WAYS AND MEANS OF U.S.

REGISTRATION OF FOREIGN
DRUGS
By- SHREYA PODDAR
REG NO.- RA2122254010005
Department of Pharmaceutics,
SRM College of Pharmacy
SRM Institute of Science and Technology
Kattankulathur, 603203
 CONTENTS
• INTRODUCTION
• TOPICS OF DISCUSION
• REGULATORY FRAMEWORK
 US. FDA
 ICH
• POTENTIAL OBSTACLES FOR FOREIGN DRUGS
 CMC,
 NON- CLINICAL ISSUES
 CLINICAL ISSUES
• STUDY DESIGN & CONTROLS
• ENPOINTS
• COLLECTING FOREIGN CLINICAL DATA
• DATA SUBMISSION
• REFERENCES
• CONCLUSION
 INTRODUCTI
ON
• There is continuing interest in the development, U.S.FDA approval and importation of foreign drugs
into the U.S. market- still the largest in the world.

• Existing FDA regulations continue to place significant challenges on both foreign and U.S.
manufacturers.

• Drivers of FDA’s position:

i. Drug safety,
ii. Political pressures,
iii.Critical path,
iv. Study design.

• Foreign companies are subject to the same FDA scrutiny as U.S. companies, and are well-advised to
appreciate these drivers and to work within them if they wish to be successful in the U.S.

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 INTRODUCTION

• The Importation of foreign drugs needs to comply with regulations because FDA has become more
enforcement-minded.

• The agency is increasingly concerned about GMP compliance in the manufacturing of Active
Pharmaceutical Ingredients(APIs) used in U.S.

• The important factor that drives foreign companies interest in obtaining FDA approval is the desire to
leverage foreign data and regulatory approvals to enter U.S. market.

• However, although the drug development process may be similar in different regions, differences in
culture, medical practice, demographics and other factors can impact on how rapidly new drugs gain
access to different markets.

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 TOPICS OF DISCUSSION

FDA
requirements

Criteria for
acceptability
Impact of
ICH
guidelines
Challenges
facing for
foreign drugs
Chemistry,
Manufacturing
& control Clinical &
Non- clinical
issues

3
 TOPICS OF
DISCUSSION

Study design
& controls

Collecting Foreign
Clinical Data
Endpoints
Data
submission

Conclusions
4
 REGULATORY FRAMEWORK

Two regulatory entities, which has impact on the issues surrounding U.S. registration of foreign drugs .

1 2 The International
U.S. Food and drug
Conference on
Administration
Harmonization
(U.S.FDA)
(ICH)

Addresses the
issue with
It sets criteria specific
for acceptance guidelines and
CTD

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 U.S. FOOD AND DRUG ADMINISTRATION

• FDA regulations governing the approval of a new drug to market are covered in the Code of Federal
Regulations (CFR), Title 21, Part 314.

• If the agency feels that the criteria listed have been met it may approve the product based on foreign
studies.

• The FDA has approved approximately 80 drugs based solely on clinical data generated outside the
United states.

• Regulation encourages consultation between applicants and FDA.

• It suggests “Pre-submission” meeting between applicants & agency officials when sponsor intends to
seek approval based solely on foreign data.

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 U.S. FOOD AND DRUG
ADMINISTRATION
Application on foreign clinical data meeting U.S. 3 criteria for
marketing approval may be approved if-

Foreign data are applicable to U.S. population and

medical practice.

Studies, performed by clinical investigator of recognized

competence.

Data may be considered valid without need for an on-site

inspection.

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 INTERNATIONAL CONFERENCE ON
HARMONIZATION
• ICH has examined ways to help make the clinical data collected in one region acceptable to the
regulatory authority of another region.

• An outcome of this ongoing effort is the ICH guideline ES, “Ethnic Factors in the Acceptability of
Foreign Clinical Data”.

• For sponsors of foreign drugs, ICH guideline E5 complements the FDA regulations.

• It notes that all data in the clinical section should meet the standards for study design and conduct and
should satisfy the regulatory requirements of the region.

• Once that has been accomplished, the sonsor must be able to extrapolate the study data to the population
of the new region, in this case, the United States.

• If the sponsor or the regulatory agency is concerned that ethnic differences could have significant impact
on safety & efficacy of the drug in the new population, additional data may be necessary.

• The core concept of ICH guideline E5 is the “Bridging Study”.

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POTENTIAL OBSTACLES FOR REGISTRATION OF FOREIGN
DRUGS

The issues that sponsors of foreign drugs must address fall into three
categories:

Non-
Clinical
CMC clinical
Issues
Issues

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 1 Chemistry, Manufacturing and Control Issues
• The FDA requires the same CMC information for foreign drugs as it does for unapproved new domestic
drugs.

• All drug manufacturers must comply with cGMPs for finished pharmaceuticals as specified in 21CFR
211.

• Manufacturers must meet USP standards for the drug substance, its excipient or the drug product, if
available.

• Sponsors of foreign drugs should follow ICH quality guidelines regarding:

Stability,
Validation of analytical procedures,
Acceptable levels of impurities,
Residual solvents, etc.

