Protecting Access to Immune Globulins for Canadians

Final report of the Expert Panel on Immune Globulin Product Supply and Related Impacts in Canada

Executive Summary

A safe and secure supply of blood and related products is a cornerstone of the health care system. Patients across Canada depend on having fresh and frozen blood components and other vital products manufactured from human plasma available to them on a daily basis for treatment of various conditions.

Over the years, the use of immune globulins (IG), the most widely used product derived from human plasma, has expanded from the treatment of patients who do not make antibodies to protect themselves from infection (immunodeficiencies) to patients across a broad spectrum of illnesses (hematologic, neurologic, rheumatologic, dermatologic) where it is used as an immune modifier. Given the high levels of IG use for increasing indications across modern medicine, and the large numbers of patients across the world who still do not have access to these medications, concerns have been raised about Canada’s long term ability to ensure the ongoing supply of IG for Canadians.

In 2016/17 the combined volume of plasma collected by Canadian Blood Services (CBS) and Héma-Québec (H-Q) only accounted for 16.7% of the plasma required to meet the needs of Canadians for IG and other PDPs. The rest of the plasma for making these products used by Canadians is collected in the US from paid donors. This situation is not unique to Canada and the global dependency on one jurisdiction for meeting the global needs of IG patients has led to recommendations from various international advisory bodies as well as the fractionation industry to encourage jurisdictions to develop strategies to protect and enhance local plasma collection to support growing demand for PDPs.

In response to concerns raised about market conditions for IG and the long-term sustainability of Canada's IG supply, Health Canada established the Expert Panel on Immune Globulin Product Supply and Related Impacts in Canada (the Panel) in July 2017. The mandate of the Panel was to assess the long-term security and sustainability of Canada's immune globulin product supply, and to examine the potential impact on the Canadian blood supply should plasma collection be permitted to expand significantly in Canada.

Over a 8 month timeframe, from August 2017 to March 2018, the Panel engaged a wide range of experts and stakeholders including patient organizations and health provider groups in Canada, the 2 blood operators in Canada, a range of international experts in regulation and public policy related to the blood sector and blood system operations, and Canadian and international fractionation industry representatives. The Panel met 6 times and attended international conferences, undertook a broad based literature review, engaged provinces and territories (PTs), the National Advisory Committee on Blood and Blood Products, and federal officials responsible for oversight of regulation of the blood system and related products.

The Panel’s task was not to make specific recommendations but to provide the information base which could inform decisions by PT governments and the government of Canada in regard to ensuring a sustained and secure supply of IG for Canadian patients and a resilient blood supply in Canada.

The Panel was very cognizant of the fact that 20 years ago, the Commission of Inquiry on the Blood System in Canada (the Krever Inquiry) tabled its final report. A significant focus of the Krever Inquiry related to the high rate of infection of Canadian hemophiliacs with human immunodeficiency virus (HIV) and hepatitis C (HCV) through their use of clotting factor concentrates which were plasma derived products. Much has changed in the 20 years since the Krever Inquiry findings were published. In the many discussions with stakeholders across Canada and internationally, the memory of this historical crisis in the safety of the Canadian blood supply and that of other countries around the world has not faded. In this context, the Panel spent a considerable effort to document the very significant changes which have occurred over the last 20 years in response to that tragedy.

Patients receiving IG can be divided into 2 major groups: those for whom the drug is life-saving and for which there is no effective alternative at this time and those whose illness can be positively impacted by the use of IG but for whom there are other therapeutic alternatives also available. There are a relatively small number of conditions and patient groups for which IG has been definitively shown to be effective and they account for the majority of use of IG.

Patients with Primary Immunodeficiency are completely dependent on IG for survival, with IG replacing antibodies which these patients cannot produce on their own. Patients with secondary immunodeficiency due to other illnesses such as chronic lymphocytic leukemia and multiple myeloma may also benefit from IG replacement therapy in some cases. Other conditions which are proven to respond to IG in some cases through its activity as a biologic modifier include: neurologic conditions (chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, Guillain-Barre Syndrome, multifocal motor neuropathy) and immune thrombocytopenic purpura (ITP). There are multiple other situations where IG is used by clinicians, but many of these lack strong evidence of efficacy.

Demand for IG continues to increase steadily in Canada (6-10% per year) and globally. Canada is now the 2nd highest global user per capita of IG. In 2015/16 IG accounted for approximately ⅔ of the total spent on PDPs in Canada and the value of IG used for Canadian patients in 2015/16 was approximately US$286M. Across provincial jurisdictions in Canada, per capita consumption varies, but utilization has grown in every jurisdiction over the last 15 years. Québec has had the greatest per capita utilization of IG in the last 5 years, and Ontario the lowest.

