Regulation of unproven stem cell therapies – medicinal product or medical procedure?

Clinical Trials Ethics and Society

MedicThis article is the second in a series of posts about unproven stem cell treatments by guest authors Casimir MacGregor, Alan Petersen and Megan Munsie. Their first post took a closer look at Germany's X-Cell Center and stem cell tourism. Here they consider the regulatory frameworks governing unproven stem cell treatments in Europe, the US and Australia.

The European Medicines Agency’s (EMA) Committee for Advanced Therapies (CAT) played a leading role early on in laying a strong regulatory framework for dealing with unproven stem cell therapies, such as those offered by the X-Cell Center in Germany. Specific regulations were introduced by the European Parliament in 2007 (Regulation (EC) No 1394/2007) to ensure that medicines involving cell therapy were subject to appropriate authorisation, supervision and controls in order to reduce and manage risks (EMA, 2013). As our previous post about the X-Cell Center highlighted, it is important for regulatory bodies at all governmental levels (regional, federal and supra-national) to enforce their legal responsibilities to ensure that patients only have access to those treatments that comply with relevant quality standards, and for which there are appropriate processes to ensure traceability of materials, defined treatment protocols and patient follow-up measures, and notification of adverse events procedures.

EMA has maintained a firm position in line with the Nuremberg Code that places the protection of patients at the centre of all regulation. This is why EMA has sought to apply strict regulation concerning safety and efficacy for all medicinal products and maintains that the quality and manufacturing of these products should meet good manufacturing practice (GMP) requirements (EMA, 2013).

In Europe the security and control of medicines derived from stem cell manipulation is tightly controlled by the advanced therapy medicinal products (ATMP) legislation, which states:

Cell therapies are defined as medicinal products when there is more than minimal manipulation of any cell type destined for clinical application or where the intended use of the cells is different to their normal function in the body. Any use of such cell-based medicines is subject to authorisation and controls, including their manufacture. Permitting manufacturers to avoid compliance with quality standards, for example by inappropriate reclassification of the treatment beyond the mandate of competent authorities for control of medicines, could risk exposing patients to cross-contamination and inadequate characterisation of the cell preparations, resulting in short and long-term risks for individual patients.

Exemptions to the ATMP legislation in Europe

Despite this clear EMA legislation, internationally the regulation of unproven stem cell therapies has been difficult to enforce and inconsistent across jurisdictions. This is in part due to two exemptions. Combined they allow unproven stem cell treatments to take place, and have become exploited by commercial operators.

The first is through ‘compassionate’ use programmes, which allow doctors to obtain treatment for a patient while the medicine is still being developed or undergoing certification. Access to compassionate use programmes has recently been accompanied by a discourse that asserts the ‘patient’s right to try’, framed within a human rights rhetoric in order to circumvent established rules and guidelines concerning safety, efficacy and evidence-based-practice. This was clearly illustrated in the recent Stamina case in Italy, and we will examine this issue in greater detail in our next post.

The second concerns a hospital or ‘medical practice’ exemption – which allows for medicinal products containing stem cells to be made available to an individual patient in a European hospital under the exclusive professional responsibility of a doctor (EMA, 2010). The treatment is usually a custom made product using the patient’s own cells that are prepared on a non-routine basis adhering to specific quality standards (EMA, 2010). Within the EU, the hospital or medical practice exemption is only authorised for use by the regulatory authority of the member state where the product is made (EMA, 2010).

The regulation of unproven stem cell therapies in Australia

Within Australia, a similar medical practice exemption exists and is being exploited as a means to offer unproven stem cell therapies using a patient’s own cells (called autologous stem cell therapies) for payment. This has created an explosion in the private stem cell therapy market (Munsie and Pera, 2014), and raises three key questions:

  1. Should stem cell therapies be classified as a medicinal product subject to stringent regulatory oversight or continue to be the object of a medical practice exemption?
  2. How much manipulation does it take to classify a stem cell-based intervention as a medicinal product?
  3. Should Australia’s regulatory focus take its lead from EMA and the Federal Drug Administration (FDA) and be concerned about the use of a patients’ own cells, where the intended use of those cells is different to their normal function in the body?

The Therapeutic Goods Administration (TGA) is responsible for regulating the safety and efficacy of medicines, medical devices and the manufacturing and advertising of therapeutic goods in Australia. In 2011, the TGA introduced a biologicals framework to specifically regulate human cells and tissues based products, with ‘biologicals’ defined as ‘a thing made from, or that contains, human cells or human tissues, and that is used to: treat or prevent disease, ailment, defect or injury, diagnose a condition of a person, alter the physiological processes of a person, test the susceptibility of a person to disease, replace or modify a person’s body parts’ (TGA, 2015). Products and practices fall under three categories of use:

  1. Biologicals regulated under the biological regulatory framework, including human stem cells, tissue and cell based products, such as skin grafts (TGA, 2015).
  2. Products regulated as therapeutic goods, but not as biologicals, such as biological prescription medicines eg vaccines or haematopoietic progenitor cells (TGA, 2015).
  3. Products not regulated as therapeutic goods, such as assisted reproductive technologies and bone marrow transplants and certain other exempt goods and practices (TGA, 2013; TGA, 2015). For example, all autologous cells and tissues from a patient that are taken and used under the supervision of a medical practitioner who is caring for that patient, for a single indication in a single course of treatment are excluded from having to comply with the rigorous standards imposed by TGA (TGA, 2013).

