NGP. CDISC standards are attempting to become more widely accepted in order to create a ‘bridge development’ to and from legacy systems. Where does EPD/eCRF technology fit in, and what are the potential benefits?
JP. CDISC standards are potentially very useful when it comes to electronic patient diaries (EPD), or electronic patient reported outcomes (ePRO). Increasingly, we are receiving requests from clients to deliver CDISC ODM XML standard data so that this data can be added to electronic new drug application (NDA) submissions. The other area where CDISC standards will emerge is in eClinical systems integration, such as with ePRO and electronic case report form (eCRF) systems. While such integration is in the early stages of development and maturity, we predict standards will become very important in this area.
GG. These standards provide interoperability between disparaged computing environments. The ePRO/EPD patient diary data is typically collected in third-party systems during the clinical trial. Then, during and/or the end of the trial, this data is uploaded into the sponsor EDC or clinical database for review and analysis along with all of the other collected data. This enables faster database locks, while having a common data format allows for more cost-effective data migrations and less validation tasks.
SR. The ability to integrate data collected directly from patients with all the other sources of data that help people manage clinical trials will, in principle, make it easier to allocate resources, so trials can succeed more quickly. PHT shares CDISC’s vision that as electronic systems are increasingly adopted in clinical research, more sponsors and site coordinators will demand seamless integration of ePRO, lab, web eCRF, safety, IVR and other eSource datastreams.
A common interface to these various systems is already well developed through CDISC. We think the benefits of greater use range from the concrete (a single login for site coordinators, rather than login to and manage as many as five different computerized systems in a given trial, as is the case today) to the prophetic (regulators and researchers can access a common store of clinical trial data and results in assessing the effects of pharmaceuticals on patients). As with the eCTD, the CDISC SDTM submissions model appears to be an adoption gateway, and should lead clinical researchers to become familiar with the other CDISC standards. We have built our systems to embrace CDISC standards, and anticipate their increasing active use as HL7 and EU, EMEA bodies endorse them.
NGP. Although interest is growing in technologies such as this, are there any concerns with these systems? If so, how are these being addressed to move forward?
GG. The EPD systems are a logical migration from paper in that they provide true ALCOA in that the machine keeps track of users and timestamp of data entry. The biggest concern surrounding this EPD is that GCP states that the investigator ‘owns’ patient diary data, but the EPD supplier is paid by the sponsor. The EPD supplier is not mentioned at all in the regulations and acts as a ‘trusted third party’. They are not prone to direct regulatory scrutiny or retribution, and act according to contract only. While there are efforts to bring this under regulation, it will probably show as guidance only.
JP. Interest in and usage of ePRO data is growing quickly in the pharmaceutical industry. There are two primary concerns, both of which can be addressed by applying appropriate expertise to ePRO implementations. Specifically, it is important to ensure that an ePRO implementation is compliant with existing regulations, and that the system design is consistent with the protocol’s requirements. invivodata has successfully addressed both of these concerns. We have applied our regulatory expertise in systems that were used to collect primary endpoint data in successful NDA programs. We have also applied our scientific expertise to ensure that the client data collected is exactly what is needed to test the protocol’s primary hypotheses.
SR. The 2004 CDISC survey on the adoption of data collection technologies offered insight into existing perceptions in the pharmaceutical industry that would prevent or delay adoption of eClinical systems. Concerns cited included a lack of perceived ROI, required change of processes, resistance from investigative sites and a lack of interoperability with other systems. These issues are being addressed by sponsors and technology providers alike.
As sponsors review the metrics from their experiences with ePRO systems, as compared to their relative costs and benefits of using paper methods, they have often found a positive ROI. With ePRO, sponsors are universally experiencing that they obtain more evaluable data than with paper. The data is of higher quality, and, with in greater quantity, leads to reduced variability, which in turn can reduce the sample size leading to considerable savings for sponsors. For sites and subjects, ePRO providers continue to invest in making systems faster, simpler and easier to use. More time and attention is also being expended to be sure that sites not only learn how to use eClinical systems but that they also understand why the particular system is important in their trial. Not only does this make sites feel more involved in the decision to use ePRO, but are then disposed to help accelerate the necessary process changes.
NGP. How does the technology integrate with other technologies? Is it easy to use and does it require much training?
GG. EPDs have benefited from the proliferation of palm pilots and mobile phones in general, because that the public accepts this technology and has no issues in operability. Typically training is performed in the investigator’s office and the patient is sent home. The common issues that arise are similar to those with other battery operated handheld devices. The key to successful implementation is proper planning through the entire trial, as well as a clear understanding of the relatively narrow role of the EPD.
