Regulatory Loophole Enables Unproven Autologous Cell Therapies to Thrive in Australia

Abstract

As in many jurisdictions around the world, there are a growing number of doctors in Australia who are offering autologous cell therapies outside of a clinical trial setting and in the absence of sound and convincing evidence of safety or efficacy. Such interventions, often marketed as “stem cell” treatments, involve the administration of the patient's own cells—or products derived from them—for a wide range of conditions at considerable financial cost to patients. At present, Australian regulations treat autologous cell treatments as medical practice, exempt from the regulatory framework for cell and gene therapy and biologicals. As a consequence, Australia risks becoming the destination of choice for those practitioners seeking to capitalize on community demand for “stem cell” therapies.

Since 2011, the growth in the Australian market has been exponential. From 1 or 2 sole practitioners, there are now more than 40 known providers.

Australian regulatory framework

The inherent risks associated with cell therapies have long been recognized in Australia. More than 10 years ago, the Australian Health Ministers Conference recommended that the Australian Therapeutic Goods Administration (TGA) introduce a national regulatory framework for human tissues and emerging biological therapies due to concerns such as the risk associated with infectious disease transmission, the need to foster international regulatory harmonization, and a requirement to provide industry with more regulatory certainty given that the use of cellular products for therapeutic purposes was predominantly unregulated [1].

From the outset, the proposed framework acknowledged the need to categorize cell and tissue therapies according to potential risk, and envisaged regulatory measures commensurate with those levels of risk. Indeed, the key features of the Biologicals Framework when finally introduced in 2011 provided stringent oversight requirements in relation to the development of new products [101] (summarized in Table 1).

Table 1.

Key Features of the Australian Biologicals Framework

Category	Requirements
Level 1	Lowest possible risk, low levels of oversight. Treatments manufactured by a medical practitioner for use on individual patients. Statement of compliance by practitioner 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 Australian Register of Therapeutic Goods and meeting good manufacturing practice standards.
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 that have been altered and do not reflect in vivo state and genetically modified products. Product requires the highest level of assessment.

However, due in part to concerns about restricting the use of human cells and tissues in contemporary Australian medical practice, the TGA also included a series of exclusions when introducing the Biologicals Framework [102]. As a result, certain practices, including the use of human hematopoietic progenitor cells for reconstitution of the blood and immune system, direct transplantation of organs, and use of reproductive tissues in infertility treatment (all of which are already overseen by existing peer-review and accreditation processes), were deemed outside the remit of the TGA and not subject to the requirements of the new framework [1].

In addition, a further broad exclusion was introduced to ensure that single surgical procedures and other medical practices involving autologous use of cells and tissues did not have to comply with TGA requirements. According to item 4q, any human tissue and cells that are “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 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” were to be excluded [102].

Although intended to exempt straightforward procedures—such as the use of veins from a patient's limb(s) for grafts in cardiac bypass surgery, or collection, processing, and administration of pancreatic islet cells for a diabetic patient—from undue regulatory interference [103], this Exclusion Order is in fact very broad and has had the unintended consequence of facilitating the proliferation of unfounded, unproven, and potentially unsafe cell treatments by clinics in the private sector.

Growth of autologous interventions in Australia

Over the last 3 years, there has been a proliferation of clinics, operated by licensed medical practitioners, offering autologous stem cell “treatments” for a myriad of conditions (Fig. 1). While the majority of available procedures involved the administration of adipose-derived extracts—sometimes marketed as stromal vascular fractions assumed to contain mesenchymal stromal cells or MSCs—there are also a number of clinics that utilize cells or plasma from peripheral blood. For around $10,000, Australian patients are being offered intra-articular injections for osteoarthritis and cartilage repair, as well as intravenous delivery of crude tissue extracts for anti-aging/rejuvenation therapy, stroke, multiple sclerosis, retinal neuropathy, spinal cord injury, amyotrophic lateral sclerosis, and even autism [2]. All of these treatments are being offered as medical procedures outside clinical trials.

FIG. 1.

Australian medical practitioners (43 to date) are offering autologous “stem” cell interventions for a variety of conditions. The majority of providers restrict their practice to musculoskeletal conditions. *Includes Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, muscular dystrophy, retinal neuropathy, asthma, headaches, hair loss, and infertility.

Since 2011, the growth in the Australian market has been exponential. From 1 or 2 sole practitioners, there are now over 40 known providers (Fig. 1). Although most providers were identified from website claims, several were first brought to our attention following correspondence with patients and relatives who reported being offered “stem cell” treatments. Indeed, this more hidden promotion via consumer word-of-mouth may mean that the actual number of Australian providers is even higher.

