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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

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  must address gaps in what is known, so you need to understand in depth what has been done already.  An in depth  review of previous and ongoing work is key. Check trial registers (see examples of registers in toolbox) as well as published literature through PubMed and other databases.
 
  • For example, if the overall efficacy of a drug in whole populations of people, you might address its efficacy in particular in young children or some other specific group. 
 
  • Your question should It should generally include specific information on (Participant–Intervention–Comparator–Outcome) 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 protocol can be seen as a detailed description of the components suggested in the proposal. It also details all the trial processes for trial staff to follow in order to carry out the clinical trial. Usually a protocol is presented to an ethics committee for approval. Both proposal & protocol can be developed at the same time.
 
  • Make sure you choose the right design that will answer the questions raised in an unbiased way.
 
  • It is good practice (and discipline) to publish a trial protocol before the actual trial report/results come put

Identify a sponsor

  • 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
 
  • Identifying a sponsor is therefore one of the earliest things to do when planning  to conduct a malaria clinical trial. 
 
  • To approach a sponsor, you will need a proposal  outline of your plan
 
  • The trial 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.

Identify a funder

  • You must 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.
 
  • Read instructions carefully. Engage with the funder if they allow it, and ask for clarification where needed. If you can, find a colleague who has been successful in gaining funding from that organization to benefit from their experience.
 
  • Give yourself enough time to prepare an application and especially allow for internal peer review. Colleagues are a real resource.
 
  • Preparation of a sensible budget that fits the needs of the planned trial and the specifications of the funder.  Here, too, consult colleagues.

Plan

Planning a malaria clinical trial has several components that span from risk assessment, once the question is defined, to obtaining research ethics approval for the trial.

Risk assessment

  • Risk management planning should take as much priority as project planning . Your goal is to assure that the study is carried out correctly so that the outcomes are reliable. 
 
  • Any risks to the safety of patients and  those who carry out the study and to the integrity of the data must all be addressed.  This is best done by working with a senior colleague who can alert you to particularly vulnerable facets of your protocol and help you identify steps to avoid the problem . The patient safety aspects will have been addressed  in the proposal  assessed during ethical clearance.
 
  • 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 identified trial sponsor ensures that an independent trial (data) and safety monitoring committees are set up to review interim analysis. Additionally the sponsor also ensures that an independent monitor is identified to audit the trial conduct: is the trial being conducted as planned in the protocol?
 
  • Consideration should be given to setting up a trial management team which runs the daily activities of the trial. This often includes logistics - making sure that all of the needed supplies are on had at the  right time.
 
  • 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

 

  • As part of trial management activities, remember to set up quality control methods for different procedures and activities within the trial. This helps to prevents mistakes and errors that could bias your results. For example, when a research staff member completes a case record form, there has to be a defined process in place on who will check the form and what they will be looking for. This also applies to laboratory and investigational product related activities.  

Data management plan

  • Good data management practices are key to the success of a clinical trial
 
  • Develop a data management plan, select & design a database, and design a data capturing instrument (case report form) that suits the objectives of your trial
 
  • Think of quality control procedures, including how you will ensure data completeness. And checks on instruments  and human procedures. For example how will 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 protocol.
 
  • Decision on which data management system to use will depend on cost and complexity of the system. Chose a system that fits the expertise within your institution, is cost effective and suits your needs. Try out any capture system and CRF on people who may be part of the actual team.

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, should be done even if not required.
 
  • Another incentive for trial registration is that journals do not publish any data from trials that were not registered at the time the first patient was enrolled. 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 outcomes are. Even if the trail outcome is not what was hoped for (the new drug is not efficacious!), this is still important information.

Ethical approval

  • Prior to commencing any trial related activities including screening and recruitment,  the trial protocol should be submitted to an ethics committee for review
 
  • This committee will give their opinion on the proposed participant involvement and on whether the proposed activities are ethical and safe.
 
  • Usually both local committee and a 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

 

 

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 to the study needs and ready to go.
 
  • Make sure all standard operating procedures (SOPs), case report forms and all necessary trial documentation are filed appropriately, and that research staff have been recruited and trained  to ensure they know what the study is about including where to find the appropriate tools such as SOPs for reference. Study staff must also be trained in Good Clinical Practice
 
  • 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  study is being done and how all in the community may benefit.  Make sure that this can be done in the local language(s). Encourage and leave time for questions.

Informed consent

  • Participants must give an informed consent before any trial procedures are undertaken. Trial information sheet and informed consent form must be approved together with the protocol by an ethics committee.
 
