A review of key issues that can make or break the success of a clinical study conducted outside the United States, with an emphasis on site, GCP issues, challenges that vary nationally, and enforcement concerns.

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Regulatory Challenges to Successful Global
Clinical Studies
Presentation to NIH
Michael A. Swit, Esq.
Special Counsel, FDA Law Practice

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Standard Disclaimers
• The views here are mine and do not necessarily
reflect those of my law firm or any of our clients.
• These slides support an oral briefing and should not,
alone, be relied upon to support any conclusion of
fact or law.
• This presentation is for general educational
purposes and is not intended to be legal advice or to
create an attorney-client relationship with any
person.
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• Keys to Regulatory Success in Global Clinical Trials
• Case Studies on Key Issues –Selected Country
Examples
• Focus on Enforcement – What Can Go Wrong
• Final Thoughts -- Lessons Learned
What We Will Cover
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Keys to Regulatory Success in
Global Clinical Trials
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Why Go Global?
• Higher number of patients, especially naive patients ‫‏‬
• Large patient populations with diseases of both
developed and developing countries (e.g., HIV/AIDS)‫‏‬
• Multi-ethnic/multiracial populations
• Wide spectrum of diseases
– Especially important for rare diseases
• Potential new markets (e.g., China)‫‏‬
• Competent/motivated PIs

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• Standards of care -- differ around the world. In
doing a clinical trial OUS, seek to ensure trials are (can
be) done the same in each jurisdiction – but, “the
universal protocol” is extremely elusive
– Can add to cost
– Example – device study – labs for three days after implant
 U.S. – to be done in hospital
 OUS – standard of care is discharge after 1 day; labs not
done
• Ethical standards -- particularly as to informed
consent are different – know this issue
General Considerations
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• Hire the right CRO -- if you lack a “presence” in the
country, right CRO is crucial to getting good data
• Follow-up -- in developing countries, can be
difficult. Subjects need access to the treatment facility
-- you may need to ensure they get there
• Equipment – if specific piece of lab or other
equipment needed, make sure they have it
• GCP Compliance – Audit before contract to ensure
trained per FDA/ICH standards
• IRBs/Ethical Committees – can be much more
bureaucratic – and slower
General Considerations …
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• Time Zone Differences – if U.S. based, need to be
able to juggle these (e.g., 10 pm call from San Diego to
Tel Aviv – 8 am next day)
– Make sure they are working (e.g., Sunday may not be the
sabbath where they are)
• Language – translations – validate; don’t rely on a
non-professional translator
• Drug import challenges – plan in advance
– EU – QP (“Qualified Person”) release required
• Record retention – some countries require that all
docs be kept “in country” (e.g., Australia)
General Considerations …
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• Multiple contracts may be needed
– Hospital, investigators, pharmacy, laboratory
• Some countries require submissions be made by a
someone who lives in that country – e.g., Italy
• Regulations – may not be available in English – e.g.,
Italy
• Summer holidays – July or August – country may be
shut down; know what their practice is and plan
• Applicability of patient populations – need to
assess this carefully due to genetic differences; will it
fly with FDA?
General Considerations …
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Sponsors – Key Required Procedures
• How they will deal with any reports of PI or CRO
non-compliance.
• U.S. sponsors – be very careful about payments to
doctors and others – in some cases, they are
government employees and the payment could trigger
Foreign Corrupt Practices Act concerns
 e.g., Eastern Europe – may ask for payments to
referring doctors
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Sponsors – Key Required Procedures …
• Ensure that local requirements are heeded
– Be aware of trend in some countries for continued duty to
provide drug after study end
• Adverse events – OUS or ex-EU adverse events still have
to be reported back to FDA or EU competent authorities
• Make sure sites know documentation requirements
 Keeping source data (e.g., blood pressure printouts from automatic
machine tossed out after being transcribed)
 “Cleaning up records” – Japanese site did not like messy records
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• Sponsors – make sure contracts with clinical
investigators and CROs have adequate provision
covering GCP compliance.
– Require an immediate escalation of compliance concerns to the
sponsor.
– CRO agreements must have a detailed transfer of obligations
form.
– Make sure CRO is not also a SMO – site management
organization – not unusual overseas and can create conflicts
– Be careful with excessive payments – even if legal and not
subject to disclosure under 21 CFR 54, might “taint” data
– Audit your sites per U.S. GCP standards
Clinical Trial Agreement -- Keys
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Key Issues by Selected
Regions/Countries
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• Scientific Advice --
– Difficult to balance going to Europe before hearing back
from FDA on EOP2 meeting and Phase 3 protocol
agreement (especially if using a SPA).
 Timing – Scientific Advice is on a more rigid schedule –
predict in advance if possible
 EMA – may be a little off-put if you are late, however
Europe
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• Insurance issues -- allow extra time for coverage and
review (especially in Germany)
– Example: Phase 3 study required an extra 6-8 months to
get coverage before would be considered by Ethics
Committee. Result -- sponsor could not use Germany in
first global study; only able to include in a parallel second
study.