While the majority of the identified Australian providers appear to restrict their practice to osteoarthritis and sports injuries, others appear prepared to treat a wide range of serious medical conditions. Such unproven treatments are widely promoted by providers via dedicated websites, and endorsed through patient networks and community groups such as an Australian charity claiming to have “over 900 doctors join and over 400 physiotherapists, chiropractors, osteopaths and other health professionals” endorse the value of what they are achieving [104].

For patients and their loved ones seeking potential means to alleviate suffering, claims of “significant success” and “improvement in their quality of life” with claimed minimal risks because the “cells are sourced from your own body” are understandably tempting [105]. However, exactly what is being injected is difficult to determine. As there are currently no requirements for these autologous cellular therapeutics to be prepared in an accredited laboratory—nor any requirement to adhere to good manufacturing practice standards in their production—the dose and composition of the product being delivered is often undefined, with no or little evidence that the preparations actually contain stem cells. Despite this lack of clarity and standards, several franchises are being established across Australia to train interested Australian doctors and to facilitate access to untested and unregulated consumables and devices used in cell manufacture.

In a disturbing development, a new provider has entered the Australian marketplace claiming to utilize patented technology of a global partner to convert autologous peripheral blood cells to pluripotent stem cells for the treatment of “Multiple Sclerosis, Cancer, Acute Myeloid Leukaemia, Stroke, Alzheimer's Disease/Dementia, Diabetes Type I and II, Cardiovascular Disease, Hepatitis B and C, Parkinson's Disease, Crohn's Disease, Facial Beauty Rejuvenation, Male Infertility and Male Erectile Dysfunction” [106]. If such an approach is actually being made available to Australian patients, it would clearly represent a very high level of risk to patient health in terms of tumorigenicity and other potential adverse events. Yet, astonishingly, such autologous therapy using reprogrammed cells would indeed be exempt from current Australian regulations.

Several of the Australian clinics are also offering to provide assistance with travel both to and from the medical facility in Australia, in likely violation of the Excluded Goods Order that envisages a medical practitioner will provide ongoing clinical care of the patient—and paving the way for Australia to become the destination of choice for “stem cell tourism” in the Asia-Pacific region.

Call for action to curb growth in unproven autologous cell therapy

The growth of unproven autologous cell interventions has not gone unnoticed in Australia. The National Health and Medical Research Council (NHMRC) is Australia's lead agency for supporting health and medical research, for provision of health care advice to the public, and for formulating ethical standards for the conduct of health and medical research and health care delivery. The NHMRC has recently called on Australian doctors to report concerns about professional conduct of these practitioners to the Australian Health Practitioner Regulation Agency (AHPRA) or to the Australian Competition and Consumer Commission, where it is believed “consumers are misled or deceived into believing that certain treatments are safe or effective when that is not the case” [107].

The growth of unproven autologous cell interventions has not gone unnoticed in Australia.

From the International Society for Stem Cell Research Guidelines

The following are conditions that must be met to support applications of unproven autologous cell-based interventions in patients outside the context of a formal clinical trial:

•provision to at most a small number of patients;

•a scientific rationale, including preclinical evidence of efficacy and safety;

•full characterization of the types of cells being transplanted and their processing;

•a peer-reviewed plan for the procedure and for clinical follow-up and data collection to assess the effectiveness and safety;

•an action plan for adverse events;

•a commitment to report results of innovative use;

•moving to formal clinical trials in a timely manner after experience with at most a few patients; and

•the ISSCR condemns the administration of unproven stem cells or their direct derivatives to a large series of patients outside of clinical trials, particularly when patients are charged for such services.

For more information, visit www.isscr.org/home/about-us/news-press-releases/2013/2013/09/12/isscr-statement-of-delivery-of-unproven-autologous-cell-based-interventions-to-patients

Currently, the only control over autologous cell therapies lies with AHPRA's authority to investigate false and misleading advertising, as well as unsafe and unsound medical practices. However, such inquiries can only be triggered ex post facto on a case-by-case basis. There is no scope for prevention of unsafe or unsound practice. Instead, under the current framework, we must wait until sufficiently egregious conduct involving actual harm is reported. With limited resources and expertise in cell therapy available to a body charged with enforcing all malpractice regulations across the health professions nationally, these mechanisms are an unsatisfactory means to tackle the growing epidemic of unfounded cell therapy clinics.

It has also been proposed that self-regulation may provide a possible interim solution to the control of autologous cell therapy [3]. There are obvious inherent conflicts of interest in any self-regulatory scheme, and it remains to be seen whether the code of conduct being developed will have sufficient power to ensure the practice of evidence-based medicine, especially when there is a high financial imperative to continue business as usual.

