Technical challenges in designing post-marketing eCRFs to address clinical safety and pharmacovigilance needs

doi:10.1016/j.cct.2009.11.004

Contemporary Clinical Trials

Volume 31, Issue 1, January 2010, Pages 108-118

https://doi.org/10.1016/j.cct.2009.11.004 Get rights and content

Abstract

To identify key challenges and propose technical considerations in designing electronic case report form (eCRF) for post-marketing studies, the author undertakes a comprehensive literature review of peer reviewed and grey literature to assess the key aspects, processes, standards, recommendations, and best practices in designing eCRFs based on industry experience in designing and supporting electronic data capture (EDC) studies. Literature search using strings on MEDLINE and PUBMED returned few papers directly related to CRF design. Health informatics and general practice journals were searched and results reviewed. Many conference, government commission, health professional and special interests group websites provide relevant information from practical experience — summarization of this information is presented. Further, we presented a list of concrete technical considerations in dealing with EDC technology/system limitations based on literature assessment and industry implementation experience. It is recognized that cross-functional teams be involved in eCRF design process and decision making. To summarize the keys in designing eCRFs to address post-market study safety and pharmacovigilance needs, the first is to identify required data elements from the study protocol supporting data analyses and reporting requirements. Secondly, accepted best practices, CDASH & CDISC guidelines, and company internal or therapeutic unit standard should be considered and applied. Coding (MedDRA & WHODD) mapping should be managed and implemented as well when possible. Finally, we need to be on top of the EDC technologies, challenge the technologies, drive EDC improvement via working with vendors, and utilize the technologies to drive clinical effectiveness.

Introduction

The electronic data capturing (EDC) technology and systems have enabled automated support for clinical study data collection, reporting, query resolution, randomization, and validation, among other features for the past two decades. There is a trend toward greater adoption of EDC tools in the clinical research industries though the EDC implementation has its sufferings such as: lack of global standardization, technology integration challenges, and certain resistance from sponsors/investigators to switch from paper based data collection (PDC) to EDC.

However, the rationale behind EDC is so strong and much accepted in the clinical research communities: eCRFs are filled and collected via computers connected to the world wide web to expedite the availability of accurate/complete data [1], [2]. EDC vendors need to take up the challenges to address some of the implementation issues via collaborating with sponsors: performance, usability, integration among Clinical data management system (CDMS), clinical trial management system (CTMS), and/or clinical safety system in order to compete and win market shares. Service-oriented architecture should be devised to meet the increasing and complex medical research by offering scalable and flexible system maintenance and new releases. Technology advance and collaboration among various clinical functional groups, regulatory agencies, standard consortiums, and the industry will push for more effective e-clinical research solutions and more interoperable EDC systems to realize several core benefits: time savings, cost reductions, and increased efficiencies.

Risk assessment during clinical product development needs to be conducted in a thorough and rigorous manner; however, it is impossible to identify all safety concerns during controlled clinical trials. Once a product is marketed, there is generally a large increase in the number of patients exposed, including those with co-morbid conditions and those being treated with concomitant medications. Therefore, post-marketing safety data collection and clinical risk assessment based on observational data are critical for evaluating and characterizing a product's risk profile and for making informed decisions on risk minimization. Regulators are demanding proactive surveillance programs that include comprehensive risk management plans and signal detection/analysis throughout a clinical product's lifecycle. Organizations that take the lead in developing a more proactive and long-term approach to manage the safety of their products, recognize that success requires a continuous, consistent process from preclinical research onward. This is achieved through developing a good clinical safety practice that shows the company was aware of and acted on every safety issue as it developed for a product or device [3].

A comprehensive literature review is undertaken to assess current industry approaches in eCRF design methodologies. The eCRF design principles, processes, standards, guidelines, and best practices for properly capturing clinical protocol and compliance-necessitated data has been reviewed, summarized, and presented from industry implementation perspective. Specifically, the issues confronted in the eCRF design of post-marketing studies using EDC tools are discussed; and, proposed technical considerations are presented and illustrated.

Refer to Fig. 1 to see a typical clinical data flow in a post-marketing study.

