Building a bridge from donors to patients—a review of the journey to personalize the collection of source plasma for plasma-derived medicinal products

Introduction

Human plasma is the essential basis for life-saving (e.g., in burns or other critical care applications) and life-improving (e.g., symptom relief, disease modification) plasma-derived medicinal products (PDMPs). While there have been innovations allowing for recombinant substitutions as well as entirely novel mechanisms of action resulting in alternatives to PDMPs, such as in the treatment of hemophilia, the need for source plasma remains unbroken. This demand has led to continuously increasing numbers of collections in the U.S. and globally, disrupted by the recent coronavirus disease 2019 (COVID-19) pandemic (1). Previous reviews have focused on the criticality of PDMPs and the fragility of the supply chain (2). The objective of this review is to summarize the relatively new trend to personalize the large-scale source plasma collection process in the U.S. in light of historic precedents and similar trends in other geographies and what could be learned to improve source plasma collection in other systems. In this review, we briefly summarize the clinical need for PDMPs, we discuss the dilemma between the need for more product availability for patients and the need to maintain highest standards of donor safety, we demonstrate how currently available personalized approaches can address this dilemma by maintaining donor safety while increasing plasma yield across the donor population, and finally we share ideas how future developments might help further personalize and improve source plasma collections.

Indispensable role of human plasma and its therapeutic applications

PDMPs have a surprisingly wide range of therapeutic applications, including medicines such as coagulation factors, albumin, and immunoglobulin. These can be used to treat acutely life-threatening conditions like trauma or shock, as well as chronic conditions such as bleeding disorders, including hemophilia and von Willebrand disease. Immunoglobulins are of special interest as they are among the rarest components in human plasma (relative to therapeutic need), have a wide range of use, and are often one of the few therapeutic options available for chronic immunological conditions like chronic inflammatory demyelinating polyneuropathy (CIDP) or primary and secondary immunodeficiencies. Many PDMPs have been included in the World Health Organization Model List of Essential Medicines, highlighting their critical contributions to patient care (3-5).

As PDMPs remain the only, or one of the few, options for many conditions, human plasma remains essential for their manufacture and for supplying patients in need. With increased awareness and diagnosis of these conditions globally, the demand for PDMPs and consequently human plasma continues to increase. Shortages of PDMPs, such as general immunoglobulin formulations or specific ones like WinRho^®(D) immune globulin (RhIG) during the first half of 2024, occur frequently and are highly disruptive and fear-inducing for patients (6,7). A year’s supply of PDMPs for a single patient commonly requires plasma from hundreds and in some cases over a thousand donations.

The vast majority of plasma for fractionation and subsequent drug manufacturing comes from what is called source plasma collections. This is plasma purposefully collected from individual donors by plasmapheresis. A smaller fraction of the global supply is contributed by recovered plasma, which is plasma left over when cellular components are retrieved from whole blood donations. The relative contribution of recovered plasma has decreased over the last few years. Source plasma collections have increased. Almost 90% of the global source plasma supply originates from the U.S. and four European countries, where plasma donations can be remunerated (1). Most other countries are not self-sufficient and have to import plasma or PDMPs to meet demand. Egypt, for example, has recently taken promising steps towards self-sufficiency (press coverage, for example, available at: https://www.dailynewsegypt.com/2024/07/16/egypt-pushes-forward-with-national-plasma-derivatives-project/), providing a potential template for other countries and regions.

History of source plasma supply at the crossroads of donor safety and patient demand

Source plasma collections are at a critical juncture, balancing the need to supply patients with safe and readily accessible medicines and the need to ensure donor safety and comfort. In the context of plasma donation, as everywhere in medicine, the precautionary principle must apply. The donor assumes risk with the donation procedure for limited to no individual health benefit. Similar to other types of donations, such as whole blood donation, gamete donation, or organ donation by a living donor, every effort must be made to minimize the risk to the source plasma donor. Considering the high frequency of source plasma donations, such as in the U.S. where donors may donate up to two times in a 7-day period, risk reduction for each individual donation is paramount to curtail a donor’s cumulative risk. Like other types of donations, the benefit-risk assessment appears lopsided towards risk when viewed solely from the individual donor perspective. However, for the aforementioned reasons, the societal benefit of source plasma donations and PDMPs cannot be underestimated. Thus, a fair assessment must balance the precautionary principle for the individual donor (primum nil nocere) with the societal need and benefit for the recipients of PDMPs collectively (non nobis solum).

