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08/06/16 1

GENEESMIDDELEN: ONTWIKKELING, REGISTRATIE en TERUGBETALING

Prof. Dr. Alain Dupont Klinische Farmacologie en Farmacotherapie UZ Brussel

Pag. 08/06/16 2

Farmacologie en Farmacokinetiek-hoofdstuk 1

ONTDEKKING / ONTWIKKELING VAN GENEESMIDDELEN

1. Synthese/Ontdekking van het geneesmiddel (“Discovery”)

ü  Kruiden, planten,… ü Nieuwe scheikundige verbindingen ü  Toevallige ontdekkingen (serendipiteit*) ü Wijzigingen bestaande moleculen ü Random screening: in vitro en in vivo farmacologie ü Rationeel ontwerp: “drug design”

* “de kunst een ongezochte vondst te doen”

Pag. 08/06/16 3


2. Niet-klinische ontwikkeling

Ø  Farmacodynamiek, farmacokinetiek

Ø  Chemische ontwikkeling

Ø  Farmaceutische ontwikkeling

Ø  Niet-klinische veiligheid / toxicologisch onderzoek

ü  Acute toxiciteit (één dosis) ü  Subacute – chronische toxiciteit (verschillende species, verschillende toegangwegen) ü  Speciale Onderzoeken

§  Mutageniciteit §  Carcinogeniciteit §  Teratogeniciteit

Pag. 08/06/16 4


Dierexperimenteel onderzoek (in vitro, in vivo) Probleem = extrapolatie naar de mens (beperkte voorspellende waarde) Ø  Verschillen in:

ü  farmacologische werking ü  farmacokinetiek ü  farmacodynamiek (adequaat diermodel ontbreekt vaak)

Ø  Verschillen in bijwerkingen/toxiciteit

Nood aan: Geneesmiddelenonderzoek bij de mens

KLINISCHE FARMACOLOGIE = De wetenschap die zich bezighoudt met de studie van de werking van geneesmiddelen op de mens, en de (in)werking van het menselijk orga- nisme op geneesmiddelen (geneesmiddelenonderzoek bij mensen/ rationele farmacotherapie)

Pag. 08/06/16 6


3. KLINISCHE ONTWIKKELING Fase I: Ø  Eerste toediening aan mensen

ü  gezonde proefpersonen (soms "patiënt-vrijwilligers") ü  dosis-escalatie

à Veiligheid, nevenwerkingen ("MTD") à Farmacokinetiek à Farmacodynamiek (als mogelijk) (PK-PD) Fase II: IIa, IIb Ø  Relatief kleine groepen, zorgvuldig geselecteerde patiënten à Therapeutisch gunstig effect (vaak surrogaat eindpunten) à Veiligheid, bijwerkingen à Optimale dosering, dosis-respons relatie à PK (bij voorkeur gerandomiseerde, gecontroleerde studies)

Pag. 08/06/16 7


Fase II:

Ø  Fase IIa:

ü  "Piloot"-studies (“exploratory development”; “proof of principle studies”)

- biomarkers; surrogaat eindpunten

Ø  Fase IIb: (“confirmatory” trials)

= vaak aantonen/bevestigen van efficaciteit – optimale dosis

Pag. 08/06/16 8


Fase III: Ø  Grotere patiëntengroepen, minder geselecteerd

Ø  Gebruik makend van de optimale dosering

Ø  Efficaciteit vs veiligheid

Ø  "Harde", klinische eindpunten

Ø  Gerandomiseerde, gecontroleerde, dubbel-blinde studies à efficaciteit

Ø  Open, "long-term", veiligheidsstudies

Ø  Trials in speciale risicogroepen (bejaarden, kinderen, nier-/leverinsufficiëntie, …) Ø  Geneesmiddeleninteracties

