Plastic pollution became a main challenge for human beings as demonstrated by the increasing dispersion of plastic waste into the environment. Microplastics (MPs) have become ubiquitous and humans are exposed daily to inhalation or ingestion of plastic microparticles. Recent studies performed using mainly spectroscopy or spectrometry-based techniques have shown astounding evidence for the presence of MPs in human tissues, organs and fluids. The placenta, meconium, breast milk, lung, intestine, liver, heart and cardiovascular system, blood, urine and cerebrovascular liquid are afflicted by MPs’ presence and deposition. On the whole, obtained data underline a great heterogeneity among different tissue and organs of the polymers characterized and the microparticles’ dimension, even if most of them seem to be below 50–100 µm. Evidence for the possible contribution of MPs in human diseases is still limited and this field of study in medicine is in an initial state. However, increasing studies on their toxicity in vitro and in vivo suggest worrying effects on human cells mainly mediated by oxidative stress, inflammation and fibrosis. Nephrological studies are insufficient and evidence for the presence of MPs in human kidneys is still lacking, but the little evidence present in the literature has demonstrated histological and functional alteration of kidneys in animal models and cytotoxicity through apoptosis, autophagy, oxidative stress and inflammation in kidney cells. Overall, the manuscript we report in this review recommends urgent further study to analyze potential correlations between kidney disease and MPs’ exposure in human. Microplastics (MPs) are defined as plastic fragments  between 1 µm and 5 mm of size, while nanoplastics are below 1 µm. MPs can be categorized as primary or secondary. Primary MPs are small plastic pieces produced as such, while “secondary MPs” are plastic fragments deriving from the corruption and fragmentation of larger plastic pieces through physical, chemical or biological processes . MicrofiMPs have been detected in soil, fresh water, sea water and the atmosphere, and they have also been found in seafood, sea salt and various foods . They haIn consideration of this increasing evidence, MPs have become a growing medical concern in recent years and increasing studies have been published investigating the presence of MPs in human tissues and fluid. Surprisingly, almost the entirety of the studies showed the presence of MPs in organs and tissues analyzed such as the placenta, lungs, liver and blood, but their potential health-damaging consequences are still being debated. Moreover, an increasing amount of research on the toxicity of MPs on human cells and animal models has been carried out, and several studies into human cell lines have shown inhibition of cell growth and various molecular alterations . ProcessIn nephrology, interest in the possible consequences of MPs’ exposure is growing too, but evidence is still scarce. Our research group is performing various research investigating the presence of MPs in the urine and kidneys and exploring their toxicity in human kidney cells also by the support of omics techniques (data still not published). To date, there is only one study investigating the presence of MPs in human kidneys, but it has not shown significant results.In this review, we provide an overview of the recent findings of the presence and deposition of MPs in human organs, tissues and fluid. Moreover, we report the most interesting findings on the toxicity of kidneys due to MPs in vitro or in animal studies. The aim of this review is to arouse the interest of the nephrological community on the presence of MPs in humans, the consequences of these nephrological concerns and the possible implications on kidney health.In 2021, Ragusa et al.  and Brau2O2) and thus to allow analysis of microparticles [Different methods have been employed to perform studies on MPs in humans . Firstlyarticles . Proceduarticles . Nevertharticles . MPs arearticles . HoweverRagusa  and BrauNowadays, MPs have been studied with different methods, as described in five literature papers. In 2021, Ragusa and Braun investigated placenta with µRaman and FTIR. In both studies, polypropylene (PP) microparticles were found. By using µRaman spectroscopy, Ragusa et al. were able to characterize 12 microparticles in the range of 5–10 µm in four out of six placentas. In addition to four particles of PP, they identified different industrial pigments such as iron hydroxide oxide, copper phthalocyanine and ultramarine blue. Differently, Braun et al. analyzed with FTIR particles bigger than 50 µm. Two out of three placentas were positive for different MPs: polyethylene (PE), PP and polyurethane (PU).More recently, three other studies have been performed on placenta using different techniques. Ragusa et al. investigated 10 human placentas using scanning electron microscopy and transmission electron microscopy . MPs of 2O2 and HNO3, Li et al. did not find MPs on 16 meconium samples. Finally, a recent study by Liu et al. analyzed 18 meconium samples with LD-IR all resulting in being positive for MPs, mainly PA and PU. This study also aimed to identify the exposure route through questionnaires on dietary habits and plastic use. Meconium has been investigated in three different studies. Braun et al.  and Li eRagusa et al. also investigated the presence of MPs in human breastmilk . They foCollectively, these findings corroborate the hypothesis of high fetal and neonatal exposition to MPs. The respiratory and gastrointestinal systems represent the main entrance route for MPs. Thus, several investigations have been carried out on the exposition to MPs in these fields.Inhalation as the intake route for airborne microparticles is corroborated by investigations in occupational illness in textile and vinyl chloride industries  In 2021,Another well-conducted study was performed by Chen et al. in 100 human lung tissue samples that underwent a surgical procedure for pulmonary cancer . They inIn consideration of the above-mentioned evidence and the human burden of MPs through inhalation, several studies have been performed to investigate their presence in sputum and bronchoalveolar lavage. In particular, two studies in 2023 confirmed the presence of MPs in lower respiratory tracts trough bronchoalveolar lavage analysis ,34.The other main way of exposure to MPs in humans is through ingestion. Indeed, the presence of MPs in table salt and drinking water is well known, as essentially their presence is in the human food chain. Thus, various studies have been performed on MPs’ presence in stool. However, to understand if MPs remain and deposit in the human digestive tract, Ibrahim et al. investigated in 2020 the presence of MPs in colectomy samples obtained by patients undergoing surgery for colorectal cancer . All theAn interesting study performed by Yang et al. has recently demonstrated the presence of MPs in the human heart and surrounding tissues using LD-IR . Most ofOther studies investigated the deposition of microparticles in the human cardiovascular system. Wu et al. investigated the presence of MPs in human arterial thrombi using µRaman spectroscopy . In theiThe presence of MPs has been demonstrated also in human vein tissue. Rotchell et al. detected MPs in four out five vein samples using µFTIR with a mean concentration (adjusted for contaminants) of 14.9 ± 17.2 MP/g of tissue . MPs werIn 2022, Leslie et al. and Pironti et al. detected MPs in human blood and urine, respectively ,21, corrAstounding results have been reported by Guan et al. in a recent study where 13 kinds of enclosed body fluids were analyzed: whole blood, cerebrospinal fluid and two main pathological body fluids (effusions and cyst fluids) . The encThe detection in human samples and healthy volunteers has stimulated research in correlating the presence of MPs with diseases or in specific clinical settings. The above-mentioned study by Chen et al. explored the correlation between MPs in human lungs and ground glass nodules (GGNs) . PulmonaFurthermore, an interesting study published in 2022 found the presence of MPs in the liver of patients with cirrhosis but not on those without underlying liver disease. Cirrhosis is one of the most relevant causes of death worldwide, regardless of its etiology . Horvatits et al. analyzed six patients with cirrhosis and five individuals without liver disease . A totalAnother interesting study investigated the correlation between MPs’ exposure and inflammatory bowel disease (IBD) in more than 100 individuals . Yan et Dethiosulfovibrionaceae, Enterobacteriaceae, Oscillospiraceae