Europe
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• Phase 1 studies
– Ethics Committee and regulatory agency have suspicion that
we (U.S.) are going to India to test because it is less likely to
have problems if the drug "poisons" the patients. Do not want
the Indian people to be guinea pigs.
 SOLUTION: convinced them that safety data about the
product was sufficient by taking extra steps to document in the
cover letter both the safety measures included in the study
protocol and outline the key points from the investigator
brochure rather than simply providing the investigator brochure.
• Fraud is rampant (former FDA General Counsel) –
although government is taking efforts to reform
India
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• Center for Drug Evaluation (CDE) Evaluation
meeting:
– Monthly meetings, over 3-4 days, held in Chinese (translators
may or may not be acceptable). Need to bring subject matter
expert (CMC, Tox, etc.).
– CDE issues final evaluation ~ 2 months after the meeting.
– Much of the information that we are used to submitting for a
NDA is required as part of the CTA in China.
– A strong, local regulatory person may get the questions before
the meeting and feed them back to the sponsor.
– Local QC testing of test article for biologicals required.
Average > 5 months to complete testing.
 Fear here – IP pirating
China
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• Challenges:
– CTA approval time ~ 15 months.
– Lack of flexibility
– Requires information about previous studies
– Two different regulatory bodies:
 Center for Drug Evaluation (CDE) reviews the trial scientifically
while the CFDA approves the trial.
 Sometimes, CDE reviews and OKs and then CFDA rejects the
trial.
– Fraud is rampant (per former FDA GC)
China …
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Comparison of Study Start-up Times
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Slide Courtesy of bioRASI, Inc.

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• Advantages/Logistics:
– Large Country
– Government and investigators receptive to industry knowledge
– GCP implemented into national laws and guidelines governing
clinical trials
– National Agency for Drug and Food Control is competent authority
for clinical trial authorization
• Disadvantages:
– Very few trials being conducted, but numbers are growing.
– ECs to be established at institutional, regional/provincial, and
national levels according to need
– Lack of population-based registries
 Example: Hospital based-cancer registries in 13 cities
A Deeper Look -- Indonesia
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• 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
• An 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
Indonesia
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• Challenge: Identifying and vetting the appropriate
CRO partner
– No local CROs
– Only a handful of Regional CROs working in Indonesia
• The 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
Indonesia
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• Challenge: Investigators and Staff experience
– Lack of clinical trial experience
– Gaps between concept and reality in the field
• The 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 source data verifications during patient
recruitment process
– Increased site monitoring
Indonesia
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• Challenge: Local infrastructure and sites constraints
– Lack computerized central patient database systems
– Lack of secure storage space
– Difficult internet and phone access
– Understaffing
• The approach:
– Site auditing prior to contract signature
– Financial investments made into resources and personnel
– Regular monitoring
Indonesia
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• 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
Indonesia
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Focus on Clinical Trials Enforcement – What
Can Go Wrong Overseas?
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Clinical Sites –
Inspections by The Numbers
(closed since 1977; as of 2009 and / = 10/1/2008 to 9/30/2013)
 U.S. – 7,920/1,082
 Canada – 159/31
 UK – 98/25
 Germany – 67/51
 France – 53/28
 Russia – 50/53
 Italy – 38/18
 Poland – 38/48
 Sweden – 38/4
 South Africa – 30/16
 Belgium – 28/4
 Netherlands – 27/8
 Argentina – 25/16
 Brazil – 20/18
 Mexico – 18/5
 Spain – 18/13
 Australia – 9/5
 India – 8/33
 China – 7/16
 Japan – 3/7
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FDA -- Enforcing GCP Compliance Overseas
• Very limited foreign examples – only a few
warning letters aimed at foreign clinical
investigators.
• But, if done under a U.S. IND, must meet all
clinical study requirements
– IND rules – Part 312
– Informed Consent – Part 50
– Financial Disclosure – Part 54
– EC/IRB – Part 56
– AE reporting
• Thus, U.S. enforcement activity provides clear
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Moscow City Hospital WL -- 2006
• You failed to maintain adequate and accurate case
histories that record all observations and data pertinent to
the investigation [21 CFR 312.62(b)] .
– For Subject #_, the baseline ECG recording obtained on June 21, 2004,
and the, Visit 4 ECG recording obtained on August 3, 2004, were
identical except for the information hand-written on each ECG,
including subject number and date of tracing.
– For Subject #_, the baseline ECG recording obtained on June 21, 2004,
and the Visit 4 ECG recording obtained on Aug 2, 2004, were identical
except for the information hand-written on each ECG, including subject
number and date of tracing.
