A Successful Study: The Principal Investigator’s Perspective

As we all know, the success of a clinical trial depends on a number of factors. With many stakeholders involved, all with different opinions and their own priorities, it can be challenging for research teams to agree the best approach to a study. Here, Dr. George Atiee, VP/Medical Director at Worldwide Clinical Trials, shares his thoughts on what it takes to run a successful study from a principal investigator’s (PI) perspective. Based on 30 years as a licensed physician and 20 years’ experience in clinical research, Dr. Atiee will share his views on important considerations for creating the perfect protocol, as well as safety, logistics and selecting the right team.

The Protocol

George Atiee

A starting point for any clinical research program, a study’s protocol outlines how a clinical trial will be conducted and is essential in ensuring the safety of the trial subjects and integrity of the data collected. Integral to the protocol are the study objectives, which should be relevant, well-considered and determined from the offset. In my opinion, simplicity is key here and researchers should be mindful of over complicating this process. By setting too many secondary and exploratory objectives, researchers could find themselves facing confusion in the long run as endpoints/outcomes required to meet the various objectives are likely to become complex and unmanageable.

Setting the inclusion and exclusion (I/E) criteria is another important consideration when creating the protocol. This identifies the specific characteristics that trial subjects must or must not have to participate in the study, for example, age, sex, race, ethnicity, and medical history, and is there to ensure the safety of the patients throughout the duration of the trial, as well as to provide justification of why a subject is or isn’t appropriate for the study. It also supports in minimizing the chance of participants withdrawing from the study and therefore can help to reduce costs.

It is critical that researchers spend time selecting the appropriate I/E criteria for their unique study, as certain characteristics are likely to be more important than others depending on the study objective(s). Since there is always a risk of participants falling ill or developing side effects during the trial, it is critical to tailor the I/E criteria in such a way so as to minimize the potential risks by eliminating those subjects most likely to be harmed by the investigational product.

While the I/E criteria needs to allow for proper safety, at the same time, they must not make it impossible to recruit the right participants in order to be able to complete the study. By discussing the study objectives with the PI and using their experience to decide whether the I/E criteria is suitable, an understanding can be reached allowing recruitment to take place within an appropriate timescale.

The next thing to think about is the schedule of events (SOEs), which will act as a timetable to guide researchers through the study, and should outline the procedures that will take place at each stage. When creating this, researchers should be aware of ‘information overload’. Too often I see poorly organized and confusing SOEs with important details hidden away in the foot notes. Ensuring timelines are met is a common issue for a PI, and a poorly-organized SOE can generate the need for clarification later in the study, and/or mistakes being made, ultimately, causing unnecessary delays.

SOEs can be improved by ensuring that important information is detailed clearly to make the schedule easier to follow and minimize discrepancies in the long run. Researchers should also consider whether a specific data point is critical to the study. Many times, “cut and paste” approaches to protocol writing result in unnecessary procedures and it is worth noting that each activity included within the SOE will add a level of complexity and cost, and realistically may not be feasible in practice due to time restraints.

The final point to discuss at this stage is setting the correct data outputs. These should be driven by the study objectives in order to answer the research question(s). If this is not done correctly, the study will not be a success as the data needed to prove the objectives will not have been captured. My advice to researchers would be to start by considering what data you want the study to provide and work backwards from there. That way, you can ensure that the collection points for blood pressures and ECG’s, for example, are completed in a timely and appropriate manner. While this may sound straightforward, as studies become more complex, the more data researchers are trying to capture, the more chance there is of running into issues, so proper planning is essential.

Safety

For a PI, one of the most important, and first, questions I ask when reviewing a study protocol is whether I can perform this study with a reasonable margin of safety. This is because it is the PI’s responsibility to ensure the safety of the participants. When the PI signs The Statement of Investigator, Form FDA 1572 – (an agreement signed by the investigator to provide certain information to the sponsor and assure that they will comply with FDA regulations related to the conduct of a clinical investigation of an investigational drug or biologic)¹. He has now assumed all responsibility for the successful completion of the study and the safety of the study participants. This responsibility cannot be off-loaded to the sponsor, clinical research associate (CRA) or medical monitor.

Frequently, I will add I/E requirements to exclude subjects that would be at increased risk based on the information in the protocol. There are also times when I will disqualify subjects that meet the I/E criteria because of something in their medical history or screening assessment which could compromise safety.  

This can often become a point of contention with sponsors, however, it is a PI’s responsibility to strike that careful balance between recruiting patients who are suitable (and safe) for the study, and doing so in an appropriate timescale for the sponsor.

Logistics

Once satisfied with the safety, for a PI, it is their responsibility to work out how to deliver the study from a logistical view point in order for the team to move through the protocol in a timely and safe manner, to deliver the outcomes needed for a successful study. Planning ahead is crucial and can also help study teams to prepare for unexpected challenges.

The Team

Sponsors, CROs, vendors and the regulatory authorities all have an important role to play in the success of any trial, and I am of the opinion that in order to achieve the best outcome possible, it is crucial that all involved act collaboratively as partners. When it comes to ‘picking a team’, there are three important factors for sponsors to consider:

• Experience: The sponsor does not need to be experienced in anything except the compound being investigated, they simply need to surround themselves with study partners which have the right level and quality of experience needed to deliver the requirements of their specific clinical trial.

• Flexibility: While each organization, and sometimes individuals, will have their own preference, there is often more than one way to complete most tasks, so the ability and willingness from all study partners to be flexible with approaches, as well as how to deal with uncertainties and unexpected events, is crucial.

• Communication: This is arguably the most important requirement for a successful study. While emails, meetings, FTP sites etc., all have their place, these alone do not equate to sufficient communication. Despite careful planning, researchers will run into unexpected issues, and communicating quickly with the PI, medical monitor or CRA, can be the difference between success and failure. Efficient communication with the right person or team will ensure that small problems are resolved before they escalate into bigger problems.

Summary

Managing a successful clinical trial, of whatever size and complexity, requires a well-choreographed dance amongst all of the stakeholders. Different groups working as partners will enable the team to achieve the goal: a successful study.

By carefully selecting their team, diligently crafting a clean protocol and keeping open lines of communication, sponsors can ensure the best possible chance of success.

Dr. George Atiee is VP/Medical Director at Worldwide Clinical Trials

References

1. https://www.fda.gov/downloads/RegulatoryInformation/Guidances /UCM214282.pdf