Bedside check of medication appropriateness (BED-CMA) as a risk-based tool for bedside clinical pharmacy services: A proof-of-concept study at the trauma surgery ward.

Background: Bedside clinical pharmacy prevents drug-related problems, but is not feasible in many countries due to limited resources. Hence, clinical rules using structural information in the electronic health record can help identifying potentially inappropriate prescriptions (PIPs). We aimed to develop and implement a risk-based clinical pharmacy service and evaluate its impact on prescribing at the trauma surgery ward. Methods: The proportion of residual PIPs per day, i.e. the number of PIPs that persisted up to 24 h after pharmacist intervention divided by the number of PIPs at T0, was evaluated before and after implementation of the intervention in an interrupted time series analysis. The pre-intervention cohort received usual pharmacy services, i.e. a 0.3 FTE clinical pharmacist trainee. Fifteen clinical rules, targeting antimicrobial, anticoagulant and analgesic therapy were implemented in the post-intervention period. The pre-intervention period was compared to two post-intervention scenarios: A) clinical rule alerts reviewed by a 0.3 FTE clinical pharmacist trainee; and B) clinical rule alerts reviewed daily for approximately 1 h by a clinical pharmacist trainee. Results: Pre-intervention, a median proportion of 67% (range 0%-100%) residual PIPs per day was observed. Scenario A showed an immediate relative reduction of 14% (p = 0.72) and scenario B a significant immediate relative reduction of 85% (p = 0.0015) in residual PIPs per day. In scenario A, recommendations were provided for 19% of clinical rule alerts, of which 67% was accepted by the surgeon within 24 h. In scenario B, recommendations were given for 56% of alerts, of which 84% was accepted. Conclusions: Using clinical rules is an effective approach to organize bedside clinical pharmacy services and improves prescribing at the trauma surgery ward. Advanced training and daily follow-up of the clinical rules are two requirements to be considered.

Home care nurses' management of high-risk medications: a cross-sectional study.

BACKGROUND: High-risk medications use at home entails an increased risk of significant harm to the patient. While interventions and strategies to improve medications care have been implemented in hospitals, it remains unclear how this type of medications care is provided in the home care setting. The objective was to describe home care nurses' management of high-risk medications. METHODS: A cross-sectional, descriptive design was set up in home care nurses in Flanders, Belgium. Participants were recruited through convenience sampling and could be included in the study if they provided medications care and worked as a home care nurses. Participants completed an online structured questionnaire. Questions were asked about demographic information, work experience, nurses' general attitude regarding high-risk medications, contact with high-risk medications and the assessment of risk and severity of harm, specific initiatives undertaken to improve high-risk medications care and the use of additional measures when dealing with high-risk medications. Descriptive statistics were used. RESULTS: A total of 2283 home care nurses participated in this study. In our study, 98% of the nurses reported dealing high-risk medications. Home care nurses dealt the most with anticoagulants (96%), insulin (94%) and hypnotics and sedatives (87%). Most nurses took additional measures with high-risk medications in less than 25% of the cases, with the individual double check being the most performed measure for all high-risk medications except lithium. Nurses employed by an organization received support mostly in the form of a procedure while self-employed nurses mostly look for support through external organizations and information sources. CONCLUSIONS: The study shows several gaps regarding high-risk medications care, which can imply safety risks. Implementation and evaluation of more standardized high-risk medications care, developing and implementing procedures or guidelines and providing continuous training for home care nurses are advised.

High-Risk Medication in Home Care Nursing: A Delphi Study.

