Commentary: Harmonizing the Regulators

The World Health Assembly has urged Member States “to cooperate in the formulation of recommendations and guidelines to harmonize global practices in the procurement, processing and transplantation of human cells, tissues and organs, including development of minimum criteria for suitability of donors of tissues and cells” (¹). Why was it thought necessary to urge Member States to cooperate and harmonize global practices? What areas of transplantation need such approaches, and what will the consequences be if “harmonization and cooperation” meet their normal fate and prove to be unachievable?

Government regulation of both food products and medicines has become an accepted mechanism by which governments protect their citizens from products that may be dangerous. These approaches have, in more recent times, been extended to the regulation of medical or therapeutic devices, such as cardiac pacemakers and diathermy machines. Blood and the various products derived from donated blood led the way for regulation of therapies derived from human material, driven by the risks to both the individual and the community at large from the transmission of bloodborne infections. Each country has sought to reduce the risks to its population from transmission of infectious organisms through blood transfusion. Member States of the World Health Assembly have not yet achieved harmonization of their approach to blood and blood products for both good and bad reasons. For example, the United States, Canada, and Australia have approached the small potential risk of transmission of prions by preventing the donation of blood by people who have lived in the United Kingdom for certain periods of time. The U.K. does not, of course, have that option.

Regulation of transplantation of tissues (such as cornea and bone) has been implemented in many countries for some years. The general approach has been to treat transplanted tissues as if they are manufactured drugs, applying the same types of licensing processes to tissue banks as would be applied to pharmaceutical manufacturers.

Regulation of organ and cell transplantation is now upon us in many countries. Here, however, the regulators have met a different series of problems. Transplantation of bone marrow and other hematopoietic stem cells has been undertaken in hematology laboratories and hospitals throughout the world, while transplantation of organs is widely embedded within the structure of most major hospitals. Histocompatibility laboratories are also widely dispersed in university and public hospitals, as well as in blood banks and as stand-alone facilities. Most of these “targets of regulation,” instead of being large commercial manufacturers familiar to the regulator, are small not-for-profit or government-funded organizations, for which the financial impost of regulation may well seem unimaginable. Along with the financial burden, the critical shortage of skilled staff and the fact that many laboratory tests are undertaken using unlicensed products manufactured in-house (or in small runs by specialist laboratories) should give regulators cause to pause. Other differences to the blood supply “industry” include the fact that dead organ donors are, of course, not available to sign statutory declarations about their previous medical, travel, and sexual histories. Until now, the feature that has kept most regulators away from organ and cell donation is the one-to-one relationship between donor and recipient. The increasing efficiency and scope of donation of cells and tissues has, however, changed this dimension with the transmission of infectious diseases, such as West Nile Virus (²), to many recipients from one donor. The regulators in each country are moving at their own pace and within the context of the clinical practice in each country, but they are all moving in the same direction.

In the field of hematopoietic stem cell (HSC) transplantation, there is one dimension that will drive global harmonization, as failure of a coordinated approach will ensure that patients are denied the very therapy that the regulators are trying to make safer. Matched unrelated HSC donations have been an increasingly common treatment for many patients with hematological malignancy. The bone marrow donor registries have recruited and tissue typed more than 9 million volunteers worldwide, in an attempt to ensure that crucially important histocompatibility-matched donors can be found for as many patients as possible. In 2003, there were 6,025 actual HSC transplants facilitated by the 61 member registries of the World Marrow Donor Association. Of these, 3,943 were transplanted in the country of donation and 2,082 (34.5%) were transplanted in another country (³). If each of these donations must come from a manufacturer licensed by the country of the recipient of the HSC, then the Food and Drug Administration, the Therapeutic Goods Administration, and equivalent European regulators will, for example, each need to license 2,500 or more hospitals as potential HSC manufacturers. Since the majority of HSC transplant units undertake HSC harvesting for other countries as an essentially charitable contribution to the collaborative network of the World Marrow Donor Association member registries, it is hard to see why they would seek expensive and constricting licensing by multiple global regulators, concentrating instead on keeping their own regulator from shutting them down. Unless the Member States urgently and actually harmonize their approach to regulation of HSC donation, then the World Marrow Donor Association estimates that the application of multiple regulatory systems will lead immediately to a 35% reduction in access to hematopoietic stem cell transplantation therapy globally. Is this the regulators’ equivalent of an own goal?

The World Health Assembly has got it right. It will be of intense interest to patients and their doctors to see if the global regulators will take this recommendation seriously.