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Q&A on the “Guideline for Ethnic Factors in
the Acceptability of Foreign Clinical Data”
(Terms)
Q1: The Guideline uses general terms to be used in the countries (regions)
participating in ICH. What should the terms “new region” and “regulatory
authority” in the Guideline particularly mean in Japan, when foreign clinical data
are used according to the Guideline in a new drug application submitted to the
Ministry of Health and Welfare of Japan?
A1: The terms are interpreted in Japan as follows:
New region: Japan
Regulatory authority: In a narrow sense, the term means the Evaluation and
Licensing Division, Pharmaceutical and Medical Safety Bureau, Ministry of
Health and Welfare, and the Pharmaceuticals and Medical Devices Evaluation
Center, National Institute of Health Sciences. In a broader sense, however, the
Organization for Pharmaceutical Safety and Research (OPSR), which affords
consultation with an applicant on bridging studies etc., should be included.
Q2: Likewise, what should the term “regulatory requirements” be interpreted in
Japan?
A2: The term “Regulatory requirements” means in Japan “MHW Ordinance on
the Guideline for Good Clinical Practice (GCP)” pursuant to Article 14, Paragraph
3 of the Pharmaceutical Affairs Law (PAL), “Standards for Reliability of
Application Documentation” (Article 18-4-3 of the Enforcement Regulations of
PAL), the requirements on attached data described in “Data to be Attached to
Applications for Approval to Manufacture or Import Drugs” (PAB Director-General
Notification No. 698 dated May 30, 1980), and the various guidelines issued by
MHW concerning clinical studies. However, data obtained not strictly in
compliance with the guidelines can be acceptable, if the clinical studies
generating the data employed appropriate methods reflecting the progress of
related sciences.
(Basic Principles of the Guideline)
Q3: The Guideline mainly supposes that most of the clinical data necessary for
application were obtained outside Japan. How is the Guideline applied to a case
where most of the clinical studies of a drug are conducted in Japan,
necessitating, as a result, the foreign data to be only partially used, or where
about the same amount each of domestic clinical data and foreign ones are used
in the approval application?
A3: In both cases, it is necessary to prove that the foreign clinical data to be
used in the application can be extrapolated to the Japanese population. If the
data of the clinical studies conducted in Japan are usable as bridging data and
the foreign data’s extrapolatability is assured, a new bridging study need not be
conducted.
Q4: If a new region’s regulatory authority assesses the extrapolatability of a
foreign clinical data package after its completion, to suggest a bridging study, the
approval in the new region can be delayed. How can a bridging study be best
designed and conducted in new regions, while the data package is being
completed in the original region, so that approval applications may be made
simultaneously in the original and the new regions?
A4: As is pointed out in the question, the Guideline primarily assumes the
existence of a clinical data package consisting mainly of foreign clinical data. The
Guideline then suggests a bridging study to assess whether the data can be
extrapolated. It is possible, however, to conduct clinical trials to construct a
clinical data package to be bridged and a bridging study in parallel, adhering to
the fundamental concept of the Guideline. Needless to say, however, the data
supporting the appropriateness of the bridging study must be obtained before its
initiation especially in terms of the safety of its trail subjects.
(On Policy on Accepting Foreign Clinical Data)
Q5: It is stated in the guideline that the judgement on the acceptance by the
authority of a new region is influenced by the external factors such as the
medical care practice of the new region as well as the regulatory authority’s
experience on the acceptance. What are the therapeutic/diseases categories for
which the diagnostic criteria and practices in medical care are so similar among
Japan, European nations, and USA that the foreign clinical data may be
extrapolated without difficulty?
A5: In the case of antibiotics whose effect-profile to clinically isolated strains is
similar between the foreign countries and Japan, for example, the extrapolation
should not be difficult, because trials for the class of drugs generally employ
common endpoints and control groups among Japan and foreign countries. Also
the data on antineoplastic agents are readily extrapolated, as the rate of tumor
reduction is commonly employed in their evaluation.
Q6: As for the definition of the term “foreign countries,” is it allowable to use
clinical data obtained in a country other than the ICH participating countries
(regions) in approval application in Japan as far as the data meet Japan’s
requirements?
A6: The Guideline in fact has been formulated at ICH, assuming the mutual
acceptance of clinical data among the three regions, which possess the
established regulations on clinical studies, such as GCP. However, if the data
obtained in a region not participating in ICH meet Japan’s regulatory
requirements (Refer to the answer A2 to Q2) and are deemed acceptable in
Japan, the Guideline is applicable to the data.