Despite the growing demand for IG in Canada and internationally, there continues to be available global capacity in the plasma and fractionation sector and the Panel felt comfortable that there appears to be no emergency or crisis related to supply of IG for Canadians.

The Panel requested that the Canadian Agency for Drugs and Technology in Health (CADTH) examine whether there was anything on the horizon which would significantly alter the demand for IG –either a sudden reduction in demand due to a replacement product which was not derived from plasma or increased demand based on evidence that IG could positively impact a high prevalence health condition such as influenza or Alzheimer’s disease. At this time there is no indication that the pattern of growth in demand for IG will dramatically change over the medium term.

The Panel felt it important to recognize that acute shortages can and have occurred in the supply of IG and PDPs over the past few decades. The variant Creutzfeldt–Jakob disease (vCJD) crisis in the UK caused an acute crisis in the supply of local plasma in the UK with resulting constraints on the supply of IG for UK patients for a significant period of time. However, a more common cause of an acute shortage is production shut-downs in individual fractionation facilities resulting in short term shortages of product from that supplier. Generally clients are able to access replacement products through other suppliers. The risks of acute shortages in the future are likely to stem from similar dynamics. There has been concern expressed in regard to the remote risk of a US Executive Order (for National Defense Resources Preparedness) or a collapse in a US/Canada trade agreement compromising supply of IG or other PDPs - the Panel concluded that this is very difficult to predict.

Strategies to risk manage acute and more prolonged shortages are essential to have in place in Canada. Over the last 15 years, both CBS and H-Q have put in place best practice strategic procurement processes to both protect against dependency on one supplier of IG and mitigate the risk of local production problems which could cause an acute shortage. Work does need to be done in Canada to develop a national prioritized list of patient groups dependent on IG and a process which will allow appropriate allocation of the product in the setting of a short term or more prolonged shortage.

Given the high usage of IG in Canada, a number of audits have been carried out in different provincial jurisdictions to understand patterns of utilization of this expensive product. These audits show that a significant proportion of IG use falls outside established criteria and guidelines. Other jurisdictions, particularly the UK, have achieved more success than Canada in optimizing the appropriate use of IG for patients for whom it is indicated, and as a result have a much lower per capita utilization rate. Overall, the Panel feels more needs to be done in Canada to enhance utilization management of IG. The Panel considers the UK IG demand management system to be a promising practice. It strengthened control / management of IG on an ongoing basis (everyday operations), and established priorities for patient access in case of a supply disruption (e.g. production issues that cause recalls and temporary shortages).

On the plasma supply side, there is growing international concern about the high global dependency on the US for the collection of source plasma which is the raw material used to manufacture IG and PDPs. Overall, the US supplies 74% of global source plasma for fractionation into IG and PDPs. The majority (>90%) of the global supply of source plasma is collected by the commercial sector from paid donors in plasma collection centres, with the majority located in the US. Capacity for commercial source plasma collection has been growing steadily in the US over the last 10 years (it increased by 168% between 2004 and 2015), both through increased capacity in existing commercial source plasma collection centres as well as a 55% increase in the number of new centres.

These expansions have been in step with the global growth in demand for IG. The Panel found no evidence to suggest that the source plasma market is reaching the saturation point. IG prices have remained very competitive during this time of significant growth in the demand for IG and PDPs, something attributed to growing competition in the fractionation industry and continued cost efficiencies in part related to economies of scale.

As noted earlier, Canada is currently only able to supply ~ 17% of the plasma needed to make IG and other PDP used by Canadians. A similar dynamic exists internationally for many countries. In response to this global dependence on US plasma collection, governments, blood operators and public policy organizations across the world are encouraging more domestic self-sufficiency in plasma collection, emphasizing the use of non-remunerated donors.

Québec in 2012 approved a plan by H-Q to start to address this by setting up sites in different geographic areas of the province where voluntary H-Q donors could donate source plasma. Since 2013/14, H-Q has established 4 Plasmavie centres and almost doubled the amount of plasma it sends for fractionation. H-Q now provides approximately 21% of the plasma needed for production of IG and other PDPs for patients in the province. CBS has also developed a business plan to increase source plasma collection from its donors.

Source plasma is also collected by the commercial sector in Canada – Prometic, a PDP manufacturer in Winnipeg, has operated a source plasma collection centre using paid donors for many years. Recently, Canadian Plasma Resources (CPR) applied for and was granted a license to collect source plasma in Saskatoon and subsequently in Moncton, New Brunswick. Both centres use paid donors. Both Prometic and CPR have plans for future expansion in Canada.

One of the important dynamics impacting the future of the global plasma supply is the strong public policy position for using volunteer unpaid donors for source plasma collection and a resistance to the use of paid donors. The rationale for this position includes concerns about safety of products made from paid donors, ethical concerns about the commodification of human plasma, and concerns that compensation for donating source plasma would diminish the commitment of volunteer donors of both whole blood and apheresis platelets.

