Early phase clinical trials mark the transition from preclinical research to clinical application, characterized by unique challenges and opportunities. Key considerations include the difference between early and late phase trials, the importance of data quality, and the specialized techniques used in dermatology.
Key Differences Between Early and Late Phase Trials
The true distinction lies in the fact that early phase trials mark the beginning of a new story in drug development. The transition from the preclinical stage to the clinical space has occurred, and there now exists an asset with potential for market introduction. This situation presents both a unique opportunity and a significant responsibility.
When considering the early phase studies, the first movement into the clinical space starts with a single ascending dose and the multiple ascending dose (SAD/MAD) study design. Typically, SAD is performed in normal healthy volunteers (NHV) and the MAD can be either NHV or patient population, all depending on the mechanism of action (MOA) and/or regulatory body requirements.
In early phase trials, the primary endpoint is assessing the safety of the study drug. When moving into the patient population, many sponsors take advantage of this first patient access to assess the potential efficacy of their study drug by adding exploratory endpoints. Such trials are usually phaseâŻ1 b/2a and sometimes referred to as proof-of-concept (POC). Adding exploratory endpoints to assess potential efficacy brings great value to the program development as it may bring confidence to both sponsor and investors on the potential value and success of the study drug. However, it is crucial to not fall in the rabbit hole of âmight as well,â i.e., add too many exploratory endpoints, where the risk of overcomplicating the operational logistics of a trial may occur and have a negative impact on the successful completion of a trial.
One of the many fun parts of studying inflammatory skin disease is the ease of access to the tissue: our skin. So many interesting measurements and assessments can be performed: imaging, tissue collections, characterizing skin barrier, etc. The key is to always ask ourselves âwhat is the questionâ and remain focused on the needs and musts when designing an early phase trial to ensure timely delivery of results while maintaining high data quality. This strategic thinking has a significant impact on how the story is written. It is all about maximizing the value of the program and making strategic decisions.
Data Quality
The emphasis is on data quality, control, and consistency. This is the stage where the narrative begins to unfold. The initial chapters of the book are being written, so the first words penned are of utmost importance. Additionally, the investment from the sponsor plays a crucial role and remaining aligned with the strategy of the program development is key to maintain focus on the key elements and avoid overextending that may hinder the operational logistics and feasibility.
Therefore, strategic planning is essential in early phase research. Typically, this is the stage where a small patient population is involved, and safety profiles are being developed with a glimpse into the efficacy if any signs are present, the latter captured as exploratory endpoint.
In these POC studies, every data point holds significant value. For instance, consider a study on atopic dermatitis where the subjects undergo treatment for 4 weeks. The exploratory endpoint may assess the change from baseline in the severity of the disease. A study with a small population of 40-50 participants in a placebo-controlled trial, it is critical to ensure the severity of the disease is assessed at the highest standard and consistently throughout the sites. With such a small trial, there is no âbufferâ for poor data quality as this can easily swallow the signal of efficacy. The same holds true for pharmacodynamic exploratory endpoints where molecular analyses of samples collected before vs. after treatment informs if mechanism of action of the study drug is successful.
How do we ensure high quality data? It all starts with the protocol: have clear inclusion/exclusion criteria with key prohibited medications and washouts, ensuring the correct severity scales are used with clear definition of required disease severity are only a few examples of protocol elements that have immense impact on data quality. Data quality is also obtained with two magic words: consistency and reliability. Ensuring that study activities are performed with consistency and reliability are of tremendous importance and this is where operational expertise is truly demonstrated. Working with the right sites with properly trained teams and investigators performing the activities is crucial to obtain and maintain quality data. Assessing the quality of the data during trial conduct is as important and critical. As one can see, many elements are required to ensure data quality and risk management is at the core to ensure all the pieces are in place and none are missing.
Dermatology Techniques in Early Phase Trials
Usually, always depending on the MOA of the study drug, the indication, and regulatory bodies where the trials are being conducted, PhaseâŻ1b trials are where we usually have the first access to the patient population. This stage of clinical development is particularly interesting because this is where the study design may include many exploratory endpoints in pharmacodynamics to gather more data and information on the study drug and impact on the disease being studied.
This is the essence ofâŻexploratory endpoints. They add significant value to the program and the asset by demonstrating a molecular signal and impact on signaling pathway. Moreover, it can be strategically beneficial for the sponsor to understand if there is any interference or additional signaling occurring.âŻSometimes, this data can guide a sponsor back to return to the bench to design a new drug that can mimic the actions in that pathway or assess its effect under different conditions. Hence, pharmacodynamic exploratory endpoints can provide crucial information and add significant value to the development of the clinical program.
There are numerous exciting possibilities in pharmacodynamic assessments, especially with dermatology. The skin is readily accessible. It can physically be touched. The specimens are easily obtainable. Genomics and all other âomicsâ can be performed, including gene expression. It can be done by skin biopsies, tape stripping, and many other methods. Additionally, the skin microbiome can be studied, which is truly fascinating. It is exhilarating to see the surge in publications in this field. Reflecting on the pastâŻ4 to 5 years, it is evident that translational research, in this field, has significantly advanced. The scientific community is now able to piece together the puzzle, linking for example, âomicsâ to lesion severity. For example, when the skin microbiome is being examined, it is possible to identify variations in the biota population by comparing different time points with baseline (i.e., change from baseline). Many recent publications have shown the link between lesions and skin flora, particularly in acne vulgaris and atopic dermatitis studies.
As mentioned previously, adding pharmacodynamic endpoints bring great value to the trial, but it is always important to keep balance between ânice to haveâ and âmustâ to avoid study designs that are very complex and have direct negative impact on operational feasibility. The success of a trial is directly dependent on site and subject engagement where excessive burden needs to be avoided.
In the early stages, opportunities arise to ask intriguing questions and receive equally intriguing answers. This could even lead to a shift in the programâs focus. As mentioned earlier, this adds immense value to the program. Working with a smaller population facilitates the efficient and manageable collection of diverse sample types. In this context, quality becomes paramount. Managing a small study population across multiple international sites with varying study designs introduces significant complexity. Ensuring uniform procedures, consistent sample storage, and preserving sample integrity during transport and analysis are critical to achieving high-quality data with minimal background noise â essential for capturing meaningful signals. The challenge lies in orchestrating all these elements into a seamless operation, much like assembling a complex puzzle. Ultimately, crafting a compelling narrative depends on how well each piece fits together.
In sum, early phase clinical trials focus on safety, dosage, and initial efficacy, involving smaller patient populations; they require meticulous planning, consistent data collection, and strategic decision-making. The insights gained from these trials not only advance scientific understanding but also pave the way for innovative treatments, ultimately enhancing patient care.
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About the AuthorÂ
Ana Palijan is Inderoâs Director of Early Phase and Translation Research. She is a molecular biologist with 20+ yearsâ experience in translational and clinical research with expertise in strategic program and study design development. She authored more than 30 publications in peer-reviewed journals. Ana has experience in multiple indications in pediatric and adult populations: dermatology, rare diseases, nephrology, cardiology and oncology. She is a specialist in biomarker research and has extensive experience in development and support of quality algorithms and pharmacodynamics assessments.
