Ethical issues and concerns about the use of biosimilar granulocyte colony-stimulating factors for the mobilisation of stem cells in normal donors

Dear Sir,

We read with interest the position statement of the Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) on the use of biosimilar granulocyte colony stimulating factors (G-CSF, filgrastim) for the mobilisation of stem cells in normal haematopoietic stem cell donors which was recently published on the SIMTI website¹. SIMTI and the Italian Bone Marrow Donor Registry (IBMDR) share the concern of the World Marrow Donor Association (WMDA) about the use of biosimilar G-CSF in donors of haematopoietic stem cell for allogeneic transplantation².

Recently, several similar biotherapeutic filgrastim products have become available on the market at lower cost than their reference therapeutic products, whose patents have expired. These products are manufactured using separately developed and similarly proprietary processes. Although a similar efficacy for primary licensing indications was demonstrated, “differences in their ultimate clinical efficacy, adverse event profile and immunogenicity” cannot be excluded and, “because of these possible differences, late-effects may also vary”². “As the efficacy for mobilization is extrapolated, with little safety analysis and no long-term follow up, the WMDA recommends that biosimilars not be used for mobilization in normal donors unless the donor is followed on a study (…). Only when comprehensive data to confirm long-term safety and efficacy is available should use of G-CSF biosimilars be considered routine²”.

The therapeutic equivalence of G-CSF biosimilars has been extrapolated to all the indications of filgrastim, including peripheral blood stem cell mobilisation and transplantation, even though they have been granted marketing authorisation on the basis of results of studies in cancer neutropenia³.

Key concepts and critical issues on biosimilars have also been conveyed in a position paper by the Italian Society of Hematology (SIE), the Italian Society of Experimental Hematology (SIES), and the Italian Group for Bone Marrow Transplantation (GITMO)³. SIE, SIES and GITMO state that the “evaluation of the appropriate use of a biosimilar in clinical practice, as for any new drug, should be based on a critical appraisal of the benefit/cost ratio, grounded on the evidence of efficacy and tolerability, in particular on the documented equivalence between the biosimilar and the reference product³”. They also state that a patient who is well treated with a particular filgrastim (independently of cost and whether it is an originator or a biosimilar) should not undergo a change in treatment for purely economic reasons. In addition to the importance of the full awareness of all the decision elements by the professionals who use biosimilars, the above scientific societies stress the role of the traceability of the prescriptions of these drugs for an effective pharmacovigilance. For this reason the current International Non-proprietary Name system (which gives the same name to drugs with the same active ingredient, irrespective of their productive process) should not be used in order to ensure that adverse events are assigned to the correct product.

Over the past decade, a major shift has occurred from bone marrow to cytokine-mobilised peripheral blood stem cells as the prevailing source of allogeneic haematopoietic cell grafts. Although haematopoietic stem cell donors generally recognise that the donation of peripheral blood stem cells is not risk-free, it is the responsibility of the transplant community to understand these risks, to minimise them and to provide donors with exhaustive information, keeping in mind that the health and well-being of the donor must be a priority.

There is a large amount of literature on the ethical value of the donation of blood. The provocative book “The gift relationship: from human blood to social policy” published in 1970 by British social scientist Richard M. Titmuss is a well-known source for this topic. Blood and haematopoietic stem cell donation are strong forms of solidarity. Solidarity, considered as a perception of mutual obligations between the members of a community, is deeply rooted in human experience and thinking. Solidarity is also a core value of many National Health Services. The literature distinguishes between “benevolent solidarity”, in which the donor can also be one of the beneficiaries, and “altruistic solidarity”, in which only other people benefit from the donation: blood and haematopoietic stem cell donors make a humanitarian gesture rewarded solely by feelings of altruism. According to “The short Routledge encyclopedia of philosophy”, “solidarity exits among a group of people when they are committed to abiding by the outcome of some process of collective decision-making, or to promoting the well-being of other members of the group, perhaps at significant costs to themselves”. Nevertheless, the prospect of asking healthy donors to assume potential and unassessed additional “costs” (in this case: physical risks) as part of their donation raises important ethical issues that we would like to address.

At present, it is unknown whether the safety profile of reference biotherapeutic products for the mobilisation of peripheral blood stem cells in normal haematopoietic stem cell donors can be extended to biosimilars. From an ethical perspective, two main elements should be considered under these circumstances: (i) risk management; (ii) decisions regarding allocation of resources.

1. The donation of any type of blood or cells must never jeopardise a donor’s health beyond standard risks for the blood and cell collection. As insufficient evidence from safety analysis and long-term follow up is available, donors treated with G-CSF should be considered human research subjects without the prospect of clinical benefit and with the potential to improve health and well-being for others. Translated from the World Medical Association’s Declaration of Helsinki, the priority principle applies to the health and well-being of the donor (article 6). This principle takes precedence over the interests of science and society. All major ethical codes and documents are unequivocal on this point.

   Moreover, potential risks due to biosimilar G-CSF (for which available scientific data are insufficient and uncertain) would require a cautionary approach. In bioethics, the precautionary principle is an action principle applied to deal with potential risks for which available scientific data are insufficient, uncertain or contradictory. Precaution has become crucial in medical ethics. Indeed, some authors have juxtaposed the so-called “principles of bioethics” (autonomy, beneficence/non-maleficence, justice) to three other principles: dignity, precaution, solidarity. In this perspective, we should take the centrality of the precautionary principle as a starting point for medical ethics. As the UNESCO Universal Declaration on Bioethics and Human Rights states: “In applying and advancing scientific knowledge, medical practice and associated technologies, direct and indirect benefits to patients, research participants and other affected individuals should be maximized and any possible harm to such individuals should be minimized”.

2. Nevertheless, the situation of volunteer donors is different from that of most other research subjects because donors are asked to donate haematopoietic stem cells for patients who are known to have life-threatening disease. The donor’s “benefit” is altruism: donation of blood and cells can only be justified as a free and disinterested expression of solidarity. Solidarity is perceived as a caring and generous attitude towards other people, as putting others’ best interests before one’s own, with no expectation of reward. Non-market values, such as altruism and solidarity, need a suitable environment. Procedures should be established to ensure both timely donation of high-quality haematopoietic stem cells and adequate safeguards for donors. Concern over the optimal allocation of health care resources has become increasingly acute in an era of rising medical costs and cost-containment. Control of pharmaceutical spending has been one of the important cost-containment measures introduced by recent Italian health care policy. Curtailment of public expenditure should not threaten the safety of the patient (and donor), which is “central to the clinical governance framework”: “The allocation of healthcare resources should aim at and be justified by the improvement in people’s health (…). Improving health should be the primary goal”. As the World Medical Association Declaration on the Rights of the Patients states: “choice must be based on medical criteria”⁵.

In conclusion, we thoroughly agree with SIMTI, SIE, SIES, GITMO and WMDA position statements, believing that the choice of using biosimilar G-CSF is not justifiable by a cost-containment policy and is in contrast with the priority principle of protecting those allogeneic haematopoietic stem cell donors who, with their donation, contribute greatly to providing transplant recipients with the essential levels of health care that the National Health Service must deliver them.