  • In malaria endemic settings where participants cannot write, a finger print should be used instead of a signature
 
  • 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 trial protocol affecting the participants  should be communicated to them
 
  • In certain circumstances, such as in children (minor) or for incapacitated person, 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 is impossible  to retrieve the information.
 
  • Retention of participants in 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
 
  • Other incentives such as money to compensate for time lost in attending the clinic for trial procedures improve retention. These need to be explicitly included in the protocol  approved by the ethical  committee.

Investigational Product

  • Clinical trials often 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 well stored, in good temperature, and procedures on how to handle the investigational product are put in place. 
 
  • Additionally, procedures on dosing, specifiying whether with or without food, and describing what to do when a participant vomits the study drug should be well documented. Research staff should be thoroughly trained in all these procedures.

 

  • 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 out to participants in the clinic.   

Clinical processes

  • A malaria clinical trial has several clinical aspects that span from the time of screening to the end of participant's follow up.
  
  • It is important to have qualified research nurses and clinicians who are trained in various aspects of the protocol as well as procedures of the trial, and are equipped with skills to handle emergency situations that might arise during participant follow up. This is the responsibility of the Principal Investigator/Lead Investigator, which has to be reinforced by the Sponsor of the trial.
 

Laboratory processes

  •  Most antimalarial safety, efficacy and pharmacokinetic malaria clinical trials or studies have a laboratory component and often this forms the bulk of the trial follow up procedures.
  • It is important to 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. 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 study procedure

Progress & safety reporting

  • You must send progress reports of the trial to Trial Steering Committee, Ethics committee (annual report) and funders.
 
  • Trial sponsors also require progress reports including safety update reports
 
  • The sponsor is also responsible for safety evaluation of trials involving malaria investigational products such as drugs.  The Data Safety Monitoring Board is the group monitoring safety on a regular schedule.
 
  • A safety standard operating procedure for the malaria trial should be set before the study begins.

Study monitoring

  • The malaria trial sponsor needs to assure oversight of the study management to ensure that the study personnel are following the protocol  and performing the procedures and data handling as planned.
 
  • An external monitor should be identified by the sponsor to conduct a study monitoring exercise. All action points/ protocol deviations (if not documented) identified by the external monitor should be documented in a report to be shared with the sponsor and the trial staff.
 
  • The malaria trial team is expected to act on the identified points within a set time frame. This will be assured by a return visit of the trial monitor

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.
 
  • 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.

Interim analysis plan

  • This plan is drawn from the main statistical analysis plan and is a brief outline of the analysis to be done to inform the data monitoring committee on the progress of the trial as well as interim results, in order to guide them in advising on the direction of the malaria trial
 
  • It should also detail any applicable trial stopping rules that the committee should apply at interim review. Since the DSMB sees unblinded data in contrast to the study personnel, they might see a very strong adverse effect among some or even many of the patients-  the safety problem.  They could then stop the study. The stopping rules should be specified beforehand.  Equally, sometimes a new intervention is working so much better than the control - usual treatment- that a trial could be stopped since the intervention is so clearly superior.

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 summary report

  • At the end of the malaria trial, a report summarizing the results of the study based on the outcomes that were planned is presented. 
 
  • The results section of this report should be structured according to the statistical analysis plan that was developed before the trial
 
  • The report is also a first step in with dissemination of results of the trial both in reports to funders and sponsor and manuscripts for publication that can be based upon it.

Dissemination

  • The outcomes of your trial should be disseminated as widely as possible. It is unethical to avoid this step.
 
  • Aim to report results from the malaria trial according to good reporting standards (see some resources in toolbox).
 
  • Publication in a reputable journal is expected, even if the outcomes of the trial are not what you or the sponsors hoped. 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.

End of trial processes

These processes involves close up activities of a malaria clinical trial such as final monitoring visit and archiving of study data or samples.

Close up monitoring visit

  • Close to the end of the trial, it is good practice to allow for a close up monitoring visit by the sponsor or an external monitor. This ensures that standards for trial conduct are adhered to until the end of the trial
 
  • It is also important 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
 
  • Termination plans should be developed at the start of the malaria trial

Archiving of data & samples

  • Data and all samples collected during the malaria trial should be archived and a log kept in a secure place.  The PI is responsible for this step in terms of how, where and for how long.
 
  • Period of archiving should depend on the duration that the participant consented to. Each patient’s decision on time and under what conditions their data can be used should be part of the  consent form.
 
  • An archiving plan should be developed at the start of the malaria trial, especially for samples since this usually requires actions that should be part of the protocol
 
  • It is good practice to develop data sharing policies to allow re-usability of the data once it is archived and to assure that the primary data are securely held in a long term archive, not just on your laptop!