Real-world evidence data generation: a should have

Xavier Fournie, MD
Corporate Medical Director, Executive Vice President Global Medical Affairs, Mapi Real-World Evidence
Patients have an increasing role in the benefit/risk assessment of health products. As the final “consumer,” they represent a critical pathway for the actual product use. Patient-centered approaches in studies are used now more than ever before. In studies, collecting Patient Reported Outcomes (PRO) with limited assessment/methodological bias and ensuring patient recruitment and retention represent both strategic and operational challenges. Assuming that the traditional study organization, where full patient management is ensured by the investigator’s staff, is the gold standard and the best way to succeed—but it can be deceiving. This is particularly the case in the post-marketing setting where investigators are, above all, treating physicians who are sometimes less experienced and committed in studies and without a dedicated staff to assist them. Non-interventional study design, without imposed patient follow-up visits and the involvement of several physicians in the patient’s care, increase the number of patients lost to follow-up rates.
Facing such real-world realities, Mapi has always been convinced of the efficacy of direct patient management in studies—and has promoted its use. In 2001, we set up a dedicated unit (ProClinica™) in order to offer and maintain expert and trustworthy services for direct patient management, i.e., contacts performed independently from the patients’ healthcare professionals (HCPs) and/or investigators using various means of communication. Successful stories in more than 35 countries and impressive metrics (see Table 1) have confirmed the relevance of this strategy.

Table 1. Average performance metrics over the past 12 years and 40 projects
Key Performance Indicator (KPI) Metric
Patient acceptance rate
= Number of COF received/number of patients included in the study
96.3% [70.3% - 100%]
Patient reachable rate 88.4% [66.7% - 100%]
Interview/data collection rate 91.8% [84% - 100%]
Questionnaire return rate
Clinic-based recruitment + longitudinal FU
All study designs

78.1% [69.4% - 100%]

70.6% [53.3% - 100%]

Patient retention rate 94.5% [80% - 99%]
Patient voluntary withdrawal rate 3.2% [0% - 8%]
Lost to follow-up rate 1% [0.5% - 2%]
Number of call attempts to reach patient/subject 2.6 attempts

 

Recent survey (n = 8,500 patients): 98% patients satisfied with their participation, study organization (two-year follow up), would be willing to participate again.
The recent development of Post-Approval Studies with safety and/or efficacy objectives has boosted the use of such services. Needs to be covered include: (a) new study design based on direct patient follow-up and pro-active pharmacovigilance systems; (b) subjects’ motivation and retention in studies where no regular visits at investigator site are scheduled; (c) minimizing Lost to Follow-Up rates (a patient can be lost to follow up due to a serious safety event or can switch from an HCP to another one over time); and (d) PRO data collection at the source from patients or their relatives or from treating HCPs who are not involved in the study.
As pioneer and mentor of this way to optimize studies, we have had to face several concerns, ethics, patient personal data protection management, and return on investment being the most frequent concerns we have experienced.
A dedicated set of Standard Operating Procedures within our quality-assurance system has been developed in order to comply with ethics and data protection requirements and to ensure full acceptance of our interventions by patients, ECs, health authorities, HCPs, and all study stakeholders. Our commitments are summarized in Table 2.

Table 2: Ethics and data protection commitments for Direct Patient Management

Independency
Patient contacts are managed by an independent staff that is exclusively dedicated to the direct and proactive management of patients for the study.
Independency serves both data privacy and methodological concerns.

Consideration of science and methods
Studies which are nonscientific may be unethical. Our services are designed and tailored by experienced direct-to-patient specialists to meet scientific and methodological requirements of each study and ensure control of potential bias and confounding factors. Medical input is solicited as appropriate.

