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Stem Cell Treatments: A quick guide for medical practitioners and FAQ: a resource for patients submission

ID: 
7
Personal Details
First Name: 
MARTIN
Last Name: 
PERA
Questions
1. Is the document in the appropriate format? If not, how could the document be better formatted?: 

We welcome the NHMRC Draft Stem Cell Treatments - a quick guide for medical practitioners (Quick guide) and the accompanying Frequently Asked Questions - A resource for patients (FAQ).

 

The format of both documents is clear and easy to understand. We particularly welcome the inclusion of the patient checklist (FAQ- page 4) and the list of questions to consider (Quick guide – page 4).

2. Is the language appropriate for the target audience (i.e. medical practitioner for the quick guide on stem cell treatments and patient for the FAQ resource)?: 

The use of language is appropriate for the target audiences. We endorse the emphasis on encouraging the patient to collect information about a potential treatment and then discuss this with their Australian doctor prior to making a decision.

3. Does the document contain relevant information? If not, which sections do you consider to be irrelevant?: 

The documents are clear and concise, and they address most of the important issues facing physicians and their patients who may be contemplating stem cell treatments. An especially important contribution of the documents to patient education lies in the distinction they draw between ‘standard practice’ and ‘experimental’ or ‘unproven’ stem cell treatments, and the clear cautions around the latter. 

 

Also valuable are the explanations for patients concerning the proper routes for development of new treatments, through preclinical research and clinical trials, as apposed to reliance on patient testimonials and ambit claims made by providers.

 

We have included some minor points of clarification regarding content in our response in Specific Comments below.

4. Does the document exclude any important information that would be useful to medical practitioners or patients?: 

While the documents address ‘stem cell tourism’, where Australians travel abroad for unproven stem cell treatment, unfortunately they do not adequately address an important category of stem cell treatments currently being offered in Australia. We refer to autologous stem cell therapies provided to individual patients by Australian practitioners and/or clinics.

 

This growing practice represents a significant concern to physicians and the scientific community.  In almost all cases, these treatments fall into the ‘unproven’ or (occasionally) ‘investigational’ categories described in the draft documents. None of the treatments are considered ‘standard medical practice’ or have been subject to peer-review. Most if not all are conducted outside the context of a clinical trial. However, they are being offered, often for a considerable fee, for a wide range of conditions (such as stroke, Multiple Sclerosis, Motor Neurone Disease, autism and osteoarthritis).

 

It should not be assumed that, just because the cells are obtained from the patient undergoing treatment, that there is no risk associated with these procedures, a point illustrated by the recent report cited in the Quick Guide (Thirabanjasak et al. (2010) J Am Soc Nephrol 21(2):1218- 1222 - Pubmed).

 

Physicians and their patients should be aware that the promotion and delivery of unfounded stem cell therapies also runs the risk of diverting patients from standard treatments that, if not curative, have demonstrable beneficial or palliative effects based on sound scientific evidence.  In this sense, unfounded therapies have the potential to harm patients even if they do not directly cause adverse effects.

 

Under the current regulations, such treatments do not fall under the remit of the Therapeutic Goods Administration provided the treatments use autologous cells for a single indication and the provision of such treatments is overseen by a registered Australian medical practitioner (see additional information provided below on Therapeutic Goods (Excluded Goods) Order Number 1 2011). Rather, regulation of such practices falls within the remit of the body that oversees medical practice, Australian Health Practitioners Regulation Agency.

 

The challenge of regulating autologous cellular therapies is not unique to Australia. As highlighted in a recent article in Nature Biotechnology, many in the stem cell community in the United States and elsewhere are alarmed that the same concerns raised about ‘stem cell tourism’ can be levelled at the providers operating “in our backyards” (DeFrancesco (2012) Nat Biotech 30(8):739-741 - Pubmed).

 

We believe that the current exemption should be revised, to ensure that any autologous cell therapy that involves non-homologous use (use of cells with the intent to achieve a physiological function other than their normal one), or more than minimal manipulation ex vivo, comes under the TGA regulations on biologicals.

