Unique Aspects of the Design of Phase I/II Clinical Trials of Stem Cell Therapy

Schulman, Ivonne H; Balkan, Wayne; Saltzman, Russell G.; DanielDaFonseca,; Caceres, Lina V.; Delgado, Cindy; Pujol, Marietsy V.; Ramdas, KevinN.; Tovar, Jairo A.; Vidro-Casiano, Mayra; Hare, Joshua M.

doi:10.5772/intechopen.72949

Cited by 5 publications

(14 citation statements)

References 141 publications

(231 reference statements)

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“…However, secondary outcomes regarding patient outcome may be useful for the development of large-scale clinical trials to reach a broader population. For instance, clinical trials are not only costly but also difficult to conduct ( Hare et al, 2013 ; Schulman et al, 2018a ). Moreover, the limited window for treatment time in some rare and life-threatening conditions can result in clinical development delays ( Jin et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…It takes an average of 10 years to achieve market approval for biologics and drugs, and over 90% of Phase I clinical trials fail to obtain approval ( Hare et al, 2013 ; Schulman et al, 2018a ). For patients with life-threatening or severely debilitating disease and limited treatment options, the right to access investigational drugs prior to approval has become a priority.…”

Section: Discussionmentioning

confidence: 99%

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The Interdisciplinary Stem Cell Institute’s Use of Food and Drug Administration-Expanded Access Guidelines to Provide Experimental Cell Therapy to Patients With Rare Serious Diseases

Khan

Bellio

Schulman

et al. 2021

Front. Cell Dev. Biol.

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The U.S. Food and Drug Administration (FDA) provides guidance for expanded access to experimental therapies, which in turn plays an important role in the Twenty-first Century Cures Act mandate to advance cell-based therapy. In cases of incurable diseases where there is a lack of alternative treatment options, many patients seek access to cell-based therapies for the possibility of treatment responses demonstrated in clinical trials. Here, we describe the use of the FDA’s expanded access to investigational new drug (IND) to address rare and emergency conditions that include stiff-person syndrome, spinal cord injury, traumatic brain stem injury, complex congenital heart disease, ischemic stroke, and peripheral nerve injury. We have administered both allogeneic bone marrow-derived mesenchymal stem cell (MSC) and autologous Schwann cell (SC) therapy to patients upon emergency request using Single Patient Expanded Access (SPEA) INDs approved by the FDA. In this report, we present our experience with 10 completed SPEA protocols.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Interdisciplinary Stem Cell Institute’s Use of Food and Drug Administration-Expanded Access Guidelines to Provide Experimental Cell Therapy to Patients With Rare Serious Diseases

Khan

Bellio

Schulman

et al. 2021

Front. Cell Dev. Biol.

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“…Notably, existing mechanistic studies support the importance of cell-cell interactions between MSCs and host cells within stem cell niches, which provide structural support and produce the soluble signals that regulate stem cell function in tissues [21,24,25,39,40]. This enhanced phenotypic and mechanistic understanding of the underpinnings of stem cell based therapy can be harnessed for improved clinical trial design as well as for development of newer generations of cellular as well as new molecular products that have greater efficacy and sustainability [36,37].…”

Section: Introductionmentioning

confidence: 95%

“…Nevertheless, studies are lacking comparing the efficacy and sustainability of the various different cell types, as well as identifying the most effective dose, time of delivery, and route of administration. Other important questions that remain to be investigated are whether concurrent pharmacologic treatments beneficially or adversely interact with the various cell therapies and whether cell therapy increases the risk for opportunistic infections or malignancy development or progression [27,35,36]. Only through the rigorous conduct of large, multicenter clinical trials that include well-defined clinical endpoints and outcomes, a longer duration of follow up (years) and larger number of patients can these questions be addressed [37].…”

Section: Introductionmentioning

confidence: 99%

“…For instance, the use of cells as therapeutic agents differs in significant ways from the established principles of pharmacokinetics and pharmacodynamics utilized in pharmacology. An important stage in the development of any new therapeutic agent is the establishment of an optimal dose and route of administration [29,36]. Biologic therapies create unique challenges in this regard because they exert their therapeutic effects via complex or undefined mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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The Management of Clinical Trials

Abdeldayem¹

2018

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Observer bias is when the investigator knows which treatment a study subject is taking with the possibility that subjects taking a new treatment may be over-scored. To eliminate observer bias, studies are conducted blind [5]. Randomization and blindingRandomization: A process based on allocation of subjects to treatment groups by chance, aiming at removing the potential bias in treatment assignment whether conscious or subconscious. This will greatly enhance the validity of the trial.Blinding is when the investigator and/or the study subject do not know which subject is taking which treatment. The investigator, the participant, and sometimes even the evaluator are all kept unaware (blinded) of the outcomes of the trial. how will data be collected, how many patients you will need?, and what is to be done in any eventuality? It specifies the standard operation procedure (SOP). It describes the background, objective(s), design, methodology, statistical considerations, and organization of the trial. It represents a guideline for the conduct, quality control of a clinical trial, and guidelines to the monitoring groups. It is considered as a legal document for regulatory bodies and may be used to procure funding. It should contain the right amount of detail necessary for the reader of each section to be able to understand exactly what is required to conduct the study [5]. Specific objectives Primary objectiveIt defines one question the investigators are most interested in answering and is capable of being adequately answered. It should define the primary endpoint, which is a defined measurement or assessment. If possible, end-points need to be objective measurements rather than subjective outcomes. However, many diseases necessitate measurements of subjective symptoms, e.g., pain, discomfort, irritation, etc. Ideally, a clinical trial has just one end point, and this is the primary end point. Common failing is too many end points. The best designed trials keep it simple as this makes a clear answer more likely and easier to achieve. Secondary objectivesSecondary objectives should be based on subgroup hypotheses that are respectively defined and based on reasonable expectations and should not distract from the primary objective.Methods include hypothesis, patient population, inclusion criteria, exclusion criteria, and trial design. Protocol amendment: A written description of a change(s) to or formal clarification of a protocol. Must be approved by IRB prior to implementation may be partial or complete. Phases of clinical trialsPhase 0: Preclinical animal studies. Phase I: First-time test of intervention in a small group of people (20-80) to evaluate safety, determine appropriate dosage, and identify side effects. Follows successful pharmacological and toxicological studies in animals start with 1/5th or 1/10th maximum tolerated dose in the most sensitive animal species.Phase II: Intervention given to a larger group (100-300) to evaluate effectiveness and safety. First administered to patients. Phase IIa (early phase II...

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