Section snippets

Real-world view on drug/device safety

A considerable number of clinical trials generally involve a very small, carefully selected patient population, which is hardly indicative of the much larger and diverse expanse of patients who may be exposed to a new product after regulatory agency approval and product launch. Therefore, the body of data accumulated during controlled clinical trials is not sufficient to adequately predict a product's future performance in the real world [4].

Adverse Event Reporting System is designed to support

eCRF development workflow

In general, the following data domains need to be collected for post-marketing safety reporting needs [7]

•
Demographics (DM)
•
Adverse Events (AE)
•
Vital Signs (VS)
•
Medical History (MH)
•
Physical Examination (PE)
•
Laboratory Test Results (LB)
•
Prior and Concomitant Medications (CM)
•
ECG Test Results (EG)
•
Disposition (DS)
•
Exposure (EX)
•
Substance Use (SU)

Fundamental eCRF design principles should be followed regardless protocol or therapeutic unit:

•
Develop as early as possible with a stable draft Protocol, based on

CDISC and CDASH standards

In recent years, there have been a number of interesting discussions and developments with clinical data standards such as Health Level Seven(HL7) and Clinical Data Interchange Standards Consortium (CDISC) [8]. The landscape of healthcare-related standards is large, complex, and interrelated with multiple players in this arena. Fortunately, CDISC has a “niche” in the development of standards for clinical research in having initiated a collaboration with the leading healthcare standards

Coding standards

The Medical Dictionary for Regulatory Activities (MedDRA) has been developed as a pragmatic, clinically validated medical terminology with an emphasis on ease-of-use data entry, retrieval, analysis, and display, with a suitable balance between sensitivity and specificity, within the regulatory environment. MedDRA is the international medical terminology developed under the auspices of the International Conference on harmonization of Technical Requirements for Registration of Pharmaceuticals for

Appropriate use of EDC technology

The recent focus on electronic data collection creates the temptation for companies to purchase a piece of software and expect to drop this into their operations and quickly gain the advertised advantages. In practice, however, this is rarely the case; most often, the purchaser realizes that there are many other complimentary pieces of the process that need to be aligned, and these changes ripple through the organization and end up being considerably more profound than anticipated [11].

The

Unanticipated adverse drug experience (UADE)

When a new drug is first marketed, findings regarding its efficacy and safety are commonly based on the experience of several thousand people who have been treated in controlled clinical trials. Despite extensive testing, rare adverse events (those that occur in less than one patient per thousand) can easily escape detection, and unforeseen interactions with coexisting clinical conditions or other drug therapies may remain unexplored. As a result, the characterization of the full safety profile

Conclusion

The market acceptance of EDC technology has fueled new demands for improvement, configurability, and intelligent features. The need to improve clinical efficiencies and accelerate study times continues to grow, driving industry sponsors to seek an eClinical environment that provides and promotes: flexible, speedy eCRF trial design and build; robust data management; real-time data visibility, reporting and analysis; and global trial management and study scalability [16], [17].

eCRF design is the

Conflict of interest

The author has disclosed that opinions or views expressed through this article represent individual perspectives only.

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ReviewTechnical challenges in designing post-marketing eCRFs to address clinical safety and pharmacovigilance needs

Abstract

Introduction

Section snippets

Real-world view on drug/device safety

eCRF development workflow

CDISC and CDASH standards

Coding standards

Appropriate use of EDC technology

Unanticipated adverse drug experience (UADE)

Conclusion

Conflict of interest

Int J Med Inform

Contemp. Clin. Trials

J Am Med Inform Assoc

The use of electronic data capture tools in clinical trials: web-survey of 259 Canadian trials

J Med Internet Res

Information technology in pharmacovigilance: benefits, challenges, and future directions from industry perspectives

Drug Healthc Patient Saf

Potential for conflict of interest in the evaluation of suspected adverse drug reactions — a counterpoint

JAMA

Observational data under the microscope

Appl Clin Trials

Knowledge innovation and clinical operational excellence

Drug Inf J

Review
Technical challenges in designing post-marketing eCRFs to address clinical safety and pharmacovigilance needs