Practical Transfusion Medicine 4th Ed.

17. Regulatory aspects of blood transfusion

William G. Murphy1, Louis M. Katz2 & Peter Flanagan3

1Health Service Executive, Clinical Strategy and Programmes, and University College Dublin, Dublin, Republic of Ireland

2America's Blood Centers, Washington, DC, USA

3New Zealand Blood Service, Auckland, New Zealand

Introduction

Blood is an irreplaceable medicine used in life saving circumstances. Because it is necessary to source the material for this medicine from biologically and behaviourally heterogeneous humans, absolute uniformity of product and its absolute safety cannot be guaranteed, no matter how extensively we test or how energetically we process the material. Ultimately pragmatic compromises must be reached between adequate safety and adequate supply. It is by now generally accepted that each country's government must ensure that its citizens and visitors are provided with an adequate supply of safe and effective blood for transfusion as these compromises are made. The World Health Organization (WHO) has identified the importance of a well-legislated and regulated blood transfusion service as a crucial component in assuring safety [1].

However, there is at best a weak international consensus on what that responsibility implies and how it may be discharged. What is adequate in terms of supply of red cells in Canada, for example, would be disastrously inadequate in Germany. What is permissible in France may be unthinkable in the USA, and vice versa. The Food and Drug Administration (FDA) in the USA takes a substantially different position from the European Commission in deciding what donor screening assays should be done on its territory. In the USA the stringency of, and the resources needed for, the Biologics License Application (BLA) process required for approval of a donor screening test thwarts the availability of a broad menu of tests, while generally resulting in assays with superb performance characteristics. In Europe a minimum only is specified and individual blood services can and do use additional tests or technologies as they consider fit, although within Europe the German authorities (the Paul Ehrlich Institute) are as rigorous and controlling as the FDA.

Nevertheless, within each state or jurisdiction, the Government, its regulatory agencies, the blood transfusion services and the hospital blood services form a publicly accountable process that is subject to regulation and regulatory oversight to a greater or lesser degree. The degree of public accountability that gives rise to and gives legitimacy to the regulatory process is demonstrated by the scale of public inquiry in several countries into systematic failures in blood safety in the late 20th century. In several cases the regulatory agencies were found wanting to a comparable degree as the blood services they were supposed to oversee.

While there are considerable differences between medicines in general and blood components in particular, regulation tends to apply the pharmaceutical paradigm to blood transfusion services. There are, however, some critical differences between the two processes. Medicine regulation normally involves a government regulator assessing pharmaceutical products manufactured by commercial organizations. A decision to approve a new medicine in no way implies an expectation that all patients will receive it. Health organizations and individual doctors will determine what is right and affordable. Blood, on the other hand, often, though not always, involves regulation of government owned or funded entities (the Blood Transfusion Services) and decisions around safety standards are incremental; i.e. once a decision is made the standard of the component changes for all recipients. The impact of regulation and the need for good decision making is therefore particularly important for blood.

Importantly, however, research and development, which are the real drivers of quality, efficacy and safety, are generally outside the regulatory process, and except within a humanitarian and professional ethos no one is held accountable if these things are not done, or not done well.

In the field of blood transfusion, separate national regulations cover the licensing of devices, kits and other materials used in the collection of blood donations, in testing or the preparation, storage and transport of blood components. These will generally be similar to the regulations covering other medical devices and tests or manufactured items put on the market within a State. This is an important mechanism whereby governments and regulators can control standards in the blood sector.

The extent of the role of regulatory authorities can be explored through the following questions:

·        Who is responsible if there is insufficient blood on hospital shelves?

·        Who is responsible if the blood on hospital shelves is not of appropriate quality?

·        Who is responsible if the blood supply or the blood supplied does not improve in response to emerging clinical science – if, for example, it fails to be adequately modified to meet a newly emerging threat or a better understanding of clinical efficacy?

Who is responsible if there is insufficient blood on hospital shelves?

It is the people's problem ultimately and therefore, hopefully, the Government's, but the fault could lie with:

·        the regulatory agency – excess stringency in applying limits for donor haemoglobin for example;

·        the blood service – inadequate skill in reaching potential donors effectively, or in managing its supply chain or customer base, or in identifying and implementing new strategies or techniques;

·        the clinical services – excess use of blood over real need as defined by a growing evidence base;

·        the hospital blood banks – excess wastage through overstocking;

·        the Departments of Health or Finance for failing to provide enough resources;

·        Government, through poor structuring and oversight of the healthcare system.

Who is responsible if the blood on hospital shelves is not of adequate quality?

