Balancing Benefits andRisks after marketing

Marieke De BruinCORS/Biopeople Workshop, Copenhagen, April 21, 2016

Declaration of Interest

• Assistant Professor of Pharmacoepidemiology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University

• Pharmacovigilance expert at the Dutch Medicines Evaluation Board (MEB)

• Independent Scientific Expert at the Pharmacovigilance Risk Assessment Committee (PRAC) - European Medicines Agency

• Professor in Regulatory Science, Copenhagen Institute for Regulatory Science (as of August 15, 2016)

This talk reflects my personal views

2000-2010, 200 new medicines, 19.5% orphans

PLoS Med 2013; 10: e1001407.

PhV system has many PhV tools

• Routine/Addtitional PhV

– Spontaneous reporting

– PSURs/PSUSAs

– PASS/PAES

– SOBs (e.g. CMA)

• Routine/Additional RMM

– SmPC

– Educational material

– DHPCs

– PPPs

• RMPs

• Referrals

• Renewals

• PRAC

Intended effect:

Public Health

Balancing Benefits and Risks after marketing

• Routine/Addtitional PhV

– Spontaneous reporting

– PSURs/PSUSAs

– PASS/PAES

– SOBs (e.g. CMA)

• Routine/Additional RMM

– SmPC

– Educational material

– DHPCs

– PPPs

• RMPs

• Referrals

• Renewals

• PRAC

2 examples

Study aim

To examine the development of the RMP after approval, to provide insight into

the knowledge gain over time, by quantifying changes in listed safety concerns

and study factors associated with change

Clin Pharmacol Ther 2014

Study methods: Cohort study

• New medicinal products EU (Nov ‘05 - Dec ‘09): baseline RMP

- Type of product , type & nature of concern, additional activities

• Subsequent RMP updates through EMA, follow-up until Dec ’12

- Outcomes of interest: Change in type of concern / Newly added concerns

• Analysis: - Time to first change (all concerns), time to resolve uncertainties

- Type & nature of newly added concerns

Results – RMPs at authorisation

• 48 medicinal products included in study cohort

- 31 small molecule drugs and 17 biologicals

• Comprising 640 concerns at authorization (baseline)

- 152 identified risks, 246 potential risks, and 242 missing information

Safety concerns at authorization, median (IQR)

Small molecules

(n=31)

Biologicals

(n=17)

All products

(n=48)

Important identified risks 4 (2-5) 3 (2-4) 3 (2-4.5)

Important potential risks 5 (4-7) 6 (4-8) 5 (4-7)

Missing information 4 (3-6) 5 (4-8) 5 (3-7)

Total 12 (10-16) 15 (11-19) 13 (10-16)

→ more uncertainties with biologicals

Results – Resolved uncertainties

• Cumulatively, 85 of the 489 (17.4%) uncertainties were resolved over time

- No difference observed between small-molecules and biologicals:

Rates = 0.04/ product-year

Log-rank p=0.95

Results – newly added information

•During follow-up, 157 concerns newly added for the 48 products

– Median 3 per product (IQR: 1 – 4.75)

•Type of concerns

– 45 identified risks

– 69 potential risks

– 43 missing information

•Approximately half related to change in context of use

New uncertainties (n=112)

Results – newly added information

Characteristics and follow-

up of post-marketing studies

of conditionally authorised

medicines in the EU

J Hoekman, TT Klamer, AK Mantel-

Teeuwisse, HGM Leufkens, ML De Bruin

[Online Early DOI: 10.1111/bcp.12940]

Conditional Marketing Authorisation (CMA)

“In order to meet unmet medical needs...it may be necessary togrant marketing authorisation on the base of less complete data than is normally the case” (Commission Regulation 726/2006)

Pathway design:• Benefit of quick access should outweigh potential risks related

to uncertainty• Medicine should have positive B/R • Post-marketing obligations and yearly renewal of licence

Specific obligations (SOBs):• “The holder is required to complete or initiate certain studies

with a view to confirming that the risk-benefit balance is positive and resolving any questions relating to the quality, safety and efficacy of the product” (Commission Regulation726/2006)

26

2006 2007 2008 2009 2010 2011 2012 2013 2014

sunitinib

stiripentol

darunavir

panitumumab

etravirine

raltegravir

lapatinib

everolimus

aztreonam

H1N1vaccine

ofatumumab

H1N1vaccine

pazopanib

fampridine

vandetanib

pixantrone

crizotinib

brentuximab

bosutinib

vismodegib

2015

bedaquiline

cabozantinib

Cancer

13 (50%)

HIV

3 (12%)Influenza

2 (8%)

Other

8 (30%)

delamanid

2016

ataluren

holoclar

ceritinib

Data Lock Point Nov 2015

Conditional MA in Europe

Aims & Methods

To examine characteristics and follow-up of post-marketing (PM) studies related to specific obligations (SOBs) of medicines that were granted a conditional marketing authorisation (CMA) in the EU

• Study population: CMA products 2006-2014, their SOBs and PM-studies

• Study outcomes

Characteristics: indication, objective, design, status

Follow-up until August 1, 2015

• Time to fullfill obligation

• Time to convert CMA in standard MA

21 medicines with CMA

59 post-marketing studies

23 medicines with CMA

2 vaccines excluded

5 (8%) observational

studies

44 (75%) interventional

studies

34 (58%) with due date before August

1, 2015

11 (19%) with due date after July 31,

2015

33 (56%) matches with online register

1 (2%) not matched

3 (5%) with due date before August

1, 2015

2 (3%) with due date after July 31,

2015

1 (2%) match with online register

2 (3%) not matched

10 (17%) other post-marketing

obligations

Analysis of characteristics

Analysis of follow-up

1 obligation excluded

61 specific obligations

Medicines (n=21)

Number (%)

Indication

Cancer 13 (62%)

HIV/AIDS 3 (14%)

Epilepsy 2 (9%)

Multiple Sclerosis 1 (5%)

Cystic Fibrosis 1 (5%)

Tuberculosis 1 (5%)

Orphan designation 10 (48%)

Pro-active request for CMA by MAA 8 (38%)

Characteristics of CMA medicines

Studies (n=59)

Number (%)

Design

Interventional studies 44 (75%)

Observational studies 5 (8%)

Other obligations 11 (17%)

General objective

Additional Efficacy data 25 (42%)

Additional Safety data 9 (15%)

Additional Efficacy/Safety data 25 (42%)

New studies (after MA) 23 (39%)

Expected time to completion in days 575 (IQR 204-1287)

Characteristics of post-marketing studies

Time to completion(studies)/conversion (license)

Delay (n=26/34): 275 days [IQR -121; 773] Delay (n=14/23): 470 days [IQR 114; 1295]

50% 29%

Discussion & Conclusions

• Obligations are started, registered and eventually completed

• Half of all studies have substantial delays

• Lack of incentive or closing a window of opportunity?

• With annual renewal of license regulators are probably aware

• Patients exposed to unnecessary treatment risks

• Difficult to balance B/R with limited data

More work to be done