The State of Feasibility
A few emerging themes have been at the forefront of discussions surrounding study feasibility assessments. Despite technological improvements and real-time access to data, we continue to be plagued by some common mistakes often overlooked in our feasibility steps. For example, most sponsors and CROs continue to provide very limited information and time to sites to respond to protocol feasibility. A two-page synopsis excluding inclusion or exclusion criteria (IC/EC) and sample size is simply not enough information for sites to adequately respond on their patients that may be eligible for a trial. As an industry, we continue to underestimate the use of site feasibility questionnaires. Sites frequently tell sponsors what they want to hear and this is often in response to the types of questions being asked. Instead of asking how many patients can be enrolled in a certain study, we should ask how many patients with this particular IC/EC will be enrolled in 1 month, 6 months, or longer. Insights into the future of feasibility and steps we can take to improve our methodology are presented in this article.
Definitions
Feasibility must be viewed as two distinct steps. First, we should consider Medical Feasibility. This can be described as the amount of patients who exist in a particular demographic and meet the study eligibility criteria. Many seek this information much too late during the execution of a clinical trial. Medical feasibility also addresses patient burden and our current standard of care. Understanding how eligibility criteria can be modified to increase probability of recruitment while preserving the scientific validity of the study should be another key consideration.
Figure 1
The second step is properly implementing an Operational Feasibility strategy that is realistic and in line with your trial goals. Many tools, service providers, and sources promise to help with this often challenging task but few can make accurate predictions once a trial is planned and initiated.
Figure 2
Tufts Center for the Study of Drug Development Impact Report, Tufts University, Vol. 13, Number 5, September/October 2011A key element of operational feasibility includes ensuring adequate time and information is provided to sites to comment on the trial specificiations with a full response to the site feasibility questionnaire. Other important factors involve allowing time for geographical assessment of countries and evaluating health authority and ethics committee requirements, as well as reviewing past performance and obtaining references (where available). Though this key step may add time to your assessment, it continues to be neglected by Pharma and can often be extracted from internal systems or networks in industry.
Feasibility Drivers
Why should we invest time and resources into improving trial feasibility assessments? The data suggests that there are four key areas that cannot be ignored. First, there is the realization that protocols have become much more complicated over the past few years. The industry is adding visits, assessments, and tests to protocols resulting in increased complexity [1].
Figure 3: Information obtained from reference [5].
Secondly, there are 2.9 amendments per protocol on average. Not only does this add a significant amount of time in writing and submitting for ethics approval, but a third of these amendments are usually avoidable [2]. Improper protocol designs and recruitment challenges equate to approximately 20 percent of all protocol amendments [3].
The third area of concern relates to cost. As an industry, we are aware that the cost of drug development has continued on a linear curve over the past 20 years. It is also clear that cost containment is critical for companies and sites to sustain growth for the long term. The data illustrates that 30 percent of all investigative sites fail to enroll more than one patient [4]. Each site costs $30,000 on average to initiate and each protocol amendment carries an average price tag of $450,000 USD [2-3].
Figure 4
Lastly, we must address the impact of timelines. Eighty percent of all clinical trials are delayed by more than a month and this can be attributed to many factors, which include additional amendments being written, recruitment difficulties, inadequate supplies, and site readiness to name a few. The opportunity cost also exists as with each day of delay in getting the product to market represents a lost opportunity of an estimated $1.4 million USD (assumes projected annual sales of marketed compound at US $500 million) [4].
Tools
There are many available tools that support the feasibility process but for the purposes of this article, three areas that have proven helpful to the author’s organization are highlighted.
EHR Databases
The use of electronic health record databases (EHR) DBs are important to note. The principle here (highlighted in Figure 4) is to take advantage of solutions that can provide access to de-identified data from patients that can allow you to “test” your protocol. A basic solution would allow you to enter your protocol eligibility criteria to test your hypothesis to see if patients exist based on the specifications that have been designed. The ability to conduct “What If” analyses and geo-mapping are powerful, advanced techniques, and should be part of the feasibility assessment.
