Authorities in the field, including Australian cell therapy pioneer John Rasko and UCL expert Chris Mason, have authored a guide claiming regional loopholes are allowing under regulated manufacturing and administration of unproven biologics.
The guide claims regulation varies between countries and types of cell therapy, creating confusion. While many unproven drugs are offered in under-regulated regions (a destination for “stem cell medical tourism”), there has also been an increase in unproven cell therapy use in “countries with strict regulation but untightened loopholes.”
The unproven cell therapy industry is worth up to $2.4bn, made up of 60,000 patients a year, some of whom pay $40,000 per treatment, say the authors. This estimated market “does not account for the considerable psychological and potential physical harm to patients and families through raising and dashing hopes of a ‘cure’ that has little or no real benefit.”
“Unproven cellular therapy has the possibility of tarnishing the reputation, business case for, and thus potential of proper cellular therapy treatments in the minds of patients and investors alike,” said Daniel J. Weiss, ISCT Chief Scientific Officer.
There is no official definition of an unproven cellular therapy shared by all regulators, but ISCT says a lack of proper clinical trials and regulatory supervision are all warning signs.
Is this cell therapy unproven? ISCT’s checklist:
- unclear scientific rationale to suggest potential efficacy
- lack of understanding on the mechanism of action and/or the biological function to support clinical use
- insufficient data from in vitro assays, animal models, and clinical studies regarding the safety profile to support the use in patients
- lack of a standardized approach to confirm product quality and ensure consistency in cell manufacturing
- inadequate information disclosed to patients to enable proper informed consent
- use within non-standardized or non-validated administration methods
- uncontrolled experimental procedures in humans
These unproven cell therapies can be based on prenatal and adult stem cells (including induced pluripotent cells and mesenchymal stromal cells).
It is relatively easy to access stem cells from marrow, adipose, cord blood, and other human tissues, and commercially available tools like reagents and manufacturing devices are becoming cheaper. There are also fewer limitations on IP rights cell-based technology methods than in small molecule drug development.
Manufacturing: global rules needed
ISCT’s document warns the widely differing levels of regulation on biologics manufacturing can harm patients and the industry.
“Complexity exists because in many countries regulations about manufacturing are related to the degree of manipulation of the product, independent of the clinical use of the product.
In some cases, says the report, large molecule manufacturing occurs in a region that is covered by one set of regulations but is independent of regulatory controls at the location of clinical treatment. Even some “competent authorities” have not established any specific regulations for large molecule production, say the authors.
Beliefs about what constitutes manufacturing are another problem. “For example, if a product requires less complex manufacturing (or “minimal manipulation”), as long as the correct manufacturing regulations are followed, clinical use in any disease indication is permitted. This is similar to the ‘off-label; use of licensed drugs prescribed for different indications.
This means that some doctors claim the handling of the cellular product is part of the practice of medicine (because production is simpler than for small molecule drugs, or because the therapy is autologous), and therefore no manufacturing is occurring.
“This viewpoint is generally not supported by many regulatory authorities,” says ISCT. “It also should not negate the applicability of external accreditation for assurance of high quality operations for the handling of cell therapy products.”
As well as manufacturing regulation, the guide points out the lack of clinical oversight and data collection in some cases:
“[…] providers of unproven cellular therapy can produce poor-quality articles in journals that lack robust scientific peer-review and persuade some research ethics boards to provide approval for unsuitable research. Consequently, this can allow some clinics to register studies in proper clinical trial databases.”
The organisation is calling for standards on reporting the success or failure of these drugs, including peer review, and a clearer global consensus on what evidence is needed to show a therapy is safe and efficacious.