and Moraxellaceae while decreasing Monoglobaceae [Bacteroides, suggesting a possible antibacterial effect. Another interesting correlation was found between meconium microbiota and the particle size of MPs (50–100 µm). PA and PU are widely used in textile products which can release microparticles during washing and use and lead to indoor exposure of MPs. This study was the first to show alterations of microbiota genera in humans. Moreover, they found high concentrations of MPs in meconium, suggesting various intrauterine exposure sources beyond the transfer of MPs from the placenta to the embryo or fetus.Finally, MPs have shown effects on the genera of placenta and meconium microbiota . Microbilobaceae . Liu et lobaceae . MoreoveNonetheless, evidence for the possible contribution of MPs to diseases is still lacking and further and urgent studies are needed to investigate their contribution to the development and maintenance of different diseases, especially new disorders, with a growing trend of incidence and new diseases with unknown etiology, with a high incidence in specific region.Collectively, the above-illustrated studies support the presence and deposition of MPs in the human body . RegardlThe growing concern among the medical community about the impact of MPs on human health has influenced the increasing number of studies performed in the last few years on human tissues and cells. Even though this trend refers to nephrology too, robust evidence on the effect of MPs and its compounds on kidney cells and tissues is still lacking.Most of the studies performed on nanoplastics (NPs) and MPs’ toxicity on kidney have been published in the last two years. Li et al. showed that PS-NPs worsen lipopolysaccharide-induced apoptosis in mouse kidney cells through the oxidative stress–endoplasmic reticulum pathway . FurtherInterestingly, the chronic exposure to MPs has been investigated in a well-written study performed on mice . Mice weMPs have become ubiquitous in the environment, leading to daily exposure and uptake for humans. Recent findings have suggested the ubiquitous presence of MPs in the human body too. Indeed, a growing number of studies are documenting the presence of MPs in all human tissues, organs and fluids. Moreover, several studies are highlighting the possible toxicity of MPs and their compounds on human cells and tissues through many different pathways. Their evidence on the human kidney is still not demonstrated, even if plausible. Conversely, various evidence in vitro and in vivo suggests a possible toxicity on kidney cells though oxidative stress, inflammation and fibrosis.Based on this evidence, more efforts are needed to increase our knowledge on the possible toxicity of MPs in humans. In particular, a wide range of epidemiological studies are essential to understand a possible contribution of MPs in the developing and maintenance of kidney diseases and other tissue diseases in humans. Moreover, further studies must be directed to standardize procedures for the collection, handling and preparation of human biological samples. Uniform protocols for digestion and filtration are fundamental. Finally, comparison studies between different methods for MPs’ characterization, the extended use of blanks and a wider adoption of tools to prevent the cross contamination of samples  is of great importance for future progress in this field and to obtain further knowledge of MPs’ detection and effects in humans.


The evaluation of clinical evidence takes account of health benefit (efficacy and safety) and the degree of certainty in the estimate of benefit. In orphan indications practical and ethical challenges in conducting clinical trials, particularly in paediatric patients, often limit the available evidence, rendering structured evaluation challenging. While acknowledging the paucity of evidence, regulators and reimbursement authorities compare the efficacy and safety of alternative treatments for a given indication, often in the context of the benefits of other treatments for similar or different conditions. This study explores the feasibility of using the Institute for Clinical and Economic Review (ICER) Evidence Rating Matrix for Comparative Clinical Effectiveness in structured assessment of both the magnitude of clinical benefit  and the certainty of the effect estimate in a sample of orphan therapies for paediatric indications.Eleven systemic therapies with European Medicines Agency (EMA) orphan medicinal product designation, licensed for 16 paediatric indications between January 2017 and March 2020 were identified using OrphaNet and EMA databases and were selected for evaluation with the ICER Evidence Rating Matrix: burosumab; cannabidiol; cerliponase alfa; chenodeoxycholic acid (CDCA); dinutuximab beta; glibenclamide; metreleptin; nusinersen; tisagenlecleucel; velmanase alfa; and vestronidase alfa. EMA European Public Assessment Reports, PubMed, EMBASE, the Cochrane Library, Clinical Key, and conference presentations from January 2016 to April 2021 were searched for evidence on efficacy and safety. Two of the identified therapies were graded as “substantial” NHB: dinutuximab beta (neuroblastoma maintenance) and nusinersen (Type I SMA), and one as “comparable” NHB (CDCA). The NHB grade of the remaining therapies fell between “comparable” and “substantial”. No therapies were graded as having negative NHB. The certainty of the estimate ranged from “high” (dinutuximab beta in neuroblastoma maintenance) to “low” . The certainty of the other therapies was graded between “low” and “high”. The ICER Evidence Rating Matrix overall rating “A” (the highest) was given to two therapies, “B+” to 6 therapies, “C+” to five therapies, and “I” (the lowest) to three therapies. The scores varied between rating authors with mean agreement over all indications of 71.9% for NHB, 56.3% for certainty and 68.8% for the overall rating.Using the ICER Matrix to grade orphan therapies according to their treatment benefit and certainty is feasible. However, the assessment involves subjective judgements based on heterogenous evidence. Tools such as the ICER Matrix might aid decision makers to evaluate treatment benefit and its certainty when comparing therapies across indications.The online version contains supplementary material available at 10.1186/s13023-023-02701-w. Evaluation of health benefit involves assessing the clinical relevance of reported outcome measures in the context of a specific disease, as well as estimating the magnitude of the effect versus comparator treatments. The relevance of outcome measures, for example surrogate endpoints, depends on their mechanism of action and link to other endpoints, such as symptom scores, quality of life or survival. The clinical relevance of the treatment effect size (magnitude) also needs to be considered and can be judged, for example, against the minimal clinically important difference (MCID) [Clinical evidence established in clinical trials and real-world studies is essential for the marketing authorisation, reimbursement, and ultimately, patient access to new medical technologies . Severaltrue . Evaluate (MCID) . MCID isAchieving high certainty that a technology is effective and safe may be particularly difficult in the case of orphan therapies for rare diseases, due to challenges associated with the populations being studied and the study designs that may need to be adopted –16.The lack of validated instruments to assess efficacy and certainty in the context of rare diseases compounds the challenges involved in evaluating each individual treatment and is even more of an issue when comparing the value of treatments for different diseases. Regulatory and reimbursement authorities conducting health technology assessments (HTA) have considered the barriers to evidence generation and high unmet medical need of patients affected by rare diseases, allowing for more flexibility in the assessment of orphan therapies , 17. AgeThe aim of the study was to test the feasibility of using the ICER Evidence Rating Matrix, (referred to below as the ICER Matrix) to guide the comparative grading of the benefit-risk and degree of uncertainty associated with each therapy .We selected the ICER Matrix, based on an evaluation of a range of tools, as in our opinion it is the only tool explicitly intended for assessing certainty alongside establishing the magnitude of added benefit . The ICEGiven the complexity of issues surrounding the assessment of evidence for orphan therapies, the aim of this study was to test the feasibility of using the ICER Matrix to compare therapies for different rare diseases