Skip to main content
NCBI home page
Stem Cell Reports logoLink to Stem Cell Reports
. 2023 Jun 29;18(8):1610–1620. doi: 10.1016/j.stemcr.2023.05.017

Unproven cell interventions in Poland and the exploitation of European Union law on advanced therapy medicinal products

Józef Dulak 1,3,∗, Marlena Pecyna 2,3,∗∗
PMCID: PMC10444563  PMID: 37390824

Summary

The global threat of unproven “stem cell therapies” develops despite the repeated statements of scientific organizations and regulatory agencies warning about the improper rationale, lack of effectiveness, and potential health risks of such commercial activities. Here, this problem is discussed from Poland’s perspective, where unjustified “stem cell medical experiments” have raised the concern of responsible scientists and physicians. The paper describes how the European Union law on advanced therapy medicinal products and the hospital exemption rule have been used improperly and unlawfully on a mass scale. The article indicates serious scientific, medical, legal, and social issues of these activities.

Keywords: unproven cell therapies, advanced therapy medicinal products, hospital exemption, ATMP-HE, stem cells, stem cell therapies

Unproven commercial interventions, improperly called “stem cell therapies” are a serious global problem. In this perspective, Józef Dulak and Marlena Pecyna analyze the scientific, social, and legal aspects of this business in Poland. The paper describes how the European Union law on advanced therapy medicinal products and the hospital exemption rule have been used improperly and unlawfully on a massive scale.

Introduction

Patients in many countries are exposed to unscrupulous offers of unproven cell interventions called “stem cell therapies” (SCTs; this abbreviation is used herein only in regard to unproven interventions, not justified stem cell-based therapies). The problem is global, and countermeasures have so far not been very effective (Master et al., 2021; Marks and Hahn, 2020). Despite the clear statements of international scientific organizations and regulatory agencies (ISSCR, 2021; European Medicines Agency, 2020; EASAC-FEAM, 2020; The Interacademy Partnership, 2021; see also Fears et al., 2021; Turner et al., 2021), unregistered therapies are still available in some European countries. The business has flourished due to the exploitation of existing rules, the lack of awareness among patients and the medical community, and the growing hype associated with stem cells, generally portrayed inaccurately as panacea for untreatable conditions. This leads to playing the legal system and manipulating public opinion, even exploiting justified stem cell-based approaches that claim to allegedly support commercial offers (Sipp, 2017).

The cell therapies used in Europe meet the definition of advanced therapy medicinal products (ATMP), based on which the Committee for Advanced Therapies of the European Medicines Agency (CAT EMA) specifically recommends to determine whether a product based on genes, cells, or tissues falls, for scientific reasons, within the definition of an ATMP (Regulation (EC) No 1394/2007, 2007). However, this recommendation does not mean that by this statement the CAT EMA accepts the treatments with those ATMPs. In fact, in Europe, only Holoclar and Alofisel have active EMA registration, in addition to a few registered gene therapy products using autologous hematopoietic cells (Iglesias-Lopez et al., 2021; Dulak, 2021).

The global problem of SCT is discussed herein from the Polish perspective. Indeed, the unproven SCTs in Poland reflect also the global situation, which has reached a level that could affect the right for justified treatments in many countries (Hills et al., 2020; Iglesias-Lopez et al., 2021; Cuende et al., 2022). We demonstrate how the activities of private entities exploit the regulation of ATMPs provided as hospital exemptions (ATMP-HE) (Hills et al., 2020; Iglesias-Lopez et al., 2021; Cuende et al., 2022). Moreover, in Poland this problem most often manifests as offers presented with a token of legitimacy. This is because they are provided to patients with claims of scientific and medical rationale. Moreover, they are presented as fulfilling the legal regulations as being accepted by bioethical commissions.

The landscape of commercial cell therapies in Poland

In Poland, SCTs are advertised for numerous conditions, from cosmetic uses through orthopedic problems, severe neurological diseases and developmental problems, to inherited blindness, muscular dystrophy, and other diseases, even infertility. Some of these applications, but only a minority—particularly the cosmetic and orthopedic ones—are offered by small private entities, in which typically the patients’ own cells, isolated from blood or adipose tissue (although also allogeneic umbilical cord-derived cells), are injected as stem cells. The extent of these small businesses is not fully known; one advertising website lists 35 private clinics in Poland offering stem cells (Komórki macierzyste, 2023), but the number 50 is also mentioned.

These SCTs, addressed mainly to adults, as with stem cell business in the United States (Murray et al., 2020), will not be discussed here. We focus on some clinics, often closely linked with academic institutions, that provide commercial SCT interventions classified as HEs for a number of severe conditions in children and adults. These entities support their business with claims of medical and scientific legitimacy and statements of full agreement with European and national law.

Unproven cell interventions in Poland provided as HEs began in the previous decade and have been associated with advertising for the banking of cord blood and umbilical cord cells. Formally, the medical experiments with cells as medicine should be introduced in Poland according to the law (Figure 1). Initially, the cell bank registers the production of cells at the Chief Pharmaceutical Inspectorate, (CPI, or GIF in Polish). After evaluating the conditions of cell manufacturing, the CPI issues a statement: agreement on production according to the GMP rules. Moreover, the producer submits the application to CAT EMA, which, based on an analysis of the product, can qualify it as an ATMP. Importantly, this is solely confirmation that the product meets the requirements of ATMPs. It means that the product is based on genes, tissues, or cells and is presented as having properties for or is used or administered to human beings with a view to regenerating, repairing, or replacing human tissue. Therefore, such a decision of the CAT EMA (and Polish CPI) cannot be recognized as confirmation of the declared biological and medical activity of a given ATMP, and this is clearly stated in the CAT EMA documents. As outlined below, the proper scheme shown in Figure 1 is abused due to the breach of EU regulations and improper application of ATMP-HE provisions (Table 1).