Q7: A clinical data package may contain evaluations based on criteria different
from those employed in Japan, as criteria in evaluating the efficacy of drugs are
generally different from country (region) to country (region). To what extent are
such differences allowed?
A7: If the criteria employed to evaluate clinical data obtained in a foreign country
are scientifically rational and deemed acceptable in Japan, the criteria need not
be strictly identical with those used in Japan.
Q8: When a drug shows similar efficacy and safety in the Japanese and the
foreigners at different doses resulting from different pharmacokinetic behaviors,
can the foreign data be extrapolated? And if so, naturally the dosage and
administration in the approval application to MHW should be different from those
approved abroad. Are such differences permissible?
A8: Similarity in the pharmacokinetic profile of a drug between populations is not
a necessary condition for the foreign clinical data to be accepted. Even with a
difference in the profile, foreign data may be extrapolated to the Japanese if
similar efficacy and safety are shown in the Japanese trial subjects by modifying
the dose (See Section 3.2.2 of the Guideline). In such a case the dosage and
administration approved in the foreign country can be different from those in
Japan.
It should be noted that even if there is no difference in a drug’s pharmacokinetic
profile between the foreigners and the Japanese, the fact alone is not enough to
ascertain the extrapolatability.
Q9: When (an) active control study(ies) of a drug conducted abroad employed,
as a comparator or the dose thereof, those not approved in Japan, are the data
of the study(ies) usable in the approval application to MHW?
A9: The data may be used for approval application in Japan as far as it can be
confirmed that the comparator has been approved in the foreign country based
on appropriate clinical data. The cogency of the data, however, depends on the
comparator’s characteristics such as how established it is as the therapy, and
how its mechanism of action resembles that of the investigational drug.
Q10: What are the concrete standards to determine whether the dose-response,
safety, efficacy, etc. of a drug are “similar” or “not greatly different” between
ethnically different populations when the result of the bridging study is assessed
to judge whether the foreign clinical data can be extrapolated to the Japanese?
A10: It is impossible to suggest concrete standards to judge whether the cited
features of a drug are “similar” or “not greatly different” across populations. It is of
note, however, that to so judge, neither statistical “equivalence” nor strict
identicalness is requisite.
For drugs with a steep pharmacodynamic (effect-concentration) curve and/or a
narrow therapeutic range, it is necessary to evaluate carefully the differences in
dose-responses, safety and efficacy, for total assessment of the extrapolatability.
Q11: What should be the recommended measures to take when a bridging study
reveals that it is impossible to extrapolate the foreign clinical data to the
Japanese?
A11: For example, a considerable difference in a drug’s dose-response between
the foreign and the Japanese subjects, or that in incidences of unexpected ADRs
can result in a different recommended clinical dose for the Japanese. In such
cases, the data of comparative studies employing the dose preferred in the
foreign country are generally difficult to extrapolate. Such are the circumstances
where a clinical data package consisting of foreign data is proven to be not
extrapolatable to the Japanese.
When a package cannot be extrapolated as a whole, it is recommended to
review the data of each trial constituting the package to judge their usability in the
approval application to be submitted to MHW. Since the salvaged (bridgeable)
data are naturally insufficient to constitute a data package to be submitted, the
applicant should conduct necessary trials to supplement and structure the clinical
package for submission.
Q12: How does MHW handle a bridging study for an orphan drug?
A12: Small patient populations receiving orphan drugs often make it difficult to
conduct bridging studies as suggested in the guideline, which demonstrate the
extrapolatability clearly. In such cases, the judgment by the authority should be
made based on the limited bridging data with a condition that the applicant
should conduct post-marketing clinical studies and/or special surveillance studies
to reconfirm the validity of the approval.
Q13: The Paragraph 2.1 of the guideline cites “a clinical trial using different
comparators at the new region’s approved dosage and dose regimen” as an
example of an additional clinical study to fulfill the regulatory requirements in the
new region. Is an active-control study always required in Japan even when the
applicant already possesses the data of placebo-control study conducted
abroad?
A13: In a therapeutic category where a standard drug/therapy has been
established, the investigational drug is clearly located in terms of its medical
relevance when it is compared with the standard drug to afford the information
concerning relative efficacy and safety. Such information is usually useful to
promote appropriate use of the drug after its marketing. This idea is reflected in
Japan’s guidelines for clinical evaluation in specific therapeutics categories.
