Generating pathways to domestically sourced plasma-derived medicinal products: Report from a workshop by the International Plasma and Fractionation Association and the Working Party on Global Blood Safety of the International Society of Blood Transfusion.

Plasma-derived medicinal products (PDMPs) are recognized internationally as essential medicines required to treat various acute and chronic conditions including congenital deficiencies of plasma proteins in haemophilia and primary immune deficiency. Global provision of these medicines is dominated by a small number of commercial companies, influencing the price and availability of the products. Achieving a level of strategic independence from this dominance is now seen as a public health priority in many countries. During the Regional Congress of the International Society for Blood Transfusion (ISBT) in Cape Town, South Africa, in November 2023, around 50 delegates from 24 countries participated in a workshop (WS) organized jointly by the International Plasma and Fractionation Association (IPFA) and the ISBT Working Party on Global Blood Safety on pathways towards provision of PDMPs from domestic plasma independent of commercial purchase in the open market. The WS was structured around three themes, each addressed by a separate group: Quality/safety requirements for plasma for fractionation (PfF) Stepwise access for safe plasma proteins Approaching contract fractionation A synthesis of conclusions from these groups included the following: The need to acquire support from government authorities for a national plasma policy, recognizing the difficulties posed by unstable political and bureaucratic environments. The value of embedding plasma and PDMPs within a patient blood management (PBM) paradigm to promote optimal clinical use of PDMPs. Training of blood/plasma collection personnel in the relevant principles of Good Manufacturing Practice (GMP), coupled with regulatory oversight of plasma product production in the engaged jurisdictions. Appreciation that limited access to contract fractionation may necessitate a stepwise approach, which may include small-scale preparation of versions of essential plasma proteins as an intermediate phase towards the manufacture of industrial-scale PDMPs from domestic plasma.

The legacy of haemophilia: Memories and reflections from three survivors.

Following the publication of a book of personal memories by one of us (CS1,2 ), we have attempted to synthesis our joint memories of three ageing men, born in the era preceding universal access to treatment, in an attempt to describe our experience, our challenges and our reflections on the development of therapies, which have ensured that our experience of growing up with haemophilia in the 1950s and 1960s has not been mirrored by the current generation of patients. We describe our upbringing in different parts of Europe in health care systems which, while of varying standards, were all unable to offer the kind of care which developed after the development of specific therapies. We assess the effect of the contamination of these therapies by blood-borne pathogens on our own development, and the development of our communities around us. In addition, we reflect on the lessons learnt, sometimes painfully, by our generation of people with haemophilia and how some of these enabled us to overcome substantial hurdles, survive and build productive lives. Finally, we survey the development of therapies in the past 20 years, and offer some reflections on how our experience can be integrated in a realistic expectation of what the future holds for our community, in our own affluent societies and in countries less advantaged economically. We hope that our thoughts may contribute to continued progress in the field of haemophilia care.

Estimation of the latent therapeutic demand for immunoglobulin therapies in autoimmune neuropathies in the United States.

BACKGROUND AND OBJECTIVES: The use of immunoglobulin (IG) solutions as an immunomodulatory therapy in certain neurological conditions has become an established modality and represents a significant proportion of total IG use. The estimation of the evidence-based potential demand designated as the latent therapeutic demand (LTD) for IG in these diseases is required for adequate planning of the plasma supply required to manufacture the product. MATERIALS AND METHODS: The diseases studied included chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain-Barré syndrome (GBS) and multifocal motor neuropathy (MMN). The LTD for IG was assessed using a decision analysis model, using Microsoft Excel. The model analysed the epidemiological and clinical factors contributing to IG usage. One-way sensitivity analysis and probabilistic sensitivity analysis derived the LTD in grams per 1000 inhabitants. The key variables included the treatment schedule and the prevalence of the disease. RESULTS: The model estimates that an average annual IG demand and standard deviation for CIDP, GBS and MMN in the United States is 83.05 ± 24.5, 6.1 ± 3.2 and 36.1 ± 25.5 g/1000 inhabitants, respectively. CONCLUSION: Together with previous work on the LTD for IG in immunodeficiencies, these results indicate that current IG usage reflects the estimated LTD for the main indications for IG in the United States The wide range of LTD found in all these studies emphasizes the need for more precise assessment of the underlying variables, particularly disease prevalence and dosage. Further studies on other indications such as secondary immunodeficiencies will augment these results and will assist in guiding demand planning for IG use and plasma collection in the United States and inform blood policy in other countries.

Health-Related Quality of Life in Patients with CVID Under Different Schedules of Immunoglobulin Administration: Prospective Multicenter Study.

OBJECTIVE: We assessed the health-related quality of life (HRQoL) in CVID adults receiving different schedules of immunoglobulin replacement therapy (IgRT) by intravenous (IVIG), subcutaneous (SCIG), and facilitated (fSCIG) preparations. For these patients, IgRT schedule was chosen after a period focused on identifying the most suitable individual option. METHODS: Three hundred twenty-seven participants were enrolled in a prospective, observational, 18-month study. Participants received IgRT for at least 2 years. The first 6 months were devoted to the educational process during which the choices related to IgRT were regularly re-assessed, and the shift to alternative regimen was permitted. During the following 12 months, clinical data were prospectively collected, and only patients who did not further modify their IgRT schedule were included in the analysis of HRQoL measured by CVID_QoL, a specific instrument, and by GHQ-12, a tool to assess minor psychiatric nonpsychotic disorders. RESULTS: Three hundred four patients were included in the analysis. CVID_QoL global score and its dimensions (emotional functioning, relational functioning, gastrointestinal symptoms) were similar in IVIG, SCIG, and fSCIG recipients. Patients receiving IgRT by different routes of administration reported similar capacity to make long-term plans, discomfort due to therapy, and concern to run out of medications. Multivariate analysis revealed the GHQ-12 status, but not the IgRT mode of administration, as the major factor impacting on treatment-related QoL items, and a significant impact of age on discomfort related to IgRT. CONCLUSIONS: IgRT schedules do not impact the HRQoL in CVID if the treatment is established after an extensive educational period focused on individualizing the best therapeutic regimen.

