4. Regulatory Authority (RA)/Competent Authority (CA)

1. Table of Contents

A content page should be included in each CTIL/CTX application dossier. A template table of content can be found in Appendix A.

2. Cover Letter

The applicant shall submit a signed cover letter with the application. Its subject line should contain the full NMRR Registration Number and the protocol number with the title of the trial. In the cover letter, the applicant should draw attention to the peculiarities of the trial, if any.

3. CTIL/CTX Application Form

The applicant shall submit a complete application form with NMRR Registration Number. The application form shall be signed and dated by the applicant and stamped with the company's stamp.

Application forms for CTIL (current version PPPK/SPKPK/F01) and CTX (current version PPPK/SPKPK/F02) can be downloaded from the NPRA website.

Only one applicant and one local contact person from the same organization, if any, can be named under Part 2 of the application form. All communication will be sent to the named applicant and the second contact person.

For CTIL/CTX applications involving FIH clinical trials, applicants are required to provide additional information as listed under Appendix D of the application form.

4. Receipt for the processing fee, if applicable.

Every application for CTIL shall be accompanied by a processing fee. The CTIL application processing fee is RM 500.00 per product. CTIL application without the correct processing fee will not be processed.

The processing fee shall be paid in the form of a credit card/bank draft/money order/postal order payable to 'Biro Pengawalan Farmaseutikal Kebangsaan'. Alternatively, the payment can be made using a credit card at the Finance, Account & Revenue Section.

Note: Foreign currencies are not acceptable. The processing fee is not refundable.

Application for CTX is free of charge.

5. A copy of the Company Registration Certificate, if applicable

The company must be registered with Suruhanjaya Syarikat Malaysia. The applicant (if said company is not the sponsor) should be authorized in writing by the sponsor to be the holder of the CTIL/CTX. Please refer to 4.4.6 for the Letter of Authorization.

https://npra.gov.my/easyarticles/images/users/1140/Malaysian-Guideline-for-Application-of-CTIL-and-CTX-8th-Ed-Final.pdf

A copy of the Company Registration Certificate is NOT required for an investigator-initiated trial.

6. A copy of the applicant’s Poison Licence Types A for a pharmacist in the private sector or ARC for a public pharmacist, whichever is applicable.

7. Letter of Authorization, if applicable

• Letter of Authorization should be submitted in cases where:
  • Sponsor or a PI decides to use a service of CRO for the conduct of a clinical trial or;
  • The applicant is not the sponsor or product owner.
• In the case of an investigator-initiated trial involving 'poison/drug', the letter of authorization should be provided by the PI to the nominated applicant/hospital pharmacist.
• A format of Letter of Authorization in Appendix B may be used as a reference.

8. A copy of the opinion(s) of the EC which is/are registered with DCA

Applications for CTIL/CTX and EC can be submitted in parallel. The favorable opinion/approval letter of EC (with attendance list) should be sent to the DCA as soon as possible when available.

Following the directive issued by the DPS on Keperluan Mendaftar Jawatankuasa Etika dengan Pihak Berkuasa Kawalan Dadah, NPRA will only accept favorable opinion/approval issued by EC that is registered with the DCA. The applicant is advised to refer to the NPRA website for the current list of EC that is registered with DCA.

For an application involving an FIH clinical trial, a positive opinion from EC shall be submitted to NPRA before the application can be tabled in the DCA meeting.

9. Clinical Trial Protocol

The final version of a clinical trial protocol must be submitted. The version submitted should be the version that has been submitted to EC. The clinical trial protocol shall be in the format provided by Section 6 of the Malaysian Guideline for GCP and include the definition of the end of the trial.

For BE study, the formula used with detailed stepwise calculation is required to justify the sample size needed. If a two-stage design is adopted in the study, a decision tree or diagram, which depicts the methodology must be stated in the study protocol.

10. Declaration by investigator/PI

An original copy of the declaration by the investigator/ PI of each trial site should be provided. The format for the document can be found in Appendix C.

The investigator protocol signature page will NOT be accepted.

11. GCP certificate and CV for investigator/PI of each trial site

It is expected that the investigator/PI will be qualified by education, approved training in GCP, and experience to assume responsibility for the proper conduct of the trial. The GCP certificate and CV for the investigator/PI of each trial site should be provided.

The GCP course should be recognized/approved by NCCR, Ministry of Health Malaysia. The requirement is in accordance with the current version of the Malaysian Guideline for GCP.

In the case of BE study, a GCP certificate, CV, and Declaration by the investigator for the clinical site investigator should also be provided if the investigator at the clinical site is not the PI.

12. Informed consent form (initial version only for one of the trial sites)

The ICF provided can be in either English or Bahasa Melayu. The initial version of ICF must be provided during submission.

13. Pharmaceutical data for all products that require CTIL/CTX

Quality data should be submitted in a logical structure, such as the headings of the following appendices. The following appendices outline the pharmaceutical data format for different types of IP:

• Appendix D1: Investigational Products in Clinical Trials
• Appendix D2: Modified Registered Comparator Products in Clinical Trials
• Appendix D3: Investigational Products Containing Generics in Bioequivalence Studies
• Appendix D4: Placebo Products in Clinical Trials
• Appendix D5: Herbal/Natural Products in Clinical Trials
• Appendix D6: Biological Investigational Products in Clinical Trials

https://npra.gov.my/easyarticles/images/users/1140/Malaysian-Guideline-for-Application-of-CTIL-and-CTX-8th-Ed-Final.pdf

Stability data

It is the responsibility of the applicant and sponsor to ensure that the product used is stable for the duration of the clinical trial.