·        The Government, through the regulatory agencies, has explicit and primary responsibility. The agencies will discharge their duties and purge their fault through inspections, accreditation and sanctions, but ultimately they have the authority to ensure the public safety and they will, or should, be held accountable for failure to do so. Nevertheless, blood suppliers should also be considered to have an ethical and professional responsibility to go beyond the minimum regulatory or legal requirements in the interest of safety if the regulator does not require sufficient quality, and in any event they have a responsibility to ensure that standards are met in a consistent manner.

Who is responsible if the blood supply or the blood supplied does not improve in response to emerging clinical science – if, for example, it fails to be adequately modified to meet a newly emerging threat or a better understanding of clinical efficacy?

·        The Blood Services (and their professional societies to the degree they influence blood operations);

·        the Regulatory Agency where it takes on a role of scientific leadership, such as the FDA in the United States, the Paul Erhlich Institute (PEI) in Germany and the French Agency for Safety of Health Products (AFSSAPS – Agence Française de Sécurité Sanitaire des Produits de Santé);

·        the Government if it fails to invest in the intellectual and scientific capacity of its blood services (though it will take a major inquiry to apportion fault in this way if it exists).

An explicit and documented ‘National Blood Policy’ along the lines of the WHO's recommended approach [1], where the responsibilities of each of the stakeholders is clearly documented, and ideally captured in legislation, may be the most secure route to success in ensuring that regulation is integrated into a national approach to blood safety.

The functional components of regulation

Regulation is made up of several components:

·        Guiding principles and law. National or international law, which has the force of justice and humanity, and which is defined and enacted by legitimate representatives of the society concerned, governs the regulations of blood components in a jurisdiction. A competent system of regulation must be backed by such law, which specifies and limits the scope and power of the regulator. The law should be explicit and production of blood for transfusion in a state should be expressly governed by statute. Within the EU member states, the national statutes are subject to the Blood Directives – a set of laws developed over several years between 1996 and the present that are binding on all the member states of the Union. There is a core or parent Directive [2] and a set of subsidiary ones covering donors and donations and component specifications [3], traceability and haemovigilance [4] and quality systems [5]. Additional updates and modifications may appear in response to emerging threats or technical advances. Elsewhere national, federal, provincial and state laws almost invariably provide a basis for regulation, though in several parts of the world such laws and regulations may be merely aspirations [6].

Guiding principles may be explicit or implicit. For example, the EU specifies the otherwise-unexplained ‘Principles of Good Practice’ as the principles covering the quality systems in blood establishments (Article 11 of 2002/98/EC – the core EU Directive on Blood Transfusion), although it does specify ‘Good Manufacturing Practice’ as an overall guiding principle in the Preamble [2]. The Preamble also contains other statements of principle, scope and intent, and these may have a legal function in the event of dispute. It states, for example, that the intent of the regulations is to ensure public health, thereby forever giving blood safety in the EU primacy over legitimate commercial interests in the drafting and execution of regulations. The Therapeutics Goods Administration (TGA) in Australia produces a specific Code of GMP for blood and tissues. This includes both quality and technical standards that must be met. The FDA states that Good Manufacturing Practices (GMPs) are the guiding principles in the functioning of blood services. GMPs (generally called just GMP outside of North America) are a dynamic and very comprehensive set of overall directions, principles, rules and regulations that reduce the entropy in a complex system, and thereby the likelihood of mishap. (Regulators, however, by definition draft regulation as well as enforce it, and may and do increase complexity beyond any possibly meaningful improvement in safety. This requires a constant dynamic in the regulatory process: see below.)

The Precautionary Principle emerged in the 1980s as a statement of best practice when faced with serious but unquantifiable risks. This principle was enshrined at the 1992 Rio Conference on the Environment and Development, as ‘Where there are threats of serious or irreversible damage, lack of full scientific certainty shall not be used as a reason for postponing cost-effective measures to prevent environmental degradation.’ Since then it has come to be explicitly adopted for health protection, for example in the European Union [7] and in Canada [6,8]. It continues to develop and evolve and to gather increased force of law through case law in Europe and elsewhere.

In European law, according to the European Commission, ‘the precautionary principle may be invoked when a phenomenon, product or process may have a dangerous effect, identified by a scientific and objective evaluation, if this evaluation does not allow the risk to be determined with sufficient certainty’. An explicit statement of precaution appears in the core Blood Directive [2]: ‘The availability of blood and blood components used for therapeutic purposes is dependent largely on Community citizens who are prepared to donate. In order to safeguard public health and to prevent the transmission of infectious diseases, all precautionary measures during their collection, processing, distribution and use need to be taken making appropriate use of scientific progress in the detection and inactivation and elimination of transfusion transmissible pathogenic agents.’ This rather stringent application of the principle results in interventions to mitigate risk that will not be considered cost-effective in other clinical venues (vide infra).

