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Acknowledgement
This presentation reflects the work of colleagues at the Department of Pharmaceutical Affairs, and exchanges with colleagues within the MEDEV Committee, EUnetHTA and other fora. Their creative input ist gratefully acknowledged. Special thanks to Engelbert Staudacher
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Disclaimer
The contents presented here reflect my personal opinion. They are not necessarily identical with those of the Department, the Federation of Austrian Social Security Institutions, its Advisory Committees or its management.
Therapeutic disclaimer: The mentioning of specific products does not imply a positive or negative recommendation of their use
2012 Main Assoc. of Austrian Social Security Institutions
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The Basics
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From http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2011/06/WC500107046.pdf
2012 Main Assoc. of Austrian Social Security Institutions
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Biomarker Definition
A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention
BIOMARKERS DEFINITIONS WORKING GROUP: BIOMARKERS AND SURROGATE ENDPOINTS: PREFERRED DEFINITIONS AND CONCEPTUAL FRAMEWORK. CLIN PHARMACOL THER 2001;69:89-95.
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Maraviroc: Before taking CELSENTRI it has to be confirmed that only CCR5-tropic HIV-1 is detectable CXCR4 or dual/mixed tropic virus not Biomarkers of (i.e. disease : covering measurement ofdetected) endogenous LA-B*5701 anAbacavir: adequately validated sensitive detection substances or using parameters indicative of and a disease process and the use of pharmacodynamic genetic markers in evidence-based method a newly drawn blood sample. The BUTonand laboratory medicine and treatment (markers efficacy); Monogram Trofile assay was used of in the clinical In any patient treated Biomarkers of exposure : covering detection and measurement of studies of CELSENTRI [] Other phenotypic and with abacavir, the internal exposure to drugs and other chemicals; genotypic assays are currently being evaluated.
clinical diagnosis of Biomarkers of response : including measures of endogenous substances or parameters indicative of pathological or biochemical suspected changes both toxicodynamic and pharmacodynamic, resulting from hypersensitivity reaction NSCLC: Objective exposure to drugs and otherGefitinib chemicals; must remain the basis of Response Rate for EGFR Biomarkers of susceptibility : including genetic factors which alter mutation positive patients: susceptibility to drugs and other chemicals. clinical decision-making
71% Objective Response Rate for EGFR-mutation Read More: http://informahealthcare.com/page/bmk/Description negative patients: 1%
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A Word of Caution
Genomics analyses from single tumor-biopsy specimens may underestimate the mutational burden of heterogeneous tumors. Intratumor heterogeneity may explain the difficulties encountered in the validation of oncology biomarkers owing to sampling bias,29 contribute to Darwinian selection of preexisting drug-resistant clones,12,30 and predict therapeutic resistance.13
Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing Gerlinger et al., N Engl J Med 2012; 366:883-892, March 8, 2012,DOI: 10.1056/NEJMoa1113205
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Legal Basics
Pharmaceuticals:
Marketing Authorisation Transparency Directive (89/105/EWG) National Regulations
Diagnostics:
Medical Devices Directive (93/42/EEC) National Regulations
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Council Directive 89/105/EEC of 21 December 1988 relating to the transparency of measures regulating the prices of medicinal products for human use and their inclusion in the scope of national health insurance systems
Legal Status: Directive, Issued by the Council of European Communities Scope: Direct or indirect controls on the price of medicinal products Content: Decisions taken must be:
Timely (90 + 90 days) Based on objective & verifiable criteria The applicant shall be informed of the remedies available to him under the laws in force and the time limits allowed for applying for such remedies
2012 Main Assoc. of Austrian Social Security Institutions
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Definition of medical device Placing on the market and putting into service Classification according to risk No regulation of reimbursement
...neither in the current Transparency Directive,
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Evaluation for Reimbursement What are the available alternatives? Is the new drug better? Is the price worth the difference?
