Slot Allocation Is A Problem For Patients And PIs In Phase 1 Oncology Trials (Part 1)

By Nehal Lakhani, MD, Ph.D., director, clinical research, START Midwest

Over the past decade, the oncology drug development pipeline has expanded dramatically, with an unprecedented number of first-in-human studies launching each year. As first‑in‑human trials evolve to play a larger role in dose‑finding, optimization, and early signal detection, the weaknesses of current slot allocation models have become more visible and more consequential. 

Academicians often discuss the pros and cons of Phase 1 trial designs, such as 3+3 variations, accelerated titration, mTPI, and Bayesian methods. However, we rarely talk about the strategies used routinely in industry-sponsored Phase 1 trials for slot allocation or cohort management. Given the dramatic shift in the size and scope of oncology Phase 1 trials, it is time for us to rethink cohort management and slot allocation strategies for these trials. Understand, in this two-part series, the limitations and consequences of current slot allocation models and discover how assigned slot allocation might serve as a fair and efficient replacement.

Current Slot Allocation Models And Their Limitations

Sponsors typically use two main strategies to manage Phase 1 oncology dose-escalation trial slots: competitive enrollment and patient waitlists.

Competitive Enrollment

Competitive enrollment remains the dominant model for most Phase 1 trials. When a sponsor announces the opening of a dose-escalation study, sites must submit slot requests on behalf of prescreened patients. Slot allocation decisions are based solely on operational considerations such as:

• earliest feasible cycle 1 day 1 (C1D1),
• completeness of prescreening,
• ability to begin required assessments promptly, and
• willingness to perform optional procedures, including biopsies.

Sponsors’ needs are placed above the needs of the trial site and patients. The site that can maximize timeline efficiency and meet the sponsor’s data needs wins. This approach often requires sites to invest time in preparing a patient’s slot request documents before knowing whether the slot will be awarded.

Patient Waitlists

The trial sponsor creates waitlists of patients that are prescreened at each site involved in the trial. These patients are then expected to remain on that waitlist, faithfully awaiting their turn for a slot to open on the trial. A slot opening may or may not occur for that patient, or it can sometimes take several weeks. By being waitlisted, these patients have implicitly chosen not to start another form of systemic therapy. As soon as a slot becomes available, patients must sign the informed consent document quickly to receive treatment. The slot may be used only for a particular patient when their turn arrives. However, if a patient’s ECOG Performance Status score has declined or their labs no longer meet eligibility criteria, they may no longer be eligible to join the trial when the slot opens. There is nothing more frustrating for a clinician at a high-volume trial site than to have a waitlisted patient who no longer meets eligibility criteria when a slot opens and not be able to use that slot for another eligible patient.

While this approach is not as overtly oblivious to the needs of patients and trial sites as competitive enrollment, things are often not as straightforward as they seem. These waitlists are often opaque to investigators and trial sites, making it impossible to determine where a given patient ranks on the list. Sponsors are frequently unable to provide accurate timelines for when a patient may receive a slot to begin treatment with the trial drug.

The Downstream Impact On Patients, Investigators, And Trial Quality

Slot allocation has direct implications for patient care, investigator engagement, and the pace of early-phase development.

Impact on Patients

Patients are often upset knowing there is a potential breakthrough treatment in clinical trials that they are unable to access due to some procedural trivia. One of the biggest issues with the current methods of slot allocation is the uncertainty. For a patient who has a relatively short amount of time to live, this information is paramount when deciding how to spend the little remaining time they may have with their families. There is so much uncertainty already for patients with end-stage cancer. Participation in Phase 1 clinical trials adds to this uncertainty, especially regarding whether the drug dose they receive will ultimately prove to be safe and/or effective. The additional uncertainty of being waitlisted for a trial slot can be quite disruptive for patients at the most vulnerable time in their lives.

The rigidity of early C1D1 timelines associated with competitive enrollment can conflict with major personal life events. For example, a grandparent who has been motivated to stay alive to attend their grandchild’s college graduation may feel pressured to choose between the trial treatment’s early C1D1 or their grandchild’s graduation to fit a narrow treatment window.

With competitive enrollment, slots are occasionally preferentially allocated to patients who agree to optional procedures, such as biopsies. When optional procedures influence slot assignment, the distinction between “optional” and “required” becomes blurred. This approach also indirectly introduces an element of bias in patient selection against patients who are not proficient in English. This is because informed consent documents need to be translated into a patient’s language of proficiency and approved by the IRB, which delays projected C1D1 timelines essentially disqualifying the patient from the trial slot availability. 

