Randomised controlled trial to assess the impact of hospital–community pharmaceutical care on drug-related problems in oncology practice for at-risk outpatients treated with oral anticancer drugs—a French Society for Oncology Pharmacy (SFPO) study: DROP-SFPO study protocol

Abstract

Introduction

Drug-related problems (DRPs) associated with oral anticancer drugs are frequent and require a new healthcare organisation to manage them on an outpatient basis. The aim of this article is to present the study protocol of the Drug Related problems in Oncology Practice (DROP) randomised controlled trial (RCT), endorsed by the French Society for Oncology Pharmacy. The main objective of the DROP RCT is to measure the impact at 6 months of the DROP community/hospital pharmaceutical intervention programme, compared with usual treatment, on the mean number of DRP (ie, adverse effects, drug–drug interactions, medication errors) related to oral anticancer drugs in at-risk outpatients.

Methods and analysis

The DROP protocol is a prospective, multicentre controlled clinical trial, with individual randomisation, comparing in parallel and in open, two groups of outpatients treated with oral anticancer drugs. The interventional group benefits from the DROP multidisciplinary intervention on oral anticancer treatment. The control group receives usual care. The primary outcome of the DROP RCT is the number of DRP due to oral anticancer drugs, per patient, identified between the inclusion of the patient and 6 months after inclusion

Ethics and dissemination

Approval to conduct this study was obtained for all participating centres from an Ethics Committee (Comité de Protection des Personnes Sud-Méditerranée V) in August 2018 in accordance with French law. The trial results will be disseminated at clinical conferences and published in peer-reviewed journals.

Trial registration number

ClinicalTrials.gov: NCT03257969, recruitment started in June 2019. The current protocol version is V.9, 13 December 2023.

Correspondence to Dr Catherine Rioufol; [email protected]

STRENGTHS AND LIMITATIONS OF THIS STUDY

• The DROP study is the first multicentre controlled clinical trial in France, comparing in parallel, two groups of outpatients treated with oral anticancer drugs, to measure the impact at 6 months of the DROP community/hospital-based pharmaceutical intervention programme versus usual treatment, on the average number of drug-related problems.

• Drug-related problems include adverse events, drug–drug interactions and medication errors related to oral anticancer drugs in at-risk outpatients.

• Due to the nature of the interventions, patients and professionals participating in the study are not blinded to the allocation of management.

Introduction

The rise of oral anticancer agents, including cytotoxic agents, targeted therapies and hormonal agents, favours outpatient management, but incurs new risks compared with injectable chemotherapy administered in hospital: non-adherence to treatment,^1–6 inappropriate management of side effects,⁷ medication errors⁸ and interactions with co-prescribed drugs.^9–14 Iatrogenic risk is greater in older patients with frequent comorbidities, taking multiple treatments.^15–18

The literature reports an increase in these drug-related problems (DRPs). DRPs have been defined by the Pharmaceutical Care Network Europe as events or circumstances involving drug therapy that actually or potentially interfere with desired health outcomes.¹⁹ DRPs associated with oral anticancer agents are reported in more than 90% of patients, with an average of 1–4 problems per patient.^20–22 The clinical consequences are particularly important, with a potential decrease in treatment efficacy and/or increase in toxicity.²³

Medical management and prevention of DRPs are difficult due to the lack of shared information and tools between hospital and community care providers. Experiments with different organisational models have often focused on the pharmaceutical analysis of prescriptions and the detection and management of DRPs, which are still underestimated.^{9 10 12 15 21 24–26} Recently, the randomised Medication Safety with Oral Antitumor Drugs (AMBORA) trial, conducted in 11 German centres, demonstrated that intensified clinical pharmacological/pharmaceutical care, including medication management and structured patient counselling, over a 12-week period, had significant positive effects on the number of medication errors, including drug–drug interactions, serious side effects and patient perception of treatment.²² In this context, the French Society for Oncology Pharmacy (SFPO) sought to assess the impact of a programme of a hospital–community pharmaceutical care programme on DRPs in oncology practice for outpatients: the DROP programme.

