1. Protocol Development
The aim of clinical development is to find out whether there is a dose range and schedule at which the drug can be shown to be simultaneously safe and effective.
Qualification of investigator:
• Qualified by Education, Training and Experience
• Familiar with the use of Investigational Product as specified in Protocol, Investigator Brochure & other Information
• Comply with GCP & other applicable regulations
• Permit monitoring & Auditing by sponsor or other Regulatory Authorities
(Malaysian guideline for good clinical practice, third edition)
”The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.” (The Nuremberg Code)
“Medical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medical person… ” (Declaration of Helsinki)
1.1 Considerations for Development of Methodology for Clinical Trial
1.1.1 Important pre-clinical data
|Type of study||Points to consider|
|Non-clinical studies||Duration and total exposure proposed in individual patients Characteristics of the drug Disease or condition targeted for treatment Use in special population Route of administration|
|Safety studies||The dose that is administered should be determined by careful examination of prerequisite non-clinical pharmacokinetic, pharmacology and toxicology evaluation.|
|Pharmacological and Pharmacokinetic studies||Pharmacological basis of principle effects (mechanism of action) Dose-response or concentration-response relationship and duration of action Study of the potential clinical routes of administration Systemic general pharmacology, including pharmacological effects on major organ system and physiological responses Studies of absorption, distribution, metabolism and excretion|
1.1.2. Choice of control group
The choice of subjects for a clinical trial was greatly influenced by the intention to maximize the chance of observing specific clinical effects of interest, and hence they may come from a very narrow subgroup of the total patient population for which the drug may eventually be indicated.
The major purpose of choosing control group is to allow discrimination of patients outcomes caused by the test treatment from outcomes caused by other factors. The control group experiences provide information on what would happened to patients if they had not received the test treatment or if they had received a different treatment known to be effective.
Control group can be classified as below:
|Types of control||Description|
|Placebo concurrent control||Subjects are randomly assigned to a test treatment or to an identical-appearing treatment that does not contain the test drug. Its purpose is to control “placebo” effect.*placebo effect is an improvement in a subject resulting from thinking that he or she is taking a drug.|
|No treatment concurrent control||Subjects are randomly assigned to test treatment or to no study treatment. Subjects and investigators are not blind to treatment assignment.|
|Dose-response concurrent control||Subjects are randomized to one of several fixed-dose groups|
|Active (positive) concurrent control||Subjects are randomly assigned to the test treatment or to an active control treatment.|
|External control (Including Historical Control)||Compare a group of subjects receiving the test treatment with a group of patients external to the study.|
|Multiple control groups||The use of more than one kind of control in a single study. E.g., use of both an active control and placebo.|
1.1.3 Design techniques to avoid bias
Intended to limit the occurrence of conscious and unconscious bias in the conduct and interpretation of a clinical trial arising from the influence which the knowledge may have on the recruitment and allocation of subjects, their subsequent care, the attitudes of subjects to the treatments, the assessment of end-points, the handling of withdrawals, the exclusion of data from analysis, and so on. Types of blinding:
- Double-blind: neither the subject nor any of the investigator or sponsor staff who are involved in the treatment or clinical evaluations the subjects are aware of the treatment receive.
- Single-blind: Investigator and/or his staff are aware of the treatment but the subject is not, or vice versa.
The aim is to randomly allocate of treatments to subjects.Different trial designs will require different procedures for generating randomization schedules. The randomization schedule should be reproducible (if the need arises).
1.1.4 Sample size
Statistical method is applicable to determine the required number of patients to meet the trial’s principal scientific objectives. A statistical approach often used in clinical trial is called power calculations which determine how likely the study will produce a statistically significant result for a difference between groups of a certain magnitude.