in a sample of paediatric indications sufficient to explore the factors contributing to the assessment.All non-topical systemic therapies with European Medicines Agency (EMA) orphan medicinal product designation licensed for paediatric (< 18 years of age) indications between January 2017 and March 2020 were identified using the OrphaNet Report and the EMA databases , 24. TheEvidence on the efficacy and safety of each designated orphan therapy was identified from the EMA European Public Assessment Reports (EPARs), published literature and conference presentations in searches undertaken in May 2021. We searched PubMed, Embase, the Cochrane Library and Clinical Key databases systematically using search strings to capture two concepts: Therapy AND Indication .Therapies: Systemic therapies approved for paediatric indications by the EMA between January 2017 and March 2020 identified from searches of OrphaNet Report and the EMA databases. Therapies of any duration and at any dosing frequency were eligible.Efficacy and safety.Quality of life.Outcomes:Study designs: Phase II, III or IV clinical trials , retrospective analyses, real-world studies, or meta-analyses were eligible. Studies reporting any length of follow-up were eligible. Phase I data, preclinical research, and case reports were not eligible.Publication dates: Studies published between January 2015 and April 2021 were eligible. Evidence published prior to 2015 was not searched, as it was assumed that the EMA would have included relevant evidence published two or more years prior to its decision in the EPAR. The search, however, did include evidence, such as longer-term follow-up results, published after EMA decisions.Studies reporting evidence on the efficacy and safety of each designated orphan therapy had to meet the following criteria to be eligible for inclusion in this study:One reviewer screened the search results against the inclusion and exclusion criteria to identify eligible studies, and a second reviewer checked all the decisions. The reviewers discussed any discrepancies, to reach consensus.Population age.Intervention details.Comparator details, where available.Outcomes: measures and results for all outcomes as reported in the trials . Survival and quality of life outcomes were also extracted where reported.Study design details for phase II, III or IV clinical trials , retrospective analyses, real-world studies, or meta-analyses.The following data were extracted for each therapy:The assessment of the efficacy benefit of each of the therapies was based on comparison of reported effect size to clinically meaningful/relevant change, i.e., to the minimal clinically important difference (MCID)  that hadGrading of certainty was based on the strength of the evidence, taking account of risk of bias, the generalizability of the trial population to the population within the licensed indication, the precision of the estimates of outcomes, consistency between studies, the directness of the comparison and the type of efficacy outcomes . To further explore the certainty associated with each therapy, the duration of each therapy was estimated based on the product’s EMA Summary of Product Characteristics and dosing reported in clinical trials. Therapies were categorised as having either a defined or an undefined duration.Four authors individually rated the evidence by assigning grades to the dimensions of comparative NHB and level of certainty in the evidence in the ICER Evidence Rating Matrix Fig. . Four grQuantitative evidence syntheses or statistical analyses were not conducted, however the individual evaluations took account of the statistical significance reported in the studies.Clinical relevance of the effect size.Clinical relevance of efficacy endpoints.Impact on health-related quality of life.Clinical relevance of adverse events.Potential curative effect.The authors considered five aspects of evidence (factors) that could contribute to the assessment of the magnitude of a therapy’s NHB:Population .Intervention .Comparator .Outcomes .Study design .The authors considered five aspects of evidence, reflecting the eligibility criteria, when considering certainty:Each aspect received a weight from one to three to reflect its contribution to the overall assessment, specifically its impact on the assessment grade . The weights were converted to percentages so that the results could be compared across therapies. Additional file The authors’ degree of agreement was measured to assess the levels of subjectivity in their assessments. If all the authors scored differently, agreement was quantified as zero. If three of the four scores were different, the agreement was quantified as one. If two authors proposed one score and two authors proposed a second score, resulting in two different scores overall, agreement was two. If three authors agreed and there was one dissenter, agreement was three. When all four authors agreed, the agreement was four. This produced a five-point scale from zero (maximum divergence in scoring) to four (full agreement), which was converted to a percentage.Eleven systemic therapies, for 16 indications, approved by the EMA as orphan medicinal products for use in paediatric rare diseases were identified: burosumab (X-linked hypophosphatemia), cannabidiol (Dravet syndrome and Lennox–Gastaut syndrome), cerliponase alfa  disease), CDCA (inborn errors of primary bile acid synthesis), dinutuximab beta (high-risk maintenance and relapsed/refractory neuroblastoma), glibenclamide , metreleptin , nusinersen ), tisagenlecleucel (relapsed/refractory B-cell acute lymphoblastic leukaemia (ALL)), velmanase alfa , and vestronidase alfa (mucopolysaccharidosis VII). Figure The literature search for evidence on efficacy and safety of the 11 orphan therapies identified a total of 3,132 citations. Following deduplication and removal of irrelevant publications, 1,353 publications and conference presentations were screened for relevance. 115 publications reporting 68 studies  was given to nusinersen in Type I SMA and dinutuximab beta in a neuroblastoma maintenance population. The NHB of CDCA for inborn errors of primary bile acid synthesis was graded “comparable”. The remaining therapies were deemed to have intermediate NHB between “comparable” and “substantial”, i.e. none of the therapies were graded as having “negative” NHB. Table Burosumab, cannabidiol, glibenclamide, metreleptin, nusinersen, velmanase alfa and vestronidase alfa had less than 30% frequency of Grade Three and Four adverse events, which was accounted for in the NHB rating.The certainty of the effect estimate was influenced by all aspects of the eligibility criteria (PICOS framework): the treated population, intervention, comparator, outcomes, and study design. Table The Matrix rating (combining NHB and certainty) was A (superior) for two therapies, B + for 6 therapies, C + for five therapies, and I (insufficient) for three therapies  for NHB, 56.3% (25–100%) for certainty and 68.8% (50–100%) for the overall rating (prior to consensus decision) over the two dimensions. Additional file This study explored the feasibility of using the ICER Evidence Rating Matrix to compare the magnitude of net health benefit and certainty around the estimate of benefit across a sample of orphan therapies, focusing on paediatric indications where evidence generation is particularly challenging. We found a comparison to be feasible, allowing for therapies to be graded separately in the two dimensions.The ICER Matrix addresses the level of uncertainty or confidence specifically in the outcomes, even when the orphan indication has imposed limitations on the study design, population eligibility criteria, and comparator choice, each of which can affect an interpretation of the magnitude and certainty of outcomes. The ICER Matrix only combines NHB and certainty, allowing for flexibility and pragmatism when estimating the two dimensions .Using the ICER Matrix facilitated the exploration of aspects of the evidence which contributed to the grading. Although this study has highlighted subjectivity inherent in the method, the level of inter-rater agreement in the rating of NHB (71.9%) can be considered high, particularly given that in all ratings at least two authors proposed the same score and there were no instances of fully divergent scoring. It is noteworthy, that all five factors considered were found to have contributed markedly to the assessment of NHB, with the clinical relevance of the efficacy endpoints and effect size, as well as the potential curative effect of a therapy assigned the greatest weight , 28, 29.Regulatory evaluation considers