Programma:

• Mignon van der WesterlakenVoorzitter HollandBIO- expertgroep Orphan Drugs

• Bert HiemstraHoofd afdeling Farmacologische, Toxicologische en

Biotechnologische Beoordeling bij het CBG

• Anthony HallHoofd wetenschappelijke raad van PSR: the Orphan Drug

Experts,

Adaptive licensing

Adaptive licensing

Verantwoorde verkorting van de time to patient

Bert Hiemstra, College ter Beoordeling van Geneesmiddelen

Adaptive licensing

1) Waarom adaptive licensing?

2) Wat is adaptive licensing?

3) Wat doen de regulators?

4) Wat moet nog opgelost?

Adaptive licensing

Waarom adaptive licensing? - 1

Adaptive licensing

Waarom adaptive licensing? - 2

Adaptive licensing

Waarom adaptive licensing? - 3

Minister aan T.K.:

“Als het lukt om geneesmiddelen op een veilige manier daadwerkelijk sneller op de markt te krijgen, hoeven patiënten minder vaak een beroep te doen op de diensten van organisaties als My Tomorrows.”

Adaptive licensing

Waarom adaptive licensing? - 4

Scenario‘s CBG 2030

Links en rechts ingehaald

Adaptive licensing

Wat is adaptive licensing? - 1

• Doel is goede geneesmiddelen z.s.m. bij de patiënt, op verantwoorde manier

• Diverse synoniemen, o.a. MAPP (Medicines Adaptive Pathways to Patients)

Adaptive licensing

Wat is adaptive licensing? - 2

• Start met specifieke patiëntengroep met grote medical need

• Geneesmiddel moet aansluiten bij die need

• Er wordt onzekerheid geaccepteerd in benefit en / of risk

• Onzekerheid in benefit en/of risk betekent niet slechte data

• Niet meer data vragen dan nodig, maar ook geen regulation light

Need

Uncertainty

Adaptive licensing

Wat is adaptive licensing? - 3

• Afspraken over verdere data verzameling na registratie

• Primair om onzekerheid te verminderen

• Data na registratie kunnen ook bijdragen aan verbreding indicatie

• Uiteindelijk worden meer data verzameld dan in regulier proces

• Zijn bovendien grotendeels real life data

Adaptive licensing

Adaptive licensing

Wat is adaptive licensing? - 5

• Alle disciplines, ook quality (bijvoorbeeld omgang met nog niet volledig gevalideerde full scale)

• Patiënt, behandelaar en andere stakeholders direct aan tafel

• Every day life perspectief van patiënt (benefit & risk)

• Vroeg in ontwikkeltraject beginnen, belang van goede fase 1 en 2.

• Adaptieve prijsbepaling en vergoeding als onderdeel van adaptive licensing

• Verschillende scenario’s ontwikkeltraject doornemen

• Belangrijke rol scientific advice, maar adaptive licensing betreft meer dan advisering alleen

Adaptive licensing

Wat doen de regulators? - 1

• CBG Strategisch Business Plan 2014 -2018

• Levenscyclus met drie kernelementen

• Patiënt belangrijkste stakeholder

• Samen met omgeving

Adaptive licensing

Wat doen de regulators? - 2

• Samenwerking met ZIN, CCMO en IGZ

• Advies op maat: vroeg, meerdere contactmomenten, laagdrempelig

• Bevorderen maar ook onafhankelijk oordelen

• Experimenteerruimte

Adaptive licensing

Wat doen de regulators? - 3

• EMA pilot

• Bedrijven melden zich

• Actieve rol CBG bij validatie, prioritering en uitvoering pilots

• Eerste pilot start binnenkort

Adaptive licensing

Wat doen de regulators? - 5

Uitgebreid palet aan wettelijke mogelijkheden:

• Conditional approval

• Exceptional circumstances

• Compassionate use

• Hospital exemption

• Named patient

• Prijs- / vergoedingsarrangementen

Adaptive licensing is een mindset, geen regelgeving

Maar gaat adaptive licensing werken binnen huidige regulering?

Adaptive licensing

Wat moet nog opgelost?

• Risico off-label gebruik

• Tien jaar bescherming gaat direct lopen

• Communicatie over en omgang met onzekerheid

• Zoeken naar rol adviseur versus regulator

• Lukt adaptive licensing bininen huidige regels?