Most formulations of the precautionary principle include rather explicit acknowledgement that decisions taken under its aegis are subject to reconsideration and modification as more complete data are accrued. This results in tensions over what constitutes sufficient evidence to undertake amendment of long-standing regulatory decisions.

·        Standards. Professional advisory bodies as well as technical standards bodies such as the International Standards Organization may set standards to be attained for accreditation, whereas regulators define rules and regulations that blood component and service providers must comply with to operate within the law. Regulators may, however, mandate accreditation by other bodies as a regulation to be complied with. In this way standards of the International Standards Organization (ISO standards) and national technical standards bodies or of professional bodies such as AABB and the College of American Pathologists (CAP) in the USA may be explicitly applied to blood component or transfusion service providers and may be given force of law. Standards used for accreditation and regulatory purposes need to be current; they also need a firm, functioning and explicit mechanism of review and change as scientific knowledge accrues, circumstances change and experience informs.

·        Application and Enforcement of Regulations. A regulation is of limited value if it cannot be enforced, either because the rule of law is lax, the enforcing agency is weak or the standard is unrealistic or unrealistically expensive. There are three levels of application of regulations and of standards in the regulatory setting.

·        Inspection/accreditation/licensing. In most countries with a robust health system all bodies participating in the business of providing blood for transfusion are required to be visible and accountable through an official process, usually by registration, accreditation or licensing. Self-inspection, or accreditation by peer review, is generally no longer considered acceptable in isolation. Different scales of licensing requirements often apply to facilities that collect and test blood from donors than to hospital blood banks, who either store blood for transfusion and issue it or who conduct minimal processing. Licences are time-limited and require renewal with re-inspection typically every one to three years.

·        Vigilance: haemovigilance/feedback/market sur- veillance. It has become obvious that clinical trials cannot be powered to measure the safety of transfusion. Very large-scale systematic well-organized surveys of clinical outcomes over tens or hundreds of thousands of recipients are required to track the occurrence and even to establish the existence of problems with the function, safety and quality of medicines, devices or processes. Within blood transfusion practice this is known as haemovigilance; originally mandated in France and voluntary in the United Kingdom, it has evolved to become mandatory throughout the European Union, and in several other countries, though it is at a relatively early stage of implementation in the decentralized blood systems of the USA. In the EU haemovigilance also extends to adverse effects in blood donors. This will force changes in approaches to donor care as more valid statistics of the incidence of very rare events emerge, as well as leading to mandatory approaches to such common events as iron deficiency.

·        Enforcement. The rule of law demands compliance. Regulatory authorities can and do apply fines, sometimes of millions of dollars, to blood establishments for failure to comply with legal requirements. Hospital blood banks may be closed for serious quality failures. Blood transfusion staff may be arrested and jailed, though usually as a result of egregious events rather than for systematic failures detected through routine application of regulatory methods.

·        Threat surveillance. Some regulatory agencies have adopted a formal threat surveillance role, by which they generally mean infectious disease threat surveillance. For example, the FDA works closely with the Center for Disease Control and other agencies in the Department of Health and Human Services in the USA, and in Europe the European Commission works with the European Centre for Disease Control. Haemovigilance systems augment this approach.

·        Cost effectiveness. Blood for transfusion is perceived as a reasonably cheap medicine, compared to similar therapeutic agents. However, the constant evolution of techniques and tests, along with the implications of the results of haemovigilance and clinical studies of safety and efficacy, inexorably drive up the costs and the price of blood components. While most countries and unions adopt some benchmark of cost-effective healthcare, regulatory agencies have a responsibility to assure quality, safety and efficacy and do not generally have a duty to ensure that their approaches and requirements do not result in unrealistic costs to the healthcare system. In the USA, for example, the FDA is specifically enjoined from considering cost as they promulgate rules, regulations and guidances, while in Australia the Jurisdictional Blood Committee takes responsibility for deciding whether new initiatives should be funded, independent from the regulatory agency, the TGA. Overall responsibility for deciding what is affordable must lie with the Government. Within the USA, Centers for Medicare and Medicaid Services (CMS) which pays for well over half of care in the USA and sets the benchmarks for third-party payers, does not pay for the cost of blood but for episodes of care by diagnosis and adjusts payment only with a substantial time lag to reflect increased costs. This results in some safety interventions being unfunded mandates for substantial intervals.

