Scientists raise alarm as Italian Government rules on unproven stem cell therapy

An unproven stem cell therapy has taken centre stage in Italy after patients successfully lobbied the Italian government to allow its use in public hospitals. The highly controversial and untested procedure was created by the privately owned Stamina Foundation, but blocked by the Italian Medicine's Agency, AIFA. Last week's decision by the Ministry of Health to override AIFA's block has horrified Italy's leading stem cell scientists. In a letter to the Ministry, they describe the decision as providing "a dangerous short circuit between patients' hopes and lucrative commercial practices" of organisations operating outside the "scientific and moral foundations" of medicine.

 

   

 

The Stamina Foundation describes its treatment as based on mesenchymal stem cells and claims to be able to treat a whole host of diseases, from spinal cord injury to motor neurone disease. But scientists warn that there is no evidence to suggest the treatment could work and no way to know that it will not cause harm. Although the Stamina Foundation claims to have treated around 80 patients, the outcomes of these treatments have not been published, nor have the details of the method used to prepare the cells. Professor Michele De Luca, a trained medical doctor and internationally recognised stem cell biologist based at the University of Modena explains:

"Mesenchymal stem cells are skeletal stem cells. They can only generate cells of the bone, cartilage and fat. So, not only is there no evidence that mesenchymal stem cells could cure all these completely unrelated diseases, but there is not even a reasonable rationale for suggesting such a thing. On top of this, there is an EU regulation stating clearly that any cells that will be used to treat patients must be grown in a way that meets a strict set of standards called GMP. The Stamina Foundation has not grown the cells under GMP conditions and did not have approval to carry out a trial. Despite this, the cells have been given to patients in a public hospital."

The therapy has been repeatedly banned in recent years, including a block from the Italian Medicines Agency, AIFA, which carried out an inspection of the Stamina Foundation's laboratories and closed the labs down, stating that they could not be trusted to produce contamination-free cells. This led to a series of legal challenges by parents hoping to obtain the treatment for their children. They were supported by a high profile public campaign by prominent Italian celebrities aiming to overturn the regulatory block.

Several of the judges overseeing the legal cases ruled that the treatment must be made available based on an Italian law allowing compassionate use of medicines. This law permits the use of unproven therapies on an emergency basis for patients who are dying and have no other treatment options. It also requires the health service to provide these therapies free of charge to patients. However, the law does require that the health authorities approve the quality of any such therapies and the exact terms on which this decision should be made are not clear.

The Italian government's Ministry of Health nominated a Committee to examine the issue of the Stamina Foundation's therapy. On 7th March, the Health Minister Renato Balduzzi went against the decision of the regulatory authorities and permitted use of the Foundation's procedure in a terminally ill three year-old. He appeared to be on the brink of announcing a decree to make the treatment more widely available, prompting a group of 13 leading Italian stem cell biologists to speak out in protest. The researchers wrote a letter (available in full with a list of signatories below) urging the Ministry to reconsider its position and arguing that permitting use of this untested treatment would be dangerous, irresponsible and "a disgraceful event". They wrote:

"The decision seems to be dictated by emotions raised by public opinion rather than by scientifically based reasons. No scientific evidence whatsoever has been produced suggesting that mesenchymal cells may have any effect on those diseases for which it is claimed they could be employed. Moreover, no scientific description has been given of the method by which it is claimed these cells may be obtained. This seems a real subversion of the scientific and moral foundations of medicine, denying both the dignity and the traumatic experiences of patients and their relatives. We are aware of these issues and they profoundly motivate the scientific community to generate and guarantee accepted, visible and public data that will change any potential scientific hypothesis into an accepted curative procedure."

In response to the legal debate about compassionate use of drugs, the scientists continued: 

"The freedom of any citizen to adopt any personal health decision, including the wish to refuse any cure, does not imply that the Government is obliged to authorize all medical procedures that anyone may suggest as appropriate. In fact, although the individual choice to use an imaginary or inappropriate therapy complies with the rights of individual citizens, such therapies should not necessarily be approved by the Government and provided by public or private health structures. It is not the Government’s role to respond to pressure from patients to translate an individual choice into a therapeutic option for ready use in any health structure. Media campaigns should not become instrumental in adopting decisions on medical or health procedures. The right of single individuals to adopt snake oil as a freely chosen drug does not mean that snake oil has to be prepared in hospital pharmacies as a result of Government-authorized procedures."

The hopes of patients around the world are focussed on the development of new stem cell therapies and the Stamina Foundation case has been the subject of impassioned public campaigns and extensive discussion in the Italian media. Similar cases have also caused debate in other countries over recent years. In their letter, the researchers express their fear that allowing even one therapy to operate outside the usual regulations and controls would open the way for many unproven therapies to become available, unchecked and unregulated:

"If Government supports even one single event of an uncertified therapy proposed by an uncertified entity in an official health structure this may be considered by people as an official recognition of the therapy, i.e. a strong support for its potential uncontrolled use ... hospitals will become simply places in which anybody may administer unproven therapies. Certain commercial interests will choose “compassionate therapies” as a useful route by which to release themselves from the vigilance of rules and to extend the use of unproven therapies as a profit-making mechanism, setting a dangerous precedent."

Professor Charles ffrench-Constant, Director of the University of Edinburgh's MRC Centre for Regenerative Medicine agrees that an Italian decision to approve an unproven therapy could have a negative impact across the globe:

"These unproven and ill-prepared stem cell therapies, for which there is no scientific basis, will do nothing for patients and their families except make them poorer. For a European country that is home to some of worlds finest and most rigorous stem cell biologists to approve such an approach sends a confused and counterproductive message to the world community."