• Sponsors may submit information regarding the chemistry and manufacturing of drug substances,
products, excipients or packaging in a Drug Master File (DMF).

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Chemistry, Manufacturing and Control Issues

IMPORTATION PROCEDURES & RELATED ISSUES

FDA INSPECTIONS OF FOREIGN MANUFACTURERS

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 IMPORTATION PROCEDURES & RELATED ISSUES

• Foreign manufacturers must register with the FDA’s Drug Listing Branch and have a drug
establishment number assigned to them.

• In order to import drug product through U.S. customs, the importer should provide relevant
documentation.

• Foreign manufacturer must also have a U.S. agent who resides in or maintain a physical place of
business in the United States.

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 FDA INSPECTIONS OF FOREIGN MANUFACTURERS

• The FDA may inspect a foreign manufacturing site.

• If the FDA conducts an inspection and finds problems, the inspector will report his or her observations
of the conditions and practices observed at the site on FDA Form 483.

• Depending on the overall findings of the firm, which can be done by the FDA’s determination as to
whether the establishment is compliant with cGMPs, and the approval process.

• It is important to be aware that lack of inspection on the part of manufacturing sites is common reason,
why FDA considers submission to be non-approvable.

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FDA INSPECTIONS OF FOREIGN
MANUFACTURERS

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 2
NON- CLINICAL
ISSUES
• The data must demonstrate safety for human subjects during clinical trials and for patients when the
drug is marketed.

• The ICH guideline M3 “Timing of pre-clinical Studies in Relation to Clinical Trails”, addresses general
considerations in regard to when non-clinical studies are conducted in a drug development programme.

• In order for the foreign Non-clinical data to be acceptable to the FDA, the testing must be conducted
according to Good Laboratory Practices (GLPs, found in 21CFR 58).

• The drug substance and drug product, or formulation, tested in the non-clinical studies should be
relevant to the product that the sponsor intends to market in the United States.

• The final safety database should reflect known safety concerns that have been observed in either animals
or humans throughout drug development.

• It is important that the sponsor conduct the non-clinical testing in species whose ADME are relevant to
humans.

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 NON- CLINICAL
ISSUES
Proper toxicology program designed with consideration are the following :

Sound
Relevant FDA & Direct Input
toxicology
ICH guidelines from FDA
advice

Results of an early risk Known safety

assessment data on drugs

Proposed exposure & use of drug in human

whether in clinical trial or on the market
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 3
CLINICAL
ISSUES

• Regulatory bodies such as FDA, are cautious about registration solely on foreign data, due to potential
impact of ethnic differences on the product labelling & selection of dose & dose regimen.

• By planning to address intrinsic and extrinsic ethnic differences throughout the drug development
process, the sponsor of a foreign drug may-

 Save time
 Reduce the need to replicate studies
 And build a stronger case for FDA acceptance.

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 CLINICAL
ISSUES

Investigation /
Site selection

Ethics Committee/
Institutional
Review Board Consent Process
Selection

Choice of comparator
& Dose

Concomitant
medication &
Patient issues drug- drug
interactions

Contraception &
Reproductive
Toxicity

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 Investigation/ Site Selection

• Selected investigators must be familiar with conducting controlled clinical trials according to Good
Clinical Practice (GLP) guidelines.

• Selected sites should have sufficient research training and experience in conducting trials that may
eventually be audited by the FDA.

• Control of investigational drug product and control over the conduct of the investigation are essential for
U.S. registration.

• Selecting academic or high- visibility centres of excellence & providing standardized investigator
training, help address concerns about quality of data.

• Key success factors for clinical data acceptance are GCP compliance & relevance of data to the
appropriate U.S. patient population.

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 ETHICS COMMITTEE/ Institutional review board selection

• FDA concern regarding some foreign studies is the lack of local control or inspection of studies by
local ECs.

• For a successful submission of foreign data, it is critical to select sites governed by ECs with
membership & rules of conduct that will be acceptable for U.S. registration.

• One common obstacle in developing countries, is independent or biased representation on ECs.

• EC should include sufficient representatives with appropriate technical expertise & patient advocate.

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 CONSENT PROCESS

• Inadequate study subject consent, as well as both overt & indirect coercion of patients to participate in
the study can undermine the acceptability of foreign data for U.S. registration.

• Lack of adequate consent can be problematic, particularly if FDA finds that study does not provide
medically indicated treatment or conducts coercive trials in locations where sufficient medical care is
not available.

• Additionally, local medical acceptability & cultural differences in patient belief may limit therapeutic
choices & excessively expand results in biased, informed consent process, preclude use of foreign data
to support application.

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 CHOICE OF COMPARATOR &
DOSE

• The relevance of foreign clinical data may also be judged by the choice of comparator as well as
relevant dose or dose range for both test and comparator drugs.

• The choice of dose and dosage of a drug in a pivotal trial that is used to support a U.S. application
should also be carefully considered.

• Active comparator need to be chosen based on whether the drug, dose & dosage are approved by
FDA.

