Regulatory harmonization, a regulatory perspective Hubert Leufkens, Medicines Evaluation Board/Utrecht University

Regulatory harmonization, a regulatory perspective

Hubert Leufkens, Medicines Evaluation Board/Utrecht University

College ter Beoordeling van Geneesmiddelen

Leufkens Regul Harmonization

• Professor of Pharmacoepidemiology, Utrecht Institute of Pharmaceutical Sciences, 0.4 FTE.

• Chairman of the Dutch Medicines Evaluation Board (MEB), since mid 2007.

• Co-opted member of CHMP PhVWP, 2006-2009; since 2009 co-opted member of CHMP.

• Director WHO-Utrecht Collaborating Centre on Pharmaceutical Policy and Regulation, since 2008.

• This talk reflects my personal views; I am being inspired and challenged on a daily basis by many colleagues from these ‘environments’.

Declaration of interests



Non-harmonized world of cellphone adaptors

Feira da Ladra, Lisbon's Flea Market, Summer 2012


There are many reasons to harmonize drug development and regulation, i.e. to

• ensure equal access to patients.• improve work-sharing and efficient use of scarce

regulatory resources.• avoid redundant use of animals in toxicity testing.• limit number of study subjects in regulatory BE

testing and pivotal clinical trials. • facilitate international trade and commerce.• contribute to a sustainable/affordable model of drug

development.• promote (global) trust in medicines.



The stakes are high ....

• Novo Nordisk shares fell 14% in the afternoon of February 11 2013.

• FDA requests additional cardiovascular outcomes data from a dedicated cardiovascular outcoms trial before the review of the NDA (Tresiba) can be completed.

• Authorities in the EU and Japan have already approved the drug.

• Novo Nordisk CEO adds ‘the FDA is more risk-averse than its counterpart in the EU which looks more at the benefits’.


WSJ 2013 February 12: 20.



Science 2011 Apr 8; 332(6026): 174-5.

Regulatory systems• Patient safety

• Public health

• Innovation



Question Today's challenges

Robust definition and diagnosis of disease?

Psychiatric morbidities, sepsis, somatic functional disorders

Clinically relevant endpoints to evaluate drug effects?

PFS and OS in oncology, HbA1C or outcomes data in diabetes

Identifiable target population (indication) that may benefit?

Biomarkers to identify responders, to evaluate response

What kind of comparison is useful, needed and feasible?

Placebo, active controls and dynamics in treatment options

Key questions in the lifecycle of a medicine


Five archetypes of problematic dossier crunching

• We don’t like this product at all.• Lost in details.• We struggle, asking for more data makes

us feel good.• Reluctant to cross borders, risk avoidance.• Why are we so positive?




… Football, like most American sports, is heavily rule-bound.

…Soccer is a more principles-based game. There are fewer rules, and the referee is given far more authority than officials in most American sports to interpret them and to shape game play and outcomes…

A bad or biased ref can ruin a soccer match in the way that no bad ref can ruin a football match, the lesson being that regulator independence is key in a principles system...

Principles-based versus rule-based regulation

Economist. Metaphor of the day, April 21, 2008



Nat Rev Drug Discov 2012; 11: 903-4.



Elgazayerly AN, de Graeff PA, Leufkens HG.N Engl J Med 2012 Mar 22 ;366 :1160-1.



2011 Jun 1;29(16):2266-72.



Scrip 2011 Nov 25:18.



JAMA 2008; 300: 1887-1896.



placebo standard treatment alternative scenario

societal effects

HTA

clinical outcome

biomarker

Outcomes and making comparisons



Rethinking the regulatory system: The Escher-project

Documents

Regulatory harmonization, a regulatory perspective Hubert Leufkens, Medicines Evaluation Board/Utrecht University