An agency of the European Union

Registers and Observational Drug Studies Regulatory Perspective

June M Raine Chair, PRAC

EULAR RODS Meeting

14-15 November 2013

Outline of presentation

Objective of regulation

Regulatory role of registers

New EU pharmacovigilance legislation

Moving forward – challenges and opportunities

What is the objective of regulation?

Promote public health

Availability of innovative treatments and technologies without unnecessary delay

Protect public health

Active vigilance based on best evidence and prompt risk management

Support individual health decisions

As much information to patients and healthcare professionals as possible on benefits and risks

4

Regulators must…

Assess changing risk benefit of medicines in clinical use

Reach prompt decisions which take into account the therapeutic context

Implement proportionate risk minimising action

Constantly seek to improve & strengthen methodologies

Number patients studied prior to approval of new medicines

Duijnhoven et al PLoS March 2013

Regulatory challenges

Access to robust evidence in post authorisation phase

- on emerging risk

- On rare risks, especially in long term use

- on background rates in exposed population

- on how medicine is being used in practice

- on real world efficacy and clinical outcomes

Effectiveness of risk minimisation

Time dimension – evolving evidence

EU strategy for pharmacovigilance

Shift from responding reactively to new safety issues, to proactively investigating drug safety in clinical use

Generate robust data, including on long term use, rare adverse reactions Monitor the effectiveness of risk minimisation and evaluating meaningful outcomes

Engage with healthcare professionals and patients

Better communications and greater transparency

Risk Management Plans

Identify

safety

questions

Assess

results

Carry out

studies

Design

studies

Update

RMP

Risk

Management

Planning

What is currently required in RMPs?

For all new MA with RMP 1/1/2010 to 31/12/2012:

How many of the RMP for new MA mention a registry?

• Of the 123 RMPs identified, 30 had a registry (24%)

• All of these were additional PhV activities

Number of RMPs by risk Identified Risk

Potential risk

Missing information

Number of RMPs with registry

11

13

24

Regulatory view of registries

Definition of registry

An organised system that uses observational methods to collect uniform data on specified outcomes in a population defined by a particular disease, condition or exposure (Good Vigilance Practice 2012)

Types of registry

• By geography, population or coverage

• By therapeutics - product, substance, class, disease

- - -

Regulatory view of registries

Patient registries are key instruments for:

• Pooling scarce data without bias for epidemiological and/or

clinical research

• Assessing the feasibility of clinical trials, and to facilitate

the planning of appropriate clinical trials

• Gathering of evidence on effectiveness of the treatment &

on its possible side effects

• Development of clinical research, specially in field of rare

diseases

• Improvement of patient care and healthcare planning

• Study of social, economic & quality of life outcomes

Important regulatory RODS

Biologics in rheumatoid arthritis

HAART in HIV/AIDS

Factor VIII, IX in haemophilia

Anti-epileptics, SSRIs in pregnancy

Betaferons, natalizumab in Multiple Sclerosis

Contributions of registries to understanding of safety of biopharmaceuticals

Serious infections, particularly tuberculosis and opportunistic infections

Malignancies in general

Lymphoma, melanoma and keratinocyte cancers

Cardiovascular events

Immunogenicity

Data Collection on Adverse Events on Anti-HIV Drugs

Collaborative, observational study

11 established cohorts of HIV-1-infected persons prospectively

followed at 212 clinics in Europe, the US and Australia

– Cohort I: 23,437 patients enrolled 1999-March 2001

– Cohort II: 10,021 patients enrolled 2001-2004

– Cohort III: 5,000 enrolled after 2004

Estimated to have accumulated 295,000-310,000 person-

years until the 13th annual data merger on 31/01/2012

Important findings on cardiovascular risk, non-AIDs

malignancies

New EU pharmacovigilance legislation

Clear legal framework for post-authorisation monitoring Implementation and delivery of risk management plans Regulatory oversight of post-authorisation studies Good Vigilance Practice standards Greater transparency, patient and public involvement

European Legislation

Implementing

measures

Good Vigilance

Practice Guidance

PRAC

requirements

interpretation

scientific oversight

framework

Pharmacovigilance Risk Assessment Committee - Mandate

All aspects of the risk management of the use of medicinal products including the detection, assessment, minimisation and communication relating to the risk of adverse reactions, having

due regard to the therapeutic effect of the medicinal product, the design and evaluation of

post-authorisation safety studies and pharmacovigilance audit

PRAC review - CVS safety of diclofenac

SOS research findings on AMI

PRAC advice - benefit risk of strontium ranelate

Periodic safety update report identified increased risk of cardiac disorders including MI

