Malaria Clinical Trials Toolkit
The Malaria Clinical Trials Toolkit is a pathway with a step by step guide for researchers on how to plan, design, execute and interpret malaria clinical trial results. It helps researchers to think of the different aspects of a malaria clinical trial and how to collect reliable and comprehensive evidence in a standardised format.
The Toolkit outlines the different components required to design and run a malaria clinical trial. Click on each component below to find out more and access various resources related to each stage of the pathway. You can navigate easily around the Toolkit allowing researchers setting up clinical trials to follow the steps chronologically or specialists to jump straight to the step specific to their work. Some of the resources and procedures can be found in different sections of the Toolkit, however you will also find a wider pool of the resources that we have in the procedures section. See also Global Health Trials for more generic clinical trial resources.
Read the study: Impact of Dolutegravir-Based Antiretroviral Therapy on Piperaquine Exposure following Dihydroartemisinin-Piperaquine Intermittent Preventive Treatment of Malaria in Pregnant Women Living with HIV, which piloted the WWARN Clinical Trials Toolkit and PK sampling and processing guidance.
Many of our tools are only available in English. If you would like to use them in another language, please email info [at] wwarn [dot] org with your request.
Please also read our Tools & Resources usage statement.
Research question
A clear and precise research question is the most important aspect and starting point of any malaria clinical trial.
Define a question
- The research question is the most important step in the whole pathway, since it will drive your clinical trial.
- Your question should address gaps in what is known, so it is important to understand what has been done already; an indepth review of previous and ongoing work is key. Check trial registers as well as published literature through PubMed and other databases, and the WWARN Literature Reviews. See also the huge amount of information on the WWARN Explorer map and the Molecular Surveyors for artemisinin, ACT partner drugs, sulphadoxine pyrimethamine, and chloroquine resistance (P Vivax). These allow you to visualise results of data from antimalarial resistance studies in Africa, Asia, Latin America and Oceania stored in the secure WWARN Data Centre, thereby understanding gaps in knowledge.
- For example, if the overall efficacy of a drug in whole populations of people is known, you might then consider addressing its efficacy in particular in young children or some other specific group.
- Your question should generally include specific information on participants, intervention(s), comparator(s), and outcomes (PICO format).
- As you make choices on these, focus on the target groups - people or organizations who might use your evidence. Is the information most useful to a local, regional, national or international audience?
Develop protocol/proposal
- A proposal is used to approach a funder for trial financing (see below), while a protocol can be seen as a more detailed description of the components suggested in the proposal; it describes all the trial processes for staff to follow in order to carry out the clinical trial (like a recipe). A protocol is then presented to an ethics committee and other authorities with other trial documents for approval before the trial may start.
- Make sure you choose the right design that will answer the questions raised in an unbiased way. See our online training page for links to short courses, including Setting the Research Question and The Research Protocol.
- It is good practice (and discipline) now to publish a trial protocol before starting the trial. You can also search publication databases for published protocols to help guide your trial design.
Identify a sponsor or funder
- A clinical trial sponsor is an individual, company or institution that accepts responsibility to initiate, help manage or finance the trial but does not necessarily carry out the investigation. The sponsor may or may not be the funder. You will need to understand the remit and scope of funding schemes for different funders. This will save time and assure that you apply to the right scheme and funder. The Global Health Network has a tool called Site Finder which is for research groups and sponsors/funders to find each other!
- To approach a sponsor, you will need a proposal outline of your plan.
- As for the protocol, the proposal describes:
- why it is important to answer your research question.
- how the trial will answer the research question.
- how you plan to design the trial so that the outcome will accomplish those goals
- the anticipated impact of your answer and your target audience.
Plan
Planning a malaria clinical trial has several components from the initial idea, developing a question, undertaking a risk assessment, obtaining research ethics and other approvals for the trial and all the organisation that needs to happen before initiating activities at the clinical site(s). The Global Health Network has a very useful interactive Process Map to take you though these extensive planning stages.