individual therapies for specific conditions in the context of relevant comparators, however comparisons across therapies for different diseases are likely to influence the evaluation process, explicitly or implicitly, as both the magnitude of the treatment effect and its associated certainty vary widely and provide context and reference points. Such comparisons between therapies are more explicit in health technology assessment, where the added benefit of therapies is typically assessed in the context of clinical practice and is often categorised or quantified using universal metrics, such as Life Years (LYs), Quality-Adjusted Life Years (QALYs) or Quality-adjusted Time Without Symptoms of disease or Toxicity (QTWIST) . The metUncertainties related to the size and characteristics of the population.Uncertainties related to the natural history of the disease and its current management.Uncertainties related to the new treatment.Uncertainties related to the health ecosystem.Our study explored the various aspects of certainty around the NHB estimates using the eligibility criteria (PICOS) as a framework. Annemans and Makady distinguished four types of uncertainties in the assessment of health technologies in their TRUST4RD  tool :UncertaiThe context or scope, including the population, intervention, comparator, and outcomes.The selection of evidence.Relative effectiveness estimates.Adverse events.Aspects related to health economic evaluation, such as costs, utilities, time horizon and perspective.In addition, the TRUST (TRansparent Uncertainty ASsessmenT) framework  for evalThe TRUST tool also addresses several aspects of uncertainty including transparency issues, methodological issues, imprecision, indirectness, and unavailability. The TRUST authors abandoned numerical scoring of uncertainties for their impact due to difficulties with the scoring process and substantial inter-rater variability experienced when applying the tool . They arSeveral systems and tools have been developed to assess certainty and risk of bias to grade levels of evidence, but few are specific to rare diseases. Evaluation of the quality or certainty of evidence is subjective, as it reflects our confidence in evidence, which is an inherently subjective concept . An asseAccording to GRADE, observational evidence is considered lower quality than RCT evidence, but both RCTs without important limitations and overwhelming evidence from observational studies are ranked as “high quality.” The system then allows upgrading or downgrading based on other factors, such as the size of the effect, consistency, precision, potential confounding, and bias , 3. CrucSmall numbers of studies and their limited size is a major factor affecting certainty. Large sample sizes and RCTs can be difficult to achieve in the context of rare diseases, as discussed earlier. If RCTs are not feasible, options include limiting the number of patients randomised to placebo, with implications for the study power and statistical analyses, or using single-active-arm trial designs, supported by within-patient or historical controls. Using ratings based on the ICER Matrix, we found that for health-related net benefit, nusinersen for Type I SMA and dinutuximab beta in maintenance therapy appear to have the highest overall rating (A), followed by burosumab, cannabidiol, dinutuximab beta for RRNB, nusinersen for Type II/III SMA and presymptomatic SMA, and tisagenlecleucel . Most of these therapies have been studied in large numbers of patients  and in RCTs, which showed statistically significant and clinically meaningful changes in endpoints following treatment –43. ImpoWe attempted to capture curative intent of treatment in the assessment of NHB. Even though there is lack of consensus on what constitutes a cure, curative treatments are evaluated differently  and the In relation to the above, it is appropriate and important to consider granting conditional marketing authorisation or authorisation under exceptional circumstances for orphan therapies once they show some evidence of benefit, while data continue to be accumulated from ongoing clinical experience to increase confidence in the effects and to potentially provide more accurate guidance on the best use of the therapy , 12. FroOur study has several limitations. We selected the ICER Matrix to structure our assessment following consideration of a range of tools, but a systematic review of available tools was not undertaken. The Institute for Clinical and Economic Review recently proposed a different approach to assessing the comparative clinical effectiveness of treatments of ultra‐rare diseases . HoweverImplementing the ICER Matrix was often challenging as we did not have a systematic way of assessing all aspects of evidence for a therapy based on clear criteria. The ICER Matrix is a heuristic that allowed us to combine various aspects of treatment benefit and certainty, but even when trying to be as objective as possible, our assessment remains very subjective. We could not even universally apply the hierarchy of evidence stating that RCTs have greater strength than observational studies in principle, recognising that small RCTs can be considerably biased, while large observational studies or single arm studies with historical controls can be more robust. Ultimately, all assessments are subjective, but we have tried to make our assessments as transparent as possible by providing the detailed data extraction  and selecting systematically all the eligible therapies approved within a specific period. We acknowledge that it is possible that other therapies, such as gene therapies, assessed by other agencies within the same period, could have posed different challenges. We have only considered positive decisions made by the EMA. We did not consider the evidence for therapies that the EMA rejected. Nor have we been able to compare European decisions to those made by other regulatory bodies, which may have used different criteria to inform their decisions and may have reached different conclusions.In terms of evidence identification, we are confident that we have conducted a sensitive search to identify the available key evidence on the eleven therapies, however there is always the chance that we may have missed relevant studies. We have assumed that the EMA would have included relevant evidence published two or more years prior to an EMA decision in the EPAR. Also, our search included evidence published at least one year after EMA decisions, allowing the inclusion of updated results. We acknowledge that this allowed for the inclusion of more evidence (with longer follow up) for older treatments. We also note that new evidence typically emerges after a treatment has been approved  and this evidence might not have contributed to the current ratings.Some of our evidence was derived from conference abstracts which are sometimes problematic sources of evidence, because they may contain errors, lack detail, provide interim and potentially unchecked data and have not been peer reviewed. We have considered data from conference abstracts as part of the totality of evidence, particularly when evaluated alongside published data. Where data were only available from conference abstracts, we downgraded the certainty of reported treatment effect.We note the lack of standardisation that can occur in study design terminology. For example, sometimes authors describe a case series in a publication as an observational study. This made deciding on the eligibility of some studies for this analysis challenging.We have established that it is feasible to use the ICER Matrix to compare diverse orphan therapies across diseases. The ICER Matrix can facilitate exploration of various aspects of the magnitude of health benefit (NHB) and certainty around the effect estimate. Both NHB and certainty varied considerably across the therapies we evaluated as did the overall rating. Our findings could inform requests from regulatory and HTA bodies for evidence generation  by helping to identify evidence gaps and uncertainties. As shown by several of the paediatric orphan therapies that we reviewed, consistent, cumulative evidence from carefully designed trials, combined with real-world experience and a good understanding of the natural history of the disease, can provide a level of certainty sufficient to support the use of these treatments in routine clinical practice.Additional file 1: Appendix 1. Search strategies.Additional file 2: Appendix 2. Example rating assessment template.Additional file 3: Appendix 3. Data extraction tables.Additional file 4: Appendix 4. Narrative summaries of the evidence.


