Within the SGS maxim framework for early-phase clinical trials, this maxim addresses the unpredictable nature of trials. It emphasizes planning for unforeseen circumstances and managing project complexity to mitigate risks and time delays, foundational principles among these 10 maxims.
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Recruitment and retention issues result in trial delays and costs and may potentially undermine trial results. Every clinical trial phase is facing its own specific hurdles. The fact that early phase trials do not offer therapeutic benefit for the subjects is a specific drawback. Phase 1 trials are typically performed in healthy volunteers, whereas from phase 2 onwards patient populations are needed. However, special populations and patient cohorts are increasingly included early on.
Subject enrollment is a key driver of clinical trial success but remains one of its biggest challenges. The exact challenges depend on the trial phase, the population specifics and study design details.
As phase 1 trials mainly involve healthy volunteers (HV), increasing general awareness, on safety for example, is paramount. Besides that, the incentive for HV to participate remains mainly a financial one.
For patients, the situation may slightly differ. Confronted with disease, they tend to be willing to help innovation. Nevertheless, fear of side effects and of getting a placebo (hence losing time to get treated) often deters them. As early phase studies typically contain frequent visits and assessments, the overall burden and time spent also becomes a decisive factor. Physicians play an important role in identifying and “convincing” eligible patients, but they are often dealing with similar constraints. In addition, eligibility criteria are more restrictive in early phase. Hence, finding participants may be a little like looking for a needle in a haystack.
To assure recruitment in a timely manner it is important to tackle these hurdles at all stages of trial preparation and execution and respect the following measures:
- Simplify the protocol if possible to lower the burden for patients and physicians
- Evaluate eligibility criteria to identify overly restrictive components
- Identify factors that impact recruitment, both positively and negatively
- Foresee a realistic recruitment period, leave some flexibility
- Include experienced sites with demonstrated patient access and dedicated recruitment staff
- Foresee recruiting activities: advertising, social media, call centers
- Provide clear information to patients and physicians
- Keep close contact with sites in prescreening period
- Keep clinical trial investigators motivated by via frequent communication and assistance
- Ensure contingency measures that can be implemented quickly
Tailoring protocols to disease targets
Although a “perfect” protocol may have been created on paper, many study aspects need to be evaluated from a practical point of view. These include:
- The recruitability of the exact study population
- Investigational Medicinal Product (IMP) preparation steps
- The use of sentinel dosing groups
- Sample-handling processes
- The frequency and types of assessments
Despite timeline pressures, clear communication on content and operational feasibility is key to avoid issues. During a feasibility review and subsequent trial preparation, all worst-case scenarios need to be considered – as the laws of Murphy and Hofstadter also apply to clinical research. With some complex assessment schedules, it is often best to organize a mock test run.
Case studies: insights unveiled
Discover two interesting stories. The first one is about SGS conducting a feasibility review for a multiple dosing study, addressing challenges in age-related criteria. Compromises were made, highlighting the importance of meticulous assessments. In the second case, a US Biotech sought SGS for a phase 1 study on seasonal allergies. Thorough risk assessment and planning were crucial, emphasizing the pivotal role of meticulous risk assessment in successful early-phase clinical trials.
Case study: The importance of a thorough feasibility review
Case scenario
In a combined HV/patient study run by SGS, an experienced patient site was struggling with recruitment. By rapid implementation of a pre-study contingency plan, the study still met the initially agreed upon study timeline.
A European biotech company outsourced a combined single and multiple ascending dose study in HV and moderate-to-severe atopic dermatitis (AD) patients.
SGS Clinical Pharmacology Unit conducted the HV part as a single site. Two patient sites in Eastern Europe with experience in early AD trials, and reliable partners to SGS, estimated they could recruit the 24 patients in six months. As a pre-study contingency measure, SGS suggested to include their patient site in Hungary as a third site.
During the first patient cohort, one of the sites had unexpected recruitment difficulties, despite their proven track record in AD studies.
The project manager and operational team immediately undertook action:
- In a combined HV/patient study run by SGS, an experienced patient site was struggling with recruitment. By rapid implementation of a pre-study contingency plan, the study still met the initially agreed upon study timeline. Follow-up with the site was intensified to investigate the patient pipeline and recruitment forecast.
- The potential to increase the committed enrolment target was discussed with the other two patient sites. The Hungarian site substantially increased their network through advertising in relevant patient groups and approaching additional collaborating specialists. Consequently, they could triple their initially committed enrolment.
- The in-between cohort time was maximally compressed. As a result, the significant recruitment delay from the first cohort was entirely cleared. Having sites with dedicated recruitment staff proved to be an enormous added value to boost recruitment capability. The study ended within a week of the initially foreseen date.
We conclude that even experienced sites can encounter unexpected recruitment issues, especially in acute indications and indications with seasonal variations. Candid communication with all sites and implementation of contingency measures can be critical to rescue a trial.
Enhancing protocol flexibility for optimal study outcomes
After an open discussion with the client, important compromises were implemented, without jeopardizing the scientific value of the data nor the recruitment and retention of the older population. In summary:
The weight matching was phrased more flexibly allowing a slightly bigger deviation
- Normal ranges were changed, where possible, for safety and some concomitant medication were allowed
- Importantly, the revised protocol contained flexibility for the eldest group to choose between in-house stays or ambulatory visits
Case study: The importance of thorough risk assessment and study planning.
Case scenario
A US Biotech contacted SGS to perform a phase 1 study in healthy subjects with a seasonal allergy.
Strategizing allergy study timelines and inclusive criteria
After a single ascending dose in healthy volunteers to assess safety and pharmacokinetics, the study included a second part to assess pharmacodynamic effects in healthy people with a seasonal allergy. The pharmacodynamic tests consisted in a nasal challenge to provoke rhinitis, a skin prick inducing a flare and a food challenge inducing oral allergy symptoms. After a nasal challenge, different read-outs for rhinitis severity were combined using a symptom score card, peak nasal inspiratory flow and nasal aspirate for inflammation analyses. As many allergic people have more than one allergy, the in- and exclusion criteria could not be too restrictive so as to exclude all co-allergies
- As people could not have rhinitis symptoms at baseline, the study needed to be conducted outside the allergy season, putting some time constraint on the study timelines
- People needed to respond to the nasal challenge to a certain extent to be able to measure an IMP effect, but putting the response criteria to severe would lead to a high screen failure rate
- The pharmacodynamic tests involved many assessments that were time critical, time consuming and needed to be performed in a standardized way
Risk mitigation strategies: Practical solutions for protocol challenges
In response to potential practical risks, a thorough review of the protocol was conducted, leading to the implementation of strategic measures.
- A workable solution was found to describe eligibility criteria, allowing those allergies that would not cause rhinitis, or could be avoided during the study
- To reduce the risk of not finishing the trial before the allergy season due to unforeseen set-backs (remember the two laws!) the trial was conducted at 2 sites, recruiting in a competitive way
- The criteria for challenge responses were evaluated together with a local specialist to predict the screen failure rate
- Staff were trained to perform the pharmacodynamic tests by a specialist and a dummy run provided real- life estimates of the timings