SR. Our systems integrate with other technologies in two ways. The first involves capturing objective measures as well as the patient reported assessments on the LogPad. Measurement devices used by subjects in a trial, such as peak expiratory flow (PEF) meters, spirometers, glucose meters, activity meters and other types of patient devices, can now capture and store such objective measures and then transfer the data automatically and wirelessly to the LogPad. These eSense products demand little more of the subject than that subjects use the measurement devices and bring them occasionally within 10 feet of the LogPad. Transfer of any new measurements then occurs, and subjects can review and/or approve such measurements in conjunction with completing their diaries.
The second way of integrating with other technologies is at the back-end where data is passed into a CDMS system or an EDC system. Here, PHT often uses the CDISC ODM standard, since many systems have demonstrated successful exchange and interoperability on the same set of clinical data using these standards for data interchange among applications.
JP. Integration with eCRF is still in its early stages. However, we have successfully integrated our eDiary system, DiaryPRO, with blood glucose and peak flow devices, and such integrations are now being used in global clinical trials. Patients become adept at using DiaryPRO after approximately 15-30 minutes of training, most of which is focused on learning how the clinical trial protocol works on our system. It takes them less than five minutes to master the system interface.
NGP. Expanding eSource collection methods and improving active analysis of trial and clinical data aims to identify administrative and safety issues early. How does the leveraging of electronic patient reported outcomes fuel that aim and what are the potential long-term risks?
GG. There continues to be a desire to cull patient safety issues directly from EPDs. The fallacy is in thinking that a diary entry can equal an AE or SAE. In reality, the primary investigator is tasked with making this decision and can certainly use flagged datapoints from patient diary sessions to determine if and when they should immediately contact the patient to follow-up. We should never replace the investigator from this critical safety evaluation.
JP. The FDA has very strict restrictions on performing interim analyses during a trial. Those restrictions apply to ePRO systems in the same way that they do to paper-based systems. Once FDA rules are followed, ePRO systems permit quicker data analysis because the information is available in real-time.
NGP. Technology is the most tangible element of an improved clinical development environment. Why are standards-based eCRF’s taking so long for industry-wide adoption?
SR. At the level of the individual field names, sponsor and provider organizations are now beginning to overcome their sense that their data conventions are proprietary. The standards have also become more robust and comprehensive, and adoption of field level standards for submissions is now accelerating rapidly. It also helps that FDA and HL7 have endorsed SDTM standards.
At the level of eCRFs for data capture, the case for the utility of standards is just now beginning to be made, and many organizations continue, possibly with some justification, to think that eCRF organization, layout and design need a high level of flexibility in order to address the varied research requirements for different entities and therapeutic areas. Standardizing some of the metadata for such design as has been done with the CDISC ODM, to enable interoperability within companies as well as continued meaningful access to archived trials. We expect this feature to become more widely appreciated in the next year or two, and that there will be some FDA encouragement of standardization at the level of data models and eCRFs.
GG. While we don’t partake in eCRF technology, from personal experience I’d say that a large barrier to adoption is the frustration felt by users about the time required to navigate one too many eCRF devices in the investigator’s office. The future consideration of culling the eCRF data from EHR systems will therefore be a welcomed path forward.
NGP. What challenges present themselves in terms of business processes, and what are the possible solutions?
JP. The primary challenge for all of us involved in clinical trials is to fully appreciate how technology impacts the process. For patients and clinical research sites, the impact is very positive because our system is simple to use. For clinical teams at pharmaceutical and biotech companies who are translating protocols into ePRO systems, there is a bit more of a challenge because they are learning something new. However, this challenge can be readily overcome with comprehensive support from an ePRO provider like invivodata that has extensive clinical trials experience.
GG. A large challenge in the EPD industry is consistency within pharma. We are finding that clinical teams are not familiar with the nuances of EPD and need to be educated. This goes smoothly until the next trial when it is repeated. The solution is wider industry adoptions that will just take time. The DIA eClinical SIAC ePRO committee is striving to provide webinars and conferences to prophesize this technology, along with the agreed assumptions due to lack of regulatory guidance. It also boils down to site selection and study coordinators willing to adopt this technology.
SR. Using an ePRO system in a trial requires more planning and work up-front than paper methods. The ePRO system must be fully designed prior to the ‘first patient in’ (FPI). In the paper world, paper must be printed prior to FPI but the back-end database can be developed after the trial is initiated as data input can be batched over time.
