A truly participant-focused clinical trial protects the safety and the rights of patients. No one will argue that point, but achieving it often proves tricky. Good intentions are not enough. Diligence isn’t enough. It requires collaboration among the three key players: the sponsor and its CRO; the site, including the investigators and the site team; and the IRB.
Regulations (including those from the FDA) and other guidance (including from the International Council for Harmonisation) outline these responsibilities. Rather than dryly reviewing the rules and regulations, let’s step back and look at the big picture.
The Sponsor: Balance Science and Safety
Sponsors have a responsibility to perform ongoing safety evaluations, and they must ensure the FDA, IRBs and all participating investigators are promptly informed of significant new adverse events or risks. If a drug is found to be an unreasonable and significant risk, they must discontinue the study within five working days.
More broadly, sponsors must pursue the interests of science and society while never compromising the safety and wellbeing of participants. They must do this throughout the research process of designing studies, assembling teams, managing resources, and continuously learning from their acquired data.
Best Practices for Sponsors Include the Following:
- Develop study protocols with patient input to ensure that safety procedures are feasible and appropriate. Involving patients in the planning phase not only respects patient perspectives but also enhances safety and data quality.
- Obtain input from investigators about issues that could arise in real-world settings. While expert opinion is essential, feedback from the average investigator can help identify potential challenges experts may not appreciate.
- Select sites that will actively collaborate and contribute to ensuring the safety of participants.
- Adjust and adapt to new information, approaches, and safety concerns as they arise throughout the research process. Be open to modifying protocols when needed. Consider employing adaptive study designs or remote trials to better gather real-world data.
This case study highlights the importance of the sponsor’s responsibility for ongoing safety evaluations.
Case Study: Your Heart Goes Out to Them
During a pediatric congenital heart disease study, the sponsor identified a safety signal that raised concerns. To avoid bias, the sponsor engaged the data monitoring committee (DMC) to review the data. The DMC recommended pausing the study. The sponsor informed all relevant parties and halted the trial. Ultimately, it was terminated early due to those safety concerns.
Outcomes:
- The sponsor demonstrated responsibility for ongoing safety evaluation by involving the DMC to ensure participant safety.
- The sponsor applied what it had learned to a new, more successful trial that led to an improved treatment option for pediatric congenital heart disease.
Investigator and Sites: Protect Participants
Sites and their investigators are the frontline protectors of research participants. They must protect participants’ rights, safety, and welfare; provide adequate medical care for any adverse events related to the trial; and promptly report unanticipated problems involving risks to humans.
Best practices for sites and investigators include the following:
- Be real. Provide honest feedback to sponsors, addressing any concerns or uncertainties. This honest communication is crucial for the participant’s safety and the overall success of the trial. Sites must also be honest with themselves about their capacity to execute the study safely and effectively. This includes assessing staffing levels, resources, and their overall suitability for the study.
- Put yourself in the participant’s shoes. Walk through the study process from the participant’s perspective. This provides a fresh perspective and makes it easier to identify areas for improvement before the trial begins.
- Solicit input from all parties: Gathering feedback from the research team, vendors and other stakeholders can help ensure all parties are aligned in their goals and expectations.
- Review and audit: Quality reviews and audits help maintain high standards throughout the trial. By conducting planned and mock audits, sites can identify potential issues before they become problems, saving time and resources. This is particularly important for new research sites or established sites with new team members.
Another case study illustrates the investigator’s role:
Case Study: A Stitch in Time Saves Nine
A trial for a new anti-cancer agent progressed smoothly through phase I and part of phase II. Then, one investigator noticed an unusual side effect in some participants. It was not immediately apparent as being related to the drug. The investigator reported their concerns to the sponsor and the IRB.
In response, the sponsor implemented additional monitoring and notified all parties about the new risk information.
Outcomes:
- The study eventually concluded with a successful outcome.
- The early detection and management of the side effect allowed it to be managed in the drug’s clinical use.
- This led to a valuable treatment option with low and manageable risks, thanks to the vigilance of the investigator and the collaborative efforts of the sponsor and the IRB.
The IRB: Provide Oversight
IRBs serve as an independent review mechanism, establishing baseline standards for research and participant protection. They provide valuable feedback on research protocols and ensure that all parties continually improve their processes.
- Establish baselines and trust: Perform internal audits and communicate with investigators to maintain trust in the review process.
- Focus on the mission: Prioritize participant rights and welfare by allocating resources and attention to the most critical aspects of the research—and don’t extend the scope beyond the core mission.
- Provide and receive feedback: Openly communicate with other stakeholders to enhance collaboration and improve processes.
- Foster a collaborative approach: IRBs should work with sponsors and investigators as partners in protecting participants. IRBs don’t need to be paternalistic or punitive. IRBs need to hold that baseline, hold it uncompromisingly, even raise it appropriately, but be polite while doing so. It’s ethical to be nice.
This case example illuminates the IRB’s role in ensuring participant safety:
Case Study: Stop Means Stop
During a first-in-human trial for an anti-cancer agent, an investigator reported a participant unexpectedly admitted to intensive care. The investigator, busy providing care to the patient, didn’t have many details. The IRB, with its knowledge of similar drugs, was able to extrapolate a potential cause and decided to suspend all study activity, notifying both the investigator and the sponsor.
The pause allowed everyone involved to focus on participant safety and gather more information. Once the site and sponsor identified a root cause and put in place an appropriate mitigation plan, the study resumed and eventually reached a successful outcome.
Collaboration Across the Journey
As each case example illustrates, safeguarding participants’ rights and safety in clinical trials is a collective responsibility among sponsors, sites and IRBs. Through collaboration, open communication, and continuous improvement, these stakeholders ensure successful trials and advance scientific knowledge, while protecting research participants’ wellbeing.
By working together, and not against each other, we can maximize trial benefits and minimize the risks. This is a win for medicine, for the future of our organizations, and most important, for patients.
Best practices for each stage
Here’s a brief look at select best practices during each stage of the clinical trial process:
During Idea Generation and Protocol Development
- Prioritize participants’ rights, safety and wellbeing over the interests of science and society during idea generation and protocol development.
- Respect safety and the need for progress. You can make a perfectly safe trial by having an exclusion that keeps everyone out –and no one will benefit.
During Study Execution
- Ensure appropriate staffing at all levels, from sponsors to investigators and IRBs.
- Provide clear and ongoing information to participants, addressing vulnerabilities and continuously updating them about the study.
- Focus on risk monitoring and reporting. Use data to identify preventable adverse events and continuously improve processes.
During Study Closure
- Share study results transparently to build public trust and contribute to a safer next trial.
- Ensure end-of-study care transitions by providing clear guidance for participants transitioning out of the study. Maintain appropriate oversight and continue to safeguard participant information even after the trial ends.
- Take lessons learned from the study—successful or not–and apply them to future research efforts.
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