Figure 1.

Figure 1

Open in a new tab

How the procedure of ATMP-HE should be applied before clinical trials according to the law

Table 1.

Summary of the differences between Polish and EU law

European law Polish regulation
REGULATION (EC) No 1394/2007 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004
Article 28 Amendments to Directive 2001/83/EC (…)
7. Any advanced therapy medicinal product, as defined in Regulation (EC) No 1394/2007, which is prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient.		 Pharmaceutical Law Act of 6 September 2001 (with later changes)
Article 2 p.33b
ATMP-HE is an ATMP in the sense of Art. 2 p.1a) of Regulation No. 1394/2007, which is prepared and produced in Poland on a non-routine basis according to specific quality standards and used in the frame of hospital supplies in Poland under the exclusive responsibility of medicinal practitioner as a performance of individually prescribed for a given patient.
Specific requirements of the European law Differences in the Polish regulation
  • -

    used (…) in a hospital;

  • -

    exclusive professional responsibility of a medical practitioner;

  • -

    an individual prescription for a custom-made product for an individual patient.
  • -

    used in the frame of hospital supplies (broader notion than EU law; hospital supplies may be supply in other medical places than hospital only);

  • -

    exclusive responsibility of medical practitioner (broader scope of the physician’s responsibility);

  • -

    individual ATMP prescription for a given patient which is non-routinely manufactured (individual prescription is not the same as individually prescribed: individually prescribed may also be other ATMPs; there is no requirement based on non-routine manufacture for an individual patient).
– Flaws
  • -

    classification as ATMP by CAT EMA and consent to manufacture issued by CPI are advertised as confirmation of ATMP utility/effectiveness for a given disease

  • -

    lack of an official registry of ATMP-HEs (only list of producers available)

  • -

    ATMP given multiple times to many patients with various diseases

  • -

    ATMP offered as a commercial treatment that is advertised

  • -

    lack of proper safety monitoring and reporting of side effects and effectiveness

  • -

    lack or delay in publication of results; poor quality of publications

  • -

    lack of randomized clinical trials
Open in a new tab

The restricted application of unproven and unregistered treatment to patients in Europe as hospital exemptions is possible in accordance with Art. 28 (2) of Regulation 1394/2007. An ATMP-HE is any ATMP that is prepared on a non-routine basis according to specific quality standards and used within the same member state in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for a given patient (Regulation (EC) No 1394/2007, 2007). A physician who wants to treat a patient should apply to the bioethical commission for a positive opinion on an ATMP-HE. According to the rules and the obvious meaning of “exemption,” the application should be for the individual patient. However, as indicated below, there are numerous flaws in the procedure.

In Poland, the cells commercially offered to patients as an ATMP-HE are most often umbilical cord Wharton’s jelly cells, less frequently adipose tissue-derived cells and cord blood (see below). Of note, the proponents call them “experimental therapies” or even “proven therapies,” as advertised on the website addressed to potential customers (Moc komórek, 2023). More information is provided by the Polish Bank for Stem Cells (PBKM, 2023), one of the registered ATMP-HE producers in Poland (as announced, PBKM is the largest commercial cell bank in Europe and the third largest in the world). The analysis reveals that bioethical commissions have approved multiple injections to different sites (intravenously, intrathecally, and into the eye) in numerous patients suffering from unrelated conditions (PBKM, 2023).

The business apparently exploits loopholes in the current regulations, similarly as in other countries (Ikonomou et al., 2016). However, in addition to these legal concerns (discussed below), there are also numerous biological and medical issues with these unproven interventions. Firstly, Wharton’s jelly cells are propagated in vitro for numerous passages; they are allogeneic but are injected without checking their immune compatibility with the patients. This approach is based on the common dogma that so-called mesenchymal stem cells (MSCs) are particularly immune tolerant to patients (for a review, see Rowland et al., 2021), despite numerous studies showing that allogeneic MSCs induce an immune response (see, for example, Ankrum et al., 2014; Rowland et al., 2021). In fact, the immune response can add to the known effect of very fast elimination of MSCs trapped in the lung after intravenous injection, as within hours after delivery, no live MSC can be found (Bianco et al., 2013).

Furthermore, among the risks associated with the injection of allogeneic cells into heterologous sites, it is necessary to consider the aggravation of thrombosis due to the expression of tissue factor in MSCs (Christy et al., 2017; Coppin et al., 2019; Moll et al., 2022). Therefore, a call for an improvement in the minimal criteria for MSCs to maximize patient safety was recently raised to include an evaluation of the tissue factor and hemocompatibility of MSC products (Moll et al., 2022). However, acknowledging this proposal, one must remember the lack of biological and medical rationale for using Wharton’s jelly or other “MSCs” for so many unrelated conditions (Sipp et al., 2018a).

The proponents of SCTs claim that their approaches are effective. However, the patient testimonials, non-reviewed stories told by physicians offering these SCTs, and disputable publications on unjustified treatments constitute doubtful proof (Rubin, 2018). Furthermore, the reasons for the temporary improvement reported by the patients cannot be verified, as the patients may be receiving other treatments or undergoing rehabilitation in addition to the SCT. Concerns are, for example, raised about corticosteroids that could be administered together with SCTs, and patients could feel temporarily better after such treatment (Rubin, 2018).

