Chapter 2 Western Medicine
Section 2 Drug Review and Registration
Article 32
When applying for drug registration, the applicant should provide photocopies of documents to justify that the hardware, software and dosage form equipment of the manufacturers comply with the GMP Guidelines. For toll-manufactured products, the paperwork should include all manufacturers involved in every step of the manufacturing process.
Active ingredients of drug products shall comply with GMP Guidelines.
Article 33
After a drug license was revoked or cancelled due to drug efficacy or safety reasons, the first application of drug with identical active ingredient, dosage form and contents should follow the regulations for the new drug registration. If the reasons for license revocation or cancelation are irrelevant to drug efficacy or safety issues, then the first application shall follow the regulations of generic drugs.
Article 34
If more than four applications for drug registration are to be filed in the same month, the applicant should apply for an approval by giving reasons and providing information on the manufacturer, including information on the equipment and technical staffs of the manufacturing and quality control departments and the manufacturer’s actual manufacturing capacity. This information has to be confirmed by the central health competent authority through dossier review or site inspection of quality control, production records, sample manufacturing processes and on-site supervision.
For manufacturers meeting the validation requirements in accordance with the schedule stipulated in Article 21 Paragraph 3, each manufacturer can file three applications for drug registration every month or 36 cases every year.
Article 35
For the application for drug registration of pharmaceutical preparations, the dosage form should comply with the following regulations:
1.If a drug has two different dosage forms, then separate applications should be made. If there are different unit strengths or concentration levels of the same dosage form, then separate applications are required.
2.For powders for injection, different content volumes can be put in one application; but, injections with different concentration levels should have separate applications.
3.Powders for injection with different solvents for muscular injection and for intravenous injection should have separate applications.
4. The registration of drug may only be approved after the dosage form of the manufacturers is passed the central health competent authority’s assessment.
If the medicinal products manufacturing license or approval document said in the preceding item are not available at the time of filing, the applicant shall provide the required documents before approval.
Article 36
The Stability study, in support of the application for drug registration should comply with the following regulations:
1.The stability study should include research on the drug degradation curve in order to estimate the period of efficacy and to ensure the effectiveness and safety of drugs in use. The study should be conducted in accordance with the Guidelines on the Drug Stability Study as announced by the central health competent authority.
2.A stability study protocol and a report should be submitted.
3.In order to ensure the sufficiency and completeness of a stability study, the applicant should provide any supplementary or necessary information upon the central health competent authority’s request. However, the applicant may retain the original data of a stability study for future inspection. No submission of such data is required.
4.In principle, the stability study of toll-manufactured drugs should be conducted to ensure drug quality. It can be conducted by (but not limited to) manufacturers involved in the toll-manufacturing process.
Article 37
In situations where Bioavailability/Bioequivalence (BA/BE) studies are required for the application for drug registration, the study should comply with the Regulation of Ba and Be Studies in the aspects of the scope of drugs, items, reference standards, test principles, test period, principles for substitution and other matters in relation to the study.
When conducting BA/BE studies, the applicant should comply with the central health competent authority’s regulation and fill out the application forms for the assessment of the BE study protocol and BE study report, the application forms for the assessment of the BA study protocol and BA study report, and for the assessment of the drug dissolution curve comparison report. The applicant should also prepare related information according to the requirements on those forms.
Article 38
The FSC from the country of origin and the CPP are not required for the application of NCE (New Chemical Entity) drugs.
In cases where the FSC from the country of origin and CPP are submitted for the aforementioned application, the central health competent authority may adjust the review process according to the actual situation.
For applications of new therapeutic compound, new administration route, new dosage form, new dose or new strength, FSC from the country of origin has to be submitted prior to license acquirement.
If the country of origin is a member of the A10 countries, then the submission of the FSC from the country of origin also satisfies the submission of CPP. If the CPP submitted by the applicant states the same manufacturer’s name, address, formulation, dosage form and contents as the information of the new drug in the application, then the submission of CPP also satisfies the requirement of submission of the FSC from the country of origin.
Article 38-1
Apart from the compliance with Article 39, the following dossiers are required for the submission of an NCE drug application:
1.Dossiers of Phase I clinical trial conducted during the development stage in Taiwan, as well as Phase III pivotal trial conducted simultaneously with other countries; or alternatively, Phase II clinical trial and Phase III pivotal trial conducted simultaneously with other countries.
2.A Post-Approval Risk Management Plan; and
3.Relevant documents and information for site inspection upon the central health competent authority’s request.
The trial results said in point 1 above have to be approved by the central health competent authority and the design of the trials has to meet the following criteria:
(1)In principle, there should be at least 10 valid Taiwanese subjects for a Phase I clinical trial, such as PK study or PD study;
(2)In principle, there should be at least 20 valid Taiwanese subjects for a phase II clinical trial;
(3)In principle, there should be at least 80 valid Taiwanese subjects for a Phase III pivotal trial; and the results have to show the similarity between Taiwan and other countries; and
(4)With the central health competent authority’s approval, the numbers of trials and subjects of the aforementioned three types of clinical trials can be adjusted on grounds of the improvement in quality, safety or efficacy of the drug, the nation’s welfare or special circumstances.
