Transcript Sample Topic - Hogan Lovells

The EU Clinical Trials Directive:
What next for the pharmaceuticals
industry?
RAPS Annual Conference
Washington DC 11 October 2004
Linda Horton, JD, LLM
Hogan & Hartson L.L.P.
Brussels and Washington, DC
What was not new
Much was not new, due to:
Existing Member State requirements
Declaration of Helsinki, ICH guidance, Council
of Europe, FDA requirements etc.
Global SOPs of global companies
What has been new: Enlargement! on 1 May
Sponsor Responsibilities:
Not much new, but articulated
Quality Assurance and Quality Control (written SOPs)
Appropriate Medical Expertise
Trial Design
Trial Management, Data Handling, Record-keeping
Investigator Selection & Monitoring
Notification/Submission to Regulatory Authorities
Confirmation of IRB/IEC Review
Investigational Products Good Manufacturing Practices
Ongoing Safety Evaluation/ Adverse Event Reporting
EU-level requirements for Ethics
Committees
Ethics Committee opinions
• Single opinion per Member State
• Increased responsibilities and increased
professionalism
• “Unfunded mandates” decline in number?
• Commission guidance on applications for
Ethics Committee opinions, especially
• Information given to trial subjects
• Protection of personal data
Lead investigator in
Member State
In each country, sponsor must decide how to handle the
requirement for a “single” Ethics Committee opinion to
go to the Competent Authority.
This requirement has led sponsors to designate one
investigator to be the lead national investigator.
The term “principal investigator” is used as the lead person
at a site so that term does not work to describe this
individual.
Oversight: Notification
To commence trial:
• Need OK from Ethics Committee, and
• No disapproval from competent authority
• Must have prior approval for gene or somatic
cell therapy, genetically modified organism
products
• May need prior approval for certain products
(e.g., biological products of human/animal
origin)
Oversight: Notification
To Ethics Committee(s) and Competent
Authorit(ies)
• Significant protocol amendments
• e.g., likely to impact safety
• Ethics Committee opinion within 35 days of
receipt
• End of trial or early termination
• Within 90 days: end of trial
• Within 15 days: early termination
What is new regarding Competent Authority
oversight
Submission to Competent Authority (CA)
• No more “CTX” in the United Kingdom (UK)
• Sponsor can amend request once to address
deficiencies
• CA review may not exceed 60 days
• 30 day extension for gene, somatic cell, GMO
• No time limit for xenogenic studies
• Member States can shorten review timeframe
• Can be simultaneous with Ethics Committee
submission
Legal representative requirement
Sponsor must have a legal entity or legal representative in
the EU or the European Economic Area (EEA)
More impact on small companies, especially companies
with only investigational products.
Even larger companies re-examined relationships with
European entities and wrote new agreements or SOPs.
Manufacturing (GMPs)
Authorization to manufacture/import IMPs
Must designate qualified person (QP)
Manufacture of IMPs
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In Member State
In Non-EU Country: equivalent to EU GMPs
Compliance with product specifications
Requirements for placebos and marketed
comparators from 3d countries
Import requires batch release certification
• Member State must keep batch certification
for 5-year minimum
New GMP Directive 2003/94/EC supersedes
91/356/EEC
Qualified persons
QP release requirement has affected all sponsors of clinical
trials in the EU.
Affects how clinical trial materials are distributed
For smaller companies and especially ones with only
investigational products, the requirement has forced
decisions on who will be QP:
• Legal representative?
• CRO?
• Can same person handle GMP QP requirement and
pharmacovigilance QP responsibilities?
EUDRACT registration
Database of EU clinical trials (EUDRACT)
• Sponsor must register trial and get number
• Confidential: only for Competent Authorities
(CAs), European Medicines Agency (EMA),
Commission
• e.g., extracts of clinical trial information,
amendments, inspections
• CA must provide details at substantiated
request of any Member State, EMEA, or
Commission
Pharmacovigilance
“Adverse reaction” reporting
• Fatal/life-threatening suspected,
unexpected serious adverse reactions
(SUSARs)
• Report ASAP to CA & Eth-Com, no later
than 7 days after knowledge
• Follow-up info within 8 additional days
• Other SUSARs
• Report within 15 days after knowledge
• Annual reports to all Member States in
which trial conducted
• Info added to database and EMEA notifies
other CAs
Pharmacovigilance
“Adverse Event” Reporting
• Report “serious adverse events”
(SAEs) immediately to sponsor
(some exceptions)
• Follow-up written reports
• In general, follow protocol for other AEs
• Sponsor recordkeeping and submission to
Member States where trial conducted
upon request
What has been difficult
Delayed implementation by Member States
Non-transparency (more difficult than it should
be to obtain regulations)
EU Privacy Directive
Ascertaining whether study requires a filing with
the Member State’s “Data Protection
Authority”
New EMEA leaflet on pharmacogenetic studies
tries to help sort out the relationship
Avoiding HIPAA problems; make sure your
European case reports do not go to a U.S.
