How do we solve the shortage of plasma derived medicines in low- and middle-income countries (LMIC)?

Introduction

In the context of this paper, we define ethics as ensuring there is sufficient medicine for patients who need it, safeguarding the health of the donors who provide the plasma to make these medicines, and ensuring the medicines are of the highest quality. We define pseudo-ethics as things such as altruism, community solidarity, belief that plasma donation must be unpaid, and such other things. Such a definition is supported by other researchers who call for a more patient-centered approach and to not prioritize social or cultural norms over patient access to medicines (1,2).

Low- and middle-income countries (LMIC) do not collect enough plasma, creating a shortage of plasma-derived medicinal products (PDMPs) for patients (3). US collects about 70% of the global source plasma supply (4). They are followed by Germany, Hungary, Austria and Czech. These 5 countries combined that have around 10% of the world’s population, collected 90% of the world’s plasma while rest of the world (90% of the population), including LMICs, contributed less than 10% to the global plasma supply (5). So, the mere existence of a large population does not guarantee adequate plasma supply.

The complete apathy in fixing the plasma shortage situation (or even preventing it from further worsening) is evident in pseudo-ethical posturing by World Health Organization (WHO) and other policy influencers that continue to preach that plasma sufficiency through unpaid donors is possible even in the face of overwhelming data over many decades that this has not been possible or achieved (6). The truth is that there is no country, LMIC or developed country that has achieved PDMP sufficiency through unpaid donors alone (3,5).

US’s ability to export plasma and PDMPs to the rest of the world for decades now has been possible through a source plasma collection system of over 1,000 locations that allows donor compensation and strict regulations to safeguard donor health and testing standards (7). Many of the LMICs import the PDMPs made from US paid plasma donors while their policymakers extol the virtues of not paying donors in their own countries, continue to put policy barriers limiting domestic plasma supply and continue their reliance on imports, doing a gross disservice to the very patients that they swore to protect (7).

There are other countries such as China, Germany, Austria, Czech, Hungary, Egypt and some Canadian provinces that have implemented the US model with some local variations (8,9). While implementation of the US model has had its fair share of controversies, there is no disagreement that the overall policy has helped many of these countries boost plasma collection volumes and achieve greater plasma and PDMP sufficiency (5). Bottom line, even if LMICs are apprehensive that the US model is suited for developed countries, it is worth noting that there is growing empirical evidence of many LMICs taking the US model and learning what works (and does not work) and adapting it to their local environments with changes that protect their donors.

For example, Czech Republic only allows plasma donations every 14 days which corresponds to roughly 24 donations in a year vs. US, which allows up to 104 donations a year and Germany, which allows up to 60 donations a year (10). The key here is to balance donor health risks and serve the patients who desperately need these medicines. The risks to a donor’s health due to frequent plasma donations in a paid system can be managed through lowering the donation frequency, monitoring Immunoglobulin and total protein levels, and frequency of donor adverse events. Such donors can be required to donate less frequently, or temporarily or permanently deferred as unsuitable donors through a determination made by the medical director.

Source plasma

Source plasma is collected using a process called plasmapheresis. This is different from recovered plasma, which is manually separated from blood donations. Most LMICs do not collect source plasma at a commercial scale. During the draw cycle of plasmapheresis, a donor is connected to an automated plasmapheresis machine that draws whole blood, mixes it with an anticoagulant to prevent clotting in the line, and sends it into a centrifuge. In the centrifuge, a bowl spins the whole blood at a set revolutions per minute (RPM) where the heavier red blood cells (RBCs) settle to the bottom and the lighter plasma travels to the top. The plasma is then transferred to a bottle. A return cycle is then initiated and the remaining RBCs in the bowl are returned to the donor. This cycle repeats a few times until a target Plasma volume for the donor is collected. All of this is done with single use disposable equipment to prevent spread of infectious diseases (11).

Donor compensation or payment is a form of monetary reward given to a volunteer donor for donating plasma. In US, companies can offer any amount for payment and is often dictated by supply and demand. During times of plasma shortage, such as during coronavirus (COVID) pandemic, donor payments were as high as $100 per donation. At normal times when supply meets demand, donors may be paid $50 per donation. In Germany, Hungary, Austria and Czech Republic, maximum donor payments are mandated by the Government. A similar system exists in other countries such as China and Egypt (8,9). These donors are often referred to as paid donors or compensated donors. This system of paid plasma donation co-exists in these countries alongside blood donations that are often unpaid. In both cases of paid and unpaid donation, the donation is voluntary.

