Submission to the TGA Public Consultation on the Regulation of Autologous Cells & Tissue Products

 

In August 2016, the TGA sought comments from interested parties on possible revised options for the regulation of autologous cell and tissue products, including autologous stem cells.

The following is the ACTS response to the consultation submitted on 6 October 2016. The ACTS response can be downloaded as a PDF by following the link. In particular, the ACTS response provides a detailed attachment and references evidencing the safety and efficacy of ACBIs in the treatment of knee and hip joints in osteoarthritis (also displayed on this website):

  • 22 publications with 3,708 patients treated by autologous bone marrow derived cells (with 4 Level II studies and 2 Level III studies)
  • 20 refereed publications with 1, 638 patients treated by autologous SVF and ASCs (with 2 Level II studies and 3 Level III studies).

INTRODUCTION AND BACKGROUND

The Australian Cell Therapy Society (ACTS) welcomes the opportunity to contribute to the TGA’s well-considered evidence-based consultation on the regulation of autologous cell and tissue products. The Australian Cell Therapy Society represents clinicians and researchers working and studying in the field of autologous cellular therapies. Our members range from single clinicians to medical technology innovators, who use, minimally manipulate or culture human autologous cells and tissue products. Our diverse range of members represents different positions on the risk-based continuum of regulatory options proposed.

ACTS was established as a forum to facilitate consultation on industry standards and practice, and improve transparency of the safety and efficacy of autologous cell and tissue therapies. ACTS developed a self-regulation Code of Practice and is currently drafting requirements for data registries and adverse events reporting to improve confidence in patient safety and efficacy outcomes in the emerging field of regenerative medical practice. It is a significant code that applies to the practice of Autologous Cell Based Interventions (ACBIs) and use of human cell tissue (HCT) under item 4(q) and sets out: regulatory requirements, professional and ethical standards, advertising regulations; guidance on the translation of safe and effective therapies to improve patient lives; principles of evidence-based medicine and good clinical practice; processes for patient informed consent, complaints and compliance; and recommendations for formal accreditation for the application of recognised standards. Self-regulation has the benefit of containing regulatory compliance costs, and can be achieved at no extra cost to the patient.

Current TGA regulations have enabled Australia to become a world leader in the research and clinical translation of autologous cellular therapies, which offer great potential in treating injury and a range of chronic diseases. Proposed changes in the regulations must be agile, and carefully balance patient safety and autonomy whilst fostering innovation in the rapidly changing field of regenerative medicine.

SUMMARY OF KEY ISSUES

  • ACTS supports the regulation of minimally manipulated autologous human cell and tissue products in Option 3 (treated as excluded from TGA regulation), as amended:
    • guidelines on the application of the minimal manipulation definition to include the EU definitions of ‘cell separation, concentration or purification’; with stromal vascular fraction as an example of minimal manipulation;
    • mandatory reporting of serious adverse events via ACTS registries; and
    • ACTS support the current restrictions on advertising overseen by AHPRA and ACCC.
    • [NOTE: ACTS understands minimally manipulated autologous human cell and tissue products would be treated as excluded from TGA regulation across all proposed options 1 – 4.]
  • In the context of evidence-based medical practice, ACTS does not support significantly increased regulatory complexity or compliance costs for Autologous Cell Based Interventions (ACBI’s), where there is satisfactory safety and efficacy data and no pattern of harm to patients. We believe there is no credible evidence, in the context of the current highly regulated Australian medical environment, to demonstrate significant risk to patient health or well-being.
  • Safety and efficacy is well documented for minimally manipulated autologous cell therapies. Attachment A sets out a body of evidence in support of the use of bone marrow (BMC) and stromal vascular fraction (SVF) cell concentrate for the treatment of osteoarthritis (OA) over 14 and 6 years respectively. The comparison to the alternative of surgical intervention for end-stage osteoarthritis, with the associated mortality and serious complications must be considered. Increased regulatory burden will increase patient costs.
  • An improvement in the transparency of safety and efficacy data on autologous cell therapies is required. ACTS proposes that it is a suitable national body to operate a detailed registry of ACBI’s procedures in Australia with an application to the Department of Health for funding. This would include serious adverse event reporting.

SPECIFIC COMMENTS:

It is important that the Australian regulatory environment facilitates companies, IP scientists and medical staff to stay in Australia. We must be careful to ensure Australia does not move towards more regulation when other countries have moved towards less regulation to encourage regenerative medicine innovation e.g. Japan: SAKIGAKE initiative. There is a risk that increased complexity in regulation may stifle investment and medical innovation without measurably improving confidence in safety.

There is a clear difference between medical practice and therapeutic goods regulated by the TGA. The risks associated with minimally manipulated ACBI’s are every-day medical risks managed by doctors. We are not aware of any TGA approved surgical procedures, although the TGA is proposing to regulate ACBI’s in a surgical context. This will introduce an additional layer of complexity and cost into the practice of medicine where regulation is currently performed effectively by APHRA, Medical Boards, HCCC and the ACCC.