 

We will be contacting the NHMRC and other parties to work towards introducing more rigorous regulation of autologous cell therapies in Australia. However we believe the draft documents should be amended to raise awareness and a warning about such practices occurring in Australia. This would be a timely and welcomed contribution.

 

We have provided suggested revisions to more adequately address this issue (Specific Comments, below).

5. How could this information best be disseminated to patients and medical practitioners?: 

In addition to having the resource available on the NHMRC website, it would be beneficial to provide electronic, and possibly printed, versions of the Q&A document to patient support and advocacy groups throughout Australia. These groups are frequently asked by their members for information and advice on treatments available overseas and in Australia, and would welcome additional authoritative material from the NHMRC. We would also be delighted to post a link to the information the Stem Cells Australia website.

 

For medical practitioners, one option would be to promote the resource via a publication such as Australian Doctor. We recently published a two part series, based in part on the Australian Stem Cell Centre’s Patient Handbook, where we sought to provide information to the medical community on stem cell science and issues such as stem cell tourism (Herbert et al. Stem cell therapies Part 1: the current situation Australian DoctorHow to Treat 11 November 2011:25-32; Herbert et al. Stem cell therapies Part 2: the future Australian DoctorHow to Treat 18 November 2011:23-30).

 

Finally, in our initial research into stem cell tourism with colleagues at Monash University, we identified that some Australians who had travelled overseas for stem cell treatment did not necessarily consult their Australian medical practitioner but rather discussed options with other health professionals (Seear et al. (2010) Hopeful Journeys: Experiences of Stem Cell Treatments Offered Outside Australia. Available online via Department of Innovation website). Therefore, we would recommend that NHMRC also consider making the resource available to representative bodies of other health professionals to ensure they are also aware of the issues associated with unproven stem cell therapies.

6. How could general practitioners best access this information (i.e. an appropriate website)?: 

In addition to promoting the resource via Australian Doctor and similar publications and their websites, we would suggest that NHMRC could sponsor a workshop at a national GP conference to raise awareness about the issues associated with unproven stem cell therapies, and the availability of these new resources.