Pag. 08/06/16 9


Fase IIIa: Vóór submissie aan autoriteiten (o.a. "FDA", "European Medicines Evaluation Agency") Fase IIIb: Ná submissie voor registratie, maar vóór op de markt komen Fase IV: Ø  Onderzoek ná het op de markt komen

o.a. PMS (b.v. opsporen van zeldzame bijwerkingen) o.a. Morbiditeits/mortaliteitstrials

Pag. 08/06/16 10


~100 Discovery Approaches

1 - 2 Products

High Risk Process 12 - 15 years

Cost of development 1.200 Mo euro on average

Drug discovery is a high-risk process

Discovery Exploratory Development

Idea Drug 12 - 15 Years

Full Development Phase I Phase II Phase III

0 15 5 10

Preclinical Pharmacology

Preclinical Safety

Millions of Compounds Screened

Clinical Pharmacology & Safety

Attrition is High in the R&D Process

Pag. 11

Source: EFPIA: Medicines for Mankind

Es#mate of R&D cost: 0,3 to 1,3 billion $; 30 to 50 new medicinal products per year

"   Introduc#on & background: R&D

importance of REA in market access

Pag. 08/06/16 12 Herhaling titel van presentatie

Total number of R&D projects


Figure 4: Pharmaceutical R&D expenditure 1980 to 2003 in billion Euro (adjusted for inflation, 2000=100)

1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 Source: Parexel’s Pharmaceutical R&D Statistical Sourcebook 2003/2004, pages 1, 289, and

296. European data based on official figures provided by EFPIA member associations. It covers all R&D spending within EFPIA countries (EU-15, excl. Lux, plus Switzerland and Norway) by national and foreign companies. The 2002 figure is an estimate. Japanese data from the JPMA Data Book 2003. US pharmaceutical spending is based on the PhRMA Annual Survey, 2003. Inflation adjustment and conversion to Euro using CPI data and exchange rates from Datastream.

Pag. 08/06/16 18 Herhaling titel van presentatie 08/06/16 18 Herhaling titel van presentatie


ü Strong upward trend of global R & D expenditure over the past decade ↔ no increase in the number of new products

Fall in innovative productivity

Pag. 08/06/16 21


KLINISCHE EVALUATIE VAN GENEESMIDDELEN Doel = "risk-benefit ratio" te kennen

~ doeltreffendheid ~ mogelijke bijwerkingen op korte en lange termijn

Geneesmiddelenonderzoek ("trials") moeten voldoen aan "Good Clinical Practice" = ethische en wetenschappelijke kwaliteitsstandaard "Een standaard voor het plannen, uitvoeren en rapporteren van klinische trials zodat de gemeenschap zeker kan zijn dat de data geloofwaardig zijn, en dat de rechten, de integriteit en de privacy van de proefpersonen beschermd zijn"

Pag. 08/06/16 22


KLINISCHE EVALUATIE VAN GENEESMIDDELEN Ø  Gebaseerd op o.a. "Declaration of Helsinki" (ethiek)

Ø  Onderschreven door "International Conference on Harmonisation" (ICH) (registratie-autoriteiten van EU-lidstaten, Japan en Noord-Amerika) Ø  Toelaatbaarheid van het onderzoek

à lokale "Medische Ethische Commissies“ (o.a. "informed consent")

Pag. 08/06/16 23


INTRODUCTIE VAN NIEUWE GENEESMIDDELEN Ø  Registratieprocedure: Dossier:

ü  Farmaceutisch deel ü  Dierexperimenteel deel (Toxico-farmacologie) ü  Humaan deel (vnl. de Klinische Studies) Fase 1à 3

à Ministerie van Volksgezondheid (Geneesmiddelencommissie/ FAGG) à Toelating om het geneesmiddel op de markt te brengen voor bepaalde indicatie en met een bepaalde informatie (wetenschappelijke en patiën- tenbijsluiter) (Basis = efficaciteit/veiligheidsratio) (Europees: centrale procedure, decentrale procedure)

Pag. 08/06/16 24


ü  Gezonde vrijwilligers ü  Patiënten

Ø  Chemisch-farmaceutisch Ø  Dierexperimenteel-farmacologisch onderzoek Ø  Klinisch farmacologisch

REGISTRATIE [N.B: • Gunstig farmacodynamisch effect betekent niet noodzakelijk ook "klinisch relevante doeltreffendheid" → "surrogaat-versus-klinische eindpunten"] • Innovatief werkingsmechanisme betekent niet noodzakelijk “therapeutische meerwaarde””

Pag.

