squire, sanders & dempsey l.l.p. roadmap to emerging regions: clinical trials in developing...
TRANSCRIPT
Squire, Sanders & Dempsey L.L.P.
www.ssd.com
Roadmap to Emerging Regions: Clinical Trials in Developing Countries
International Clinical Trials ConferenceNew York, 26 February 2009
Written By:Cristiana SpontoniPartnerSquire, Sanders & Dempsey L.L.P.Brussels
Presented by:Michael A. Swit, Esq.Vice PresidentThe Weinberg Group Inc.San Diego, California
Squire, Sanders & Dempsey L.L.P.
www.ssd.com
US and EU Data on Trials in Emerging Regions
www.ssd.com
The Global Landscape
3
69,175 clinical trials are being carried out in 161 countries1
Majority of trials are conducted in the U.S. and Western Europe
Increasingly being conducted in Central & Eastern Europe, Latin America and Asia
Trials increasingly outsourced to Clinical Research Organizations
www.ssd.com4
Globalization of Trials: European Data
According to the EMEA, around one quarter of patients recruited in pivotal trials submitted in MAAs to EMEA between 2005 and 2008 were recruited in:
• Latin America
• Asia
• CIS
• Africa
www.ssd.com5
Recurrent Themes in Global Trials
• Good central coordination but flexibility to local requirements/habits/culture (eg, CTA templates)
• Sound use of resources: CRO, PIs, Sites: how much should be delegated and how much should be kept under control (eg, negotiating/entering CTAs, filing for regulatory approvals)
• All the more true in emerging economies…
Squire, Sanders & Dempsey L.L.P.
www.ssd.com
Advantages and Challenges
www.ssd.com7
Advantages Of Emerging Economies
• Limited costs: drugs, hospitalisation, travel and other general expenses, basic support services
• Higher number of patients, especially naive patients (i.e., patients who never received a treatment)
• Large patient populations with diseases of both developed and developing countries (e.g., HIV/AIDS)
• Multi-ethnic/multiracial populations
• Wide spectrum for diseases
• Potential new markets (e.g., China)
• Competent/motivated PIs
www.ssd.com
• Conducting trials in emerging regions poses a number of challenges:
– Different treatments and standard of care
– Differing levels of clinical research experience and sophistication
– Different capabilities of CROs in the region
• Requires greater direct management efforts
• Many apparent similarities in challenges requiring different responses
Clinical Trials in Emerging Regions
8
www.ssd.com
• Regulatory– Trial Designs– Regulatory Authorities and IRB/ECs– Translation requirements– Import/Export licenses
• Legal– Contracts/Clinical Trial Agreements– Insurance requirements– Intellectual property issues
• Other– CRO Partnering– Site/Investigator Identification– Adherence to Good Clinical Practice– Assuring the Ethical Conduct of the Trial– Quality Control issues– Cultural and infrastructure considerations
Challenges of Conducting These Clinical Trials
9
Squire, Sanders & Dempsey L.L.P.
www.ssd.com
An ordinary day in an ordinary global trial-- Some real life experiences --
www.ssd.com11
Practical Challenge: Control of Temperature
• “Control of storage and transportation temperatures is essential in maintaining the quality of medicines and in helping to protect patients from sub-standard or ineffective medicines that may result from inadequate control” (J. Taylor, Quality and Standards Manager, MHRA)
• Increased risks for biotech products, vaccines, blood products, semi-solids, chemically unstable at certain temperatures, and of course, study drugs.
www.ssd.com12
Let’s Get a Fridge!
• Sponsor wants to perform a study at site x
• Site x does not have a way of keeping Study Drug at appropriate controlled temperature
• Let’s get a fridge there!
OK BUT…
• Can sponsor sell/donate the fridge?
– To whom? Under what circumstances? Do we need a written contract? Do we need to get prior authorizations? From whom?
• What if Site is a public hospital?
• What if we are talking about very expensive medical devices?