The purpose of this study is to present the protocol of the DROP prospective, randomised controlled trial (RCT). The primary objective of the trial is to measure the impact of the DROP community-based/hospital-based pharmaceutical intervention programme versus current management on the mean number of DRPs (ie, adverse events, drug–drug interactions, medication errors) associated with oral anticancer drugs in at-risk ambulatory patients after 6 months. The study hypothesis was that the DROP programme makes treatment with oral anticancer drugs safer than usual care.

Methods and analysis

Study design and settings

The DROP protocol is a prospective, multicentre, controlled clinical trial, with 1:1 parallel, open randomisation, comparing two groups of outpatients treated with oral anticancer drugs: an intervention group with DROP multidisciplinary intervention on oral anticancer treatment and a control group with usual care.

The DROP RCT recruited 15 French cancer centres. Three of them finally withdrew from the study before inclusion due to the implementation of another programme dedicated to patients treated by oral anticancer drugs, which would have biased the present study. In each study centre, a dedicated team of health professionals will lead the multidisciplinary programme, including hospital pharmacists and oncologists, in liaison with the patient’s chosen community pharmacist.

Eligible patients will be recruited by the hospital oncologist during the consultation for initiation or change of oral anticancer drugs (table 1). Outpatients with the following characteristics may be included in the study: age greater than 18 years, with cancer, with initiation or change of oral anticancer drugs according to the market authorisation, with life expectancy≥6 months, and oral anticancer therapy expected for ≥6 months. Eligible patients are also at risk of DRPs: polymedication (daily intake of ≥5 drugs, including oral anticancer treatment) and/or treated with an oral anticancer drug with a complex administration regimen (combined or sequential intake of two or more oral anticancer drugs) and/or combination with an injectable anticancer drug. Patients must be able to read, write and understand French, be covered by health insurance and have given written consent to participate in the study. They must not have any psychiatric disorder likely to interfere with the DROP programme and must have sufficient autonomy to manage treatment at home, according to the investigating oncologist.

Table 1

Patient eligibility criteria

Inclusion criteria	Exclusion criteria
Adults over 18 years of age	Treatment with oral anticancer drug under clinical trial or compassionate use
Diagnosed cancer	Legal protection or institutionalisation
Initiation or change of oral anticancer drugs according to the market authorisation	Psychiatric disorder likely to interfere with the DROP programme
Life expectancy ≥6 months	Treatment managed at home by a caregiver exclusively
Oral anticancer therapy expected for ≥6 months	Absence of French language skills (the ability to understand written and spoken French)
Considered by the oncologist to be at risk of drug-related problems: Daily intake of ≥5 drugs, including oral anticancer treatment Or treated with an oral anticancer drug with a complex administration regimen (combined or sequential intake of two or more oral anticancer drugs) Or combination with an injectable anticancer drug	Patient unable to give consent
Sufficient autonomy to manage treatment at home, according to the investigating oncologist

DROP, Drug Related problems in Oncology Practice.

The allocation of patients to the two study groups will be done via a centralised online randomisation system, in a balanced ratio 1:1. Allocation will not be blinded to participants, medical staff nor the clinical trial staff.

During the course of the study, in the event of a change in the treatment and/or a complete discontinuation of the oral anticancer agent, the patient will be withdrawn from the study; however, its data will be considered and analysed.

The inclusion period began in June 2019. Randomisation will be implemented after obtaining informed consent in accordance with the principles of good clinical practice.

Intervention

Baseline and follow-up procedures are illustrated in figure 1.

Figure 1. DROP-SFPO programme. C, medical consultation; M, month; SFPO, French Society for Oncology Pharmacy.

Usual care

Patients allocated to the control group will receive the current management in the respective study centres, without any specific intervention. The hospital pharmacist will not be involved as oral anticancer agents are supplied by the community pharmacist on a monthly basis. When dispensing anticancer agents, the community pharmacist may give some advice on taking the medication, particularly in relation to other treatments taken by the patient.

DROP programme

Patients included in the intervention group will be treated according to a multidisciplinary programme involving information and education sessions with a hospital or community pharmacist. To carry out these sessions, an interview guide has been developed to standardise the intervention, detailing the various steps: (1) medication information (how to take treatment, medication plan, prevention and management of side effects and drug–drug interactions); (2) medication history; (3) assessment and management of DRPs; and 4) communication with community and hospital health professionals.

