoren • Abhängig von subjektiven
individuellen Wertungen
Regulators’ Decision versus Treatment Decision
Regulatory decision for a clearly defined group of patients or target population
positive
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benefit risk
risk
risk benefit
benefit
benefit
risk
Treatment decision individual patients depend on objective findings depend on subjective perception
or judgment
Regulatory decision for a clearly defined group of patients or target population
positive but benefit risk may be negative for individual patients
Regulators’ Decision versus Treatment Decision
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benefit risk
risk
risk benefit
benefit
benefit
risk
Treatment decision Objective findings make benefit risk negative in individual patients • If predictable
treatment must not be started • modified indication or
contraindication
contraindication
Decision Based on Objective Findings
Regulatory decision for a clearly defined group of patients or target population
positive
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benefit risk
risk
risk benefit
benefit
benefit
risk X
X Regulatory decision is modified for a more clearly defined group of patients or target population
positive
Treatment decision Objective findings make benefit risk negative in individual patients If predictable • Do not use product • modified indication
or contraindication
Contra-indication
Decision Based on Objective Findings
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benefit risk
risk
risk benefit
benefit
benefit
risk
Treatment decision Objective findings make benefit risk negative in individual patients If NOT predictable • Stop treatment when necessary • Define stopping criteria
Regulatory decision for a clearly defined group of patients or target population
positive
Stop treatment
Decision Based on Objective Findings
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Federal Institute for Drugs and Medical Devices | The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)
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• Origin of the licensing of medicines
• Present licensing of medicines in the EU • Principles • Limitations
• Future development of benefit risk
decisions in the licensing of medicines
Agenda
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risk benefit
Treatment decision Individual patients may perceive or weigh benefits and/or risk differently depending on their personal preference
risk benefit
? ?
Decision Based on Perception and Personal Judgment
• Treatment decisions may differ from regulatory decisions
• Final decision by individual patients and their physicians (Opt in, Opt out)
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Importance of Patients’ Perception for Treatment Decisions
Regulators’ view : An increased cure rate in cancer, a potentially life-saving treatment will always outweigh a grade 1 or 2 AE (e.g. (permanent hair loss) - positive regulatory decision
Some patients’ view: This permanent hair loss is important, severe enough for me to decline the potentially curative and life-saving adjuvant therapy – negative treatment decision “The mastectomy and loss of breast are NOTHING compared to the loss of my hair.”
“Not a day goes by that I don’t regret doing the NN (therapy). Oh, if we could only turn back the hands of time!”
“I never, never, never would have agreed to take NN if I was informed of this 6.3% risk; even a 3% risk…or any risk…”
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risk benefit
Treatment decision: Individual patients may perceive or weigh benefits and/or risk differently depending on their personal preference
risk benefit
? ?
Decision Based on Perception and Personal Judgment
• Treatment decisions may differ from regulatory decisions • Final decision by individual patients
supported by their physician (Opt in, Opt out)
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benefit risk
risk
risk benefit
benefit
benefit
risk
Treatment decision negative • Individual patients perceive or
weigh benefits and/or risk differently
• Individual preference, judgment and final decision
Opt out
Patients’ “Opt out” (based on personal judgment)
Regulatory decision a clearly defined group of patients target population
positive
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risk benefit
benefit
benefit risk
risk
risk
benefit
Opt in Treatment decision would be positive • Individual patients perceive or weigh
benefits and/or risk differently • Individual preference and
judgment for final decision
Regulatory decision group of patients target population
negative
Patients’ “Opt in” (based on personal judgment)
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risk benefit
benefit
benefit risk
risk
risk
benefit
Opt in Treatment decision would be positive • Individual patients perceive or weigh
benefits and/or risk differently • Individual preference and
judgment for final decision
Regulatory decision group of patients target population
negative
Patients’ “Opt in” won’t work !
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Federal Institute for Drugs and Medical Devices | The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)
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• Origin of the licensing of medicines
• Present licensing of medicines in the EU • Principles • Limitations
• Future development of benefit risk
decisions in the licensing of medicines
Agenda
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Federal Institute for Drugs and Medical Devices | The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)
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Important Steps for New Medicines
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milestone
clinical development
marketing authorization
price and re-imbursement
treatment decision
decision maker
industry investors
regulators (EUC, NCA)
HTA bodies payers
physicians patients
rationale for decision
economic success expected
evidence of positive benefit-risk
evidence of acceptable cost-effectiveness
individual benefit expected
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Federal Institute for Drugs and Medical Devices | The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)
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• Marketing Authorization is but one stepping stone from bench to bedside
• Sequential decisions: usually positive decision for earlier milestone necessary for decision on next milestone
Important Steps for New Medicines
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milestone
clinical development
marketing authorization
price and re-imbursement
treatment decision
decision maker
industry investors
regulators (EUC, NCA)
HTA bodies payers
physicians patients
rationale for decision
economic success expected
evidence of positive benefit-risk
evidence of acceptable cost-effectiveness
individual benefit expected
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Federal Institute for Drugs and Medical Devices | The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)
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• Provide the first impartial assessment of benefit-risk • Description of benefits and risks (strengths and weakness) • Judgment on benefit risk balance
• Understand their assessment as a stepping stone for subsequent decisions • Give rationale for judgment / decision • Comprehensible and useful for non-regulators
• Respect (and give room for) divergent value judgments • From social communities (HTA bodies, payers) • From individuals (patients and physicians)
• Remember the common ultimate goal • Benefit the (individual) patient
Developing Role of Regulators (PURR)
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Thank you for your attention!
Federal Institute for Drugs and Medical Devices | The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health (Germany)