Malaria Clinical Trials Toolkit

A clear and precise research question is the most important aspect and starting point of any malaria clinical trial.

• 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 organisations who might use your evidence. Is the information most useful to a local, regional, national or international audience?

View the related resources

Tool

ACT Partner Drug Molecular Surveyor

Publication 

Methods and techniques for assessing exposure to antimalarial drugs in clinical field studies

Tool

SP Molecular Surveyor

Tool

Artemisinin Molecular Surveyor

• 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.

View the related resources

Publication

Methods and techniques for assessing exposure to antimalarial drugs in clinical field studies

Document

P. vivax Drug Efficacy: Protocol Template

Document

WHO Template Protocol For Therapeutic Efficacy Studies

• 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 ensure 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.

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 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.

View the related resources

Procedure

SAF06

General evacuation of the clinical trial facility

A process for the evacuation of a clinical trial facility in the event of a non-medical emergency

Version: v2.0 Author: WWARN

Procedure

SAF02

Evacuating a patient in the event of a medical emergency

A process for safely evacuating a patient due to a medical emergency from the clinical trial facility

Version: 2.0 Author: WWARN

Procedure

SAF03

Post-exposure prophylaxis in the clinical trial facility

A process for dealing with inadvertent exposure to potentially infectious fluids during a clinical trial

Version: 2.0 Author: WWARN

Procedure

QA07

Trial risk assessment (by the site)

A process for assessing the risk of an institutional team conducting a trial

Version: 2.0 Author: WWARN

Procedure

SAF01

Safety assessment and reporting

A process for the identification, management, assessment, and reporting of adverse events/adverse drug reactions

Version: v1.0 Author: WWARN

• Adequate trial oversight and 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.

View the related resources

Procedure

AD02

Set up and maintenance of the Investigator Site File

A process for sites for generating important documents and a systematic filing system

Version: 2.0 Author: WWARN

Procedure

QA10

Organising trial initiation meetings

A process for when the trial site arranges the initiation meeting/visit for a trial

Version: 2.0 Author: WWARN

Procedure

QA09

Trial staff training

A process for how training of trial staff will be planned and documented

Version: 2.0 Author: WWARN

Procedure

AD03

Identifying critical suppliers of trial services

A process for sites to use when identifying and managing critical service providers/vendors

Version: 2.0 Author: WWARN

Procedure

AD01

Clinical trial project management

Some basic guidelines for team members responsible for project management

Version: 2.0 Author: WWARN

Procedure

QA02

Standard operating procedure management

A process for authorship, review, authorisation, issue and control of standard operating procedures by a site

Version: 2.0 Author: WWARN

Procedure

QA03

Non compliance

A process for sites for identifying, documenting and reporting non-compliance during a clinical trial

Version: 2.0 Author: WWARN

Procedure

QA04

Site handling of monitoring visits

A process for sites to use to help staff involved with attending or arranging monitoring visits

Version: 2.0 Author: WWARN

Procedure

QA05

Pre-trial site assessment

For when an investigator/institution may take responsibility for selecting sites for a clinical trial

Version: 2.0 Author: WWARN

Procedure

QA06

Set up and maintenance of the Sponsor File

For when an investigator/institution takes responsibility for setting up and maintaining the sponsor file

Version: 2.0 Author: WWARN

Procedure

QA08

On-site monitoring

For when an investigator/institution takes responsibility for on-site monitoring of a clinical trial

Version: 2.0 Author: WWARN

Procedure

QA01

Quality management plan (clinical conduct)

A system for applying quality management at the trial site so there is effective compliance with sponsor, applicable regulatory and ethical requirements

Version: 2.0 Author: WWARN

• 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) (link is external)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.

View the related resources

Procedure

DMSTAT02

Database construction, security, backup, close and lock

Construction, security and backup of a clinical database

Version: 2.0 Author: WWARN

Procedure

DMSTAT03

Data receipt, entry and validation

Receiving, data entry and validating data within a clinical trial

Version: 2.0 Author: WWARN

Document

Clinical Data Management and Analysis Plan

Document

In Vitro Data Management and Statistical Analysis Plan

Document

Pharmacology Data Management and Statistical Analysis Plan

Document

Molecular Data Management and Statistical Analysis Plan

Procedure

Malaria Case Record Form (CRF)

Malaria Clinical Trial Case Record Form

Version: 2.0 Author: WWARN

Page

CDISC malaria therapeutic area data standard (TAUG-malaria)

Procedure

AD11

Data recording by clinical trial staff

A process for how clinical trial staff should record source and Case Record Form (CRF) data for trials

