Advertisement

Current state of Health Canada regulation for cellular and gene therapy products: potential cures on the horizon

  • Author Footnotes
    ⁎ These authors contributed equally to this work.
    Jolene Chisholm
    Footnotes
    ⁎ These authors contributed equally to this work.
    Affiliations
    Cell Therapy Program, University Health Network, Toronto, Ontario, Canada

    Arthritis Program, University Health Network, Toronto, Ontario, Canada
    Search for articles by this author
  • Author Footnotes
    ⁎ These authors contributed equally to this work.
    Crystal Ruff
    Footnotes
    ⁎ These authors contributed equally to this work.
    Affiliations
    International Society for Cellular Therapy North American Legal and Regulatory Affairs Committee (NA LRA), Vancouver, British Columbia, Canada

    Illumina Cambridge Ltd., Cambridge, UK

    DRI Biotechnologies, London, UK
    Search for articles by this author
  • Sowmya Viswanathan
    Correspondence
    Correspondence: Sowmya Viswanathan, PhD, Arthritis Program, Krembil Research Institute, University Health Network, 60 Leonard Street, Room 5KD424, Toronto, ON, M5T 2S8, Canada.
    Affiliations
    Cell Therapy Program, University Health Network, Toronto, Ontario, Canada

    Arthritis Program, University Health Network, Toronto, Ontario, Canada

    International Society for Cellular Therapy North American Legal and Regulatory Affairs Committee (NA LRA), Vancouver, British Columbia, Canada

    Institute of Biomaterials & Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
    Search for articles by this author
  • Author Footnotes
    ⁎ These authors contributed equally to this work.

      Abstract

      We provide an overview of the regulatory framework, pathways and underlying regulatory authority for cell, gene and tissue-engineered therapies in Canada. Canada's regulatory approach uses three sets of regulations, namely, the Cells, Tissues and Organs Regulations, the Food and Drug Regulations and the Medical Devices Regulations. We provide an overview of each these sets of regulations as they apply to clinical investigation to post-market product lifecycle stages. Information is provided on the current sources of relevant Health Canada guidance documents. We highlight several regional success stories including Prochymal, a cell therapy product that achieved Canadian regulatory approval using the conditional marketing approval system. We also examine the perceived gaps in the Canadian regulations and how those gaps are being addressed by interactions between the government, stakeholders and international bodies. We conclude that the risk-benefit approach used by Health Canada for regulatory approval processes is sufficiently flexible to enable to development of novel cell and gene therapy products in Canada, yet stringent enough to protect patient safety.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Cytotherapy
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Becker AJ
        • McCulloch EA
        • Till JE
        Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells.
        Nature. 1963; 197: 452-454
      1. United States National Institutes of Health. https://clinicaltrials.gov/. [Accessed April 4, 2019].

        • Government of Canada
        Food and Drugs Act (R.S.C., 1985, c. F-27).
        Minister of Justice: Department of Justice, Ottawa2016
        • Government of Canada
        Food and Drug Regulations (C.R.C., c. 870).
        Minister of Justice: Department of Justice, Ottawa2016
        • Government of Canada
        Medical Devices Regulations (SOR/98-282).
        Minister of Justice: Department of Justice, Ottawa2016
        • Government of Canada
        Safety of Human Cells, Tissues and Organs for Transplantation Regulations (SOR/2007-118).
        Minister of Justice: Department of Justice, Ottawa2015
        • United States Department of Health and Human Services
        Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use.
        Food and Drug Administration. Center for Biologics Evaluation and Research, 2017
      2. The International Society for Stem Cell Research. ISSCR letter to Health Canada on Regulation of Cell Therapies 14 Jun 2018.

