Assessing value of orphan drugs and personalised medicine

Anna Bucsics, Hans Seyfried

Department of Pharmaceutical Affairs
Main Association of Austrian Social Security Institutions

2012 Main Assoc. of Austrian Social Security Institutions

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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
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The Basics

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Orphan Designation Criteria

RARITY (prevalence) Medical condition affecting not more than 5 in 10,000 persons in the Community (around 250,000) OR RETURN ON INVESTMENT: Without incentives it is unlikely that the marketing of the product would generate sufficient return to justify the necessary investment SERIOUSNESS: Life threatening or chronically debilitating ALTERNATIVE METHODS AUTHORISED If satisfactory method exist the sponsor should establish that the product will be of significant benefit

From http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2011/06/WC500107046.pdf
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What is personalised medicine?

Personalised medicine aims to provide the right diagnosis leading to prevention or treatment at the right dose to the right patient at the right time. Rather than having an unique treatment for each individual, patients can be sub-divided into groups based on their individual biological characteristics.
Personalised Medicine Opportunities and Challenges for European HealthCare. Workshop report, Bad Hofgastein, 7. October 2010

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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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Biomarkers an Expanding Field

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
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Council Directive 93/42/EEC of 14 June 1993 concerning medical devices

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,

nor in the proposed changes

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THE FOURTH HURDLE

Marketing Authorization Quality Efficacy Safety

Evaluation for Reimbursement What are the available alternatives? Is the new drug better? Is the price worth the difference?

Marketing Authorization vs. Reimbursement

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Domains of the Core Model

1. Health Problem and Current Use of the Technology 2. Description and Technical Characteristics of Technology 3. Clinical Effectiveness 4. Safety 5. Costs and Economic Evaluation Evaluation 6. Ethical Analysis 7. Organisational Aspects 8. Social Aspects www.eunethta.eu www.eunethta.net 9. Legal Aspects
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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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Therapeutic Value of a New Product and Price

Is it the first and only drug for treatment of disease?
therapeutic advantage, limited potential for price negotiations

Is it safer and/or more effective for most patients?

Therapeutic advantage, higher price justified

Is it safer and/or more effective for a certain group of patients?

Therapeutic advantage but limitations may apply; higher price or marketing advantage

No advantages, but important disadvantages?

Usually not a desirable product, therefore no price negotiations

Same therapeutic value as available alternatives

Must offer an economic advantage

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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)
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The Price of Orphan Medicinal Products

Prices of Orphan Medicines are extremely high They are creating concerns about affordability and solidarity.

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

Loss of orphan status orphan price remains

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Proposals for improving access through better affordability

Change one to both
To qualify for orphan designation, a medicine must meet both of these criteria: It is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 people in the EU at the time of submission of the designation application; It is intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition and without incentives it is unlikely that the revenue after marketing of the medicinal product would cover the investment in its development.

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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Mechanism of Coordinated Access to Orphan Medicinal Products

Framework: Process on Corporate Responsibility in the field of Pharmaceuticals Specific objectives linked to the work packages
WP1: assessment/evaluation WP2: Mechanisms of selection of targets and funding WP3:Treatment (individual access)

Participants: DG ENT, MS and stakeholders (Patients, Payers, Pharma), assisted by EMINet

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Proposal for a Transparent Value Framework

Criterion
Number of Patients in EU (Pop. 500 000 000) Available Alternatives/Unmet Need, including non-pharmaceutical treatment options (Innovation) Relative Effectiveness, Degree of Net Benefit (Clinical Improvement, QoL, etc. vs. side effects) relative to alternatives, including no treatment Response Rate (based on best available selection criteria) Degree of Certainty (Documentation)

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

yes, new medicine does not address unmet need

yes, but major unmet need still remains

incremental

major

curative

<30% promising but not welldocumented

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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Personalised Medicine Challenges & Concerns

Managing Complexity
Co-Assessing Diagnostic & Therapeutic Different procedures, different agencies, different criteria? Bi1

Orphanisation
Deteriorating levels of evidence, increasing prices?
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The Challenge of Complexity: Coordinating Information on Drugs, Diagnostics and Devices

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.

Vision: the eSPC

Putting the information provided in the SPC into a structured database which can be queried and cross-referenced

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

Challenges to Estimating Efficiency of Personalised Medicines

Limitations of Clinical Data - Status quo:
Usually generated for marketing authorisation, not for determining reimbursement status Scarcity of head-to-head comparisons Scarcity of clinical endpoints Product may be appropriate (cost-effective) for a special group of patients, but data for this (sub)group are missing

Key Questions for Biomarker-Based Medicines :

Validity of Biomarker Will the level/quality of evidence for the diagnostic be of the same standard as the current one for pharmaceuticals? How best to assess two interdependent dossiers?
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Key Economic (and other) Concerns

Salami slicing no economies of scale Blockbuster tests and orphan prices? Lock-in of diagnostics and therapies? How to make sure that post-marketing evidence is valued fairly? Access to registries? Uncertainty due to regulatory variations in diagnostics and therapeutics
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Blockbuster-Tests and Orphan-Prices?

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

5.1 Determination of BRAF mutation status

Costs: Ca. 100.000 per patient per year*

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
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...Thank you very much for your attention!

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