Put yourself in this scenario: Your compound is a newly validated mutated receptor that is present in only a limited number of cancer patients, and there is no approved diagnostic test. Your product, an antibody-like molecule that inhibits the receptor’s activity, also stimulates a potent immune response.
Further complicating things, much of the preclinical data suggests the compound will synergize with unapproved newer molecules that are in later-stage trials. And you are in the very early stage of codeveloping biomarkers and diagnostic kits to define those patients who will best respond to your investigative therapy.
In our white paper Driving Product Development and Finding the Fast Track in Early-Phase Oncology Programs, Premier’s Luke Gill, Peter Larson, and George Hemsworth look at some of the many considerations that must go into planning and executing an early-phase trial of this compound, from performing a regulatory gap analysis and developing a target product profile to identifying the right patients.
Mapping the regulatory approach
The first major goal when advancing a novel oncology product is conducting a first-in-human study, often a Phase I safety, tolerability, and pharmacokinetics study in a limited number of cancer patients. Unfortunately, these sponsors often face a shortage of skilled clinical trial professionals and have limited regulatory knowledge and experience. Thus, a logical first step is a regulatory gap analysis, a technical review of data — both its content and adequacy to support preclinical meetings with the FDA or with regulatory authorities outside the United States.
The gap analysis typically includes pharmacology, Good Laboratory Practices, non-clinical safety, and Good Manufacturing Practices information leading to original INDs or clinical trial applications. The results provide high-level guidance for additional work that may be necessary to resolve data limitations and deficiencies.
In a first-in-human trial of a novel oncology compound, a pre-IND meeting with the appropriate oncology team at the FDA is the optimal first step. It’s an opportunity for the sponsor to provide critical pharmacology, manufacturing, and non-clinical safety information and to propose a clinical synopsis of the IND-enabling trial. The FDA Draft Guidance on Formal Meetings Between the FDA and Sponsors or Applicants [PDF] outlines the structure, format, content, and timelines for a pre-IND meeting request.
There are several options for accelerating the regulatory pathway for novel oncology programs. In its guidance on Expedited Programs for Serious Conditions—Drugs and Biologics [PDF], the FDA describes the qualifying criteria for Fast Track, Breakthrough Therapy, and Regenerative Medicine Advanced Therapy designations.
The European Union has similar expedited approval programs for serious conditions, namely the PRIME (PRIority Medicines) program and the Advanced Therapy Medicinal Products classification, a relatively new European Medicines Agency (EMA) initiative to provide for expedited development of groundbreaking opportunities to treat disease or injury.
Other useful FDA guidance documents include:
- Qualification Process for Drug Development Tools, describing the qualification process for biomarkers that may be used as endpoints in clinical studies intended to support product labeling
- In Vitro Companion Diagnostic Devices, defining an in vitro companion diagnostic device as one that provides information essential for the safe and effective use of a corresponding therapeutic product
- Codevelopment of Two or More New Investigational Drugs for Use in Combination, for cases in which the investigational product has the potential to provide additional clinical benefit when co-administered with another late-stage clinical development product
Considerations for the clinical development strategy
Strategy development should begin with a target product profile. When developing a TPP and considering what is needed to ensure that a product is successful, consider these factors:
- The right target. There should be a strong link between the target and the disease, differentiated efficacy, and access to available and predictive biomarkers.
- The right tissue. You need adequate bioavailability and tissue exposure, defined pharmacodynamic biomarkers, clear visibility of preclinical and clinical PK/PD, and understanding of drug-drug interactions.
- The right safety. It’s important to have clear and differentiated safety margins and to understand secondary pharmacology risks; reactive metabolites, genotoxicity, and drug-drug interactions; and target liability.
- The right patients. What patients will be most responsive, and how will you weigh risks vs. benefits for a given population?
- The right commercial potential. You need a differentiated value proposition, a good understanding of market access, and a personalized healthcare strategy that includes diagnostics and biomarkers.