AIMS: The aims of the study were to reach consensus on which medications in home care nursing should be considered high-risk medication (HRM) and to obtain recommendations about which interventions home care nurses can perform to improve quality of care and safety in managing these HRM. DESIGN: This is an international Delphi study with 13 purposively selected experts from 4 different countries. METHODS: A 3-round iterative Delphi survey was conducted from May 2018 to October 2018, based on a list of 32 medications previously reported as HRM in community care. A proposal for HRM was based on this literature search, and experts were asked to reflect on which (groups of) medications should be considered HRM by home care nurses (completeness of the list, risk assessment per [group of] medication, the need for home care nurse interventions, and the need for an HRM care procedure). The cutoff point for consensus was set at 80% of expert agreement. RESULTS: The panel assessed the initial list and added 30 (groups of) medications. In the last round, consensus of 80% or more was reached for 27 (groups of) medications to be considered HRM by home care nurses. For 28 medications, additional interventions by a home care nurse were considered warranted. A procedure or protocol for home care nurses was deemed necessary for 12 medications. CONCLUSIONS: We identified a set of (groups of) medications that should primarily be considered HRM by home care nurses.Impact:• What problem did the study address? This study clarified which medications should be considered HRM by home care nurses.• What were the main findings? Experts identified a set of 27 (groups of) medications that should primarily be considered HRM by home care nurses.• Where and on whom will the research have an impact? The results provide essential information for home care agencies when setting up an HRM policy.

From basic to advanced computerised intravenous to oral switch for paracetamol and antibiotics: an interrupted time series analysis.

OBJECTIVES: Early switch from intravenous to oral therapy of bioequivalent drugs has major advantages but remains challenging. At our hospital, a basic clinical rule was designed to automatically alert the physician to review potential intravenous to oral switch (IVOS). A rather low acceptance rate was observed. In this study, we aimed to develop, validate and investigate the effect of more advanced clinical rules for IVOS, as part of a centralised pharmacist-led medication review service. DESIGN AND SETTING: A quasi-experimental study was performed in a large teaching hospital in Belgium using an interrupted time series design. INTERVENTION: A definite set of 13 criteria for IVOS, focusing on the ability of oral absorption and type of infection, was obtained by literature search and validated by a multidisciplinary expert panel. Based on these criteria, we developed a clinical rule for paracetamol and one for ten bioequivalent antibiotics to identify patients with potentially inappropriate intravenous prescriptions (PIVs). Postintervention, the clinical rule alerts were reviewed by pharmacists, who provided recommendations to switch in case of eligibility. PRIMARY AND SECONDARY OUTCOME MEASURES: A regression model was used to assess the impact of the intervention on the number of persistent PIVs between the preintervention and the postintervention period. The total number of recommendations, acceptance rate and financial impact were recorded for the 8-month postintervention period. RESULTS: At baseline, a median number of 11 (range: 7-16) persistent PIVs per day was observed. After the intervention, the number reduced to 3 (range: 1-7) per day. The advanced IVOS clinical rules showed an immediate relative reduction of 79% (incidence rate ratio=0.21, 95% CI 0.13 to 0.32; p<0.01) in the proportion of persistent PIVs. No significant underlying time trends were observed during the study. Postintervention, 1091 recommendations were provided, of which 74.1% were accepted, resulting in a total 1-day cost saving of €4648.35. CONCLUSIONS: We showed the efficacy of advanced clinical rules combined with a pharmacist-led medication review for IVOS of bioequivalent drugs.

Overall performance of a drug-drug interaction clinical decision support system: quantitative evaluation and end-user survey.

BACKGROUND: Clinical decision support systems are implemented in many hospitals to prevent medication errors and associated harm. They are however associated with a high burden of false positive alerts and alert fatigue. The aim of this study was to evaluate a drug-drug interaction (DDI) clinical decision support system in terms of its performance, uptake and user satisfaction and to identify barriers and opportunities for improvement. METHODS: A quantitative evaluation and end-user survey were performed in a large teaching hospital. First, very severe DDI alerts generated between 2019 and 2021 were evaluated retrospectively. Data collection comprised alert burden, override rates, the number of alert overrides reviewed by pharmacists and the resulting pharmacist recommendations as well as their acceptance rate. Second, an e-survey was carried out among prescribers to assess satisfaction, usefulness and relevance of DDI alerts as well as reasons for overriding. RESULTS: A total of 38,409 very severe DDI alerts were generated, of which 88.2% were overridden by the prescriber. In 3.2% of reviewed overrides, a recommendation by the pharmacist was provided, of which 79.2% was accepted. False positive alerts were caused by a too broad screening interval and lack of incorporation of patient-specific characteristics, such as QTc values. Co-prescribing of a non-vitamin K oral anticoagulant and a low molecular weight heparin accounted for 49.8% of alerts, of which 92.2% were overridden. In 88 (1.1%) of these overridden alerts, concurrent therapy was still present. Despite the high override rate, the e-survey revealed that the DDI clinical decision support system was found useful by prescribers. CONCLUSIONS: Identified barriers were the lack of DDI-specific screening intervals and inclusion of patient-specific characteristics, both leading to a high number of false positive alerts and risk for alert fatigue. Despite these barriers, the added value of the DDI clinical decision support system was recognized by prescribers. Hence, integration of DDI-specific screening intervals and patient-specific characteristics is warranted to improve the performance of the DDI software.

