Conducting Clinical Trials

Part 2
Author: Dr. Cheryl L. Rowe-Rendleman

In the United States, “biological products” are subject to a different premarket pathway and differing intellectual property protections than products regulated as “drugs”. This blog series describes practices of the U.S. Food and Drug Administration (FDA), across key practices and processes for obtaining marketing approval for Biologic products. 

Part 1: Obtaining Early Regulatory Advice-INTERACT Meetings (October)
Part 2: Conducting Trials (November)
Part 3 Data information and disclosure (December)

In Part 1 we talked about meetings for early advice from the FDA. The take home message was timelines are long for FDA advice on critical regulatory issues. It may take up to 75 calendar days to get a written response from the FDA. Face-to-face meetings are rare.

In Part 2 of this series, we will discuss clinical trials (1). Finding safe and effective cures for diseases that cause blindness is difficult. Before these cures can be made available to the public, safety and efficacy are evaluated through regulatory review of the product, including manufacturing, nonclinical (animal and in vitro) data, and clinical studies. Typically, sometime during the early development phases of a biologic –sponsors should discuss their regulatory and clinical strategy with the FDA.

What Types of Studies can be Conducted?

When a sponsor approaches the FDA for early regulatory advice—they almost always ask whether the data presented in their briefing packet will support a proposed clinical study. The FDA will respond—but the answer is always nuanced. A final and binding determination regarding the adequacy of the proposed studies in the regulatory briefing package cannot be made without a complete review of the materials submitted with the Investigational New Drug Application package. The type of clinical studies to be conducted depends on the questions being asked, stage of development, risk factors, and standard of care.

Types of Clinical Trials and Landmark Studies in Biologics for Ophthalmology

Type of Study	Scope/Aim
Treatment Research	Generally involves a trial of an intervention such as medication. During the early development (preIND) phase the aim is to demonstrate that the biologic can be reliably manufactured, evaluated, and tested. During the clinical trial phase, the aim is to demonstrate safety and efficacy of the biologic without harming the patient.
Prevention Research	Different kinds of prevention research may include study medicines, vitamins, vaccines, minerals, or lifestyle changes (2). There are few biologic vaccines in ophthalmology–but some vaccines to change the gut microbiota are in development for ophthalmic disorders.
Diagnostic Research	There are several genetic diagnostic tools already in use in ophthalmic practice. Often these genetic tests are required prior to administration of a biologic-to insure that the medication is delivered to a targeted population. Diagnostic research is the practice of looking for better ways to identify a particular disorder or condition.
Screening Research	Screening research finds better ways to detect certain disorders or health conditions. This may involve changing a practice, inventing a new one, or creating a new diagnostic tool. Biologics screening research includes finding biomarkers that could indicate a future response to biologics-based therapy.
Quality of Life Research	New quality of life measures are needed for patients with low vision. Currently, few biologics are approved based on quality-of-life research. However, patient reported outcomes are needed to help demonstrate that biologic-led therapies can improve comfort and the quality of life for individuals with chronic illnesses (3,4).
Genetic Research	Genetic research aims to improve the prediction of disorders by identifying and understanding how genes and illnesses may be related (5). Many “natural history studies” that include people with a similar clinical illness (e.g. macular degeneration) but distinct genetic backgrounds are conducted to understand how a chronic disease progresses with time. Patients in the natural history study may eventually be included in an interventional treatment trial with a biologic.
Epidemiological Research	Epidemiological research seeks to identify the patterns, causes, and control of disorders in groups of people (6).

All clinical studies share a few common characteristics. These include written protocols containing detailed methodology, descriptions of the test systems, instructions for handling results and analyses.

For interventional or treatment research, a certain amount of toxicology and pharmacokinetics is almost always needed to justify a safe starting dose for a drug or biologic that has never been used in humans.

Since biologics are derived from heterogeneous and complex materials in contrast to chemically synthesized drugs, methods to detect safety, potency and purity are required before the biologic can be administered to people. During early development appropriate controls over the manufacturing process must be employed to ensure that the product is free from harmful effects and extraneous matter. The identity, potency, and purity of the biologic must be monitored during the trial to ensure that the biologic has the capacity to yield the same result in all patients.

References

1. What Are the Different Types of Clinical Research? | FDA. Accessed at https://www.fda.gov/ on October 25, 2023.
2. Zhao M, Yu Y, Ying GS, Asbell PA, Bunya VY; Dry Eye Assessment and Management Study Research Group. Age Associations with Dry Eye Clinical Signs and Symptoms in the Dry Eye Assessment and Management (DREAM) Study. Ophthalmol Sci. 2023 Jan 12;3(2):100270.
3. Assi L, Chamseddine F, Ibrahim P, Sabbagh H, Rosman L, Congdon N, Evans J, Ramke J, Kuper H, Burton MJ, Ehrlich JR, Swenor BK. A Global Assessment of Eye Health and Quality of Life: A Systematic Review of Systematic Reviews. JAMA Ophthalmol. 2021 May 1;139(5):526-541.
4. Yu K, Bunya V, Maguire M, Asbell P, Ying GS; Dry Eye Assessment and Management Study Research Group. Systemic Conditions Associated with Severity of Dry Eye Signs and Symptoms in the Dry Eye Assessment and Management Study. Ophthalmology. 2021 Oct;128(10):1384-1392.
5. Moore, B.A., Leonard, B.C., Sebbag, L. et al. Identification of genes required for eye development by high-throughput screening of mouse knockouts. Commun Biol 1, 236 (2018).
6. Mark E. Reynolds & Weidong Gu (2023) Trend of Incidence of Ocular Injury in Service Members of the U.S. Armed Forces in 2016–2019, Ophthalmic Epidemiology, 30:4, 434-440.