• Can the fridge be imported in country x?
www.ssd.com13
www.ssd.com14
Legal Challenge: Study in 21 Jurisdictions in the EMEA Region
• Can a CTA be entered by a non-local Sponsor?
Answer:- Yes, BUT -- in one jurisdiction, still need to go through local entity or mediator- Yes BUT -- in Israel, sites often will object to contracting with a non-Israeli entity- Yes BUT -- certain regulatory procedures will have to be performed by local entities either because it is required by law (e.g., Ukraine) or because -- that’s the way we do things here (Middle East)
www.ssd.com15
Legal Challenge 2: What’s the Right Price?
• Sponsor sells x vials of Study Drug to a non EU European country
• Custom authorities google name of Study Drug and find its price in the US: 10,000 USD
• Custom authorities apply a custom duty considering that value of the Study Drug
• Should Sponsor pay?
• What’s the practice in other countries?
www.ssd.com16
Ethical Challenge: Unusable Data
• Violations result in unusable data: in requesting marketing authorisation, a company submits a file to the EMEA, which includes the description of the trial performed. In examining the file, the EMEA evaluates the respect of GCP, the granting of informed consent and the approval by ECs.
– Illustrates just how important compliance with GCP will be
Squire, Sanders & Dempsey L.L.P.
www.ssd.com
The Emerging European Jurisdictions and Their Rules
www.ssd.com18
The Rules in Emerging EU Jurisdictions
• Estonia, Hungary, Latvia, Lithuania, Czech Republic, Slovakia, Slovenia, Poland, Bulgaria, Romania, Malta, Cyprus: now all EU countries
• Directive 2001/20/EC on clinical trials applies:
- GCP standards- Uniform regulatory requirements- BUT: local challenges still remain
• Highly educated and competent investigators
www.ssd.com19
The EU Directive on Clinical Trials
• Same rules (in principle!) across 27 jurisdictions
• Commercial + Non-commercial trials
• Phases I,II,III,IV
• All trials except “non-interventional” trials
www.ssd.com20
• Industry, Government, Research Council, University, …
• Does not need to be EU-based but must appoint EU-based representative that bears civil and criminal liability as EU-based sponsors
• Sponsor can delegate (NOT transfer!) sponsor responsibilities to third parties (e.g., CROs) BUT sponsor bears ultimate responsibility
The Sponsor
www.ssd.com21
• Informed consent
• Special consideration for children and incapacitated adults
• Data protection:
– Directive 95/46/EC regulates strictly any processing or transfer of data outside the EU
– Medical data qualifies as “sensitive”
– The US is considered not a “safe place” for the purpose of data protection
Protection of Trial Subjects
www.ssd.com22
Commencement of Trials in the EU
• 60 days max 1 x clock stop for info.
• 60+30+90 days max
• No Time Limit (exception)
FavorableOpinion of
EC
CA no grounds for
non-acceptanceExplicit
authorization required only
in certain cases
One opinion per MS
Separate proceduresbut can run in parallel
Sponsor applies for EUDRACT number
Application to EC Notification to CA
www.ssd.com23
• Substantial amendments to be notified to ECs and CAs (35 days max)
• Safety measures adopted to protect safety of subjects
• Notification of trial end (90 days or 15 if early termination)
• Notification of SUSARs
– fatal or life threatening: 7 days
– other SUSARs: 15 days
– annual reporting
• Notification of Serious Adverse Events
Guidance on reporting and standard forms
Conduct of a Trial – Reporting Obligations
www.ssd.com24
• Manufacture/importation authorisation
• Authorisation holder must have QP at disposal: check compliance with EU GMPs or standards that are “at least equivalent”
• IMPs must be supplied free of charge
IMPs – Investigational Medicinal Products
www.ssd.com25
• CAs can suspend or prohibit trials if:
– conditions for granting authorisation for trial conduct are not met anymore
– doubts about safety/scientific validity
• Must consult with sponsor/investigator except in cases of “imminent risk”
• CA will inform other CAs, EMEA and European Commission
• You may have duty to inform FDA as well
Suspension of Trials - Infringements
www.ssd.com26
• Before, during or after completion of a trial
• As part of marketing authorisation process or follow-up to it
• At: trial sites, IMP manufacturing site, any laboratory used in the trial, or at sponsor’s premises
• Conducted by CAs
Inspections on GCP/GMP Compliance
www.ssd.com27
GCP Violations = Unusable Data
• Drugs reviewed by the EMEA can be granted a marketing authorization only if they are based on clinical trials conducted in compliance with the Declaration of Helsinki
• In requesting marketing authorisation, a company submits a file to the EMEA, which includes the description of the trial performed. In examining the file, the EMEA evaluates the respect of GCP, the granting of informed consent and the approval by ECs.