Returning to Elective Orthopedic Surgery During the COVID-19 Pandemic: A Multidisciplinary and Pragmatic Strategy for Initial Patient Selection.

OBJECTIVE: The aim of the study was to design an objective, transparent, pragmatic, and flexible workflow to assist with patient selection during the initial phase of return to elective orthopedic surgery during the COVID-19 pandemic with the main purpose of enhancing patient safety. METHODS: A multidisciplinary working group was formed consisting of representatives for orthopedics, epidemiology, ethics, infectious diseases, cardiovascular diseases, and intensive care medicine. Preparation for upcoming meetings consisted of reading up on literature and testing of proposed methodologies on our own waiting lists. RESULTS: A workflow based on 3 domains, that is, required resources, patient fitness, and time sensitivity of the procedure, was considered most useful. All domains function as standalones, in a specific order, and no sum score is used. The domain of required resources demands input from the surgical team, results in a categorical (yes or no) outcome, and generates a list of potential patients who can be scheduled for surgery under these particular circumstances. The (weighted) items for the domain of patient fitness are the same for every patient, are scored on a numerical scale, but are likely to change during the pandemic as more data become available. Time sensitivity of the procedure is again scored on a numerical scale and becomes increasingly important when returning to elective surgery proves to be acceptably safe. After patient selection, an augmented informed consent, screening, and testing according to local guidelines will take place. CONCLUSIONS: A workflow is proposed for patient selection aiming for the safest possible return to elective orthopedic surgery during the COVID-19 pandemic.

Sharing of Clinical Trial Data and Samples: The Cancer Patient Perspective.

Introduction: Today, many initiatives and papers are devoted to clinical trial data (and to a lesser extent sample) sharing. Journal editors, pharmaceutical companies, funding agencies, governmental organizations, regulators, and clinical investigators have been debating the legal, ethical, and social implications of clinical data and sample sharing for several years. However, only little research has been conducted to unveil the patient perspective. Aim: To substantiate the current debate, we aimed to explore the attitudes of patients toward the re-use of clinical trial samples and data and to determine how they would prefer to be involved in this process. Materials and Methods: Sixteen in-depth interviews were conducted with cancer patients currently participating in a clinical trial. Results: This study indicates a general willingness of cancer patients participating in a clinical trial to allow re-use of their clinical trial data and/or samples by the original research team, and a generally open approach to share data and/or samples with other research teams, but some would like to be informed in this case. Despite divergent opinions about how patients prefer to be engaged, ranging from passive donors up to those explicitly wanting more control, participants expressed positive opinions toward technical solutions that allow indicating their preferences. Conclusion: Patients were open to sharing and re-use of data and samples to advance medical research but opinions varied on the level of patient involvement and the need for re-consent. A stratified approach for consent that allows individualization of data and sample sharing preferences may be useful, yet the implementation of such an approach warrants further research.

High-risk medication in community care: a scoping review.

