Investigator-initiated clinical trials trials play an important role in advancing medical knowledge, exploring novel uses for existing therapies, and addressing clinically relevant questions that industry trials may overlook. However, these trials come with unique challenges and responsibilities, especially when the investigator assumes the dual role of sponsor and researcher. Here are some essential elements to get right when conducting an investigator-initiated trial:
Clearly define the research question and objectives in a realistic protocol
A focused, answerable research question is the foundation of a successful trial. Whether you’re testing a new application for an approved drug or comparing treatment protocols, your objectives must be:
- Scientifically valid
- Clinically meaningful
- Feasible within the available resources
Poorly defined goals can derail the trial design and compromise outcomes. The trial protocol should include study design and methodology, in- and exclusion criteria, primary and secondary endpoints, a statistical section and risk mitigation strategies. Ensure the protocol undergoes internal review and external peer input before submission to ethics committees.
Protocol amendments should be carefully considered. A protocol amendment to help boost recruitment is inevitable if the preset number of patients would otherwise not be reached. However, the amendment should not introduce any weaknesses to answer the research question.
For trials lasting several years, there is a likelyhood of new information being published while the trial is ongoing. In order to increase the chance of producing clinically meaningful data, a protocol amendment might have to be introduced rather sooner than later, for example to include subset analyses.
Secure regulatory approvals
As the sponsor-investigator, you’re responsible for securing regulatory approval, according to the locally applicable laws and regulations. One of the first things to do is to define the necessary route for approval, for which the main determining factor is whether a trial is interventional or observational. For interventional trials, read the EMA Clinical Trials Information System (CTIS) Sponsor handbook and follow the online modular training programme. This will help you create a list of documents which are required to be submitted.
Implement effective data management and monitoring
Reliable data is the backbone of any clinical trial. Consider partnering with an academic clinical trial unit or hiring an independent monitor. Put in place:
- Secure, validated electronic data capture systems
- Source data verification procedures
- Plans for data cleaning and quality control, throughout the trial and prior to database lock
In case of limited budget, a monitoring plan should be designed that focusses on data that are critical for the primary and secondary endpoints.
Manage drug supply and accountability
If the trial involves investigational or off-label drug use, the following must be arranged:
- Proper storage conditions and labeling specifically for the trial
- Adequate documentation and accountability covering the full chain of logistics
- Pharmacy oversight at every site
- Adherence to local and international drug handling regulations
This is not only applicable to the investigational drug, but also to the direct comparator or any placebo if applicable. Consider if the trial design requires single or double blinding and plan the labelling and emergency unblinding procedures accordingly.
Track safety and report adverse events promptly
Patient safety is paramount. You should:
- Establish predefined treatment stopping rules in the protocol and escalation pathways for unexpected safety concerns.
- Setup a Data Safety Monitoring Plan and consider if a Data Safety Monitoring Board would be necessary for ongoing independent (unblinded) review of patient safety during the trial
- Monitor adverse events (AEs) and serious adverse events (SAEs)
- Report SAEs to regulatory authorities in required timelines
Maintain transparent and accurate documentation
Good documentation is critical for credibility, reproducibility, and audits. Being the sponsor of a trial, you have the responsibility to keep a Trial Master File (TMF) for documentation that covers topics on trial or country level.
You are responsible for archiving all essential documents according to ICH-GCP (typically for 25 years after trial completion). Any activities, information about and decisions made during the trial have to be documented, to be able to reproduce what happened. Typical essential documentation includes the Protocol, IMPD, Informed Consent Form, Data management Plan, Statistical Analysis Plan, submission packages and ethical approval letters, meeting minutes, independent monitoring visit reports, training log, delegation log, protocol deviation log etc. When different versions of those documents are created throughout the trial, version control is essential.
On top of the TMF, an Investigator Site File should be kept by the PI of each site covering all information related to the conduct of the study at that site.
Plan for publication of trial progress and results
Choose the most appropriate public database to register the trial at the start and keep the information updated throughout the trial (clinicaltrials.gov or euclinicaltrials.eu or national register).
At the end of the trial, results should be made public. Positive, negative or even inconclusive results are still valuable. Write a (abbreviated) Clinical Study Report (CSR) within 12 months of trial completion (within 6 months for a paediatric trial) and submit this to the regulatory authorities. In case of a trial approved through CTIS, the CSR has to be published in CTIS.
Present findings at conferences and/or publish in peer-reviewed journals. For long-term trials, even baseline data or interim results can be considered important for publication.
Final thoughts
Investigator-Initiated Trials empower clinicians and researchers to explore meaningful questions and advance patient care. Following ICH-GCP is usually a common understanding, and by getting the additional elements mentioned in this article right, investigator-initiated trials can deliver high-quality research that is as valuable as sponsor-initiated research.
