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Umbilical cord blood (CB) banking and therapeutic use raise several ethical issues: medical indications, legal framework, public versus private biobanks, autologous versus allogeneic use, ownership, commercialisation, quality assurance and many others. Surrogate informed consent is one of the most notable controversial ethical issues. The aim of this study was to analyse and compare informed consent forms for CB collection, storage and use in the 18 accredited biobanks of the Italian Network.
The first part of the article gives a brief overview of the scientific framework, the comparison of allogeneic and autologous use and Italian regulations. In the second part the contents of the consent forms from the 18 Italian biobanks are compared with the “NetCord-FACT International Standards for Cord Blood Collection, Banking, and Release for Administration”.
Most of the Italian consent forms differ significantly from the NetCord-FACT Standards, with regards both to formal and substantial aspects.
Italian forms for CB collection, storage and use need standardisation to meet international criteria.
Until the beginning of the 1990s bone marrow was the only source of stem cells used for transplantation and leukaemia was the only disease treated by means of transplantation. In 1989 the first umbilical cord blood (CB) transplant performed by Elaine Gluckman and collaborators was described in the New England Journal of Medicine1. CB transplantation is now successfully used to treat myeloid leukaemia, lymphatic leukaemia, lymphoma, myelodysplasia, aplastic anaemia, haemoglobinopathies, thalassaemia, metabolic storage diseases, immune deficiency, autoimmune diseases and other diseases2,3, both in paediatric4 and in adult patients5,6.
In order to provide suitable CB units for transplantation, biobanks have been developed to collect, process and cryopreserve CB. Optimal techniques are critical to ensure the appropriateness, quality, safety and potency of the transplant. Over 400,000 CB units are now stored in more than 100 public biobanks in the world7.
Public banks collect CB that has been altruistically donated for haematopoietic stem cell transplants, similar to bone marrow donation8.
The Italian Bone Marrow Donor Registry (IBMDR)9, located in Genoa, participates in a worldwide collaboration with international registries to find suitable matches for patients who require a haematopoietic stem cell transplant.
The chance of using one’s own CB is very low: estimates are imprecise but range from 1:2,500 (0.04%) to 1:200,000 (0.0005%)10. Patients who need a CB transplant, indeed, need cells from a donor, not their own blood cells to cure their disease. Autologous CB transplantation is not effective for clinical treatments predominantly because CB usually carries the same genetic defect as the patient’s. CB transplantation cannot, therefore, be used to treat genetic diseases such as leukaemia, haemoglobinopathies, immune deficiencies and storage disorders. Moreover, a CB unit contains too few cells: usually it is suitable for a child of 20–30 kg of body weight. If the individual is heavier more than one unit is necessary.
At the moment no clinical protocol of tissue regeneration (e.g. in myocardial infarction, Alzheimer’s or Parkinson’s disease) with autologous CB is effective.
At present, “the most optimistic view is that there are infinitesimal chances for the clinical indication to occur where a transfusion of a child’s own umbilical cord blood would be therapeutically effective (…). It is therefore clear that currently there is no indication for transfusion to a child from preserved placental blood derived from that child’s own umbilical cord. Advertisements for creating such banks are intentionally ambiguous regarding the absence of an indication and the potential future use of the properties of stem cells”11.
Collecting and keeping a baby’s cord blood may be recommended if one of the baby’s parents or siblings have a disease that can be treated by CB transplantation. In all other cases donating CB to public banks is highly recommended by several scientific organisations, who have published position statements. For example, according to the French National Consultative Ethics Committee for Health and Life Sciences, “Preserving placental blood for the child itself strikes a solitary and restrictive note in contrast with the implicit solidarity of donation. It amounts to putting away in a bank as a precaution, as a biological preventive investment, as a biological insurance, whereas the true usefulness of the action in the present state of scientific knowledge, may be negligible”11.
Despite the scientific evidence, the business of personal storage of CB has grown considerably. Aggressive marketing by banks offering private collection and storage of CB tries to convince parents to consider storing their newborns’ CB for possible future use. Several scientific organisations at national and international level have published position statements discouraging autologous conservation.
