Trial design
A prospective, parallel group randomised controlled trial (RCT) design was chosen to evaluate the impact of the PMC. Contemporaneously, an in-depth evaluation of the process and the perspectives of patients and pharmacists was planned to collect information for further development of the service. The study setting considered community pharmacies in a range of representative regions of Switzerland (with and without self-dispensing physicians, city versus country, German-speaking part (D-CH) versus French-speaking part of Switzerland (F-CH)). For each patient the observation period lasted 28 weeks from study start (T-0) until study end (T-28).
Eligibility for study pharmacists
The recruitment of 70 pharmacists was intended; thus, community pharmacies in the cantons Aargau (AG), Basel-Land (BL), Basel-Stadt (BS), Solothurn (SO), Fribourg (FR), Neuchâtel (NE), Genève (GE), Vaud (VD) und Valais (VS) were invited to participate in the study. Basing on the principle of "first in, first served", the ideal recruiting target was 50 pharmacists from the German speaking and 20 from the French speaking part of Switzerland in line with the national proportion of the population. Study pharmacists were required to take part in a study-specific training, and to give written consent regarding the study design as well as a memorandum of understanding through the pharmacy owner to collaborate on the project until the end of study; in addition, they were asked to commit to transfer patient’s refill data to the study centre, and to collaborate with either IFAK or OFAC (the two main clearing companies in Switzerland administering the charges between pharmacies and health insurance and therefore also holding the corresponding patient data). The three-hour training session provided by the study centre included an overview over the study, highlighted the need for compliance to the study protocol, and clarified rights and responsibilities of the study pharmacists. No further training on the execution of a PMC was offered as the study aimed at assessing and evaluating current practice.
Screening for eligible patients
In order to avoid selection bias through study pharmacist (e.g. Individual prejudices, preferences), a random sample of 100 potential PMC candidates (age >18, ≥4 prescribed drugs for ≥3 months) was created for each study pharmacy in collaboration with the two main clearing companies IFAK and OFAC. The latter performed an independent screening for each study pharmacy and listed all patients fulfilling the selection criteria for a PMC. Out of this sample of potential PMC candidates, a random primary sample of 100 was selected by IFAK and OFAC (Fig. 1).
Patient recruitment
The study pharmacist checked this primary sample for exclusion criteria and consecutively invited subsamples of ten patients by a letter to participate in the study. Exclusion criteria for final recruitment were the following: living in a retirement home, prior PMC, receiving weekly dosing aids filled by the pharmacy or another person, cognitive impairment, move or death, insufficient knowledge of written and spoken German or French. In addition, study pharmacists re-checked if a patient met the primary inclusion criteria. The study centre received information on gender, date of birth and the reasons for exclusion of a patient. If the patient had expressed his interest in the participation, the study pharmacist informed him about the schedule, potential risks, and compensation and handed over the declaration of consent.
Randomisation process
The patients were assigned by 2 x 4 block randomisation into intervention or control group. Initially, each study pharmacist received two blocks containing eight dossiers (four intervention and four control) each packed in sealed and unlabelled envelopes. Once the first patient had consented, the study pharmacist opened one envelope out of the first block to reveal what arm of the study the patient had been randomised to. Once all eight envelopes of block No. 1 had been assigned, the next block was used. Upon request, further blocks were available.
Structure of the intervention vs usual care
The intervention at T-0 included the execution of a PMC according to the official guidelines. The adapted study PMC protocol was used as assessment form. In a structured face-to-face counselling with the patient, the study pharmacists screened all medicines currently used. The pharmacists checked for any gaps in knowledge or other pharmaceutical care issues including handling and adherence problems. The interview took place in a separated area. Pharmacists were instructed to use open questions to detect pharmaceutical care issues and to decide if there was need for further investigation. For each medication, the PMC protocol (Additional file 1) required documentation whether the patient knew the reason why he/she took the medicines (yes/no), if he/she needed any counselling (yes/no) or had adherence problems (yes/no). Additionally, handling difficulties were enquired, and the pharmacist documented all resulting interventions such as consultation with the general practitioner (GP), referral of the patient, potential suggestion and implementation of a weekly dose reminder system, or any other recommendations or interventions. Where necessary, an individual patient education and a medication plan could be provided on the basis of the information gained from the interview. None of this follow-up interventions was standardised.
