By Brad Miller, Biosceptre
Many small and emerging biotechs and cell/gene therapy companies regard clinical development as a closely guarded trade secret of consultants and CROs and any attempt to understand the process or to develop their own clinical development strategy as futile. This belief likely stems from many early-stage researchers having had little exposure to the clinical aspects of drug development. While the simplest option is to outsource protocol and clinical development to a consultant or CRO, a disengaged or absent sponsor is unlikely to have its clinical and commercial objectives realized. Prior to engaging with a consultant or CRO, you can take the following six preliminary steps that are likely to leave both parties engaged in the clinical development process.
1. Benchmark FDA Approved Therapeutics
Benchmarking your therapeutic agent against competitors’ products is often an underutilized and underappreciated approach to drug development. The U.S. FDA’s clinical review performed as part of a marketing authorization request (e.g., a biologics licensing application [BLA]) provides significant commentary and direction from the agency on its approach to marketing approval.
Within the cell therapy space, we are fortunate to have access to five detailed FDA clinical reviews that span a first-in-class therapeutic agent (tisagenlecleucel) that required an oncologic drugs advisory committee meeting1 to the most recent approval (idecabtagene vicleucel), which didn’t require a review due to the drug not raising significant efficacy or new safety concerns,2 demonstrating the FDA’s increasing knowledge and confidence in this new class of therapeutic.
One of the more significant outcomes of the tisagenlecleucel clinical review (in terms of benchmarking) was the requirement for a risk evaluation and mitigation strategy with elements to assure safe use (REMS ETASU), with an emphasis on cytokine release syndrome (CRS) and neurotoxicity, together with a post-marketing requirement to conduct an observational, non-interventional safety study with a recommended enrollment of 1,000 patients. Since that first approval in 2017, each approved cell therapy has required similar warning and precaution language with incidence and time-to-event metrics of CRS and neurotoxicity, as well as the development of a REMS ETASU. Sponsors of early-stage cell therapy studies would be well advised to consider these requirements (including the associated time and expense) in their clinical development program.
2. Develop A Target Product Profile
One of the best tools available in the clinical development of your therapeutic is the target product profile (TPP), a document that outlines and supports the desired characteristics of your market authorized product. Your TPP should include your desired indications and usage, proposed dosage and administration, planned dosage forms and strengths, indicative warnings and precautions, potential adverse reactions, likely clinical pharmacology, expected nonclinical toxicology, and an overview of likely clinical studies.
While a number of these sections cannot be finalized until clinical data becomes available, your indicative response or placeholder text will often assist in driving your clinical program. Some considerations for the “indications and usage” section may include:
- Is your therapeutic targeted to adult or pediatric populations?
- Do you propose a relapsed/refractory population, or do you intend to move up the treatment algorithm and seek marketing authorization as a second-, third-, or fourth-line therapy?
- Will patients only be eligible to receive your therapeutic if they have failed a specific drug or class of drug or, alternatively, do they need to have received a certain number of prior therapies?
- Does your therapeutic rely on the presence of a specific biomarker and will an FDA approved companion diagnostic require concurrent development?
- Are you intending to use an FDA expediated pathway (e.g., accelerated approval) to improve your speed to market?
Alongside your indicative indication and usage text, you should consider the internal notes that document the activities and studies you propose to undertake in support of your desired characteristics. The supporting activity for some sections (i.e., clinical pharmacology) will likely include only relevant data from your clinical study. However, if a literature search, for example, is likely to be sufficient to support the use of a specific biomarker, then a reference to that internal literature review report should be provided or, alternatively, a list of proposed preclinical studies you plan to undertake should be documented instead. While the list of proposed supporting studies should be considered a working draft, and indeed this list is likely to be heavily influenced by your early interactions with the applicable regulatory agencies, having this data available and referenced in your TPP will greatly assist your chosen consultant or CRO to undertake a gap analysis (to compare your current state of development against an ideal state of development) as well as assist in the creation of the full-form protocol, the investigator brochure, and the required regulatory submissions.
Within specific therapeutic modalities, some adverse events are much more likely to occur (e.g., CRS and neurotoxicity in cell therapies) and are therefore more likely to result in a boxed warning on the product label. If a boxed warning is likely, given the class of therapeutic, the TPP should outline placeholder text and identify the anticipated and acceptable outcomes for further discussion with the appropriate regulatory agencies. For instance, a 100% incidence of CRS in your proposed clinical studies may be acceptable if the CRS is limited to ≤ Grade 2 in a relapsed/refractory population that has had four prior lines of therapy; however, an incidence of > 50% Grade 4 CRS in a first-line therapy population may be unacceptable. Not only will the incidence and grade of CRS be applicable for the product label, but the median time to onset and median duration will also be reported in the product label. By including placeholder text (based, where possible, on nonclinical studies and literature reviews), the consultant or CRO will confirm that appropriate assessments are included in the schedule of activities, understand the data that is required to be collected in case report forms, and ensure that appropriate statistical tables are developed to report on that data.
While lisocabtagene maraleucel conducted a seamless dose finding, dose expansion, and dose confirmation study, it is unlikely that a small and emerging biotech will have the financial resources to conduct a Phase 1/2 pivotal registrational study without first undertaking smaller exploratory studies to build data and confidence in the therapeutic and to raise further capital. Accordingly, the internal notes associated with the TPP can document each stage of the proposed clinical development, with headline details on the Phase 1 (dose finding), Phase 2 (dose expansion), and Phase 3 (dose confirmation) studies. By detailing each stage of development, you can perform further critical evaluation of each section of the TPP. For instance, while you may be positioning your product to be approved as a third-line therapy, you should consider whether to undertake your Phase 1 study in a healthy volunteer or relapsed/refractory population (dependent on disease indication) as you build the safety profile of your drug.