The scientific arguments against autologous commercial CB banking can be summarised as follows12:
In 2005 the U.S. Committee on Establishing a National Cord Blood Stem Cell Bank Program highlighted some ethical and legal key issues in informed consent for CB collection and storage13. Recommendations from the Committee include the need for clear policies about:
Moreover, the Committee recommended adequate policies about disclosure of information regarding screening and other risks, maintenance of donors’ records and patients’ privacy and uses for research purposes.
Informed consent should generally cover all aspects of the collection, quality assessment, storage and release procedures. Particular attention to risks (physical, social and financial) is recommended. Most CB banks consider the mother’s surrogate consent for the newborn sufficient. Some authors have argued that parents of the newborn should consent to CB donation when sensitive personal information is collected for the purpose of protecting the recipient from infectious and genetic diseases14.
In Italy the storage and use of CB are regulated by a specific ministerial decree, finally defined at the end of 200915.
The Italian regulation foresees four possible scenarios for the conservation and use of CB stem cells: allogeneic (in which the recipient is different from the donor); dedicated for newborns who suffer from a disease included in the official lists of pathologies that can be treated by haematopoietic stem cell transplantation; dedicated for families at risk of generating children affected by a disease included in the official list; autologous-dedicated in the case of pathologies at present not included in the official list but potentially curable by means of haematopoietic stem cell transplantation according to strong scientific evidence. In these conditions CB collection and storage in public biobanks are voluntary and free, that is, the expenses are charged to the National Health Service.
Allogeneic donation is anonymous. Dedicated and autologous-dedicated banking are allowed upon adequate clinical documentation.
The regulation of CB donation and use is complex and to analyse it in detail is not the aim of this article. Instead we want to delve into the issue of informed consent, which, as seen before, is essential to define the relationship between the bank and the donor, and thereby evaluate the quality of the bank’s work. For these reasons we think it is useful to compare the informed consent forms currently used in Italian banks with the more recent international standards.
The fourth edition of the “NetCord-FACT International Standards for Cord Blood Collection, Banking, and Release for Administration” (Standards) is a collaborative effort between NetCord, the international cord blood banking arm of EuroCord, an international registry for the European Group for Blood and Marrow Transplantation (EBMT), and the Foundation for the Accreditation of Cellular Therapy (FACT).
The mission of NetCord is to promote high quality CB banking and clinical use of umbilical CB for allogeneic stem cell transplantation, while the mission of FACT, founded in 1996 by its two parent organisations, the American Society for Blood and Marrow Transplantation (ASBMT) and the International Society for Cellular Therapy (ISCT), is to promote quality medical and laboratory practices of cellular therapy through its peer-developed standards and voluntary inspection and accreditation programme16.
Among other recommendations, section C4 (dedicated to informed consent about “Cord Blood Donor Management and Collection Standards”) of the cited Standards lists the following as essential elements of informed consent:
In our study we analysed the informed consent forms of the 18 biobanks accredited in the Italian public CB biobank network. The forms were obtained through the Italian National Blood Centre, in cooperation with the Italian National Transplant Centre, which is, according to the law, responsible for the organisation and surveillance of the Italian Network. The forms came from the following biobanks:
We compared the forms from these Italian banks with the previously mentioned Standards. From a methodological point of view, when a point of the Standards is not explicitly present in the Italian forms, for example because it is considered “obvious” or “tacit”, we assumed it as missing. As a consequence, a form can be formally incomplete even if used and useful in concrete clinical practice according to the substance of FACT guidelines.
All 18 public biobanks have forms for general (non-specified) donation, while four banks also have a specific form for family donations, eight banks have a specific form for dedicated donations, two banks have a specific form for autologous donations and one bank has a specific form for preliminary consent. As a result, in the Italian Network 29 different forms for all possible types of donation are available. In two cases the same form can be used to give consent to a family, a dedicated or an autologous donation.