In a statistical approach that focus on single outcome of patient response which dichotomous (i.e. success or failure), there are four items to consider:
- p1 = percentage of success expected on one treatment
- p2= percentage of success on the other treatment which one desires to detect as being different from p1
- a= the level of the X2 significance test used for detecting a treatment difference (often set a= 0.05)
- 1-ß= the degree of certainty that the difference p1 – p2, if presents would be detected (often set 1-ß=0.90)
a, commonly called type I error is the probability of detecting a “significance difference” when the treatments are really equally effective (i.e. represents the risk of a false-positive result)
ß, commonly called type II error, is the probability of not detecting a significance difference when there really is a difference of magnitude p1 – p2(i.e. represents the risk of a false-negative result)
1-ß are called the power to detect a difference magnitude p1 – p2.
|Decision||Treatments are not different||Treatments are different|
|Conclude treatments are not different||Correct decision||Type II error (ß)|
|Conclude treatments are different||Type I error (a)||Correct decision (1-ß)|
In clinical trials that measure quantitative response of patients, a need arise to specify the mean response (µ1) and standard deviation (s). Then decision has to be made regarding the changes in mean response d = µ2- µ1 achieved by the other treatment by using a two-sample t-test at some pre-specified significance level (i.e. p<0.05). The degree of certainty (1-ß) also needs to be specified.
Statistical estimation methods such as confidence limitsmay be employed to give some idea of what the true percentage in the whole population of future patients might be.Confidence limits are the lower and upper boundaries or values of a confidence interval. It may be obtained from standard errors. Standard error expresses how accurately the percentage difference has been estimated which represents the standard deviation of sampling distribution.
The confidence interval is the estimated amount of error that is allowed in the statistical data and analysis. The width of the confidence interval presented some ideason how uncertain the unknown parameter.Meanwhile, confidence level is a probability (1-a) associated with confidence interval. It represents how often the true percentage of the population who would pick an answer lies between the confidence interval. The most common confidence levels are 90% confident, 95% confident and 99% confident.The confidence level corresponds to a Z-score. The constant values are as below:
• 90% – Z score = 1.645
• 95% – Z score = 1.96
• 99% – Z score = 2.326
Necessary sample size may be calculated using equation:
Necessary sample size = (Z-score)2–Standard deviation x (1-Standard deviation) / (Margin of error)2
Note: Investigators are advised to seek for professional consultation to calculate sample size.
Reference: Stuart J.P. Clinical Trials A Practical Approach. England: John & Wiley Sons Ltd; 1983.
2. Online Registration and Submission.
In Malaysia, registration of clinical trial is via National Medical Research Register (NMRR). Online form for registration is filled in by research investigator/ Sponsor/ Project Team. The required data include research details, research documents and investigator’s documents. (NIH guidelines for conducting research in the MOH institutions and Facilities) (Data elements for submission to NMRR).
Complete online form will be submitted to NIH via NMRR. The approval notification via written Institutional Approval document by one of NIH institute.
For other countries, the clinical trial registrars are as below:
|Europe||EudraCT (https://eudract.ema.europa.eu/) (https://www.clinicaltrialsregister.eu/ctr-search/search)|
|India||Clinical Trials Registry -India (http://ctri.nic.in/Clinicaltrials/login.php)|
|China||Chinese Clinical Trial Registry (http://www.chictr.org/en/)|
|Australia||Clinical Trial Registries (http://www.australianclinicaltrials.gov.au/node/230)|
3. Research submission to Medical Research & Ethics Comitte review & approval via NMRR
In Malaysia, clinical trials conducted in Ministry if Health facilities will require approval from Medical Research and Ethics Committee while research to based on research institution facilities need to seek for approval from institution ethics committee such as USM Research Ethics Committee (Human), UKM Research and Ethics Committee and UiTM Research Ethics Committee.
An approved study protocol will be further submitted via online NMRR to Ethic Committee. If the study is proposed to be conducted in Ministry of Health facility, MREC will review the study protocol for approval or disapproval.