– Source records for Subjects #_ and #_, document that the same
individual performed the baseline physical examinations on the same day
(June 21, 2004) and at the same time (0900).
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Moscow City Hospital WL – 2006 …
• You failed to maintain adequate records of the
disposition of the drug including dates, quantity
and use by subjects [21 CPR 312.62(a)] .
– Dispensing records show 5 mg. given out to Subject X, but
2.5 mg. tabs returned by same Subject
• Length of inspection – 3 days
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Children’s Hospital of E. Ontario WL -- 2003
• You failed to protect the rights, safety, and welfare
of subjects under your care and failed to ensure
that the investigation was conducted according to
the investigational plan. [21 CFR 5 312.60]
– overdoses of the study drug interleukin-2 (IL-2) that were
22 to 25 times higher than the dose specified in the protocol
 One death
– Cause – incorrect dosing form used that did not jibe with
the protocol
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Children’s Hospital of E. Ontario WL …
• You failed to ensure that the investigation was conducted
according to the investigational plan. [21 CFR 312.60].
– Subject hospitalized for three days, but not so documented.
– Records did not say at all how long she was in hospital
– CRFs submitted 4 months late; required under protocol to be filed in
one week
– No record of storage in refrigerated conditions as required by protocol
• Length of inspection – 5 days per WL
• Average length of U.S. inspections leading to WL’s –
sampling of 10 from last two years, showed average
number of days (measured start to finish) was 28 days
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• Bioequivalence study in Argentina – pivotal to
application
• FDA audited site -- retained samples of drug were
thrown out
• FDA -- not clear which patients got Study drug vs.
brand
• FDA – Complete Response Letter -- we can’t verify
what drugs the patients got, thus the study results are
not acceptable
• Company – the test drug was very different looking than
the comparator (but do the CRFs, etc., reflect that)?
Adventrx
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Final Thoughts
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• 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? Have one!
Lessons Learned
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• International Compilation of Human Research Protections
(OHRP) [new version coming soon]
 http://www.hhs.gov/ohrp/international/intlcompilation/hspcom
pilation-v20101130.pdf
• European Forum for Good Clinical Practice (EFGCP) – state
by state info available
– http://www.efgcp.be/efgcpreports.asp?l1=5&l2=1
• Legislations, Regulations and Guidelines – from
GCPHelpDesk – country by country links
 http://www.gcphelpdesk.com/index.php/gcp-guidelines
• Reviewing Clinical Trials: A Guide for the Ethics
Committee; Editors: Johan PE Karlberg and Marjorie A Speers
 http://www.pfizer.com/files/research/research_clinical_trials/et
hics_committee_guide.pdf
Some Resources
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Acknowledgements
• My thanks to these clinical research, legal and
regulatory professionals who contributed key points
included in this presentation:
– Damien Bove, Bove Consulting
– Robert Church, Hogan Lovells
– Susanna Corritori, Corritori Consulting
– Stephanie Finnegan, bioRASI
– Laurie Halloran, Halloran Consulting
– Donald Harkness, Edwards Lifesciences
– Kristine Rapp, Hospira
– Jerry Stein, Halloran Consulting
– Laurie Taddonio, Taddonio Consulting
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Questions?
• Call, e-mail or fax:
Michael A. Swit, Esq.
Special Counsel, FDA Practice
Duane Morris LLP
San Diego, California
direct: 619-744-2215
fax: 619-923-2648
maswit@duanemorris.com
• Follow me on:
– LinkedIn: http://www.linkedin.com/in/michaelswit
– Twitter: https://twitter.com/FDACounsel
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About Your Speaker
Michael A. Swit, Esq., is a Special Counsel in the San Diego office of the international law firm,
Duane Morris, LLP, where he focuses his practice on solving FDA legal challenges faced by
highly-regulated pharmaceutical and medical device companies. Before joining Duane Morris in
March 2012, Swit served for seven years as a vice president at The Weinberg Group Inc., a
preeminent scientific and regulatory consulting firm in the Life Sciences. His expertise includes
product development, compliance and enforcement, recalls and crisis management, submissions
and related traditional FDA regulatory activities, labeling and advertising, and clinical research
efforts for all types of life sciences companies, with a particular emphasis on drugs, biologics and
therapeutic biotech products. Mr. Swit has been addressing vital FDA legal and regulatory issues
since 1984, both in private practice with McKenna & Cuneo and Heller Ehrman, and as vice
president, general counsel and secretary of Par Pharmaceutical, a top public generic and specialty
drug firm. He also was, from 1994 to 1998, CEO of FDANews.com, a premier publisher of
regulatory newsletters and other specialty information products for FDA-regulated firms. He has
taught and written on many topics relating to FDA regulation and associated commercial
activities and is a past member of the Food & Drug Law Journal Editorial Board. He earned his
A.B., magna cum laude, with high honors in history, at Bowdoin College, and his law degree at
Emory University.
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