• Dominante aandacht voor risico’s

• Prijsbepaling / vergoeding nationale aangelegenheid

• Opzetten van goede patientenregistraties ism stakeholders

• Gezamelijke wil om stap terug te doen indien resultaten uit de dagelijkse praktijk tegen vallen

Adaptive licensing

“Adaptive Licensing”

HollandBIO Orphan CaféSociëteit De Vereeniging, Mariaplaats 14, Utrecht

12th June 2014

Dr Anthony Hall

Rationale for adaptive licensing

• Too few drugs reaching market

• Increasing costs of development

• Earlier access for high unmet needs

• Binary nature of drug authorisation

• EMA roadmap to 2015

New drugs launched in the UK from 1982 to 2011

Eroom’s Law: The number of new drugs approved by the FDA per billion dollars (inflation- adjusted) spent on R&D has halved roughly every 9 years

From Scannell JW et al. Nature Reviews Drug Disc. 2012; 11: 191-200

Earlier access for high unmet needs

• Strong voice of patient groups

• Halpin Protocol

• Saatchi Medical Innovation Bill

• Early Access to Medicines Scheme

Current model of licensing“The Magic Moment”

Adapted from Eichler, EMA, London, March 2012

Binary nature of drug authorisation

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Experimental therapy

Fully vetted, safe & efficacious therapy

Definition of Adaptive Licensing

AL can be defined as a prospectively planned, adaptive approach to bringing drugs to market.

’staggered approval’, ’progressive licensing’, and ’adaptive licensing’ are often used interchangeably

Definition of Adaptive Licensing

• Start with an authorised indication (e.g. “niche” indication), through iterative phases of evidence gathering and progressive licensing adaptations.

• Seeks to maximize the positive impact of new drugs on public health by balancing timely access for patients with the need to provide adequate evolving information on benefits and harms.

Initial MA

Adapted from Eichler, EMA, London, March 2012

Adaptive licensing

Time

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Updated MAUpdated MA

Roadmap to 2015

Strategic vision for the operation of the EMA from 2011 to 2015.

“…a key issue for regulators will be whether a more 'staggered' approval (or progressive licensing) concept should be envisaged for situations not covered by conditional marketing authorisations or marketing authorisations under exceptional circumstances…”

“It should be emphasised that progressive licensing should not lead to a reduced level of evidence for first-time marketing authorisation.”

International proposals for AL

• Europe: “staggered approval”

• US: progressive reduction of uncertainty

• Canada: progressive authorization

• Singapore: test bed for adaptive regulation

• MIT NEWDIGS: adaptive licensing project

• CASMI: streamline the research, licensing and market access processes

Adapted from Eichler, EMA, London, March 2012

CASMI

• Centre for the Advancement of Sustainable Medical Innovation

• Partnership between Oxford University and UCL

• Created to develop new models for medical innovation

• Aims to address the issues that have led to current failures in the translation of basic bioscience into affordable and widely adopted new treatments

MIT-NEWDIGS

• Massachusetts Institute of Technology (MIT)

• New Drug Development ParadIGmS

• International multistakeholder collaborative developing approaches to AL

• Currently testing new ideas & models for drug development in “live” demonstration projects using actual pipeline candidates from pharmaceutical companies

Legal framework for AL

• Using existing legal framework(at least for now)

• Scientific advice (multi-stakeholder)

• Conditional Marketing Authorisation

• MA under Exceptional Circumstances

• Registries

• Pharmacovigilance tools

From HALL & CARLSON. The current status of orphan drug development in Europe and the US. Intractible & Rare Diseases Research. 2014; 3(1): 1-7

Pharmacovigilance tools

• Risk Management Plans (EU)

• Risk Evaluation and Mitigation Strategies (US)

• Periodic Safety Update reports

• 5-year renewal of MA

Serious vs non-serious conditions

• Acceptable level of uncertainty may be higher for serious conditions with no treatments available vs less serious conditions with treatments available.

• Highly applicable to orphan drugs.• Currently 14 drugs have CMA, of which 7

are orphan drugs & 6 oncolgy drugs

• One size doesn’t fit all.