In terms of safety, the global tragedy of the 1980s (as described in Canada by Krever) resulted in a significant international overhaul of legislation and regulation, systems and processes involved in screening and testing blood and plasma donors and their donations, the handling of plasma for fractionation, and the manufacturing processes involved in the production of PDPs. Current measures ensuring the safety of IG and PDPs are based on a multi-pronged approach. Many of the steps taken to assure the safety of these products are embedded in regulation and legislation and apply to all plasma donors, volunteer or paid, as well as those agencies and facilities collecting and processing plasma to make PDPs. In addition to the regulatory framework, fractionation industry associations have rigorous quality programs (Quality Standards of Excellence, Assurance and Leadership (QSEAL)/International Quality Plasma Program (IQPP) standards in particular) which call for requirements beyond regulations which further enhance the safety of IG and other PDPs. The outcome of these changes has been dramatic: there have been no confirmed cases of disease transmitted through PDPs in over 2 decades.

The issue of paid source plasma donors was referenced frequently by patient groups and providers who spoke to the Panel. Their submissions reflect the international dynamics on this topic. Essentially patient groups are knowledgeable about the difficulties inherent in meeting collection targets and the high operating cost of collecting sufficient source plasma using exclusively volunteer unpaid donors. For patients and their representative organizations, given the remarkable safety record of IG and PDPs over the last 20 years, the major concern is not the issue of using paid donors but relates to assuring an adequate supply of plasma for patient needs which they view as the paramount safety risk. Their position is that both paid and unpaid donors are necessary to ensure an adequate supply of IG and other PDPs for patients.

The Panel spent considerable time and effort examining volunteer and paid donor plasma collection operations – the data are interesting and reflect the significant changes which have occurred in the plasma and PDP sector over the last 20 years. Across Europe, Australia and North America, the only jurisdictions that have achieved 100% self- sufficiency for plasma collection are those that have permitted paid plasma donors. Jurisdictions that permit payment of source plasma donors have a significantly higher plasma collection capacity on a per capita basis compared to those jurisdictions where compensating source plasma donors is prohibited. In addition, the cost of collecting large volumes of source plasma utilizing volunteer donors is 2-4 times more expensive than the commercial plasma collection model and thus it remains more economical for jurisdictions to purchase IG and PDPs from the commercial market, all of which are made from plasma from paid donors. Finally evidence indicates that notwithstanding the funding for blood operators to meet collection targets to achieve self-sufficiency, often source plasma programs based on volunteer donors just simply can’t make their targets.

The Panel recognizes that “voluntary/volunteer” and “paid” are imperfect terms
to differentiate donors and the donation event, but they are used in this report
to distinguish between unpaid/uncompensated/nonremunerated and
paid/compensated/remunerated donors/donations. There is no suggestion
that any donations are “involuntary” in the sense of being mandatory or forced.

Other evidence revealed the evolving nature of a voluntary donor – data from the European Union reveal that in Europe, incentives for voluntary donors are diverse and in many instances have a value equivalent or even greater to what would be considered payment in Canada and other jurisdictions – thus the definition of a volunteer donor is shifting. Furthermore, there is increasing discussion amongst longstanding non-profit blood operators that greater incentives are going to be needed to sustain engagement and commitment of volunteer blood and source plasma donors – the recent plans announced by Sanquin the national transfusion service of the Netherlands is a good example of this trend.

The question of whether Canada should increase its self-sufficiency in plasma collection and to what degree was a major focus of the Panel. The Panel had a strong consensus that Canada needs to make a much more significant contribution to the collection of source plasma – the Plasmavie program and the desire of CBS to increase collection of source plasma from their donors are an appropriate response to the significant dependency on the US as a source of plasma. On the issue of what level of self-sufficiency should be targeted, it is appropriate for Canada at a minimum to be able to provide sufficient plasma to meet the needs of the one group who are truly life dependent on IG – those patients with primary immunodeficiency (PID). This would ensure that these patients are protected in the unlikely event of a severe shortage. Volume targets beyond this minimal expectation should reference priority clinical needs.

Importantly, the move to collect more source plasma by CBS and H-Q needs to be based on solid business principles and learnings and/or partnerships with the private sector who have significant expertise. Increased source plasma collection by CBS and H-Q cannot be undertaken at any cost. There is a significant premium related to the cost of collecting high volumes of plasma from volunteer source plasma donors (between 2-4 times more costly) – this is recognized by CBS and was reaffirmed by discussions with other jurisdictions. There is a growing acceptance across jurisdictions that self-sufficiency strategies should avoid being totally dependent on any one country for source plasma donors, and achieve a balance between dependency on the commercial market, and the incremental cost of collecting source plasma from local volunteer donors. The approach taken in Australia where the cost and feasibility issues of source plasma collection using volunteer unpaid donors are weighed against the benefits of a higher level of self-sufficiency – on a regular basis, plasma collection targets and related budgets are set by the National Blood Authority (NBA); the rest of the needs of Australians are met through competitive procurement of PDPs off the commercial market.