This means that all unproven autologous interventions marketed as ‘stem cell therapies’ fall outside the remit of the TGA, as they are not considered to be therapeutic goods as specified under the Therapeutic Goods Act 1989 and its amendments, but a part of a medical practice exemption. Within Australia, this exemption enables an individual clinician to use autologous stem cell therapy to treat an individual patient, for conditions and procedures that would not otherwise be permissible without extensive regulation or where there is no clear evidence for efficacy. No regard is paid to the degree of manipulation of the cells, how invasive the method of delivery is or whether the intended use is homologous ie consistent with the inherent biological capacity of the isolated cells. In addition, some of these cellular therapies are being sold, most often without first having been evaluated through proof of principle, pilot clinical study data or through a clinical trial process. Concerned about these practices, the TGA has recently conducted a public consultation on how autologous stem cell therapies should be regulated.

What does the FDA say?

The recent Regenexx case (USA vs Regenerative Sciences) in the US prompts some complex questions about the regulation of unproven stem cell therapy in other countries. The fundamental question raised by Onel, Hinckle and Bolin is whether a procedure that harvests a patients stem cells from their own bone marrow for re-injection into the patient for the treatment of joint, muscle or bone pain constitutes the practice of medicine or manufacturing of a drug or biological product?

Regenerative Sciences was a Colorado clinic run by doctors Christopher Centeno and John Schultz, who used a procedure called RegenexxTM to treat joint, muscle and bone related conditions with autologous stem cells (Chirba & Noble, 2013). Drs’ Centeno and Schultz were the majority shareholders in Regenerative Sciences, and licensed the Regenexx procedure to the clinic. The Regenexx procedure involved taking mesenchymal stem cells (MSC) from blood and bone marrow samples from patients at the clinic, and then transporting the cells to their Regenerative Sciences business where the autologous stem cells were isolated and cultured to create more cells for therapy (Chirba & Noble, 2013). Once the cells were expanded for therapy they were transferred to the Colorado Genetics Laboratory for visual inspection for the presence of abnormalities. The laboratory would return the cells to the clinic four to six weeks after extraction, for them to be re-injected into the patient (Chirba & Noble, 2013).

Regenerative Sciences maintained the position that the Regenexx procedure constituted the practice of medicine, and was therefore outside the remit of the FDA (Cyranoski, 2012). However, the FDA took the view that the Regenexx procedure more than minimally manipulated the stem cells and therefore did not meet the medical practice exemption (Cyranoski, 2012). The Court suggested that the Regenexx procedure exceeded the mere processing of cells in that the procedure changed their relevant biological and physiological characteristics.

According to the FDA the stem cells offered by the Regenexx procedure constituted an ‘adulterated’ and ‘misbranded’ drug and biologic under the relevant regulation. Within this case the autologous stem cells were deemed to be a drug because they were ‘intended to affect the structure or function of the body’ (Chirba & Noble, 2013). They were also considered to be a biologic because like ‘therapeutic serum, blood, blood component or derivative, protein or autologous product …it is applicable to prevention, treatment or cure of a disease or condition in human beings’ (Chirba & Noble, 2013).

By framing their procedure as a medical practice, Regenerative Sciences sought to obscure the process, systems and techniques involved. By examining what constitutes a medical practice, as the FDA did in this case, rather than taking it at face value, we can gain a better understanding of the complexity of the procedure.

Medical practice vs advanced therapies

In light of the FDA decision and EMA legislation, we would argue that Australia also needs to unpack the meaning behind ‘medical practice’ in the current medical practice exemption that governs the use of autologous stem cell use in Australia. By closely examining the process we should attend to the degree of manipulation in stem cell therapies, as well as intended use. Like the EU, in Australia there needs to be a regulatory distinction made between ‘advanced therapies’ and less risky therapies.

Australian regulation should follow the lead of countries in Europe and North America, and institute a strong framework that differentiates between the different levels of cell products. It is only with strong safeguards in place that prioritise patient safety that unproven stem cell therapies can be given any sort of legitimacy. The current medical practice exemption in Australia places patients at risk. Other jurisdictions, such as the EU provide an ideal model that Australia should follow.

Notes, references and acknowledgements