PRAC advised safety restrictions

CHMP referral under Art 31

PRAC Agenda Issues – All items

Post-authorisation studies

“It is necessary from a public health perspective to

complement the data available at the time of

authorisation with additional data about the safety

and, in certain cases, efficacy of medicines

Competent authorities should therefore be

empowered to impose on the MAH the obligation to

conduct post-authorisation studies on safety and on

efficacy”

Such studies may be aimed at collecting data to

enable the assessment of safety or efficacy… in

everyday medical practice”

Good Vigilance Practice Module V

Guideline on Risk Management Systems

Refers to registries

Further module specifically on biologics under development

Article 22a of Directive 2010/84/EU

“If the same concerns apply to more than one medicinal product, the national competent authority shall, after consultation with the PRAC, encourage the marketing authorisation holders concerned to conduct a joint post-authorisation safety study”

Article 22a of Directive 2010/84/EU

“The national competent authority may impose an obligation to conduct a post-authorisation efficacy study when the understanding of the disease or the clinical methodology indicate the previous efficacy evaluations may have to be revised significantly”

EMA workshop 24-25 October 2013

Further legislation…

Moving forward

Strengthening the science base - building an EU “infrastructure”

Anticipating the scientific challenges

Developing new methodologies – adaptive licensing

Engaging with companies, academia, health professionals and patients

A clear vision of success

Regulatory Science

“The areas of science used in assessment

of quality, safety & efficacy of medicines

throughout their lifespan, as well as the

scientific areas used in regulatory

decision-making

…..It encompasses basic and applied

medicinal science and social sciences

and contributes to the development of

regulatory standards and tools”

Strengthening the science base

European network to promote access to European pharmacoepidemiological resources

Improve research standards

Increase independence and transparency in research

Stimulate collaboration and exchange of information and experience

Pharmepi and Drug Safety

2012; 20: 690-696

ENCePP Centres with experience in registries

Centres distribution by geographical origin

UK – 13 Spain – 11 Germany – 10 Less than 10 in descending order – Italy, France, the Netherlands, Denmark, Finland and

Portugal, Sweden and Greece and Belgium, Ireland, Slovakia, Switzerland

Of 77 centres in EU listed in ENCePP that mention ‘Registry’

51 centres have drug registry/ies 51 centres have disease registry/ies 34 have other registry/ies (e.g. from observational studies,

family database, mortality registry, adverse events registry, etc.)

Centres distribution by organisation/affiliation

University based (44) Hospital based (23) Government based (13) Charity of non-for-profit organisation (16) For profit organisation (15) Other (not listed specifically under the categories above) (8)

ENCePP Centres with experience in registries

Scientific challenges

New risks

Traceability

Biosimilars

Children

Rare diseases, orphans

Early access

Stakeholder engagement - how to encourage

collaboration?

By imposing on several different companies the obligation to

create a registry at the same time?

Not imposing registry but bringing companies together to

discuss creating of a disease registry?

Identify and approach a suitable academic/patient

organization and suggest collaboration with relevant

companies?

Bring together relevant companies and relevant ENCePP

centres to start the collaboration?

A clear vision of ideal registry

• Built around a specific disease or a defined group of diseases

• Number of individuals on the registry must be adequate to provide sufficient power in relation to defined questions

• Optimal geographic scope

• Direct reporting by healthcare professionals as well as patients to improve completeness and robustness of data collection

• Measures for quality assurance/control, requirements for updates

• Linked with data and biological specimens when possible

• Robust and appropriate case definition

• Accurate and as complete as possible data to guarantee scientific integrity, internal/external validity

• Interoperable, harmonized format and standards

• Transparent, impartial governance inclusive of all stakeholders, complying with data protection and confidentiality legislation

Conclusions

Registries and observational studies have played a critical role in understanding risk benefit in real world use of medicines

New European legislation has placed observational studies at the centre of new strengthened regime

Scientific innovations in therapeutics require new regulatory approaches and methodologies

From risk to benefit:risk life-cycle monitoring opens opportunities for new models of regulation

Collaboration between all stakeholders is key to ensuring we achieve optimum value from RODS