PURPOSE: To review the international literature related to high-risk medication (HRM) in community care, in order to (1) define a definition of HRM and (2) list the medication that is considered HRM in community care. METHODS: Scoping review: Five databases were systematically searched (MEDLINE, Scopus, CINAHL, Web Of Science, and Cochrane) and extended with a hand search of cited references. Two researchers reviewed the papers independently. All extracted definitions and lists of HRM were subjected to a self-developed quality appraisal. Data were extracted, analysed and summarised in tables. Critical attributes were extracted in order to analyse the definitions. RESULTS: Of the 109 papers retrieved, 36 met the inclusion criteria and were included in this review. Definitions for HRM in community care were used inconsistently among the papers, and various recurrent attributes of the concept HRM were used. Taking the recurrent attributes and the quality score of the definitions into account, the following definition could be derived: "High-risk medication are medications with an increased risk of significant harm to the patient. The consequences of this harm can be more serious than those with other medications". A total of 66 specific medications or categories were extracted from the papers. Opioids, insulin, warfarin, heparin, hypnotics and sedatives, chemotherapeutic agents (excluding hormonal agents), methotrexate and hypoglycaemic agents were the most common reported HRM in community care. CONCLUSION: The existing literature pertaining to HRM in community care was examined. The definitions and medicines reported as HRM in the literature are used inconsistently. We suggested a definition for more consistent use in future research and policy. Future research is needed to determine more precisely which definitions should be considered for HRM in community care.

What Does Society Value About Cancer Medicines? A Discrete Choice Experiment in the Belgian Population.

BACKGROUND: Debate on pricing and reimbursement of cancer medicines highlights the need to establish the value of cancer medicines. OBJECTIVE: This study aims to elicit the trade-offs in cancer medicine characteristics that the Belgian population is willing to make. METHODS: A discrete choice experiment used six attributes with three levels each, based on literature and focus group discussions. The survey was sent to a random sample of 3500 Belgian citizens. Based on the choice of 961 respondents, individual parameters were estimated with a mixed logit model. RESULTS: Societal value of cancer medicines was positively affected by a higher number of patients eligible for treatment, a high initial life expectancy and quality of life of patients, a high gain in quality of life and life expectancy due to treatment, and a low treatment cost. The value of 1-year gain in life expectancy was independent from the initial life expectancy of the patient. However, the value of one-point gain in quality of life was higher for patients with a low initial quality of life than for patients with a high initial quality of life. CONCLUSIONS: This study has shown that gain in quality of life with cancer medicines is valued higher by Belgian society for patients who have lower initial quality of life before the start of treatment.

Development and implementation of "Check of Medication Appropriateness" (CMA): advanced pharmacotherapy-related clinical rules to support medication surveillance.

BACKGROUND: To improve medication surveillance and provide pharmacotherapeutic support in University Hospitals Leuven, a back-office clinical service, called "Check of Medication Appropriateness" (CMA), was developed, consisting of clinical rule based screening for medication inappropriateness. The aim of this study is twofold: 1) describing the development of CMA and 2) evaluating the preliminary results, more specifically the number of clinical rule alerts, number of actions on the alerts and acceptance rate by physicians. METHODS: CMA focuses on patients at risk for potentially inappropriate medication and involves the daily checking by a pharmacist of high-risk prescriptions generated by advanced clinical rules integrating patient specific characteristics with details on medication. Pharmacists' actions are performed by adding an electronic note in the patients' medical record or by contacting the physician by phone. A retrospective observational study was performed to evaluate the primary outcomes during an 18-month study period. RESULTS: 39,481 clinical rule alerts were checked by pharmacists for which 2568 (7%) electronic notes were sent and 637 (1.6%) phone calls were performed. 37,782 (96%) alerts were checked within four pharmacotherapeutic categories: drug use in renal insufficiency (25%), QTc interval prolonging drugs (11%), drugs with a restricted indication or dosing (14%) and overruled very severe drug-drug interactions (50%). The emergency department was a frequently involved ward and anticoagulants are the drug class for which actions are most frequently carried out. From the 458 actions performed for the four abovementioned categories, 69% were accepted by physicians. CONCLUSIONS: These results demonstrate the added value of CMA to support medication surveillance in synergy with already integrated basic clinical decision support and bedside clinical pharmacy. Otherwise, the study also highlighted a number of limitations, allowing improvement of the service.

Tamoxifen Metabolism and Efficacy in Breast Cancer: A Prospective Multicenter Trial.

