Project Management

The key issues affecting the speed at which an early phase oncology trial proceeds are: site administrative timelines for study start-up, investigator interest in and dedication towards enrollment to the study at hand, patient interest in the context of available experimental treatment options, patient eligibility criteria, required patient assessments, and site data submission characteristics. Addressing each of these topics:

• Site Administrative Timelines- Theradex tracks historical performance among the cancer centers participating in early phase clinical trials over the past decade. While Theradex is happy to accommodate a Sponsor’s wishes to include particular sites within a multi-site study, we seek to include several sites with a record of rapid study administrative start-up among the participants.
• Investigator interest and Dedication to the Study- The plethora of new investigational oncology agents has overwhelmed many cancer center key investigators, dividing their clinical research attention among many trials. Theradex seeks to engage investigators who have a scientific interest in the biological mechanism targeted by the investigational agent as well as an interest in making new treatment approaches available to their patents. The selection of investigators is developed from among scientific meeting authors, recommendations from key opinion leaders (who often are too busy to devote adequate attention to a new study) with whom Theradex has worked previously, and upon discussion with Theradex clinical staff involved in NCI audits who help assess the capabilities of the clinical research programs at major cancer centers. Beyond feasibility questionnaires, Theradex relies on these mechanisms and frequent review of a site’s clinicaltrials.gov and institutional website listing of trials to assess the ability of the investigator and site to dedicate staff and patient resources to the trial under consideration.
• Patient Interest- Cancer patients considering enrollment in an early phase cancer drug trial now often find they have a menu of potential trials to choose from. Ease of study treatment (e.g., oral vs. intravenous) as well as the logistics and invasiveness of study requirements factor heavily in a patient’s decision for enrollment, especially early on when little information can be shared regarding potential toxicity or hints of anti-tumor activity. Theradex works with the Sponsor to keep these issues in mind during study development so that study variables that can be controlled (assessments, clinic visit requirements) do not become detrimental to enrollment.
• Eligibility Criteria- In the current era of targeted therapies, sponsors often lose sight of the purpose of Phase I studies and burden the study eligibility criteria with overly restrictive organ function or tumor biology restrictions. In their effort to avoid possible adverse events or to achieve an early “proof of principle”, respectively, sponsors often create unnecessary hurdles to speedy Phase I study enrollment. Theradex seeks to scrutinize the eligibility criteria during protocol development so that the goal of the study remains focused on safety and toxicity, while biological assessments are gathered secondarily. When appropriate, refinement of eligibility criteria, both organ function and tumor biology, may be planned for later during an expansion segment of the Phase I study.
• Study Assessments- As with eligibility criteria, sponsors often delay the launch and subsequently the conduct of early phase oncology trials by building a long list of study assessments (e.g., repeat scans, tumor biopsies, correlative biology tests) into the protocol that nearly mimic the pre-clinical development of the experimental agent. While it is tempting to try to gather “as much information as possible” from the first patients receiving the new agent, these assessments often overtax both the patient and the investigative site personnel. This circumstance can slow accrual and diminish site enthusiasm for the study. Again, Theradex works with the Sponsor during protocol development to scrutinize each study assessment regarding its necessity and the value added/lost by its inclusion/exclusion.
• Data Submission- While enrollment is a key factor for speedy study conduct, the site’s ability to submit data and respond to data queries in a timely and high-quality manner is necessary to successfully complete the trial. Theradex tracks metrics for site data submissions and query resolution, and these are factored in to site selection and site monitoring.

Theradex’s extensive experience with early phase oncology clinical trials provides a unique opportunity to help sponsors utilize a Quality by Design approach. A thorough Risk Assessment is the first step in Theradex’s Quality by Design (QbD) and Risk Based Monitoring (RBM) approach. The Risk Assessment Plan not only addresses items in the protocol, which may be lacking a QbD approach, but also outlines Theradex’s suggestions regarding the appropriateness of implementing RBM into the clinical study.

Theradex routinely requests an early review of the draft protocol or study synopsis to identify potential risks in the study design that may result in slow patient accrual, poor quality data, site compliance difficulties or data that does not support the study objectives. Examples of such risks include excessive PK sampling requirements or ill-considered correlative assays, collection of inconsequential data points, misunderstanding site capabilities or their standard clinical practice, as well as underestimating necessary site training.

