Dr Gholamreza Roshandel; MD,MPH,PhD Ethical issues of the PolyIran study: A cluster randomized trial nested within Golestan cohort study Dr Gholamreza Roshandel; MD,MPH,PhD Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran

Golestan Province on Asian belt of Upper GI cancers

Golestan Cohort Study (GCS) (Largest Prospective Adult Cohort study in Iran and Middle East) Main AIMs: 1- To determine major risk factors of esophageal cancer in Golestan province Started in 2004 Number of participants: 50,000 subjects

The PolyIran study Main aim: To assess the effectiveness and safety of polypill tablet (aspirin, atorvastatin, hydrochlorothiazide and either enalapril or valsartan) for primary and secondary prevention of cardiovascular diseases

Design Study Setting: Randomized Controlled Trial nested within GCS Study population: GCS participants, lived in rural areas, age>=50 Sampling: Randomization method: Clustering Arms: Intervention arm: polypill tablet + minimal Care Control arm: Minimal care Third Arm: Usual Care Definition: Polypill tablet: Comprising hydrochlorothiazide, aspirin, atorvastatin and either enalapril or valsartan Minimal care: Non-pharmacological preventive interventions (recommendation on life style modification) Usual care: Medical care routinely provided to all population members by the public and private sectors Outcomes: Primary: Major cardiovascular Events (MCVE) Duration of study: 5 years

Data collection Enrollment: Follow up: Outcome ascertainment: Started: February 22th, 2011. Sampling: All participants within a cluster were randomized to receive the intervention or control conditions Totally 8410 subjects were enrolled to the study. Follow up: Started: May 26th, 2011 Outcome ascertainment: Primary outcomes of PolyIran study are being assessed by the GCS follow-up team They are located in different geographical location from PolyIran team and are blind to all aspects of PolyIran study including allocation of participants.

Ethical issues 1. Justification for using cluster randomization 2. Obtaining informed consent 3. Dealing with current clinical practice in the study population 4. Post-trial provisions

1. Justification for using cluster randomization In this population, residents of the villages have close familial relationships and it is a common behavior to share medicines among residents. Therefore, The issue of contamination due to sharing of medicines was a major concern in this study. We consider cluster randomization to avoid of this contamination. Cluster randomization at the level of villages minimizes the risk of contamination through pill sharing.

2. Obtaining informed consent Although the PolyIran trial is a cluster randomized trial, the interventions of interest (polypill tablet and minimal care) are delivered to subjects individually. Accordingly, written informed consent was obtained from each subject. The subjects were aware that they may be allocated to the polypill arm (intervention) or the minimal care arm (control). The majority of GCS participants (about 80%) were illiterate and obtaining informed consent therefore raised many obstacles.

Dedicated local (native) interviewers were trained and assigned to obtain inform consent. Interviewers were trained to provide all information (according to informed consent) to participants and to make sure that all information was comprehensive and clear to participants.

3. Dealing with current clinical practice in the study population Some of the PolyIran subjects (in both arms) suffered from CVD before recruitment. These subjects had already been referred to a specialist physician in study area and were under treatment using different medications. In these cases, for control arm participants, we just recorded their medications and recommended them to continue the medications according to their physician’s advice.

3. Dealing with current clinical practice in the study population (cont’d) But, for intervention participants, we sent a letter to patients’ physician, explaining the study plan and the combination of polypill tablet to the physician and asked the physician (if it is applicable) to adjust the participants’ medication according to polypill components. In these cases, all medications and physicians’ orders were recorded for future follow-up and analysis.

4. Post-trial provisions Post-trial provision is a major ethical issue in this study. If the polypill is shown to be safe and effective, it will be provided to all study subjects, including those in the minimal care arm, after termination of the project. But, for how long should we continue providing the polypill tablet to subjects? Naturally, there are concerns regarding feasibility of this decision for long-term access.

The GCS team in front of the Gonbad-e Qabus tower Thanks for your attention The GCS team in front of the Gonbad-e Qabus tower