2009 Convegno Malattie Rare Schieppati [22 01]

Oggi possiamo curare meglio le

1

Oggi possiamo curare meglio le malattie rare ?

Arrigo Schieppati

Rare diseases: the facts

�5000-8000 rare diseases

�Prevalence in EU <5/10,000

�About 6-8% of the EU population (30 million) have a RD

2

Rare diseases: the facts

�>50% are pediatric

�>85% are serious/life-threatening

�Chronic

�No effective treatment available

�Heterogeneous�Heterogeneous

�Very vulnerable, underserved populations

JM Walshe BMJ 1975 4

US Orphan Drug Act - 1983

�Tax incentives

�Exclusive or modified patent protection

�Priority Review

�Grants from FDA

�Amendments to antitrust laws to permit limited �Amendments to antitrust laws to permit limited exchange of data, pooling of resources, other collaborative efforts

�Government purchase of orphan drugs

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A long way to Orphan Drug Regulation in the EU

� 1993 Rare diseases a priority for healthcare area in EU

� 1994 “Towards an orphan drug policy in EU”

� Aug ‘96 1st draft of Regulation on Orphan � Aug ‘96 1st draft of Regulation on Orphan Medicinal Products

� July ‘98 7th draft approved by EU Commission

� Sept ‘98 EU Parliament (EP) receives Proposal

� Dec ‘99 Regulation (EC) 141/2000 on Orphan Medicinal Product approved

7

Underlying Principles

�Prevalence

Article 3.1.a: introduces two alternative tests for designation of OMPs

Prevalence criteria:Disease affecting no more than 5/10,000 persons in

A. Rappagliosi 8

Disease affecting no more than 5/10,000 persons in the EU

Profitability criteria:Need for incentives to justify the investment


�Equity

« Patients suffering from rare conditions should be entitled to the same quality of treatment as other patients. »

�Investment

9A. Rappagliosi

�Investment

« Promising drugs to treat these conditions would not be developed unless specific measures are taken to stimulate research and development of orphan drugs»


�Access

« The purpose of this regulation is…. to provide incentives for the research, development and placing on the market, of designated OMPs. »

A. Rappagliosi 10

« Medicinal products designated as orphan shall be eligible for incentives made available to support research into, and the development and availability of, orphan medicinal products…»

ORPHAN DRUGS AVAILABLE: 12

• alemtuzumab • imiglucerase

Orphan Drug in Europe: Before 2000

• alemtuzumab

• alitretinoin

• deferiprone

• factor VII A

• factor IX

• factor IX

• imiglucerase

• mercaptimine

• phenylbutyrate

• protein C

• riluzole

• temozolomide

Joppi, Bertelè, Garattini B J Clin Pharm 2006 11

250

300

350

400

450

500

550

292

365

463

536

EMEA: Orphan drug designation and marketing

2001 2002 2003 2004 2005 2006 2007 20080

50

100

150

200

250

58

96

145

212

3 7 12 18 22 30 42 47

designation marketing

ORPHAN DRUG DESIGNATIONS 536

Orphan Drug in Europe: 2000-2008

ORPHAN DRUGS APPROVED 47

8 %13

FDA: Orphan drug designation and marketing

1500

2000 1951

Orphan drug designation and marketing (N)

83

0

500

1000

325

designation marketing

20081983


Orphan Drug in USA : 1983 - 2008

ORPHAN DRUGS APPROVED 325

16.6 %15


Orphan Drug in Europe: 2000-2004

DRUGS APPROVED UNDEREXCEPTIONAL CIRCUMSTANCES 12

51%Joppi, Bertelè, Garattini B J Clin Pharm 2006 16

� The indications is intended for condition so rarely that cannot reasonably be expected to gain comprehensive evidence

� In the present state of scientific knowledge, comprehensive information cannot be provided

Under exceptional circumstances

comprehensive information cannot be provided

� it would be contrary to generally accepted principles of medical ethics to collect such information

17

Marketing authorisation may be granted on the following conditions:

�Complete the studies and reassess risk/benefit profile

Under exceptional circumstances

�Drug dispensation only through hospitals

�Patients and doctors well informed about the limited evidence of efficacy

18

Drug Disease Prevalence N. Pts

Algasidase Fabry 0.25 41Anagrelide Essential 2-3 1446

throbocytemiaArsenic trioxyde APML NA 52Bosentan Pulm Hypert0.005 32Carglumic ac, NAG synth def 0.000125 20Celecoxib Fam. Polyposis 0.3 970Celecoxib Fam. Polyposis 0.3 970Cladribine Hairy Cell L NA 120Ibuprofen Patent ductus NA 131Iloprost Pulm Hypert0.005 203Imatinib CML 0.18 1225Laronidase MPS1 0.025 45Migulstat Gaucher 0.33 28Mitotane Adrenal CA 0.1 500Pegvisomant Acromegaly 0.5 112Porfimer Na Barrett’s esop 2.3 208Zync acet. Wilson 0.6 148

