Is Harmonization an Adequate or Achievable Goal? · Presentation Slide Template (DIA) Author:...

Is Harmonization

an Adequate or

Achievable Goal?

Ingrid Klingmann, MD, PhD

EFGCP, Belgium

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DISCLAIMER

2www.diahome.orgDrug Information Association

Despite all individual/national efforts from lawmakers,

regulators, pharma industry, and academia development

of a new drug takes longer than ever and costs have

exploded.

Clinical development is by far the most costly portion of

drug development with the worst impact of attrition costs

on the overall costs.

The Current Situation

I. Klingmann www.diahome.org 3

Despite undisputable ICH achievements clinical drug

development is full of duplication of efforts, inefficiencies,

differences of opinion – or even contradictions – all to be

sorted out by the sponsor.

ICH is a great infrastructure to define “state-of –the-art”

but legally “weak” as it does not have any implementation

power.

“Clinical Research” and the staff involved are under

national jurisdiction with the obligation to protect patients

participating in research. There is no legal obligation to do

research, to develop new treatments.

The Current Situation


With very few exceptions the different professions in

clinical development are not based on widely agreed

formal educational requirements and demonstrated

competencies (like for physicians working as responsible

specialists in hospitals or private practice) or minimally

required experience (like “Qualified Person” or “Qualified

PV Person” but “happen” (“I ended up in regulatory

affairs...”).

National Medical Professional Bodies do not consider

“Clinical Research” to be a “speciality” for physicians

(like “Cardiology”, “Nephrology”, etc.) or require for staff

a formal educational pathway like “nurse”.

Professional Framework


Beside the potential for increased income, performing

clinical trials is not attractive for physicians – neither the

performance of industry-sponsored trials nor of

Investigator-Initiated-Trials (IITs):

– clinical trials do not “fit” into the hectic daily routine of patient

care

– Create conflicts with physicians’ believe in autonomy of

individualized diagnostic and treatment

– “working for industry” is often a block to “academicall

recognised” career



The European Medical Research Council of the

European Science Foundation (ESF) has intensively

analysed the current problems faced in IITs.

They developed 26 high-level recommendations to

improve patient-oriented clinical research in Europe:



The top 5 recommendations were:

Better conditions for education, training and career

for clinical researchers

Level of funding for clinical research in Europe

Risk-based approach to regulating clinical trials

Improved clinical trial authorization process, ideally

with a single CTA

Adequate scale for Investigator-Initiated Trials:

funding infrastructure for correctly powered trials



So far, harmonization as a basic requirement for faster

and more efficient new treatment development has been

primarily a need

– for pharmaceutical companies for commercial purposes in times

of increasing competition and financial pressure

– for big academic institutions performing multinational trials for

treatment optimization and publications/career development

– for regulatory authorities to ensure optimal patient protection and

to enable attractivity of the country as a research place

Ethics committees are not in need for harmonization:

they are obliged to do the best for “their” patients to their

best ability, according to national health care conditions

and their cultural environment.

Who Needs Harmonization?


Today Patient Organisations (POs) become increasingly

powerful in requesting faster, more efficient and safer drug

development.

They increase the public pressure on all stakeholders

involved to create an infrastructure that gives rapid and

equal chances to patients to benefit from new treatment

options.

More and more POs want to be seen as “Partners” in drug

development, even raise money to drive drug development

themselves.

Thus the public pressure for harmonization of the

regulatory and professional infrastructure increases rapidly.

Who needs Harmonisation?


Released in 2001, the European Clinical Trials Directive

was implemented in 2004 with the aim to achieve

regulatory harmonization of clinical trial conditions in the

EU as far as the legal system in the EU allowed for that:

– A “Directive” defines the principles (e.g. Clinical Trial

Authorisation by competent authority and in parallel or

sequentially by one single ethics opinion per country, maximum

60 days per approval, development of a central clinical trial

database and a pharmacovigilance databse, etc.) but it is up to

each Member State how these principles are implemented

– Detailed guidances on how to implement the principles were only

released in 2004 and later.