Usual care included no specific intervention and no documentation at T-0. Patients of the control group only received the two self-report questionnaires at study start and study end, and the two telephone interviews. Normal counseling for any new prescription or arising question from the patient was always allowed and guaranteed, so patients from this arm were not restricted from contacting the pharmacist for advice if they wished to do so. If a PMC became indispensable during the study period (e.g. by another pharmacist than the study pharmacist), this patient of the control group was excluded. Overall, the study took seven months for each patient and included two visits at the pharmacy with the completion of questionnaires and participation in two telephone interviews. Patients were able to contact the study centre in case of further interest for the study purposes or any problem with the study process (e.g. missed telephone interview) using a separate telephone hotline available 24 h seven days a week.
Classification of detected drug-related problems and addressed interventions
To classify the addressed drug-related problems and describe the pharmacists’ interventions, the GSASA classification tool was used [39] This instrument comprises five main categories: i) problem, ii) type of problem, iii) cause, iv) intervention, and v) outcome. We adapted the category ‘causes’ by dividing the section ‘Insufficient knowledge of the patient’ into three subdomains focussing on patients’ individual needs for information about a) safe and effective use of his medicines b) the medicines’ potential adverse drug reactions c) his lifestyle, nutrition or empowerment in general. Further on, we added the category ‘More cost-effective therapy available’ as the recommendation of generic drugs might be likely triggered throughout a PMC.
Case report forms for study pharmacists
In order to support study pharmacists in their compliance to the study protocol and to ensure coherent data capture, case report forms (CRF) were developed. The study pharmacist documented his interventions or recommendations resulting from PMC, classified the underlying problems according to their urgency (low, medium, high urgency) added any abnormalities or changes in the care of the patient.
PMC protocol form
We used the official documentation form for PMC with minor changes to ease data capture for the purpose of the study (Additional file 1). This assessment form still showed the format of one A4 side. At study end (T-28), in addition to the PMC protocol the study pharmacist documented observed drug-related problems, the frequency of falls, and all changes in therapies since T-0 reported by the patient (dosage change, generic substitution, start/stop, no change). The documentation of these changes was needed to identify eligible therapies for objective adherence calculation.
Patient self-report questionnaires
Patient self-report questionnaires were developed to collect demographic data (age, gender, living situation, education and employment status, smoking status), but also to describe his limitations in executing everyday activities (four items extracted form of the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire [40]) and assess his subjective adherence at T-0 and T-28. The patient therefore had to assess his adherence to all his prescribed medicines for the last two weeks using a visual analogue scale (VASAD) 0–100 mm representing 0 for ‘taken none’ and 100 for ‘taken all my medicines’. Patients were asked to fill in the questionnaires in the pharmacy at T-0 and T-28, seal them in an envelope and return the envelope to the study pharmacist. Thus, the study pharmacists had no knowledge of the responses given by their patients.
Telephone interviews
In collaboration with a clinical psychologist and an economist, two comprehensive in-depth patient telephone interviews were developed aiming at monitoring possible impact of the intervention on patient’s knowledge and medicines use. After literature research, the Rob Horne’s ‘Beliefs about Medicines Questionnaire’ [41] and two questions out of the ‘8-item Morisky Medication Adherence Scale’ (German version, 8-MMAS-D) [42] were defined as suitable to be used as validated questionnaires fulfilling our criteria for telephone interview 1. In addition, we developed new rating questions to report their adherence to their therapy management. Patient had to answer the same question as in the patient questionnaire T-0 to describe their adherence, but in a spoken percentage value. We also chose consistently a 10-item Likert scale. Options ranged from 1 (= ‘not at all’) to 10 (= ‘very much’). The response category ‘no answer’ was always available. Number of open questions (N = 7) was limited to ease documentation.
The first telephone interview contained 58 questions, divided into five sections: i) knowledge of their medicines and daily use, ii) subjective adherence estimation/use of reminder devices, iii) visits at general practitioner/hospital, iv) beliefs about medicines questionnaire, v) support by pharmacists. The interview 2 contained 53 questions, divided into the same sections as in the first interview. Compared with the first interview, 18 questions were excluded and 13 new questions were added. The telephone interviews were carried out two (T-2) and 16 weeks (T-16) after study start by clinical psychologists. The interviewers were blinded to the intervention and without any knowledge of the content of the PMC or the patient’s questionnaire T-0. A telephone interviewer’s coaching and monitoring of compliance with the study protocol was continuously provided by an independent academic psychologist as external expert. A structured interview guide was created using the software program Flexiform 2.6.9 to enable data entry during the interview. Piloting of all study documents and preparation of telephone interviews (recruiting interviewers, briefing and test interviews) were carried out in collaboration with the department of psychology of the University of Basel. All survey instruments were translated into French and retranslated into German to check for differences.
