Most leadership teams would agree that it is better to meet the timeline of a well-thought-out clinical study schedule than repeatedly miss the mark on an over-zealous one, even if the timeline is longer. No matter what your advisors told you, do not commit to your board or investors that you will have your entire pivotal study enrolled in six months. This almost never happens.
A common rule of thumb is to take the principal investigator’s estimated enrollment rate and double the number of months estimated. Bright prefers a more systematic approach to developing realistic study timelines. In today’s blog post, our CEO and founder, Andrea Fenton Abbs, shares five tips to help you set and meet clinical study enrollment goals.
1. Consider regulatory approval timelines
Sites cannot begin enrolling subjects until the study is reviewed and approved by the following bodies:
- The U.S. FDA for investigational device exemption (IDE) studies
- A centralized or local institutional review board (IRB) for all studies
- The Centers of Medicare and Medicaid Services (CMS) for investigational products with procedure or product costs that may be reimbursed
While these bodies have goals to complete their initial reviews within 30-60 days, questions and requests for clarifications often arise during review. As such, Bright recommends including a buffer in your plan to allow time to address requests for additional information and subsequent review time. (For additional tips to further to streamline your FDA submissions, including IDEs, refer to our blog post on using the FDA Pre-Submission Program.)
CMS approval often takes longer than their 6-week turnaround goal, and their approval/disapproval letter is often delayed (hot tip: frequently check the CMS website for the most up-to-date information). Many sites will not proceed with subject enrollment until they are sure costs will be covered by CMS, the insurance company, or the sponsor. If this is applicable to your study, make sure to include generous CMS approval timelines in your study plans.
2. Vary the types and sizes of study sites
Not all study sites are created equal when it comes to efficient start-up processes. Consider inviting a mix of smaller regional medical centers, physician-owned clinics, and larger academic institutions that are located across urban, suburban, and rural areas. Traditionally, the larger academic centers are busy and … slow. They support many studies, have additional internal review requirements, will usually not allow use of quicker central IRBs, and they typically have lengthy contract and budget negotiation processes. In our experience, academic centers take 4-6+ months to get through their contracting, budget, and IRB processes. These centers are led by savvy thought leaders who provide valuable guidance and have huge caseloads, so while they may be slower out of the gate, they still add tremendous value to your research program.
While the big machines slowly churn their start-up activities, you can activate smaller regional centers more quickly. By drawing patients from a large geographical area, these sites are competitive in terms of an eligible patient population, and they often have the benefit of faster negotiations. In addition, regional sites often use a central IRB. Similarly, physician-owned or smaller commercial sites can often negotiate their contract and budget promptly and can typically use a central IRB; they may even be your first site activated.
Based on the pros and cons of small regional medical centers vs. large academic sites, for larger studies we recommend a mix of site types to expedite your timelines while still benefiting from the academic influence and larger eligible populations.
Our last bit of advice on this topic is to identify and qualify your sites months before the IDE is submitted. Sponsors that wait to identify and qualify sites until the IDE is approved have already lost 3-6 months in their timeline. Many (though not all) sites are now willing to negotiate clinical trial agreements and budgets prior to IDE approval. Some sites may even submit to their IRB prior to IDE approval (but will wait to begin enrollment until authorization is received).
3. Prepare for the complexities of contract & budget negotiations
Negotiations take time and sponsors will need subject matter experts and legal reviewers for all site and investigator agreements and budgets. These reviews take time – especially if you are contracting third-party experts.
Regardless of the site type, contract and budget negotiations always go more quickly when you provide clear and accurate information. Prepare a clinical trial agreement and budget template that is generally applicable to all sites, and then work with your legal team to incorporate each site’s edits. Similarly, draft site budgets with knowledgeable estimates on standard of care costs, study-specific costs to be paid for by the sponsor, and industry expectations around associated research costs (e.g., start-up fees). Sites may still negotiate the details, but when you start from a consistent and informed position, the process will take less time overall. Be sure your budget template aligns with the case report forms, which will prevent future budget amendments and related delays.
If your internal legal team is overwhelmed, consider bringing in external legal support to minimize delays. Got a site that’s lagging? Pull in the “big guns” and have your sponsor executive leadership, national PI, or key medical advisor ask where they are having trouble or advise on how to encourage their contracts and budgeting departments to move things along.
4. Understand patient referral patterns
For some studies, the investigator is dependent on patient referrals from other doctors and institutions. Before your sites begin enrolling, be sure you understand the patient referral pattern, and establish methods to engage those referring physicians and their patient population. When possible, include referring physicians in study-related communications to acknowledge the important role they play in the success of the study.
5. Engage the sites with active communication
Even before the clinical trial agreements are executed and approvals are in hand, it’s time to step up site communications. We use several strategies to keep our studies front of mind, which keeps the sites engaged to actively enroll subjects.
To generate enthusiasm for the study, send frequent and concise email communications to confirmed and potential investigators. Consider sharing study-wide activation and enrollment status to stoke friendly competition among the sites. Be strategic with your approach because you do not want to spam your investigators. Ensure your messaging is meaningful, concise, accurate, and timely.
Another engaging communication tool we like to use is a study-branded newsletter that is sent at regular intervals to generate excitement and enthusiasm. We use bar charts and graphs to communicate goals and timelines, include brief bios or profile stories to build rapport with the study team, answer frequently asked questions, and provide tips to avoid observed protocol deviations. When developing content, know your audience. What’s in it for them, what do they already know, and what do they need to know? (refer to Bright’s blog on developing strong relationships). Make it visually appealing, concise, and worth the read.
Conclusion
When you use a systematic approach to establish realistic study timelines, you’ll be more likely to hit the mark with subject enrollment, one of the key drivers of the overall study timeline. Too many entities are involved in this process to simply follow informal rules of thumb. Instead, consider regulatory approval times, methodically select your sites, prepare your team for the rigors of contract and budget negotiations, understand patient referral patterns, and keep your study front of mind with frequent and engaging site communications.