Rationale and knowledge gap

Previous research papers have talked about the importance of plasma as a strategic resource and the need for LMICs to achieve self-sufficiency (13). There have also been discussions around the need for LMICs to better utilize recovered plasma from blood donation (12). Lastly, there have been fractionation methods and partnerships recommended for LMICs to start making their own PDMPs towards the path to plasma and PDMP self-sufficiency (14).

While our research builds on this knowledge, we posit that shortage of plasma and PDMPs in LMICs is due to: (I) lack of understanding that source plasma allows collecting significantly more plasma per donor; (II) paying donors does not affect donor health or quality of plasma that is collected; and (III) paid plasma donation and unpaid blood donation system can co-exist and altruistic donors will not stop donating blood because plasma donors are paid.

In some LMICs, factors such as capital, workforce and expertise may be lacking. However, if governments were to make achieving national plasma self-sufficiency a priority by removing policy obstacles and inviting global companies, this gap can be overcome. Take, for example, Egypt, where a government entity partnered with a global company to overcome these factors (8).

To be clear, this is not a developed countries vs. LMICs comparison or US vs. LMIC comparison but rather comparing facts vs. misinformation in the context of achieving plasma self-sufficiency for the sake of patients in LMICs. The reason this is important and needs to be addressed is because the misinformation today is depriving patients in LMICs from lifesaving PDMPs and the goal is to solve this problem through empirical evidence rather than hearsay, hopes and beliefs.

The “Secret Sauce” for the 5 countries (US, Germany, Hungary, Austria and Czech) that have achieved national plasma sufficiency (and surplus) is the following:

• Collecting source plasma through plasmapheresis: source plasma allows collecting 4 times more volume of plasma per donation versus recovered plasma (from blood donations). For example, in most countries, you can donate 800 mL of source plasma vs. 200 mL of recovered plasma (8). Source plasma can also be collected more frequently in countries that allow anywhere from 24–104 plasma donations a year since the RBCs are returned to the donor (7).
• Compensating donors to encourage participation: these countries also compensate donors that encourages participation from non-altruistic donors. In US, nearly 6% of the eligible population participates in plasma donation. This number is around 1–2% in LMICs (5).
• Regulatory oversight: US Food and Drug Administration (FDA) has clear standards for donor eligibility [Code of Federal Regulations (21 CFR) 630 Subpart B]. Lab testing of each unit for transfusion-transmitted infections [human immunodeficiency virus (HIV), hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), Parvo-B19 and syphilis] irrespective of donor pronouncements (21 CFR 640 Subpart G) (14). Last but not least, a robust pathogen inactivation process within fractionation to prevent spreading of infections through PDMPs and lab testing of each lot of PDMPs prior to being released in the market for the patients to use (15).
• Voluntary standards: Plasma Protein Therapeutics Association (PPTA) is an industry association that has developed a National Donor Deferral Registry (NDDR) to ensure high-risk donors do not enter the plasma donation system. A cross-donation check system (CDCS) to ensure donors do not donate more frequently than is allowed by the country’s law. International Quality Plasma Program (IQPP) that ensures additional regulations are adopted voluntarily to safeguard donor health and Plasma Protein Quality Standards (QSEAL) for fractionators to ensure only the highest quality PDMPs enter the market for patient use. Given the recent technology advancements, the feasibility and cost of implementing such a robust regulatory system have come down significantly. Even then in resource-limited LMIC settings, which may lack the digital infrastructure or regulatory capacity, this can be further addressed through subsidies from government or global organizations (16).

All the above have contributed to minimizing the risk of transfusion-transmitted infections through PDMPs and the empirical evidence over the last 3 decades shows no difference in the quality or safety of PDMPs made from paid donors (4). There is no separate process at any fractionator for paid or unpaid plasma. The majority of plasma that is fractionated today for PDMPs is from paid donors (3). So, when we talk about how safety is achieved in PDMPs through S/D treatment, it covers both paid and unpaid plasma.

Double standards against compensating plasma donors in LMICs

There is often an argument that poor people in LMICs will resort to donating plasma for money if compensation is allowed. The answer to this is, why not if they are healthy? If the donor meets the health requirements and it is healthy for the donor to donate, a system should not discriminate against a person based on socio-economic standards. The only two mandatory criteria for donating plasma must be: (I) Is it safe for the donor to donate; and (II) is the plasma safe for the patient to receive. We address the first criterion with strict donor eligibility standards (21 CFR 630), and we address the latter with strict cGMP and testing standards (21 CFR 606 and 21 CFR 640).

