groups » Trial Management » June Issue of the Month and Ask the Expert: Quality Assurance in clinical research
This month, we’re discussing quality assurance. We are very lucky to have Barbara Malungu on hand to answer your questions. Barbara is the Ugandan Country Head of PHACT (the Public Alliance for Clinical Trials) and organiser of the African Conference on Quality in Clinical Research, which was held in Uganda earlier this year and will be in Ghana next year.
Quality Assurance is integral to all areas of clinical research, and a QA plan should be developed at an early stage in the research process. The main goals of a QA plan are to make sure that the trial is able to answer the research question, to make sure data and results are reliable, the study is conducted ethically and in compliance with the protocol and regulatory requirements and the safety and rights of the patients are protected. The Quality Assurance Plan should outline monitoring plans, possible audits and also the setting up of Data Safety and Monitoring Boards and Trial Oversight Committees if required. Global Health Trials contains many resources, discussions, template SOPs, and guidance articles about aspects of QA – but we’d be delighted to have other examples so please send in any QA documents that you’ve created for your research.
It’s important to remember that QA planning also needs consideration for research other than RCTs. As part of our QA month, we’re delighted that the Joanna Reynolds of the ACT Consortium (www.actconsortium.org) has shared their Quality Assurance and Strengthening (QAS) guidelines for Qualitative research. You can read the guidelines here, and view an example protocol: http://globalhealthtrials.tghn.org/articles/quality-assurance-qualitative-research-suggested-approach-assessing-and-strengthening-qualitative-research-within-global-health/
We’re fortunate to have Barbara available to answer any questions you have about Quality Assurance, and Joanna available to answer questions specific to QA in qualitative research. Please post your comments here! We look forward to hearing from you.
Thank you so much Barbara (and sorry for the delay replying, I was on leave!). I hope to meet you one day. Liz
Cordelia and Ali, you are welcome; please continue to post your questions, I will be happy to respond.
In response to the question from Liz Allen about small teams:
This is a great question. There are two sides to quality; one is Quality Control (QC) and the other is Quality Assurance (QA). I will respond to this question from the “Sponsor-Investigator” perspective, as these are the groups that tend to be met with challenges when it comes to meeting the obligations of quality, as outlined in the GCP Guidelines. ICH Good Clinical Practice Guideline (E6) will be used as the reference and the following should be considered when thinking about this question:
1.47 Quality Control (QC): The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled.
1.38 Monitoring: The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).
1.46 Quality Assurance (QA): All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the applicable regulatory requirement(s).
1.6 Audit: A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported according to the protocol, sponsor's standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).
5.1 Quality Assurance and Quality Control
5.1.1 The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s).
It can be challenging for small research centers to fulfil their obligations with regards to Quality Assurance (QA) and Quality Control (QC), with the QA component being the most challenging. I see Monitoring as a QC function, making is easy to address, as it is part of operations and can be performed by several individuals within the study team. This can be achieved with a good monitoring plan and Standard Operating Procedures, to ensure that there is a system where colleagues QC each other’s work, and avoid having an individual checking their own work.. ICH 5.1.3 Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly.
The ICH guidelines states the following: 5.19.2 Selection and Qualification of Auditors
(a) The sponsor should appoint individuals, who are independent of the clinical trials/systems, to conduct audits.
(b) The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly. An auditor’s qualifications should be documented.
In reference to QA, it is a little more complicated, but still achievable, with proper planning and delegation of responsibilities, by the PI. Audits are a part of the QA function. There are two options for small teams, to addressing QA. The fact that Auditors need to be independent from the clinical trial system, means that a trial manager would not be the best person to manage the Quality plan, as they are an integral part of the Clinical trial System. Option one would be to consider a regulatory person, who would be responsible for handling the regulatory documentation and interacting with the agencies and or the Ethics committees. This individual should not be involved in the day to day conduct of the trial. Ensure that the person is trained as an auditor and has experience. The second option is to hire a qualified, independent, Quality Management consultant to support the team and provide guidance. I know that funds tend to be a hindrance for this, but all study teams should consider their obligations with regards to quality and every funding/study proposal should include a line item for Quality, which should cover both QC and QA.
Thank you Babara for taking the time to respond to my questions. Truly helpful
In response to "How would you structure the QA Plan to address study deviations, in order to decide whether a study should be closed down or not?"
The audit plan may have a specific section to address study deviations. However it is difficult to determine study closure, solely on study deviations. Consideration should be giving to whether it is a single site or multisite trial, as the impact of the deviations will affect the trial differently. Deviations at one site or even two sites may not warrant study closure.
When assessing deviations, consider the following:
• what types of deviations are observed, do they impact subject safety?
