Researchers working at universities or in independent research centers cannot by themselves change the fate of the sick. They can identify crucial mechanisms underlying a disease and find out how to correct them; they can test their intuitions in vitro and in animal models, they can even perform the first stage of a clinical trial, if they find the appropriate funding, but, especially when it comes to innovative therapies, they will never be able to bring the treatments to all those who need them.
Working with the pharmaceutical industry becomes necessary at some point: however, how can we prevent this support from interfering with research freedom, from influencing research for purely commercial purposes?
Dialogue is needed
"With regard to innovative therapies, which we deal with at the HSR-TIGET, the question is always tricky, but not as crucial as for trials involving the so-called blockbusters, i.e. medicines for very common diseases which attract stronger financial interests" says Luigi Naldini, Director of the Telethon Institute in Milan. «In the field of rare diseases, the challenge is how to get the pharmaceutical companies involved; they are essential for the development and marketing of treatments, even if these treatments do not guarantee a great return on investment, while involving a number of difficulties relating to their characteristics: in fact, they are often not just medicines to be administered by mouth or intravenously, but special treatments that require cells and genes manipulation».
Knowing that at the end of the process, in exchange for their investments, they will not have a simple product to be packaged and displayed on pharmacies' shelves is an additional obstacle for companies. «While, sometimes even researchers and clinicians find it difficult to understand each other on these issues, doing so with industry representatives is even more difficult », admitted the researcher. Yet dialogue is essential, although even the legislation struggles to keep up with scientific advances and is designed and developed for traditional drugs.
«An example? Industry representatives wonder: 'How can we market a product that has not been sterilized? How can we take on this responsibility and assume liability for any legal consequences?But the cells cannot be sterilized», says Naldini. Indeed, we use viruses in order to introduce in the cells the genes that will alter them so that they can treat the patient. And for the purposes of the authorization procedure, the "drug" is the cell itself so manipulated, which can also take the designation of "orphan drug", which is required to take advantage of the benefits available to treatments for rare diseases.
«The whole process should be reviewed in light of these new therapies», adds the researcher: «The study of the drug biodistribution and its toxicity, for example, in this case cannot be studied on the animal model as is the case for traditional medicinal products»
The whole question should therefore be reviewed collectively by researchers, the authorities and the industry. «We must acknowledge, however, that European regulators, compared to those overseas, have shown greater openness, which allowed us to obtain some important results in this area. Probably the fact that most of the research originated from the academia, and the lesser weight of the industry on this side of the Atlantic, assured regulators that the trials were not conducted for purely financial purposes», says the researcher.
From Telethon to GlaxoSmithKline
Naldini, who was recently invited to become a member of the Committee for the International Rare Diseases Research Consortium, IRDiRC, in recent years has obtained important results working with his group.
The most significant HSR-TIGET clinical success to date concerns the rare congenital immunodeficiency called Ada-SCID, which forces children to a total aseptic isolation because even the most trivial infection can be lethal for them. This condition is extremely rare, but the gene therapy developed by HSR-TIGET, the San Raffaele-Telethon Institute in Milan, was included in the list of the ten most important scientific discoveries of 2009 in the annual ranking compiled by Science. Before this discovery, the only possible treatment was a bone marrow transplant, provided that a compatible donor could be found. The treatment developed in Milan, instead, envisages taking the stem cells from the patient, correcting the inherited genetic defect via a viral vector to insert normal genes into their DNA and the reinfusion of the cells thus manipulated. There is no need for a donor and the results are sometimes even better. "In this case, it was only thanks to funding from Telethon that we were able to carry out the early I and II trial stages, to demonstrate the safety and efficacy of the treatment" explains Naldini. "But for the next steps we still need the support of a company."
Meanwhile, in the laboratories on the outskirts of Milan, researches were studying the option of using a different vector on two other rare diseases: Wiskott-Aldrich syndrome, in which lymphocytes are altered because of an abnormality in a protein involved in the operation of the cytoskeleton, and metachromatic leukodystrophy. The latter is not an immune deficiency, but a disease that affects the central nervous system, against which not even the bone marrow transplant can be used.
«A couple of years ago all this attracted the attention of an international pharmaceutical giant, GlaxoSmithKline, which at that time was considering an investment in the field of rare diseases», says the director of the Milan centre. The reasons for such a choice from a business perspective are various: ethics and image, of course, even in the wake of the strong pressure that the Associations for rare diseases are currently exerting on public opinion, but also a forward-looking scientific approach.
«The therapies in this field, in fact, do not offer the same market prospects as those developed for example for cancer», says Naldini, «but they are a valuable testing ground due to their linearity: while cancer development is determined by many factors, rare hereditary diseases usually depend on a single genetic defect which, if corrected, may lead to recovery. Once established the efficacy of a therapeutic strategy in this field, one can then study how to extend it to other diseases.»
Thus, GlaxoSmithKline purchased the rights to this therapy in the more advanced stage, that for Ada-Scid, and put an option on the results of the other two, in exchange for ten million euro to fund research on other genetic conditions, including beta thalassemia
New rules for a new reality
«Research independence shall not be affected by this support», concludes Naldini. «We keep control of the project and remain owners and managers of current trials. The Company will be responsible for managing the trials in the later stages, those that are most subject to sensitive and complex regulatory issues, once it has exercised the option and the possible exploitation of the process, if it proves successful».
Researchers, in fact, do not have all the necessary skills to deal with the complex rules provided for clinical trials in the more advanced stages. Standards that help ensure the safety of research, but which may complicate its implementation, with the risk of depriving patients of valuable therapeutic resources. «According to today's regulatory framework, life-saving treatments such as the bone marrow transplant would never have been allowed to undergo trials» adds the researcher. « On the other hand, it is understandable that the new frontiers of research and the genetic manipulation involved, raise concerns that cannot be underestimated».
If the game changes, so should the rules, taking into account, on the one hand, that genes and cells can become drugs, and, on the other, that between the non-profit research and industry-sponsored research collaboration is growing, still to be shaped, but a factor to be increasingly taken into account.