Seventeen banks explicitly require the informed consent from the mother, while in one case it is not specified who (mother or father) must sign the form. In five cases informed consent is required from both the mother and, when available, the father: within these, in one case, if the father does not sign the form, his consent is assumed as tacit, while in another case the part of consent about collection of reference and maternal samples does not require the father’s consent.
The other aspects of the informed consent are listed below, with the number of banks incorporating the particular item and in which types of forms:
Besides the NetCord-FACT items, a few items specific to Italian forms deserve attention:
Our analysis shows that only a few items of the FACT Standards are present in the Italian forms. This does not necessarily mean that the forms do not meet the FACT’s requirements: at least two Italian banks (Milan and Pavia) are FACT accredited. No form contains all the FACT’s points. Indeed, only four items are present in almost all the forms (27 or 28 of the total of 29 forms): (i) informed consent from the mother, (ii) the possible risks of CB collection, (iii) collection of reference and maternal samples for clinical and/or genetic testing and (iv) confidentiality of information. Six other items are included in more than half the forms (between 15 and 22 of the 29 forms: (i) the overall purpose of the collection, (ii) the intent of the donation for either unrelated or directed transplantation, (iii) the mother asked to provide a personal and family medical history, (iv) personnel can review the medical records of the mother and infant donor, (v) reference and maternal samples stored for future testing and (vi) possible uses of the unit for purposes other than clinical transplantation. Thus the majority of voices important, according to FACT, for obtaining consent that is truly informed are present in less than half of Italian consent forms.
On the other hand there are some specific items in Italian forms that are not included in the FACT Standards. Among them, the following seem particularly interesting.
In the forms from 17 banks it is clearly stated that there are no costs for donor, and all the banks declare the donor has no rights to or advantage from the donation; it appears important for Italian banks to clarify donors’ rights and duties.
Another peculiar item of Italian consent forms is the stated possibility, when required by circumstances, to not proceed to the collection even though consent has been expressed (13 banks/18): the bank has no obligation to do it anyway. In 3 forms from 2 banks is also specified that the collection will be made according to the priorities of the delivery room’s staff. It is, therefore, important that the rights and duties of the banks are also expressed.
Two forms (from the same bank) refer to the Convention on Human Rights and Biomedicine (by the Council of Europe), to the Declaration of Helsinki (by the World Medical Association) and to the Universal Declaration of Human Rights. This does not mean that the other banks disregard ethics and human rights. Actually, these documents are very general and do not apply directly to the specific case. Moreover, the Declaration of Helsinki has been developed “for medical research involving human subjects” (art. 1): although the Declaration includes “research on identifiable human material and data” (art. 1) it is not directly enforceable in the case of collection, storage and transplantation for therapeutic purposes.
Only one form outlines the problem of legal ownership of donated CB units and their duration of storage.
In general, little attention is paid to the role of the father, if not requiring his consent to the donation, at least assessing his possible objections to it.
Another important missing item is the time of informed consent, which should be given, according to FACT Standards, during pregnancy, before labour, when the mother can concentrate on information. This is probably taken for granted, like discussing the concepts with the mother in understandable language and giving her the opportunity to ask questions.
All the banks describe the risk of donating CB, but almost none describes the possible benefits or alternatives to collection (2 and 1, respectively).
In brief, the main gaps in Italian consent forms can be divided into two groups: those involving important ethical principles and those involving important formal aspects.
The former group includes:
For these reasons the National Blood Centre, the National Transplantation Centre and the Bioethics Unit of the National Institute of Health are developing, in co-operation with the ITCBN, a standardised informed consent format for the collection, storage and allogeneic use of CB. For samples unsuitable for therapeutic use, the form includes the possibility of donating for research purposes. The aim is to provide all ITCBN banks with a common instrument for assessing the issues analysed above, even though every centre will conserve the faculty to adapt it to its specific situation.
The authors are very grateful to the personnel of the Italian biobanks (listed in the paragraph “The Italian forms”), of the National Blood Centre and of the National Transplant Centre who kindly provided the forms and agreed to the study.