In Poland, unproven ATMP-HEs are offered in the form of “therapeutic experiments” (according to Art. 21 p. 2 of the Polish Act on the Professions of Physician and Dentist). On the basis of that, such SCTs are claimed to be applied according to European and Polish law. However, it should be stressed that HEs were considered largely for use by clinical researchers to carry out cutting-edge treatment, under exceptional circumstances and to a few patients (under the legal definition, for an individual patient), and used on a non-routine basis. This does not amount to permission to develop a commercial product without CAT EMA registration (Hills et al., 2020; Coppens et al., 2020; Cuende et al., 2022).

Meanwhile, the regulation of the HE procedure of cell therapy in several analyzed European countries, including Poland, appears to be far from adequate (Hills et al., 2020). The Polish CPI states (unofficially) that “non-commercial production means no more than 20–50 cases per year” (Hills et al., 2020). Meanwhile, this number is much larger (see below). It also appears that there are no reporting obligations under Polish law, and there is the question of proper follow-up of the patients. This raises important ethical issues about offering patients commercial treatments without a robust scientific rationale (Hills et al., 2020).

Analysis of commercial offers of SCTs in Poland provided as hospital exemptions

Although the official numbers of these unproven SCTs in Poland are unknown, their extent can be calculated based on some available information. Consequently, in commercial advertisements, the PBKM reported on the preparation of stem cells for the treatment of 3,000 patients. In a recent statement published on social media, the PBKM informed that 1,846 preparations of Wharton’s jelly-derived cells have been processed (PBKM, 2022). On another webpage, but also run by this private bank (Moc komórek, 2023)—called “The Power of Cells: We choose proven cellular therapies”—one can learn that 22 healing centers have treated 1,500 patients. The latter website also states that in Poland from 2014 to 2020, MSCs were administered to 1,500 patients, “which means that every month about 30 new patients join the therapy” (Moc komórek, 2023). Note that this website states that the treatments offered in Poland as medical therapeutic experiments are confirmed cellular therapies (in Polish, potwierdzone terapie komórkowe). More information on unproven SCTs provided as HEs is available on the PBKM webpage named “List of lifesaving transplantations” (PBKM, 2023). Based on that, the following data on the use of Wharton’s jelly cells in “experimental therapies” in Poland can be presented.

Accordingly, from 2011 to 2022 (the data on the website were for December 1, 2022), 1,868 patients in Poland were injected with Wharton’s jelly cells, of which 1,790 received the cells as an “experimental therapy”; the remainder was part of “clinical trials,” as stated on the website. In addition, 43 patients were injected with adipose tissue-derived cells and 20 with cord blood-derived cells. Figure 2A shows how many patients in a given year were injected with Wharton’s jelly cells. The number increased very much in the period 2015–2018, decreasing by half or more from 2020 to 2022 (Figure 2A). The reasons for this decrease are unknown, though the COVID-19 pandemic and/or warnings about the unproven nature of these treatments might have played a role, as such awareness-raising became more prevalent in the beginning of autumn 2019. Among the conditions claimed to be treated, the largest number of patients (1,255) suffered from various neurological problems, followed by ophthalmologic and orthopedic patients (Figure 2A). The highest number of patients were children (the majority of which were under 10 years of age) (Figure 2B). In total, more than 95 different neurological conditions are listed as being treated (Table S1). Most of them (50) included only one patient (Figure S1A); however, there are 20 disorders in which more than 10 patients have been injected (Figure S1A), with cerebral palsy, amyotrophic lateral sclerosis (ALS), and autism, in which more than 150 patients have been exposed to these cells (Figure S1B). Within ophthalmologic patients, conditions such as optic atrophy, retinitis pigmentosa, and Stargardt’s disease have mostly been treated (Figure S1C).

Figure 2.

Figure 2

Open in a new tab

Unproven cell interventions with Wharton's jelly cells in Poland

(A) Number of patients with different types of diseases in Poland injected with Wharton’s jelly cells from 2011. The most frequent were neurologic, ophthalmologic, and orthopedic applications, shown separately. The others are listed in Table S1.

(B) Number of patients by age injected with these cells; based on data available at https://www.pbkm.pl/en/about-us/list-of-life-saving-transplantations.

The website does not provide information on the number of injections to individual patients. However, a private clinic stated that since 2015, several hundred injections have been given to more than 150 patients. According to information provided by a bioethical committee, Wharton’s jelly cells were administered in the period 2018–2020 to more than 220 children, who received more than 750 injections in total. A Facebook profile of a child suffering from Krabbe disease states that this now 7-year-old boy has received 31 injections of Wharton’s jelly cells. As presented in Figure S1, at least seven neurological conditions and two ophthalmologic diseases involved more than 30 patients. This raises questions about the rationale and outcome of these injections and, more importantly, the classification of so many treatments as HEs.

Analyses of PubMed revealed several publications from private institutions that offer commercial therapies (Barczewska et al., 2019, 2020; Siwek et al., 2020; Boruczkowski and Zdolińska-Malinowska, 2019a, 2019b; Świątkowska-Flis et al., 2021). However, the studies were not randomized, the patient groups analyzed were heterogeneous in terms of disease and age, the patients received various numbers of injections, the “control” groups did not exist or were created from publicly available sources from numerous unrelated studies, and the methods for monitoring patients were poor. Furthermore, taking into account the number of patients listed in the PBKM database and those reported in the articles, it is evident that the majority of data have not been published so far, as is the case with ophthalmologic disease, for example. In the latter, at least in a few cases, very serious consequences (loss of vision) have been claimed to occur, which were reported to the prosecutor (as announced on the radio program “Eksperyment” [“Experiment”] from October 4, 2022) (Janczura, 2022).