Purpose: Levels of endoxifen, the most active metabolite of tamoxifen, vary by the highly polymorphic cytochrome P450 (CYP) 2D6 enzyme. We prospectively investigated tamoxifen efficacy by serum endoxifen levels and the tamoxifen activity score (TAS).Experimental Design: A prospective observational multicenter study included postmenopausal women with an estrogen receptor-positive breast cancer receiving first-line tamoxifen, 20 mg daily in the neoadjuvant or metastatic setting, recruited between February 2009 and May 2014. The primary endpoint was the objective response rate (ORR) using RECIST criteria 1.0. Secondary endpoints were clinical benefit (CB), progression-free survival (PFS), and tolerability of tamoxifen. The main analysis used logistic regression to relate ORR to serum endoxifen levels after 3 months. Endpoints were also related to other tamoxifen metabolites and to TAS.Results: Endoxifen levels were available for 247 of all 297 patients (83%), of which 209 with target lesions (85%). Median follow-up time for PFS was 32.5 months, and 62% progressed. ORR and CB were 45% and 84%, respectively. ORR was not related to endoxifen, and the OR of ORR was 1.008 per µg/L increase in endoxifen (95% confidence interval, 0.971-1.046; P = 0.56). In general, none of the endpoints was associated with endoxifen levels, tamoxifen metabolites, or TAS.Conclusions: Under the prespecified assumptions, the results from this prospective clinical trial do not suggest therapeutic drug monitoring of endoxifen to be of clinical value in postmenopausal women treated with tamoxifen for breast cancer in the neoadjuvant or metastatic setting. Clin Cancer Res; 24(10); 2312-8. ©2018 AACR.

Time Investment in Drug Supply Problems by Flemish Community Pharmacies.

Introduction: Drug supply problems are a known problem for pharmacies. Community and hospital pharmacies do everything they can to minimize impact on patients. This study aims to quantify the time spent by Flemish community pharmacies on drug supply problems. Materials and Methods: During 18 weeks, employees of 25 community pharmacies filled in a template with the total time spent on drug supply problems. The template stated all the steps community pharmacies could undertake to manage drug supply problems. Results: Considering the median over the study period, the median time spent on drug supply problems was 25 min per week, with a minimum of 14 min per week and a maximum of 38 min per week. After calculating the median of each pharmacy, large differences were observed between pharmacies: about 25% spent less than 15 min per week and one-fifth spent more than 1 h per week. The steps on which community pharmacists spent most time are: (i) "check missing products from orders," (ii) "contact wholesaler/manufacturers regarding potential drug shortages," and (iii) "communicating to patients." These three steps account for about 50% of the total time spent on drug supply problems during the study period. Conclusion: Community pharmacies spend about half an hour per week on drug supply problems. Although 25 min per week does not seem that much, the time spent is not delineated and community pharmacists are constantly confronted with drug supply problems.

Managed Entry Agreements for Oncology Drugs: Lessons from the European Experience to Inform the Future.

Objectives: The aim of this study is to conduct an analysis on the regulation and application of managed entry agreements (MEA) for oncology drugs across different European countries. Methods: Literature search and document analysis were performed between September 2015 and June 2016 to collect information on the regulatory framework and practice of MEA in Belgium, The Netherlands, Scotland, England and Wales, Sweden, Italy, Czech Republic and France. An overview of the content and typology of MEA applied for oncology drugs between 2008 and 2015 was generated based on publically available sources and contributions by national health authorities. Semi-structured interviews were conducted with representatives of national health authorities involved in the management or negotiation of MEA. Results: The application of MEA differs across countries and across different indications for the same drug. Financial based agreements are prevailing due to their simplicity compared to performance-based agreements. Performance-based agreements are less commonly applied in the European countries except for Italy. In the Netherlands, application of performance-based agreements was stopped due to their inability to deal with dynamics in the market, which is highly relevant for oncology drugs. Conclusions: MEA constitute a common policy tool that public payers in European countries use to ensure early access to highly priced oncology drugs. In light of strengths and weaknesses observed for MEA and the expected developments in the oncology area, the importance of MEA is likely to grow in the future.

Time spent by Belgian hospital pharmacists on supply disruptions and drug shortages: An exploratory study.