Conservative vs transformative AL

Conservative

• Using exisiting legiaslation

• Small incremental steps

Transformative

• “Delinking” efficacy and safety populations

EMA Pilot Project on AL

• Launched 19 March 2014

• Purpose to provide a framework for informal interactions by discussing ‘live assets’ (medicines in early stage of development)

• Sponsors invited to submit applicaitons

• Status as of 6 June 2014 (20 applications; reviwed 9; accepted 2

For further information or to initiate a pilot case, contact adaptivelicensing@ema.europa.eu

Involvement of all stakeholders

• Regulators

• Sponsor

• HTA bodies

• Groups responsible for guidelines

• Patient organisations

Discusisons in a “safe harbour” environment

AL continues throughout life-cycle

Schematic reproduced from Lim. The Path to Adaptive Drug Regulation. IRGC International Conference 2013

Evidence generation would encompass all methodologies:RCTs, other clinical trials, observational studies, registries & post-markeing surveillance

Communication & perception

• New models of information for patients

• Interaction between patients, physicians & pharmacists

• Differences in risk tolerance between different cultures & social groups

Obstacles & disadvantages of AL

• Gradual market entry may lead to lower ROI

(but development time may be shorter / cheaper)

• Concerns over reduced standards

• Variable acceptability of increased uncertainty

• Possible need for new legislation

• Questions over industry commitment

• Restricting prescriptions to the target popuation

• Ethics of RCTs after MA

Obstacles & disadvantages of AL

• Difficulties with global launches

• Risk of litigation

• Need to collect data post-approval• Logistics

• Costs

• Need for CA / EC approval?

• Local reimbursement in EU• Problems of high-priced drugs with CMA

Comparison with Early Access to Medicines Scheme (UK)

• UK launched scheme March 2014

• Promising Innovative Medicines (PIM) designation

• Early Access to Medicines scientific opinon

• Late in development (close to launch)

• Drug must be provided free by company

• NICE has to assess after MA

Case studies

Case Study 1

Unlikely to be acceptable

• Open-label, non-inferiority study with soft endpoints

• Approach lacks scientific rigour

Case Study 2

Broaden treatment-eligible population

• Novel anti-obesity drug

• Initially show benefit-risk in narrowly defined group with high medical need• high expected responsiveness

• acceptable side-effects

• high treatment concordance

• tightly controlled management

• Post CMA, further RCTs in wider population

Time course of evidence generation and accrual rates of patients treated with a new drug under the current and adaptive licensing (AL) scenarios.(a) Current scenario; before the license, nearly all patients treated with the new drug are enrolled in interventional studies. Once the license is granted, thetreated population expands rapidly.(b) AL scenario; the number of patients in prelicensing RCTs may be smaller and the initial license may be granted earlier than under the current scenario.

Reproduced from Eichler et al. Clin. Pharm. Ther. 2012; 91(3): 426-437

Case Study 3

Reduce statistical uncertainty

• Ideal for rare diseases

• Initial CMA based on small study with larger alpha

• Inform patients of increased uncertainty

• Further RCTs likely impossible

• Knowledge expansion rely on uncontrolled studies

The threshold approach to evidence generation when randomized controlled trials (RCTs) are not practically or ethically feasible after an initial license.The sponsor would initially conduct one (or possibly more) small RCTs. If successful, an initial license may be granted on the basis of this limited information.Subsequent uncontrolled observational studies would aim to show that the treatment outcome under real-life conditions remains above a pre-agreed threshold.

Reproduced from Eichler et al. Clin. Pharm. Ther. 2012; 91(3): 426-437

Case Study 4

Enable new-new combination development

• May be unethical to compare combination with individual components & SoC

• Initial licence based on combination vs SoC

• Post MA, contribution of individual components assessed e.g. by randomised withdrawal trials

Case Study 5

Ensure “real world” effectiveness

• e.g. Antimicrobial for multi-drug resistant infections

• Initial MA based on non-clinical data plus RCT in one of diseases

• “real world” assessment of larger number of diseases

Case Study 6

Reduce uncertainty around surrogate EP

• Surrogate EPs are not always predictive

• “reasonably likely to predict a real clinical benefit”

• Initial MA based on surrogate

• Further studies confirm effect on clinical EP

• CMA may close window for further RCTs

Case Study 6a

Nitisinone for alkaptonuria

• AKU is a metabolic disease affecting tyrosine metabolism

• Accumluation of HGA leads to ochronosis

• Ochronotic symptoms usually appear in 4th or 5th decade

• HGA is an obvious but unvalidated surrogate

“Adaptive Licensing”

HollandBIO Orphan CaféSociëteit De Vereeniging, Mariaplaats 14, Utrecht

12th June 2014

Dr Anthony Hall