Risk assessment
- Risk management planning should take as much priority as project planning . The goal is to assure that the study is carried out correctly so that the outcomes are reliable and valid, and participants are safe. Plans will be put in place for monitoring participant safety and reporting safety data according to sponsor, ethics committee and regulatory authories
- Any risks to the safety of patients and those who carry out the study, and to the integrity of the data should be identified in advance where possible so they may be mitigated.
- Data collected during the study must be reliably and correctly gathered, carefully entered into the appropriate clinical record form and safely secured. If that is not done, the study cannot fulfill its purpose.
Set up trial monitoring & management activities
- Adequate trial oversight & monitoring ensures that trial participants are safe and appropriate results are reported at the end of the trial. The trial sponsor needs to assure oversight of the trial to ensure that personnel are following the protocol and performing the procedures, handling data as planned. The sponsor will also ensure that an independent monitor is identified to review the trial conduct and if the trial is being conducted as planned in the protocol and according to local and international ethical and quality standards.
- The invesigational team, meanwhile, is expected to work within its own project management and quality assurance plans, including any necessary quality control checks, and act on any points identified by the monitor within a specified time frame.
- It may be necessary to establish an independent trial data and safety monitoring committee to review the protocol and interim analyses.
- A trial steering committee can also be selected to manage any scientific decisions that might arise during the trial and is advised by the trial monitoring committee.
Data management plan
- Good data management practices are key to the success of a clinical trial so we have included tools to help with the development of data management plans, and the selection & design of an appopriate database and data capturing instrument (case record form, CRF) that suits the objectives of your trial.
- To help investigators implement the Malaria Therapeutic Area Data Standard (TAUG-malaria) developed in partnership with CDISC we are delighted to share a standardised CRF within the Toolkit, which facilitates the collection of relevant clinical data according to CDASH (Clinical Data Acquisition Standards Harmonization) standards and will map the data to the SDTM (Study Data Tabulation Model). Our CDASH compliant CRF is intended to be used by those involved in the planning, collection, management and analysis of antimalarial clinical trials and clinical studies to ensure compliance to relevant regulatory requirements for submission. We also hope it will promote data interchange allowing data to be pooled and shared, and ensure that clinical malaria data is appropriately archived and available for further analysis and reporting.
- Think of quality control procedures, including how you will ensure data completeness. And checks on instruments and human procedures - for example, how will the quality of microscopic counting of malaria parasites in blood samples be assured? Consider use of electronic versus paper data capturing methods. All of these should aim to ensure clean and accurate data as per the protocol.
- The decision about which data management system to use will depend on its cost and complexity; choose one that fits the expertise within your institution, is cost-effective and suits the study needs. If needed, we have developed a freely-available REDCap template database compatible with our template CRF - please see our information sheet for details of how to access this.
Trial registration
- A trial register is a platform for registering clinical trials that provides accessible information about the trial to researchers, patients and the general public.
- Registering a trial is a legal requirement in most countries, and should be done even if not required.
- Another incentive for trial registration is that many journals do not publish results from trials that were not registered at the time the first patient was enrolled. Most funders also require that the trials they fund should be registered.
- Trial registration also reduces selective publication of clinical trial results since it is known from the onset what the trial design is. Even if the trial outcome is not what was hoped for (the new drug is not efficacious!), this is still important information.
Ethical and regulatory approvals
- Prior to commencing any trial related activities including screening and recruitment, the trial protocol should be submitted to an ethics committee for review. In addition, you may need to submit to the national regulatory authority or other interested parties. The US National Institute for Allergy and Infectious Diseases (NIH) has an excellent online database of trial regulatory requirements around the globe called ClinRegs.
- These committees will give their opinion on the proposed participant involvement and whether activities are ethical and safe.
- Sometimes both local ethics committee and an ethics committee at the institution of the sponsor need to approve the trial.
- Submissions to committees should be done in good time to allow adequate time for review, especially as some require to see the other's approval before they give their final approval!
If you are interested in resources relating to global health research ethics see Global Health Bioethics, Research Ethics and Review.