Comparing objective and self-reported measures of adherence in haemophilia.

AIM: To compare subjective and objective measures of adherence to prophylaxis in haemophilia. METHODS: In this cross-sectional study, we compared participants' self-perceived adherence and their estimate of the number of clotting factor concentrates (CFCs) that had been missed over the last period of CFC dispensation with an objective measure of adherence based on counts of CFC vials returned by participants. RESULTS: We included 29 out of 31 eligible patients in the study. There was no significant correlation between self-perceived degree of adherence and the objective classification of adherence (Rho: 0.10, 95% CI: -028 to 0.46, P: 0.61) and between the classification of adherence based on the proportion of missed CFC doses assessed by participants' self-report and objectively (Rho: 0.32, 95% CI: -0.01 to 0.59, P: 0.11). Conversely, we found evidence of moderate correlation between the proportion of missed CFC doses as assessed by participants' self-report and objectively (Rho: 0.56, 95% CI: 0.24 to 0.77, P: 0.003). Participants' self-perceived adherence was 3 times more likely to be rated as very good or good than it was for the objective assessment to be classified as adherent or suboptimally adherent. CONCLUSION: Our results showed significant discrepancies between subjective and objective measures of adherence, which likely reflect the influence of social desirability bias in self-reported measures and different concepts of adherence between patients/caregivers and haemophilia experts. Additionally, our results allow us to hypothesize that studies on adherence to prophylaxis in haemophilia relying exclusively on information from self-reports and questionnaires may substantially overestimate adherence levels.

The dynamics of contract plasma fractionation.

Plasma Derived Medicinal Products (PMDPs) are an essential component of the modern therapeutic armamentarium. They are differentiated from most other medicines in several ways, particularly the unique nature of the raw material used for their manufacture. Human plasma has been fractionated to PDMPs for the past 75 years, and the economics of manufacturing requires currently that as many products are harvested from each litre as is feasible and reflective of clinical needs. PDMPs may be purchased on the open market from the various commercial and not-for-profit (NFP) manufacturers. They may also be manufactured under contract (CM) from plasma supplied by government and similar agencies as a product of blood transfusion services. Clients for CM aspire to make full use of donated plasma, hence maximizing the donors' gift after the standard components of transfusion have been harvested. Many such countries also aspire to making their national clinical needs self-sufficient in PDMPs, attempting to acquire strategic independence from the vagaries of the commercial open market. The increasing commercial imperatives operating in the PMDP sector generate a tension with such ethical aspirations which are not easily resolved. In particular, the need to harvest as many proteins as possible may generate products which are surplus to national needs, necessitating an ethical paradigm for the optimal provision of such products. In addition, traditional relationships between blood services and domestic fractionation agencies may come under stress as a result of the competitive processes underpinning such transactions, which are now subject to international norms of free trade. Blood services engaged in the supply of hospital transfusion components are detached from the pharmaceutical Good Manufacturing Practices (GMP) culture needed for the production of plasma for CM, while the generation of such plasma through extraction from whole blood donations deflects the focus from that of a dedicated raw material for CM to a byproduct of the donation process. We review the field of CM, assess the current tensions within the sector, and offer suggestions for the strategic positioning of governments and other clients to ensure optimal outcomes for all the stakeholders involved.

Safety Issues of Plasma-Derived Products for Treatment of Inherited Bleeding Disorders.

The infection by blood-borne pathogens of a large proportion of the treated hemophilia population over the 1970s to 1990s represents a major tragedy that is embedded in the history of this condition. To avoid this historical repetition, the community of patients, treaters, and policy makers that contribute to hemophilia care need to learn from the events that gave rise to it. This requires an appreciation of the measures, which, through scientific developments, have enhanced greatly the safety of plasma-derived coagulation factor concentrates (pd CFCs). The objective conditions underlying and influencing the safety of all biological materials also require recognition. Although the stringent measures which ensure the safety of pd CFCs are very effective, pathogen transmission by other blood-derived therapeutics has continued due to a lack of effective technology and the continued emergence of new agents which transmit disease. This emphasizes the reality that the basic environmental factors influencing blood pathogen safety have not changed, albeit our capacity to counter them has improved greatly. These factors lead to threats to blood safety that are unpredictable and imposable on a global scale. The likelihood of a continued role for pd CFCs in hemophilia care, particularly in emerging countries challenged to maintain blood safety measures, ensures that these issues are more current than historical.

Where now for transfusion: the evolution of a paradigm and its logical progression.

The development of transfusion over the past century and a half has been described as one of the blessings of modern medicine. But, in some ways, it is emerging as a decidedly mixed blessing, bringing epidemics as well as improved health. Given all the practice has been through, now is the right time to take a critical look at blood transfusion as it is practiced today, and whether it serves the individual patient as effectively as the interests of those who administer it.