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Adverse events are critical in early phase studies. Early planning can avoid regulatory setbacks.
The possibility of adverse events (AEs) is inherent in all studies but are particularly critical in early-phase clinical studies. Their occurrence (or lack of such) combined with investigator assessment of their causation, severity, and relation to the drug enables researchers to answer the primary question of any drug study: "At a level of drug exposure that is likely to have beneficial on-target effects, is that drug exposure acceptably safe?"
Because AEs pose risks to study participants and, later on to patients, identifying and preventing unsafe drug exposure is a major concern for product developers, investigators, and regulators. Regulations mandate Good Clinical Practices in AE management, including how AEs are defined; how they must be detected, managed, interpreted, and reported; and what must be disclosed in consenting. The requirements are complex and continually in flux due to advances in science and changing experience with the practical implications of regulation.
To help illustrate, the following real-life redacted case examples in early phase trials in healthy volunteers reveal how an experienced investigator's knowledge of current regulations and the "strictly safety" regulatory climate can help achieve a reasonable approach to study design, efficient study conduct, accurate AE assessment, and timely reporting. A sponsor working in partnership with a CRO or directly with clinical staff can help anticipate risks and write a Plan B into the study protocol so that if Plan A runs afoul, a smooth way forward will already be in place. This anticipation saves time and avoids unnecessary stress, as well as demonstrates a concern about safety, and avoids a return to the IRB or REB to modify the protocol.
Keys to Avoiding Regulatory Setbacks
A first-in-human, single-ascending-dose protocol required that dose escalation be stopped if two or more trial participants experienced AEs of Grade 2 or higher (based on the CTCAE version 3.0 criteria). The protocol also specified a high-fiber diet. The trial team was surprised and then dismayed to find that trial participants developed Grade 2 diarrhea, forcing the study to stop and triggering AE reporting to the FDA. In later discussion, investigators learned that the new chemical entity was known to be structurally similar to other agents that had caused increased GI motility. They realized that the protocol might have been written to anticipate that possibility and to allow a judgment based on safety review instead of mandating a study stop at Grade 2.
Despite the advice of an investigator managed by a CRO, a sponsor designed a repeat-dose Phase I protocol that did not specify exercise restrictions. It stated that healthy participants were to receive the study drug on Day 1 on-site at a Phase I CRO facility, be discharged on Day 2, and then have outpatient visits for subsequent doses and safety clinical labs.
The lab data included a muscle enzyme known to be sensitive to exercise. Labs on three participants were reported with values that substantially exceeded normal limits, and this triggered an FDA safety report. On inquiry, the participants reported that they had engaged in vigorous exercise; thereafter, the protocol was modified and the participants were instructed to restrict activity for the study duration. No further above-limit values were seen and the investigator reported the elevations as "not drug-related." However, the FDA reviewer expressed concern that a causal relationship to the study drug could not be excluded and required that subsequent clinical studies add exclusion criteria and more intensive testing for muscle toxicity.
Had the investigator's up-front suggestion that the protocol require activity restrictions and inpatient confinement during significant drug exposure, the elevated enzyme levels would not have occurred or would have been correctly attributed to patient noncompliance. Additionally, the sponsor could have required an exercise diary or included higher enzyme levels in the study.
A multiple-ascending-dose study was conducted in healthy volunteers. On Day 6, the ECG for one subject taken four hours post-dose showed a three-beat run of nonsustained ventricular tachycardia. Looking back at the subject's baseline screening data as well as data gathered in the preceding single-dose study, the limited runs (only 10 seconds) of ECG recording had shown no rhythm abnormality. This AE was flagged as a safety issue. The subject was taken off the study, and the investigator reported this unresolved AE to the FDA as possibly related to the study drug.
After one week, the subject was reassessed by Holter monitoring. This showed a Day 8 episode of nonsustained ventricular tachycardia. On review of the full cohort's Day 8 data, and considering the study drug's 36-hour half-life, the Safety Monitoring Committee decided that the study should be stopped pending results of additional Holter follow-up after the complete wash-out of the study drug. Data were then collated and submitted to the FDA. Reviewers required protocol amendments specifying admittance on Day 2 to acquire baseline Holter ECG data from all participants from Day 2 to Day 1, to obtain stat Holter analyses, and to exclude any volunteer showing ventricular dysrhythmia on baseline Holter recording.
The FDA permitted the study to restart, but dose escalation was rolled back to the prior cohort's dose level with a net delay in study completion of three months. The FDA further required subsequent Phase I-II studies to include extra cardiac monitoring requirements. With an added exclusion criterion based on more extensive pre-enrollment Holter screening, no other dose-emergent ECG events occurred.
In subsequent studies, after installing a telemetric 12-lead ECG monitoring system, investigators revised protocol requirements for continuous ECG monitoring and data recording, both pre-enrollment and post-dose.
In the best-case scenario, drug development and clinical research professionals track changes in both science and regulation, and translate their understanding into optimally designed study protocols. AEs occur and are dealt with appropriately; if delay occurs, it is recognized as truly necessary. As a result, both human subjects and the research process are protected from avoidable risk.
If unprepared for an AE, the project team and FDA can be unnecessarily alarmed, and the project significantly delayed. One of the drawbacks to not anticipating and then having to modify a study design is putting the modification back through the IRB/REB prior to reinitiation. The quandary facing researchers is how to proceed with the appropriate caution while maintaining a quick pace.
As the preceding case examples illustrate, the keys to avoiding interruption are experience and collaboration and attention to detail in protocol planning. In particular, considerations need to be defined in inclusion and exclusion criteria, pertinent data needs to be collected, and the criteria and trigger points for AE-based study decisions and reporting need to be defined early on.
Regulatory guidelines offer only general objectives, and while meetings with the FDA can be critically important, most FDA reviewers have not actually run trials. They may not anticipate impediments that can arise during logistical implementation of the proposed study. Despite plans laid in accordance with the guidance and advice of reviewers, gaps between optimistic planning and AE realities can pose substantive threats to study objectives and timelines.
To guard against and remedy these situations, researchers need both a detailed plan of action and access to appropriately experienced consultants who can advise beyond those guidelines to address details of study design that may affect occurrence, detection, management, and reporting of AEs. Such foresight and planning should produce time efficiencies and cost savings, as well as ensure that clinical development milestones are achieved on schedule and within budget.
Royce Morrison, MD, CPI, is Director of Clinical Strategy, email@example.com, and Lauren E. Black, PhD, is Senior Scientific Advisor, firstname.lastname@example.org, both for Charles River.