EU Experience


I. Klingmann

Mean Time To Obtain Authorization per NCA

2000 2001 2002 2003 2004 2005 2006 2007MEAN / NCA in the EU (d) 64 63.83 70.14 60.38 50.43 49.63 47.34 48.66

Example 1:

Results from the EU-Commission funded ICREL

Project

www.diahome.org12

I. Klingmann

Mean Time To Obtain Authorization in

Multi-national Clinical Trials

Time lines from CT protocol finalisation to inclusion of first patient and

from (substantial) amendment release to first implementation in 2003

and 2007

Time Periods 2003 2007Unadjusted change (%)

Adjusted change (%)

Days from protocol release to FPI 115 152 32.4 89.33

Days from (substantial) amendment release to first implementation

40 53 31.7 37.13

www.diahome.org 13

14

Number of Clinical Trial Authorizations from

Non-Commercial Sponsors

0

100

200

300

400

500

600

700

1999 2001 2003 2005 2007 2009

Year

Num

ber

of C

TAs

ABCDEFGHIJKLMNOPQRSTUVWXYZZZ

Example 2: Results from the EU-Commission funded ICREL Project

14I. Klingmann www.diahome.org

In July 2012 the European Commission released a “Draft

Regulation on Clinical Trials”, which is currently under

negotation between the European Commission, the

European Parliament and the European Council

(representing the governments of the Member States).

Supposed to come into force in 2016/2017 with a

transition period for ongoing trials.

“Regulation” means that all Member States have to adhere

to this text in exactly the same way.

Based on the experiences of the “Voluntary Harmonization

Procedure (VHP)” but forcing also national ethics

committee systems to enable adherence to this law.

Recent Development in the EU


It is a REGULATION

Single portal, single dossier

Coordination of assessments in multi-national trials

shifted from sponsor to competent authorities

Coordinated 2-Part assessment procedure amongst

Member States

Role of ethics committees

Maintaining national decision via EU Portal

Risk-based approach

Streamlined safety reporting

Equally protective indemnification provisions

Key Changes in the Draft Regulation


This Regulation will reliably harmonize the regulatory

conditions for clinical trials in Europe because the EU

has a legal instrument to enforce harmonization.

For multi-regional or global trials such legal mechanisms

do not exist. Here harmonization can only be achieved

through voluntary collaboration between the

governments (“Global VHP for Clinical Trial

Authorization”?).

Strengthening the legal power of ICH outcomes in the

interest of the patients?

Harmonization on a Global Basis?


However,

the Regulation will only cover drug trials,

the Regulation will not change the professional

environment for staff in industry and academia involved

in clinical research,

the Regulation will not enforce standardization of

required competences and accreditation of clinical trial

infrastructure and education.

These areas require “bottom-up” efforts of professional

organizations to implement and harmonize infrastructure

for education, competence profiling and accreditation of

sites and education providers

Weaknesses of the Draft Regulation


“PharmaTrain”: one of the 5 education and training projects

of the European “Innovative Medicines Initiative”, the

largest (2 Billion Euros) public-private partnership in

biomedicine, between the European Commission and

EFPIA

PharmaTrain is a standard-setting network of pharma

companies, universities, regulatory agencies and standard

setting societies that has developed and is maintaining

high-quality Shared Standards for postgraduate Education

& Training in drug development, regulatory affairs and

investigator training.

Other Harmonization Initiatives


The content from molecule to marketplace (Syllabus) is

mapped against Learning Outcomes and Competencies.

The Implementation Process of the Shared Standards

includes assessment of course providers, recognition of

courses and centralized examination and certification.

Currently, PharmaTrain has 45 global affiliate university

members. In May 2014 the IMI project will be finished but

the sustainability of PharmaTrain is given and will move

PharmaTrain to a truly global organization.



The “Clinical Investigator Certification (CLIC)” Initiative

aims at creating an understanding of the need and

recognition of investigator training beyond GCP training.

CLIC provides syllabus, examination and certification

conditions for site staff, principal investigators and

sponsor-investigators as well as a concept for integrative

course provider assessment and recognition.

The aim is to align this concept with site standardization

initiatives in all other regions of the world.



Harmonization is not only “adequate”, it is mandatory!

Harmonization is achievable but requires

a lot of good will,

many competent, engaged people,

much patience and persistence

development of strong global networks of people and

organizations willing to improve the infrastructure for better drug

development in the interest of the patients

public and private funding to enable people on a global basis to

collaborate in concept development and implementation

Conclusions


THANK YOU

FOR YOUR ATTENTION !!!

Conclusions


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