Specific Comments
Specific Comments: 
Frequently Asked Questions - Q3
  • Suggest that a statement that participants in clinical trials are not usually charged should be included in paragraph 3, as some companies are calling their treatment ‘clinical trials,’ but still charging large sums of money.  This cost of participation constitutes a potential harm to human subjects, as specified in the National Statement on Ethical Conduct in Human Research (NHMRC, Chapter 2.1).
  • Footnote for ‘efficacy’ should be used at the first mention at the end of paragraph 3.
  • Rather than describing a Phase I clinical trial as a small ‘scale’ trial, suggest state that definition could be ‘A trial performed on a small number of human subjects’. Perhaps a figure could also be included (<50).  We query whether Phase I are always conducted in healthy volunteers.
Frequently Asked Questions - Q4
  • Suggest the first paragraph includes an additional statement about availability of unproven treatments in Australia as well as overseas. Without a strong statement in this section about unproven treatments available in Australia, there is a possibility that Australian patients will have the idea that because the treatment is being sold in Australia it must be proven. Possible wording could include:
    • In Australia, unproven stem cell treatments are also available outside the clinical trial process. Such treatments are considered experimental and have not been shown to be safe and effective for many conditions.
  • Having asked patients to ‘research’ whether there are any TGA approved stem cell treatments available in Australia, it might be helpful to elaborate how they can best do this. Entering the phrase ‘stem cells’ into any search engine will provide links to paid advertisements from providers in Australia and overseas, including those offering unproven treatments.
  • Consider including these additional warnings in this section:
    • Undertaking unproven treatments may prevent the patient participating in a future clinical trial
    • Claims that one type of stem cell treatment can provide benefit for a wide and diverse range of conditions should be regarded with suspicion. This is raised in the fourth dot point of the Patient Checklist on page 4 but could be highlighted earlier.
  • The reference to the FDA in Footnote 3 appears incomplete.
Frequently Asked Questions - Q5
  • Suggest following modification to first sentence as it would be good to reinforce the conflict of interest of the provider selling the unproven treatments:
    • ‘It is strongly recommended that you seek additional information, from a source other than the provider, in order to make a well informed choice regarding …….’
  • Paragraph 2 should not be restricted to overseas providers. Suggest ‘the providers’ could substitute for ‘overseas stem cell institution’.
  • Patient checklist:
    • It is unclear what is meant by ‘cerebral heart disease’
    • There should be a separate dot point (and tick box) for the questions related to ‘How many treatments do I need?...’
  • The ASCC Patient Handbook is also available through the Stem Cells Australia website and will soon be available from the National Stem Cell Foundation of Australia (NSCFA). The NSCFA is the charity that was established when the Australian Stem Cell Centre closed. It would be ideal to incorporate an active URL to make sure that this resource, and any further updated versions, are available to the broader public and medical practitioners.
  • In addition to linking to the ISSCR Patient Handbook, a link to their ‘A closer look at stem cell treatments’ would be valuable as this site has many excellent resources.
Stem Cell Treatments - Q1
  • The final dot point should not be restricted to providers overseas. Suggest following rewording:
    • ‘….before deciding whether to participate in unproven stem cell treatments being offered in Australia and abroad.’
Stem Cell Treatments - Q4
  • It is important to include a statement in this section (or possibly in response to Question 3) that many so-called stem cell treatments being offered may not in fact involve stem cells at all, but rather ill-defined and heterogeneous mixtures of different cell types extracted from tissues through relatively crude means. It is not impossible that such treatments may have benefit, but the mechanism of benefit is unknown and quite possibly unrelated to stem cells, may likely be short lived, and does not involve long-term engraftment (see Dai et al (2012) Cell Transplant doi: 10.3727/096368911X627570. [Epub ahead of print] - Pubmed)
Stem Cell Treatments - Q5
  • Suggest modifying title to capture provision of unproven stem cell treatments in Australia, such as:
    • ‘Why should patients be cautious about unproven stem cell treatments being offered in Australia and overseas?’
  • Include additional information about provision of unproven stem cell treatments in Australia in opening sentence, such as:
    • ‘An increasing number of people travel overseas for stem cell treatments which are experimental, often referred to as ‘stem cell tourism’. In recent years, a number of Australian clinics have also started to offer autologous cell therapies that have not been evaluated through clinical trials. Although such treatments are outside the remit of the TGA, they are not yet ‘standard medical practice’ and are not without risks as demonstrated by reports of adverse events (see footnote 2).
  • Remove ‘International’ from first sentence of second paragraph as this statement applies to alleged stem cell treatments being offered overseas and in Australia.
  • Modify third paragraph so that information is not exclusive to provision of overseas treatment.
  • Suggest add other dot points to the list on how to identify clinics offering unproven stem cell treatments:
    • lack independent ethics committee oversight to protect welfare and rights of patients
    • charge substantial fees (many thousands of dollars) for unproven treatments
  • Suggest raising the lack of peer-reviewed publications higher in the list of dot points.
Stem Cell Treatments - Q6
  • Modify text in second paragraph to capture those providing unproven treatments in Australia:
    • ‘Whilst it is ultimately the patient’s decision whether they decide to undertake unproven stem cell treatments, in Australia or overseas, medical practitioners…….’
  • Modify the list of points to consider as follows:
    • Remove current No.1 – just because the treatment is offered in Australia does not make it safe and effective even if it involved the use of the patient’s own cells.
    • Include ‘standard practice’ as an option instead of ‘proven’ under ‘2. What is the status of the treatment?’ as both the Quick guide and the Q&A documents use this term.
    • Add ‘patient’s own cells from bone marrow or fat’ to ‘4. What type of stem cells are being used?’
    • Add to ‘7.Is the person who performs the stem cell treatment a specialist in treating the patient’s condition?’
  • Add a paragraph indicating that physicians should, where appropriate, advise their patients not to abandon standard medical therapy in favour of unproven and unfounded stem cell treatments.
  • Note NIH is National Institutes of Health
  • In addition to linking to the ISSCR Patient Handbook, a link to their ‘A closer look at stem cell treatments’ would be valuable as this site has many excellent resources.
  • Liaise with the National Stem Cell Foundation of Australia to obtain a permanent hyperlink to the ASCC Patient Handbook (new website to soon be launched – see note above).
Stem Cell Treatments - Q4