Marketing Authorisation in Europe

  A medicinal product may only be placed on the market in the European Union when a marketing authorisation has been issued by the competent authority of a Member State for its own territory (“national authorisation”)

or an authorisation has been granted in accordance with Regulation (EEC) No 2309/93 for the entire Community (“Community authorisation”)

Pag.

National Authorisations   For marketing authorisations in more than one Member State, the person responsible for placing the product on the market may:

  - make an application in one of the Member States (the Reference Member State) and once the marketing authorisation has been granted, make applications in other Member States concerned,requesting them to mutually recognise the marketing authorisation already granted-MUTUAL RECOGNITION   - or make (parallel) applications in each of the Member States concerned and request a national authorisation in each

Pag.

Community Authorisations   A centralised Community procedure for the authorisation of

medicinal products has been created, for which there is a single application, a single evaluation and a single authorisation allowing direct access to the single market of the Community

  The “European Medicines Agency (EMA)” is responsible for co-ordinating the existing scientific resources put at its disposal by the competent authorities of the Member States for the evaluation and supervision of medicinal products

  Within the EMA, the “Committee for Proprietary Medicinal Products (CPMP)” is responsible for preparing the opinion of the Agency on any question relating to the evaluation of medicinal products for human use

Pag.

Centralised Procedure   Types of products for which the Community

Procedure has to be or can be followed:

  -Medicinal products derived from biotechnology   to obtain marketing authorisation, application must be

submitted to the EMEA and the application will be processed via the centralised procedure

  -Innovatory medicinal products   applications for medicinal products containing a new active

substance may use the centralised procedure;   in addition, applications for innovatory medicinal products with

novel characteristics may at the request of the applicant, be accepted for consideration under the centralised procedure

Pag.

Centralised Procedure

  the EMA ensures that the opinion of the CPMP is given within 210 days

  the CPMP Assessment Report is forwarded to the Commission, the Member States and the applicant stating the reasons for its conclusion within 30 days of its adoption

  the EMA makes the “European Public Assessment Report (EPAR)” available from the date of the Commission’s Decision to grant the marketing authorisation

  Marketing authorisation granted under the centralised procedure: valid for the entire Community market ( the product may be put on the market in all Member States)

Pag.

Mutual Recognition Procedure

  A pharmaceutical company wishing to market a medicinal product in more than one Member State must use

  -either the “centralised” procedure for medicinal products falling under the scope of this procedure

  -or the “mutual recognition”(decentralised) procedure

  Mutual Recognition can be achieved by asking to other Member States to mutually recognise,within 90 days,the marketing authorisation granted by the “Reference Member State”

Pag.

Mutual Recognition Procedure

  A marketing authorisation in one Member State ought in principle to be recognised by the competent authorities of the other Member States, unless there are grounds for supposing that the authorisation of the medicinal product concerned may present a “risk to public health” (this refers to the quality, safety and efficacy of the product)

  In the event of disagreement between Member States, which has not been resolved by day 90, a scientific evaluation will be done by the CPMP in the EMA, leading to an opinion arising from which the Commission will prepare a single decision on the area of disagreement, binding all the Member States

Pag. 08/06/16 32


1.  Ministerie van Economische Zaken (gebaseerd op nationale prijzenpolitiek) 2.Commissie Tegemoetkoming Geneesmiddelen

ü  Op basis van vergelijking met andere medicamenten; al of niet terugbetaling, voorwaarden voor terugbetaling ü  Relatieve therapeutische waarde ü  Farmaco-economische analyse ü  Budgettaire impact ü  Beslissing (binnen 180 dagen)à Minister van Sociale Zaken