• When problems are identified, namely regarding ethical aspects, the EMEA can advise the Commission to refuse the marketing authorisation or can advise the withdrawal of marketing authorisation already delivered by Member States. This information is also made public.
• However, the EMEA intervention happens after the clinical trial is finalised and presented in the file and not before or during the trial.
www.ssd.com28
Inconsistent Approach/Interpretation
An example…
• Question: can sponsor be non-EU based?
• EU law answer: yes, if it appoints a EU-based representative
– Answer in BG, Czech Rep., Estonia, Latvia, Lithuania, Malta, Romania, Slovakia, Slovenia: yes, if it appoints an EU representative
– Answer in Cyprus: NO!
Squire, Sanders & Dempsey L.L.P.
www.ssd.com
EU Rules on Trials Conducted in Third Countries
www.ssd.com30
EU Rules on Trials in Third Countries
• Financial penalties apply in case of failure to comply with clinical trials requirements
• Sites in third countries can be inspected by the competent authorities of Member States. The EMEA has a system of GCP inspections in third countries since 2006 which has led to an increasing number of inspections in Latin America, Africa and Asia
• Inspections concentrate primarily on: informed consent and appropriate EC (IRB) approvals
• EU assisting on GCP capacity building/inspections a number of countries - in last EMEA GCP Inspectors’ WG workprogramme: Croatia, Macedonia, Turkey
www.ssd.com31
Increased Regulatory Scrutiny
• A European Commission paper of 2002 indicated that:
– The regulatory framework for clinical trials is expected to adapt to the globalization.
– the budget and number of international/national GCP inspectors is expected to increase
– more information on all these clinical trials should be available through an international database
– the key role of IRBs and of capacity building in this area
www.ssd.com32
• Opinion 17 of the European group on ethics in science and new technologies to the European Commission: “Ethical aspects of clinical research in developing countries” (February 2003)
• 2006-2008: Series of Parliamentary Questions on trials in poor countries
• On 5 December, the EMEA issued a strategy paper on: “Acceptance of clinical trials conducted in third countries for evaluation in Marketing Authorisations”
Increased Regulatory Scrutiny …
www.ssd.com33
EMEA Action Plan: Watch This Space!
Three-year-s action plan includes:
• Clarify application of ethical standards
• Consider issues driving recruitment of subjects in third countries
• Consider tools to respond to non-compliance/step up GCP inspections
• Training of EMEA/sponsors/experts
• Increased transparency: EPAR should include a clear description of the assessment of ethical standards of trials in emerging economies
• Promote capacity building also through EU funding instruments
www.ssd.com34
Wrap-Up
• Clear opportunities ahead of sponsors in emerging regions
• Require strong central coordination and resource management
• But, also must understand need for flexibility in approach and understanding of local specificities
• Beware of compliance pitfalls no matter where you conduct your trial!