Separation of data
Patient’s health data and contact details (identifiable data) are strictly kept separated one from the other (i.e., in different files or databases). If Direct Patient Management staff is in charge of collecting health data, we ensure that those data are transferred only with the patients’ study/program identification number to other study/program stakeholders.
Documented individual commitment to confidentiality
Each staff member works under a signed confidentiality agreement and is committed and trained to strictly respecting professional confidentiality
No health product advertising
The Direct Patient Management unit does not advertise any health products or express opinions about them during their contacts.
Non-interference & non-substitution
The Direct Patient Management staff does not serve as substitutes to the patients’ healthcare professionals nor do they interfere with usual healthcare management and usual patient-healthcare professionals relationship. This relationship is even promoted and patients/relatives are reminded to contact their healthcare professionals for any question related to their treatment or health status.
However, a medical backup is ensured by a physician to liaise with HCPs when appropriate.
Use of contact details for intended purpose
The Direct Patient Management unit never uses patients’ (or relatives’/treating physicians’) personal contact details as well as health data for any other purpose than the study or health program.
Patients temporarily share their contact details with the Direct Patient Management unit for the only purpose of a study/program. Once the necessary contacts are finished, we document the destruction of the contact details. Patients’ names and contact details that are retained by the Direct Patient Management unit are never transferred, sold, or let out to any other person involved or not in the study/program. For obvious reasons, this restriction does not apply to the healthcare professionals involved in the study and patient’s healthcare who need such personal data to ensure continuity of care, to our partners directly involved in our processes, and when transfer of information is formally requested by law (for safety purposes, for example).
Subject agreement and transparency
Patients or their legal representatives are asked to complete and sign a “Contact Order Form.”
From an ethical and personal data-protection perspective, this written patient information and agreement provides evidence that the patients and/or their legal representatives have voluntarily communicated their personal (and treating physician’s, as appropriate) contact details to the Direct Patient Management unit. This will allow them to follow through with the contacts as described in the protocol during the study.
Compliance to data privacy regulations
The Direct Patient Management unit processes are in accordance with Directive 95/46/EC of the European Parliament and with the Council on the protection of individuals with regard to the processing of personal data and on the movement of such data. The Direct Patient Management unit activities have been declared to the French Data Protection Authority (i.e., the CNIL - Commission Nationale Informatique et Libertés). The declaration covers the management of patients’ contact details. In addition, our US-based unit is U.S.-EU Safe Harbor certified: both the European directive and USA act are aimed at enhancing data privacy protection for their citizens.
Compliance to ethics regulations
In accordance with applicable international and local regulations, the studies we perform are submitted to regulatory and ethics committees and competent health authorities in all concerned countries. No direct contacts with patients are initiated until the necessary approvals are obtained in each country.

 

Separation of data
Patient’s health data and contact details (identifiable data) are strictly kept separated one from the other (i.e., in different files or databases). If Direct Patient Management staff is in charge of collecting health data, we ensure that those data are transferred only with the patients’ study/program identification number to other study/program stakeholders

Documented individual commitment to confidentiality
Each staff member works under a signed confidentiality agreement and is committed and trained to strictly respecting professional confidentiality

No health product advertising
The Direct Patient Management unit does not advertise any health products or express opinions about them during their contacts.
Non-interference & non-substitution
The Direct Patient Management staff does not serve as substitutes to the patients’ healthcare professionals nor do they interfere with usual healthcare management and usual patient-healthcare professionals relationship. This relationship is even promoted and patients/relatives are reminded to contact their healthcare professionals for any question related to their treatment or health status.
However, a medical backup is ensured by a physician to liaise with HCPs when appropriate
Use of contact details for intended purpose
The Direct Patient Management unit never uses patients’ (or relatives’/treating physicians’) personal contact details as well as health data for any other purpose than the study or health program.
Patients temporarily share their contact details with the Direct Patient Management unit for the only purpose of a study/program. Once the necessary contacts are finished, we document the destruction of the contact details. Patients’ names and contact details that are retained by the Direct Patient Management unit are never transferred, sold, or let out to any other person involved or not in the study/program. For obvious reasons, this restriction does not apply to the healthcare professionals involved in the study and patient’s healthcare who need such personal data to ensure continuity of care, to our partners directly involved in our processes, and when transfer of information is formally requested by law (for safety purposes, for example).
Subject agreement and transparency
Patients or their legal representatives are asked to complete and sign a “Contact Order Form.”
From an ethical and personal data-protection perspective, this written patient information and agreement provides evidence that the patients and/or their legal representatives have voluntarily communicated their personal (and treating physician’s, as appropriate) contact details to the Direct Patient Management unit. This will allow them to follow through with the contacts as described in the protocol during the study.
Compliance to data privacy regulations
The Direct Patient Management unit processes are in accordance with Directive 95/46/EC of the European Parliament and with the Council on the protection of individuals with regard to the processing of personal data and on the movement of such data. The Direct Patient Management unit activities have been declared to the French Data Protection Authority (i.e., the CNIL - Commission Nationale Informatique et Libertés). The declaration covers the management of patients’ contact details. In addition, our US-based unit is U.S.-EU Safe Harbor certified: both the European directive and USA act are aimed at enhancing data privacy protection for their citizens.
Compliance to ethics regulations
In accordance with applicable international and local regulations, the studies we perform are submitted to regulatory and ethics committees and competent health authorities in all concerned countries. No direct contacts with patients are initiated until the necessary approvals are obtained in each country.

Return on investment plays an important role for sponsors to determine if Direct Patient management services are valuable in a study. The financial investment may be beneficial regardless of the cost to ensure completion by the patients, thus meeting the scientific study objectives. But it could generate cost savings as well. The cost savings are mainly related to the cost of a patient lost to follow up, thus they depend on the expected rate of patient LFU with/without Direct Patient Management services and the planned patient sample size.
Direct Patient Management in studies is just a component of a more global patient-centered approach. We continuously anticipate forthcoming needs and develop new combined activities to give voice to the patients.
More information about Proclinica on www.proclinica.info