However, an active-control study is not an absolute requisite; when the drug’s
efficacy has been demonstrated in placebo-control studies abroad and its
usefulness in Japan’s medical settings confirmed, an active-control study is not
established in Japan, should be additionally conducted.
Q14: How does MHW handle extrapolation of foreign clinical data in a special
population such as the elderly and the renally or hepatically impaired, to the
corresponding Japanese subpopulation?
A14: In general, when the foreign clinical data on a drug’s general patient
population are demonstrated to be extrapolatable, so deemed are those on
special populations without the necessity of additional bridging studies.
Furthermore, while the “Guideline on Clinical Trials in Geriatrics” requires the
total of about 100 elderly subjects included in trials of a drug, an applicant is
allowed to combine the numbers of the elderly in the foreign studies and that in
Japanese ones, if the extrapolatability is confirmed as above. This principle
applies to other guideline's requirements as well.
(Evaluation of the Influence of Ethnic Factors)
Q15: How are the effects of the medical practice and the diet of a region, the
main extrinsic ethnic factors, assessed? Is accumulation of the experiences
necessary to clarify those?
A15: There is not general method to evaluate the effects of the medical practice
and the diet, because their influence on a drug’s pharmacokinetic and
pharmacodynamic behavior varies from drug to drug. Thus the evaluation should
be performed on a case by case basis, though it is sometimes advisable to seek
reference with drugs of a similar structure or a mechanism of action.
Q16: Is it possible to conduct a clinical study of a drug with the participating
institutions in plural countries (regions), or an international multi-center
cooperative study), and perform a race-stratified analysis on the result to assess
the ethnic factors?
A16: If the study is appropriately conducted with single protocol and a sufficient
number of trial subjects to allow the analysis of ethnic differences are included,
the analysis in the question should be feasible. By making a drug’s principal trials
designed with this concept, the necessary information to assess the
extrapolatability of the drug’s foreign clinical data can be obtained.
Q17: Clinical data contained in new drug applications submitted to MHW have
not been analyzed taking the trial subjects’ ethnicity into consideration. Will it
become necessary to take into consideration ethnic factors?
A17: It is beyond saying that an analysis on ethic factors should be performed in
a clinical study conducted on plural ethnic populations.
Q18: When the inclusion criteria of a foreign trial are different from those
accepted for the class of drugs in Japan, is it necessary to perform an analysis
based on a sub-dataset comprising cases meeting the Japanese criteria?
A18: As stated in the “Guideline for Structure and Content of Clinical Study
Reports” (PAB/PCD Notification No. 335 dated May 1, 1996), and “Statistical
Principles for Clinical Trials (PMSB/ELD Notification No. 1047 dated November
30, 1998), the validity of such analysis as mentioned in the question is
conditioned on the similarity of the result of the analysis on full data set
(containing all the cases) and that on the partial data set (consisting of the cases
fulfilling certain conditions, extracted from the full set).
If, however, the inclusion criteria and diagnostic criteria employed in a foreign
clinical trial are scientifically valid and acceptable from the viewpoint of Japan’s
medical practice, the data of the study can serve as those attached to a new drug
application, even if the criteria etc. are not strictly identical to those used in
Japan.
(Bridging Studies on Efficacy)
Q19: When the result of Phase II (dose response) studies of a drug conducted in
Japan indicates that the foreign clinical data on the drug can be extrapolated to
the Japanese population, a confirmative study comparing the drug with an
existing drug or a placebo is not required in Japan?
A19: In general, when dose-response studies conducted in Japan have proven
extrapolatability of a drug’s foreign clinical data, confirmative comparative studies
need not be conducted in Japan.
Q20: Is it possible to give a concrete description of the appropriate bridging study
on efficacy, including its size, design, etc., on which the Guideline’s Section 3.2.3
touches, to meet a specific situation expected?
A20: Section 3.2.3 cites three typical situations and the design etc. of necessary
bridging studies for each situation. In the present situation, MHW proposes a
dose-response study to be considered as the first candidate of the study
(Paragraph “Controlled Clinical Trials” in Section 3.2.3. specifies “It will usually be
necessary to carry out controlled clinical trial, often a randomized, fixed dose,
dose-response study, in the new region”). Information on dose-response in the
Japanese often plays an important role in assessing the extrapolatability. It is of
note, however, that a comparative study is sometimes unnecessary as a bridging
study especially for drugs insensitive to ethnic factors. It is impossible to
categorically specify the sample size of a study (i.e. the required number of
subjects), because the trial’s object and endpoint primarily determine its size.