The total economic value of this business in Poland is not known. According to a 2018 report of the International Society for Cell & Gene Therapy, the global SCT market, which affects 60,000 patients, is estimated at $2.4 billion, but Poland is not listed among the countries (Master et al., 2021). Some assumptions on the costs of SCTs provided as HEs in Poland can be made based on online data. A commercial website stated that three injections of Wharton’s jelly cells, which are claimed to help for ALS, cost 54,000 PLN (about 13,000 EUR). The patients were also offered advice on finding a bank that could give them a loan for such treatment. Another document stated that the price of 10 injections of MSCs in a patient with an unknown neurological condition was assessed at 237,000 PLN (which in 2016 was equivalent to approximately 55,000 EUR).

Overall, based on information available on the internet, one can presume that the cost of one injection was about 10,000–20,000 PLN (about 2,200–4,400 EUR), which in case of 30 injections amounts to about 300,000 PLN using the lowest estimate (this is the equivalent of about 70 months of median net salary in Poland).

Consequently, the pecuniary damage and non-pecuniary injury to patients and their families can be serious. Unproven interventions are expensive, although the promoters of these businesses in Poland present their approach as cheaper than similar injections offered in other countries.

Another problem is the kind of information that is provided to patients when a “treatment” is offered. Advertisements on websites clearly call the interventions “stem cell therapies,” which apparently is attractive to both patients and some physicians who are unaware of the complexity of the field. Consequently, there are concerns about the competence of the bioethical commissions evaluating the application of ATMP-HE and the understanding of the commissions’ members regarding the complexity of stem cells, the experimental nature of numerous therapies, and the lack of a rationale for the treatment with a single (allogeneic) cell type for so many diseases. The agreements of bioethical commissions to multiple injections of allogeneic cells to heterologous sites in the same person and to treatment of hundreds of children with the same disease raise serious alarms.

Legal analysis of the problem: Breach of EU Regulation No. 1394/2007

The definition of an ATMP-HE describes the special legal status of advanced therapy medicinal products. An ATMP that cannot be qualified as an HE may only be placed on the market with the authorization of the proper member state authority, in accordance with Directive 2001/83 or with Regulation No. 726/2004. It is important to keep this in mind because there are serious doubts concerning Polish law. The Polish legislature decided to implement the notion of ATMP-HEs from Regulation No. 1394/2007 into Polish Pharmaceutical Law by amending the statute in 2018, but there is a difference between the definitions of an ATMP-HE in Regulation No. 1394/2007 and the Polish Pharmaceutical Law (Table 1).

According to Regulation No. 1394/2007, an ATMP-HE refers to an ATMP produced in accordance with a particular recipe for an individual patient, and not an ATMP individually prescribed for a given patient. In fact, an individually prescribed ATMP can also be produced for many patients; this is not the same as an individual, particular prescription for a given patient. Therefore, the analysis of Polish law leads to the conclusion that it is incompatible with EU law.

Under Art. 38a of the Pharmaceutical Law, an ATMP-HE is manufactured with the consent of the Polish CPI. The applicant declares that its application concerns an ATMP or ATMP-HE without needing to prove that the product is manufactured for a given patient. Polish law even assumes that an ATMP-HE will be manufactured and used for many diseases, because the applicant must specify (in the application) the types of disease to which the ATMP-HE will apply. The application for authorization does not require the submission of preclinical or clinical data or any information concerning the mechanism of action in order to justify the intended therapeutic use. The CPI does not consider whether an ATMP product will be made for an individual patient according to the individual recipe prepared by the physician. This decision is used by physicians in private companies to apply such manufactured ATMP as HE in hundreds of cases, which breaches the principle of hospital exemption.

Under Polish law, there is no control of or information about the number of ATMP-HEs manufactured on the basis of the authorization made by the CPI (Hills et al., 2020). There is only a public list of ATMP-HE producers. The requirement of “non-routine” manufacturing is also beyond the control of any public authority, as is the individual use of manufactured ATMPs as HEs. The CPI does not decide on the use of ATMP-HEs (cf. Hills et al., 2020). The other serious problem under Polish law goes beyond the interpretation of the “non-routine” requirement: Polish law regulates ATMP-HE manufacturing as de facto mass production and use of these products without public control. This is a different situation from that in other EU member states, where there is a discussion about standards for “non-routine” manufacturing of ATMPs as HEs (Hills et al., 2020).

Polish law does not implement a procedure of compassionate use as established by Art. 83 Regulation (EC) No. 726/2004, which allows for the use of an unauthorized medicine. For this purpose, a drug must undergo clinical trials or have entered the approval application process. While early studies will generally have been completed, its safety profile may not be fully established. In the status quo are interested businesses that apply ATMP-HEs in many cases (patients and diseases) without applying to register the medicine, but only on the basis of the CPI’s authorization to manufacture the ATMP.

By comparing Polish law with the systems of other EU member states, it can be seen that Poland is an exemption in terms of the content of the regulations, as well as its applications. Taking this into account, an amendment to the Polish law is needed. The definition of ATMP-HEs should comply with Regulation No. 1394/2007. A comparison with other EU national regulations shows that the regulatory standards and authorization of ATMP-HEs should be harmonized throughout Europe. The most important factor is using ATMP-HE according to the actual state of knowledge, in a limited number of patients and for a restricted time. The law should protect this requirement in regulations concerning the application of ATMP-HEs within a clear, transparent procedure.