Early-phase studies by biotech and specialty pharma companies increasingly are going beyond proof of concept, adding enrichment cohorts in expansion Phase I or Phase II studies. Organizations are using efficacy data to expand their Phase I/II designs and initiate discussions with the FDA regarding accelerated pathways. For small and midsize companies, it’s important to understand not only what the budget allows, but also how to be nimble enough within study designs to explore additional indications in parallel if the investigative drug demonstrates efficacy in other tumor types.
Combination therapy is becoming more common in early-phase studies of immuno-oncology products. Unlike monotherapies, the maximum tolerated dose for a combination therapy is not a single number but a space on the dose curve between the two drugs, and the recommended Phase II dose is the point within that space that is predicted to give maximum tumor growth rate inhibition.
Unlike studies of cytotoxic chemotherapies, which often rely on a traditional 3+3 design, investigations of immuno-oncology products that target tumor mutations may be better suited to a basket study design. Basket studies concentrate on a specific mutation found in the tumor, regardless of where the cancer originated. Such a study might be appropriate if the interest is in studying the effect of a specific treatment within a particular biomarker-positive group of patients.
Another study type to consider is an adaptive dose escalation design in which a single dose regimen is used to determine the maximum tolerated dose before switching to a multiple dose regimen to determine the recommended Phase II dose. Adaptive dose escalation studies may include multiple cohorts and multiple tumor types.
Operationalizing early-phase studies
Defining a patient population for a Phase I oncology trial is challenging due to complexities associated with previous treatment regimens and comorbidities. The standard treatment algorithm for the indication can serve as a guideline for identifying appropriate subjects and should be applied with thoughtful consideration of individual circumstances, as illustrated in this example from a Phase I acute myeloid leukemia trial.
It’s important to ensure that the patient population is consistent with the defined disease and the criteria outlined in the protocol and exhibits the appropriate marker(s) for treatment. Performing a real-time eligibility review helps ensure that the patient population selected is consistent with the defined disease and the criteria outlined in the protocol.
Subjects in Phase I studies typically have limited further treatment options. Real-time review of eligibility at the time of enrollment will help sponsors:
- Develop an eligibility or slot assignment document to be used by study staff.
- Identify critical source documents for medical review to confirm key eligibility criteria.
- Establish processes for querying the site regarding eligibility criteria.
- Limit turnaround time between submission and approval.
Should you include healthy subjects? Healthy volunteers have been included in some first-in-human trials using molecularly targeted agents due to their considerably lower toxicity profiles. Important factors to consider in the design of oncology trials that include healthy volunteers include careful observation of effects on major organ systems, early detection of adverse effects, limited exposure to the drug, a conservative dosing scheme, and immediate cessation of exposure at the first evidence of toxicity.
The advantages of using healthy subjects include rapid enrollment, investigation of bioavailability/pharmacokinetics, metabolic profiling, dose-finding, and the ability to acquire data not confounded by diseases. However, extrapolation of results from these studies to patients with cancer might be limited, and the low-dose pharmacokinetics in healthy volunteers may differ from therapeutic-dose pharmacokinetics in patients with cancer.
Managing cohorts is more art than science, and engaging a CRO experienced with cohort management can mean the difference between success and failure. It’s especially critical in the multi-center, global dose escalation studies that are typical for Phase I oncology trials. Dose escalation data review and codification prior to enrolling into the next dose cohort is also essential, not only for subject safety, but also for data appropriateness and quality.
There are many factors to consider when developing early-phase oncology programs, but biotech and specialty pharma sponsors are not alone. Many highly skilled individuals and organizations can help plan and execute studies of novel oncology compounds. Some contract research organizations specialize in these scenarios and can help sponsors meet their goals, ideally getting involved immediately after, if not before, sponsors face critical funding milestones.
For a more detailed treatment of this subject, check out our white paper.