Version: 2.0 Author: WWARN

Procedure

DMSTAT01

Data management protocol generic

Instruction to those data management team members delegated responsibility for producing and working on a data management protocol

Version: 2.0 Author: WWARN

Procedure

DMSTAT04

Serious adverse event data reconciliation

For when there is a need to reconcile safety data that are stored in two different databases during a clinical trial

Version: 2.0 Author: WWARN

Procedure

PHA_DM03

Master validation plan

For listing and documenting the objectives for all parties responsible for validation of computer equipment and software for a clinical trial

Version: v1.0 Author: WWARN

Procedure

Data management tables for standard efficacy analysis

These are template database tables for use in a typical malaria efficacy trial analysis

Version: v2.0 Author: WWARN

Document

Building an electronic data management system using the WWARN annotated Case Record Form

Procedure

WWARN Malaria Data Dictionary

Understand the data variables in data files

Version: 1.0 Author: Kalynn Kennon

Document

Data handling and analysis convention ECG data (malaria)

• 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.

View the related resources

Document

Trial registration

• 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.

This involves the daily activities of conducting a malaria clinical trial.

• 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.

View the related resources

Procedure

AD04

General preparation for clinical trial conduct

A process for ensuring that stock, equipment, documentation, staff and venue are adequately prepared for a new clinical trial

Version: 2.0 Author: WWARN

Procedure

QA10

Organising trial initiation meetings

A process for when the trial site arranges the initiation meeting/visit for a trial

Version: 2.0 Author: WWARN

Procedure

AD07

Preparing for scheduled trial admission periods

A process for ensuring that issues such as stock, equipment, staff, participants and venue are adequately prepared for scheduled ward admission periods

Version: 2.0 Author: WWARN

Procedure

AD09

Pre- and post-admission team meetings

The rationale and conduct of pre- and/or post-admission team meetings which help ensure the trial team works together correctly and efficiently

Version: 2.0 Author: WWARN

Procedure

AD11

Data recording by clinical trial staff

A process for how clinical trial staff should record source and Case Record Form (CRF) data for trials

Version: 2.0 Author: WWARN

Procedure

QA09

Trial staff training

A process for how training of trial staff will be planned and documented

Version: 2.0 Author: WWARN

Procedure

AD08

Clinical conduct of scheduled admission periods

A process for ensuring that scheduled ward admission periods are conducted appropriately

Version: 2.0 Author: WWARN

Procedure

SAF06

General evacuation of the clinical trial facility

A process for the evacuation of a clinical trial facility in the event of a non-medical emergency

Version: v2.0 Author: WWARN

Procedure

SAF02

Evacuating a patient in the event of a medical emergency

A process for safely evacuating a patient due to a medical emergency from the clinical trial facility

Version: 2.0 Author: WWARN

Document

Training materials for obtaining accurate malaria case GPS coordinates

• 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.

View the related resources

Procedure

AD06

Informed consent

A suggested process for how informed consent may be obtained from competent adults in a typical antimalarial clinical trial

Version: 2.0 Author: WWARN

• 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.

View the related resources

Procedure

AD05

Screening visits

A process for preparing for and conducting participant screening during a clinical trial

Version: 2.0 Author: WWARN

Procedure

AD06

Informed consent

A suggested process for how informed consent may be obtained from competent adults in a typical antimalarial clinical trial

Version: 2.0 Author: WWARN

Procedure

AD10

Follow-up visits

A process for preparing for and conducting participant follow-up visits during a clinical trial

Version: 2.0 Author: WWARN

• 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.   

View the related resources

Procedure

CL17

Collection of samples for pyronaridine pharmacology analysis

These guidelines aim to standardize the sample collection procedure during clinical studies of pyronaridine antimalarial drugs

Version: 2.0 Author: Chris Lourens

Procedure

IP01

Central receipt of investigational product

For when a PI/institution may need to receive investigational product (study drug) for several sites at a central location before they are allocated to individual sites

Version: 2.0 Author: WWARN

Procedure

IP02

Packaging and labeling investigational products/study drugs

Generating labels for, and packaging, investigational product/study drug (IP) by the trial site in accordance with a typical Good Pharmacy Practice guideline

Version: 2.0 Author: WWARN

Procedure

IP03

Dispensing, dosing and return of investigational product/study drug

Dispensing and dosing of investigational products/study drugs and their return to a pharmacy/drug store for a clinical trial.