The medical practice innovation pathway does not come by the costly and slow ‘big pharma’ route but begins with the reliance on lower quality data (beginning, in all cases, with anecdotal experience), case series and continual studies but has the advantages of flexibility and a shorter timeline from discovery to clinical implementation. Physicians typically publish smaller studies that are reactive to problems encountered in daily clinical practice, and result from the rapid adoption of new therapies that appear to be effective in a semi- or uncontrolled setting1.

Increased regulation with significant compliance costs and delays may impact innovation, the financial viability of autologous cell therapy clinics and the ability to attract investment for research and innovation. If autologous cell therapies are no longer available in Australia, patients may be forced overseas to less regulated environments with lower safety standards.

CODE OF PRACTICE

ACTS has developed a code of conduct to guide evidence-based medicine:

  • the code, in conjunction with the NH&MRC guidelines, provides a tiered risk–benefit ratio to guide the translation of safe and effective autologous cell therapies;
  • based on the NH&MRC body of evidence matrix, ACTS does not support the use of ACBI therapy for diseases other than osteoarthritis.

Excerpt from the ACTS Code of Practice:

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SAFETY

Sensationalist media reports, with little regard for accurate reporting of objective evidence, have been successful in increasing patient concern and destroying public confidence in the Australian medical profession and scientific community. It is imperative to separate opinion and commentary from scientific fact in order to progress innovation in medical practice. Evidence-based decisions should always be the primary consideration of regulatory decisions in this complex field.

There is no evidence of a pattern of harm, including international research and longevity studies over a period of 14 years, supporting the need to influence broad social policy with higher regulatory complexity for ACBI therapies.

REGISTRY & ADVERSE EVENTS REPORTING

ACTS supports the mandatory reporting of serious adverse events; and is currently drafting requirements for data registries to improve transparency and restore confidence in patient safety and efficacy outcomes.

Excerpt from the ACTS Code of Practice:

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ACTS will approach the Department of Health, dependent on support from the TGA, for funding to develop a national clinical-quality registry, with the aim of implementing a clinically credible method of monitoring autologous cell therapies and outcomes.

EFFICACY

Autologous cell based interventions should be available for patient use when there is robust scientific evidence of safety and efficacy in the treatment of a disease. Autologous cell therapy tends to be investigator led (e.g. only 6% of autologous cell therapy clinical trials in the EU were company-led (2012)) 2. Despite this lack of support by industry, there is a robust body of evidence for the safe and effective treatment of knee and hip disease with ACBI’s (5,336 patients; 44 scientific publications over 14 years). Of the 44 peer-reviewed publications, there are 6 Level II studies and 4 level III studies which evidence over 20 publications with 1,628 patients for SVF-derived cells; and 22 publications with 3,708 patients for bone-marrow derived cells (Attachment A). Applying the NH&MRC guidelines on the interpretation of peer-reviewed data:”Levels of Evidence and Grade for Recommendations for Developers of Guidelines”, a rating of ‘C Satisfactory’ may be applied to ACBI’s for the treatment of osteoarthritis.

The safety and efficacy of a procedure should be assessed in comparison to the standard conservative treatment of the disease. ACBI’s compare favorably to orthopedic treatments with key advantages of low toxicity and a high safety margin:

  1. An excess mortality rate of 0.12% has been observed for total knee and hip arthroplasty3. We can estimate from this that 1 Australian patient dies every 4 days from total knee and hip arthroplasty (76,357 primary total knee and hip replacements were performed in Australia (2014)) 4. In contrast, 1 mortality has been reported in 6 years for the liposuction procedure required for autologous cell therapy, and appropriate medical regulatory action was taken in response.
  2. A high complication rate has been reported of 4.5% (1 in 22 patients) with total knee arthroplasty (TKA)5. Few complications have been observed with autologous cell therapy in the treatment of joints.
  3. Approximately 1 in 5 primary total knee arthroplasty patients are dissatisfied with the outcome 6,7.
  4. Recovery period is minimal after cell concentrate therapy in comparison to knee and hip arthroplasty. Patients want and expect their lives, in particular their time away from work, disrupted as little as possible.

In general, patients who are medically fit enough to have a knee or hip replacement are offered a procedure which is invasive, may cause death, has a large number of complications, and a variable outcome. We need better treatment options for patients.

There has been a failure to communicate the benefits of the ACBI’s. Small clinics do not have the substantial marketing budgets of pharmaceutical companies who can deploy teams of medical reps to educate doctors.

ADVERTISING

AHPRA regulations prohibit: false, misleading or deceptive claims; unreasonable expectations of beneficial treatment; or encouragement of unnecessary procedures. Medical practitioners are expected to comply with a code of conduct which includes providing fully informed consent. Concerns about the conduct of medical practitioners can be reported to AHPRA, HCCC and ACCC.