Objective adherence measurement
Objective adherence rates based on refill data of the pharmacies and patient reported dosing regimen. Two methods for objective adherence calculation were used: a) Medication Possession Ratio (MPR) [43], calculated by dividing the days’ supply of a medication dispensed by the number of days in the time interval of interest, representing the adherence per each medicine and b) Daily Polypharmacy Possession Ratio (DPPR) [44], the proportion of time a patient had medication available for use by considering the presence or absence of multiple medications on each day in the observation period, representing the adherence per patient with his chronic polypharmacy. In this analysis only medicines were included, of which the patient reported at T-28 a daily use over the whole study period. Only oral drug forms with definite dosage where considered. Further, a prescription for the medicine had to be redeemed at least once before T-0. Therapies were excluded if prescribed by self-dispensing physicians (cantons BL/SO), changed in dosage during study period, chronic ‘on demand therapies’ (namely pain killers (ATC N02 and M01A), anxiolytics (ATC N05BA), or magnesium supplements (ATC A12CC). Also creams or drops where excluded from analysis due to imprecise assumption concerning dosing regimen. According to the theoretical calculation for both, the MPR and the DPPR, refill data was exported from the patient’s pharmacy. The export included the history of patient’s refills from at least 200 days before T-0 and the study period (T0 to T28, 196 days). For each dispensed medicine, the export comprised the date of refill, a product unique identifier number (pharmacode), the drugs’ ATC-Code, and the number of packages delivered. Subsequently, the pharmacode was matched with the Swiss index database GALDAT®/pharmINDEX® [45] to add the products’ package size (number of tablets) and complemented with the patient reported dosing regimen at T-28 (taken from the PMC protocol of both, intervention and control group). The calculation algorithm started with a look-back loop of 200 days before T-0 taking any packages of medicines postponed to the patient, equalising the fact that the patient was already on therapy before study start. As in previous trials, objective non-adherence was defined as MPR <80 % [46]. Also for the patient’s individualised aggregated measure DPPR, the cut-off for non-adherence was set <80 %.
Subjective adherence measurement
Subjective non-adherence was defined in patient reported questionnaires (T-0 and T-28) as VASAD <100 m, in telephone interview 1 and 2 as Likert scale <10 and in telephone interview 2 additionally as 8-MMAS-D <6.00.
Unplanned visits at the general practitioner/hospital
In order to evaluate a negative impact on the health system, patients’ unplanned visits at the general practitioner or hospital were assessed within the patient’ self-report at T-0 and T-28 and during telephone interview at T-2 and T-16.
Sample size
To determine the required sample size, a power analysis was conducted. In the present study, the null hypothesis is rejected if the primary outcome adherence (as measured by MPR) improves by 5 % through the PMC on an assumed baseline MPR of 60 %. These suggestions were based on experiences from comparable projects [47]. We assumed a standard deviation of 20 % for both groups and used the conventional alpha error of 5 %. To have a statistical power of 80 % we would require 252 patients at T-28 in each group. Assuming a dropout rate of 35 % [48], this would lead to a total sample size of 780 at T-0 (calculated with http://sampsize.sourceforge.net). Thus, we expected from each study pharmacists an enrolment of 10–20 patients. There was no minimal/maximal number for recruited patients per study pharmacist.
Statistical methods
Frequencies were evaluated using the chi-square test, ordinal scales were tested with the non-parametrical Mann-Whitney-U-test. The time course of the various endpoints was calculated using a general linear model (GLM) for repeated measurement method. The study groups were recorded as between-subject variable and the course of the corresponding values as within-subject variable in the model. In case of many missing values, individual templates mixed models analysis was chosen as an alternative method. All statistical tests were two-sided with a significance level of 5 %.
Handling missing data
The intention-to-treat analysis included all enrolled subjects, divided into intervention and control groups. Patients were rated as a drop out when they were excluded at their request or when they were no longer available at study end. Reasons for drop out were documented if available. Patients who missed one or both telephone interviews remained in the study.
Ethical approval
The study was approved by the responsible local ethic commission ‘Ethikkommission beider Basel (EKBB)’ (23.05.2012, registry number EKBB 50/12) as the leading committee for this multicentre study. Following the positive decision from the EKBB, the project was also approved by the local ethics committees of the following cantons: AG/SO (26.11.2012), VS (05.03.2013), VD/NE (12.03.2013), GE (22.03.2013), and FR (25.03.2013). The study was registered with the https://clinicaltrials.gov/ trials database (NCT 01739816). The fee for providing the PMC was covered by basic health care insurance. Study pharmacists received a compensation of CHF 150 for participating in the training session and CHF 50 for the delivery of each complete patient data set. Patients were paid CHF 20 for their time spent for the telephone interviews, and as a compensation for obligatory co-payment to the PMC-fee.