Regulatory considerations for developing a phase I investigational new drug application for autologous induced pluripotent stem cells-based therapy product.

Induced pluripotent stem cells (iPSC)-based therapies have been hailed as the future of regenerative medicine because of their potential to provide treatment options for most degenerative diseases. A key promise of iPSC-based therapies is the possibility of an autologous transplant that may engraft better in the longer-term due to its compatibility with the patient's immune system. Despite over a decade of research, clinical translation of autologous iPSC-based therapies has been slow-partly due to a lacking pre-defined regulatory path. Here, we outline regulatory considerations for developing an autologous iPSC-based product and challenges associated with the clinical manufacturing of autologous iPSCs and their derivatives. These challenges include donor tissue source, reprogramming methods, heterogeneity of differentiated cells, controls for the manufacturing process, and preclinical considerations. A robust manufacturing process with appropriate quality controls and well-informed, prospectively designed preclinical studies provide a path toward successful approval of autologous iPSC-based therapies.

The US Direct-to-Consumer Marketplace for Autologous Stem Cell Interventions.

Hundreds of businesses and clinics in the United States are engaged in direct-to-consumer marketing of unproven and unlicensed stem cell-based interventions. This essay provides an overview of this marketplace, examines advertising techniques companies use to draw clients and legitimate marketing claims, and summarizes the roles the Food and Drug Administration (FDA) and other agencies are supposed to play in regulating the direct-to-consumer marketplace for stem cell interventions. The essay also reviews federal regulations, describes how many businesses selling purported "stem cell treatments" appear to violate these standards, and considers ethical issues and harms associated with widespread promotion of unapproved stem cell products.

Between the Local and the Global: Evaluating European regulation of stem cell regenerative medicine.

Current European regulations hinder the compilation of the evidence that would be required to bring safe and effective autologous stem cell-based interventions (SCBIs) into standard clinical care. European agencies have expanded their regulations to cover all new SCBIs and research. They establish demanding conditions for cell retrieval, processing, and application. Drawing on empirical sociological findings from the implementation of the first phase III stem cell clinical trial in Europe, this article examines ethical problems effected by that policy, such as that the costs of bringing treatments to market means new autologous SCBIs may remain untested and that this plays in favor of the growing direct-to-consumer market, and that the research pathways in regenerative medicine and the role of clinician-scientists in developing new treatments are restricted, because the regulations are biased to enable specific SCBIs that are of interest to industry. This situation contradicts the moral and social concerns in favor of new treatments and patient interests, which the regulations supposedly safeguard. To align the aims and effects of policy better, European regulatory authorities should reconfigure their regulations to advance a fair and effective governance regime that allows pursuit of all promising SCBIs.

Challenges in the Regulation of Autologous Stem Cell Interventions in the United States.

The direct-to-consumer marketing of stem cells for unproven therapeutic uses has grown rapidly in the United States in recent years. This development is surprising since the marketing and distribution of human cell-based medical products is stringently regulated in the US. This essay describes ambiguities, gaps, and inconsistencies in the current regulatory system that have enabled such businesses to thrive. In addition to directly challenging the authority of the Food and Drug Administration (FDA) over autologous cell-based products in the courts, stem cell marketing firms have also identified and exploited regulatory loopholes, such as the same surgical procedure exception, which exempts from FDA oversight human cell-based products that are harvested and reimplanted in a single procedure. Many businesses also advertise stem cell clinical studies on a pay-to-participate basis, which requires patients to pay large sums to enroll in clinical research. This business model not only shifts many of the cost and risks of medical experimentation from providers to patients but may also indemnify sellers from fraud litigation. Lastly, stem cell advertisers borrow heavily from the language and concepts of science-based medicine in their marketing. The inaccurate promotion of autologous stem cell injections as a form of "personalized" medicine lends a veneer of credibility and precision that may encourage patients to undergo procedures of uncertain effectiveness and to sympathize with stem cell businesses in their efforts to evade oversight.

Vulnerabilities and the Use of Autologous Stem Cells for Medical Conditions in Australia.

Australia has a booming market of unproven autologous stem cell- based interventions (SCBIs) for a wide range of medical conditions. Multiple SCBIs are provided in private practices outside of formal clinical trials. Some defend the provision of unproven SCBIs on grounds of patient choice. This essay interrogates this argument for patient choice and explores patients' vulnerabilities in clinical practice with autologous SCBIs. While all patients are inherently vulnerable, the regulatory framework for autologous stem cells in Australia exacerbates the problems associated with inherent vulnerabilities and generates situational and pathogenic vulnerabilities. A just state ought to implement regulatory measures that mitigate vulnerabilities and foster patients' autonomy.

The Need for Beneficence and Prudence in Clinical Innovation with Autologous Stem Cells.

