Preclinical and Clinical Trial Requirements
All legal aspects surrounding preclinical and clinical trial requirements in Zimbabwe. Prepared in association with Honey & Blanckenberg, a leading law firm in Zimbabwe, this is an extract from The Pharma Legal Handbook: Zimbabwe, available to purchase here for USD 99.
1. Are clinical trials required to be conducted locally as a condition (stated or implicit) for marketing approval?
There is no such requirement. The Medicines and Allied Substances Control Act only requires that a medicine be registered. In considering an application for registration, the Authority may, however, conduct any investigation or inquiry as it deems necessary into the medication (Section 33 of the Act), which could possibly include a clinical trial.
In addition, in terms of Section 23 of the Act, to ensure adequate protection of the general public against any risks or adverse effects from the clinical trial of any medicine authorized in terms of section eighteen, the Authority shall monitor such clinical trial from the beginning to the end so as to satisfy itself that all specific and general conditions subject to which the trial was authorized are being strictly observed by the person conducting the trial, and that to all intents and purposes the trial will achieve its aims and objectives.
2. How are clinical trials funded?
Clinical trials would be funded by the person or entity conducting the same.
3. What are the requirements for preclinical and clinical trial protocols? Who must approve the protocols?
Protocols must be approved by the Medicines Control Authority before they can be conducted.
In accordance with the MCAZ Guidelines for Good Clinical Trial Practice in Zimbabwe, protocols must contain the following:
- Protocol title, protocol identifying number, and date. Any amendment(s) should also bear the amendment number(s) and date(s);
- Name and address of the sponsor and monitor (if other than the sponsor);
- Name and title of the person(s) authorised to sign the protocol and the protocol amendment(s) for the sponsor.
- Name, title, address, and telephone number(s) of the sponsor’s medical expert (or dentist when appropriate) for the trial.
- Name and title of the investigator(s) who is (are) responsible for conducting the trial, and the address and telephone number(s) of the trial site(s).
- Name, title, address, and telephone number(s) of the qualified physician (or dentist, if applicable), who is responsible for all trial-site related medical (or dental) decisions (if other than investigator).
- Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or technical department(s) and/or institutions involved in the trial.
The protocols must also have the following background information:
- Name and description of the investigational product(s);
- A summary of findings from non-clinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial;
- Summary of the known and potential risks and benefits, if any, to human subjects.
- Description and justification for the route of administration, dosage, dosage regimen, and treatment period(s);
- A statement that the trial will be conducted in compliance with the protocol, GMP, GCP and the applicable regulatory requirement(s);
- Description of the population to be studied; and
- References to literature and data that are relevant to the trial, and that provide background for the trial.
It is also a requirement that the protocol must contain trial objectives and purpose which include a detailed description of the objectives and the purpose of the trial.
The protocol must also contain a Trial Design. This is the scientific integrity of the trial and the credibility of the data from the trial depend substantially on the trial. It should include:
- A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial;
- A description of the type/design of trial to be conducted (e.g. double-blind, placebo controlled, parallel design) and a schematic diagram of trial design, procedures and stages.
- Use of placebo alone as a trial treatment for trial subject is not acceptable where there is known treatment.
- A description of the measures taken to minimise/avoid bias, including randomisation and blinding;
- A description of the trial treatment(s) and the dosage regimen of the investigational product(s). Also include a description of the dosage form, packaging, and labelling of the investigational product(s);
- The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up, if any.
- A description of the “stopping rules” or “discontinuation criteria” for individual subjects, parts of trial and entire trial.
- Accountability procedures for the investigational product(s), including the placebo(s) and comparator(s), if any; and
- Maintenance of trial treatment randomised codes and procedures for breaking codes.
- The identification of any data to be recorded directly on the CRFs (i.e. no prior written or electronic record of data), and to be considered to be source data.