On Thursday 21st March, Renato Balduzzi went ahead and issued an official decree permitting use the Stamina Foundation's cells in 32 terminally ill patients, although the stem cells involved are not manufactured according to Italy’s legal safety standards. The regulatory agency AIFA has not commented on the decree but says it stands by its original ban. Scientists continue to express strong objections and serious safety concerns.

 

Leading scientists' comments on the Italian Government decision

Prof Austin Smith, Director of the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute: "This situation highlights the need for proper understanding of the scientific process and especially of the requirement for evidence. If politicians, doctors or patient organisations ignore the facts, they may unwittingly become party to exploitation of the most vulnerable members of society by approving meaningless “treatments”."

Prof Steve Dunnett, Co-director of the Brain Repair group in the School of Biosciences, University of Cardiff: "Many novel and unproven stem cell therapies involve significant risk and very high cost while offering no detectable benefit for desperate patients and their families threatened with life changing illnesses. As a scientist it is natural to be cautious. However our government has a responsibility to protect all citizens from unsubstantiated marketing of therapies of no demonstrated value, and has a particular duty to protect vulnerabile patients from being conned out of their savings for treatments that have no realistic hope of benefit, undemonstrated safety and potential significant risk. European law, directions and regulation provide a well established framework for determining the safety and efficacy of new treatments, including lowering the bar for novel treatments for orphan or life threatening diseases. However, when companies such as this latest example rely on personal claims of benefit, but withold access to any scientific assessment, and never publish their results on mechanisms, safety or efficacy in the properly reviewed scientific literature according to widely accepted scientific critera, then our starting position has to be that the marketing is a scam to which the correct response should indeed be to refuse a licence, and certainly not pay for a spurious 'treatment' out of the public purse. The decision of the Italian minister to ride roughshod over existing European licencing criteria, which have been establish for very sound reasons both of health and safety and of protecting patients from blatant fraud, set a dangerous precedent, perpetuating false hopes but with considerable potential to cause real harm and distress for no actual benefit."

Prof Roger Barker, Professor of Clinical Neuroscience at the University of Cambridge: "The use of unproven stem cells therapies for patients with incurable neurological diseases causes concerns at two levels. One is the exploitation of desperate patients and families seeking cures for diseases that sadly do not have one at the moment. The other is that a complication or death with this type of therapy would run the risk of essentially bringing to a stop all stem cell therapies for neurological disorders and this would include some of the more promising therapies that have a strong scientific rationale for working in patients with certain types of disorders such as Parkinson's Disease."

Prof Michele De Luca, Centre for Regenerative Medicine at the University of Modena, Italy: "Not only is there no evidence that mesenchymal stromal cells (the cells used by Stamina Foundation) can cure all those diseases, there is no rationale for this and no evidence that these procedures are not dangerous for patients. The way things are being authorized is simply illegal. These decisions conflict with European and Italian regulations and laws on advanced therapies and clinical trials. This creates a dangerous precedent. Anyone could avoid using evidence-based medicine procedures and regulations by doing what the Stamina Foundation has done - using the media and patients' hopes to exert pressure. And English, German French and other patients could start a sort of medical tourism and ask Stamina to provide them with such unproven therapies."

 

Letter to the Italian Government and its signatories

Letter by 13 leading Italian stem cell biologists, ethicists, legal and other experts IN ITALIAN (pdf)

Letter by 13 leading Italian stem cell biologists ethicists, legal and other experts IN ENGLISH (pdf)

Signatories:

  • Paolo Bianco, Ordinario di Anatomia Patologica, Direttore Laboratorio Cellule Staminali Dip. Medicina Molecolare, Sapienza Universita' di Roma
  • Andrea Biondi, Ordinario di Pediatria Generale e Specialistica, Università degli Studi di Milano Bicocca
  • Giovanni Boniolo, Ordinario di Filosofia della Scienza, Università degli Studi di Milano e Istituto Europeo di Oncologia, Milano
  • Gilberto Corbellini, Ordinario di Storia della Medicina, Università La Sapienza Roma
  • Giulio Cossu, Ordinario di Istologia e Embriologia, Università degli Studi di Milano
  • Elena Cattaneo, Ordinario di Farmacologia, Direttore Centro di Ricerca UniStem, Università degli Studi di Milano
  • Michele De Luca,  Direttore Centro di Medicina Rigenerativa "Stefano Ferrari", Università degli Studi di Modena e Reggio Emilia
  • Silvio Garattini, Direttore Istituto di Ricerche Farmacologiche Mario Negri  IRCCS, Milano
  • Alberto Mantovani, Ordinario di Patologia Generale, Università degli Studi di Milano e Direttore Scientifico Istituto Clinico Humanitas, Rozzano, Milano
  • Graziella Pellegrini, Direttore Unità di Terapia Cellulare Centro di Medicina Rigenerativa "Stefano Ferrari", Università di Modena e Reggio Emilia
  • Giuseppe Remuzzi, Direttore Dipartimento di Medicina, Ospedali Riuniti di Bergamo
  • Amedeo Santosuosso, Ordinario Università degli Studi di Pavia e giudice Corte d?Appello di Milano
  • Gianluca Vago, Ordinario di Anatomia Patologica e Rettore dell'Università degli Studi di Milano

 

Further information