Issues propagating the problem

Undoubtedly, the main reason for the perpetuation of unproven SCTs in Poland is the same as in other places: the recognition of stem cells as a panacea by both the public and unfortunately also some physicians. This misconception is the basis for the direct-to-consumer marketing (Sipp et al., 2018b).

The severity of the unjustified SCTs in Poland is aggravated at numerous levels, firstly by the involvement of some academic physicians and the links between private clinics and medical universities. Private businesses also receive state-funded grants to conduct clinical trials with SCTs based on poorly justified rationales. Apparently, in Poland a few years ago, the expectations of funding bodies for the rapid development of innovative therapies mixed with the insufficient knowledge of reviewers led to not only funding of the proposal to apply deer horn “stem cells” for medical purposes but also the acceptance of applications of Wharton’s jelly cells for various conditions. In this way, the proponents of these unproven treatments receive a kind of scientific legitimacy. The SCT business can then use the fact that research grant support is available as a justification for the same activities offered commercially. As such, funding agencies expecting fast applications while not preserving the quality of the review process add to the problems.

This hype is also related to the promotion of cord blood banking, with claims that these stored cells can be used in the future for treating a baby in the case of disease, forgetting that autologous applications of cord blood are limited (Passweg et al., 2021). Obviously, such an activity of a private bank, which is also the supplier of ATMP for “therapies,” cannot be adequately assessed by laypeople who are unable to recognize the discord between the claimed rationale for cell banking for private use and its unjustified therapeutic applications.

Advertising is also intensified by business-supported articles, for example, in the main journal of Polish physicians, Gazeta Lekarska, as well as online activities directed at a larger audience. In these materials, information about some potentially (although not proven) legitimate experimental approaches (such as using bone marrow stromal cells to treat graft-versus-host disease) is mixed with patients’ “testimonials” or physician stories on the unproven effects of Wharton’s jelly cells.

Notably, this promotional activity was supported by legal regulations on around-birth medical services, which obliged medical professionals to inform patients about the possibility of cell banking, though this service is, in fact, only offered by private companies, one of which dominates. It should be noted that this regulation has recently been removed by the Polish Ministry of Health as a consequence of the action of journalists highlighting the problem.

There is also an apparent conflict of interest of some academic physicians. Their participation in “stem cell” clinics can be recognized as a token of the legitimacy of this business (Sipp et al., 2017). There is a concern about revealing such a conflict when publishing papers that support the unproven SCTs.

There are concerns about the work of bioethical commissions, which can even have members of the personnel employed in private “stem cell” business. Insufficient knowledge on stem cells and cellular therapies and a lack of knowledge about the ATMP-HE rules can be recognized in decisions that positively evaluated the application of “stem cells” in so many patients with so many different medical problems. There is apparently insufficient or even no supervision of the bioethical commissions, which are supposed to control the performance of the therapeutic experiments. In Poland, there is no registry of side effects for treatments applied as HEs. Consequently, the extent of side effects is in fact unknown, and patients or parents may not report side effects if they are not properly monitored (Akkas et al., 2022).

Finally, it is important to note that the activity of some patients, consumer advocacy groups, and journalists can increase the use of hyped clinical interventions (Sugarman et al., 2018). This happened recently in Poland, when after warnings about unproven SCTs (see below), requests for the allowance of “last chance” therapies appeared. This should not be mistaken with the “compassionate use” according to the CAT EMA regulation, as these cases do not meet its requirements. In fact, claims about “last chance therapies” are presented as an emotional argument, again suggesting that SCTs are legitimate and proven.

Actions undertaken by scientists, physicians, and journalists

Recently, in April 2022, the Polish Supreme Medical Council, which represents all physicians in Poland, issued a statement prepared by its special expert group (Naczelna Rada Lekarska, 2022). In this document, patients and medical professionals are warned about the threat of unproven interventions offered by private clinics, the danger that potentially threatens patients and in consequence also affects scientifically and medically legitimate experimental approaches. The council’s statement stemmed from the previous activities of other professional groups in Poland. In 2016, after the first ISSCR guidelines were published, the Polish Ophthalmological Society issued a public statement warning against any unjustified SCT that is claimed to have a therapeutic effect on blindness. The Biotechnology Committee of the Polish Academy of Sciences (PAS) in 2014 raised the alarm about the unjustified state financial support for the deer horn “stem cells” mentioned above. In September 2019, the Biotechnology Committee issued a letter to the Polish authorities responsible for controlling the procedures of transplantation and cell therapies. A few months later, this statement was highlighted by publications in the journal Polityka that described the business of unproven cell therapies in Poland (Rotkiewicz and Walewski, 2019). Then, the CAT EMA warning statement was published on April 28, 2020, followed by the EASAC-FEAM report on regenerative medicine (June 2, 2020). The concerns of both the CAT EMA and EASAC-FEAM were the same as raised by the PAS Biotechnology Committee in September 2019. Recognizing the importance of the educational activity, the PAS and its Biotechnology Committee on November 2020 organized an open webinar, attended by more than 400 people, in which the EASAC-FEAM report was presented (Polish Academy of Sciences, 2020). The ongoing discussion and growing concerns led to the Supreme Medical Council’s statement mentioned above. Finally, in October and November 2022, several hours-long radio broadcasts on the radio station TOK FM described in detail the SCT business in Poland. This was followed by the reaction of several authorities, raising the hope of clarifying the problem.