Implementing an ePRO system for the first time is often an educational process for all stakeholders in the trial, and all parties must work together with the technology provider to reach a satisfactory requirements specification. Once a particular trial configuration is specified, implementation and validation can be accomplished with surprising speed, but the consequences of last minute changes in trial design are much greater than in the paper age because they may require substantial revalidation of the eClinical system. The solution is to automate configuration options where possible and to sensitize the team to developing a precise and detailed understanding early on of how eSource data capture systems must operate in order to fulfil the trial objectives.
A business process change is also required in order to take full advantage of real-time access to the ePRO data throughout the trial. Monitors can be more effective and focused during site visits if they have appropriate remote access to metrics on enrolment, patient diary compliance and submitted patient data. Project managers can better manage global and complex trials by taking quick action if needed upon review of real-time metrics on recruitment, site performance and subject drug and protocol compliance. Sites can better manage the their patients both clinically and operationally if they have access to ePRO data. But such access for all these stakeholders requires process changes to ensure preliminary preparation, training and technical capacity. The solution is to commit to take full advantage of the selected eClinical methodologies at the beginning of a study, and not to minimize the key importance of operational logistics.
In order to get this commitment in an ePRO study, all parties must be educated on the benefits of ePRO in order to help them understand why they need to change their established processes. Technical and operational training is also essential. PHT’s clients are now requesting more intuitive and accessible ‘on-demand’ training before and during a trial. We have partnered with ePharmaLearning and will soon roll out these self-guided online training tools for sites and monitors.
NGP. What differentiates your solutions from any another and what successes have you seen in their use?
GG. The CRF Inc. solution is unique in that our product offering is based on a validated deployed platform that is tailored for each trial. This allows a shorter design and validation effort, providing a more consistent product as opposed to our competition, which must initiate a full validation design effort for each trial. We also have been providing wired and wireless solutions globally since our inception and feel quite comfortable with our more than 100,000 patient, 95 clinical trial, 58 country, 54 language, 32 therapeutic indication base of experience.
JP. Our system is based upon a long history (18 years) of development and use by behavioural scientists. This experience helps to ensure that the system designs we develop with our clients will meet their clinical protocol requirements. Furthermore, our system has a proven track record in the regulatory environment (as evidenced by approved NDAs where invivodata’s eDiary system was used to capture primary endpoint data).
SR. PHT has established superior capabilities in its product and a strong commitment to excellence in delivery. Our key differentiators include the quality of our trial experience, (ISO 9001 certification), product innovations (iron clad data security, eSense Sensors, cognitive testing), user-friendly diary designs (best practices from 185 trials), and global and localization capabilities (Over 50 languages, including support for complex Indic fonts, validated international time stamping, Export for strong encryption). We also have a comprehensive XML study archive, expert internal helpdesk, and technical expertise in protecting the integrity and security of the clinical data captured using our systems.
This all means that we can undertake multinational global trials with confidence that the system and team will perform reliably. The clinical team sponsoring the project will be able to document the symptoms, behaviours and outcomes of subjects and the resulting submissions to regulatory authorities for approval will have a compelling level of detail and documented evidence of validity.
Greg Gogates has over 26 years of experience in the pharmaceutical, electrical engineering, cellular telephone, electro-magnetic compatibility, and nuclear power industries. Fields of expertise include software quality assurance, quality systems, GCP/GMP/GLP, technical/quality auditing, environmental simulation, process automation, computer networking, theatrical automation, data acquisition, nuclear power, plant commissioning, training, electrical testing, and management. Gogates is a senior member of IEEE, DIA Agency, American Association for Laboratory Accreditation, and represents the US on the EUROLAB Software Validation committee for Laboratory Accreditation.
Jean Paty’s responsibilities at invivodata include working with scientific, technical and clinical operations components of the company to ensure all aspects of the business meet FDA and international data standards for the pharmaceutical industry. Paty has published extensively in the area of the regulations guiding development and implementation of ePRO, and has worked with industry and regulatory agency groups on ePRO best practices. He has also worked and published with invivodata’s Chief Science Officer for the past 17 years on the development of real-time, real-world solutions to study patient experience.
Stephen Raymond co-founded PHT Corp in 1994 with the goal of improving clinical research by obtaining better information from the human subjects of clinical trials. Raymond holds a number of patents and serves PHT in a multitude of capacities, including chief visionary, product design, leader of PHT’s innovation team, and liaison for academic medicine. He is responsible for providing PHT the scientific, regulatory, quality and information management expertise needed to achieve its vision of transforming clinical research through innovative technology.