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Use of Foreign Data for Approval
Ann Farrell, MD
Division of Oncology Drug Products
Center for Drug Evaluation and Research
Food and Drug Administration
Disclaimer
• The views expressed are the result of
independent work and do not necessarily
represent the views or findings of the
United States (US) Food and Drug
Administration (FDA) or the United States.
FDA Acceptance of Foreign Data
• Guidance for Industry- Acceptance of
Foreign Clinical Studies
– if performed under an IND - 21 Code of
Federal Regulations (CFR) 312
– if not performed under an IND- 21 CFR
312.120 (c)(4)
FDA Acceptance as the sole basis
for marketing approval
• 21 CFR 314.106
– applicable to the US population and US
medical practice
– studies performed by competent clinical
investigators
– valid data
ICH - E5
• Drug development package must satisfy the
regulatory requirements of the new region.
• Drug development package must allow
extrapolation to the new region.
ICH E-5 Definitions
• Extrinsic Ethnic Factors--Factors associated
with environment and culture in which a
person resides. These factors tend to be less
genetically, more culturally and
behaviorally determined.
• Intrinsic Ethnic Factors--Factors that help to
define and identify a subpopulation and
may influence the ability to extrapolate
clinical data between regions.
ICH E-5 Intrinsic and Extrinsic
Factors
• Intrinsic
– Genetic
(polymorphisms,
gender, race)
– Physiologic/Pathologic
(age, liver impairment,
renal impairment,
cardiac disease)
– height/weight
• Extrinsic
– Environmental
(cultural,
socioeconomic,
medical practice,
regulation, clinical
trial design /conduct
/endpoints)
– Habits (smoking,
alcohol)
ICH E5-No Bridging Studies
Necessary
• if the drug is ethnically insensitive and
extrinsic factors are similar
• if drug is ethnically sensitive, but the two
regions are ethnically similar and there is
sufficient clinical experience with
pharmacologically related compounds
ICH E-5 Pharmacologic Bridging
Studies
• if the region are ethnically dissimilar and
the drug is ethnically sensitive, but extrinsic
factors are generally similar and the drug
class is familiar in the new region, a
controlled PD study reflecting relevant drug
activity may suffice
• Simultaneous PK encouraged
ICH E-5 Controlled Clinical
Bridging Trial Required
• Doubts about the choice of dose
• Little experience with acceptance of
controlled clinical trials carried out in
foreign region
• Medical practice is different--concomitant
meds, conduct of clinical trials
• Drug class is not familiar to new region
ICH E5- Bridging Studies for
Safety
• A study to assess efficacy, such as a doseresponse study, could be powered to address
rates of common adverse events
• A separate safety study could be required
– Concerns about reporting differences
– Index case of serious adverse event in foreign
clinical data package
Bridging Studies
• The request for a bridging study using either
pharmacologic endpoints or controlled
clinical trials does not infer that foreign
clinical data is of poor quality.
New Molecular Entities 1997present
• 28 New Drug Applications (NDAs)
submitted and granted approval
• 4 NDAs had pivotal trials which were
conducted exclusively in the United States
• 20 NDAs had pivotal trials which were
conducted in the United States and other
regions
NMEs 1997 to present
(continued)
• Other regions were other North American
countries, Western and Eastern Europe
(Slovakia, Russia), Middle East (Israel,
Lebanon, Egypt), Africa (Republic of South
Africa, Tunisia), South America, Asia
(Taiwan, Japan, India, China), Australia,
New Zealand
NMEs 1997 to present
(continued)
• 4 NMEs did not have pivotal trials which
enrolled United States patients
• Indications - advanced stage breast cancer
and lung cancer
• 2 NMEs had supporting or
pharmacokinetic/pharmacodynamic studies
which included United States patients
• 2 NMEs did not
Foreign data acceptable for
NMEs 1997 to present
• because met the FDA regulatory
requirement for adequate and wellcontrolled trials
• etiology, natural history, pathology,
prognosis and treatment of the disease similar in both regions
• ethnically similar
Foreign data acceptable for
NMEs 1997 to present
(continued)
• control group used was widely accepted as
the standard of therapy in the US
• pivotal trials usually conducted under the
auspices of cooperative groups such as
EORTC, NCIC
• endpoints acceptable based on stage of
disease
• trials were replicated
Recent Unsuccessful NDA
Submissions with Foreign data
• natural history, etiology, staging and
prognosis differ
• medical practice differs
• endpoints not acceptable
• no replication of results
FDA CDER Oncology division
• Although differences in intrinsic ethnic
factors may exist between the two regions,
currently differences in extrinsic ethnic
factors are playing a more important role in
designing types of bridging study
requirements in oncology.
Intrinsic Ethnic Factors
– Patient Size, Lean Body Mass--may be
corrected by use of body surface area dosing
– Use of maximum tolerated doses (unique to
oncology) could theoretically unmask genetic
polymorphic differences
– For intrinsic ethnic factors, oncology drugs may
not pose any unique situations than other drugs
Extrinsic Differences in
Oncology
•
•
•
•
•
Oncology medical practices differ
Patient and societal view on cancer
Different cancer epidemiology
Clinical trial design and execution
Endpoints used for approval
Medical Practice Differences
• Who administers cancer care?
– US and Western Europe- Medical Oncology as
a academic discipline, conducting trials,
primary care for cancer patients
– Multidisciplinary care emphasis coordinating
efforts of medical, radiation, surgical
oncologists and oncology nursing
– Other regions may have other providers as
primary care for cancer patient
Medical Practice Differences
• Outpatient vs inpatient administration-reflects schedules of agents
• Different chemotherapy doses--acceptance
of toxicity by patients and physicians,
differences in supportive care
• Different drugs and therapy duration --oral
agents, prolonged adjuvant therapy
Patient Factors, Epidemiology
• regional differences in what information a
patient has and patient’s participation in
care
• patients not being told diagnosis
• regional differences in prevalence and
etiology for various cancers
Clinical Trial Infrastructure
• Who conducts oncology drug trials in US?
– Role of Medical Oncologist
– Role of site data manager, research nurse
– Continuing education, special protocol
meetings
Clinical Trial Infrastructure
• Who conducts oncology trials in US?
– National Cancer Institute
– Cooperative Groups (SWOG, ECOG),
established 30-40 years ago with significant
expertise in trial design and execution
– Industry trials--physicians employed on
industry to design, execute, interpret trials
Need for controlled bridging
clinical trials
• doubts about dose and schedule
• little or no experience with acceptance of
controlled clinical trials carried out in foreign
region
• Medical practice (e.g. use of concomitant
medications and design and/ or conduct of clinical
trials are different)
• drug class is not familiar one in the new region
Recent recommendations for PreIND and IND meetings
• Sponsor wished to do entire clinical
development plan in different region
– FDA - recommended that one trial could be
conducted in foreign region and another trial be
conducted in the US
• lack of familiarity with clinical trials in that region
• less well developed cancer treatment infrastructure
• etiology of that particular cancer differs in the
region compared with the US
Recent Recommendations from
Pre-IND and IND meetings
• Sponsor wanted to use all foreign clinical
data especially PK data
– FDA considered that (1) the ethnicity of the
patients who participated in the PK study
constituted a small percentage of the ethnicity
of the US population (2) potentially some
genetic differences in metabolism exist that a
US PK study would be helpful and that the
results of both studies would be in the label
Keys to a Successful Submission
• Plan ahead and schedule a pre-IND meeting
with the FDA
• Discuss development strategy
– planned regional development
– consider potential intrinsic and extrinsic ethnic
factors (especially clinical trial design,
endpoints, and trial execution)