|Exempt Review||Chairperson review the study||Decision to PI : 10 working days post screening|
|Expedited Review||Secretariat assigns to MREC members (3 members including 1 non-scientific member)||Receive review from members : 10 working days Decision to PI : 10 working days Comments from PI : within 30 working days post-review|
|Full Board Review||Panel meeting of completed study package||Scheduled for panel meeting: 10 working days Decision to PI: 10 working days post-meeting|
|Final decision||Approval/disapproval letter by MREC chairman||10 working days|
For other countries, the ethics committees are as below:
|Europe||Scientificand Research Ethics Committee of the Medical Research Council)|
|US||Presidential Commission for the Study of Bioethical Issues|
|India||Indian Council of Medical Research|
|China||Ethics Committee, Ministry of Health|
|Australia||Australian Health Ethics Committee (NHMRC)|
Documents required for Ethic review are:
|Informed consent form||“For all biomedical research involving humans, the investigator must obtain the voluntary informed consent of the prospective subject or, in the case of an individual who is not capable of giving informed consent, the permission of a legally authorized representative in accordance with applicable law. Waiver of informed consent is to be regarded as uncommon and exceptional, and must in all cases be approved by an ethical review committee.(CIOMS, International Ethical Guidelines, Guideline 4) “Sponsors and investigators have a duty to… renew the informed consent of each subject if there are significant changes in the conditions or procedures of the research or if new information becomes available that could affect the willingness of subjects to continue to participate… ” (CIOMS, International Ethical Guidelines, Guideline 6)|
|Clinical trial agreement (CTA)||To ensure and document understanding of the protocol “the sponsor should obtain the investigator’s/institution’s agreement: (a) To conduct the trial in compliance with GCP, with the applicable regulatory requirement(s), and with the protocol agreed to by the sponsor and given approval/favourable opinion by the IRB/IEC…” (ICH Good Clinical Practice, Section 5.6)|
|Study protocol||A protocol “describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents.” (ICH Good Clinical Practice, Section 1.44) Protocol must be capable to generate statistically and scientifically sound answers to the questions that are being asked and meet the objective(s) of the study. The objective(s) should also justify the risk; that is, the potential benefits (if any) of participation in the study should outweigh the risks. (WHO GCP Principle 2: Protocol)|
|Trial design||Commonly used designs for controlled clinical studies include: placebo concurrent control; no-treatment concurrent control; dose response concurrent control; active (positive) concurrent control; external control (including historical control); and combination (multiple control group) designs. (ICH E10 Clinical Trials: Choice of Control Group and Related Issues in Clinical Trials)|
|Subject recruitment||“The subjects must be volunteers and informed participants in the research project.” (Declaration of Helsinki) “An agreement to participate in research constitutes a valid consent only if voluntarily given. This element of informed consent requires conditions free of coercion and undue influence.” (The Belmont Report)|
|Randomization and Blinding||Randomization is the “process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias.” (ICH Good Clinical Practice, Section 1.48) Blinding or masking is “[a] procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s). Single blinding usually refers to the subject(s) being unaware, and double blinding usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst being unaware of the treatment assignment(s).” (ICH Good Clinical Practice, Section 1.10)|
|Data handling||Establish an independent data-monitoring committee (IDMC) to assess the progress of a clinical trial, safety data and critical efficacy endpoints at intervals. (Malaysian Guideline for Good Clinical Practice)|
|Record keeping||Retain all sponsor-related essential documents in conformance with the applicable regulatory requirement(s) of the country (ies) where the product is approved, and/or where the sponsor intends to apply for approval(s). Maintain all sponsor-specific essential documents for at least 2 years after formal discontinuation or in conformance with the applicable regulatory requirement(s). (Malaysian Guideline for Good Clinical Practice) “Storage” (or “archiving”) implies that records are appropriately stored for future use, for example, to ensure their preservation and to enable direct access to the records when required by the sponsor, IEC/IRB, monitor or regulatory authorities. “The investigator/ institution should take measures to prevent accidental or premature destruction of these records.” (ICH Good Clinical Practice, Section 4.9)|