Counteractions of private industry

In response to the warnings raised by the international and Polish scientific organizations, the proponents of unproven cell interventions undertook counteractions. First, they claimed that the concerns raised by the CAT EMA do not apply to the private cell industry in Poland, stating that their interventions are performed according to rules and that SCTs are proven therapies (Moc komórek, 2023). Apparently, the language used by private entities in Poland offering unjustified interventions is based on the exploitation of well-known tricks, as indicated by Sipp et al. (2017). Scientists and journalists are sued and scared by demands for high compensation (Rotkiewicz and Walewski, 2019; Rynek Zdrowia, 2021; Rotkiewicz, 2021, 2022; Janczura, 2022). Complaint letters are issued by private entities to the authorities of scientific institutions accusing scientists of wrongdoing (Committee of Biotechnology and Polish Academy of Sciences, 2021). In response to such unacceptable threats, the PAS authorities in September 2020 issued a statement defending the freedom of scientific discussion (Polish Academy of Sciences statement, 2020).

Conclusions

There is an urgent need to harmonize Polish law with the European regulations and to directly apply Directive 1394/2007 into Polish law. The CPI should clearly define the extent to which it agrees for the production of ATMP. ATMP producers should not be involved in the active promotion of unproven interventions based on the cell products they provide. Bioethical commissions should properly assess the applications of ATMP-HE-based treatment experiments. The rules of HE as a real exception offered to individual patients on the basis of a personalized prescription must be strictly applied, and the exploitation of HEs should be limited in accordance with the rule of law. All these countermeasures, together with the concerted educational actions of scientists and some physicians in Poland, as well as global efforts (Master et al., 2021), can hopefully stop the spread of this business.

Resource availability

Corresponding authors

jozef.dulak@uj.edu.pl and marlena.pecyna@uj.edu.pl.

Author contributions

Both authors contributed equally, conceived the idea, analyzed the data, and wrote the text.

Acknowledgments

The critical reading of the manuscript by Prof. Agnieszka Łoboda is highly appreciated. The crucial and helpful comments of two anonymous reviewers are greatly acknowledged. The cost of publication was covered by the statutory funds of the Department of Medical Biotechnology of the Jagiellonian University.

Conflict of interests

No financial support was obtained for the preparation of this work. J.D. is a member of the Presidency of the Biotechnology Committee of the Polish Academy of Sciences, which announced the scientific opinions on unjustified cell therapies. J.D. is a defendant in an SLAPP (strategic lawsuit against public participation) lawsuit designed by a private bank to block or limit public debate about the risks of unproven therapies. M.P. is a member of the Biotechnology Committee of the Polish Academy of Sciences. M.P. is the defendant’s attorney in the above-mentioned SLAPP lawsuit by the private bank. The Department of Medical Biotechnology of Jagiellonian University is a member of the EuroGCT consortium (www.eurogct.org) but does not receive any financial support.

Footnotes

Supplemental information can be found online at https://doi.org/10.1016/j.stemcr.2023.05.017.

Contributor Information

Józef Dulak, Email: jozef.dulak@uj.edu.pl.

Marlena Pecyna, Email: marlena.pecyna@uj.edu.pl.

Supplemental information

Document S1. Figures S1 and Table S1
mmc1.pdf (132.8KB, pdf)
Document S2. Article plus supplemental information
mmc2.pdf (2.8MB, pdf)