For the first 5 months, follow-up is hospital-centred, while integrating the community-hospital link, allowing for a learning curve for the community pharmacist. For the following 4 months, follow-up is provided by the community pharmacist, while maintaining the community-hospital link and possibly involving the hospital pharmacist.

The first pharmaceutical interview takes place immediately after the medical consultation in the form of a 30 min information session focusing on the oral anticancer drug: the importance of adherence, the occurrence and management of side effects and optimisation of the medication plan, including drug–drug interactions. Pharmacist uses the SFPO’s open-access OncoLien website dedicated to oral anticancer agents (https://oncolien.sfpo.com/). Information sheets detailing how to take each oral anticancer drug are available for both patients and healthcare professionals. The hospital pharmacist informs the community pharmacist of the patient’s inclusion in the DROP study and the modalities of the community–hospital link. Together, the hospital pharmacist and the community pharmacist draw up a complete list of medications, prescribed or not, taken by the patient, including complementary and complementary medicine, enabling drug–drug interactions to be detected and managed. At each subsequent hospital consultation, the link between the two pharmacists is reactivated, making treatment even safer.

Between days 4 and 10 after the initiation of the oral anticancer drug, the hospital pharmacist contacts the patient at home to assess his or her needs and optimise treatment use. The pharmacist asks the patient how the first few days of treatment have gone and whether any difficulties have been encountered in taking the treatment, experiencing occurrence side effects, using support drugs and self-medication. This interview lasts around 30 min.

Subsequent hospital pharmacy consultations are scheduled monthly for a total of four consultations of around 45 min each. The hospital pharmacist provides further information on the patient’s anticancer drugs and any other treatments, any reported side effects, dietary advice, corrective treatments, etc, and on the risks of self-medication.

Between months 5 and 9, the intervention group’s pharmaceutical follow-up is carried out by the community pharmacist for approximately 30 min per month concerning drug intake and potential DRPs. The community pharmacist contacts the hospital pharmacist after each consultation with the patient and shares the information gathered concerning oral anticancer drugs (adverse effects, adherence, drug–drug interactions) or any other information of significant interest. All the community health professionals involved in the patient’s care (general practitioner, community pharmacist and homecare nurse if applicable) are encouraged to share any advice given to the patient using an individual liaison booklet.

Outcome measures and data collection

Primary outcome

The primary outcome of the DROP RCT is the number of DRPs of oral anticancer agent per patient, from inclusion to 6 months after inclusion. DRPs are defined as adverse events, drug–drug interactions or medication errors with clinical consequences for the patient. Adverse events are grade 2, 3 or 4 effects on the National Cancer Institute Common Terminology Criteria for Adverse Events (V.4.0) severity scale,²⁷ reported by any healthcare professional involved in the patient’s care or by the patient, and attributable to the anticancer drug. Drug–drug interactions include interactions between the oral anticancer drug and other prescribed medications or self-medications taken by the patient. Medication errors involving oral anticancer agents are those that have impacted the patient with proven harm or require appropriate monitoring (grade D to I) according to the Medication Error Index of the National Coordinating Council for Medication Error Reporting and Prevention.²⁸

The potential seriousness of DRP is assessed by a panel of four oncology experts: two physicians (one onco-haematologist and one medical oncologist) and two hospital oncology pharmacists.

Secondary outcomes

Secondary outcomes assessed at inclusion and at the 3, 6 and 9 months after inclusion include the total number of DRPs due to all drugs (prescribed or self-medicated) per patient.

Secondary outcomes assessed only at baseline, at months 3 and 6 months after inclusion include (1) number DRP-related oral anticancer drug prescription adjustments per patient: dose adjustment, course spacing, treatment interruption or cessation of treatment; (2) relative dose intensity of the oral anticancer drug, assessed as the ratio between the overall dose prescribed during the 6 months of follow-up to the theoretical dose according to the market authorisation; (3) adherence, based on the questionnaire on the French Health Insurance website (patients considered adherent if they answer ‘no’ to all six questions²⁹) and medication possession ratio (MPR), defined as the sum of days of supply for all fills of a given drug during the 6-month period divided by the total number of days during the period (adherence defined as MPR≥80%); (4) unscheduled outpatient care for DRPs (number and nature of imaging or biology acts, medical consultation and/or hospital admission); (5) quality of life according to the European Quality of Life 5 Dimensions (EUROQOL 5D) (EQ5D-3L)³⁰ and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30 questionnaires); (6) satisfaction with therapeutic management according to the Treatment Satisfaction with Medicines Questionnaire (SAT-MED Q) scale³¹; (7) self-treatment capacity according to the therapeutic self-care tool³² and (8) disease perception on the Brief Illness Perception questionnaire.³³

Primary care workers’ involvement in the DROP programme is also assessed at 9 months, by the number of and reasons for primary care actors’ interventions per patient, as recorded in the patient’s booklet, as well as by the number of and reasons for requests to hospital pharmacists and oncologists by primary care workers, as part of information sharing.

