(If you haven’t had a chance, check out our first in the series: From IND to FPI: How to Set Up Your US Study for Success, where we focused on some of the regulatory considerations that may impact study enrollment strategy and timelines.)
At PSI, getting sites activated and enrolling on time is inherent in our mission and is a key factor in how we measure our success. To our sponsors, the ability to meet enrollment targets can be vital to their financial security and corporate interests. Therefore, we invest a lot of time and energy into developing start-up plans for our sponsors that maximize efficiencies and minimize time to First Patient In (FPI).
Here is an example illustrating a common question we receive at PSI:
Our target for enrollment initiation is end of March, 2019; however, our protocol will not be final until mid-February, 2019, and we will need to complete enrollment by the end of the year. How can we reduce the time from final protocol to FPI?
To reduce time to site activation and enrollment, the following strategies contribute significantly:
1. Start planning early – before beginning clinical study operations, consider timelines and strategy for protocol and study document development; site feasibility, qualification, selection, and initiation; regulatory and ethics submissions; contract negotiation with sites and/or third-party vendors; regulatory review for investigational product release to sites; and any product-/study procedures-/therapeutic area specific review processes required (e.g., specialized committee review for human gene transfer protocols; radiology review bodies; patient advocacy funding agencies). It’s also important to determine which activities can occur in parallel, and which activities should occur consecutively.
2. Get input from key opinion leaders (KOLs), patient advocacy groups, prospective Principal Investigators, and/or other specialized site staff (if applicable) on the study design prior to protocol finalization and IND/CTA submission. This input may be requested from KOLs/sites via a feasibility survey or via direct communication and discussions.
3. When planning a clinical program, consider in which countries/regions pre-submission meetings or consultations with the regulatory authorities are possible and afforded by the regulations. Such meetings/consultations allow the applicant to discuss with the regulatory agencies any potential risks (and mitigation strategies) associated with the IND/CTA submission. The focus of such consultations is to discuss any issues involving the nonclinical, chemistry, manufacturing, and controls (CMC), and/or clinical (including protocol design) program plans and/or data that may be novel, controversial, or otherwise may pose a risk to patients’ safety and may result in questions or concerns from regulatory authorities. In case a pre-submission meeting/consultation with the authorities is planned, allow enough time to incorporate feedback into the protocol and submission dossier prior to submitting the application for review. Consider how scientific advice from regulatory authorities will impact the submission strategy globally.
4. Identify and preselect sites for study participation based on sponsor and/or CRO experience with the sites and studies of similar scope, therapeutic and/or product-specific experience, and geographical considerations. This preselection process, which may involve initial feasibility questionnaires (based on the synopsis, draft or final protocol) and/or direct correspondence or teleconferences with the sites, can occur in parallel with regulatory submission activities.
5. Develop and finalize the site contracting strategy before completing site selection activities to avoid unnecessary delays to downstream contract and budget negotiations with study sites. This includes finalizing the proposed site contract and budget templates prior to Site Selection/Qualification Visits, if possible, to allow for in-depth discussions with sites on their contracting processes and timelines prior to choosing which sites should participate in the study.
6. Once the sites are officially selected for study participation, consider implementing a tiered site activation process to focus start-up efforts and resources on high-priority sites. Prioritization should take into consideration factors such as site enrollment estimates (and patient access), contract and budget negotiation timelines, ethics board and institutional review timelines, and other site-specific policies that may slow or hinder progress towards FPI targets.
7. Before submitting the protocol as part of the US IND/ex-US CTA, the sponsor/CRO may share the draft and/or final protocol with the sites for qualification purposes, collect site regulatory documents, draft additional study documents, begin contract and budget negotiation (depending on site preferences/policy), and tentatively schedule site initiation visits based on the targeted IND/CTA submission or clearance date. However, there is a risk associated with starting these activities prior to submission, especially for a new clinical program, given potential changes to the protocol following IND/CTA submission may result in downstream changes to the study documents, which would then need to be revised in accordance with the amended protocol and likely delay subsequent start-up activities.
In summary, taking advantage of proven and responsible tactics to shorten study timelines makes good business sense for the sponsors, CROs, and partners responsible for conducting the clinical study. Most importantly, however, reducing time from the clinic to the market means patients will have earlier access to life-changing therapies.
by Lauren Neighbours, PhD, RAC
US Head Regulatory, PSI CRO