        • Chisholm J
        • von Tigerstrom B
        • Bedford P
        • Fradette J
        • Viswanathan S
        Workshop to address gaps in regulation of minimally manipulated autologous cell therapies for homologous use in Canada.
        Cytotherapy. 2017; 19: 1400-1411https://doi.org/10.1016/j.jcyt.2017.08.015
        • Health Canada
        Revised Fee Proposal for Drugs and Medical Devices.
        Government of Canada, 2018
        • Government of Canada
        Biologics and Genetic Therapies Directorate, Health Products and Food Branch. Guidance Document for Cell, Tissue and Organ Establishments - Safety of Human Cells, Tissues and Organs for Transplantation.
        Minister of Health: Health Canada, Ottawa2013
        • Norris S.
        Canada's Blood Supply Ten Years After the Krevner Commission.
        Library of Parliament, 2008
        • Krevner H
        Final report.
        Commission of Inquiry on the Blood System in Canada, 1997
        • Government of Canada
        Therapeutic Products Directorate, Health Products and Food Branch. Guidance for Industry: Management of Drug Submissions.
        Minister of Health: Health Canada, Ottawa2013
        • Government of Canada
        Guidance Document: Preparation of Clinical Trial Applications for use of Cell Therapy Products in Humans.
        Minister of Health: Health Canada. Health Products and Food Branch, Ottawa2015
        • Health Canada
        Notice to Industry: Aligned reviews between Health Canada and health technology assessment organizations.
        Government of Canada, 2018
        • International Conference On Harmonisation
        Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Huma or Animal Origin (Q5A(R1)).
        in: International Conference On Harmonisation Of Technical Requirements For Registration Of Pharmaceuticals For Human Use. 1999
        • International Conference on Harmonisation
        General Principles to Address Virus and Vector Shedding.
        in: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. 2009
        • International Conference On Harmonisation
        General Principles to Address the Risk of Inadvertent Germline Integration of Gene Therapy Vectors.
        in: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. 2006
        • International Conference On Harmonisation
        Oncolytic Viruses.
        in: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. 2009
        • United States Department of Health and Human Services
        Design and Analysis of Shedding Studies or Virus or Bacteria-Based Gene Therapy and Oncolytic Products.
        Food and Drug Administration. Center for Biologics Evaluation and Research, 2015
        • United States Department of Health and Human Services
        Guidance for Industry: Guidance for Human Somatic Cell Therapy and Gene Therapy.
        Center for Biologics Evaluation and Research: Food and Drug Administration. Center for Biologics Evaluation and Research, Rockville1998
        • European Union European Medicines Agency
        Reflection paper on management of clinical risks deriving from insertional mutagenesis.
        European Medicines Agency: Committee for Advanced Therapies, London2013
        • European Union European Medicines Agency
        Draft Guideline on the Quality, Nonclinical and Clinical Aspects of Gene Therapy Medicinal Products.
        European Medicines Agency: Committee for Advanced Therapies, London2015
      3. Government of Canada. New Substances Notification Regulations (Organisms). 2005.

        • Government of Canada
        Canadian Environmental Protection Act, 1999 (S.C. 1999, c. 33).
        Minister of Justice: Department of Justice, Ottawa2016
      4. Government of Canada. Policy: Drug/Medical Device Combination Products. Ottawa: Minister of Health: Health Canada; 1999.

        • Government of Canada
        Inspection Strategy for Cells, Tissues and Organs Establishments (POL-0057).
        Minister of Health: Health Canada, Ottawa2012
        • Government of Canada
        Cells, Tissues and Organs (CTO) Inspections.
        2016
        • Government of Canada
        Guidance Document For Clinical Trial Sponsors: Clinical Trial Applications. 2016;
        • Government of Canada
        Medical Device Inspections.
        2016
        • Government of Canada
        Protecting Canadians from Unsafe Drugs Act (Vanessa's Law) (S.C. 2014, c. 24).
        Minister of Justice: Department of Justice, Ottawa2014
        • Government of Canada
        Guidance on Evidence to Demonstrate Drug GMP Compliance of Foreign Sites (GUI-0080).
        Minister of Health: Health Canada. Health Product and Food Branch Inspectorate, Ottawa2009
      5. Government of Canada. Quality Systems ISO 13485. n.d.

        • Government of Canada
        GD210: ISO 13485:2003 Quality Management System Audits Performed by Health Canada Recognized Registrars.
        Minister of Health: Health Canada. Medical Devices Bureau, Ottawa2007
        • Government of Canada
        Guidance Document GD211: Guidance on the Content of Quality Management System audit reports.
        Minister of Health: Health Canada. Medical Devices Bureau, Ottawa2011
        • Government of Canada
        Policy for the Inspection of Medical Device Companies (POL-0035).
        Minister of Health: Health Canada, Ottawa2012
        • Viswanathan S
        • Bubela T.
        Current practices and reform proposals for the regulation of advanced medicinal products in Canada.
        Regenerative Medicine. 2015; 10: 647-663https://doi.org/10.2217/rme.15.28
        • Government of Canada
        Guidance Document: Notice of Compliance with Conditions (NOC/c).
        Minister of Health: Health Canada. Therapeutic Products Directorate. Bureau of Policy, Science and International Programs, Ottawa2011
      6. United States Food and Drug Administration. Regenerative Medicine Advanced Therapy Designation 2 Feb 2018. https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ucm537670.htm (Accessed February 13, 2019).

        • Government of Canada
        Guidance for Industry - Priority Review of Drug Submissions.
        Minister of Health: Health Canada. Therapeutic Products Directorate, Ottawa2009
        • Government of Canada
        Guidance for Industry and Practitioners: Special Access Programme for Drugs. 2013;
        • Prasad VK
        • Lucas KG
        • Kleiner GI
        • Talano JA
        • Jacobsohn D
        • Broadwater G
        • et al.
        Efficacy and safety of ex vivo cultured adult human mesenchymal stem cells (Prochymal) in pediatric patients with severe refractory acute graft-versus-host disease in a compassionate use study.
        Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. 2011; 17: 534-541https://doi.org/10.1016/j.bbmt.2010.04.014
        • Martin PJ
        • Schoch G
        • Fisher L
        • Byers V
        • Anasetti C
        • Appelbaum FR
        • et al.
        A retrospective analysis of therapy for acute graft-versus-host disease: initial treatment.
        Blood. 1990; 76: 1464-1472
        • Arai S
        • Margolis J
        • Zahurak M
        • Anders V
        • Vogelsang GB
        Poor outcome in steroid-refractory graft-versus-host disease with antithymocyte globulin treatment.
        Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. 2002; 8: 155-160
      7. United States Food and Drug Administration. FDA announces comprehensive regenerative medicine policy framework 2017.