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Types of Assessment
Rapid Assessment Assesses single product in comparison to alternatives Used for new drugs, so subject to Transparency Directive
Full Assessment Reviews whole group of drugs used for one indication Re-evaluates existing therapeutic group Less time constraint
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Orphan Drugs are too Expensive Yearly Cost of Orphan Drugs per Patient Minimum Median Maximum 1 251 32 242 407 631
Estimating the budget impact of orphan medicines in Europe: 2010 2020 Orphanet Journal of Rare Diseases 2011, 6:62 doi:10.1186/1750-1172-6-62, Carina Schey (carina@gmasoln.com), Tsveta Milanova (tmilanova@celgene.com), Adam Hutchings (adam@gmasoln.com)
2012 Main Assoc. of Austrian Social Security Institutions
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Average Cost per Package excl. VAT of all Drugs in Austria in 2011
Average Cost per Package excl. VAT of Orphan Drugs in Austria in 2011
20,90
2.698,96
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Regulate the monopoly granted by orphan drug status Differentiate between orphan drugs developed de novo and those which have been extensively used before marketing authorisation Re-evaluate the definition of Orphan: At the time of the introduction of the Orphan Drug Legislation in 2001, Europe had 377 million inhabitants, now it has 500 million
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10
Lower Degree
25 000 to 250 000
Medium Degree
2 500 to 25 000
High Degree
less than 2 500 no alternatives except best supportive care new drug addresses major unmet need
incremental
major
curative
30-60% plausible
>60% unequivocal
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Paying for the Orphan Drug System: break or bend? Is it time for a new evaluation system for payers in Europe to take account of new rare disease treatments?
Orphanet Journal of Rare Diseases 2012, 7:74 doi:10.1186/1750-1172-7-74, Wills Hughes-Wilson (wills.hughes-wilson@sobi.com), Ana Palma (apalma@shire.com), Ad Schuurman (ASchuurman@cvz.nl), Steven Simoens (steven.simoens@pharm.kuleuven.be)
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Managing Complexity
Co-Assessing Diagnostic & Therapeutic Different procedures, different agencies, different criteria? Bi1
Orphanisation
Deteriorating levels of evidence, increasing prices?
2012 Main Assoc. of Austrian Social Security Institutions
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Status quo:
Currently, the Summary of Product Characteristics (SPC) is a text document, approved by competent authorities (EMA/CHMP EC), summarising the characteristics, dos and don'ts of a drug, addressed to (primarily) the prescribing physician and intended to guide prescribing. Even in electronic form, it is a lengthy and cannot be crossreferenced.
e-SPC delivering drug information in the 21st century : Developing new approaches to deliver drug information to prescribers; Simon Maxwell, Hans-Georg Eichler, Anna Bucsics, Walter E Haefeli and Lars L Gustafsson, on behalf of the e-SPC consortium; DOI: 10.1111/j.13652125.2011.03981.x
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Slide 23 Bi1 Who pays for the test? Helicobacter-Eradicaton & Helicobacter-Test HDL/LDL-Assay and statins
Anna Bucsics, 15/10/2012
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Crizotinib (Xalkori): Costs $116.000 per patient per year in the US Indicated for 3-7% of pre-treated patients with ALK+ Non-Small-Cell-Lung Cancer Test costs ca. $250-$1.500 per Patient
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Vemurafenib Zelboraf
Indication
Vemurafenib is indicated in monotherapy for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma (see section 5.1). .
SmPC
Before taking vemurafenib, patients must have BRAF V600 mutation-positive tumour status confirmed by a validated test. In the phase II and phase III clinical trials, eligible patients were identified using a real-time polymerase chain reaction assay (the cobas 4800 BRAF V600 Mutation Test). This test has CE marking and is used to assess the BRAF mutation status of DNA isolated from formalin-fixed, paraffin-embedded (FFPE) tumour tissue.
*Source Austrian price list June 2012
Health Technology Assessment World Europe 2012 Seite 28 Page 28
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