|Reporting||Expedite the reporting to all concerned investigator(s)/ institution(s), to the IRB(s)/IEC(s), where required, and to the regulatory authority (ies) of all adverse drug reactions (ADRs) that are both serious and unexpected. (ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting) Submit to the regulatory authority (ies) all safety updates and periodic reports, as required by applicable regulatory requirement(s) Ensure that the clinical trial reports in marketing applications meet the standards of the ICH Guideline for Structure and Content of Clinical Study Reports “The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRFs and in all required reports. Data reported on the CRF, which are derived from source documents should be consistent with the source documents or the discrepancies should be explained.” (ICH E6, Section 4.9; see also, ICH E6, Section 4.10: Progress Reports; ICH E6, Section 4.11: Safety Reporting, and ICH E6, Section 4.13: Final Report(s) by Investigator/Institution.)|
|Serious adverse events (SAE)||All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g. investigator’s brochure) identifies as not needing immediate reporting. The immediate reports should be followed promptly by detailed written reports.” “… The investigator should also comply with the applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to the regulatory authority (ies) and the IRB/IEC.” (ICH Good Clinical Practice, Section 4.11)|
|Monitoring||In most cases of research involving human subjects, it is unnecessary to appoint a DSMB. To ensure that research is carefully monitored for the early detection of adverse events, the sponsor or the principal investigator appoints an individual to be responsible for advising on the need to consider changing the system of monitoring for adverse events or the process of informed consent, or even to consider terminating the study.” (CIOMS, International Ethical Guidelines, Commentary on Guideline 11) Establish an independent data-monitoring committee (IDMC) to assess the progress of a clinical trial, safety data and critical efficacy endpoints at intervals. (Malaysian guideline for Good Clinical Practice)|
|Auditing||Implementing and maintaining QA/QC systems to ensure compliance with protocol, GCP and applicable regulatory requirement(s)(Malaysian guideline for Good Clinical Practice)|
|Financing and insurance||The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution. Provide insurance or should indemnify (legal and financial coverage) the investigator/the institution against claims arising from the trial except for claims that arise from malpractice and/or negligence Address the costs treatment of trial subjects in the event of trial-related injuries in accordance with applicable regulatory requirement(s)(Malaysian Guideline for Good Clinical Practice)|
|Investigator’s Brochure||Ensuring that an up-to-date IB is made available to the investigator(s) and the investigator(s) are responsible for providing the up-to-date IB to the responsible IRBs/IECs Ongoing safety evaluation of the investigational product(s). Control receipt, administration, and disposition of the investigational product. (Malaysian Guideline for Good Clinical Practice)|
(Clinical research documents)
(Acknowledge Request Form)
4. Registration of Clinical Trial Drug
In Malaysia, investigational drug is registered with Centre for Investigational New Drug, National Pharmaceutical Control Bureau. Documents are submitted to Deputy General of Centre for Investigational New Drug, NP
|Administrative Documents||Pharmaceutical Data||Investigator’s Brochure|
|Application form: CTIL : Form BPFK 442 CTX: Form BPFK 443||Finished product: Description Composition||Summary|
|Application submission form: Form BPFK 001||Standardisation of extract||Introduction|
|Submission checklist: Form BPFK 002||Manufacture of product||Physical, Chemical and Pharmaceutical properties formulation|
|Processing Fee||Quality control||Non-clinical studies|
|Company registration certificate||Validation of analytical method||Effects in human|
|License A||Contents of Validation Protocol & Report||Summary of data and Guidance for the Investigator|
|Good Clinical Practice (GCP) Certificate||Stability of Product||References on Publications and Reports|
|Letter of Authorisation||Containers Closure System||Appendices|
|Approval letter by Ethics Committee|
|Good Manufacturing (GMP) Certificate|
|Informed consent form|
5. Research notification to Clinical Trial and Compliance Section, NPCB and IRB/IEC(s)
Online notification will be sent to Clinical Trial and Compliance Section.
6. Research publication submission to NIH
Research publication in Malaysia is conducted as below:
There are two methods available for application:
1. Hard copy submission to NIH Committee with cover letter and Form P1/P2
59000 Kuala Lumpur.
2. Online submission via NMRR
For purpose of publication, applicant needs to state the title of journals (included online journals) and include the Acknowledgment paragraph start with below stated sentence:
The author(s) would like to thank the Director of Health Malaysia for permission to publish this paper.
For presentation, applicant needs to state abstract of presentation, date and venue for presentation. Application for presentation must arrived at NIH Committee not late than 3 weeks before the date of presentation.
6.2 Evaluation by NIH institute
Applicant must show commitment on any corrective or improvement comments suggested by NIH Institute.
6.3 Approvement by Deputy General
According to SuratKetuaPengarahKesihatan dated 23rd April 2012:
TimbalanKetuaPengarahKesihatan (Penyelidikan&SokonganTeknikal) is authorized to approve an application.
Step 1: NIH Committee will submit corrected and evaluated application to TKPK (P&ST) Office.
Step 2: Written application status will be notified by KetuaUrusetia NIH to applicant via a letter.