• Will the deviations invalidated the trial?
• What has been done by the study team to address the deviations, and has there been any improvement?
At times a high number of deviations may signal the need to change a process, or an amendment to the Protocol A root cause analysis should be done, to determine the cause and impact of the deviations, as this will help you to decide if a trial should be closed or not.. Three, deviations at a site with 30 subjects, may not have the same impact as 3, or even 30, deviations at site with 300 subjects. Each deviations or type of deviation should be evaluated. E.g. a subject missing a visit window by three days, where safety lab and IP were to be administered, versus a Subject who’s visit is within the window, but the required assessments are not done, and this is demonstrated over and over again.
If Subjects’ safety is at risk, then serious consideration should be given to suspend the study until compliance can be achieved, or close the site if compliance cannot be achieved
In response to "How much source data verification would you think is needed and practical on a medicines trial?":
Historically, for Monitoring, 100% Source Data Verification (SDV) was expected. However, recently, risk-based SDV has become more acceptable. Risk- based SDV is dependent on several variables, such as, complexity of the trial, the trial size, expected adverse events, etc. There is no set, acceptable SDV percentage; but whatever one decides, should provided assurance that the data recorded on the Case Report Forms (CRF) is accurate, complete and attributable. If risk-bases SDV is to be applied, I would suggest starting with 30-40% SDV and if issues are found, then the data review could increased by 30%, or up to 100%. Whichever approach one chooses to use, this should be clearly documented in the Trial Monitoring Plan.
Audits are based on risk assessment and should look at similar variables to determine the acceptable SDV to be performed. This too should be documented in a Trial Audit Plan. At a minimum the following data should be reviewed for all selected subjects: Inclusion/Exclusion, Serious Adverse events reporting, Investigational product compliance, primary and secondary endpoints.
Dear Global Health Trials members, unfortunately Barbara is unable to reply for a few days because due to travelling problems. However, she will return her responses to your questions shortly. We apologise for the delay!
Question for Barbara - how do you recommend very small teams where staff multitask implement a quality plan? i.e. trial manager may also oversee quality at the site level. It seems clearer when a group is big enough to have distinct roles (or even groups) with responsibility for a function and when there is a Sponsor. When the team is small and/or there is a Sponsor/investigator, however, the boundaries between trial conduct and quality assurance get blurred.
As a non-qualitative researcher I think I chose to pursue embedding qualitative work in our clinical trial because of its inherent reflexivity on the trial processes (including interpretation of data). Not sure if that makes sense Jo?!
How would you structure the QA Plan to address study deviations, in order to decide whether a study should be closed down or not?
How much source data verification would you think is needed and practical on a medicines trial?
Thank you so much for your response Joanna. It answers my question and I hope someone with qualitative experience in clinical trials will input so we can have an understanding of what occurs in the real world scenario.
Thanks for your question, Cordelia. My answer is very much limited by my position as a qualitative (only) researcher working in an academic setting, and with no experience of commercial trials, but I will attempt to respond.
I would argue that reflexivity is a fundamental principle of (good) qualitative research, and as such, should be practised whether conducting qualitative research in a clinical trials setting or elsewhere. I think reflexivity is perhaps particularly valuable for reflecting on how a clinical trials research context may shape the planning, conduct and interpretation of qualitative research carried out within it.
There may be some tensions faced, however, with promoting the practice of reflexivity in qualitative research embedded in a research setting where quality assurance processes follow strict, structured guidelines (eg GCP for clinical trials). Aligning what constitutes good qualitative research practice with the requirements for clinical trials would require negotiation and mutual understanding of different epistemological perspectives between the different groups of researchers.
As my experience comes from within effectiveness studies of behavioural interventions (a more operational research perspective), I don't know whether the tensions would be similar or possibly heightened in the context of efficacy trials of drugs or technologies (either in commercial or non-commercial contexts). The very strict trial protocols may be at odds with the more interpretive principles of quality in qualitative research, such as reflexivity. However, if investigators recognise the value of qualitative research for feeding into such trials, then hopefully they would be open to the principles of what constitutes good qualitative research (including reflexivity).
It would be really helpful to hear from someone with experience of qualitative research conducted in such (commercial) drugs / efficacy trials...
Do you feel there is a place for reflexivity in the qualitative work done in clinical trials and how would one go about the implementation of this into the market situation
Although this comes from Pfizer and is therefore commercial-trial based, I thought this overview of QA may be useful since it contains some nice examples of QA visits and how the findings from the visit are overcome. http://www.pfizer.com/files/research/research_clinical_trials/QualityManagement_ClinicalTrials_030209.pdf
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