Evidence syntheses cite retracted publications. However, citation is not necessarily endorsement, as authors may be criticizing or refuting its findings. We investigated the sentiment of these citations—whether they were critical or supportive—and associations with the methodological quality of the evidence synthesis, reason for the retraction, and time between publication and retraction.Using a sample of 286 evidence syntheses containing 324 citations to retracted publications in the field of pharmacy, we used AMSTAR-2 to assess methodological quality. We used scite.ai and a human screener to determine citation sentiment. We conducted a Pearson’s chi-square test to assess associations between citation sentiment, methodological quality, and reason for retraction, and one-way ANOVAs to investigate association between time, methodological quality, and citation sentiment.Almost 70% of the evidence syntheses in our sample were of critically low quality. We found that these critically low-quality evidence syntheses were more associated with positive statements while high-quality evidence syntheses were more associated with negative citation of retracted publications. In our sample of 324 citations, 20.4% of citations to retracted publications noted that the publication had been retracted.The association between high-quality evidence syntheses and recognition of a publication’s retracted status may indicate that best practices are sufficient. However, the volume of critically low-quality evidence syntheses ultimately perpetuates the citation of retracted publications with no indication of their retracted status. Strengthening journal requirements around the quality of evidence syntheses may lessen the inappropriate citation of retracted publications. Scientific discovery is not a linear process; it requires verification, replication, and correction. This correction may come in the form of retraction of scientific publications and could be necessitated by a range of reasons, from errors in methodology or reporting, ethical concerns or authorship disputes, or data falsification and fabrication. Retractions are becoming an increasingly common corrective mechanism, growing from an average of 240 retractions per year in the 2000s to over 1500 retractions per year in the subsequent decade ey words and/or MESH terms should be reported and the full search strategy available upon request” , there iPrevious research on the experience of information professionals engaged in evidence syntheses has found significant challenges in ensuring methodological rigor. Surveys have found that between 28 and 68% of information professionals report challenges with researchers not following appropriate systematic review methodology , 47. WhiThe majority of citations to retracted publications in these evidence syntheses did not indicate that the publication had been retracted. We found that the majority of our citations were positive, followed by citations that mentioned the retracted publication in passing but did not indicate that it had been retracted. This would indicate that, in our sample, evidence syntheses that cite retracted publications are not identifying that the publication has been retracted. These findings are consistent with previous research, including two studies which independently found that over 94% of citations to retracted publications do not indicate that the publication was retracted , 49. FutWe found an association between publications retracted due to ethical misconduct and positive citation, while publications retracted due falsification and manipulation were more associated with negative citations. In the context of Bar-Ilan and Halevi’s taxonomy, this does indicate that the most potentially damaging science is being recognized as such in our sample. However, the continued positive citation of publications previously retracted for ethical misconduct is nevertheless problematic. While retraction is meant to correct the scientific record, it is also intended to disincentivize unethical behavior. While some previous research has found that retracted publications receive fewer citations than their non-retracted counterparts , both ciNegative citations were associated with a significantly longer time between publication and retraction. This may initially appear counterintuitive, as one might expect that a publication that has a longer time in the scholarly ecosystem without correction would become more entrenched and therefore more likely to accrue positive or neutral citations. However, it should be noted that of the 66 negative citations in our sample, 28 were associated with 4 primary authors, 3 of whom have the dubious distinction of being in the top 5 on Retraction Watch’s Leaderboard . The retWhile it is not possible to state conclusively why individuals are citing retracted publications positively based on publication data alone, previous research describes the inconsistency with which the retracted status of publications is displayed. One 2018 study looked at this issue across different bibliographic databases, finding that some platforms display fewer than 5% of retracted publications as retracted . A more Authors of systematic reviews can play a dual role in both modifying their existing practices and in advocating for clearer and more consistent representation by publishers and aggregators. A recently launched NISO Working Group is developing recommended practices for metadata display and transfer “to improve the dissemination of retraction information and to support consistent, timely transmission of that information to the reader” . Such guEvidence syntheses are a powerful tool to identify, appraise, and synthesize scholarship and to improve patient care, accelerate research, and contribute to evidence-based policy. However, for evidence synthesis to perform these functions, it must be based upon sound science. Evidence syntheses that include retracted publications without indication of their retracted status perpetuate the citation and use of those publications and raise questions regarding the rigor of these evidence syntheses and the validity of their findings. As evidence syntheses may impact clinical decision making and policy, the downstream impact of evidence syntheses that incorporate retracted publications, including their incorporation into policy and practice guidelines would be a useful area for future research.Our study has several limitations. We focus specifically on evidence syntheses in the field of pharmacy due to its breadth and impact. Previous research has established concerns around methodological quality of systematic reviews in a range of fields , 36 and Citation sentiment analysis cannot determine why an author chose to cite a particular article or conversely how they became aware of the retracted status of an article. It also cannot determine whether existing methodological guidance was influential in uncovering the retracted status of an article. Future research should consider how authors become aware of the retractions and which mechanisms and interventions are most effective.Science requires continual revision; it is a process of adjusting theories in response to contradictory evidence . However


Evidence syntheses of randomized clinical trials (RCTs) offer the highest level of scientific evidence for informing clinical practice and policy. The value of evidence synthesis itself depends on the trustworthiness of the included RCTs. The rising number of retractions and expressions of concern about the authenticity of RCTs has raised awareness about the existence of problematic studies, sometimes called “zombie” trials. Research integrity, i.e., adherence to ethical and professional standards, is a multi-dimensional concept that is incompletely evaluated for the RCTs included in current evidence syntheses. Systematic reviewers tend to rely on the editorial and peer-review system established by journals as custodians of integrity of the RCTs they synthesize. It is now well established that falsified and fabricated RCTs are slipping through. Thus, RCT integrity assessment becomes a necessary step in systematic reviews going forward, in particular because RCTs with data-related integrity concerns remain available for use in evidence syntheses. There is a need for validated tools for systematic reviewers to proactively deploy in the assessment of integrity deviations without having to wait for RCTs to be retracted by journals or expressions of concern issued. This article analyzes the issues and challenges in conducting evidence syntheses where the literature contains RCTs with possible integrity deficits. The way forward in the form of formal RCT integrity assessments in systematic reviews is proposed, and implications of this new initiative are discussed. Future directions include emphasizing ethical and professional standards, providing tailored integrity-specific training, and creating systems to promote research integrity, as improvements in RCT integrity will benefit evidence syntheses. Even though the process for the detection and correction of error and fraud might be fairly well established and “standardized”, such as in COPE or ICMJE guidelines, inter-journal and inter-publisher variability, including editorial responsibilities, will continue to limit the effective correction of erroneous and fraudulent literature globally” [Evidence syntheses of randomized clinical trials (RCTs) offer the highest level of effectiveness evidence validity for informing clinical practice and policy . They malobally” . This baEvidence synthesis is a type of research method that collates all relevant studies and interprets their collective findings. There has been sustained growth in systematic review publications during the last decade .The fundamental steps of evidence synthesis are as follows: defining the question(s); searching for relevant studies (screening and selection against defined inclusion and exclusion criteria); appraising the quality of the studies included and extracting relevant data; collating data, undertaking meta-analyses where appropriate; and interpreting the findings . The appThe evidence used in the systematic reviews may include a range of study designs, from RCTs to observational studies, including case series too. RCTs are ranked the highest in the hierarchy of evidential validity due to their unique design that randomly assigns participants into experimental or control groups to compare outcomes. Randomization targets the minimization of selection bias in generating evidence about the effectiveness of interventions. To robustly implement and report trials, researchers performing RCTs are required to undertake regular training , and trials are required to be prospectively registered in registries