BEPALING VAN DE KOSTPRIJS VAN EEN GENEESMIDDEL

Pag. 08/06/16 33


TERUGBETALING VAN GENEESMIDDELEN

Ø Klasse A : volledig terugbetaald (b.v. insuline)

Ø Klasse B : gedeeltelijke, proportionele terugbetaling

(b.v. antibiotica)

Ø Klasse C : gedeeltelijke, beperktere terugbetaling (b.v. "cerebrale vasodilatoren")

Ø Klasse D : geen terugbetaling

(b.v. tranquillizers)

Betaald door : - RIZIV - Mutualiteiten

Pag.

Minister F. Vandenbroucke (16 okt 2000) “Vernieuwd geneesmiddelenbeleid :

Doelstellingen en beleidslijnen”

”huidige situatie” (in 2000) Ø Overconsumptie van (vaak onnodige) geneesmiddelen Ø Vertraagde terugbetaling en beschikbaarheid van

innovatieve geneesmiddelen

Pag.

  Objectieven:

Ø Adequaat gebruik van de middelen: medicatiegebruik baseren op evidentie en richtlijnen

Rationeel voorschrijven promoten

Ø Versnelde en adequate evaluatie en snellere toegang tot de markt van nieuwe innovatieve geneesmiddelen met therapeutische meerwaarde

Nieuwe terugbetalingsprocedure

Pag. 08/06/16 36 Herhaling titel van presentatie 01-12-2008 36 Evidence Based Reimbursement

28 members (2002) •  22 voting members :

7 academics 8 sick funds 4 physicians association 3 pharmacists association

•  6 non voting members : 3 ministry representatives 1 INAMI/RIZIV 2 Pharma.be (later: Febelgen, Budget)

7

84

3

6

academicssick fundsphysician's assocpharmacists assocnon voting members

Reimbursement Procedure Belgium

Commission Reimbursement of Medicines


Reimbursement Procedure

•  Submission of dossier

Commission

• D8 Acceptance

• D30: 1st evaluation

• D60 main evaluation

• First Proposal

• Final Proposal

•  Reimbursement decision

Econ Affairs

Applicant

Minister Decision

R.D. of Dec 21st 2001

Pag.

* Fundamentele principes: - ”Key elements”:

- Werkzaamheid → - Doeltreffendheid → Therapeutische - Veiligheid → waarde - Toepasbaarheid → - Gebruiksvriendelijkheid →

- “Key drivers”:

- EBM - Farmaco-economie → Klasse 1 - Budget-impact analyse

Evaluatie van de aanvraag

Pag.

Therapeutische meerwaarde   Drie meerwaardeklassen

Ø Klasse 1 : aangetoonde therapeutische meerwaarde t.o.v. bestaande therapeutische alternatieven (herziening)

Ø Klasse 2 : geen aangetoonde therapeutische meerwaarde maar geen generiek of copie

Ø Klasse 3 : generiek of copie

Aanvrager stelt klasse voor, minister (op voorstel CTG) beslist


•  Therapeutic value * •  Price and proposed reimbursement level •  Position of the drug in medical practice

(therapeutic and social needs) •  Budgetary impact to National Insurance Agency •  Class I only: Efficiency (cost health insurance /

therapeutic value)

* Introduction of EBM based reimbursement

Cl III

Cl III

CTG/CRM: Reimbursement Procedure

Evaluation Criteria (since 2002)


•  Efficacy •  Safety •  Effectiveness •  Applicability •  Convenience

Therapeutic value

= sum of elements

As determined by : •  Morbidity •  Mortality •  Quality of life

> class I added value

> class II * comparable value

Ø class III * copy/generic * with subtypes

R.D Dec.21st, 2001 via: www.riziv.be


Questions addressed by reimbursement procedure:

  Clinical data (RCT)   Epidemiological data   Real Life data   Health economics

data   Budget impact data

Efficacy controlled setting

Effectiveness daily practice

Efficiency cost-effective

= Does it work ?