The myth that paid plasma donors are somehow coerced just because they are compensated for their plasma donation is inaccurate. The definition of voluntary is when someone does something on their own will. Paid plasma donors are informed of the risks of plasma donation by a medical professional. They sign informed consent prior to donating plasma. There is no harm in poor people donating plasma and being compensated if they are healthy. The only criterion is whether the donor is healthy to donate plasma—which must be determined by a medical professional and through lab tests. Economic status (poor or rich) must not have any bearing on plasma donation. If it is not safe for a donor to donate plasma, they must not be allowed to donate irrespective of whether they are poor or rich.

Second argument that is often used against compensation is that donors will lie and not be truthful as they want the money. Even the compensated plasma donation system in the 5 countries has a small percentage of donors who may lie. There are controls in place to address this such as checking donor addresses to ensure they are not transient in nature, that donors reside in the community, comparing donor history questionnaire responses and deferring unreliable donors permanently, checking database to ensure they are not exceeding donation frequency and lab testing standards that ensure that infectious donors are flagged and deferred by entering them into national database. PPTA is an industry association that provides systems, processes and certifications to ensure global quality standards are consistently followed across various countries (7,10,11).

Lastly, a fear-mongering tactic that is used against compensating plasma donors in LMICs is that it will affect the voluntary blood donation system. Even in the 5 countries that allow compensation for plasma donors, voluntary blood donation numbers have not changed much. Whole blood and RBC demand in general is going down due to the entry of minimally invasive surgeries and better transfusion practices. So, it is to be expected that we will see a decline or flattening of whole blood and RBC needs (10).

Table 1 covers some of the common misinformation that is prevalent and tries to counter it with facts.

A glaring double standard here is that the majority of the PDMPs produced today are manufactured using plasma from paid donors. LMICs that publicly posture about how their system is proud not to compensate donors create shortages of lifesaving PDMPs for their patients. They then resort to either not treating patients adequately or quietly importing PDMPs from compensated donors (4,5).

However, these influencers and agencies, such as WHO, continue to misguide LMICs in following their playbook, of only collecting recovered plasma from unpaid donors, which has not worked for many decades and there is no real evidence it will work in the future either with the growing demand for plasma and PDMPs (1,3,5). So, LMICs are cautioned to use rational thinking based on empirical data on whether to follow the 5 countries that have achieved plasma sufficiency or continue the path that they are now which has resulted in plasma shortage, importing PDMPs, and worse, depriving patients of life-saving medicines (5).

Conclusions

Beware of the misinformation. Numerous influencers and organizations whose pronouncements are internationally influential have long asserted that achieving plasma self-sufficiency through unpaid donors must be the goal, with national sufficiency allegedly just within reach if one remains committed to the goal. However much one might find such an assertion appealing, it is not only unsupported by empirical evidence; it has repeatedly been shown to be nothing but a pipe dream as the patients in LMICs are suffering from a severe shortage of plasma and PDMPs (3,5).

Even at current levels of demand for immunoglobulin, for instance, the uncompensated approach is only contributing 20% to the global supply (3). Given that the actual patient need (the latent demand) is almost certainly four or five times the current level of demand, any assertion that unpaid donors can deliver the majority of the plasma needed for PDMPs is surely the triumph of hope over experience—the triumph of dreams over reality. And we can’t treat patients with hope. We need more plasma—lots of it, urgently.

The latent demand for immunoglobulin and other important PDMPs—the actual underlying patient need—does not seem at all likely to reduce in the foreseeable future (17). Potential improvements in yield, production efficiency, and the introduction of recombinant products, and other alternative treatments may well stem the rising tide a little, in future years, but the current global shortage of plasma and the huge currently unmet need for plasma-derived-medicines are factors that will inevitably defeat all efforts at self-sufficiency (supply adequacy) unless bold steps are taken urgently to correct the imbalance. The vast population of undiagnosed individuals suffering from primary immunodeficiency (PID) alone implies a demand for immunoglobulin that far exceeds the World’s current capacity to meet it.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Jan Hartmann) for the series “Source Plasma” published in Annals of Blood. The article has undergone external peer review.

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-25-23/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-25-23/coif). The series “Source Plasma” was commissioned by the editorial office without any funding or sponsorship. N.R. is founder & president of Life Plasma Inc. D.M. is founder and current Chair, UK Plasma Action & Former General Manager in Scottish National Blood Transfusion Service. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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