Additional information on the Therapeutic Goods (Excluded Goods) Order Number 1 2011

Below we explore some implications of the Excluded Goods Order in the regulation of cell and tissue therapy in Australia that are of serious concern to the field of regenerative medicine and its future here. The current Excluded Goods Order enables the legal operation of clinics that are delivering unproven and unfounded treatments outside of the regulatory framework that governs cell therapy in this country.  There is an urgent need for review and amendment of this Order, to protect patients and to ensure ethical advancement of cell therapies with a sound scientific basis.

 

Background to the Regulation of Cell and Tissue Therapy in Australia

The Therapeutic Goods Administration issued a new framework for the regulation of cell and tissue therapy in Australia in 2011 (Regulatory Framework for Biologicals). The framework categorizes cell and tissue therapies according to potential risk, and applies regulatory measures commensurate with those levels of risk (see Trickett and Wall (2011) Pathology 43(6):627-34 - Pubmed). 

The key features of the classification system are as follows:

  • Level 1  Lowest possible risk, low levels of oversight.  Treatments manufactured by a medical practioner for use on individual patients.  Statement of compliance by practioner required.  No product dossier, but entry on to the Australian Registry of Therapeutic Goods is required.
  • Level 2  Products manufactured with minimal manipulation intended for homologous use (homologous use means use in the tissue of origin to carry out the same biological function of the cell or tissue that is harvested).  Requires entry into ARTG and GMP practice.
  • Level 3  Products requiring more than minimal manipulation that may or may not be intended for homologous use.  Product meets all level 2 requirements, plus information on safety, quality, and efficacy must be presented in dossier.
  • Level 4  Products which have been altered and do not reflect in vivo state, and genetically modified products.  Product requires the highest level of assessment.

 

The Therapeutic Goods (Excluded Goods) Order Number 1 2011

Certain products are exempt from the regulations by the Therapeutic Goods (Excluded Goods) Order Number 1 2011.  Section 4q of this order excludes human tissue and cells that are:

       i.         collected from a patient who is under the clinical care and treatment of a medical practitioner registered under a law of a State or an internal Territory; and

      ii.         manufactured by that medical practitioner, or by a person or persons under the professional supervision of that medical practitioner, for therapeutic application in the treatment of a single indication and in a single course of treatment of that patient by the same medical practitioner, or by a person or persons under the professional supervision of the same medical practitioner

 

Implications of the Excluded Goods Order

Though it may have been drafted to enable very straightforward procedures, such as minimal manipulation of patient tissues ex vivo during surgical procedures, this exemption is in fact very broad. 

As drafted, the Order may have many unfortunate and unintended consequences that facilitate the delivery of unfounded, unproven, and unsafe treatments by clinics in the private sector. 

Such clinics, operated by licensed medical practitioners, already exist in Australia.  They are often advertised as providing stem cell therapies, though in fact the preparations in use are not stem cells at all.  Instead, these clinics are currently offering autologous therapy to patients using ill-defined cellular preparations derived from tissues such as fat.  The treatments are provided at high cost without reimbursement.  The indications claimed for the therapies in some cases go well beyond homologous use.  Actually, the practitioners may claim benefits for an astonishingly wide range of medical conditions.  The manufacturing processes may entail extensive ex vivo manipulation of the patient’s cells, and indeed some clinics are now extending their franchises through provision of training, consumables and devices to members of the medical community. 

In summary, this exemption allows individual practitioners to undertake patient customised cell therapy that would otherwise come under the highest levels of regulations in the new Framework. At the same time the exemption means that these clinics do not even need to meet the minimal Level 1 requirements in place for regulation of non-exempt therapies. The practices enabled by this exemption could well present high risks to patients, to say nothing of their financial costs. For example, under this exemption, a physician could offer a service in which a patient’s cells are harvested, converted into induced pluripotent stem cells, and then administered to the patient to treat a range of ailments. (Note is now possible to generate iPS cells without genetic manipulation so such treatment would evade regulation of gene therapy.)