such as Clinicaltrials.gov, amongst other requirements ,11. TherResearch integrity is a term that captures compliance with ethical and professional standards in the conduct of scientific studies . In ordeFocusing evidence syntheses on the best available study designs, carrying out selected study appraisal, and basing inferences on the highest quality subgroup of studies targets avoidance or minimization of the risk of bias. Current review methodology does not explicitly target study integrity. It is important to recognize that, conceptually, study quality assessment and integrity evaluation are not synonymous. Inherently, systematic reviewers tend to rely on the editorial and peer-review systems established by journals, which appear as a custodian of research integrity assessment. However, there are well-known gaps in journals’ authors’ instructions, editorial and peer-review evaluations, and investigation policies about post-publication allegations of scientific misconduct . Study iThe incorporation of RCT integrity assessment in evidence syntheses is an important consideration because the number of studies with expressions of concern has been rising exponentially .Based on data retrieved on 2 February 2023, from the Retraction Watch Database, the top five countries with the highest number of retracted clinical studies per country are the United States, Japan, China, Germany, and India, with 299, 281, 245, 192, and 98 retractions, respectively. This data indicates that the retraction of studies is a global issue, and developed countries bear a great deal of responsibility for studies lacking integrity .These issues, in turn, raise concerns about the integrity of evidence syntheses as inclusion of studies with retractions due to issues in “data/analyses/results” lead to summary estimates in systematic reviews that depart from the studies without these issues .In this paper, we focus on evidence syntheses that deploy RCTs, as it is a high-validity study design to underpin evidence-based medicine. We focus specifically on potential data-related integrity issues in RCTs. Behind every disease prevention and treatment breakthrough, there are thousands of volunteer participants in RCTs whose data are collated in evidence syntheses. Despite the need for obtaining ethics approval, confirming informed consent, and applying independent oversight during trial conduct, RCTs are not exempt from the possibility of (un)intentional integrity deviations. The general fact that expressions of concern  and retrEvidence syntheses affected by inclusion of RCTs that have integrity deficits are not difficult to find. The need for change in the attitude towards integrity assessment within reviews is highlighted by the following examples. Recently, Hill et al. retracted a meta-analysis of RCTs concerning COVID-19. The significant benefits initially observed could not be sustained after several of the included studies in the meta-analysis were withdrawn due to fraudulent data or other additional problems ,31. AvenThese examples confirm that a specific methodology is required to address the issue of RCT integrity in systematic reviews head-on. It is important to recognize that the purpose of this methodology ought to focus on the protection of patients and public health. The precursors of failure to comply with responsible research conduct are many, including misconduct, recklessness, carelessness, lack of training, etc. . It is nA systematic approach is required on various evidence synthesis fronts, including but not limited to the identification of honestly conducted research in searching, assessment of integrity (separately from bias assessments) of included studies, prior planning of sensitivity analyses for integrity, and transparency in generating inferences, given the cautious possibility of compromise in underlying data .To assess the integrity of included RCTs, it is important to follow rigorous tool development methodology that has been widely applied previously in the development of study quality or risk of bias assessment tools ,37. OnceEvidence synthesis, mindful of research integrity, will need to attempt to collate all empirical evidence that fits pre-specified eligibility criteria, excluding studies with proven integrity concerns, using explicit methods to detect and quantify these concerns, evaluating their impact in planned statistical analyses and minimizing or eliminating the pollution of the inferences that may arise due to inclusion of studies with possibly compromised data. Periodical updates of reviews to detect integrity concerns of included studies should be performed .There are many issues to consider. A controversial aspect here is whether to include studies with expressed concerns but without proven misconduct. This controversy is not too different to the inclusion of RCTs with varying levels of risk of bias arising due to faulty randomization, lack of allocation concealment, or blinding. This is now routine in effectiveness reviews. The development, validation, and application of advanced methods that can accurately detect integrity breaches in publicly available RCTs are needed ,44,45. HA particularly important issue that impinges on the critical appraisal of integrity is the enormous literature size and growth of publication rates. In 2015, there were about 28,100 and 6450 English-language and non-English-language science, technology, and medicine journals, respectively, growing at about 3% annually . DefectiSystematic reviews presently take much time and require large amounts of human resources. In the light of the ever-increasing volume of published studies, application of existing computing and informatics technology should be applied to decrease this time and resource burden” [The inclusion of efficient tools that will automate integrity assessment in evidence synthesis is the next methodological advance required. Review projects usually require a team of reviewers who screen and identify literature and evaluate included study quality. They will additionally need to perform integrity assessments before collating findings and generating recommendations. Currently, reviews take up human effort and take too long to collect and evaluate the data included, undertaking double-checks to minimize errors. The review process is estimated to take, on average, 67.3 weeks (IQR 41.6) to complete an evidence synthesis, and publishing the synthesis involves 5.3 review team members (IQR 3), on average . In addi burden” . The use burden”  and, alt burden” .These assessments need development and validation of new instruments to enable the detection and exclusion of questionable evidence from evidence syntheses, without the need to wait for retractions. Automated detection of retractions, specifically for data-related misconduct associated with fabrication, falsification, and other types of forgery, are needed . This waEvidence syntheses collating RCTs influence practice and health policies, directly impacting patient care. The investigation and retraction of RCTs with integrity concerns is a slow process. Thus, defective RCTs remain in circulation, putting patients at risk. Even after retraction, defective studies continue to be cited in systematic reviews as they are not removed from databases and their signposting is poor. Evidence syntheses fail to issue corrections even when retractions are identified. All this entails risk as patients remain exposed to interventions that are futile or even risky for their health. Evidence syntheses need to urgently upgrade their methods to incorporate integrity assessments as a routine, as outlined in Despite 15 journal articles detailing the results, no physician published a letter criticizing the Tuskegee study. Informed consent was never sought; instead, Public Health Service researchers deceived the men into believing they were receiving expert medical care”. These articles remain formally unretracted from the literature to this date. Note that ethics and consent standards were not covered by us in this article as we focused on data-related integrity, but it remains a key aspect demanding future research and development for its proper implementation and monitoring in RCTs. There are many articles showing deficits in informed consents in clinical studies [Research integrity, a broad concept holistically incorporating both ethical and professional standards , needs t studies ,53,54, aThere ought to be an emphasis on prevention, metaphorically nipping the evil studies in the bud . This be


The European Medicines Agency (EMA) fosters access to innovative medicines through accelerated procedures and flexibility in the authorization requirements for diseases with unmet medical needs, such as many rare diseases as well as oncological diseases. However, the resulting increase of medicines being marketed with conditional authorizations and in exceptional circumstances has lead to higher clinical uncertainty about their efficacy and safety than when the standard authorizations are applied. This uncertainty has significant implications for clinical practice and the negotiation of pricing and reimbursement, particularly as high prices are based on assumptions of high value, supported by regulatory prioritization. The burden of clinical development is often shifted towards public healthcare systems, resulting in increased spending budgets and opportunity costs. Effective management of uncertainty, through appropriate testing and evaluation, and fair reflection of costs and risks in prices, is crucial. However, it is important not to sacrifice essential elements of evidence-based healthcare for the sake of access to new treatments. Balancing sensitive and rational access to new treatments, ensuring their safety, efficacy, and affordability to healthcare systems requires thoughtful decision-making. Ultimately, a responsible approach to timely access to innovative medicines that balances the needs of patients with healthcare systems’ concerns is necessary. This approach emphasizes the importance of evidence-based decision-making and fair pricing and reimbursement. In recent years, there have been significant technological advances in biomedical research that have been quickly translated into clinical practice . The phaThe European Medicines Agency (EMA) plays a significant role in evaluating pharmacological innovations and issuing opinion for their commercialization in the European Union (EU) countries . The EurThere is a demand that the process of access to innovative medicines should be faster, and patients should have timely access to new and innovative medicines . For lifThe EMA has acknowledged the existence of unmet medical needs and have established laws and regulations aimed at expediting the development and