INTRODUCTION: Supply problems of drugs are an increasing and worldwide problem, also in Belgium. Hospital pharmacists try to manage drug supply problems to minimize the impact on patient care. This study aims to quantify in a detailed manner how much time employees of 17 Belgian hospital pharmacies spend on drug supply problems. METHODS: During six months, employees of Belgian hospital pharmacies filled in the daily time spent on drug supply problems using a template containing all steps which can be executed to manage drug supply problems. Additionally, Belgian hospital pharmacists were asked to report the drugs which experienced drug supply problems together with the solution for this problem. RESULTS: Hospital pharmacists spent a median of 109 minutes a week on drug supply problems, with a minimum of 40 minutes per week and a maximum of 216 minutes per week. Fifty-nine percent of the total time spent on drug supply problems was executed by hospital pharmacists, 27% by pharmacy technicians; the rest was performed by logistic or administrative personnel. About one third of the total time spent was invested in gathering information on the supply problem. About two third of the supply disruptions caused drug shortages, meaning there was a need to switch to another (generic) therapeutic alternative. For most drug shortages, a Belgian generic medicine could be found. However in some cases, the alternative had to be ordered abroad or for some drug shortages, no alternative was available. CONCLUSION: These exploratory results on time spent by hospital pharmacists on drug supply problems in Belgium highlight the economic impact of drug supply problems for hospital pharmacies. A fully reliable, daily updated list on the federal agencies websites would be a major help to hospital pharmacists.

Are products with an orphan designation for oncology indications different from products for other rare indications? A retrospective analysis of European orphan designations granted between 2002-2012.

BACKGROUND: Orphan designated medicinal products benefit from regulatory and economic incentives for orphan drug development. Approximately 40% of orphan designations target rare neoplastic disorders, referring to rare cancers. In order to provide more insights in drugs for rare neoplastic disorders that are under development and to better understand the role of orphan designation in the development of oncology drugs, this study investigates the characteristics of the product, the indication and the applicants as well as the stage of development of products with an orphan designation for rare neoplastic disorders and compares them with products with an orphan designation for other rare indications. Therefore, orphan designation application files and annual reports submitted by the applicant were reviewed at the premises of the European Medicines Agency. RESULTS: At the time of application, 41.6% of products with orphan designation for rare neoplastic disorders were in pre-clinical phase; this was 65.1% for other rare conditions (p < 0.05). Thirty percent of orphan designations for rare neoplastic disorders had reached phase 1; compared to 19.3% of orphan designations targeting other rare conditions (p < 0.05). The same trend was observed for the stage of development at the time of the latest annual report. Significant benefit was more often considered for orphan designations for rare neoplastic disorders compared to orphan designations for other rare conditions. CONCLUSION: Orphan designations for rare neoplastic disorders involve products that are in a more advanced stages of development compared to orphan designations for other (non-oncology) rare conditions.

Clinical, Economic and Policy Implications of Drug Shortages in the European Union.

Drug shortages are an international problem, which seems to worsen. In this paper, the clinical, economic and policy implications of drug shortages are discussed, based on data available for the EU. Research on the clinical impact is scarce. Most data describe that patients will experience more side effects or need to postpone their treatment. However, more detailed research such as case studies and the number of patients affected are lacking. Information on the economic impact is described as an estimation of the time spent by hospital pharmacies. Other stakeholders are also burdened: manufacturers loose part of their profit, patients may pay more for the alternative treatment and society pays for additional health-care costs. However, no data are available. Again more detailed and objective research is necessary to know where the problem is situated and how solutions can be proposed. Policy implications are also rather scarce. However, once more detailed and objective research has been conducted, policy changes will follow. All stakeholders should be involved in the discussions, prior to the implementation of policy measures.

Industry Perspectives on Market Access of Innovative Drugs: The Relevance for Oncology Drugs.