Pre-Investigator Meeting
This is relatively simple concept but with very powerful implications. The purpose of this meeting is to invest as much time as possible early on with your potential investigators and coordinators to obtain their feedback and comments on the protocol design. Most investigators would be more than happy to provide their input if it will be taken into consideration [4]. This typically introduces the question of why would we want to engage all of our investigators together? Shouldn’t a clinical trial be set up as “competitive enrollment”? Both are valid points but there is great potential in engaging collaborators early with sponsors and sharing best practices in the interest of achieving a successful clinical trial. One or two may hesitate from this approach though the overwhelming response has been positive for both sites and sponsors. The meeting itself should cover an overview of the compound, an operational overview of the planned assessments, and a question and answer session. Using a webinar format, you can quickly and easily engage sites across the world for a minimum of one hour ensuring they have direct access to the medical and operations team.
Figure 5
Keeping sites “warm” from the beginning is another area of site engagement to consider [4]. This is a powerful yet simple tactic to ensure sites do not lose interest as you continue to refine the protocol and setup for the formal Investigator meeting. The frequent time lag of several months after that first conversation means that requesting items like the CDA, Investigator CV, MSA, etc., will not only alert your sites of the timelines approaching but also keep them engaged and ahead on the regulatory documents needed for the ethics submission, thus allowing them to focus on the more critical duties of engaging patients for the trial.
Web-based Feasibility Questionnaire
Paper-based feasibility questionnaires are still commonly used and continue to have merit in the process, but available technology highlights the limitations. The industry has access to many applications that can help quickly set up a web-based system. Instant advantages include a completely online system with audit trail, reporting tools, electronic tracking and quick setup and response. The opportunity for an immediate response to potential collaborators allows tremendous savings on time and resources in decision-making and trial setup. Sponsor should have thoughtful conversations early on with research staff members. The socalled “interest queries” which can often derail the site questionnaire process should be limited. Industry experts know that site enrollment estimates are often based on guesswork. Using a “Funnel” approach (see Figure 5) may help sites estimate the number of patients they can contribute and should be part of the feasibility questionnaire. Lastly, we do not use these responses as learning experiences and this is where the added benefit of technology can help run reports on historical responses to compare with current requests.
Conclusion
A proper feasibility assessment should include a balance of available technology and simple yet powerful best practices which require time and resources to implement. “Back-up” sites are frequently relied on much too late in the trial commencement stage, adding cost and time to all clinical studies. The benefits of a proper assessment are realized during the execution of the trial. With proper planning, unnecessary protocol amendments and delays due to recruitment challenges can be avoided. Though sponsors may make the mistake of not validating enrollment figures provided by sites, this can be rectified by simply looking at trials in your own internal systems. Peer-to-peer reviews are invaluable and references from sites should be requested where possible. Feasibility is an evolving process and a crucial step in drug development as it facilitates our ability to recruit patients with high unmet medical need.
References
- Journal of Clinical Research Best Practices, Vol. 8, No. 1, January 2012
- Stone, Judy, M.D., Conducting Clinical Trial Research, Chapter 2: “Scrounging Your First Study.” http://conductingclinicalresearch.com/ sample_chapter.php
- Tufts Center for the Study of Drug Development Impact Report, Tufts University, Vol. 13, Number 5, September/October 2011
- Applied Clinical Trials, Enrollment Performance: Weighing the “Facts”, May 2012
- Getz et al. “Measuring the Incidence, Causes, Repercussions of Protocol Amendments”. Drug Information Journal. Vol. 45, pp. 265-275, 2011.
Sameer Tandon is a Global Supplier Performance and Innovation (SP&I) Manager for R&D at Novartis. Mr. Tandon focuses on the capabilities and technologies in the company’s supply base, identifying opportunities and partnerships that deliver value, efficiencies, and innovative approaches to support drug discovery and development.