Development of harmonised approaches for detecting and recording participant-reported anti-malarial drug safety data: The Delphi process

Eliciting adverse event (AE) and non-study medication reports from clinical research participants is integral for evaluating drug safety. However, using different methods to question participants yields inconsistent results, compromising the interpretation, comparison and pooling of data across studies. This is particularly important given the widespread use of antimalarials in vulnerable populations, and their increasing use in healthy but at-risk individuals as preventive treatment or to reduce malaria transmission. Experienced, qualified antimalarial drug clinical researchers were invited to participate in a Delphi process, to facilitate consensus on what panellists consider to be optimal (relevant, important and feasible) methods, tools, and approaches for detecting participant-reported AE and non-study medication data in uncomplicated malaria treatment studies. This Delphi built on a previous survey conducted among malaria clinical researchers about different elicitation methods they used. The findings thereof, and a summary of relevant literature, were presented to Delphi panellists in round one after which they were asked to suggest further questioning methods or approaches that they considered as important and feasible for asking participants (or their caregivers) about their health to collect adverse events, and use of non-study medications to collect previous or concomitant medication data. In round two, the panellists were presented with the collated suggestions from round one to rate each type of question in terms of its relevance, importance and feasibility. Here, panellists would rate methods or approaches as either optimal or not optimal for inclusion in a 'menu' of harmonized or standard types of core questions to be used in a variety of uncomplicated antimalarial treatment studies. In round three, panellists were presented with a summary of items which had achieved consensus in round two and, for items that had not achieved consensus they were asked whether or not they wished to change their response in view of the group's overall response. Of the 72 invited, 25; 16 and 10 panellists responded to the first, second and third rounds of the Delphi process respectively. Overall, 68% of all questioning items presented for rating achieved consensus. When asking general questions about health, panellists agreed to include a question/concept about any change in health, taking care to ensure that such questions/concepts do not imply causality. Eighty-nine percent (39/44) of structured items about specific signs and symptoms, were rated as optimal. For non-study medications, a general question and most structured questioning items were considered an optimal approach. The use of mobile phones, patient diaries, rating scales as well as openly engaging with participants to discuss concerns were also considered optimal complementary data-elicitation tools. This study succeeded in reaching consensus within a section of the antimalarial drug clinical research community about using a general question concept, and some structured questions for eliciting data about AEs and non-study medication reports. The findings suggest that one method of questioning may not be superior to another, or sufficient to fulfil its purpose on its own and that the use of a combination of methods may be optimal. As malaria clinical research is often conducted in children (and other vulnerable groups), this becomes an important consideration in the design of appropriate elicitation methods cognisant of any particular factors that may impede accurate reporting in these groups. The concepts and items found in this Delphi survey to be relevant, important and feasible should be further investigated for potential inclusion in a harmonised approach to collect participant-elicited antimalarial drug safety data. This, in turn, should improve understanding of antimalarial drug safety

Evaluation of the pharmaceutical availability of erythromycin from topical formulations

Erythromycin (ERY) is a macrolide antibiotic which is used in the treatment of acne vulgaris.Acne is a common skin condition that occurs when the sebaceous glands and hair shafts become infected by the bacteria Propionibacterium acnes. Acne is a chronic condition that may last for years and the severity of the effects of the disease on patients is often undermined especially in third world countries where more emphasis is placed on other more life-threatening diseases. It may cause considerable physical and emotional distress to sufferers along with the possibility of permanent scarring. Although use of topical ERY formulations is not the first line of treatment it has proven to be effective in treating inflammation of skin and skin structures cause by the responsible bacteria. To-date there are a variety of vehicles which are used in preparing topical ERY formulations namely ointment and gel bases, alcoholic solutions and pledgets. All the gel formulations on the market contain hydroxypropyl cellulose, alcohol and water along with the active ingredient(s). However, some gel formulations contain propylene glycol in addition to these excipients an example being Emgel®. Propylene glycol has been shown to affect the penetration of topically applied drugs through the skin suggesting that it would be highly likely that those formulations which contain propylene glycol may release more ERY into the skin following application. With this in mind, two ERY gel formulations were produced which contained different percentages of propylene glycol. According to the FDA guidelines, pharmacokinetic measurements in blood, plasma and/or urine of topical dermatological drug products are not feasible to document bioequivalence since the active ingredient(s) in topical formulations is/are not intended to be absorbed into the systemic circulation and in addition, concentrations in extracutaneous biological tissues would generally not be measurable. This limits determination of bioavailability and assessment of bioequivalence of such products to pharmacodynamic measurements, clinical trials and dermatopharmacokinetic (DPK) measurements such as tape stripping (TS) and microdialysis (MD).TS is a sampling technique which involves sequential removal of layers of the stratum corneum using strips of adhesive tape. This technique has found increasing use in DPK studies for investigation of drug kinetics in the skin following the application of a topical formulation. The technique has also been used as a diagnostic tool in assessing the quality of the stratum corneum in diseased skin. In the current research study, the tape stripping technique was used to investigate the pharmaceutical/biological availability of topical gel formulations containing ERY. MD is another DPK sampling technique which has been used to determine the amount of a topically applied drug that penetrates through the stratum corneum to reach deeper tissues of the skin. The in vivo sampling technique involves the insertion of microdialysis probes beneath the skin surface in the dermal tissue and allows for real-time sampling of the analyte at its target site. Recently in vitro MD has also been successfully used to assess the pharmaceutical availability of a topical corticosteroid, mometesone furoate, from topical formulations. Based on this work, microdialysis was used to determine the pharmaceutical availability of ERY from gel formulations which were developed for use in this research. The results of the pharmaceutical availability of ERY from in vivo tape stripping studies and the in vitro microdialysis studies were compared to establish correlation between the data. Pharmaceutical equivalence and bioequivalence data obtained from the respective studies on the gel formulations were investigated by statistical analysis of the data generated from both the in vitro and in vivo experiments. In summary the objectives of this research were: 1. To develop and validate a high performance liquid chromatography method suitable to analyse ERY concentrations obtained from in vitro microdialysis studies and in vivo tape stripping studies. 2. To prepare two different ERY gel formulations with different percentage content of propylene glycol. 3. To determine the pharmaceutical availability of ERY from two different gel formulations using in vitro microdialysis. 4. To develop and validate a tape stripping technique which could be used to determine percutaneous penetration and bioequivalence of the gel formulations. 5. To compare in vitro microdialysis and in vivo tape stripping data and attempt to establish a correlation between the two different approaches