References

  1. Akkas F., Turner L., Richardson E. Adverse events related to unapproved stem cell products and other regenerative interventions: recommendations for more robust regulation of the direct-to-consumer marketplace. Regen. Med. 2022;17:63–68. doi: 10.2217/rme-2021-0124. [DOI] [PubMed] [Google Scholar]
  2. Ankrum J.A., Ong J.F., Karp J.M. Mesenchymal stem cells: immune evasive, not immune privileged. Nat. Biotechnol. 2014;32:252–260. doi: 10.1038/nbt.2816. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barczewska M., Grudniak M., Maksymowicz S., Siwek T., Ołdak T., Jezierska-Woźniak K., Gładysz D., Maksymowicz W. Safety of intrathecal injection of Wharton’s jelly-derived mesenchymal stem cells in amyotrophic lateral sclerosis therapy. Neural Regen. Res. 2019;14:313–318. doi: 10.4103/1673-5374.243723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barczewska M., Maksymowicz S., Zdolińska-Malinowska I., Siwek T., Grudniak M. Umbilical cord mesenchymal stem cells in amyotrophic lateral sclerosis: an original study. Stem Cell Rev. Rep. 2020;16:922–932. doi: 10.1007/s12015-020-10016-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bianco P., Cao X., Frenette P.S., Mao J.J., Robey P.G., Simmons P.J., Wang C.-Y. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat. Med. 2013;19:35–42. doi: 10.1038/nm.3028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Boruczkowski D., Zdolińska-Malinowska I. A retrospective analysis of safety and efficacy of Wharton’s jelly stem cell administration in children with spina Bifida. Stem Cell Rev. Rep. 2019;15:717–729. doi: 10.1007/s12015-019-09902-6. [DOI] [PubMed] [Google Scholar]
  7. Boruczkowski D., Zdolińska-Malinowska I. Wharton’s jelly mesenchymal stem cell administration improves quality of life and self-sufficiency in children with cerebral palsy: results from a retrospective study. Stem Cells Int. 2019;2019 doi: 10.1155/2019/7402151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Christy B.A., Herzig M.C., Montgomery R.K., Delavan C., Bynum J.A., Reddoch K.M., Cap A.P. Procoagulant activity of human mesenchymal stem cells. J. Trauma Acute Care Surg. 2017;83:S164–S169. doi: 10.1097/TA.0000000000001485. [DOI] [PubMed] [Google Scholar]
  9. Committee of Biotechnology. Polish Academy of Sciences Stanowisko Komitetu w sprawie pisma Prezesa PBKM. 2021. https://kbiotech.pan.pl/pl/301-stanowisko-komitetu-w-sprawie-pisma-prezesa-pbkm
  10. Coppens D.G.M., Hoekman J., De Bruin M.L., Slaper-Cortenbach I.C.M., Leufkens H.G.M., Meij P., Gardarsdottir H. Advanced therapy medicinal product manufacturing under the hospital exemption and other exemption pathways in seven European Union countries. Cytotherapy. 2020;22:592–600. doi: 10.1016/j.jcyt.2020.04.092. [DOI] [PubMed] [Google Scholar]
  11. Coppin L., Sokal E., Stéphenne X. Thrombogenic risk induced by intravascular mesenchymal stem cell therapy: current status and future perspectives. Cells. 2019;8:E1160. doi: 10.3390/cells8101160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cuende N., Ciccocioppo R., Forte M., Galipeau J., Ikonomou L., Levine B.L., Srivastava A., Zettler P.J. Patient access to and ethical considerations of the application of the European Union hospital exemption rule for advanced therapy medicinal products. Cytotherapy. 2022;24:686–690. doi: 10.1016/j.jcyt.2022.03.007. [DOI] [PubMed] [Google Scholar]
  13. Dulak J. Gene therapy. The legacy of Wacław Szybalski. Acta Biochim. Pol. 2021;68:359–375. doi: 10.18388/abp.2020_5805. [DOI] [PubMed] [Google Scholar]
  14. EASAC-FEAM Challenges and potential in regenerative medicine: a joint report from EASAC and FEAM. 2020. https://easac.eu/publications/details/challenges-and-potential-in-regenerative-medicine/
  15. European Medicines Agency EMA warns against using unproven cell-based therapies. 2020. https://www.ema.europa.eu/en/documents/public-statement/ema-warns-against-using-unproven-cell-based-therapies_en.pdf
  16. Fears R., Akutsu H., Alentajan-Aleta L.T., Caicedo A., Campos de Carvalho A.C., Čolić M., Cornish J., Cossu G., Debré P., Dierckxsens G., et al. Inclusivity and diversity: integrating international perspectives on stem cell challenges and potential. Stem Cell Rep. 2021;16:1847–1852. doi: 10.1016/j.stemcr.2021.07.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hills A., Awigena-Cook J., Genenz K., Ostertag M., Butler S., Eggimann A.-V., Hubert A. An assessment of the hospital exemption landscape across European Member States: regulatory frameworks, use and impact. Cytotherapy. 2020;22:772–779.e1. doi: 10.1016/j.jcyt.2020.08.011. [DOI] [PubMed] [Google Scholar]
  18. Iglesias-Lopez C., Obach M., Vallano A., Agustí A. Comparison of regulatory pathways for the approval of advanced therapies in the European Union and the United States. Cytotherapy. 2021;23:261–274. doi: 10.1016/j.jcyt.2020.11.008. [DOI] [PubMed] [Google Scholar]
  19. Ikonomou L., Freishtat R.J., Wagner D.E., Panoskaltsis-Mortari A., Weiss D.J. The global emergence of unregulated stem cell treatments for respiratory diseases. Professional societies need to Act. Ann. Am. Thorac. Soc. 2016;13:1205–1207. doi: 10.1513/AnnalsATS.201604-277ED. [DOI] [PubMed] [Google Scholar]
  20. ISSCR Guideliness for stem cell research and clinical translation. 2021. https://www.isscr.org/guidelines [DOI] [PMC free article] [PubMed]
  21. Janczura M. Eksperyment. Radiowy serial dokumentalny. 2022. https://audycje.tokfm.pl/audycja/518,Eksperyment-Radiowy-serial-dokumentalny?offset=2
  22. Komórki macierzyste Komórki macierzyste. 2023. https://www.kliniki.pl/zabiegi-z-uzyciem-komorek-macierzystych/
  23. Marks P.W., Hahn S. Identifying the risks of unproven regenerative medicine therapies. JAMA. 2020;324:241–242. doi: 10.1001/jama.2020.9375. [DOI] [PubMed] [Google Scholar]
  24. Master Z., Matthews K.R.W., Abou-El-Enein M. Unproven stem cell interventions: a global public health problem requiring global deliberation. Stem Cell Rep. 2021;16:1435–1445. doi: 10.1016/j.stemcr.2021.05.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Moc komórek Moc komórek. 2023. https://mockomorek.pl/
