US Food and Drug Administration (FDA) approval is only the beginning of our understanding of how a therapy performs in everyday clinical practice. Investigator-initiated trials (IIT) – sometimes referred to as investigator-initiated studies (IIS) – can help answer many of the questions that FDA registration studies leave behind, from real-world outcomes and patient-reported experiences to treatment performance in patient populations not fully represented in pivotal trials. As more clinicians collaborate with industry partners to generate this evidence, understanding how to develop and lead an IIT has become increasingly valuable.
Ideation
Over the years clinicians have told us that they find generating an idea the most challenging part of beginning a research study. However, generating ideas can be made much easier if you spend time reading industry news and studying the latest peer-reviewed literature, as well as speaking with colleagues and sponsor representatives.
While not a strict rule, industry partners are typically most interested in supporting IITs related to their most recently-launched product – they want to continue generating buzz around their product and are also interested in developing new evidence that will support the use of it. This evidence could be related to on-label use in patient sub-populations, patient reported outcomes that better illustrate how the product will be accepted in the real world, or testing questions that may have been too risky to include in the pivotal trials.
When developing a product, a sponsor typically has one goal in mind: to get a safe and effective product to market. Therefore, protocols need to be as streamlined as possible to avoid collecting data that is challenging to interpret. For example, if a sponsor were to use two similar but complementary symptoms surveys and one survey found exciting results while the other demonstrated lackluster results, the sponsor would need to explain these results to regulators, and the conflicting results could jeopardize or delay product approval. Thus, the sponsor may elect to not collect interesting data during the product approval pathway and instead decide to collect these data through an IIT approach later. IITs also provide the added benefit of fewer biases (e.g., expert clinicians collecting data rather than the sponsor).
With this in mind, we have found that the best way to generate new ideas is to review conference abstracts, press releases, and peer-reviewed manuscripts to understand the data that have been collected thus far, and then to look for real-world gaps that should be filled. These gaps can be found by comparing past work to everyday issues your patients experience and then identifying data that would help them or you to manage these issues.
Understanding the landscape
After developing an idea (and maybe discussing it with a colleague to understand utility and potential knowledge gaps), it is best to meet with the potential sponsor to determine if they are interested in the concept. These meetings may likewise help uncover additional potential needs.
While the interactions with a company vary by company and by the size of company, Medical Science Liaisons (MSL) are often the first person to meet with to discuss a concept. MSLs are sponsor representatives who are topical experts tasked with disseminating scientific information in a non-biased way (not marketing materials), attending conferences, meeting with key opinion leaders, collecting product feedback, and helping manage IITs with the medical affairs team. With smaller companies, it is possible to meet directly with a research and development team member.
In these meetings, you can get valuable feedback related to whether the sponsor is interested in prioritizing your concept, if there is available funding, and if they have any feedback that might make the concept more appealing. While the sponsor can provide initial, unofficial feedback, they are not typically allowed to drive study design under the IIT pathway. This approach helps minimize sponsor bias during an IIT process.
Submitting a concept
After determining that there is an initial interest in your concept, the next step is to complete a formal submission. Larger companies often have a submission portal while smaller companies may accept concepts via email. You can find the best method for submitting your concept during your initial meeting with the sponsor. Some sponsor may just request a succinct paragraph as an initial submission, while others may request a fully written proposal/protocol.
An IIT protocol is typically much simpler than one you would see for an FDA-regulated drug or device trial. While an FDA-regulated trial protocol is often 70-plus pages long, an IIT protocol is usually under 10 pages and typically contains the following sections: title page (including contact information), introduction, specific aims, outcomes, study design, inclusion and exclusion criteria, sample size, visit schedule, statistical plan, timeline, publication plans, budget, conclusions, and references. You will likely need to engage a collaborator with study design and statistical experience to help you develop your protocol. The study plan should likewise be developed in a way so that you and your collaborators can enroll the desired patient population in a timely manner. If you are unfamiliar with the IIT process, we recommend working with an experienced investigator who can help you write and critique your proposal. After submitting your proposal, the sponsor should notify you of acceptance or not.
Startup
After being awarded the project and contracting, your work will begin with finalizing all the study documents (e.g., protocol, surveys) and submitting the project to an Institutional Review Board (IRB) for ethics approval. If you are conducting a clinical trial, you will also need to register your trial on ClinicalTrials.gov, which is an industry standard to help minimize bias by stating your objectives to the world before you start.
ClinicalTrials.gov registrations are now often requirements for conference abstracts and peer-reviewed journals. If you are conducting a multi-site trial, you will need to meet with your collaborators and develop a plan that allows you to conduct the trial in the same manner at every site. You will also need to set up a method for collecting data in an efficient manner; this is typically done with an electronic data capture system, though spreadsheets are sometimes used. Spreadsheets can be challenging because they are difficult to implement in a clean manner, especially if more than one clinical site is involved with the study.
Implementation
Once ethics approval and the infrastructure is in place, data can be collected. Data collection is a coordinated effort between a study coordinator(s) who is helping manage patient enrollment and data collection and the investigator(s) who are performing the exam visits. It is important to have a study team in place to help ensure enough staff in case a masked and unmasked team member is needed, as well as to help ensure coverage during vacations and sick leave.
Understanding the data
After the study has fully enrolled and the last participant has exited the study, the data is typically reviewed for errors/typos. Once data review is completed, the statistical analysis can occur, and the study reports can be generated. IITs have an emphasis on public visibility; therefore, a typical expectation of an IIT is that the final work is presented at one or more conferences. Conference presentations allow the information to be received by a greater audience than might not otherwise have occurred with a peer-reviewed publication.
After the last conference abstract is submitted, the peer-reviewed manuscript can be submitted. The peer-reviewed manuscript also often serves as the final study report. With all these publications, the sponsor is typically allowed to review them and provide feedback, though the specific of this arrangement is typically stated in the IIT contract.
Key takeaways
While IITs bring additional challenges compared to FDA-regulated trials (such as needing to develop your own protocol, setting up the project, and implementing the project without sponsor oversight), they can mark an excellent way for motivated clinicians to be creative, expand scientific knowledge, and gain notoriety in their field. There is likewise a need for more qualified IIT investigators. If you have an interest, we encourage you to team up with an experienced clinician and submit your concept together.