In assessing cost effectiveness, a measure such as an incremental quality-adjusted life year (QALY) with a defined monetary value can be used to decide whether to pay for a new drug in the community - how many years of what degree of benefit will this therapy provide per taxpayer's dollar? The cut-off value for buying the treatment for the community will vary on the country's economic state and culture, but by any measure in use worldwide NAT testing of blood donations provides a very poor return by several orders of magnitude. A general consensus on how to resolve this conflict, due in some measure to the public's perception of blood safety and the blood industry after the HIV and HCV disasters of the last century, has yet to emerge. Ultimately the decision is a political one on whether to mandate a costly change in practice. Professionals in the field of blood transfusion should do their best to ensure that the political decision-making process is publicly visible and recorded, perhaps especially in the event of an explicit political decision not to fund a new safety step.

Table 17.1 Agencies involved in regulatory processes in blood transfusion.

Table017-1

Table017-1

Table017-1

The regulatory bodies (Table 17.1)

There are several types of bodies involved in the regulatory framework or structure in blood transfusion. They contribute either to the formulation or application of the law, the formation, application or review of standards, or they can enforce the regulations.

·        National Statutory bodies with powers of enforcement. Most high and medium development index countries have a more-or-less functioning National Medicines Agency that sets and applies standards for drugs being prescribed, imported and sold in that country. Similar bodies, in many cases the same body, set and apply standards for blood components. They have the force of law and can seek to imprison or fine those who break the law. A person setting up their own blood collection service within the EU, for example, without a licence from the relevant Government agency would face serious charges. Examples are the Food and Drug Administration (FDA) in the USA, the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK, Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSAPS) in France, the Paul Erhlich Institute (PEI) in Germany, Therapeutic Goods Administration (TGA) in Australia, Health Canada and the various national agencies in the EU and other European countries. They are not all the same – some, notably the FDA, the PEI and AFSSAPS, have developed roles as scientific leaders in blood transfusion science and participate actively in developments in the field. In several countries, including some of the older Eastern bloc members of the EU, the agency within the State responsible for regulation (in the EU these agencies are called ‘Competent Authorities’) is also the National Transfusion Service, reflecting older Communist structures. In these cases it is very difficult to maintain the perception of separation of conflicting interests.

·        Supranational agencies with statutory powers. The European Commission in the European Union – essentially the civil service of the European Union – has very broad powers in the field of consumer safety and citizens' health, including explicit powers under the founding treaty in ensuring blood safety. A series of laws (Directives) were enacted since 2002 that cover licensing of blood establishments, accreditation of hospital blood banks and technical specifications, from donor qualification to component transportation. In addition the Directives address traceability and haemovigilance. The Commission has very little in-house expertise in blood transfusion and uses industry expertise, sourced mainly through the Departments of Health in the member states, to provide support.

The FDA in the USA is of a similar scale and scope – insofar as it has a remit across the 50 States, a number of territories and commonwealths, and the district of Columbia. The USA carries substantial weight in the industry far beyond other national statutory agencies. It has a very mature and heavily resourced function in defining standards, direction of research and, uniquely, decides which tests or other technologies must and may be applied within its jurisdiction.

·        Supranational agencies with treaty-defined powers and remits. There are two – the World Health Organization (including the Pan American Health Organization, PAHO) and the Council of Europe. They may exclude countries from membership, but in reality their power is soft and their function is essentially advisory, though they can provide support with funding or with channelling of funding from others. While the WHO involvement in blood transfusion carries considerable weight in medium and low development index countries, this is not the case in high index ones. The WHO's approach is essentially to promote national policies around a central nationally coordinated blood transfusion service with accountability to government.

·        Professional organizations within the blood transfusion community itself that set or define professional standards. These bodies have no statutory powers. Examples include the AABB and ISBT (the International Society of Blood Transfusion), and national professional organizations. They have an important regulatory function in providing professional support including defined standards for the state agencies.

·        Other agencies. There are other agencies with more limited input into the regulatory process, especially those with a lobbying role at Government or international level: the International League of Red Cross and Red Crescent Societies, America's Blood Centers (ABC), the European Blood Alliance (EBA), the Alliance of Blood Operators (ABO) and professional trade associations such as the International Plasma Producers Congress (IPPC), the Plasma Protein Therapeutics Association (PPTA) and the International Plasma Fractionation Association (IPFA).

·        Patient involvement. The voice of the patient in regulation of blood transfusion, where expressed, is generally through the political process and the governance arrangements for regulators, hospitals and blood suppliers. In addition, several well-organized groups representing users of blood components – people with thalassaemia and sickle cell anaemia – and plasma products – people with haemophilia or primary immune deficiencies – have valid concerns and often formal input into regulatory processes [10].