The requirements must also contain Selection and Withdrawal of Subjects. This must include:
- Subject inclusion criteria;
- Subject exclusion criteria;
- Subject withdrawal criteria (i.e. terminating investigational product treatment/trial treatment) and procedures specifying:
- When and how to withdraw subjects from the trial/investigational product treatment;
- The type and timing of the data to be collected for withdrawn subjects;
- Whether and how subjects are to be replaced.
- The follow-up for subjects withdrawn from the investigational product treatment/trial treatment.
It is also a requirement that information on the treatment of subjects be provided. This includes:
- The treatment(s) to be administered, including the name(s) of all the product(s), the dose(s), the dosing schedule(s), the route/mode(s) of administration, and the treatment period(s), including the follow-up period(s) for subjects for each investigational product treatment/trial treatment group/arm of the trial;
- Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the trial;
- Procedures for monitoring subject compliance.
The protocol must also contain an assessment of efficacy which includes methods and timing for assessing, recording, and analysing of efficacy parameters.
An assessment of security must also be conducted. This includes:
- Specifications of the efficacy parameter;
- Methods and timing for assessing, recording, and analysing of efficacy parameters;
- Procedures for eliciting reports of and for recording and reporting adverse event and intercurrent illnesses; and
- The type and duration of the follow-up of subjects after adverse events.
Statistics to be provided include:
- Description of the statistical methods to be employed, including timing of any planned interim analysis;
- The number of subjects planned to be enrolled. In multi-centre trials, the numbers of enrolled subjects projected for each trial site should be specified. Reason for choice of sample size, including reflections on (or calculations of) the power of the trial and clinical justification;
- The level of significance to be used;
- Criteria for the termination of the trial;
- Procedures for accounting for missing, unused and spurious data;
- Procedures for reporting any deviation(s) from the original statistical plan (any deviation(s) from the original statistical plan should be described and justified in protocol and/or in the final report, as appropriate; and
- The selection of subjects to be included in the analyses (e.g. all randomised subjects, all dosed subjects, all eligible subjects, valuable subjects).
Finally, all protocols must contain:
- Direct Access to Source Data/Documents;
- Quality Control and Quality Assurance of Data and Procedures;
- Description of ethical considerations relating to the trial;
- Data Handling and Record Keeping; and
- Insurance of Trial Subjects.
4. What are the requirements for consent by participants in clinical trials?
In terms of Section 20(1) of the Act, where authorisation for a clinical trial for a medicine has been granted by the Authority, the following shall be furnished before the trial takes place:
- in the case of a medicine for the treatment of adult persons, the voluntary written consents of all such persons taking part in the clinical trial have been freely obtained; and
- in the case of a medicine for the treatment of minors or persons under legal disability, the voluntary written consents of their parents or legal guardians, as the case may be, have been freely obtained; and
- in the case of a medicine for the treatment of animals, the voluntary written consents of the owners of all animals taking part in the clinical trial have been freely obtained.
5. May participants in clinical trials be compensated?
There is no prohibition against compensation for participation.
6. How are participants in clinical trials protected and indemnified against any harm that arises as a result of participation in the trial?
In terms of Section 23 of the Act, to ensure adequate protection of the general public against any risks or adverse effects from the clinical trial of any medicine authorized in terms of the Act, the Authority shall monitor such clinical trial from the beginning to the end so as to satisfy itself that all specific and general conditions subject to which the trial was authorized are being strictly observed by the person conducting the trial, and that to all intents and purposes the trial will achieve its aims and objectives.
Furthermore, if the Authority is satisfied that having due regard to the initial risks, discomforts or other adverse effects caused to persons or animals taking part in the trial it is in the public interest to stop or suspend the trial, it shall seek and obtain forthwith the Secretary’s written approval to stop or suspend the trial immediately, and, if such approval is obtained, the Authority shall notify in writing the person conducting the trial accordingly.
In terms of the Guidelines for Good Clinical Trial Practice in Zimbabwe, an ethics committee should be appointed before any clinical trial takes place. One of the Committee’s duties is to provide for compensation/treatment in the case of injury or death of a subject if attributable to a clinical trial, and any insurance or indemnity to cover the liability of the investigator and sponsor.