Potential risks of plasmapheresis include phlebotomy-related issues, adverse reactions to citrate needed for anticoagulation, or allergic reactions and air emboli, among others. However, the most common adverse events are hypotensive (vasovagal/hypovolemia) in nature. These hypotensive events range from minor events (e.g., pre-faint without loss of consciousness) to severe events that can be characterized by convulsions or seizures, for example. Rarely, donor deaths have been reported that are related to a plasma donation. Overall, plasma donations in the U.S. have an excellent safety record (8).

To minimize the risk of hypotensive events, plasma collection organizations historically developed various nomograms to determine target collection volumes. Due to their complexity and potential variations across and within sites, they were prone to human error. To address this risk and simplify the process, in 1992, the U.S. Food and Drug Administration (FDA) introduced a standard nomogram that all plasma collection establishments could adopt without needing further review by the agency. This 1992 nomogram has been widely used across plasma collection centers in the U.S. It categorizes donors by weight into three categories, determining which of three target volumes a donor is eligible to give. The nomogram solely considers weight; other factors included in prior nomograms and known to influence plasma volume, such as height, hematocrit, and gender, do not influence target volume determination by this nomogram (9,10).

The limitation to three weight-based categories is a weakness of the 1992 nomogram. An analysis of data from over 100,000 donations highlighted a few theoretical concerns (Figure 1). The percentage of their total plasma volume that donors donate can range from 15–42%, almost a threefold difference between the highest and lowest values. Donors with the lowest total plasma volume generally donate the highest percentages of their plasma volumes, and donors with very high plasma volumes are capped to donate less than they could. This is particularly relevant in light of the demographic shifts and the increase in average weight that occurred since the early 1990s when the standardized nomogram was first introduced. Moreover, because of the stepwise approach, a donor’s target collection volume can vary significantly depending on a weight difference of as little as 1 lb (10). For example, using the standard U.S. nomogram, a 150 pound donor donates 125 mL more plasma than a 149 pound donor. These shortcomings are reflected to varying degrees in other countries, many of which use weight-based plasma collection nomograms.

Figure 1 Large-scale (>100,000 collections) data set of U.S. plasma donations following the U.S. FDA 1992 nomogram for plasma collection, showing the percentage of collected plasma volume (target volume) of the total plasma volume (calculated) relative to the total plasma volume of the donor. Each red dot represents one collection. The three red bands of collections are a result of the three weight bands introduced by the U.S. FDA 1992 plasma collection nomogram. Adapted from Hartmann et al. (10) “Source plasma collection in the United States: Toward a more personalized approach”. Am J Hematol 2020;95:E139-42.

Advent of novel methods to safely personalize plasma collections

Given the advent of reliable plasma collection system technology with programmable software that reduces, if not eliminates, human error, new and more personalized nomograms are now possible again. Indeed, a continuous nomogram for plasma collection, integrating the weight, height, and hematocrit of the donor was recently tested in a randomized controlled trial (RCT) of over 3,000 source plasma donors and over 23,000 plasma collections. The technology-enabled software uses a nomogram that calculates the estimated total plasma volume of the donor on the day of the donation and applies a consistent 28.5% of estimated total plasma volume as target to all donors, with a cap of 1,000 mL for the maximum plasma collection volume. This RCT, the IMPACT (IMproving PlasmA CollecTion) trial (NCT04320823), showed that the safety of this personalized nomogram was non-inferior to the 1992 nomogram, while collecting on average ~8% more plasma across the donor population. This volume increase was the result of the higher allowable maximum donation volume in the context of changed donor demographics. Important to note is that with this novel nomogram ~75% of donors were able to donate more, while ~25% were limited to donate less plasma than before (11).

Further analysis of the IMPACT trial data showed that repeat donation rates and donor deferral rates were unchanged with the new nomogram, suggesting that there were no significant issues with donor comfort or safety during the approximately 12 weeks long trial (12).

With the novel nomogram in use by some plasma collection centers, there is now large-scale real-world data (RWD) to analyze the safety profile of this novel technology. An initial analysis was conducted roughly one year into the introduction of the new nomogram in the U.S., comparing close to 5 million source plasma collections with the novel nomogram to collections according to the old nomogram. The RWD analysis confirmed the non-inferior safety profile and the average plasma yield gain (based on analysis of target volumes). While deferral data were not available in this RWD dataset, donation frequency was. Multiple analyses, such as a comparison of monthly donation rates, a comparison of week-to-week return donations, and a mirrored framework analysis, suggested no impact with the introduction of the novel technology in a real-world setting (13).