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• ALGASIDASE- αααα/ ALGASIDASE- ββββ FABRY DISEASE

• MIGLUSTAT / IMIGLUCERASE GAUCHER

• ARSENIC TRIOXIDE / RETINOIC ACID PROMYELOCITIC

LEUKEMIA

• BOSENTAN / ILOPROST / PULMONARY

• SILDENAFIL / HYPERTENSION

Orphan Drugs for the same indication: no comparative studies

• SILDENAFIL / HYPERTENSION

• IBUPROFEN / INDOMETHACIN PATENT DUCTUS

ARTERIOSUS

• CLADRIBINE / IFN-ALPHA HAIRY LEUKEMIA

• ZICOTINIDINE / MORPHINE INTRATHECAL

ANALGESIA

Joppi, Bertelè, Garattini B J Clin Pharm 200620

Major problems with Orphan Drug approval

�LACK OF DOSE FINDING

�LACK OF PHASE 3 TRIALS

�SURROGATE END-POINTS

�SHORT DURATION OF TREATMENT

SMALL NUMBER OF PATIENTS�SMALL NUMBER OF PATIENTS

�POOR KNOWLEDGE OF ADVERSE REACTIONS


�It is certainly difficult to find a balance between the urgent need for drugs for patients with rare diseases while guaranteeing at least their quality, efficacy and safety and, when necessary, making comparisons with existing drugs

�Probably the lack of reliable methods for evaluating the effect of drugs on small numbers of patients is partly responsible for the general poor quality of the dossiers.


Itraconazole to Prevent Fungal Infections in Chronic Granulomatous Disease

John I. Gallin, M.D., et al. 2003

Thirty-nine patients with chronic granulomatous Thirty-nine patients with chronic granulomatous disease were enrolled in the study.

Accrual lasted from October 1991 to March2000.

�There are orphan diseases that are difficult to study because they don't have biological markers.

�For example, neurological diseases: you cannot get a brain biopsy to prove that an experimental get a brain biopsy to prove that an experimental treatment has changed brain chemistry, or prevented further neurodegeneration.

�For many disorders how do you prove "prevention", or "delay of progression" in a six-month or one-year clinical trial for a chronic disease that has slowly evolving symptoms?

CONTROLLED TRIALS IN RARE DISEASES: HOW MANY? HOW INFORMATIVE? ADEQUATE?

Annalisa Perna, Giovanni Antonio Giuliano, Arrigo Schieppati, Marco Costantini, Mariya Ganeva, Erica Daina,

Rumen Stevanov, Giuseppe Remuzzi

Istituto di Ricerche Farmacologiche ‘Mario Negri’

Centro di Ricerche Cliniche per le Malattie Rare ‘Aldo e Cele Daccò’

Society for Clinical Trials, 28th Meeting , Montreal 2007

�Diseases classified as rare, available in thedatabase of the Information Center for RareDiseases (ICRD), IRFMN

�The first 50 diseases, sorted by the

QUALITY OF PUBLISHED RCT IN RARE DISEASES

Robinson KA., Int J Epidemiol, 2002

�The first 50 diseases, sorted by thenumber of contacts at May 23, 2003

�Identification of Randomized Clinical Trials(RCT) in MEDLINE was done, according to therecommended Cochrane search strategy forretrieval of reports of controlled trials

Rare diseases selected (50)

Rare diseases with potentially interesting abstract reviewed (49)

Rare diseases with at least one RCT identified (27)

Excluded (1) (No interesting title)

Excluded (22) (non randomized or reviews)

Excluded (7) (cross-over: 2) identified (27)

Rare diseases with at least one eligible RCT identified (20)

Rare diseases with at least one eligible RCT evaluated (18)

(cross-over: 2) (other reasons: 3) (cross-over + other reasons: 2)

Excluded (2) (not found)

Titles identified through the bibliographic search (7,410)

Potentially interestingabstracts reviewed (1,026)

Excluded (6,384) (No interesting title: 6,252) (No abstract available: 132)

Excluded (855) (Non randomized or reviews)

Abstracts with an RCT identified (171)

Potentially appropriate RCTs (107)

RCTs included (79)

Excluded (64) (Cross-over: 37) (Different disease: 12) (Other reasons: 15)

Excluded (28) (Full article not available)

80

60

40

%

51 %45 %

40

20

0No difference In favour of

STANDARD treatment

In favour of EXPERIMENT

ALtreatment

4 %

80

60

40

%74 %

40

20

0Surrogate endpoints

Survival

26 %


�Weak points found

- Power calculations

- Interim analyses/early stopping rules

- Recruitment period definition- Recruitment period definition

- No. of assessable patients at study end

- Clear report of primary and secondary outcome

- Choice of important clinical endpoints

- External validity of study findings


�Whenever feasible, RCTs in rare diseasesshould be performed with the highest standards.Weak points found in RCTs on common diseasesbecome issues of great concern in rare diseasesbecome issues of great concern in rare diseases