Article 38-2
Apart from the compliance with Article 39, applicants of NCE drugs should submit a CPP issued by any one of the A10 countries, plus the dossiers of clinical trials to clinically and statistically justify drug safety and effectiveness in the population in Taiwan. The results of these clinical trials have to be reviewed and approved by the central health competent authority. If necessary, the central health competent authority may request the submission of post-approval risk management plan.
The aforementioned clinical trials have to meet the following criteria:
1.In principle, there should be at least 10 valid subjects for a Phase I clinical trial, such as PK (Pharmacokinetics) study or PD (Pharmacodynamics) study, conducted in Taiwan.
2.In principle, the number of valid Taiwanese subjects in a multi-national and multi-center Phase II clinical trial should be at least 20 or more than 10% of the total subjects.
3.In principle, the number of valid Taiwanese subjects in a multi-national and multi-center Phase III clinical trial should be at least 80 or more than 10% of the total subjects.
4.For a multi-national and multi- center Phase III study involving any A10 countries and the trial result is going to be used to support the NDA filed to the US FDA or the EU EMA, one of the following conditions has to be met:
(1)In principle, the number of valid Taiwanese subjects should be at least 30 or 5% of the total subjects in a single trial of over 200 (inclusive) subjects; or
(2)In principle, there should be at least10 valid Taiwanese subjects in a single trail of less than 200 subjects.
5.With the central health competent authority’s approval, the numbers of trials and subjects of the aforementioned four types of clinical trials can be adjusted on grounds of the improvement in quality, safety or efficacy of the drug, the nation’s welfare or special circumstances.
Article 38-3
With the approval from the central health competent authority, clinical trials in compliance with the regulations set out in the previous two articles can be qualified for an exemption of, or a substitution for bridging studies.
Article 38-4
NCE drug applications with the submission of two or more CPPs issued by the A10 countries should comply with regulations set out in Article 39 and 22-1. If necessary, the central health competent authority may request the submission of a Post-Approval Risk Management Plan.
Article 38-5
For drugs received designations of treatment of pediatric or rare severe disease from the central health competent authority, CPPs are not required for the application of NCE. If FSC from the country of origin are not available at the time of filing, the applicant shall provide it before approval. If relevant domestic clinical trial data to the claimed indications in Taiwan is provided, the FSC from the country of origin is not required.
Article 39
Information that should be submitted for the application for drug registration of new drugs, new dosage forms, new administration doses or new unit strength are as specified in Appendices 2 and 3.
Regulations for new drugs stipulated in this Chapter are also applicable to pharmaceutical preparations with new dosage forms, new administration doses and new unit strengths.
Article 40
Information that should be submitted with the application for drug registration of generic drugs are as specified in Appendices 4 and 5.
Article 41
Information that should be submitted with the application for drug registration of bio-pharmaceutical drugs are as specified in Appendices 6 and 7.
Article 42
Information that should be submitted with the application for drug registration of active pharmaceutical ingredients are as specified in Appendices 8 and 9.
Article 43
Information that should be submitted with the application for drug registration of radiopharmaceutical drugs are as specified in Appendices 10 and 11.
The application should comply with the Guidelines on Clinical Trials of Radiopharmaceutical Drugs and the Guidelines on the Assessment of Radiopharmaceutical Drugs as announced by the central health competent authority.
Regulations for new drugs stipulated in this Chapter are also applicable to radiopharmaceutical drugs with new dosage forms and new doses.
Article 44
When applying for licenses for export products, the applicant should submit the original copy and a duplicate copy of the application form, assurance statement A, assurance statement B, assurance statement for the export-only product, form for sticking package inserts and labels (two copies), form for sticking licenses, the testing specifications, methods and certificate of analysis of API and final product respectively, and a photocopy of GMP compliance certificate. The manufacturer should retain the Manufacturing and Control Standards (including the actual amount or materials used as specified in batch records), batch record, the testing specifications, methods and certificate of analysis of excipients, stability study data, and validation of analytical methods and validation of critical manufacturing processes for future inspection. If necessary, the central health competent authority may request the applicant to provide samples for testing. Such requests should be answered.
When applying for an export license, if the applicant imports semi-products to manufacture export-only final products, and has obtained a license for importing the semi-products, then in addition to the above mentioned documents, the applicant should also provide the original copy of a commission letter, therein authorizing the applicant to register the product in Taiwan and export them to other countries. If the applicant does not hold a license for importing semi-products, then the CPP or the FSC from the manufacturing country of the semi-products should also be provided.