The term innovation is frequently used as a justification for allowing clinicians to offer unproven autologous stem cell-based interventions (SCBIs) to their patients. Proponents of this kind of innovation (which we refer to as "clinical innovation") argue that physicians should be free to administer whatever interventions they choose, and informed consumers should be free to receive them. This article refutes the notion that clinician autonomy and consumer demand are a sufficient justification for offering patients unproven autologous SCBIs. We argue that, while clinician and consumer preferences need to be taken seriously, access to unproven SCBIs can only be fully justified when it is based on a commitment to beneficence and prudence. We also argue that there is a need for a clearer distinction between the definition of clinical innovation with autologous stem cells, which is morally neutral, and its justification, which entails a commitment to beneficence and prudence. Finally, we argue that regulation of clinical innovation with autologous stem cells needs to be based on a bioethics of innovation that attends to beneficence and prudence alongside other ethical principles.

Estabelecimento de protocolo para armazenamento de pele autógena refrigerada / Establishment of a protocol for storage of refrigerated autologous skin

Introdução: Enxertos de pele autólogos são utilizados em tratamento de pacientes queimados. Esses enxertos podem ser armazenados e preservados, desde que o processo de armazenamento seja realizado com rígido controle de qualidade, para garantir a redução dos riscos de infecção. Métodos: Foi realizado um estudo de coorte retrospectivo na Unidade de Queimados do Hospital das Clínicas de São Paulo no período de fevereiro de 2015 a julho de 2016, em que foi estabelecido um protocolo para armazenamento de pele refrigerada com controle de coleta, preservação, embalagem e registro de todos os processos. Para garantia de qualidade, foram coletadas biópsias dos enxertos para microbiologia pré e pós-armazenamento e realizado um estudo transversal de prevalência de contaminação pré e pós-estocagem. Resultados: Os pontos críticos encontrados foram inadequação de embalagem, ausência de registros de processos, falta de coleta de biópsias para microbiologia e falhas no descarte. A maior parte das amostras estava contaminada tanto pré como pós-estocagem (84,2%). Apenas dois pacientes apresentaram microbiologia estéril no pré e contaminada no pós, porém foram encontrados germes da pele do tipo gram+. Conclusão: Foi estabelecido um método promissor de armazenamento de pele refrigerada que necessita alguns pequenos ajustes para adequação ao controle de qualidade.

Introduction: Autologous skin grafts are used for treatment of burn patients. These grafts can be stored and preserved, as long as the storage process is performed with strict quality control to reduce the risk of infection. Methods: A retrospective cohort study was conducted in the Burn Unit of the Hospital das Clínicas de São Paulo from February 2015 to July 2016. During this period, a protocol was established to store refrigerated skin, with control of collection, preservation, and packaging, and recording of all processes. To ensure quality, graft biopsies were collected for pre- and poststorage microbiology testing and a cross-sectional study for contamination was performed. Results: Critical deficiencies included inadequate packaging, lack of processing records, lack of biopsies for microbiology testing, and failure to discard specimens. Most of the samples were contaminated before and after storage (84.2%). Only two samples were sterile before storage but became contaminated after storage, with growth of Gram-positive skin bacteria. Conclusion: A promising method for the storage of refrigerated skin was established, but requires minor adjustments in quality control.

Ethical and Regulatory Challenges with Autologous Adult Stem Cells: A Comparative Review of International Regulations.

Cell and tissue-based products, such as autologous adult stem cells, are being prescribed by physicians across the world for diseases and illnesses that they have neither been approved for or been demonstrated as safe and effective in formal clinical trials. These doctors often form part of informal transnational networks that exploit differences and similarities in the regulatory systems across geographical contexts. In this paper, we examine the regulatory infrastructure of five geographically diverse but socio-economically comparable countries with the aim of identifying similarities and differences in how these products are regulated and governed within clinical contexts. We find that while there are many subtle technical differences in how these regulations are implemented, they are sufficiently similar that it is difficult to explain why these practices appear more prevalent in some countries and not in others. We conclude with suggestions for how international governance frameworks might be improved to discourage the exploitation of vulnerable patient populations while enabling innovation in the clinical application of cellular therapies.

The deadly business of an unregulated global stem cell industry.

In 2016, the Office of the State Coroner of New South Wales released its report into the death of an Australian woman, Sheila Drysdale, who had died from complications of an autologous stem cell procedure at a Sydney clinic. In this report, we argue that Mrs Drysdale's death was avoidable, and it was the result of a pernicious global problem of an industry exploiting regulatory systems to sell unproven and unjustified interventions with stem cells.

Regulatory challenges for autologous tissue engineered products on their way from bench to bedside in Europe.

Since the late eighties of last century the high potential of tissue engineered products (TEP)s has been shown for the treatment of various diseases and many scientific publications appeared in this field. However, only few products reached the market since. Development of TEPs is a promising but owing to its novelty a very challenging task that requires experts in this still developing field as well as ample financial resources. This paper summarises relevant regulatory challenges during quality, preclinical and clinical development of autologous TEPs in Europe. Selected strategies on how to manage major issues are presented, together with some examples from the development of an autologous TEP for urethroplasty. Considering these aspects may help other investigators with potential strategies during the development of novel TEPs.

A policy for the disposal of autologous hematopoietic progenitor cells: report from an Italian consensus panel.