Q21: Section 3.2.3 of the Guideline cites, as one of the cases where a
comparative study is required as a bridging study, “(when) there is little or no
experience with acceptance of controlled clinical trials carried out in the foreign
region.” Is this to be understood, under the present Japanese situation, that a
controlled study is required as a bridging study?
A21: As is pointed out, MHW has limited experience of basing its new drug
approvals mainly on the data of comparative clinical studies conducted abroad.
Conduct of a comparative study in Japan, therefore, should often be necessary
for the time being.
Q22: What is the definition of the term “pharmacologically related compounds”
and “drug class” cited in Section 3.2.3 “Controlled Clinical Trials?”
A22: These terms refer to the compounds which are judged to be similar to the
drug in the light of chemical structure, pharmacological action, and other
characteristics combined.
(Bridging Studies for Safety)
Q23: In what cases is it necessary to conduct a separate bridging study for
safety?
A23: As for the extrapolation of a drug’s data on its safety, the incidences of side
effects (adverse events) need not be identical between populations, nor is
precise comparison required. In fact, a small difference in the incidence of a mild
side effect, for example, between populations neither cause serious problem nor
affect the extrapolatability. A separate bridging study for safety need not be
conducted unless the bridging study for efficacy or the findings on analogous
drugs arouses a grave safety concern on the drug’s safety in the Japanese.
Detection of a low-frequency side effect (advance event) and accurate
determination of its incidence should be done in a drug’s post-marketing
surveillance.
Q24: Section 3.2.4 of the Guideline gives specific figures in its discussion on the
accurate determination of the rates of relatively common adverse events and the
detection of a serious adverse events (adverse events occurring with a frequency
around 1% generally need about 300 patients to detect). What is the ground of
the figures?
A24: The figures (1% and 300 patients) are calculated and indicated based on
the idea that adverse events with an incidence of 1% or more should be detected
in the clinical studies conducted before approval. The idea is employed in
another MHW Guideline “The Extent of Population Exposure to Assess Clinical
Safety for Drugs Intended for Long-term Treatment of Non-life Threatening
Conditions” (PAB/PCD Notification No. 592 dated May 24, 1995) based on ICH
E1 Guideline.
However, the E1 Guideline does not require the long-term safety data be
composed solely of those obtained in a single ethnic group. The exposition in
Section 3.2.4 should be interpreted that the total number of the long-term cases
regardless of ethnicity should exceed the given figure.
Thus it is generally needless to conduct a bridging study on 300 subjects only to
collect data on safety (to detect, for example, a side effect occurring at a
relatively high incidence, etc.), unless in exceptional situations where the safety
profile of a drug such as the adverse events caused and their incidences is totally
different between the Japanese and the foreigners. Utilization of the foreign
clinical data on a drug naturally reduces the number of the Japanese cases
included in the drug’s safety evaluation, which the applicant should supplement
in the post-marketing phase.
Q25: When appropriate bridging studies prove the extrapolatability of a drug’s
foreign clinical data to the Japanese population in terms of its safety, and the
long-term safety data in accordance with ICH E1 Guideline have been obtained
abroad, is it right to assume that no long-term trial in Japan is required ?
A25: When foreign clinical data on safety, including those of long-term
administration trials, are judged to be extrapolatable to the Japanese, it is not
necessary to carry out in Japan a long-term exposure trial.
(Clinical Pharmacology Studies)
Q26: Are foreign pharmacokinetic data generated in the following populations
usable as those in the Japanese population?
a. Those who had been born of Japanese parents and brought up in Japan,
and were living in the foreign countries when the trials were conducted
b. Second-or-third generation Japanese (those who had been born of
Japanese parents living in foreign countries, or those with their Japanese
grandparents having emigrated to the foreign country and both of their
parents being Japanese living in the country).
A26: The data described in the question are usable, except where difference in
the diet and the environment is expected to alter the drug’s pharmacokinetic
behavior.
Q27: What are the points to consider when the pharmacokinetic profiles are
compared between the Japanese and the foreigners.