Working towards consensus on methods used to elicit participant-reported safety data in uncomplicated malaria clinical drug studies: a Delphi technique study

BACKGROUND: Eliciting adverse event (AE) and non-study medication data reports from clinical research participants is integral to evaluating drug safety. However, using different methods to question participants yields inconsistent results, compromising the interpretation, comparison and pooling of data across studies. This is particularly important given the widespread use of anti-malarials in vulnerable populations, and their increasing use in healthy, but at-risk individuals, as preventive treatment or to reduce malaria transmission. METHODS: Experienced and knowledgeable anti-malarial drug clinical researchers were invited to participate in a Delphi technique study, to facilitate consensus on what are considered optimal (relevant, important and feasible) methods, tools, and approaches for detecting participant-reported AE and non-study medication data in uncomplicated malaria treatment studies. RESULTS: Of 72 invited, 25, 16 and 10 panellists responded to the first, second and third rounds of the Delphi, respectively. Overall, 68% (68/100) of all questioning items presented for rating achieved consensus. When asking general questions about health, panellists agreed on the utility of a question/concept about any change in health, taking care to ensure that such questions/concepts do not imply causality. Eighty-nine percent (39/44) of specific signs and symptoms questions were rated as optimal. For non-study medications, a general question and most structured questioning items were considered an optimal approach. The use of mobile phones, patient diaries, rating scales as well as openly engaging with participants to discuss concerns were also considered optimal complementary data-elicitation tools. CONCLUSIONS: This study succeeded in reaching consensus within a section of the anti-malarial drug clinical research community about using a general question concept, and structured questions for eliciting data about AEs and non-study medication reports. The concepts and items considered in this Delphi to be relevant, important and feasible should be further investigated for potential inclusion in a harmonized approach to collect participant-elicited anti-malarial drug safety data. This, in turn, should improve understanding of anti-malarial drug safety

Eliciting adverse effects data from participants in clinical trials.