While consultants and CROs are unlikely to have your deep product knowledge, a great consultant or CRO will question the assumptions in your TPP based on their experience in similar therapeutic areas and their discussions with regulatory agencies, which is likely to further solidify the commercial and clinical positioning of your therapeutic.
3. Consider Your Objectives And Endpoints
While intuitively all clinical researchers will be able to paraphrase the aims of a clinical study, few would articulate those aims as formal objectives and endpoints without the intervention of a consultant or CRO. However, the aim of considering your objectives and endpoints isn’t to draft them using the most clinically appropriate language (the specific language can be finalized by the consultant or CRO), but rather to establish your expectations of objectives and endpoints that you would like to explore.
Depending on the stage of clinical development and the disease indication under investigation, these objectives and endpoints should be separated into primary, secondary, and potentially exploratory objectives. The primary objectives of a first-in-human Phase 1 study are likely to include safety and tolerability and, if the study involves dose escalation, an evaluation of dose limiting toxicities, maximum tolerated dose, and recommended Phase 2 dose, whereas the primary objective of a pivotal registrational study will be efficacy related (e.g., objective response rate, duration of objective response, overall survival, etc.). The feasibility of manufacturing the study drug and incidences of “manufacturing failures” are also likely to be primary objectives in early-phase cell therapy studies.
When designing your clinical development program, you must remember that each phase of development is attempting to provide new knowledge regarding the utility of your therapeutic. While you are likely to propose a significant number of objectives and endpoints, not all questions will be answered in a single study, especially not a Phase 1 first-in-human study. However, early or preliminary data can assist in the refinement of your clinical development strategy and provide you the flexibility to pivot when and where required. Within cell therapy, while it will not be statistically significant in a Phase 1 first-in-human study, understanding preliminary correlation and regression models between the occurrence and severity of CRS and neurotoxicity may be of particular interest.
Where a consultant or CRO can add significant value is to identify the objectives and endpoints that satisfy regulatory agency requirements (e.g., the requirement for QT/QTc interval prolongation assessments,1 the requirement for replication competent retrovirus assessments in cell therapy products,2 etc.) and the more standard objectives and endpoints that are common across studies.
4. Identify Key Opinion Leaders
While it’s unrealistic to expect a small and emerging biotech to have a deep knowledge across all the medical decisions required in clinical development, it’s not unrealistic to identify key opinion leaders in your field of interest and disease indication and to develop a commercial relationship. Fortunately, as cell therapy studies increase in prevalence, especially within hematological malignancies, the number of clinicians with considerable and credible experience to draw upon will also strengthen significantly.
While access to key opinion leaders is unlikely to be free, clinicians strive day-to-day to improve patient outcomes and many would encourage collaboration between clinicians and sponsors on early-stage clinical activities where their wealth of knowledge and expertise on comparator products, drug positioning, clinical study design, likely subject recruitment, potential inclusion/exclusion criteria, and upcoming competing studies will be invaluable. Involvement of specialist clinicians in reviewing your TPP, and proposed objectives and endpoints, is likely to uncover opinions and perspectives that will further develop and refine your clinical and commercial objectives.
5. Collaborate To Develop The Ideal Study Design
Once you understand the characteristics that permitted your competitor products to be marketed via the benchmarking exercise and have outlined the desired characteristics of your marketing authorized product in your TPP, developed an outline of your objectives and endpoints, and received feedback from your key opinion leaders, it may be time to engage a consultant or CRO with considerable cell therapy experience to collaborate on the development of your proposed schedule of activities and clinical trial design.
While some small and emerging biotechs may have the skillset and experience to develop a draft of the study design, it is important to understand that the perfect study will involve feedback from multiple disciplines, including clinical operations, biostatistics, data management, project management, and medical monitoring. While you should present your case and be prepared to argue your position, there are likely valid operational and/or regulatory reasons that your consultant or CRO may recommend otherwise. Regardless of the outcome of those discussions, a robust conversation between sponsor and consultant/CRO is likely to identify the best possible study design.
6. Discuss Your Clinical Development Program With Regulatory Agencies Early
Notwithstanding the benchmarking exercise undertaken above and the improvements and suggestions proposed by the consultant or CRO, the opinions and stance of regulatory agencies on various matters are likely to change over time as the industry further develops and new drugs are brought to market. This is most clearly evident in the involvement of the oncologic drugs advisory committee in early cell therapy approvals and the refinement and publication of new and updated guidance to industry documents.
There are many early opportunities available to discuss your proposed clinical development program with the regulatory bodies to receive first-hand feedback on your proposed clinical development program. You should explore these opportunities at every available occasion to ensure your clinical development program is progressing along the regulatory pathway toward marketing authorization, with the shared goal of facilitating earlier availability of safe and effective therapeutics.
As the cell therapy market matures and additional products obtain marketing authorization, sponsors should be prepared for increased regulatory oversight and additional regulatory hurdles. While consultants and CROs certainly have a role in assisting the small and emerging biotechs to develop, improve, and enhance their clinical development strategies, the smart, engaged sponsor must ensure that the most critical, expensive, and time-consuming program it will undertake is adequate, well controlled, well designed, well considered, and well positioned to address its clinical and commercial objectives.
- USFDA BLA Clinical Review Memorandum of Tisagenlecleucel, Section 5.4.1.
- USFDA BLA Clinical Review Memorandum of Idecabtagene Vicleucel, Section 5.4.1.
- U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Guidance for Industry: E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, October 2005.
- U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research, Guidance for Industry: Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up, January 2020.
About the Author:
Brad Miller is the clinical operations director at Biosceptre, a company developing antibody and CAR-T therapeutics against nfP2X7. He can be found on LinkedIn.