Version: 2.0 Author: WWARN

Procedure

IP04

Disposal of investigational products/study drugs

Returning investigational products/study drugs to the sponsor or arranging for their destruction at the trial site

Version: 2.0 Author: WWARN

Procedure

IP05

Randomisation and blinding

Ensuring integrity of the trial through a randomisation and blinding process

Version: 2.0 Author: WWARN

• 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

View the related resources

Procedure

CL13

Collection of blood by peripheral venipuncture

Collecting peripheral blood samples

Version: 2.0 Author: WWARN

Procedure

CL11

Collection of blood by finger prick or heel stick

Obtaining fingerprick and heel stick blood samples for preparing thick/thin blood smears and filter paper samples

Version: 2.0 Author: WWARN

Procedure

MOL03, CLI06

Filter paper preparation for molecular genetic analysis

Preparing and preserving dried blood spot samples for genetic analysis

Version: v1.2 Author: WWARN

Procedure

EXT01

Collection of blood on filter paper

Molecular Testing for Malaria - preparing dried blood spots by finger prick

Version: 1.0 Author: Mekong Molecular Surveillance Network

Publication

Methods and techniques for assessing exposure to antimalarial drugs in clinical field studies

Procedure

CL18

Collection of samples for amodiaquine / desethylamodiaquine pharmacology analysis

These guidelines aim to standardize the sample collection procedure during clinical studies of amodiaquine / desethylamodiaquine antimalarial drugs

Version: 2.0 Author: Chris Lourens

Procedure

CL19

Collection of samples for lumefantrine / desbutyl-lumefantrine pharmacology analysis

These guidelines aim to standardize the sample collection procedure during clinical studies of lumefantrine / desbutyl-lumefantrine antimalarial drugs

Version: 2.0 Author: Chris Lourens

Procedure

CL20

Collection of samples for mefloquine / carboxymefloquine pharmacology analysis

These guidelines aim to standardize the sample collection procedure during clinical studies of mefloquine / carboxymefloquine antimalarial drugs

Version: 2.0 Author: Chris Lourens

Procedure

PHA08

Guidelines for the collection of samples for piperaquine pharmacology analysis

These guidelines aim to standardize the sample collection procedure during clinical studies of piperaquine antimalarial drugs

Version: 1.0 Author: Chris Lourens

Procedure

CL21

Guidelines for the collection of samples for primaquine / carboxyprimaquine pharmacology analysis

These guidelines aim to standardize the sample collection procedure during clinical studies of primaquine / carboxyprimaquine antimalarial drugs

Version: 2.0 Author: Chris Lourens

Procedure

CL22

Collection of samples for artemisinin pharmacology analysis

These guidelines aim to standardize the sample collection procedure during clinical studies of artemisinin antimalarial drugs

Version: 2.0 Author: Chris Lourens

Procedure

CL14

Blood PK sample processing and transport

A process for taking pharmacokinetic samples from the participant through an interim processing laboratory and onto an analytical laboratory

Version: 2.0 Author: WWARN

Procedure

CL16

Extraction and storage of genetic material

A general process for collecting and processing of genetic material from blood samples in clinical trials

Version: 2.0 Author: WWARN

Procedure

CL15

Urine PK sample processing and transport

A process for collecting and sampling for urine pharmacokinetic measurements in clinical trials

Version: 2.0 Author: WWARN

Procedure

CL09

Management of acute haemolysis (low dose primaquine)

A simplified process for field site staff to identify and manage any cases of suspected acute haemolysis in a clinical trial (such as trials involving low-dose primaquine)

Version: 2.0 Author: WWARN

Procedure

CL03

Collection of ECG data in antimalarial clinical trials

A general process for collecting the standard 12-lead clinical trial ECG data, to support any trial-specific instructions

Version: 1.2 Author: WWARN, Banook Group & LSTM

Procedure

CL01

Measuring temperature by ThermoScan

A procedure for measurement/recording of tympanic membrane temperature using the Braun ThermoScan in participants enrolled in malaria drug trials

Version: 2.0 Author: WWARN

Procedure

CL02

Digital measurement of axillary temperature

A process for measurement and recording of axillary body temperature of participants enrolled in malaria drug trials

Version: 2.0 Author: WWARN

Procedure

CL04

Measuring body weight

A process for calibrating scales, measuring and recording weight of participants enrolled in malaria drug trials

Version: 2.0 Author: WWARN

Procedure

CL05

Measuring respiratory rate

A process for measuring and recording respiratory rate in participants enrolled in an antimalarial drug trial

Version: 2.0 Author: WWARN

Procedure

CL06

Management of hyperparasitaemia

A process for case management of patients with hyperparasitaemia in field malaria drug trials