Execute
This involves the daily activities of conducting a malaria clinical trial.
Site preparation & engagement
- Preparation of the site should include making sure that all required facilities at the site are adequate for the trial, including any necessary equipment and consumables.
- Make sure all trial documentation necessary at the time of trial start is filed appropriately, and that enough appropriately qualified research staff have been recruited and trained (including in Good Clinical Practice) so that they know what the study is about and what their own role is. There are plenty of template procedures in the drop down below for preparing for trial conduct, for simple and more complex trials.
- Engage the community from which your participants will come. Identify leaders who can facilitate community engagement and support those who could participate to understand why the trial is being done and how the community may benefit. Make sure that this can be done in the local language(s). Encourage and leave time for questions. Many organizations have communications experts who can help with this and there are good resources relating to community engagement such as on MESH site.
Informed consent
- Participants must give informed consent before any trial procedures are undertaken. The trial information sheet and informed consent form must be approved together with the protocol by an ethics committee. See our template information and consent form in the drop down menu below which can form the basis of your own form for a malaria efficacy trial. We've included some suggested text to cover the relatively new area of data sharing (in anticipation for secondary data analysis).
- In malaria-endemic settings where some participants cannot write, a finger print may be used instead of a signature, as long as a literate witness is there to assure the information given was accurate.
- Consent is an on-going process, participants should continuously be asked for their willingness to continue taking part in the trial and assured that withdrawal will not mean that they will not be treated for their illness. Changes to the trial protocol affecting the participants should be communicated to them in a new approved informed consent process.
- In certain circumstances, such as with children (minors) or for incapacitated persons, a legal representative (a person who is able to consent to treatment) can give consent. In some studies older children may also need to give their assent.
Recruitment & retention
- Once consent to participate is given by a participant or their legal representative, enrolling the participant into the study is the next step. Make sure all baseline data and documentation are complete. If key patient variables are missing, it may be impossible to retrieve the information later on.
- Retention of participants for the needed follow up visits is crucial, so procedures like telephone reminders/visiting non-responders at their homes can improve retention. Community enthusiasm also helps and Malaria Control Programmes may agree to follow up participants who do not return for a visit.
- Money to compensate for time lost in attending the clinic for trial procedures improves participation retention. This should be explicit in the information given to the participant and approved by the ethics committee.
Investigational Product
- Clinical trials involve administering an investigational product such as an antimalarial drug once a participant gives consent to take part in the trial.
- It is important to make sure that the investigational product is securely stored under the correct conditions (e.g. correct temperature), and procedures are available as to how to handle the drug, especially if any dilutions are necessary.
- Additionally, documented procedures on dosing, specifiying whether it should be taken with or without food, and what to do if a participant vomits the study drug, should be well understood by the staff therefore they should be thoroughly trained in all these issues.
- Accountability of investigational product is a key component in clinical trials. It is good practice for the clinical trial pharmacist to document all stocks of the investigational product and be able to account for all drugs issued to participants in the clinic.
Clinical processes
- A malaria clinical trial relies on various clinical assessments from the time of screening to the end of participant's follow up. Each of these processes should be performed according to the trial requirements so that they are consistent and accurate. However, most such processes (like taking a temperature or weight, both critical for malaria trials, and performing ECGs) are quite standard, so we've included some templates for those
- We've also added some malaria-specific guidelines for collecting samples for smears and various antimalarial drug pharmacology analyses (plus some general guidance on collecting samples by various means: finger prick, heel stick, venipuncture)
- As it is important to have qualified staff equipped with the necessary skills to handle any medical situations that might arise during participant follow up, and some regulatory authorities expect the site to have a standard procedure for dealing with medical emergencies, we have included some relevant template procedures for these.