ACTS support the current standards of regulation implemented by AHPRA and ACCC.

Excerpt from the ACTS Code of Practice: 

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We are aware that AHPRA, Medical Councils, HCCC and ACCC have already taken action this year against health practitioners perceived to be operating outside the guidelines.

The Australian Competition and Consumer Commission (ACCC) expressed the view that patients should be able to receive accurate and relevant information in order to make informed decisions in their dealings with medical professionals. With the conflicting medical viewpoints on treatment options available it is important the patient is kept fully informed with knowledge of options and services available.

MINIMAL MANIPULATION

We propose that guidelines on the application of the minimal manipulation definition include the EU definitions of ‘cell separation, concentration or purification’; with stromal vascular fraction and bone marrow cell concentrate as examples of minimal manipulation.

  1. The TGA propose that physical disruption of a tissue will lead to changes in their properties i.e. activation state or surface molecule expression, which may impact the cells characteristics or functions leading to more than minimal manipulation.We understand this but observe that other examples of minimal manipulation processes (e.g. centrifugation, washing, refrigeration and freezing) would all similarly impact the activation state and surface molecule expressions of the tissue or cells (e.g. cells and tissues react to environmental changes such as temperature, washing reagents used, and centrifugation). All of the current minimal manipulation definition process actions seek to modify the tissue or cells in some way for further use.
  1. ACTS supports the propose definition of more than minimal manipulation:

Cells or tissue are subject to a process that is more than minimal manipulation if the process results in the alteration of any of the biological characteristics, physiological functions or structural properties that are relevant to the intended use of the cells or tissues.”

SUMMARY

We understand the challenge in developing an agile and pragmatic regulatory framework that balances patient safety and autonomy whilst fostering continuing innovation. Regenerative medicine will modify medical practice in ways as yet unseen. It is critical that investment and medical innovation is not hindered by unnecessary regulation or uncertainty. To reduce the perception of investment risk, regulation must be predictable, stable, comprehensive, consistently applied and transparent.

Regenerative medicine is a new concept, though cell therapy has been used safely and effectively for more than 50 years 9. The TGA raised concerns in the consultation paper regarding communicating evidence of safety and efficacy; reporting data on therapies and adverse events; and direct-to-consumer advertising.  The issues raised have been addressed, in part, by the initiatives of ACTS to: communicate peer-reviewed evidence of safety and efficacy for osteoarthritis (Attachment A); draft requirements for data registries and adverse event reporting; and implement a code of practice that documents safety and advertising standards, and guides evidence-based practice to provide therapies for osteoarthritis only at this time.

The concerns raised must be reviewed in context. The recent informal review (based on Yahoo searches) estimated that there are 19 clinics in Australia engaged in direct-to-consumer marketing of stem cell interventions 10. This is a small number in comparison to over 100,000 registered medical practitioners in Australia 11. Over the last 6 years, there has been a slow but steady uptake of autologous cell procedures by medical practitioners as evidence accumulates in support of efficacy for osteoarthritis.  There has been no demonstrated evidence of any pattern of harm to patients over a period of 13 years internationally with ACBI’s.

In the context of evidence-based medical practice, ACTS cannot support significantly increased regulatory complexity or compliance costs for ACBIs where there is satisfactory safety and efficacy data and no pattern of harm to patients. We believe there is no credible evidence, in the context of the current highly regulated Australian medical environment, to demonstrate significant risk to patient health or wellbeing.

We agree with the TGA that a flexible regulatory approach is required that preserves the gold standard for safety and efficacy but also takes into account the unique aspects of cell therapies and the need to support patient access to treatments that not only treat common orthopedic injuries, but also show great promise for the future treatment of diseases such as chronic migraine, heart disease, and neurological diseases such as Parkinson’s disease and Alzheimer’s. A regulatory environment that fosters innovation and translation into clinical practice is important for patients in Australia.

Thank you for the opportunity to provide feedback on regulations associated with cell therapies. We look forward to continued engagement with the TGA to support the regulations of cell therapies.

acts-code-7ATTACHMENTS

The ACTS response can be downloaded as a PDF by following the link. In particular, the ACTS response provides a detailed attachment and references evidencing the safety and efficacy of ACBIs in the treatment of knee and hip joints in osteoarthritis (also displayed on this website):

Attachment A is a publication list of knee and hip joints treated by autologous bone marrow derived cells and autologous SVF and ASCs:

  • 22 publications with 3,708 patients treated by autologous bone marrow derived cells (with 4 Level II studies and 2 Level III studies)
  • 20 refereed publications with 1, 638 patients treated by autologous SVF and ASCs (with 2 Level II studies and 3 Level III studies).

References for Attachments A can be viewed in the PDF version of the ACTS response.