= Is it worthwile ?

= Can it work ?

Drummond MF. Et al., « Methods for the Economic Evaluation of Health Care Programmes”, Ch.8

Pag. 43


•  Submission of dossier

D0

Commission

• D8 Acceptance

• D60 main evalua#on

• DraK Proposal • Final Proposal D150

Econ Aff.

Price D90

Applicant

Minister

Reimbursement

Decision

D180

R.D. of Dec 21st 2001 "   Study results: REA and reimbursement decision

Evalua#on criteria: I.  Therapeu#c value

II.  Medical and social need

III.  Price

IV.  Budget impact

V.  Efficiency (if class1)


Marketing Authorization versus Reimbursement Approval

Marketing Application Authorization (MAA) >

1.  European Centralized or MRP/DCP

2.  Dossier based on

•  Efficacy

•  Safety

•  Pharmaceutical quality

3.  Benefit/risk balance of the drug on its own

Reimbursement decision >

1.  Per member state

2.  Evaluation builds on MAA-elements:

+ Effectiveness

+ Convenience, applicability

3.  Relative therapeutic value as compared to alternatives

4.  Relative economic value as compared to alternatives ∆C/ ∆E

Pag. 45


§ Rela#ve efficacy and effec#veness (REA)

the extent to which an interven.on does more good than harm compared to one or more alterna.ve interven.ons -‐either under ideal circumstances (usually controlled clinical trials): “efficacy” -‐or under the usual circumstances of health care prac.ce (daily prac.ce): “effec.veness” High Level Pharmaceu#cal Forum 2005-‐2008. Final Conclusions and Recommenda#ons of the High Level Pharmaceu#cal Forum.

"   Key defini#ons

Pag. 46


§  Health Technology Assessment (HTA)

-‐  systema.c evalua.on of proper.es, effects, and/or impacts of health care technology

-‐  may address the direct, intended consequences of technologies as well as their indirect, unintended consequences Its

-‐  main purpose is to inform technology related policymaking in health care

-‐  conducted by interdisciplinary groups using explicit analy.cal frameworks drawing from a variety of methods.

Interna#onal Network of Agencies for Health Technology Assessment (INAHTA). URL: hap://www.inahta.org/HTA/Glossary/#_G


Pag. 47


§  Added therapeu#c value (ATV):

HTA core template: medical need, clinical benefit, cost-effectiveness, budget impact, organisational aspects..

REA: efficacy, safety, effec#veness, convenience, applicability, …

ATV as outcome of REA


Pag. 08/06/16 48 Herhaling titel van presentatie 48

Market Authorisation

Evaluation outcome =

efficacy , safety & pharmaceutical quality

> absolute benefit/risk balance

Evaluation outcome =

therapeutic value including efficacy and effectiveness…, efficiency (∆C/∆E), budget impact…

as compared to existing alternatives

Pricing & Reimbursement

= elements of relative efficay/effectiveness

"   APPLICABILITY OF RE

RE / assessment results in B FR & NL

Health Technology Assessment

Pag.

COST AND EFFECTS: the key graph To

tal c

ost (

Euro

per

pat

ient

)

Effect (LY, QALY, …)

A

0

delta Enet

delta

Cne

t

LY = Life Years, QALY = Quality Adjusted LY

20,000 Euro/LY

100,000 Euro/LY

500 Euro/LY B

Pag. 50


"   Study results: REA and reimbursement decision

Van Wilder PB, Dupont AG, Acta Clinica Belgica, 2009.

Submission type N (%)

Class 1 (new product, claiming ATV) 67 (5,2%)

Class 2 NME (new product, similar ther. value) 92 (7,2%)

Class 2 LE (exis#ng product, similar ther. value) 184 (14,3%)

Class 3 (generics and copies) 461 (35,9%)

New indica#on (listed product, addi#onal indica#on) 240 (18,7%)

Other (parallel trade, price modifica#ons…) 241 (18,8%)

Total 1285 (100%)

Table 1: Submissions in 2002-‐04, split by type of submission

Pag. 51



Van Wilder PB, Dupont AG, Acta Clinica Belgica, 2009.

