The clinical trial landscape is changing. What do organisers need to know to navigate potential disruption? Source: Shutterstock.
As smaller, leaner organisations that must utilise resources carefully, biotechs face unique challenges as they enter clinical trials. These challenges are compounded by the fact that many biotechs are taking the lead in new and emerging modalities, from cell and gene therapies (CGTs) to antibody-drug conjugates and mRNA-based therapies — meaning that traditional approaches to clinical trials may not be the best option. Nevertheless, appropriately planning and conducting early phase clinical trials is critical to setting the stage for successful pivotal studies and, eventually, approval.
To better understand the concerns of biotechs in early phases, ICON conducted a survey of 149 professionals representing small- and medium-sized biotech organisations from North America and Europe. According to the respondents preparing to enter Phase I trials, the leading challenges anticipated include protocol uncertainty (31%), biomarker selection (35%) and navigating compliance and regulatory requirements (38%). This blog will explore some of the considerations for biotechs facing these key challenges.
Establishing a protocol
Clinical trial protocols can encompass many important elements, such as trial design and methodology. Of these, a central concern in Phase I trials is whether to enrol patients or healthy volunteers. Because early studies most often use a subtherapeutic dose, healthy volunteers are the typical choice. Without additional pathological complications, this group also offers the advantage of more generalisable data. On the other hand, for severe and life-threatening conditions, such as cancer, it can be more ethical to enrol patients.
Aside from these standards, there are benefits and drawbacks for each approach. Healthy volunteers tend to take less time to recruit, shortening timelines and lowering expenses as a result. Patients, on the other hand, allow trials to begin gathering efficacy data much earlier, enabling faster progress into later phases. Further considerations include the modality of the investigational product: Some newer modalities, such as CGTs, are considered too high of a risk to administer to healthy volunteers.
Another critical element of protocol is selecting the right endpoints. In early phases, endpoints should primarily focus on establishing safety data, and informing dose recommendations for subsequent phases. Secondary to these goals are any exploratory endpoints, which may include gathering preliminary data on efficacy. When utilising exploratory endpoints, it is important to be able to establish a logical connection with endpoints used in later phase trials, as doing so is necessary to meeting regulatory expectations.
Selecting biomarkers
Often closely tied to endpoints, biomarkers can provide invaluable data throughout clinical trials, including in early phases. However, selecting the biomarkers to study in a given clinical trial can be challenging, particularly in the case of new or emerging modalities for which standards have not been firmly established. Any selected biomarkers must be a suitable representative of the disease state or its progression, and be appropriate for demonstrating the effect of the investigational product. At the same time, biomarkers that do not meaningfully contribute to the rationale for developing a specific drug should not be included. One central question to consider is whether it would be worthwhile to continue in that drug’s development if a particular biomarker were not impacted by the investigational drug.
Biomarkers can be critical in early phases because they help to prove the investigational product’s mechanism of action relevant and impactful. To that end, mechanism-driven biomarkers are particularly useful because they demonstrate a therapy’s biological engagement in human systems and show that its mechanism of action is functioning as intended. Further, proving how a prospective therapeutic drives biological activity can help to guide later trials and their ability to test the therapy’s efficacy.
Meeting regulatory requirements
Regulatory requirements provide necessary guardrails to drug development; however, ensuring adherence to them can be a complex undertaking. This is particularly true when the role of regulations differs slightly depending on the phase of clinical trials. For early phases, particularly Phase I, the main regulatory priority is to demonstrate the safety of an investigational product, and to provide rationale for continuing into further clinical trials. First-in-human studies, in particular, can face significant risk. So, rigorous safety monitoring and the reporting of any severe adverse events is a critical expectation.
A significant exception to these priorities is early conditional approval, which can be sought in the case of severe unmet needs or a public health emergency. These are held to the same safety standards, but must also follow more stringent requirements, such as the approval of a predetermined clinical trial strategy, and the need to use regulatory endpoints even in early phases. Sponsors seeking such an approval should be prepared for significant regulatory obligations from the start of any clinical trials.
Regardless of which route is chosen, many regulatory agencies make themselves available for consulting early in the development process. Taking advantage of this offering can be beneficial for ensuring that a clinical trial is on track for regulatory requirements, and gaining regulatory advice tailored to the specific needs of a given investigational product.
A strategy for success
No matter what challenges an organisation may face, having a sound development strategy in place will help clinical trials stay on track. This strategy will serve as a compass for all decisions throughout the clinical trial process and beyond, giving the drug candidate the best opportunity for success. For biotechs entering clinical trials, there is little room for error — making it critical to have a plan in place from the beginning.
To learn more about the challenges and considerations facing biotechs in early phase clinical trials, read ICON’s whitepaper: Early phase challenges for biotechs https://www.iconplc.com/sectors/biotech/early-phase-challenges-biotechs
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