Protocol development is the first step in the clinical portion of QbD. The protocol describes the study design for all investigators who are participating in the study. To optimize the protocol compliance and increase the output quality of the clinical study, Theradex requires appropriate investigator input prior to protocol finalization. The goals of investigator input include: 1) review of inclusion/exclusion criteria to ensure that the interpretation of the criteria are as intended by the Sponsor, the criteria are not unnecessarily restrictive and are appropriate to the study so that accrual goals can be met, 2) review of the timing, frequency and appropriateness of any clinical procedures and follow-up visits, 3) review of study treatment procedures to assure that pharmacy and nursing practice logistics are considered appropriately. By discussing the study design with investigators prior to launch, Theradex seeks to avoid potential impediments to study accrual and minimize protocol deviations and site compliance problems. In addition to protocol review by the Sponsor, Theradex medical monitor, and principal investigator to optimize study design, the Theradex data management group also conducts a protocol review to ensure that an optimized dataset will be collected. Minimizing data output errors occurs by ensuring only essential data is to be collected. Theradex defines essential data as data that is relevant and critical to safety and effectiveness endpoints, meets all guidance recommendations with a “less is more” approach, and avoids duplicate data entry.

Ongoing risk assessment occurs throughout the study on a quarterly basis. These risk assessment discussions take place with the Sponsor during the quarterly contract review meetings. Issues related to previously identified risks are discussed and solutions provided. When a new risk is identified, it is added to the Risk Assessment Plan and a remediation plan is put in place. Any revisions to study plans, binders or re-training that are necessary as a result of the newly identified risk are implemented as soon as possible.

The Risk Assessment Plan and ongoing risk assessments also dictate whether the study is an appropriate candidate for “risk-based monitoring”. While the FDA and EMA guidances suggest that RBM is not suitable for most early phase oncology trials, Theradex is extremely experienced in the realm of RBM and has been performing RBM for the National Cancer Institute’s early phase clinical trials since 1985. Along with the NCI experience, Theradex continues to analyze each industry study to assess the suitability of RBM and currently utilizes the process in several Phase II industry trials.

Quality by Design is an integral part in the development of a successful early phase trial. The first step of the process is a thorough risk assessment of the study protocol to identify the primary risks associated with the experimental agent, patient population, and protocol design. Once risks are identified, Theradex next assesses that data collection aligns with the study objectives. In parallel to the design of data collection tools, conversations with sites and principal investigators occur to ensure that the protocol complies with the investigative site’s clinical and logistical procedures and confirms the investigator’s scientific agreement with the study design for the experimental agent under study. This investigator input helps define potential risks to study accrual based on the protocol defined eligibility criteria. Lastly, Theradex ensures that thorough training mechanisms are in place with SIVs, during which the Theradex trainer critically evaluates the site personnel regarding their understanding and capability to efficiently carry out the study. Following the SIV, the project team is debriefed and site-specific considerations for future support are discussed. Re-training occurs at Routine Monitoring Visits as necessary when items critical to quality are missed by site personnel (e.g., frequent protocol deviations of the same type). Theradex is able to identify and track ongoing site issues through the Monitor Express system.

There are multiple technology platforms that Theradex utilizes to centrally monitor studies in order to be proactive in our risk assessment of studies.

• Theradex’s Monitor Express system tracks issues such as protocol deviations or other site complications.
• Theradex’s EDC system utilizes front-end edit checks to increase the quality of data initially received from the sites. This also allows remote central monitoring of the data for early identification of protocol compliances issues.
• Theradex’s Safety Database, Argus, tracks safety measures across a study.
• Theradex’s J-Review system allows data leaders to analyze data trends across a study for identification of potential toxicities or other issues affecting a study’s primary objectives.

As a service provider for early clinical trials, Theradex provides scientific oversight and business oversight through different mechanisms. In early phase oncology trials, scientific and regulatory oversight has to be built into day to day operations, especially in first in man trials. It may be more appropriate for certain trials or programs to review the operational and regulatory delivery using integrated Steering Committees. Also, since Theradex expects that early phase trial designs will become more innovative utilizing multiple drugs and patient populations, flexible models for steering committees should be utilized to ensure that there is both oversight and effective information sharing. An Integrated Provider Steering Committee meeting no less than quarterly is recommended. Different approaches would be evaluated taking into consideration the overall development plan. For example, a drug in Phase III development as a single agent or in combination and in early phase development for another indication or combination would possibly be governed by a Steering Committee chaired by the provider with oversight of the later phase development. This blended approach to the committee could be applied to various provider models.

Project oversight by corporate and scientific leadership is ongoing in the Phase I and II setting. Theradex uses quarterly scientific and business review meetings to ensure that all critical issues are escalated and addressed proactively. Specific escalation steps, their timing, and assignment of responsibility for resolution are outlined at these meetings. Critical issues can be escalated at any time during the project.

In our experience, this frequency of issue examination ensures effective oversight of operational deliverables, study scientific integrity and regulatory compliance for early phase projects. It is envisioned that many new oncology programs will be conducted using innovative designs that are developed in collaboration with regulators possibly leading to accelerated approval based on early phase trial results. This governance model also provides a clear record of decisions made during study conduct.