Table 2: Class 1: cross-‐tabula#on of reimbursement decision and approval of ATV

ATV Yes No

Total

Reimbursement decision

Pos 29 (90,6%) 18 (51,4%) 47 (70,1%)

Neg 3 (10,3%) 17 (48,6%) 20 (29,9%)

Total 32 35 67

Pag. 52


Results from the logis#c regression analysis (n = 110 files, 2002-‐07):

•  the gran#ng of ATV (p < .001) was the most significant factor with a main impact on the reimbursement decision:

% of posi#ve decisions if ATV was:

granted: 90%

refused: 43%

•  other determinants of the reimbursement decision

•  year of submission (p = .014), (< 0,50 in 2004-‐05 to > 0,75)

•  type of molecular en#ty: no significant impact (p > .15).

•  The model explained 46% of the variance in the reimbursement decision

(adjusted R2 = 0.461).


Van Wilder P, Zhu Q, Veraverbeke N. Drug Informa.on Journal, 2009.

Pag. 53

§  Klasse 1 indieningen is kleine minderheid (5%) van alle aanvragen voor terugbetaling

§  Klinische evidentie van therapeutische meerwaarde (gebaseerd op adequate RCT’s) in minder dan 50%; terugbetaling toegestaan aan hogere prijs voor 90% van deze geneesmiddelen

§  Aanvragen zonder evidentie van therapeutische meerwaarde: terugbetaling in slechts 50% van de gevallen (vaak verlaagde prijs; restricties)

“Evidence based” terugbetaling van nieuwe geneesmiddelen

Pag. 54


"   Study results: REA in Belgium, France and The Netherlands

Assessment methods

q  Only Dutch website provides 2 Guidelines on REA; others refer to

Evidence Based Medicine (EBM) as general principle

q  Main data source: European Public Assessment Report (EPAR)

q  Comparator = mainly regulatory comparator from pivotal trials

q  If placebo control: no appropriate indirect treatment comparison

method

q  Assessment reports:

q  Similar but specific template per Member State

q  French authority is most produc#ve

Analysis of a common set of 72 submissions (2007-‐10)

Van Wilder PB, Bormans VV, Dupont AG, Eur J Clin Pharmacol, 2013.

Pag. 55


"   Study results: REA in Belgium, France and The Netherlands

Assessment results

q  Member States evaluate different medicinal products

q  ATV-‐ approvals: q  BE 51% q  FR 42% q  NL 54%

q  Level of agreement between Member States (MS):

q  Between 2 MS: between 72% and 76%

q  Between 3 MS: only 54%

q  Not impacted by level of evidence, presence of alterna#ves, ATC-‐1

Analysis of a common set of 72 submissions (2007-‐10)

Van Wilder PB, Bormans VV, Dupont AG, Eur J Clin Pharmacol, 2013.

Pag. 56


"   Summary of all study results:

q  REA-‐outcome ATV is most significant

factor in reimbursement decision;

effect size of budget impact, cost-‐

effec#veness and other determinants is

s#ll unknown

q  Applicability of REA is challenged in

case of OMP and ATMP

q  Only moderate agreement between 3

similar Member States in REA-‐

outcome; few published assessment

methods

q  Transparency Direc#ve

objec#ve, verifiable and

transparent decision

q  HLPF

medicinal products ranked by

ATV

q  Cross-‐border Direc#ve

HTA-‐collabora#on between

Member States

Pag. 08/06/16 57


WEESGENEESMIDDEL

Ø  voor diagnose, preventie of behandeling van “orphan disease” (weesziekte)

Ø  voor erkenning als weesgeneesmiddel in Europe moet een adequate methode voor diagnose, preventie of behandeling ontbreken Ø  moet significant beter zijn in vergelijking met de bestaande producten voor de weesziekte