approval of drugs to address these specific diseases . A groupIn this article we will delves into the complex subject of medications authorized with limited clinical evidence. There are several reasons for granting access to medicines with limited evidence . We aim Medicine regulation by the EMA aims to ensure that only medicines with a favorable balance of benefits and risks are authorized for marketing. This requires the assessment of three criteria: quality, efficacy, and safety . HoweverThe European Union incentivizes the development of medicines that are intended to treat small patient populations, assuming that the development of these types of medicines may not be financially viable under normal market conditions. The EMA’s Committee for Orphan Medicinal Products (COMP) grants orphan designation to medicines that treat life-threatening diseases with a low prevalence in the EU and offer significant benefits over existing treatments or fill a gap where no satisfactory treatments exist. Orphan drug designation recognizes that the drug is addressing a relevant unmet need, and offers several incentives, including reduced or waived fees, protocol assistance (scientific advice specific to orphan drugs), and 10 years market exclusivity in the EU . Orphan Accelerated review processes have been developed to reduce the time required by the EMA to review a marketing authorization application for medicines that are considered important therapeutic innovations and are of great public health interest. This expedited review process reduces the review procedure time from 210 days to 150 days, if the applicant provides good cause for an expedited review .The PRIME (PRIority MEdicines) program is an initiative developed by the EMA to improve and accelerate the evaluation and approval process of medicinal products aimed to treat serious and life-threatening conditions with unmet medical needs. The program offers ongoing assistance for the advancement of qualified medications, which have been chosen based on their potential to provide substantial therapeutic benefits compared to current treatments or to benefit patients who lack treatment options altogether. The primary objective is to streamline the medicine development process and expedite access to these innovative treatments . The PRIA comprehensive review of the PRIME scheme’s experience since inception and up to June 2021 has been carried out . The monThe impact of the regulatory procedures mentioned above has been a progressive increase in the authorization of medicines with orphan and advanced therapies designations  Table 2Table 2. It must be emphasized that currently the European Commission is proposing a review of European Union pharmaceutical legislation, consisting of a new Directive and a Regulation to simplify and replace the previous legislation. The new legislation will promote innovation in the development of new medicines by speeding up the authorization process with simplified procedures, offering tailored scientific support and advice for innovative products, and providing special incentives for rare diseases. The reform aims to provide all patients in the EU with timely and equitable access to safe and effective medicines, and offering incentives for the development of innovative medicines addressing unmet medical needs .However, rapid access to new medicines from the regulatory side means that in most cases, more uncertainty is accepted at the time of approval, and there is still debate about the optimal balance between speed and evidence for developing new medicines. A review of oncology medicines approved by the EMA from 2015 to 2020 found that most medicines were approved for marketing based on surrogate outcomes, without evidence of improved overall survival (OS) or quality of life benefits .Moreover, there is concern on the actual magnitude and relevance of the clinical benefit, and balance with added toxicities of newly authorized products. An analysis of OS data of new cancer medicines approved by the US Food and Drug Administration (FDA) and the EMA between 2003 and 2013 found that only 43% of the drugs showed an increase of at least 3 months, 11% showed less than 3 months, and 30% showed no improvement in OS. The average increase in OS was of 3.4 months, and the majority of the new cancer medicines were also associated with increased toxicity . The anaTo note, clinical trials are increasingly adopting methodologies that allow early interruption led by interim analysis, if supporting positive results. However, early trial interruption may led to overestimation of effects, especially if decisions are not taken blinded to treatment groups, or are based on uncontrolled designs . Often, On top of that, the evidence on new drugs that are addressed to small populations, such as OMPs and ATPMs, may also be flawed by the use of weak methodological approaches. A review of the European Public Assessment Reports (EPARs) of 125 OMPs approved by the EMA between 1999 and 2014 found that one third of the trials did not include a control arm, one third did not use randomization, half of the trials were open-label, and 75% used intermediate or surrogate outcomes as the primary endpoint. The size of the population exposed at the time of OMPs approval was smaller than needed to classify adverse reactions as clinically relevant, and 10% of the OMPs were approved despite the results of the pivotal trials being negative . This suCurrently, some ATMPs have already been commercialized. A review of pivotal clinical trials (CTs) supporting the approval of ATMPs by EMA found that their approval was mainly based on small CTs, single-arm, no control group, compared to historical controls, and using surrogate outcomes as the primary endpoint . AdditioFrom 2009 to 2013, the EMA approved the use of 48 anticancer medicines for 68 indications. In 12% of the indications pivot trials had a unique arm study, in 35%, OS data were not available, and in those that were available, the median overall survival benefit was 2.7 months (range 1–5.8 months). Quality of life data only were available in 10% of cases. In post-marketing follow-up data only 3 of 44 indications that initially had no overall survival data showed an overall survival gain or benefit in post-marketing outcomes. Median follow-up after authorization was 5.4 years . Of the 23 drugs with an ESMO score, 12 (52%) had a score indicating non-significant improvement. For about half  the post-marketing benefit was still uncertain. Therefore, about 50% of medicines authorized for licensed oncology indications remained uncertain after an average of 5.4 years after approval .Conditional marketing authorizations should be reversible if benefit assumptions are not met, but in clinical practice, they barely are. For instance, in the case of ataluren, the conditional marketing authorization by EMA was issued without conclusive evidence on efficacy in pivotal clinical trials, but based on contextual reasons and a reasonably safety profile . SubsequPricing and reimbursement (P&R) decisions for innovative medicines are a complex and challenging task for health systems, as they balance the need to provide access to new treatments with the need to control costs and ensure long-term sustainability. The P&R process involves evaluation of the clinical and economic value of new medicines, considering factors such as clinical efficacy, safety, cost-effectiveness, and budget impact. It also requires taking into account the perspectives of various stakeholders, including patients, pharmaceutical companies, healthcare providers, payers, and policymakers. When there is a great unmet medical need and no therapeutic alternatives available, the decision making process becomes even more challenging. The perception of high value for accelerated, conditional, or exceptional authorizations can lead to high expectations, associated with high prices, from agents of interest and social pressure for hard bargaining. In these cases, there are no competitors, and therefore no comparative data to go on.Companies are unwilling to set low prices for their products, tend to overestimate the cost-effectiveness of their therapies, and claim theoretical prices that are expected to return costs of manufacturing, R&D investments and reward value of innovation . HoweverAccess to innovative medicines for patients with rare diseases and unmet medical needs is crucial. However, the uncertainties inherent in developing those medicines with a limited evidence pose significant challenges to traditional health technology assessment, and P&R processes.Firstly and foremost, it is vital to enhance the scientific evidence of those medications. Classic confirmatory clinical trial designs with randomization and control groups, with the best available treatment option, should be the best option, as longas it is feasible . This apSecondly, payers may have doubts about the effectiveness, safety, and therapeutic value of a treatment that has not been fully confirmed because they need accurate information to decide P&R of these innovative medicines . There iThe regulatory approval process has undergone meticulous review and adaptation to facilitate access of innovative medicines. Similarly, there seems to be a need to revisit the P&R system, through a transparent and evidence-based approach, as well as an effective price regulation, that is able to manage the greater amount of uncertainty resulting from regulatory measures to accelerate access of innovation .Fixing a price on a population level, as well as a spending cap per patient, in an uncertain setting should not result in premium prices based on expectations, but on prices that are proportional to its value at the time of P&R, considering the magnitude of benefit but also the strength and different levels of the evidence supporting it. If the evidence for a medicine’s efficacy and safety is weak, the price should also be lower, regardless of other factors, at least until the expectations can be robustly confirmed.A strategy often applied to manage clinical uncertainty of expensive medicines aimed to small populations are risk-sharing agreements or managed access agreements (MAA) . Thus, wCuriously, the introduction of a medical product to the market with substantial uncertainty, does not inherently lead to the implementation of performance-based agreements. Between 2006 and 2016, managed entry agreements based on clinical outcomes were not commonly used for products that had a conditional marketing authorization or those that were authorized under exceptional circumstances. Of the 48 products that received marketing authorization under exceptional or conditional circumstances in recent years, only a few were found to have managed entry agreements involving the