Both the above methods of slot allocation — competitive slot allocation and patient waitlists — create in patients a perceived scarcity of the clinical trial drug. This subconsciously introduces bias in the human brain and influences decision-making in favor of the trial. In fact, patients waiting for a trial slot often hesitate to start another form of systemic therapy because doing so would require a washout from the standard treatment and may delay the start of the clinical trial treatment. We should not be using slot allocation methods that introduce scarcity heuristics, inadvertently influencing decision-making in a patient population that one might argue is quite vulnerable. 

Impact On Investigators And Sites

Physicians and site staff play an important role in helping pharmaceutical companies achieve their accrual goals and meet trial endpoints. But physicians have an even bigger responsibility to care for patients with end-stage cancer and help them make decisions that ultimately align with their goals. Clinical investigators can only provide comprehensive care to cancer patients if they are supported by trial sponsors. The uncertainty introduced by slot allocation can often make it confusing or difficult for physicians to make medical decisions, which can occasionally lead to adverse outcomes and poor patient care. For example, a patient waitlisted and highly interested in a particular clinical trial who forgoes systemic therapy in hopes of getting on the trial has rapid disease progression and dies from cancer earlier than they would have if they had been on the systemic therapy. These situations can become emotionally charged enough for families to implicate treating physicians medicolegally.

Delays in slot allocations to sites can also result in loss of confidence in a sponsor by trial sites or investigators. Physicians are supposed to recognize early patterns in adverse events for drugs in early-phase dose-escalation trials. However, if an investigator is only afforded a trial slot once every four to six months, their experience with the drug is diluted, resulting in an inadequately characterized adverse event profile and mitigation strategies. Long gaps between treated patients at a site make it challenging for an investigator to develop familiarity with an investigational agent or recognize emerging toxicity patterns. Engagement can naturally wane when sites enroll only one patient every few months.

Operationally, clinic staff invest considerable time reviewing patient eligibility criteria and coordinating assessments before a slot request is made to a sponsor. When a slot is allocated elsewhere and this work does not translate into enrollment, it increases strain on already busy early-phase teams. At high-volume early-phase oncology trials sites, managing waitlists and available slots has become a full-time and often frustrating job.

Impact On Trial Data Quality

Competitive enrollment has the potential to skew enrollment to sites that can get patients to trial C1D1 fastest. This comes with the inherent risk of concentrating trial participants at a few sites. This may result in relying on very few sites for a large majority of trial data and the interpretation of safety and efficacy signals. This also increases the regulatory compliance risk if protocol deviations are discovered at these sites. Competitive enrollment defeats the purpose of having many sites participating in a trial.

Patient waitlists create the risk that by the time a patient is allocated a treatment slot, either their physical condition or labs have deteriorated to such an extent that they are no longer a trial candidate. Sometimes patients deteriorate clinically, but they are just well enough to meet the trial eligibility criteria. Such patients may be at high risk of poor tolerance of the investigational drug leading to a dose limiting toxicity (DLT) or inability to complete treatment through the DLT evaluation period resulting in an in-evaluable patient that must be replaced. This risk could be easily averted if sponsors allowed principal investigators to pick the best candidate at their site for a trial without imposing the trial waitlist.

A Fair, More Efficient Alternative

In part two of this series, explore how assigned slot allocation can serve as an alternative approach to competitive slot allocation and patient waitlists, which is both efficient and fair to the patients, sites, and sponsors involved in Phase 1 clinical trials.

About The Author:

Nehal Lakhani, MD, Ph.D., is a medical oncologist and director of clinical research at START Midwest, part of The START Center for Cancer Research’s global network of clinical trial sites. Dr. Lakhani received his MD from the Maharaja Sayajirao University of Baroda in India and his Ph.D. in pharmaceutical sciences from the National Cancer Institute in Bethesda, MD. He was a Fogarty Fellow at the National Institutes of Health (NIH), trained in internal medicine at Michigan State University, and completed a medical oncology/hematology fellowship at the NIH in Bethesda. He has been involved in the development of several new anticancer therapies including immunotherapy agents, antibody drug conjugates, and targeted therapies.