This promotion and delivery of unfounded stem cell therapies also runs the risk of diverting patients from standard treatments that, if not curative, have demonstrable beneficial or palliative effects based on sound scientific evidence.  In this sense, unfounded therapies have the potential to harm patients even if they do not directly cause adverse effects.

Some have argued that this medical practice exemption serves the important function of allowing for the development of therapeutic innovation by individual physicians. 

The International Society for Stem Cell Research (ISSCR) has recognized the potential contribution of medical innovators to regenerative medicine, but provides a very clear set of guidelines around the very exceptional circumstances under which innovative stem cell treatments may be attempted outside the context of a clinical trial (see Recommendation 34 in ISSCR Guidelines for the Clinical Translation of Stem Cells 2008 and further explored in Lindvall and Hyun (2009) Science 324(5935):1664-5 – Pubmed).

 

Possible solutions:

It is imperative to amend the Excluded Goods order to rectify the unintended consequences that are following on from its adoption.  Although in principle unsafe and unsound practices permitted under the Excluded Goods order could be policed by the Australian Health Practitioner Regulation Agency (AHPRA), through its notification procedures, in fact this is an unsatisfactory mechanism to tackle this problem, for the following reasons:

  1. The AHPR can only act after the fact to limit unfounded and unsafe practices.  There is no scope for prevention, only for action once a specific case has become sufficiently egregious so as to come to the attention of the AHPR.
  2. The AHPR can only deal with this problem on a case-by-case basis. There is a growing epidemic of unfounded cell therapy clinics that will rapidly deplete the AHPR bandwidth.
  3. The AHPR have no expertise in cell therapy.
  4. The problem is not really a single physician based issue, rather there are corporate entities delivering and disseminating cell therapy technologies through networks of clinics via the Excluded Goods loophole.

 

In summary, many autologous therapies should come under the TGA Regulatory Framework for Biologicals. The TGA should bear the authority to regulate any cell therapies that involve non-homologous use and anything more than minimal ex-vivo manipulation.  We are developing a strategy to approach the issue of amending the Excluded Goods Order.

General Comments
Comments: 

(Introduction to submission:

The provision of unproven stem cell treatments continues to concern physicians and the scientific community in Australia and overseas. We believe that proper route for development of new treatments, including cellular therapies, is through preclinical research and clinical trials.

 

We welcome the NHMRC Draft Stem Cell Treatments - a quick guide for medical practitioners (Quick guide) and the accompanying Frequently Asked Questions - A resource for patients (FAQ) as an additional authoritative resource to raise awareness and discussion about the importance of taking a cautionary approach when considering unproven stem cell treatments.

While the documents address ‘stem cell tourism’, where Australians travel abroad for unproven stem cell treatment, unfortunately we do not believe they adequately address a growing issue in Australia - the provision of unproven autologous stem cell therapies to individual patients by Australian practitioners and/or clinics.

We believe that many of the same concerns raised about ‘stem cell tourism’ can be levelled at the providers of unproven stem cell treatments operating in Australia:

-       direct to consumer marketing;

-       promoting success based on patient testimonials rather than objective scientific evidence;

-       single treatments promoted for multiple, unrelated diseases;

-       lack of evidence of safety;

-       scientific rationale not offered or available;

-       results of treatment not available in peer-reviewed journals, and

-       significant fees per treatment (many thousands dollars with no reimbursement).

In this submission we address each of the questions raised in the consultation and provide specific suggestions about how the draft documents could be amended to raise awareness and caution about unproven stem cell therapies abroad and in Australia.

We also discuss the current regulatory environment in Australia, where and why autologous cell therapies do not fall under the remit of the Therapeutic Goods Administration, the implications of the exemption of certain autologous treatments from the regulatory framework, and possible solutions to this problem.

With some minor amendments, we believe that the draft NHMRC documents will make a valuable and timely contribution to addressing this important issue.)

Page reviewed: 7 February, 2014