covered entity like a hospital
Barnett International Philadelphia, May 5, 2004
The challenges ahead
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Delayed implementation
Compliance by partners
Meeting EU and FDA rules
More GMP audits, enforcement
Combination product issues
More changes on horizon
More changes on horizon
Amendments to Community Code on medicinal
products: the “Clinical Studies Requirement”:
Studies conducted in non-EU countries must be
conducted in accordance with ethical
requirements of EU Clinical Trial Directives
FDA has proposed to change regulation on
non-IND studies to substitute delete
reference to Declaration of Helsinki and
substitute reference to ICH GCPs
1 July draft Commission
directive on GCPs
The European Commission has published a
draft Commission Directive that ties together
and builds upon earlier legislation and
guidance on good clinical practices (GCPs) in
investigations of medicinal products for
human use and on the manufacturing and
importation of these products.
Why a new Directive?
Commission legal advisors concluded that, in order to
for GCPs to apply at the Member State level as
binding norms, a directive rather than mere
guidance is required.
The proposal also was influenced by earlier
Commission consultations, in 2002, on the
requirements to obtain an authorisation to
manufacture or import an investigational medicinal
product and on the key elements of the Trial Master
File, inspections procedure and qualification of
inspectors to be included in a Directive.
Also, the “non-commercial research” debate
Another key aim of the draft Directive is to respond to
complaints from academic researchers, received by EU
and Member State officials, about the applicability of the
Clinical Trials Directive to non-commercial clinical trials.
The new Draft Directive refers to the great benefit of such
trials to the patients concerned and would enable
Member States to relax certain requirements through
application to non-commercial trials of “specific
modalities,” particularly as to manufacturing, importing,
and documentation requirements.
Member States must ensure that the objectives of the
protection of the rights of the patients and the principles
of GCPs generally are achieved
Stronger legal basis for
obligations
Should the draft Directive be adopted in its current
format, the legal obligation of sponsors,
investigators and other participants to take into
account the scientific guidelines concerning quality,
safety and efficacy of medicinal products for human
use as agreed by the relevant EU bodies, i.e., the
Committee for Medicinal Products for Human Use
(CHMP) and the EMEA (the European Medicines
Agency), and the European Commission, would be
on a firmer legal basis.
Key elements of the Trial Master
File
The Trial Master File consists of essential documents
that enable the evaluation of the conduct of the trial
and the quality of the data produced.
The draft Directive provides that the sponsor and the
investigator must retain essential documents for 5
years after the completion of the trial.
Also, documents would have to be archived in a
coherent way, to ensure their prompt availability in
case of a request on the part of public authorities.
Any transfer of ownership of the data or of the
documents would have to be documented.
Qualification of inspectors
Guidelines on minimum standards would be required
on the qualification, education and training of clinical
trials inspectors conducting GCP inspections.
Member States would be responsible for ensuring that
inspectors had completed adequate university
education, that their training is appropriate, and that
their knowledge includes the provisions of applicable
EU law, national legislation, and guidelines on
conduct of clinical trials and marketing
authorizations.
GCP inspection procedures
The draft Directive states that Good Clinical
Practices inspections may take place at any
time (before, during, and after the conduct
of clinical trials). Inspections may be
requested and coordinated by the EMEA.
GCP inspection procedures
Member States would be requested to:
• define what access inspectors and the Member
State drug regulatory agency would have to clinical
trials sites and relevant data found there;
• establish procedures for verification of compliance
with good clinical practices;
• establish rules in order to ensure confidentiality by
inspectors and other experts; and
• maintain a database on the inspectors, their
qualifications, training and experience.
Current Status and timeline
The Draft Directive is currently being examined and
comments from Member States were requested by
30 July 2004.
Final adoption of the draft Directive is not expected
before the end of 2004.
Member States would be expected to transpose the
text of the Directive into national legislation within 6
months after the entry into force of the Directive,
which would be 20 days following publication in the
Official Journal of the European Communities,
probably sometime during 2005.
Strategic issues
Do we want to continue to do clinical trials in
the EU? What alternatives are there?
Should we continue to do global studies under
an FDA IND?
Should we instead conduct the EU component
as a non IND study under an identical
protocol and use meta analysis to pool data?
Contact Information
Linda R. Horton, Partner
Hogan & Hartson L.L.P.
[email protected]
www.hhlaw.com
Washington, DC 20004
AS OF 27 Sept: Rue de l’Industrie 26
Brussels, 32 2 505 0931
OR 202.637.5795
Hogan & Hartson, LLP (1904-)
Washington, D.C.
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