• Demonstrating superiority or non- inferiority Vs an active comparators is only meaningful if the

comparator, dose & dosage are labelled in previously approved U.S. marketing application based on
establishment safety & efficacy trials.

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 CONCOMITANT MEDICATIONS & DRUG-DRUG
INTERACTIONS

• Drug- drug interaction data from foreign studies may have limited utility in U.S.

• A wide range of factors, may complicate the extrapolation of foreign data to support labelling for the
U.S. population.

• The sponsor & ultimately FDA may determine the additional drug-drug interaction trails may be
necessary to support U.S. labelling.

• These includes-
 Cultural difference,
 Economic difference,
 Genetic difference,
 Ethnic difference.

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 CONTRACEPTION & REPRODUCTIVE
TOXICITY

• Local practice, economic conditions, levels of education & cultural differences, drive decisions
regarding contraceptive methods.

• FDA is particularly concerned with safety of test products for trial participants as well as with
defining appropriate level of reproductive safety for labelling.

• FDA requires any study to assure the safety of female & male patients & their off-springs.

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 PATIENT ISSUES

• Study treatment compliance, or lack can also be a barrier to acceptance of foreign data.

• In populations with low- levels of education, it can be difficult to assure patient compliance & diary
retention.

• Under reporting adverse events may also be common due to cultural differences.

• Incomplete reporting of adverse events leads to inadequate reporting of incidence for expected
adverse events needed for U.S. labelling.

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 STUDY DESIGN &
CONTROLS
• When designing a study designed for eventual U.S. registration it is helpful to begin with the
intended labelling in mind.
• Pivotal trials, should be designed prospectively.
• When studies are not conducted under IND, little opportunity exist to obtain FDA input.
• In such cases, it is advisable to obtain external, expert consultations regarding regulatory strategy
that incorporates consideration of FDA’s ability to label safety & activity claim.
• In U.S. labelling claims principally depend on data derived from 2 adequate & well- controlled
pivotal trials.
• U.S. labelling claims often are-
 Limited to specific patient population studied.
 Limited to route of administration, dose and dosage form.
 Limited to prospectively stated objectives in the pivotal trails, proved to be statistically significant.

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 STUDY DESIGN & CONTROLS

• It will be difficult for FDA to interpret safety data or to compare drug activity, if the agency
is not familiar with the active comparator, dose, route of administration or dose regimen.

• Whenever ethically possible, sponsor consider placebo control, rather than active control for
pivotal trails.

• FDA considers placebo controlled trails to be the “gold standard” for demonstrating &
labelling safety & efficacy.

• Exception is in case of life- threatening indications such as those in field of oncology &
infectious diseases.

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 ENDPOINT
S
• In addition to study design considerations, an appropriate choice of clinically relevant
endpoints is key to help drive labelling & gain FDA acceptability of foreign data.

• Clinical relevant endpoints means-

 Disease activity,
 Patient mobility,
 Symptom control,
 Survival.

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 COLLECTING FOREIGN CLINICAL
DATA
• FDA accepts such studies, that are well designed, well conducted, performed by qualified
investigators, conducted in accordance with ethical principles acceptable to the world
community.

• Studies meeting these criteria may be utilized to support clinical investigations in U.S. or
marketing approval.

• Marketing approval of new Drug based solely on foreign clinical data is governed by section
314.106.

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 DATA
SUBMISSION
• Sponsor wishes to rely on foreign clinical study to support an IND or to support an
application for marketing approval shall submit to FDA the following information-
 A description of investigator’s qualifications.
 A description of research facilities,
 Detailed summary of protocol & results of the study & should FDA request, case
reports maintained by the investigator.
 Description of drug substance & drug products used in clinical study if available.
 Study intended to support the effectiveness of drug product, information showing
that the study is adequate & well controlled under section 314.126.

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 CONCLUSIO
N

• In many ways, development of foreign drug for approval in U.S. market is similar to the development of
U.S. drugs.

• Regardless of where the drug originates, or, where data were collected, sponsors must meet the same
requirements adhere to recognized standard, protect patient rights, design studies that support labelling
safety & efficacy claims, ensure the quality & integrity of the data and submit clear marketing application.

• To minimize the impact of differences & to reduce need to duplicate traits in multiple regions, companies
that develop foreign drugs, must plan carefully & communicate with FDA “early & often”.

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 CONCLUSIO
N

• Foreign drug sponsors facilitate the process of obtaining U.S. approval by communicating with FDA
appropriately & frequently.

• They should look after the details of development work conducted outside U.S. to ensure that it is in live
with FDA expectations & requirements.

• Finally, when sufficient data have been collected, sponsor should make a solid case for approval.

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 REFERENCES

• https://www.slideshare.net/NivaRaniGogoi/us-registration-for-foreign-drugs

• Ways and Means to U.S. Registration of Foreign Drugs | Request PDF (researchgate.net)

• Ways and Means to U.S. Registration of Foreign Drugs and David Skarins (taylorfrancis.com)

• Ways and Means to U.S. Registration of Foreign Drugs | Semantic Scholar

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THANK
YOU!