Given that there are a number of provinces in which commercial plasma operations are currently permitted, the Panel agreed that options could be carefully examined to ensure that all source plasma collected in Canada from Canadian donors (whether paid or volunteer) be made available for the needs of Canadian patients. There are a number of mechanisms whereby this could be achieved.

Finally the Panel recognizes that over the last 2 decades, CBOs have pursued multiple strategies to protect the supply of IG and PDPs for Canadian patients including strategic procurement, collection of local recovered and source plasma, supply guarantees, the use of toll fractionation and the concept of regional self-sufficiency. These strategies should continue and be further enabled by enhanced source plasma collection by CBOs and the securing of all plasma collected in Canada to be returned for the use of Canadian patients.

One of the important issues the Panel was asked to review was the impact, if any, of expanded source plasma collections on the whole blood supply. The Panel examined the issue from a number of perspectives and acknowledges that there has not been a lot of research undertaken on this issue. The concern is in part confounded by the overall lower demand for red cells over the last 10 years, which was very pronounced in the US, but which is clearly attributable to changes in transfusion practice and reduced demand for blood. There is no compelling data to suggest that expansion of source plasma collection – whether with paid or unpaid donors - has negatively impacted the whole blood supply. However, we would caution that this is an issue which should be further researched and it requires ongoing oversight and vigilance. One particular issue worth monitoring is whether source plasma operations could affect recruitment of future volunteer apheresis platelet donors.

In the Panel’s review of the full scope of the IG and related plasma sector, information was collected to provide a more robust understanding of the regulatory systems in place to protect the public in both Canada and other jurisdictions. Generally the Panel concluded that the sustained safety of IG and PDPs over the last 20 years reflected effective regulation and oversight of the blood, plasma and PDP sectors. There were a number of areas where the Panel felt enhancements could be considered to further strengthen oversight and align with evolving international best practice. Canada would benefit from a more structured and coherent approach to surveillance and early warning in regard to threats to the blood supply. Currently, much of the surveillance activity depends on various data sets and the voluntary sharing of data by PTs resulting in time lags in reporting and a lack of consistency and comprehensiveness. Ideally there should be one committee which has the exclusive mandate to acquire comprehensive data on a regular and timely basis and provide the appropriate, regular analysis and advice to Health Canada or PTs in regard to evolving threats. Health Canada could also consider incorporating into the blood regulations some of the voluntary standards developed by the PDP sector including the requirement to report source plasma donor data – both in regard to seroprevalence rates and donor safety issues for source plasma donors given their frequent donations.

While the focus of this report is assuring continued access to IG for Canadians, we also heard from patient groups who expressed concerns about how the current system limits access to other PDPs they need. The Panel is concerned about these issues and suggests a first step would be ensuring a review of any new PDPs being considered for Canada be done by CADTH to ensure clarity in regard to their effectiveness and the appropriate indications. There was significant concern by patient groups and some clinicians that there would be a move to place PDPs on provincial drug plans which would increase the cost for many patients due to co-pays (an issue which the Panel felt was outside their mandate). However the Panel noted that in Canada, the longstanding principle that plasma-derived products be provided to patients at no cost along with all other blood and component products, is something which should be reaffirmed or at least revisited by the PTs and the federal government together. Given donors across the country contribute their plasma for these products now, and potentially will do so to a greater degree in the future, clarification of this longstanding principle and the development of a transparent approach across the country to this equity of access issue would be helpful.

In summary, much has changed since the release of the Krever Commission report in 1997. PDPs are safe, the plasma sector has been able to respond and react to continuing changes in demand over the last 20 years ensuring care for patients in Canada. New products continue to be developed to address serious health conditions. Our CBOs use sophisticated strategies with the support of provincial, territorial and federal governments to ensure the sustained supply of safe and affordable products for patients in Canada. However, like most of the world, we are too dependent on one jurisdiction (US) for the supply of the vital raw material used to make these products. Canada needs to do more to collect plasma and take other steps to enhance our self-sufficiency in meeting the needs of our citizens for PDPs. As discussed there are a number of decisions to be made and strategies to be considered. In the implementation of the strategies, there needs to be transparency for the public and stakeholders, adherence to good business principles with flexibility in the approach where appropriate, due consideration of the taxpayer, and ongoing attention to the outcomes with the capacity to adjust where necessary. The Panel has consolidated much of the evidence available related to these issues in this report and we respectfully submit it to the Deputy Minister of Health Canada in the hopes that it will enable a robust discussion across the country on the way forward in a critical area of public health care in Canada.

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