- Sites may also like to have standard processes in place for staff to identify and manage certain medical conditions such as treatment failure and haemolysis
Laboratory processes
- Most antimalarial safety, efficacy and pharmacokinetic malaria clinical trials have a laboratory component and, indeed, often this forms the bulk of the trial procedures
- It is important to therefore define the different laboratory processes that a participant is supposed to go through while participating in the trial, and these have to be well understood by all research team members involved. Sample collection can easily be missed during a clinical trial and this affects conclusions made from such studies. It is good practice to have well documented standard operating procedures that define how to conduct each such laboratory procedure, whether at the clinic or laboratory (analytical) level. See the Clinical Processes section above for sampling-related procedures and this section for laboratory-level procedures. You will find some related videos for these in our News and Information section.
- Should staff need training in laboratory-related activities, visit Global Health Laboratories and the Global Health Network's Training Centre for online course, including the World Health Organization (WHO) Basic Malaria Microscopy and Good Clinical Laboratory Practice options.
Progress & safety reporting
- The sponsor is responsible for the safety evaluation of investigational products, while the investigator monitors his/her participants for any medical issues which are then managed appropriately. In addition, there may be a Data Safety Monitoring Board (or equivalent) appointed to periodically review the trial results and advise the sponsor and investigator on any safety concerns.
- Progress reports on the trial may then need to be send to various stakeholders, such as ethics committee, regulatory authorities and funders. These often require a summary of any safety concerns, including listings of adverse events observed at sites.
- Standard operating procedures relating to safety should be finalised before the study begins so that all staff understand their role, including how to manage and report adverse events.
- See Global Pharmacovigilance for additional open access resources for monitoring safety during your trial.
Analyse
Analysis of malaria clinical trials data starts with developing a statistical analysis plan which then informs both interim and final data analyses
Statistical analysis plan
- A statistical analysis plan is a detailed outline of how the data will be analyzed (including any interim analyses).
- Although mentioned at this stage of the pathway, it is planned at the time of designing the malaria trial.
- It ensures all planned hypotheses will be evaluated in a manner that is scientifically valid and that appropriate documentation is done during the data collection.
- It further explains how results will be reported.
Defining analytical tools
- It is good practice to decide on the analytical softwares and tools that you will use to analyse your data. This has to be explained in the statistical analysis plan.
- There is a variety of these resources and consideration has to be made on what will offer you the optimal output to help you intepret your data.
- WWARN has developed several resources that can help analyse and interpret clinical and laboratory data.
Report
Malaria clinical trial reports can comprise of trial summary reports, manuscript for publication or any materials used for disseminating findings of the trial.
Trial report and dissemination of findings
- At the end of the malaria trial, a report summarizing the results based on the analysis as planned is presented. This can be presented to funders and/or the sponsor and form the basis of manuscripts for publication. It is very useful to follow recognised reporting guidelines, such the CONSORT Guidelines for randomised trials (part of the EQUATOR Network outputs), when publishing results, as these ensure all the relevant information needed for readers to assess the trial is included. Publishing negative outcomes is as important as positive ones.
- Decide who your target audiences are and engage with relevant audiences to inform them of your findings, and to collaborate on how best to share your data to inform the wider malaria community. Many organizations have communications experts who can help with this and there are good resources relating to community engagement such as on MESH site.
End of trial processes
These processes involves close up activities of a malaria clinical trial such as the final monitoring visit and archiving of study data or samples.
Close up monitoring visit
- At the end of the trial the monitor visits the site(s) to work with staff to conclude any trial activities. This ensures that standards for trial conduct are adhered to until the end of the trial and that all data are collected, any onoing safaty concerns are discussed, that there is a plan for what to do with remaining equipment and consumables, and the trial documentation.
- It is also important also to have an early termination plan, to allow easy close down when advised to terminate the trial by the data monitoring committee e.g. due to safety concerns.
- All relevant stakeholders are then contacted as to the final status of the trial, registers are updated as such, and plans made for publication.
Archiving of data & samples
- Data collected during the malaria trial should be archived according to a documented process.
- The period of archiving will depend on local and international expectations.
- If biological samples are retained this should be enacted as per the protocol, informed consent process etc.
- It is also good practice to have data sharing policies in place, to allow re-usability of the data, and to assure that the primary data are securely held in a long term archive, not just on your laptop!