IRB Review of Phase I Research: Balancing Ethics and Efficiency

Phase I research is a crucial part of drug and therapy development. Because it differs in important ways from later phase research, Phase I studies raise unique challenges, in both their design and implementation as well as for the institutional review board (IRB). Proactive strategies for identifying and addressing these challenges can enable ethical IRB review and timely study implementation.

What is Phase I Research?

Phase I studies are typically the first studies conducted in human beings and most often involve a drug or biologic. Perhaps the most common objectives for Phase I studies involve establishing parameters for an investigational agent’s pharmacokinetics (how it is absorbed, metabolized, and excreted by humans) and pharmacodynamics (the agent’s effects on humans, including its mechanism of action). Studies with other objectives, such as establishing bioequivalence and/or bioavailability between a reference and investigational product, may also be considered Phase I research.

While Phase I studies will under certain conditions be conducted in sick patient populations, oncology being the most notable example, much of Phase I research is distinguished by limiting its study population to healthy volunteers.

In addition to their unique objectives and healthy study populations, Phase I studies can also be distinguished from a participant perspective by the types and frequency of study procedures involved. Many Phase I studies require frequent blood collection and monitoring, often necessitating inpatient stays for participants at dedicated Phase I units, sometimes for extended periods of time.

Challenges with Phase I Research

Participant safety

Because Phase I studies often administer interventions that have not been evaluated in humans before, extra attention to participant safety is warranted. In most cases, the intervention will have been evaluated in animals prior to Phase I use, and the FDA has standards for moving from animal to human dosing to ensure an adequate safety margin, which sponsors and the IRB should ensure are met.

In addition, Phase I studies evaluating an intervention for the first time in humans are usually well-advised to employ sentinel dosing. This means administering the first dosage, and in some cases each new dose level of the product, to a small number of participants and allowing sufficient time to pass to detect adverse events before more people are exposed.

Sentinel dosing ensures that, should the intervention be poorly tolerated, the number of participants adversely impacted will be minimized. Intensive monitoring is also needed to ensure that adverse events are detected and addressed in a timely manner.

Payment and house rules

Phase I studies enrolling healthy volunteers often offer more robust payment and incentive for participation than research involving sick patient populations, where the prospect of receiving a new investigational treatment may be sufficiently motivating.

While there is nothing inherently problematic about payment, clear compensation schedules are paramount for both participants and the IRB. Such plans should include the amounts and timing of payment, whether and how payment will be pro-rated in case of early participant withdrawal, information about any completion bonus, and the conditions under which full payment will be made (e.g., if full payment will be made when a withdrawal is the result of a side effect from the test agent).

Many Phase I facilities have “house rules” that participants must follow to remain in studies. IRBs should be aware that house rules may contain information pertinent for certain aspects of their review and may request them as needed. Information that is contained in the house rules generally need not also be reiterated in informed consent documents.

Operational challenges

In addition to features of Phase I research that pose challenges for IRB review, Phase I studies also pose unique operational challenges for sponsors, CROs, and sites. Many Phase I studies are on tight timelines and face pressure to recruit and schedule participants as quickly and efficiently as possible. This makes identifying and proactively addressing the ethical and regulatory challenges posed by Phase I studies crucial so that IRB review does not needlessly become the rate-limiting step for Phase I studies.

Balancing Ethics and Efficiency

Appreciation of the unique features of Phase I research can help build a research ecosystem that meets demands on efficiency without sacrificing quality ethical IRB review. IRBs should clearly delineate their standards for review of Phase I research to sponsors and sites, including expectations around the common sticking points discussed above (e.g., when sentinel dosing will be expected; policies relating to payment and completion bonuses; etc.). Sponsors and sites should take that information and build protocols and IRB applications that proactively address the ethical and regulatory features of Phase I research. This can mitigate the need for IRB deferrals and speed review times while assuring ethical standards are maintained.

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