BACKGROUND: Analysis of drug safety in clinical trials involves assessing adverse events (AEs) individually or by aggregate statistical synthesis to provide evidence of likely adverse drug reactions (ADR). While some AEs may be ascertained from physical examinations or tests, there is great reliance on reports from participants to detect subjective symptoms, where he/she is often the only source of information. There is no consensus on how these reports should be elicited, although it is known that questioning methods influence the extent and nature of data detected. This leaves room for measurement error and undermines comparisons between studies and pooled analyses. This review investigated comparisons of methods used in trials to elicit participant-reported AEs. This should contribute to knowledge about the methodological challenges and possible solutions for achieving better, or more consistent, AE ascertainment in trials. OBJECTIVES: To systematically review the research that has compared methods used within clinical drug trials (or methods that would be specific for such trials) to elicit information about AEs defined in the protocol or in the planning for the trial. SEARCH METHODS: Databases (searched to March 2015 unless indicated otherwise) included: Embase; MEDLINE; MEDLINE in Process and Other Non-Indexed Citations; Cochrane Methodology Register (July 2012); Cochrane Central Register of Controlled Trials (February 2015); Cochrane Database of Systematic Reviews; Database of Abstracts of Reviews of Effects (January 2015); Health Technology Assessment database (January 2015); CINAHL; CAB Abstracts; BIOSIS (July 2013); Science Citation Index; Social Science Citation Index; Conference Proceedings Citation Index - Science. The search used thesaurus headings and synonyms for the following concepts: (A): Adverse events AND measurement; (B): Participants AND elicitation (also other synonyms for extraction of information about adverse effects from people); (C): Participants AND checklists (also other synonyms as for B). Pragmatic ways were used to limit the results whilst trying to maintain sensitivity. There were no date or sample size restrictions but only reports published in English were included fully, because of resource constraints as regards translation. SELECTION CRITERIA: Two types of studies were included: drug trials comparing two or more methods within- or between-participants to elicit participant-reported AEs, and research studies performed outside the context of a trial to compare methods which could be used in trials (evidenced by reference to such applicability). Primary outcome data included AEs elicited from participants taking part in any such clinical trial. We included any participant-reported data relevant for an assessment of drug-related harm, using the original authors' terminology (and definition, where available), with comment on whether the data were likely to be treatment-emergent AEs or not. DATA COLLECTION AND ANALYSIS: Titles and abstracts were independently reviewed for eligibility. Full texts of potentially eligible citations were independently reviewed for final eligibility. Relevant data were extracted and subjected to a 100% check. Disagreements were resolved by discussion, involving a third author. The risk of bias was independently assessed by two authors. The Cochrane 'Risk of bias' tool was used for reports comparing outcomes between participants, while for within-participant comparisons, each study was critically evaluated in terms of potential impact of the design and conduct on findings using the framework of selection, performance, detection, attrition, reporting, and other biases. An attempt was made to contact authors to retrieve protocols or specific relevant missing information. Reports were not excluded on the basis of quality unless data for outcomes were impossible to compare (e.g. where denominators differed). A narrative synthesis was conducted because differences in study design and presentation meant that a quantitative meta-analysis was not possible. MAIN RESULTS: The 33 eligible studies largely compared open questions with checklist-type questions or rating scales. Two included participant interviews. Despite different designs, populations and details of questioning methods, the narrative review showed that more specific questioning of participants led to more AEs detected compared to a more general enquiry. A subset of six studies suggested that more severe, bothersome, or otherwise clinically relevant AEs were reported when an initial open enquiry was used, while some less severe, bothersome, or clinically relevant AEs were only reported with a subsequent specific enquiry. However, two studies showed that quite severe or debilitating AEs were only detected by an interview, while other studies did not find a difference in the nature of AEs between elicitation methods. No conclusions could be made regarding the impact of question method on the ability to detect a statistically significant difference between study groups. There was no common statistical rubric, but we were able to represent some effect measures as a risk ratio of the proportion of participants with at least one AE. This showed a lower level of reporting for open questions (O) compared to checklists (CL), with a range for the risk ratios of 0.12 to 0.64. AUTHORS' CONCLUSIONS: This review supports concerns that methods to elicit participant-reported AEs influence the detection of these data. There was a risk for under-detection of AEs in studies using a more general elicitation method compared to those using a comprehensive method. These AEs may be important from a clinical perspective or for patients. This under-detection could compromise ability to pool AE data. However, the impact on the nature of the AE detected by different methods is unclear. The wide variety and low quality of methods to compare elicitation strategies limited this review. Future studies would be improved by using and reporting clear definitions and terminology for AEs (and other important variables), frequency and time period over which they were ascertained, how they were graded, assessed for a relationship to the study drug, coded, and tabulated/reported. While the many potential AE endpoints in a trial may preclude the development of general AE patient-reported outcome measurement instruments, much could also be learnt from how these employ both quantitative and qualitative methods to better understand data elicited. Any chosen questioning method needs to be feasible for use by both staff and participants

Evaluating harm associated with anti-malarial drugs: a survey of methods used by clinical researchers to elicit, assess and record participant-reported adverse events and related data.

BACKGROUND: Participant reports of medical histories, adverse events (AE) and non-study drugs are integral to evaluating harm in clinical research. However, interpreting or synthesizing results is complicated if studies use different methods for ascertaining and assessing these data. To explore how these data are obtained in malaria drug studies, a descriptive online survey of clinical researchers was conducted during 2012 and 2013. METHODS: The survey was advertised through e-mails, collaborators and at conferences. Questions aimed to capture the detail, rationale and application of methods used to obtain relevant data within various study designs and populations. Closed responses were analysed using proportions, open responses through identifying repeating ideas and underlying concepts. RESULTS: Of fifty-two respondents from 25 counties, 87% worked at an investigational site and 75% reported about an interventional study. Studies employed a range of methods to elicit, assess and record participant-reported AEs and related data. Questioning about AEs in 31% of interventional studies was a combination of general (open questions about health) and structured (reference to specific health-related items), 26% used structured only and 18% general only. No observational studies used general questioning alone. A minority incorporated pictorial tools. Rationales for the questioning approach included: standardization of assessment or data capture, specificity or comprehensiveness of data sought, avoidance of suggestion, feasibility, and understanding participants' perceptions. Most respondents considered the approach they reported was optimal, though several reconsidered this. Four AE grading, and three causality assessment approaches were reported. Combining general and structured questions about non-study drug use were considered useful for revealing and identifying specific medicines, while pictures could enhance reports, particularly in areas of low literacy. CONCLUSIONS: It is critical to evaluate the safety of anti-malarial drugs being deployed in large, diverse populations. Many studies would be suitable for contributing to a larger body of evidence for answering questions on harm. However this survey showed that various methods are used to obtain relevant data, which could influence study results. As the best practices for obtaining such data are unclear, anti-malarial clinical researchers should work towards consensus about the selection and/or design of optimal methods