Satisfaction with the DROP programme was assessed 9 months after inclusion on a 10-point visual analogue scale for patients, general practitioners and community pharmacists.

Table 2 summarises all evaluations and time points.

Table 2

Outcomes measurements

Outcome	Inclusion	Month 3	Month 6	Month 9
Number of DRPs of oral anticancer agent	x	x	x	x
Total number of DRPs due to all drugs	x	x	x	x
Relative dose intensity of the oral anticancer drug	x	x	x
Adherence	x	x	x
Medication possession ratio	x	x	x
Unscheduled outpatient care for DRPs	x	x	x
Quality of life	x	x	x
Patient satisfaction with therapeutic management	x	x	x
Patient self-treatment capacity	x	x	x
Patient disease perception	x	x	x
Number of and reasons for primary care actors’ interventions per patient				x
Number of and reasons for requests to hospital pharmacists and oncologists by primary care workers				x
Satisfaction with the DROP programme for patients, general practitioners and community pharmacists				x

DRP, drug related problem.

Data collection

Patients will be managed according to usual follow-up practices, with four consultations for data collection during the 12-month study period, corresponding to the usual schedule with the hospital oncologist. At each consultation, data will be collected from hospital clinical records, the dedicated diary kept by the patient, and questionnaires, and recorded on an electronic case report form. On-site data monitoring will be planned, and additional data quality control will be performed throughout the study.

Statistical considerations

Sample size calculation

DRPs due to oral anticancer drugs are insufficiently assessed. Without specific follow-up to reduce the rate, pharmaceutical analysis of prescriptions with consultation of medical files reveals an average of 0.75 adverse reactions²¹ and 0.7–1.8 drug–drug interactions^{10 20 34}, that is, a mean of two DRPs linked to oral anticancer drug per patient. We hypothesise that the average number of DRPs related to oral anticancer drugs will be reduced by 25% by the DROP programme. Taking into account an SD of 1.5, a first-order alpha risk of 0.05 and 80% power on one-tailed tests, 112 patients per group will be required. Taking into account a 10% loss to follow-up, a total of 248 patients will be included in the study.

Main analysis

Concerning the primary outcome, the analysis is based on the time point at 6 months. A multivariate regression analysis shall be used to adjust for potential confounders (numbers of drugs). An intention-to-treat analysis will be performed in the whole population after imputation of missing data.

Data regarding secondary outcomes will be described for each group. Missing data will be documented but there will be no imputation for secondary outcomes. Mixed models for repeated measures will be used to estimate the evolution of the different patient-reported outcomes and of cancer-related quality of life.

A pre-established statistical analysis plan will be provided before the database is frozen and before the analyses are carried out. All persons involved in data management, and statistical analyses as well as the principal investigator and the methodologist, will have access to the final data set.

Ethics and dissemination

The study is funded by a grant from the French Ministry of Health and is sponsored by the Hospices Civils de Lyon, a university hospital, as responsible for its management. Patient participation or refusal will not affect medical and nursing care. The study will be conducted in accordance with the Declaration of Helsinki. The study protocol was reviewed and approved at national level for all participating centres by an ethics committee (Comité de Protection des Personnes Sud-Méditerranée V; French registration number 2018-A01047-48) on 4 August 2018, and data processing was declared to the French national data protection agency (Commission Nationale de l’informatique et des libertés) in accordance with French law. It was registered at clinicaltrials.gov (NCT03257969). It has been drafted in line with international recommendations, in particular the Standard Protocol Items: Recommendations for Interventional Trials guidelines. All amendments to the protocol will be submitted for approval and will be communicated; the current protocol is V.9, 13 December 2023. Due to the COVID-19 pandemic, inclusions were interrupted for 7 months. To date, 141 patients have been included and 139 randomised (two screening failure). The completion date of the study is expected to be December 2025.

