Resources:

• Busdev@innovaderm.com: Use this email to let us know what you want to hear about.
• Art of Protocol Writing
• Best Practices in Skin Microbiome Sample Collection
• Using Biomarkers in Clinical Research
• The Role of Skin barrier Dysfunction in Atopic Dermatitis, The Microbiome

We are pleased to welcome Ana Palijan, the Director of Early Phase and Translation Research. She is known for her scientifically robust and efficient approach to operations and study execution. Ana brings a wealth of experience in clinical research, including study design, project management, clinical operations, medical writing, and the development of training materials. 

We will dive into the study design considerations of early phase trials, focusing on 3 key aspects:

1. Key Differences Between Early and Late Phase Trials
2. Data Quality
3. Dermatology Techniques in Early Phase Trials

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 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, there are typically the single ascending dose and the multiple ascending dose (SAD/MAD), depending on the type of investigational product (IP) involved. If it is a systemic drug, the process begins with the healthy population and then transitions to the patient population, usually in the 1b or 2a stages. This is the point at which the patient population is involved. The study design diverges here because the exploration is primarily focused on safety, which is usually the primary endpoint. The goal is to determine the level of absorption and to get the first hint of whether the drug works by looking at its efficacy. In dermatology, which is particularly interesting, the process is visible, the lesions can be seen on the skin, especially when the focus is on inflammatory disease. The progression of the disease with treatment is clearly observable. This measurement is achieved through various methods, acknowledging the complexity and uniqueness of dermatology. For the primary investigator’s (PI) with visual symptoms, the clearance over time is visually evaluated.

This is where the early phase becomes crucial for everyone—sponsor, sites, CRO, researchers. It 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 space. 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. This includes the budget, the finances of the study, the trial itself, and the funding.

Therefore, strategic planning is essential. 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.

In these proof of concept (POC) studies, every data point holds significant value. For instance, consider a study on atopic dermatitis (AD) where the subjects undergo treatment for 4 weeks. The objective is to observe a change from the baseline after the treatment, which serves as one of the endpoints in a POC study. A high placebo responder rate is not desirable in this context. With only 40 or 50 subjects and a 1:1 or 2:1 randomization of placebo versus the IP for treatment, a high placebo responder rate could lead to a false negative study due to uncertainty about the actual response of the subjects. This situation can occur in dermatology due to the way the protocol is written, which might allow for other treatments. For instance, if the skin is dry, itching, or burning, emollients or creams can be applied, which might affect the lesion. Inconsistencies can also arise in the assessment of the severity of the lesion. Typically, multicenters are required to conduct many sites in a study or trial. Therefore, it is crucial for every PI to be well trained to assess consistently, and this consistency must be maintained across all sites. Otherwise, a signal problem may occur. Thus, quality is paramount in early phase studies and trials, from the first day to the last.

Dermatology Techniques in Early Phase Trials

The focus is primarily on Phase 1B or 2, essentially the POC stage, when there is access to the patient population. This stage is particularly interesting. It is during this phase that the trial and program are designed, and discussions with sponsors occur about how to gather more data and information on the IP.

This is the essence of exploratory endpoints. They add significant value to the program and the asset. It can be demonstrated by showing a molecular  signal. Moreover, it can be strategically beneficial for the sponsor to understand if there is any interference or additional signaling occurring. 

Sometimes, this data can guide a Sponsor back to the lab to design a new drug that can mimic the actions in that pathway. This can provide crucial information. Even more importantly, it can be observed if a pathway is impacted. As a result, it might be worthwhile to explore other indications.

There are numerous exciting possibilities, especially with dermatology. The skin is readily accessible. It can physically be touched. The specimens are easily obtainable. Genomics and all other “omics” 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. It is truly fascinating.It is truly exhilarating to see the surge in publications in this field. Reflecting on the past 4 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, “omics” to lesion severity. When the skin microbiome is being examined, it is possible to identify variations in the biota population. This allows for correlations to be observed between the severity in molecular or “omics” phenomena. The same applies to lipidomics.

Exploration is underway to design studies that yield necessary information and tissue samples while ensuring feasibility for the sites conducting these experiments and collections. The aim is to create an enjoyable experience for subjects, particularly those participating in early phase trials for research purposes. Generous time contributions from these individuals further understanding and generate more information. This is the stage where expert endpoints significantly amplify contributions to science.

In the early stages, opportunities arise to ask intriguing questions and receive equally intriguing answers. This could even lead to a shift in the program’s focus. As mentioned earlier, this adds immense value to the program. Handling a smaller study population allows for more manageable collection of various types of samples. However, quality becomes paramount here. Dealing with a small population across multiple sites with various study designs, where numerous sites across different countries are conducting these collections, presents challenges. Uniform procedures, consistent sample storage, and maintaining sample integrity during shipping to the lab and analysis are ongoing concerns. The challenge lies in assembling the pieces to make this operationally viable, much like solving a large puzzle. When crafting a story, it is about how everything fits together.

As we conclude another illuminating episode of Phase Forward, we find ourselves at the crossroads of science and progress. Remember that behind the jargon and statistics, lies stories of unwavering commitment, meticulous observation, and the pursuit of evidence that shapes our understanding of health and disease. Stay at the forefront of knowledge and innovation and follow Phase Forward on your preferred platform. My name is Valerie Coveney. Thank you for joining us. Until next time.

Let’s shape the future of research and make a difference in the industry, gain Innovaderm’s support in your upcoming trial and propel your study to new heights. 

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