Roadmap to Emerging Regions: Sponsor Experiences in Central Europe
and Asia
Carlos F. PezaFebruary 26, 2009
Phase IV trial in Oncology conducted in 5 countries (France, Germany, Greece, Italy, Slovenia) 250 sites 8,448 valid subjects (3,719 valid controls) Field period from November 2005 to October 2008
Cross-Sectional Survey on Tobacco Prevalence in Indonesia Inclusion criteria similar to control inclusion criteria in
European study 11 sites 1,500 valid subjects Field period from January to October 2007
Research was financially supported by Philip Morris International
Recent Experiences in Emerging Regions
37
Slovenia
38
Small number of sites provided access to almost every subject in the country who was suffering from the target condition
Regulatory Agency and Central Ethics Committee are among the most efficient in Europe
Highly educated and motivated Investigators Local CROs charged competitive fees for their
services Relatively few challenges for study start up and
conduct
Why Slovenia?
39
Small country, well reachable Centralized healthcare system with developed
referral network Approximately 100 clinical trials are performed
annually Laws and regulations for conducting clinical trials
are based on EU Clinical Trials Directive (2001/20/EC)
Agency for Medicinal Products and Medical Devices (JAZMP) is the competent authority for clinical trial authorization
EC approval given at the national level by the National Medical Ethics Committee
National Cancer Registry
Specifics of Slovenian Situation
40
Challenge: Identifying and vetting the appropriate CRO Identify the strength and weaknesses of
potential vendors Understand how you will have to supplement
for the potential weaknesses Our approach:
Vetted international and national CROs Decided on National/Local CRO
Identified its strengths Worked with them to shore up their potential
weaknesses
Overcoming the Challenges in Slovenia
41
Challenge: Obtaining ethics approval for a controversially funded study
Our approach: Recruited Principal Investigator wisely
Provided him with the information needed to fully understand and promote the study
Became invested in the study Good reputation, leadership skills, and willing to act as a
key advocate of the study Set the stage with Ethics Committee
Identified, recruited and developed good working relationship with Key Opinion Leaders in order to understand local considerations
Understood the potential concerns of the members Addressed these during the submission Gained support of stakeholders and who demonstrated
this support to EC
Overcoming the Challenges in Slovenia
42
Challenge: Achieving potential subject recruitment
Our approach: Developed Principal Investigator and sub-investigators
as key promoters and coordinators Coordination and promoting activities of different sites Coordinating and promoting study within site
Developed investigator network where subjects were identified in the periphery and “treated” in the central location
Motivated site team Actively recognize the role of each site member CRA partnership with sites
Kept site team informed and involv
Overcoming the Challenges in Slovenia
43
1 Local/National CRO 16 Sites 1 Country Principal Investigator, 24
investigators/subinvestigators, more than 20 study nurses
Comparably high recruitment rate First patient in: April 2007 1,391 valid subjects (721 valid controls) 16% of total study subjects recruited within one
year Recruitment rate stable over the year (no holiday
gaps)
Slovenian Participation in the Study
44
Excellent experience in Slovenia High subject recruitment rate Qualified and motivated medical professionals Uniformed regulatory issues as in Western
Europe EU Clinical Trials Directive, ICH and GCP
already implemented Relatively lower CRO costs to conduct the
trial
Our Experience in Slovenia
45
Indonesia
46
Originally intended to conduct a series of studies to understand the relative risks of smoking for a several disease end point
Planned to conduct several case-control studies for each of the disease endpoints
In planning the studies, it was determined that there did not exist valid epidemiological data to be able to guide the design of the studies
A pilot study of patients in hospitals to be used in the case-control studies was conducted
Indonesian Smoking Prevalence Study
47
Large Country Very few trials being conducted, but numbers are
growing. Government and investigators receptive to industry
knowledge GCP implemented into national laws and guidelines
governing clinical trials ECs to be established at institutional,
regional/provincial, and national levels according to need National Agency for Drug and Food Control is competent
authority for clinical trial authorization Lack of population-based registries
Hospital based-cancer registries in 13 cities
Specifics of the Indonesian Situation
48
Cross-sectional study on the smoking prevalence of Indonesian male hospital patients