  26. Moll G., Ankrum J.A., Olson S.D., Nolta J.A. Improved MSC minimal criteria to maximize patient safety: a call to embrace tissue factor and hemocompatibility assessment of MSC products. Stem Cells Transl. Med. 2022;11:2–13. doi: 10.1093/stcltm/szab005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Murray I.R., Chahla J., Frank R.M., Piuzzi N.S., Mandelbaum B.R., Dragoo J.L., Members of the Biologics Association Rogue stem cell clinics. Bone Joint Lett. J. 2020;102-B:148–154. doi: 10.1302/0301-620X.102B2.BJJ-2019-1104.R1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Naczelna Rada Lekarska Statement of the Supreme medical council. 2022. https://nil.org.pl/aktualnosci/5996-terapie-komorkowe-sukcesy-i-zagrozenia
  29. Passweg J.R., Baldomero H., Chabannon C., Basak G.W., de la Cámara R., Corbacioglu S., Dolstra H., Duarte R., Glass B., Greco R., et al. Hematopoietic cell transplantation and cellular therapy survey of the EBMT: monitoring of activities and trends over 30 years. Bone Marrow Transplant. 2021;56:1651–1664. doi: 10.1038/s41409-021-01227-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. PBKM 2022. https://www.pbkm.pl/o-nas/zapytania-ofertowe/2022/stanowisko-pbkm
  31. PBKM List of life saving transplantations. 2023. https://www.pbkm.pl/en/about-us/list-of-life-saving-transplantations
  32. Polish Academy of Sciences Medycyna regeneracyjna. 2020. https://konferencja.pan.pl/medycyna-regeneracyjna/index.html
  33. Polish Academy of Sciences statement Stanowisko prezydium PAN dotyczące prób blokowania wolności debaty naukowej i wyrażania naukowych opinii (PAN) 2020. https://kbiotech.pan.pl/pl/282-stanowisko-prezydium-pan-dotyczace-prob-blokowania-wolnosci-debaty-naukowej-i-wyrazania-naukowych-opinii
  34. Regulation (EC) No 1394/2007 Regulation (EC) No 1394/2007 of the European Parliament and of the council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004. 2007. https://eur-lex.europa.eu/legal-content/EN/LSU/?uri=CELEX:32007R1394 EUR-Lex [WWW Document]
  35. Rotkiewicz M. Spisek antykomórkowy. Czy komórki macierzyste pomagają na covid? Polityka. 2021. https://www.polityka.pl/tygodnikpolityka/nauka/2104981,1,spisek-antykomorkowy-czy-komorki-macierzyste-pomagaja-na-covid.read
  36. Rotkiewicz M. Sąd za pisanie o procederze “leczenia” komórkami macierzystymi. Polityka. 2022. https://www.polityka.pl/tygodnikpolityka/nauka/2151312,1,sad-za-pisanie-o-procederze-leczenia-komorkami-macierzystymi.read
  37. Rotkiewicz M., Walewski P. Śledztwo Polityki. Kliniki złudzeń. 2019. https://www.polityka.pl/tygodnikpolityka/nauka/1935142,1,sledztwo-polityki-zludne-terapie-komorkami-macierzystymi.read
  38. Rowland A.L., Miller D., Berglund A., Schnabel L.V., Levine G.J., Antczak D.F., Watts A.E. Cross-matching of allogeneic mesenchymal stromal cells eliminates recipient immune targeting. Stem Cells Transl. Med. 2021;10:694–710. doi: 10.1002/sctm.20-0435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Rubin R. Unproven but profitable: the boom in US stem cell clinics. JAMA. 2018;320:1421–1423. doi: 10.1001/jama.2018.13861. [DOI] [PubMed] [Google Scholar]
  40. Rynek Zdrowia . Rynek Zdrowia; 2021. PAN o ograniczaniu wolności dyskusji naukowej nt, komórek macierzystych.https://www.rynekzdrowia.pl/Prawo/PAN-o-ograniczaniu-wolnosci-dyskusji-naukowej-nt-komorek-macierzystych,219019,2.html [Google Scholar]
  41. Sipp D. The malignant niche: safe spaces for toxic stem cell marketing. NPJ Regen. Med. 2017;2:33. doi: 10.1038/s41536-017-0036-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Sipp D., Caulfield T., Kaye J., Barfoot J., Blackburn C., Chan S., De Luca M., Kent A., McCabe C., Munsie M., et al. Marketing of unproven stem cell-based interventions: a call to action. Sci. Transl. Med. 2017;9 doi: 10.1126/scitranslmed.aag0426. [DOI] [PubMed] [Google Scholar]
  43. Sipp D., Robey P.G., Turner L. Clear up this stem-cell mess. Nature. 2018;561:455–457. doi: 10.1038/d41586-018-06756-9. [DOI] [PubMed] [Google Scholar]
  44. Sipp D., Munsie M., Sugarman J. Emerging stem cell ethics. Science. 2018;360:1275. doi: 10.1126/science.aau4720. [DOI] [PubMed] [Google Scholar]
  45. Siwek T., Jezierska-Woźniak K., Maksymowicz S., Barczewska M., Sowa M., Badowska W., Maksymowicz W. Repeat administration of bone marrow-derived mesenchymal stem cells for treatment of amyotrophic lateral sclerosis. Med. Sci. Monit. 2020;26 doi: 10.12659/MSM.927484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Sugarman J., Barker R.A., Kerridge I., Lysaght T., Pellegrini G., Sipp D., Tanner C. Tackling ethical challenges of premature delivery of stem cell-based therapies: ISSCR 2018 annual meeting focus session report. Stem Cell Rep. 2018;11:1021–1025. doi: 10.1016/j.stemcr.2018.10.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Świątkowska-Flis B., Zdolińska-Malinowska I., Sługocka D., Boruczkowski D. The use of umbilical cord-derived mesenchymal stem cells in patients with muscular dystrophies: results from compassionate use in real-life settings. Stem Cells Transl. Med. 2021;10:1372–1383. doi: 10.1002/sctm.21-0027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. The Interacademy Partnership The I. IAP statement on regenerative medicine. 2021. https://www.interacademies.org/statement/iap-statement-regenerative-medicine
  49. Turner L., Munsie M., Levine A.D., Ikonomou L. Ethical issues and public communication in the development of cell-based treatments for COVID-19: lessons from the pandemic. Stem Cell Rep. 2021;16:2567–2576. doi: 10.1016/j.stemcr.2021.09.005. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Document S1. Figures S1 and Table S1
mmc1.pdf (132.8KB, pdf)
Document S2. Article plus supplemental information
mmc2.pdf (2.8MB, pdf)

Articles from Stem Cell Reports are provided here courtesy of Elsevier

RESOURCES