To enable medical innovation in the field of cell therapy, scientists, physicians, and regulators need to ensure that prospective new treatments are introduced in a responsible fashion, and that patients are provided with a realistic perspective of the proposed interventions. Australians need to be better informed of the risks and true benefits of pursuing “stem cell” treatment (Table 2). We need to dispel the view that stem cells are a “silver bullet” capable of knowing where in the body they are needed and being able to restore function. Most stem cell therapies are experimental. Patients and their families and friends need to be aware that the benefits of most treatments are unknown, and that some treatments do pose real risks to their health—even if they use the patient's own cells. They need to know that just because a treatment is being offered in Australia, that does not make it legitimate. All stem cell treatments should be shown in phase I, II, and III clinical trials to be safe and effective before being introduced into widespread practice. Patients should also consider whether these expensive interventions are diverting them, and their resources, from standard treatments based on sound scientific evidence that, even if not curative, have demonstrable beneficial or palliative effects.

Table 2.

Tips on How to Recognize Unproven Stem Cell Interventions

Distinguishing characteristics	Why this is a problem?
The experimental treatment being offered is not part of a registered clinical trial.	Clinical trials are the appropriate way to evaluate an experimental stem cell treatment. There are no guarantees that a new treatment being tested in a clinical trial will be shown to be safe and effective. Evidence should be collected through clinical trials before the treatment is offered widely to patients.
The treatments are being advertised on the Internet, Facebook, or in newspaper advertisements rather than via referral from your treating doctor.	Direct-to-consumer advertising generally uses very persuasive language, rather than accurate information, and implies benefit and “success” where there is little evidence to justify the claims. You would usually expect your treating specialist to refer you for any new treatment. If they don't know about it, chances are that it is unproven.
The doctor or clinic is offering to treat many different diseases or conditions with the same stem cells procedure.	Unless the diseases are related, different conditions in different organ systems, such as cerebral palsy, diabetes, and heart disease, would usually have very different treatments. In addition, you would usually expect to be treated by a doctor who is a specialist in your condition. Just because a new treatment may offer improvements in one condition, it does not mean that it will work for lots of different conditions. Stem cells are not a “silver bullet.”
The use of patient testimonials to support claims of benefit with no independent verification or published data.	While they can be very convincing, individual reports of apparent success have to be viewed with caution. Claims made are often difficult to substantiate and verify. The benefit may be real, or may be due to the placebo effect, or due to a desire to report a positive outcome because of the amount of time and money invested in obtaining the treatment. Without proper medical and clinical research scrutiny of these claims, they remain unproven and are not valid “evidence” of success.
Where there is no scientific rationale offered or the “evidence” is implied from the work of others.	Many treatments being offered use completely unproven techniques that have not been tested for their safety or efficacy in clinical trials in humans. “Patents pending” is not an acceptable excuse to conceal scientific methods from the scrutiny of respected colleagues. A doctor or clinic offering experimental treatment is usually expected to operate in a registered clinical trial and to collect data and publish their results in peer-reviewed medical journals so that others can learn from their experience.
When there is a lack of after care and follow-up once the procedure is completed.	After any medical procedure, patients are at risk of complications. Responsibility should be taken by the doctor for the management of complications. A simple phone call after the treatment is not sufficient. For those seeking treatment away from home if complications occur, they may be left with large bills and even expensive medical evacuations.
When you are asked to pay for a treatment that is not yet an accepted medical practice.	It is not usual to have to pay for an experimental treatment in a registered clinical trial and those being offered are very expensive and not reimbursed by Medicare (Australia’s publically funded universal healthcare scheme) or insurers.
Where there is no Medicare or private insurance rebate for the treatment.	Accepted medical procedures are usually recognized by Medicare or other insurance rebates. This not only provides financial assistance, it also ensures that the cost is a reasonable reflection of the actual cost in providing the treatment and not inflated.
The stem cells are prepared on-site at the doctor's surgery.	Any manipulation of cells, even if they come from you, carries risk of infection and other complications. They should be prepared in an accredited laboratory, where there are exacting quality control standards independently verified, or using a device that has been approved by regulators such as the Australian Therapeutic Goods Administration.

Adapted from The Australian Stem Cell Handbook [110]. Courtesy of The National Stem Cell Foundation of Australia.

Restraint is required from medical practitioners fervent about stem cells and their potential. The International Society for Stem Cell Research (ISSCR) has long 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 [108]. More recently, ISSCR has issued a statement on autologous cell interventions that calls on medical licensing bodies, legal authorities, patient advocacy organizations, physicians, and others to exercise their influence to discourage commercial provision of unproven autologous cell-based interventions outside of clinical trials [109]. Ultimately evidence, not simply enthusiasm, must underpin the translation of stem cell science into clinical practice in Australia and throughout the world.

Acknowledgments

Authors are members of Stem Cells Australia, a special research initiative funded by the Australian Research Council.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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