More Than Document Collection: The eTMF As the Conductor of Study Start-Up Part 2 – Ethics Submission and Approval

Study start-up (SSU) is all about speed, because in the costly world of clinical trials, time is literally money. A study conducted by the Tufts Center for the Study of Drug Development found that start-up for an individual site (pre-visit to site initiation) takes about eight months, a significant portion of the overall time and expense of a clinical trial[1].  Clinical trial delays can cost a sponsor between six hundred thousand and eight million dollars per day[2], but despite the high stakes and costs, 11% of selected sites are not activated[3], and in a given trial, 30 to 70% of sites will fail to deliver a single enrolled patient[4].

As TMF professionals, we play an outsized role in SSU, especially during essential document collection. SSU, however, is not just difficult because of the number of documents collected but because of what those documents represent—many critical and interdependent events occurring simultaneously. Each individual event is like an instrument in an orchestra. There are individual sites, stakeholders, regulatory requirements, and documents. Each has their own location, identity, and score, but all must move in harmony to produce a symphony. What SSU needs is a conductor, and the eTMF is capable of filling this role.

In this blog series we’ll examine some key events of SSU, and show how an eTMF, when used to its full potential, can play a central role in mitigating the drivers of delay by helping the many stakeholders of a clinical trial work together. In the last post, we considered how the eTMF can mitigate the main drivers of delay in the site ID and selection process.  In this post, we’ll discuss how the eTMF can eliminate delays associated with the ethics submission and approval process.

Ethics Submission and Approval

Ethics committees, or as known in U.S. clinical trial regulation as Institutional Review Boards (IRBs), are vital to the conduct of safe and ethical clinical research. An IRB is a committee made up of at least five individuals who are diverse in experience, expertise, and institutional affiliation. It’s the duty of these five or more IRB members to review the methods of a clinical trial to ensure that they are ethical. The regulatory basis for the IRB is found in the Common Rule (45 CFR 46[5] ) and the requirements for IRB composition and conduct are outlined in 21 CFR 56[6].

IRBs determine whether a clinical trial is ethical by examining the risks and benefits to patients. In order to make this determination, IRBs require an ethics submission package from the site that contains various regulatory documents, including the clinical trial protocol, informed consent form, and evidence of the investigator’s qualifications. If the submission package is complete, the investigator is qualified, and the protocol is ethically sound, the IRB will issue an approval for the protocol to proceed at that trial site. Common SSU delays related to the ethics submission and approval process include:

Country-Specific Regulations: The regulatory and ethics review requirements necessary to activate a clinical trial site vary greatly from country to country. Regardless of the comparative administrative burden to U.S. ethics requirements, however, clinical operations professionals must have a plan for identifying all the country-specific requirements that impact their study and trial sites and the resulting interdependencies of the country-specific requirements with other clinical trial events and documents. As different countries may require certain regulatory documents generated at different points in the SSU timeline, placing country-specific regulations within the overall timeline of SSU is critical to avoid unexpected delays stemming from one country or region becoming out-of-synch with the trial as a whole.

eTMF Solution: The features of your eTMF system are already designed to account for and help you organize differences in regional regulation by allowing customization of expected zones, sections, and artifacts of the TMF filing taxonomy. As part of the development of a TMF plan, information during feasibility should alert the study team to expected regional regulatory documentation before it is filed so that the TMF can be updated accordingly. Expected regional documentation should also be incorporated as part of study-specific TMF training in advance of trial start-up.

Local IRBs: Some clinical trial sites require the use of a local IRB that is part of their institution, such as a hospital network or university, while other sites allow the use of a centralized IRB arranged by the sponsor. A centralized IRB, in contrast to a local IRB, governs many or all of the sites in a clinical trial regardless of their institutional affiliation or location. While local IRBs may allow an institution to have better oversight of the research conducted by their associate investigators, there are many downsides. Each local IRB adds different professional contacts, online portals, applications, and review calendars that must all be closely tracked. The potential for error and delay is high. A central IRB, on the other hand, allows for standardized processes, applications, and schedules, greatly reducing the administrative burden of ethics submission and approval. The overall impact on efficiency is significant: a recent study found central IRBs reduced the cycle time of IRB review from five weeks down to one week[7].

eTMF Solution: A healthy and contemporaneous TMF allows clinical trial stakeholders to quickly access data about a local IRB, so key pieces of information, like the dates of IRB meetings and the checklist of documents required for a complete submission, are available to all. Once the requirements of a local IRB are well characterized, clinical trial stakeholders can efficiently integrate the local IRB into the overall ethics submission and approval work stream. This means instead of having to understand and respond to local IRB requirements individually (which essentially means starting from scratch with each local IRB application), clinical trial stakeholders can easily copy, re-use, or adapt existing regulatory documents from the eTMF.

Infrequent IR Meetings: IRBs meet to review clinical trial applications on a schedule. Given the requirement of IRB members to be diverse in experience, expertise, and institutional affiliation, it’s very likely that most IRB members have other professional obligations. For this reason, IRBs, especially smaller non-profit local IRBs, might meet as infrequently as twice per year. Even the largest central IRBs might only meet once a week. Once holidays and vacations are factored in to an already infrequent meeting schedule, it’s entirely possible that a document delay of just a few days could add months or weeks to a site’s activation date.

eTMF Solution: A contemporaneous TMF allows stakeholders to quickly and easily access the TMF documents with information about the specific requirements of local IRBs. With complete visibility to local IRB requirements and calendars, stakeholders are unlikely to miss a key meeting date, and a complete timeline of IRB submissions can be constructed. Once a complete timeline is constructed, it’s possible to work backwards from the latest submission date and identify the latest delivery date for key documents or work products based on key trial stage gates. Trial decision makers can then, for example, recognize that certain sites should be prioritized for submission before a national holiday or that a current goal IRB submission date requires finalization of the contract much earlier than central IRB sites.

Ethics submission packages are complex and require significant cross-department coordination. Adding the additional burden of country-specific and local IRB-specific requirements, it’s no wonder that key IRB meeting dates are often missed and site activation is delayed as a result. As regulatory expectations and protocol complexity increase, the risk-benefit analysis conducted by IRBs will continue to grow in scope, and submission requirements will expand in response. The eTMF, by improving trial oversight and streamlining manual processes, may be the best weapon trial stakeholders have against the ethics submission and approval process becoming the main bottleneck of timely SSU.

[1] START Study Tufts CSDD, 2012. Ken Getz’s presentation entitled: Uncovering the drivers of R&D costs.