Study performed to regulated standards of a clinical trial
11 hospital sites in Jakarta, Solo, Surabaya, Padang 1 Principal Investigator, 22
investigators/subinvestigators, 60 CRA/interviewers More than 18,000 medical records evaluated 1,533 valid subjects recruited 38 week field period
Indonesian Smoking Prevalence Study
49
Challenge: Designing a clinical trial to account for the specifics of the region Cultural issues Inclusion/Exclusion Criteria Trial Length and approval timings Infrastructure issues Investigator and Staff Training
Our approach: Trial designed to account:
Differences in medical practice (disease diagnosis, investigator-patient relationship)
Translation of study/regulatory documents Validation of measurement scales (patient questionnaire)
Understood need to apply “partnership approach” to build supportive relationships
Overcoming the Challenges in Indonesia
50
Challenge: Identifying and vetting the appropriate CRO partner No local CROs Only a handful of Regional CROs working in
Indonesia Our approach:
Decided on one regional CRO Worked on setting clear expectations on how the
study should be conducted Task distribution (assigning of responsibility) Which SOPs were going to be used
Increased communication Thorough training of CRO staff and co-monitoring
visits
Overcoming the Challenges in Indonesia
51
Challenge: Investigators and Staff experience Lack of clinical trial experience Gaps between concept and reality in the field
Our Approach: Incorporation of GCP, ethical practices, clinical
management training into Investigator Meetings, CRA/interviewer training, monitor training Special emphasis on informed consent process The training methods paralleled the expected
performance of the study team Site based CRAs conducting SDVs during patient
recruitment process Increased site monitoring
Overcoming the Challenges in Indonesia
52
Challenge: Local infrastructure and sites constraints Lack computerized central patient database
systems Lack of secure storage space Difficult internet and phone access Understaffing
Our approach: Site auditing prior to contract signature Financial investments made into resources and
personnel Regular monitoring
Overcoming the Challenges in Indonesia
53
Challenge: Cultural Complexities Hierarchical social structure impacts recruitment
Investigator Site Patient
Our approach: Build trust and cultivate relationships
Principal Investigator Key Opinion leaders
Involve hospital administration in site selection and start up activities
Train and inform on “foreign” practices and international expectations
Overcoming the Challenges in Indonesia
54
Untapped potential Large patient pool Many potential sites
Government and Investigators very eager to bring more clinical research into the country
Need for capacity building Limited infrastructure Continued need to help local authorities
adjust their regulatory environment to allow high quality clinical research
Our Experience in Indonesia
55
Advance preparation and strategy development Thorough knowledge of local processes and operations Design trial with an implementable protocol Upfront dialogue and partnership-oriented approaches Identify a CRO that is suitable for you Know your limitations and how much you are willing to
concede to your vendors Audit CRO, site and monitors GCP training before start of the study Close monitoring during the study What is your plan B?
Approaches to Consider
56
Questions?
Carlos F. PezaConsultant
The Weinberg Group Inc.One Embarcadero, Suite 500
San Francisco, CA 94111P +1 415.293.1031
About Your SpeakerCarlos Peza is a Consultant at The Weinberg Group. He recently served as Project Manager for a large international Phase IV oncology trial. The study was carried out in more than 250 sites in five European countries and enrolled more than 8,500 valid subjects.
Mr. Peza also managed a cross-sectional study on smoking prevalence in Indonesia. The study field period took place over a period of 38 weeks in 2007 in 11 sites in Indonesia. More than 18,600 medical records were reviewed and valid data was collected from more than 1,500 subjects.
His main tasks in these studies were interacting with international, national, and regional CROs to assure comprehensive management of the studies. In addition, he managed the development and implementation of the data collection instruments and all interview-related project components, including the development of a computerized questionnaire instrument for the European study, translation of the data collection instruments into the appropriate country languages, as well as the training and monitoring of interviewers.
Through his experience at The Weinberg Group, Mr. Peza has developed a significant knowledge of protocol design, questionnaire design, data collection methods, survey quality, coverage error, and interviewer effects.