All eligible patients are informed and receive a written notice explaining the objectives of the study and the terms of their participation; they must consent to participation before being included (online supplemental material). Data management complies with the European General Data Protection Regulation. Data are pseudonymised using a unique identification number for each participant; only authorised persons can access the patient’s health information. Since no risk is expected from participation in the study, there is no need to set up an independent monitoring committee.

A scientific committee has been set up to validate the final version of the protocol, oversee the implementation of the study and draft the resulting reports and publications. Trial results will be communicated at clinical conferences and published in peer-reviewed journals; the guidelines of the International Committee of Medical Journal Editors will be followed.

Discussion

The DROP study is the first French randomised trial designed to assess the impact of hospital–community pharmaceutical care on drug-related problems in oncology practice for outpatients. Implementation of the DROP programme should help decrease the rate of DRPs associated with oral anticancer drugs by actively involving the patient and strengthening collaboration between community and hospital healthcare professionals. Hospital and community pharmacists have a central role to play in the safe use of oral anticancer drugs, that is, in the prevention and management of DRPs, including side effects, drug–drug interactions, non-adherence and medication errors in the ambulatory setting. The study design should provide robust results that could confirm those of the only RCT published to date, in Germany.²² The primary endpoint of the DROP study will be analysed at 6 months, whereas in the AMBORA trial it was at 3 months.²² These results could be very useful for healthcare decision-makers at national level, as a medical decision aid to support this type of patient follow-up, based on an intensified programme of clinical pharmacological/pharmaceutical clinical care in addition to standard care. The study will also clearly identify the added value, in multidisciplinary management of patients receiving oral anticancer drugs, provided by pharmacists as drug experts and thus experts in the management of DRPs. Importantly, it is expected that the DROP programme should strengthen the community–hospital link between healthcare professionals, which is an urgent challenge to optimise patient treatment.

Beyond the clinical impact of this study, the results will also enable us to discuss the organisational and economic implications of this type of programme. The DROP programme is adapted from the ONCological care for outpatients with ORAL anticancer drugs (ONCORAL) programme deployed locally in Lyon (France),³⁵ and a cost-effectiveness analysis is underway. An estimation at 12 months, by comparing the difference in total costs and quality-of-life-adjusted years gained between the ONCORAL programme and usual care, is planned.³⁶ More recently, a French national programme named Onco’Link was deployed with a 33-month assessment of an innovative community–hospital follow-up for 15 000 outpatients enrolled by 45 health centres, including the ONCORAL programme as a pilot.³⁷ Taking all these results into account will enable us to define tomorrow’s cancer care organisations and the need for human resources.

Moreover, digitisation of part of this hospital–community pharmaceutical care programmes is under consideration as tele-monitoring has yielded interesting results for safety and survival of cancer patients.^{38 39} Digital follow-up, combined with nurse or pharmacist consultation, could also help balance resource utilisation. For example, pharmacist-led video consultation with patients with cancer is feasible and can effectively address potential drug–drug interactions, decrease medication complexity and improve adherence.⁴⁰ An assessment of the additional costs and burden on healthcare professionals recently demonstrated the cost–benefit of this type of remote patient monitoring.⁴¹

Finally, one of the strengths of this study is the potential for translation to other cancer therapies such as immunotherapy as treatment is increasingly implemented at home or alternating between in-hospital and home care.

The DROP study has its limitations. Blinding of patients and physicians is not possible for practical and ethical reasons. In addition, the content of pharmaceutical consultations may vary between the 15 study centres. To overcome this bias, pharmacists have been specifically trained and interview guides have been developed by the SFPO.

Ethics statements

Patient consent for publication

Not applicable.

Footnote

X @AAF-6943-2021

Contributors IM, CB, PT, FL and CR designed the study. LH and CR proposed the methodology. JLC, BP and FR participated in the development of the study. FR and CR drafted the manuscript. LH, IM and FL participated in the drafting of the manuscript. All authors have read and approved the final manuscript. CR is the guarantor.

Funding The French Ministry of Health (DGOS) supported this work (PRME-16-342). The funding body had no role in the design of the study.

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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