·        Donor involvement. Donor associations exist as separate entities to blood transfusion services in several countries and have an international body – the International Federation of Blood Donor Associations. From time to time these groups may lobby regulators, governments and blood suppliers.

·        Other groups. Public bodies, for example lesbian, bisexual, gay and transgender groups rights and allied groups, may become involved in public debates and issues surrounding blood transfusion from time to time.

The role of blood transfusion agencies and health professionals vis-à-vis regulatory agencies

Laws, regulations, ethics and social values evolve. What is accepted as ethical and proper in one time and place may not be legal in another. Laws governing gender and sexuality are but one example. So while the law as it is must be observed and respected, it need not be revered as complete, correct or immutable. Neither should it be seen to be outside the sphere of influence of the public to whom it applies. In contrast, it is the civic duty of citizens of a state and the ethical duty of scientists and physicians everywhere to attempt to correct deficits or address shortcomings in the law, whether through contributing to the drafting of new statutes, correcting technical errors, including omissions, in the law itself or advocating repeal when the prevailing conditions render laws obsolete. This must be effected through legal and transparent processes, perhaps ideally through competent and legal organization for this purpose, including, in blood transfusion, the AABB, ABC, EBA and similar bodies.

In almost no country are the regulatory authorities concerned with improvements in the efficacy of red cells or platelets, or with treatment protocols and guidelines. These remain the preserve of the professionals in the field. Blood remains a problematic medicine; regulation tends by its nature to be very conservative and tends to preserve the status quo at the expense of development. This may give rise to a natural and often constructive tension between regulators and practitioners, to whom it is obvious that there is much to be improved.

Regulatory compliance is always part of professional and scientific integrity and endeavour, but it is never all of it, and much less a substitute for it.

Key points

1. A well-legislated and regulated blood transfusion service is a crucial component in assuring safety of the blood supply within a country or state, although there are large differences among different jurisdictions in how this is addressed.

2. Regulations should, but do not always, address issues of adequacy of supply and availability of blood within a State, as well as quality, safety and scientific developments.

3. Regulations are based in law, which should be explicit in statute, and are governed by guiding principles, often in practice a version of the Precautionary Principle and the principles and rules of Good Manufacturing Practice.

4. State regulatory agencies apply Standards; these are often set by national accreditation or standards bodies, or by professional bodies within the field.

5. The nature and scope of regulations may be influenced by forces inside or outside blood transfusion – lobbying by professional groups, trade organizations, patients and groups and other interested bodies can apply pressure for change at the political and public level.

References

1. World Health Organization. Resolutions relating to blood safety adopted by WHO governing bodies. WHO 2006. Available at: www.who.int/bloodsafety/en, accessed March 2012.

2. Directive 2002/98/EC of 27 January 2003 of the European Parliament and of the Council setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components and amending Directive 2001/83/EC. Official Journal of the European Union 2003; L 33/30.

3. Commission Directive 2004/33/EC of 22 March 2004 implementing Directive 2002/98/EC of the European Parliament and of the Council as regards certain technical requirements for blood and blood components. Official Journal of the European Union 2004; L 91/25.

4. Commission Directive 2005/61/EC of 30 September 2005 implementing Directive 2002/98/EC of the European Parliament and of the Council as regards traceability requirements and notification of serious adverse reactions and events. Official Journal of the European Union 2005; L 265/32.

5. Commission Directive 2005/62/EC of 30 September 2005 implementing Directive 2002/98/EC of the European Parliament and of the Council as regards Community standards and specifications relating to a quality system for blood establishments. Official Journal of the European Union 2005; L 256/41.

6. Epstein J, Seitz R, Dhingra N, Ganz PR, Gharehbaghian A, Spindel R, Teo D & Reddy R. Role of regulatory agencies. Biologicals 2009; 37: 94–102.10.

7. Europa.eu. Summaries of EU legislation. The Precautionary Principle. Available at: http://europa.eu/legislation_summaries/consumers/consumer_safety/l32042_en.htm. 2011 (accessed March 2012).

8. Vamvakas EC, Kleinman S, Hume H & Sher GD. The development of West Nile virus safety policies by Canadian blood services: guiding principles and a comparison between Canada and the United States. Transfus Med Rev 2006; 20: 97–109.

9. Medicines and Healthcare Products Regulatory Agency (MHRA). Rules and Guidance for Pharmaceutical Manufacturers and Distributors (The Orange Guide). London: Pharmaceutical Press; 2007.

10. O'Mahony B & Turner A. The Dublin Consensus Statement 2011 on vital issues relating to the collection and provision of blood components and plasma-derived medicinal products.Vox Sanguinis 2012, February; 102: 140–143.