Teri Stokes
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Subject diaries are used in about one-fourth of all clinical trials to collect data on primary and secondary endpoints.1 Part 1 of this four-part series on developing and implementing subject diaries compared and contrasted traditional paper
and electronic diaries.2 In that article, we examined both methods in the context of existing FDA and ICH regulations and guidance for capturing diary
data. We concluded that newer, electronic methods are in fact more compliant with FDA and ICH data standards than traditional
paper diaries. The rest of this series focuses solely on electronic patient diaries (EPDs), in an effort to help clinical
researchers better understand the process of implementing an electronic system to be used in their clinical trials.
In our experience, clinical teams evaluating the use of an electronic diary system often express that they
- are uncertain about the regulatory compliance of electronic systems (see Part 1).
- do not know how an electronic system is specified, built, and deployed.
- are unsure about the effect of including an electronic diary in the clinical trial development process and timelines.
- wonder what changes an electronic diary will require from the participants in the clinical trial process-sponsor staff, monitors,
investigators, and subjects.
Jean Paty
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To address these concerns, this and the following articles in the series present the clinical, technical, and regulatory issues
involved in the development and implementation of EPD trials that meet regulatory requirements. Although clinicians have reasonable
concerns about adopting technology, we plan to demonstrate that the collaboration of clinical and technology teams can result
in a robust clinical trial executed in a timely fashion.
Our experience is primarily with EPD systems implemented on handheld computing devices (personal digital assistants, or PDAs).
Consequently, such systems are used as the example in the rest of the series. There are, however, a number of other ways to
implement EPDs-interactive voice response systems (IVRSs), for example. Although such systems are not the focus of our discussion,
the principles discussed here can be applied to a broad array of subject-based data collection systems, including IVRS.
Protocol development for an EPD study The first step for any clinical trial is to develop a protocol. For studies that make use of an electronic diary component,
it is important to understand the role of the protocol in developing an EPD system that delivers data that meets FDA and ICH
electronic data regulations and guidance. Along with our discussion of the role of the protocol in developing an EPD system,
we discuss the roles and responsibilities of the participants in a clinical trial. Finally, we mention the software development
life cycle (SDLC) approach to the development and deployment of an EPD study-an approach that will get more attention later
in this series.
Here, we address several questions about regulatory issues in subject diary research.
- What is the process of producing a protocol for an EPD study?
- What role does the clinical protocol play in the development of an electronic subject diary system?
- What are the sponsor, investigator, and subject roles in an EPD study?
- How do the clinical trial life cycle and the system development life cycle interact in the design, development, and deployment
of electronic subject diaries?
Producing a protocolClinical-regulatory perspective (Paty). Fundamentally, preparing a protocol for an EPD study is much like preparing a protocol for any traditional subject diary
study. The clinical team responsible for the trial delineates the primary and secondary objectives, and then documents the
trial design, treatment of subjects, and assessment of efficacy and safety in the protocol-per section 6 of the ICH Guideline
for Good Clinical Practice.
A slight departure
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The key difference between the protocol for an EPD study and one using a traditional paper diary is that EPD technology enables
researchers to implement novel study designs. To better understand how EPD systems enable new study designs, it is first useful
to consider the factors that influence the study designs typically used in a paper diary trial.
All subject diaries aim to directly capture the subject's experience at a medical moment. We use the term medical moment to
describe the subject experience prescribed for capture by the clinical protocol. Longstanding clinical lore, now supported
by empirical studies,3-5 maintains that a number of subjects will not complete their paper diary, will give out-of-range answers, and/or will complete
the diary long after-sometimes even before3-the relevant medical moment.
In response to these known issues with paper diaries, clinical teams often reduce the scope of study objectives or the amount
and type of data to be collected in a diary protocol. Studies using paper diaries, for example, often ask subjects to complete
their diaries once a day.6 The end-of-day diaries often ask subjects to report on several events that occurred during the day (for example, micturitions
in urinary incontinence trials) or to aggregate their experience for the day (for example, average pain level in arthritic
subjects). Because we ask subjects to retrospectively recall a number of brief events and/or to summarize their experience,
such designs are vulnerable to recall-based bias and error.7 A number of studies have shown that even these brief periods of recall can be biased and inaccurate.8, 9
Figure 1. The user requirements specification (URS) for e-diary design.
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To optimally capture brief medical moments, subjects should be able to enter data in real time, at the occurrence of the medical
moment.10 This approach yields the most reliable and accurate data, and therefore allows the strongest test of the study objectives.11 For example, the most accurate count of daily micturitions would be derived from having subjects make entries when the micturitions
occur, rather than at the end of the day. The most accurate reflection of daily pain would be an aggregate of multiple momentary
pain assessments captured across the day.12 Such real-time protocols have been successfully implemented with electronic subject diaries; for examples, see Hufford and
Shields.6 Thus, by facilitating real-time recording of events, electronic diaries can extend diary study designs in clinically significant
ways.
Technical-regulatory perspective (Stokes). The use of electronic subject diary technology gives the clinical research team an array of options to support the quality,
integrity, and regulatory compliance of self-reported data. The use of electronic diary technology should also enhance and
expand the medical horizon for a clinical protocol and not restrict it to an electronic version of past experience with paper
diaries. To accomplish this, the clinical protocol must closely describe the subject's experience in the medical context and
define experience reports and collection time strategies in detail.
In other words, the clinical protocol must identify what medical moments the subject should observe, how the subject is to measure or describe those medical moments, and when the subject is to report the medical moments. By doing this, the clinical protocol provides the basis for some of the key
sections of a user requirements specification (URS) for an electronic diary (Figure 1). The clinical team may choose to include
sufficient details in the protocol to make it act as the URS, but most often a separate URS document is developed with the
aid of a technical team. The URS document contains the technical details necessary to develop the EPD for that trial. The
URS is based on a final protocol, and typically developed after the protocol has been fully specified.