        • Turner L.
        Direct-to-consumer marketing of stem cell interventions by Canadian businesses.
        Regen Med. 2018; 13: 643-658
        • Ogbogu U
        • Du J
        • Koukio Y
        The involvement of Canadian physicians in promoting and providing unproven and unapproved stem cell interventions. - PubMed - NCBI.
        BMC Med Ethics. 2018; 19
        • Master Z
        • Robertson K
        • Frederick D
        • Rachul C
        • Caulfield T
        Stem cell tourism and public education: the missing elements.
        Cell Stem Cell. 2014; 15: 267-270https://doi.org/10.1016/j.stem.2014.08.009
        • Caulfield T
        • McGuire A.
        Athletes’ use of unproven stem cell therapies: adding to inappropriate media hype?.
        Molecular Therapy : The Journal of the American Society of Gene Therapy. 2012; 20: 1656-1658https://doi.org/10.1038/mt.2012.172
        • Du L
        • Rachul C
        • Guo Z
        • Caulfield T
        Gordie Howe's “Miraculous Treatment” Case Study of Twitter Users’ Reactions to a Sport Celebrity's Stem Cell Treatment.
        JMIR Public Health and Surveillance. 2016; 2: e8https://doi.org/10.2196/publichealth.5264
        • Rachul C
        • Caulfield T
        Gordie Howe's Stem Cell “Miracle” A Qualitative Analysis of News Coverage and Readers’ Comments in Newspapers and Sports Websites.
        Stem Cell Reviews. 2015; 11: 667-675https://doi.org/10.1007/s12015-015-9606-8
        • Dobkin BH
        • Curt A
        • Guest J
        Cellular transplants in China: observational study from the largest human experiment in chronic spinal cord injury.
        Neurorehabilitation and Neural Repair. 2006; 20: 5-13https://doi.org/10.1177/1545968305284675
        • Amariglio N
        • Hirshberg A
        • Scheithauer BW
        • Cohen Y
        • Loewenthal R
        • Trakhtenbrot L
        • et al.
        Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient.
        PLoS Medicine. 2009; 6e1000029https://doi.org/10.1371/journal.pmed.1000029
        • Thirabanjasak D
        • Tantiwongse K
        • Thorner PS
        Angiomyeloproliferative lesions following autologous stem cell therapy.
        Journal of the American Society of Nephrology : JASN. 2010; 21: 1218-1222https://doi.org/10.1681/ASN.2009111156
        • Saraf SS
        • Cunningham MA
        • Kuriyan AE
        • Read SP
        • Rosenfeld PJ
        • Flynn HW
        • et al.
        Bilateral Retinal Detachments After Intravitreal Injection of Adipose-Derived “Stem Cells” in a Patient With Exudative Macular Degeneration.
        Ophthalmic Surgery, Lasers & Imaging Retina. 2017; 48: 772-775https://doi.org/10.3928/23258160-20170829-16
        • Kuriyan AE
        • Albini TA
        • Townsend JH
        • Rodriguez M
        • Pandya HK
        • Leonard RE
        • et al.
        Vision Loss after Intravitreal Injection of Autologous “Stem Cells” for AMD.
        The New England Journal of Medicine. 2017; 376: 1047-1053https://doi.org/10.1056/NEJMoa1609583
      8. Master Z, Caulfield T. Patient Booklet: What you need to know about stem cell therapies. 2014. http://www.hli.ualberta.ca/Research/Public_Outreach_Award.aspx

        • Master Z
        • Resnik DB
        Stem-cell tourism and scientific responsibility. Stem-cell researchers are in a unique position to curb the problem of stem-cell tourism.
        EMBO Reports. 2011; 12: 992-995https://doi.org/10.1038/embor.2011.156
        • Caulfield T
        • Zarzeczny A
        • Toronto Stem Cell Working Group
        Stem cell tourism and Canadian family physicians.
        Canadian Family Physician Medecin de Famille Canadien. 2012; 58 (e182-5): 365-368
        • Cyranoski D.
        Stem-cell therapy faces more scrutiny in China.
        Nature. 2009; 459: 146-147https://doi.org/10.1038/459146a
        • Stafford N.
        Germany tightens law on stem cell treatments.
        Bmj. 2009; 339: b2967https://doi.org/10.1136/bmj.b2967
      9. United States Food & Drug Administration. Owner of Arizona company charged and convicted of introducing an unapproved new drug—stem cells—into interstate commerce 2011.

      10. The International Society for Stem Cell Research. Patient Handbook on Stem Cell Therapies. 2008.

      11. International Society for Cellular Therapy. International Society for Cellular Therapy: Connect, Communicate, Translate. n.d.

        • Ruff C
        • Wilcox J
        • Fehlings M
        Stem Cell Treatments for Cerebral Palsy.
        Factsheet for patients and families. 2011;
      12. CellCAN. What You Need to Know. 2016.

      Linked Article