Key Points - Representatives of the pharmaceutical industry call for a broader recognition of value within the assessment and appraisal of innovative drugs- Focus on value within the assessment and appraisal of drugs is jeopardized by financial drives as the side of industry and at the side of the payers- A well-considered value-framework, with attention for patient reported outcomes, societal preferences and dynamic approach on the drug life cycle, needs to be incorporated in assessment and appraisal at national and European level in order to coordinate the views of different stakeholders and allow efficient resource allocation This study presents industry perspectives on the challenges related to market access of innovative drugs in general and oncology drugs in specific. Fifteen interviews were conducted with representatives of pharmaceutical companies and industry associations. Interviewees call for a broader recognition of value within the assessment and appraisal of drugs. According to interviewees, focus on value is jeopardized by the lack of a common value definition across Europe, poor availability and validity of value measures and cost-saving measures such as external reference price setting and cost-effectiveness analysis at the side of the payers. Centralized assessment of relative-effectiveness at European level would provide a common value estimate across member states, independent of financial drivers. Empirical evidence on PRO and societal preferences is however essential in the development of a value definition. Furthermore, value-based pricing would imply a dynamic approach where the price is differentiated across indications and across the lifecycle of the drug, especially in fields such as oncology. Financial drivers however also threat the application of value-based pricing at the side of the industry, making value-based profitability a more appropriate term.

It is time to revise the international Good Clinical Practices guidelines: recommendations from non-commercial North-South collaborative trials.

The Good Clinical Practices (GCP) codes of the WHO and the International Conference of Harmonization set international standards for clinical research. But critics argue that they were written without consideration for the challenges faced in low and middle income countries (LMICs). Based on our field experience in LMICs, we developed a non-exhaustive set of recommendations for the improvement of GCP. These cover 3 domains: ethical, legal and operational, and 8 specific issues: the double ethical review of 'externally sponsored' trials; the informed consent procedure in minors and in illiterate people; post-trial access to newly-developed products for the trial communities; the role of communities as key research actors; the definition of sponsor; and the guidance for contractual agreements, laboratory quality management systems, and quality assurance of investigational medicinal products. Issues not covered in our analysis include among others biobanking, standard of care, and study designs. The international GCP codes de facto guide national legislators and funding agencies, so the current shortcomings may weaken the regulatory oversight of international research. In addition, activities neglected by GCP are less likely to be implemented or funded. If GCP are meant to serve the interests of global society, a comprehensive revision is needed. The revised guidelines should be strongly rooted in ethics, sensitive to different sociocultural perspectives, and allow consideration for trial-specific and context-specific challenges. This can be only achieved if all stakeholders, including researchers, sponsors, regulators, ethical reviewers and patients' representatives from LMICs, as well as non-commercial researchers and sponsors from affluent countries, are transparently involved in the revision process. We hope that our limited analysis would foster advocacy for a broad and inclusive revision of the international GCP codes, to make them at the same time 'global', 'context centred' and 'patient centred'.

Sponsorship in non-commercial clinical trials: definitions, challenges and the role of Good Clinical Practices guidelines.

BACKGROUND: Non-commercial clinical research plays an increasingly essential role for global health. Multiple partners join in international consortia that operate under the limited timeframe of a specific funding period. One organisation (the sponsor) designs and carries out the trial in collaboration with research partners, and is ultimately responsible for the trial's scientific, ethical, regulatory and legal aspects, while another organization, generally in the North (the funder), provides the external funding and sets funding conditions. Even if external funding mechanisms are key for most non-commercial research, the dependence on an external funder's policies may heavily influence the choices of a sponsor. In addition, the competition for accessing the available external funds is great, and non-commercial sponsors may not be in a position to discuss or refuse standard conditions set by a funder. To see whether the current definitions adequately address the intricacies of sponsorship in externally-funded trials, we looked at how a "sponsor" of clinical trials is defined in selected international guidelines, with particular focus on international Good Clinical Practices codes, and in selected European and African regulations/legislations. DISCUSSION: Our limited analysis suggests that the sponsors definition from the 1995 WHO Good Clinical Practices code has been integrated as such into many legislations, guidelines and regulations, and that it is not adequate to cover today's reality of funding arrangements in global health, where the legal responsibility and the funding source are de facto split. In agreement with other groups, we suggest that the international Good Clinical Practices codes should be updated to reflect the reality of non-commercial clinical research. In particular, they should explicitly include the distinction between commercial and non-commercial sponsors, and provide guidance to non-commercial sponsors for negotiating with external funding agencies and other research counterparts. Non-commercial sponsors of clinical trials should surely invest in the development of adequate legal, administrative and management skills. By acknowledging their role and specificities, and by providing them with adapted guidance, the international Good Clinical Practices codes would provide valuable guidance and support to non-commercial clinical research, whose relevance for global health is increasingly evident.