Cell Therapies Clinical Trial Best Practices

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Cell Therapy Clinical Trials Part I

The five articles or white papers/research papers that provide recommendations on how to design and conduct a clinical trial for cell therapy include the "Guidelines for Phase I clinical trials," "The first decade of advanced cell therapy clinical trials using perinatal cells (2005–2015)," "Stem cell therapy clinical research: A regulatory conundrum for academia," "Bioethics of Clinical Applications of Stem Cells," and the "FDA Stem Cell Therapy Warning."

Cell Therapy Clinical Trials

1. Guidelines for Phase I clinical trials, 2018 edition

  • This white paper published by The Association of the British Pharmaceutical Industry (ABPI) in 2018 gives specific guidelines on how to design and conduct different clinical trials, including cell therapy trials.
  • ABPI has been publishing guidelines into conducting clinical trials since 1970s, and the 2018 edition reflects "the current EU legislation for the performance of Phase I clinical research as set down in the EU Clinical Trials Directive."
  • The guidelines white paper includes specific directions for conducting trials in the European Union in accordance with the Clinical Trials Directive, and it provides the regulatory guidelines for the process.
  • The main recommendations include answering initial questions such as population, age groups, etc. before the trial clinicians even apply for regulatory permits. Additionally, different types of trials require different regulatory permits, such as first-in-human trial (phase I exploratory trial), and subsequent parts/studies (clinical pharmacology trials).

2. The first decade of advanced cell therapy clinical trials using perinatal cells (2005–2015)

  • This review of advanced cell therapy trials with perinatal cells was published in November 2017 in the magazine called Regenerative Medicine, and was written by Pedro S. Couto, Alexey Bersenev, and Frances Verter.
  • This research provides the first review of advanced cell therapy trials with perinatal cells, and the review presented spans across 10 years (2005 – 2015).
  • In the review, 281 clinical trials are summed up that line out the best practices for advanced cell therapy clinical trials that involve perinatal cells. The results include the most common cell source in the trials being "cord blood, but the cell type that provides the mechanism of action in the majority of trials is mesenchymal stem/stromal cells."
  • The main recommendations include giving special attention to the most common cell sources, which include cord blood, as those have been proven to give the best results in clinical trials with perinatal cells.

3. Stem cell therapy clinical research: A regulatory conundrum for academia

  • The research titled "Stem cell therapy clinical research: A regulatory conundrum for academia" was published in December 2017 by Anjali Nagpala, Chris Juttnera, Monica Anne Hamilton-Bruce, PaulRolan, and Simon A. Koblara.
  • This review gives a summary of the most recent developments in regulatory frameworks in the countries that are at the forefront of stem cell clinical research.
  • It discusses the "implications of these developments for researchers aiming to make the challenging transition from laboratory to clinical development of these therapies and considers possible pragmatic solutions that could accelerate this process that is essential to maintain research credibility and ensure patient safety."
  • The main recommendations include the researchers applying for an industry-based clinical trial grant as those studies have been proven to be expedited.

4. Bioethics of Clinical Applications of Stem Cells

  • "Bioethics of Clinical Applications of Stem Cells" was first published in April 2017 and revised and republished in December 2017. It was written by Carlo Petrini in the International Journal of Molecular Sciences.
  • The academic review of clinical applications of stem cell clinical trials includes an overview of a multitude of problems, which include "safety, efficacy, information and consent, the right to unproven treatments, the right to try, costs, access, sustainability, scientific scrupulousness, patents, and regulatory aspects."
  • Additionally, the main recommendations of the review include a comparison of the consequentialist and deontological approaches, and describes the top–down and bottom–up models of trials. Moreover, the review gives a suggestion about the practical frameworks for addressing the ethical issues, specifically when it comes to the "medical indications, patient preferences, quality of life, and contextual features."

5. FDA's Stem Cell Therapy Warning

  • In its white paper published in 2019, the U.S. Food Drug Administration warns patients about the danger of unauthorized cell therapy clinical trials.
  • In the review, the FDA notes it is increasing its "oversight and enforcement to protect people from dishonest and unscrupulous stem cell clinics, while continuing to encourage innovation so that the medical industry can properly harness the potential of stem cell products."
  • It outlines the FDA approval process as well as safety concerns of clinical trials for cell therapy.
  • The main recommendations include the fact that each study should be reviewed by the FDA before being submitted to be put into action by the hospitals. The FDA recommends that the agency will start taking harder action on clinical trials in the cell therapy field, which haven't been properly reviewed by the FDA.
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Cell Therapy Clinical Trials Part II

Several guidelines for the conduct of cell therapy clinical trials from organizations such as the Food and Drug Administration, Foundation for the Accreditation of Cellular Therapy, The Association of the British Pharmaceutical Industry, and the International Society for Stem Cell Research recommend that clinical trials must have preclinical studies, authorization to conduct, and must pass the ethics review before implementation. They also recommend proper study population selection, staff selection, site requirements, and others.

Guidelines for Stem Cell Research and Clinical Translation

  • The fundamental requirements in conducting clinical trials for stem cell therapy include possessing suitable preclinical data, informed consent, peer review and independent oversight, research subject monitoring, impartial subject selection, trial reporting and registration, and investigating of study conduct.
  • This paper recommends that stem cell-based studies must be "subject to review, approval, and ongoing monitoring" by independent review committees. Furthermore, it is advised that clinical trials be backed by systematic evaluation of evidence upholding the intervention.

Guidelines for Phase I Clinical Trials 2018 Edition

  • This paper is prepared by the Association of the British Pharmaceutical Industry in reference to the EU Clinical Trials Directive for the conduct of clinical trials for investigational medicinal products (IMPs) that involve cell therapy products.
  • It indicates that clinical trials should be authorized and reviewed by the Research Ethics Committee.
  • For Phase 1 clinical trials, most utilize healthy subjects. For the study design, factors to be considered include timelines, site logistics, doses, unexpected events, and flexibility to changes.
  • It is suggested that the initial dose of an IMP must be less than 10% of the anticipated therapeutic dose. In terms of dose administration, the intravenous administration is considered to be the most flexible.

Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products : Guidance for Industry

International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration

  • This paper presents the standards being structured based on the three significant functional divisions within cellular therapy, which include laboratory processing, cell collection, and the clinical program.
  • The standard requires that there should be a suitable location with sufficient space and design that lessens airborne microbial contamination. Additionally, it suggests that the personnel of the clinical program have appropriate licenses, experience, and other qualifications.
  • Also, the paper provides the minimum number of new patients both prior to the accreditation and yearly during the trial, depending on the transplant population, available clinical sites, and the type of transplant to be conducted.

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

  • Here is a link to the article.
  • The authors of this article are Wayne Balkan, Russell Saltzman, Ivonne H. Schulman, Lina V. Caceres, Jairo Tovar, Cindy Delgado, Marietsy V. Pujol, Joshua M. Hare, Kevin N. Ramdas, Mayra Vidro-Casiano, and Daniel DaFonseca.
  • The article was published on June 6, 2018.

Research Strategy:

For this request, we searched for a list of guidelines, standards, and recommendation on the conduct of clinical trials for cell therapy. We located a Landscape Report that provided us with such a list. Next, we searched for the available papers presented in the report and looked for additional guidelines relevant to cell therapy clinical trials. These guidelines were provided by reputable organizations dedicated to cell therapy and government agencies. Though some guidelines were published earlier than 2017, we included them as they are the latest guidelines provided on the website and recent documents still consider these guidelines.