�When applicable, novel approaches should bebetter implemented, particularly when focused onsaving the number of patients enrolled

Halpern SD et al.. JAMA, 2002

Lagakos SW., N Engl J Med, 2003

European Clinical Research Infrastructures Network

www.ecrin.org

SwedenSweCRIN

GermanyKKS

DenmarkDCRIN

UKUKCRN

Ireland ICRIN

EFGCP

Austria

EORTC

FinlandFinnCRIN

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FranceInserm

Spain SCReN Italy

IRFMN & CIRM

HungaryHECRIN

National networks of Clinical Research Centres / Cl inical Trial Units

AustriaATCRIN

SwitzerlandSCRN

Challenges to clinical research in Europe

�Main bottlenecks :

Access to patients: fragmentation of health systems

Cost: fragmentation of public funding

Quality of infrastructures

ECRIN, an integrated infrastructure for clinical trials in the EU

� ECRIN-1 (2004-2005) :

Identifying bottlenecks

� ECRIN-2 (2006-2008) :

Design of the infrastructure

� ECRIN-3 (2008 -> ) : ESFRI roadmap

Preparation, construction and operation

of the infrastructure supporting

multinational clinical trials in the EU

� In line with expectations of FP7

‘Innovative Medicines Initiative’

2001

1991

Gaucher’s disease

Imiglucerase

One year treatment with imiglucerase:

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imiglucerase:

400.000$

FBignami: 6th ERTC workshop Barcelona ona - 9 July 200739

40FBignami: 6th ERTC workshop Barcelona ona - 9 July 2007

Time to availability of OMPs

In Italy

OD with market autorization in EU 44

Available in Italy 27

Days before MA in Italy 437

Range 106-1004

44Source of Data: ISS web page. Data at March 31, 2008

OMP price in EU

�Countries with a small population suffer from a longer delay in availability of OMPs

�In some countries with high GDP there are only a small number of OMPs really available


small number of OMPs really available

�This situation is also a result of commercial strategies, but patients cannot accept it and it is against the legislation.

Positive Outcomes of the Orphan Drug legislation

�Building biotech science

�Growth of large and small pharmaceutical firms

�Support to the economy

�Development of cutting-edge technology

Trends in Orphan Product Development

�Targeted therapies

�Recombinant therapies

�Monoclonal antibody therapies

�Gene therapy

Problems Encountered

Cost + Access

� Loss of some orphan drugs

� Drug prices

� Access remains an issue

And So…

�Orphan Products Development in the US and EU has proved beneficial for

Patients

Families

IndustryIndustry

Economy

PRESCRIZIONE OFF-LABEL

1. assunzione di responsabilità da parte del medico prescrittore

il paziente non può essere utilmente trattato con medicinali autorizzati

l’impiego del medicinale proposto è sostenuto da studi clinici almeno di fase II[Legge Finanziaria 2008]

prescrizioneoff-label per Malattia Rara=

prescrizione off-label per Malattia

2. consenso informato da parte del paziente

3. I farmaci possono essere rimborsati solo se:

prescritti da un medico che opera presso un Presidio della Rete MR

prescritti per mezzo dell’apposito PT

Malattia NON Rara

ACCESSO AI FARMACI

Ai pazienti affetti dalle malattie rare di cui al D.M. 18 maggio 2001, N. 279 possono essere forniti gratuitamente:

1. tutti i farmaci registrati sul territorio nazionale, di classe A

(compresi quelli di fascia H) e C

2. i farmaci inseriti nello specifico elenco AIFA ai sensi della legge

648/96

3. i farmaci registrati all’estero, previsti dai protocolli clinici

concordati dai Presidi di rete col Centro di Coordinamento

ACCESSO AI FARMACI

Il competente medico specialista del Presidio di rete predispone il piano terapeutico (PT) attraverso la compilazione dell’apposita

scheda per la prescrizione dei farmaci

Copie di detta scheda dovranno essere fatte pervenire:

1. al medico curante dell’assistito (MMG o PLS)

2. alla ASL di residenza dell’assistito

ACCESSO AI FARMACI

La fornitura dei farmaci deve avvenire tramite:

1. il Presidio di rete

somministrazione ambulatoriale dei prodotti

2. la ASL di appartenenza del paziente

farmaci necessari al trattamento dei pazienti inseriti nei programmi di assistenza domiciliareprogrammi di assistenza domiciliare

farmaci di fascia H

farmaci non registrati in Italia e/o compresi nell’elenco AIFA legge 648/96 per le terapie domiciliari

3. Le farmacie aperte al pubblico

farmaci di classe A e C, per le terapie da assumere al domicilio al di fuori di programmi di assistenza domiciliare

2009 Convegno Malattie Rare Schieppati [22 01]

Health & Medicine

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