A27: The pharmacokinetic profiles of the two populations are compared in terms
of the appropriate parameters (AUC, Cmax, clearance, etc.), which are obtainable
through standard pharmacokinetic studies or using the principles of population
pharmacokinetics. This presupposes the comparability of the parameters, which
is ensured by the trials’ sufficient sample size, the calculation based on the blood
level obtained at plural (at least three) doses, the same trial conditions (blood
sampling time points, quantification of the drug, etc.), the same method of
calculation, etc. The factors above should be taken into consideration from the
planning stage of pharmacokinetic studies.
It should be heeded in interpreting the results that absence of statistically
significant difference in pharmacokinetic parameters at a particular dose does not
indicate “absence of difference” in the pharmacokinetic profiles between
populations. In order to detect difference in the profiles, at least confidence
intervals of the “difference” or “quotient” between parameters obtained from the
two populations should be calculated and analyzed, after (non)linearity of the
drug’s pharmacokinetic behavior is examined.
Q28: What are the points to consider in utilizing foreign clinical data of Phase I
studies of antineoplastic agents?
A28: A full-scale study to obtain the maximal tolerable dose need not be reperformed in Japan for an agent with clear cytocidal effect, if appropriate foreign
data are available on the drug. Instead, the applicant is required only to confirm
the Japanese patients’ safety treated at the dose determined on the foreign data.
Also a pharmacokinetic study affording pharmacodynamic information should be
conducted to assess the necessity to adjust the dose for the Japanese.
Q29: Are results of foreign bioequivalence studies conducted in non-Japanese
acceptable as clinical data attached to new drug applications?
A29: Unless there is a major difference in the pharmacokinetic profiles between
the Japanese and the foreigners, foreign clinical data are usable to prove the
bioequivalence between dosage forms of a drug with different strengths or those
before and after the change in its formulation, necessitated in the course of the
drug’s development. This principle applies also to changes and additions in
strengths, dosage forms, and formulations made after the drugs’ approval.
As for bioequivalence studies on generic drugs, refer to the “Guideline for
Judgment of Bioequivalence of Generic Drugs” (PMSB/ELD Notification No.487
dated December 22, 1997) and the Questions &Answers (issued on October 30,
1998) on the Notification.
(Others)
Q30: Is it mandatory to attach all the foreign clinical data concerning a drug to its
new drug application submitted to MHW or are the applicants allowed to submit
only the data they judge necessary?
A30: In addition to the foreign clinical data which the applicant uses to support
the drug’s usefulness, a list of all the foreign clinical studies on the drugs
regardless of whether the data thereof are used in the application, as well as the
summaries of the major studies listed should be submitted. (This applies also to
the foreign trials completed after the application concerning the drug is submitted
to MHW.) Moreover, taking into account the increase in the number of drugs
developed simultaneously in plural regions of the world, MHW requests the lists
etc. cited above to be submitted, even when an applicant, having foreign clinical
data on a drug, can constitute the clinical data package on the drug to be
submitted without using foreign clinical data.
It should be noted here that when an applicant possesses data that cause doubt
on the drug’s safety and efficacy, the applicant must submit them with the results
of scrutiny and assessment thereof, as stipulated in Article 18-4-3 of the
Enforcement Regulations of PAL.
Q31: How should the side effect information be presented in the precautions for
use or package insert, when foreign clinical data are utilized in new drug
application ?
A31: Information on safety in overseas clinical data submitted as the application
data is dealt in the same manner as domestic data, and both foreign and
domestic data should be incorporated in the precautions for use, etc. If there is a
rational reason, for example when it has been clarified that an ethnic factor has a
great influence on evaluation of safety, then it is possible to describe domestic
data and overseas data separately.
(Discussion with the Regulatory Authority)
Q32: This Guideline recommends a discussion between the applicant and the
regulatory authority on the necessity, the type, etc. of a bridging study, and the
regulatory authority in Japan will be OPSR. We hope that the structure of the
regulatory authority participating in the discussion is strengthened and the results
of discussion will be made public to the extent possible.
A32: General principles about the conduct of bridging studies are
described in this Guideline, though the design of individual bridging
studies should be determined based on the characteristics of each drug,
medical care environment around the target disease, accumulation of
clinical experience with analogous drugs, etc. Therefore it is advisable
to utilize the clinical trial consultation system of OPSR to discuss
about the type of a bridging study necessary for individual drugs. The
details of clinical trial consultations cannot be disclosed from the
standpoint of maintaining company confidentiality, but we would like to
make rules for disclosure of the results in generalized cases.