Version: 1.0 Author: CCOAT

Procedure

CL07

Late antimalarial treatment failure

A process for case management of patients with uncomplicated malaria who fail first line treatment in antimalarial drug field trials

Version: 1.0 Author: CCOAT

Procedure

CL08

Management of acute hemolysis (primaquine for P vivax)

An approach to managing suspected haemolysis in participants taking part in trials using primaquine for P vivax infection

Version: 1.0 Author: IMPROV trial group

Procedure

SAF01

Safety assessment and reporting

A process for the identification, management, assessment, and reporting of adverse events/adverse drug reactions

Version: v1.0 Author: WWARN

Document

Collection of participant-reported safety data in antimalarial trials

• 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. There are also related videos for these procedures.
• 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.

View the related resources

Procedure

MOL01

Sample Preservation

Collecting and preserving DNA, RNA and parasite isolates from infected blood samples

Version: v1.5 Author: WWARN

Procedure

MOL02

Leukocyte Depletion of Whole Blood Using CF11 Columns

Version: v1.3 Author: WWARN

Procedure

INV02

Preparation of Culture Medium

Preparing complete medium for Plasmodium falciparum cultures

Version: v1.1 Author: WWARN

Procedure

INV04

Synchronisation of Plasmodium falciparum

Synchronising culture adapted Plasmodium falciparum isolates in ring stage

Version: v1.1 Author: WWARN

Procedure

INV01

Culture of Plasmodium falciparum blood stages

Methods for short- and long term culture of Plasmodium falciparum laboratory strains and fresh isolates

Version: v1.0 Author: WWARN

Procedure

MOL06

DNA Extraction: Preparing Rapid Diagnostic Tests

Storing and processing malaria Rapid Diagnostic Tests (RDTs) for DNA extraction

Version: v1.1 Author: WWARN

Procedure

MOL05

Copy number estimation of the Plasmodium falciparum pfmdr1 gene

Estimating pfmdr1 gene copy number by real-time PCR

Version: v1.1 Author: WWARN

Procedure

INV03

Preparation of drug plates for susceptibility assays

Preparation of drug dilutions in dry or fresh plates for drug susceptibility assays

Version: v1.2 Author: WWARN

Procedure

INV07

Estimation of Plasmodium falciparum drug susceptibility by the 3H-hypoxanthine uptake inhibition assay

Drug susceptibility assay measuring radioactive hypoxanthine uptake in laboratory strains and fresh isolates.

Version: v1.0 Author: WWARN

Procedure

CL10

Preparing malaria blood smears

Preparing thick and thin blood smears with Giemsa staining

Version: 2.0 Author: WWARN

Procedure

INV09

Estimation of Plasmodium falciparum drug susceptibility ex vivo by HRP2 ELISA

Drug susceptibility assay measuring histidine-rich protein production by ELISA in fresh isolates

Version: v1.0 Author: WWARN

Procedure

INV08

Estimation of Plasmodium falciparum drug susceptibility by the SYBR® Green assay

Drug susceptibility assay measuring SYBR®Green I fluorescence in laboratory strains and field isolates

Version: 1.0 Author: WWARN

Procedure

EXT02

DNA extraction by Chelex

Extracting Plasmodium spp. DNA from dried blood spots by Chelex 100

Version: 1.0 Author: Mekong Molecular Surveillance Network

Procedure

EXT03

DNA Extraction by QIAamp DNA Mini Kit

Extracting Plasmodium spp. DNA from dried blood spots by QIAamp DNA Mini Kit

Version: 1.0 Author: Mekong Molecular Surveillance Network

Procedure

EXT05

msp1 PCR

PCR amplification of the polymorphic marker msp1 to distinguish recrudescences from reinfections

Version: 1.0 Author: Mekong Molecular Surveillance Network

Procedure

EXT09

msp2 PCR

PCR amplification of the polymorphic marker msp2 to distinguish recrudescences from reinfections

Version: 1.0 Author: Mekong Molecular Surveillance Network

Procedure

EXT06

glurp PCR

PCR amplification of the polymorphic marker glurp to distinguish recrudescences from reinfections

Version: 1.0 Author: Mekong Molecular Surveillance Network

Procedure

EXT08

Manual size estimation of msp1, msp2 and glurp PCR products on gel

Manually determining the size of Plasmodium falciparum polymorphic markers to distinguish recrudesent from reinfecting infections in clinical trials