A minimum of one (1) batch of stability studies under accelerated and real-time conditions for a minimum of 3 months should be provided. Stability studies should be conducted in compliance with ASEAN/ICH stability guidelines.

For the First-in-Human Clinical Trial, a minimum of one (1) batch of stability studies under accelerated and real-time conditions for a minimum of 1 month should be provided. Stability data of the IP after reconstitution or dilution, if applicable, should be submitted to support the in-use period of the reconstituted or diluted IP (ICH Q1A (R2)).

BE study

For BE study, the test product should usually originate from a batch of at least 1/10 of the production scale or 100,000 units, whichever is higher, unless otherwise justified.

Appendix D3, Section 4.S Drug Substance shall be provided only for BE study involving chemical entity that has not been registered in Malaysia.

DCA-registered IP (Relabeling/Secondary Packaging Modification)

In case the IP used is a DCA-registered product, the applicant is not required to submit pharmaceutical data for the IP. However, a declaration letter from the sponsor to confirm that the quality of IP is the same as the DCA-registered product should be provided.

14. Label all products that require CTIL/CTX

The applicant must ensure labels of products for clinical trials meet the labeling requirements, according to Appendix E. The particulars on the outer packaging of the investigational product, or where there is no outer packaging, on the immediate packaging, shall appear in Bahasa Melayu or English.

15. Good Manufacturing Practice (GMP) Requirement

Investigational products are required to be produced in accordance with the PICS Annex 13. 

A current copy of the Certificate of GMP Compliance for the manufacturer of the drug product and/or final/batch releaser only should be submitted.

The name and address of the manufacturer should be identical between the application form and the GMP certificate provided. Any discrepancy in the information shall be justified. The certificate must be valid at the time of submission.

Local manufacturer in Malaysia
A valid copy of "Lesen Pengilang" issued by NPRA should be submitted. For high-claim herbal/natural products and health supplements manufactured locally, products should be manufactured at PIC/S GMP-grade manufacturing facilities.

Manufacturer outside Malaysia

1. For manufacturers in PIC/S member countries, a valid Certificate of GMP Compliance issued by participating authorities of member countries shall be provided.
2. For manufacturers from a non-PIC/S member country that has been inspected by a recognized regulatory authority, a valid Certificate of GMP Compliance issued by the inspecting regulatory authority shall be given. The recognized regulatory authorities are listed in Directive No. BPFK/PPP/07/25 (4) Jld. 1.
3. For manufacturers in ASEAN countries, a valid Certificate of GMP Compliance issued by NDRA as mutually agreed in ASEAN Sectoral Mutual Recognition Arrangement (MRA) for GMP Inspection of Manufacturers of Medicinal Products shall be furnished.
4. For a manufacturer who has been inspected by the United States Food and Drug Administration (US FDA), a document that shows the listing of the manufacturer in the US FDA Drug Establishment Current Registration Site should be submitted to fulfill the requirement of GMP compliance.

Note: 

Other proof of GMP compliance documentation can be considered based on a risk-based approach for the following conditions:

1. For manufacturers in PIC/S member countries, for phase I clinical trials including FIH.
2. For manufacturers in the US, for all phases of clinical trial.

16. Investigator’s Brochure

For content and format of the IB, reference is made to section 7 of the current version of the Malaysian Guideline for GCP.

The unavailability of IB is generally acceptable for most of the BE study. However, IB shall be provided for a BE study involving a chemical entity that is not registered in Malaysia.

Generally, toxicity studies are expected to be performed in compliance with Good Laboratory Practice (GLP).

17. Overall Risk and Benefit Assessment

This section should provide a brief integrated summary that critically analyzes the non-clinical and clinical data in relation to the potential risks and benefits of the proposed trial unless this information is already provided in the protocol. In the latter case, the applicant should cross-refer to the relevant section in the protocol. The text should identify any studies that were terminated prematurely and discuss the reasons.

The assessment is not mandatory for a BE study.

18. A copy of scientific advice from other regulatory agencies, if available.

19. Evidence of Phase 1 Unit Accreditation by NPRA

The Phase 1 Unit shall be on the NPRA Phase I Unit Accreditation Programme. Evidence of this listing shall be submitted for FIH clinical trial.

20. Proof of Insurance Cover

Proof of insurance shall be submitted for the FIH clinical trial for compensation for any damage suffered by the subject resulting from participation in an FIH clinical trial.

21. Declaration by Sponsor for CTIL/CTX Application Involving FIH Clinical Trial

Declaration by the sponsor shall be submitted in original copy for FIH clinical trial. A format for Declaration by Sponsor can be found in Appendix F.

22. Electronic Format

One electronic copy of all documents shall be submitted in a CD-ROM. Please refer to section 4.6.3 for the preparation of the CD-ROM document.

https://npra.gov.my/easyarticles/images/users/1140/Malaysian-Guideline-for-Application-of-CTIL-and-CTX-8th-Ed-Final.pdf

23. Other or additional documents

Any other trial-related documents that could be relevant for the review of the clinical trial application by DCA may be submitted, e.g. published clinical data, if applicable.