Recently another plasma collection system was cleared by the FDA that subsequently also received clearance for an individual nomogram. This platform was tested in a clinical study demonstrating its technical performance in 124 evaluable products (14). Larger-scale data, especially safety data has not been published as of the date of this review, nor the exact algorithm or nomogram used in the technology.

Other methods of personalization have also been explored, especially outside of the U.S. where the 1992 FDA nomogram does not apply. For example, the nomograms used in the Germany-based IPS (Individualisiertes PlasmaSpendeprogramm) study maintain a tiered weight-based approach while also adding the second dimension of baseline immunoglobulin G (IgG) to determine allowable donation frequencies and maximum volumes. As of the published interim analysis containing almost two million donations across ten years, results suggest no safety impact compared to donations conducted under current country guidelines (15). Similarly, Japan has for years implemented a continuous, personalized approach for target volume determination. Factors influencing the target volume in Japanese plasma donors are weight, height and gender. The maximum for each individual collection is capped at 12% of total blood volume or 600 mL (16). In Quebec, Canada, “the volume of plasma collected (455, 500, 625, 750 or 800 mL) depends on the donor’s weight and size. This quantity corresponds to less than 18% of the donor’s estimated blood volume.” (accessed on 10/15/2024, at: https://www.hemaquebec.ca/en/plasma-donation).

Opportunity for further modifications to improve individual donor safety

While the personalization with these technologies is a welcome step in the right direction, it appears that certain populations continue to show higher hypotensive donor adverse event rates than others (e.g., female donors, donors 21 years and younger, first-time donors). This suggests that further personalization for example by gender, age and donor status is warranted. Such changes could be facilitated by technology enabled nomograms and plasma collection devices that allow operation of complex personalization algorithms while minimizing the risk of human error.

As further modifications are considered globally, it is important to keep donor safety at the forefront. This will require a systematic approach to identify and address evidence gaps regarding adverse events (17). While hypotensive events are immediate and can be studied well in the context of clinical studies in donor centers, other aspects of donor health should be equally addressed. This includes long-term effects of donation, such as potential reduction in plasma-based proteins, specifically immunoglobulins (15). While the IMPACT trial data analysis included longitudinal data and it did not show a significant increase in donor deferral rates, and the repeat donation rates were similar, the trial design did not allow study of effects beyond the 12-week trial duration. Likewise, the real-world data analysis is limited in that while it was based on a large data set over a full-year period, it lacked direct donor deferral data or information about protein levels, and the number of donations available in the earlier half of the year was comparatively low. The IPS interim analysis found that IgG concentrations remained at consistent levels after an initial drop at the initiation of donations (15). Sufficiently powered longitudinal analyses are needed to rule out potentially detrimental effects of long-term donation under different personalized nomograms with higher intensity for select donors.

Possible protein depletion and potential clinical sequelae, such as weakened immune response, higher rate of respiratory infections, etc., appear to be the most important to follow up. Other concerns that have been raised over the years include the theoretical risk of osteoporosis in response to exposure to anticoagulants over extended periods of time, as well as concerns about potential increase in hematological malignancies. Causal relationships for these issues have never been proven, but were rightfully raised and studied. Based on observational data it appears unlikely that there is a high risk of osteoporosis nor hematological malignancies, such as leukemia, lymphoma, and myeloma (18,19). However, additional research specifically targeting plasma donations at maximum allowable volumes and frequencies could provide stronger evidence to overcome concerns. On the other hand, some studies have also shown potential benefits of regular plasma donations, including blood pressure and cholesterol reduction for some donor groups (20,21). Likewise, the data are not strong enough for any definitive conclusions. It is reasonable, however, to think that these potential benefits may similarly vary from donor to donor. In other words, there may be personalized benefits along with personalized risks as discussed previously.

Conclusions

As initiatives like patient blood management (PBM) and more personalized PDMP dosing regimens drive precision medicine on the patient side, there is an opportunity for increased personalization on the donor side as well. Plasma donation builds a bridge between donors and patients. Personalizing plasma donation extends that bridge, aiming to enhance outcomes for both.

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-24-22/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-24-22/coif). J.H. is the Chief Medical Officer for Haemonetics, a manufacturer of medical devices, including plasma collection systems. E.H. is an employee of Haemonetics, a manufacturer of medical devices, including plasma collections systems. 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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