Version: 1.0 Author: Mekong Molecular Surveillance Network

Procedure

EXT07

Agarose Gel Electrophoresis of msp1, msp2 and glurp

Separating and visualising amplified PCR products of msp1, msp2 and glurp

Version: 1.0 Author: Mekong Molecular Surveillance Network

Procedure

INV10

Ring-stage Survival Assays (RSA) to Evaluate the In-Vitro and Ex-Vivo Susceptibility of Plasmodium Falciparum to Artemisinins

Evaluting Plasmodium falciparum susceptibility to artemisinins in laboratory strains and fresh isolates

Version: v1.2 Author: Institut Pasteur du Cambodge & National Institute of Allergy and Infectious Diseases/NIH

Procedure

MOL08

PCR and sequencing for genotyping of candidate Plasmodium falciparum artemisinin resistance SNPs in the Kelch 13 gene

Genotyping of SNPs in the Kelch 13 gene (PF3D7_1343700), associated with artemisinin resistance

Version: 1.0 Author: D. Menard & F. Ariey Institut Pasteur

Publication

Methods and techniques for assessing exposure to antimalarial drugs in clinical field studies

Procedure

EXT10

Microscopy for the detection, identification and quantification of malaria parasites on stained thick and thin blood films in research settings

This manual was developed to guide a move towards common standards for undertaking and reporting research microscopy for malaria parasite detection, identification and quantification.

Version: 1.0 Author: Research Malaria Microscopy Standards Working Group

Procedure

EXT11

Guidelines for the Cryopreservation of field isolates

The purpose of this document is to standardize the methodology for cryopreservation of malaria parasites using glycerolyte

Version: 1.0 Author: Dr. Kesinee Chotivanich

• 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.

View the related resources

Procedure

SAF01

Safety assessment and reporting

A process for the identification, management, assessment, and reporting of adverse events/adverse drug reactions

Version: v1.0 Author: WWARN

Analysis of malaria clinical trials data starts with developing a statistical analysis plan which then informs both interim and final data analyses

• A statistical analysis plan is a detailed outline of how the data will be analysed (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.

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Procedure

Data management tables for standard efficacy analysis

These are template database tables for use in a typical malaria efficacy trial analysis

Version: v2.0 Author: WWARN

• 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.

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Tool

IVART

Online automated tool that can quickly produce accurate and reproducible estimations of antimalarial drug efficacy, known as IC50 estimations.

Page

IVART Methodology

Tool

Parasite Clearance Estimator (PCE)

Consistent and reliable method to estimate the rate of parasite clearance from patients - a vital tool for assessing signs of change in antimalarial drug efficacy. Version 2.0

Document

IVART data template

Document

IVART example tagging

Document

IVART step-by-step guide

Tool

Obare Method Calculator

High quality microscopic examination of stained blood films continues to be a major reference standard for the detection, identification and quantitation of malaria parasites in research.

Document

The Obare Method Calculator

Procedure

Data management tables for standard efficacy analysis

These are template database tables for use in a typical malaria efficacy trial analysis

Version: v2.0 Author: WWARN

Procedure

PHA09

WWARN Piperaquine PK PD Study Group NONMEM code

NONMEM code for Piperaquine PK/PD Study Group

Version: 1 Author: Junjie Ding & Joel Tarning

Procedure

PHA10

WWARN Antimalarial – Lumefantrine POP/PK Study Group NONMEM codes 1 & 2

NONMEM code for Antimalarial – Lumefantrine POP/PK Study Group

Version: 1 Author: Junjie Ding and Joel Tarning

Procedure

WWARN Amodiaquine PK/PD Study Group NONMEM code

Author: Ali Mohamed Ali and Paolo Denti

Malaria clinical trial reports can comprise of trial summary reports, manuscript for publication or any materials used for disseminating findings of the trial.

• At the end of the malaria trial, a report summarising 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 organisations have communications experts who can help with this and there are good resources relating to community engagement such as on MESH site.

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

• 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.

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Procedure

QA04

Site handling of monitoring visits

A process for sites to use to help staff involved with attending or arranging monitoring visits

Version: 2.0 Author: WWARN

Procedure

QA08

On-site monitoring

For when an investigator/institution takes responsibility for on-site monitoring of a clinical trial

Version: 2.0 Author: WWARN

Procedure

AD13

Communicating end of trial results to participants

A suggested process for communicating end of trial results to people who took part in a typical antimalarial drug trial

Version: v1.0 Author: WWARN

• 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!

View related resources

Procedure

AD12

Archiving of clinical trial Essential Documents

A process for archiving Essential Documents generated during a malaria clinical trial

Version: 2.0 Author: WWARN