collection of additional data. The complexity of collecting outcomes data in clinical practice led stakeholders to refrain from utilizing MAA approaches . BesidesCollaboration and early dialogue between stakeholders, including patients, is also crucial to manage expectations and to ensure that access mechanisms are transparent and appropriate . The newThe Oslo Medicines Initiative (OMI) is a collaborative effort between the WHO Regional Office for Europe, the Norwegian Ministry of Health and Care Services, and the Norwegian Medicines Agency. The OMI aims to provide a neutral platform for the public and the private sectors to jointly outline a vision for equitable and sustainable access to and affordability of effective, novel and high-priced medicines, OMI in a technical report summarizes existing policy options for payers that support innovation and access to medicines in the WHO European Region. It identifies various tools, such as early assessment schemes, managed entry agreements, and innovation funds in 48 countries. The report describes methods for generating evidence and manage access to innovation, such as value-based pricing, pooled procurement, and subscription fee-based procurement. It also acknowledges potential limitations of the identified policies, such as financial sustainability of healthcare systems and trade-offs between incentivizing innovation and principles of evidence generation, transparency, and budget impact .The health and economic impact of making decisions on access to innovative medicines with limited evidence are significant, and it is essential communicating these issues more effectively to the public. Medicines regulation is designed to protect public health, and the requirement of robust evidence is an ethical obligation to ensure that new treatments are safe and effective. The decision-making process on the price and financing of these innovative medicines must be transparent and based on efficacy, efficiency and affordability, to ensure best use of resources and health system sustainability. Both are safety measures aimed to improve the good for the most, acting as filters rather than barriers, and it would be desirable to ensure that this is perceived as such by the public. Filters are a necessary step to ensure that innovative medicines are safe and effective and that they provide value for money, rather than being bureaucratic obstacles to access. A better communication can help to build a more informed and engaged society, trusting and empowering bodies in charge of veiling for public interests, and ultimately improve public health outcomes.In summary, while the EU regulatory process for access to medicines with limited evidence demonstrates flexibility in addressing rare diseases and unmet medical needs, it also introduces substantial clinical uncertainty for public system payers regarding the efficacy and safety of marketed medicines. The consequence of this is uncertainty about the therapeutic place of these drugs in clinical practice, difficulties in making decisions about the price and financing of medicines, and increased budgets for spending on drugs with little evidence.Based on the above concepts, it is recommended to ensure a balance between flexibility in order to facilitate access to medicines for rare diseases and unmet medical needs, and the need for rigorous clinical research to provide evidence of safety and efficacy at reasonable and affordable prices in order to make the health system sustainable. This could involve implementing well designed clinical trial and gathering post-marketing real world data for innovative medicines granted accelerated authorization, as well as the implementation of a balanced P&R system, through a transparent price regulation, evidence-based approach withprices proportional to the strength and level of evidence and value-based pricing or managed access agreements.Lastly, it is crucial to communicate the reasoning behind regulatory and financing decisions in a balanced manner. Presently, when regulatory and financing entities seek substantial evidence to guarantee the efficacy, safety, and efficiency of new innovative treatments, the messaging conveyed by media to healthcare professionals and the broader society often frames it as “barriers to innovation”. While there is always area for improvement in procedural efficiency, it is important to visualize the role of public administration bodies in pursuing the best interest for the most. An excessive simplification of messages may push political decisions on access in absence of guarantees on efficacy and safety of those innovative medicines that eventually could be against the general interest. New treatments must be made available to patients as soon as possible, but in a safe, efficient and responsible way. Being fast should not mean rushing but being more responsive. In the fast-paced world of modern medicine, it is easy to get caught up in the race for speed and efficiency. However, true progress lies in balancing speed with accuracy, and we must strive to move forward quickly without sacrificing the essential elements of patient care.


Supervised consumption services have been scaled up within Canada and internationally as an ethical imperative in the context of a public health emergency. A large body of peer-reviewed evidence demonstrates that these services prevent poisoning deaths, reduce infectious disease transmission risk behaviour, and facilitate clients’ connections to other health and social services. In 2019, the Alberta government commissioned a review of the socioeconomic impacts of seven supervised consumption services in the province. The report is formatted to appear as an objective, scientifically credible evaluation of these services; however, it is fundamentally methodologically flawed, with a high risk of biases that critically undermine its authors’ assessment of the scientific evidence. The report’s findings have been used to justify decisions that jeopardize the health and well-being of people who use drugs both in Canada and internationally. Governments must ensure that future assessments of supervised consumption services and other public health measures to address drug poisoning deaths are scientifically sound and methodologically rigorous. Health policy must be based on the best available evidence, protect the right of structurally vulnerable populations to access healthcare, and not be contingent on favourable public opinion or prevailing political ideology. People in Canada are dying from drug poisoning at an alarming rate; the immediate cause of the dramatic increase in deaths is the increasingly toxic unregulated drug supply  . Moreover, “the merits of SCS as a harm reduction tool” (p. 2) were outside the review’s scope  (Government of Alberta, Confirmation bias is the over-weighting of hypothesis-supporting evidence and under-weighting of hypothesis-refuting evidence. Failure to situate results within existing literature that contradicts a study’s claims increases the risk of confirmation bias when drawing conclusions, and undermines the development of evidence-based recommendations (Jakovljević & Ostojić, Lack of peer review: Finally, an absence of external, independent peer review calls into question the credibility of the report’s findings, as peer review is designed to detect and minimize errors and biases in methods and reasoning (Cowell,  Cowell, . In a su Cowell,  identifi Cowell, . While L Cowell, .The Alberta government SCS review report has already been used to counter efforts to increase the availability of life-saving services for PWUD in Canada and internationally, and it may continue to reinforce harm. Following the March 2020 release of the report, the cancellation of all plans for proposed new SCS across Alberta was publicly announced. In August 2020, government funding was retracted from North America’s busiest SCS in Lethbridge, forcing it to close its doors (Kalinowski, Outside of Canada, the report has been cited in civil litigation concerning Safehouse, a proposed overdose prevention site in Philadelphia. The report was cited by the United States federal government as a lone piece of evidence demonstrating that SCS can have negative impacts on their surrounding communities (Safehouse, A similar, though failed, strategy was used against SCS in 2008 when the Government of Canada used opinion statements by federally funded law enforcement agencies to propose ending the legal exemption of Canada’s first SCS, Insite (Hyshka et al., It is critical that the report be retracted by the Alberta government, and that any of its scientifically trained authors distance themselves immediately from its contents. There is no room for a report with a high risk of multiple biases in making decisions affecting the health and well-being of structurally vulnerable populations and their communities. Rather, there is a need for a peer-reviewed, methodologically sound, and ethically principled evaluation of SCS in Alberta that accounts for both health and social benefits and potential harms and outlines strategies for balancing participant and community health and safety as needed. SCS, like other population health interventions, should continue to be scientifically evaluated to ensure that they are accomplishing their objectives and not causing unintended harm. However, assessments of SCS must use robust methodologies and fair evaluation criteria that prioritize the health of the target population, their families, and communities over public perceptions.Safe Supply Committee, The continued existence of this pseudoscientific government report risks legitimizing similar approaches to future evidence generation and policy formation. In early 2022, the Alberta government proceeded with methodologically flawed evidence review activities concerning another harm reduction topic—safer supply—generating a June 2022 report intended to guide future government action (Despite peer-reviewed studies demonstrating that supervised consumption services prevent poisoning deaths and reduce other harms for PWUD, SCS continue to face opposition. The Alberta government’s pseudoscientific report—although presented as credible findings—is methodologically flawed with a high risk of multiple forms of bias. Drug policy should be based on the best available evidence, aim to protect structurally vulnerable populations’ access to healthcare, and not be contingent on prevailing ideology. There is an urgent need to shift away from commissioning reports that at their core seek to create moral panic. The Alberta government’s SCS review report could continue to be used to justify decisions that jeopardize the health and well-being of PWUD for years to come and erode trust in public health policies and practices.