Pag. 08/06/16 58


WEESZIEKTE

Ø  Europese definitie

ü  levensbedreigende of zeer ernstige aandoening

ü  ≤ 5 in 10.000 mensen in Europese Gemeenschap (inclusief tropische ziekten)

Ø  USA definitie

ü  < 200.000 patienten in USA

ü  > 200.000 patienten in USA en voor wie er redelijkerwijze kan verwacht worden dat de ontwikkelingskost niet kan gerecupereerd worden door de verkoop van het middel # Ultra-orphan disease: NICE: < 1.000 mensen in Engeland en Wales

Pag. 08/06/16 59


USA ORPHAN DRUG ACT (1983) &

EU ORPHAN DRUG REGULATION (2000)

ü  Wetgeving om de ontwikkeling van weesgeneesmiddelen te stimuleren

ü  markt exclusiviteit in USA (7 jaar) & EU (10 jaar) tenzij aangetoonde therapeutische superioriteit

ü  assistentie van de registratie autoriteiten in design van klinische trials in USA & EU

ü  tax kortingen + research grants (enkel USA)


Added therapeutic value and cost-effectiveness of orphan drugs

§  Orphan drugs obtain reimbursement in 88% of cases despite poor clinical evidence, high cost per patient and uncertainty regarding cost-effectiveness

§  Pharmaco-economic analysis mandatory for reimbursement for “non-orphan” innovative medicinal products, not for orphan drugs

§  Perceived societal value is a more determinant factor than incremental cost-effectiveness for orphan drugs

§  Orphan drugs are given more priority than other drugs for equally severe but more common diseases

Pag. 61


"   Study results: applicability of REA to OMPs and ATMPs

q  % reimbursed: 88% vs 63% (p = 0.02)

q  > 1 RCT: 52% vs 84% (p < 0.01)

q  Severe disease: 96% vs 86% (p = 0.20, NS)

q  Problems (even if adjusted for rarity): q  Use of clinical end-‐points (e.g. agalsidase β and α, Fabry disease) q  Dose-‐finding (e.g. aglucosidase α , Pompe disease) q  Long-‐term follow-‐up q  Uncertainty on clinical effec#veness and safety

q  Conclusions: q  Lower level of evidence, greater willingness to pay q  Need for EU-‐wide post-‐marke#ng evidence development

BE / Analysis of 25 orphan submissions (2002-‐07), compared to non orphan med products

Dupont AG, Van Wilder PB, Bri.sh Journal of Clinical Pharmacology, 2011.

Pag. 62


"   Study results: applicability of REA to OMPs and ATMPs

Orphan drug Indica<on Other therapy available

Therapeu<c evidence

CARBAGLU carbamyl-‐ glutamate/

carglumic acid

Hyperammonemia due to N-‐acetylglutamate synthase deficiency

No

effec#veness “assumed” based on a retrospec#ve analysis of its effect on a

surrogate endpoint (decrease of ammonia concentra#on) in 12 pa#ents; dose used was

“empirically” chosen.

MYOZYME alglucosidase α

Pompe’s disease (enzyme replacement

therapy) No

-‐open, dose-‐ranging study; n=18 (<6 months) in the infan#le, progressive form of the

disease; 52 weeks comparison with historical control; clinical endpoints: mortality data second open label; n=18 (6-‐36 months);

52 weeks historical control -‐late onset disease: n=5, open, uncontrolled

(op#mal dose remains unknown)

Dupont AG, Van Wilder PB, Bri.sh Journal of Clinical Pharmacology, 2011.


Access to orphan drugs despite poor quality of clinical evidence

  -Orphan drug status is a strong predictor of reimbursement: orphan drugs gain more easily market access than innovative drugs for more common diseases.

  -Lower quality of clinical evidence, a higher level on uncertainty on the clinical effectiveness, safety and incremental cost-effectiveness, and a higher budgetary impact are accepted for orphan drugs.

  -Authorities value the benefits of orphan treatment more highly compared to benefits of treatments of equally severe more common diseases.

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