BACKGROUND: Autologous stem cell transplantation (ASCT) requires collection and cryopreservation of hematopoietic progenitor cells (HPCs), which in turn may be partially or never reinfused. Thus, HPC storage has become a logistic, ethical, and economic issue. SIDEM, GITMO, and CNT/ISS endorsed a project aimed to define national criteria for HPC disposal aimed to guarantee appropriateness and equity. STUDY DESIGN AND METHODS: A multidisciplinary panel was convened including HPC harvest and manipulation experts from apheresis units, hematologists with clinical expertise in ASCT, a representative of the national health authority, and a bioethicist. An analytic hierarchy process (AHP) was carried out to select disposal criteria. RESULTS: The AHP selected two criteria for prompt disposal of freshly collected HPCs: an abnormal freezing procedure causing highly reduced viability or major microbiology contamination. Moreover, AHP selected six major criteria, each one of them allowing for the disposal of stored HPC units: patient death, withdrawal of consent to ASCT, contraindications or loss of indications to ASCT, a damaged label that prevents correct identification of the unit, and time elapsed since harvest longer than 10 years. Three minor criteria were additionally identified that allowed to anticipate disposal only provided that viability levels are below the limit of acceptance: a documented cold chain interruption, loss of bag integrity, and total amount of stored CD34+ cells lower than 1 × 10(6) /kg or lower than 2 × 10(6)/kg in patients with a successfully completed stem cell transplantation program. CONCLUSIONS: A formal consensus process allowed SIDEM and GITMO to propose a policy for autologous HPC disposal that fulfills clinical, ethical, and economic criteria.

Challenging the FDA's authority to regulate autologous adult stem cells for therapeutic use: Celltex therapeutics' partnership with RNL Bio, substantial medical risks, and the implications of United States v. Regenerative Sciences.

This Article examines the convergence of three corporations that have attempted to capitalize on translating emerging research into clinical procedures by manufacturing and facilitating the process for patients to obtain mesenchymal stem cell (MSC) injections. Although the Food and Drug Administration (FDA) has asserted its authority to regulate somatic cell therapy products like MSCs under the Public Health Service Act and the Food, Drug, and Cosmetic Act, some manufacturers have attempted to circumvent FDA regulation through various mechanisms and argue that their products do not fall within the definition of a biological product or drug. However, scientific knowledge of using MSCs for clinical therapy remains in its infancy, and MSCs pose a number of serious risks to patients. This Article focuses on the development of Celltex, a company based in Sugar Land, Texas that manufactures and facilitates the injection of autologous MSCs; RNL Bio, a company that licenses its operations technology to Celltex; and Regenerative Sciences, a company based in Broomfield, Colorado that was recently involved in litigation with the FDA. Corporate circumvention of intended regulatory oversight exposes patients to potentially inefficacious products that could contribute to serious medical injuries such as viruses, myocardial infarction, cancer, or death.

Research using autologous cord blood - time for a policy change.

• Type 1 diabetes results from the loss of normal immunological self-tolerance, which may be attributable to the failure of Foxp3+ regulatory T cells (Tregs). Umbilical cord blood is rich in Tregs and therefore has the potential to prevent or delay the onset of type 1 diabetes. A pilot trial is currently underway in Australia to examine whether infusion of autologous cord blood can prevent type 1 diabetes in high-risk children with serum antibodies to multiple ß-cell antigens. • A number of other potential therapeutic indications for autologous cord blood have been proposed, including cerebral palsy and hypoxic-ischaemic encephalopathy. • Recruitment to clinical trials using cord blood is influenced by divergent public and private cord blood banking policy in Australia. The burgeoning consumer demand for storage of cord blood highlights the need for regulatory bodies to develop and adapt policies to facilitate research that may extend the use of cord blood beyond currently recognised indications. • Consumers, researchers and policymakers must also recognise specific ethical issues associated with collection and storage of cord blood, including storage in public and private banks, informed consent, ownership, access and the principle of beneficence.

Ethical and legal issues raised by cord blood banking - the challenges of the new bioeconomy.

• Cord blood banking raises ethical and legal issues which highlight the need for careful regulatory approaches to the emerging bioeconomy. • Consent processes for both private and public banking should be inclusive and representative of the different familial interests in the cord blood. • Property law is a potentially useful way of understanding the mechanisms for donation to both public and private banks. • Increasing tensions between public and private models of banking may require the adoption of hybrid forms of banking.

Autologous cell therapies: challenges in US FDA regulation.

Cell-based therapies (CBTs) have been hailed for the last two decades as the next pillar of healthcare, yet the clinical and commercial potential of regenerative medicine has yet to live up to the hype. While recent analysis has suggested that regenerative medicine is maturing into a multibillion dollar industry, examples of clinical and commercial success are still relatively rare. With 30 years of laboratory and clinical efforts fueled by countless billions in public and private funding, one must contemplate why CBTs have not made a greater impact. The current regulatory environment, with its zero-risk stance, stymies clinical innovation while fueling a potentially risky medical tourism industry. Here, we highlight the challenges the US FDA faces and present talking points for an improved regulatory framework for autologous CBTs.