Exclusion of older adults from randomized controlled trials in rheumatoid arthritis.

OBJECTIVES: To assess eligibility criteria that either explicitly or implicitly exclude older patients from randomized controlled trials (RCTs) in RA. METHODS: Our analysis included RCTs of pharmacological interventions registered with ClinicalTrials.gov and started between 2013 and 2022. Co-primary outcomes were proportions of trials with an upper age limit and the eligibility criteria indirectly increasing risk of the exclusion of older adults. RESULTS: A total of 143/290 (49%) trials had an upper age limit of 85 years or less. Multivariable analysis showed that the odds of an upper age limit were significantly lower in trials performed in the USA [adjusted odds ratio (aOR), 0.34; CI, 0.12-0.99; P = 0.04] and intercontinental trials (aOR, 0.4; CI, 0.18-0.87; P = 0.02). In total, 154/290 (53%) trials had at least one eligibility criterion implicitly excluding older adults. These included specific comorbidities (n = 114; 39%), compliance concerns (n = 67; 23%), and broad and vague exclusion criteria (n = 57; 20%); however, we found no significant associations between these criteria and trial characteristics. Overall, 217 (75%) trials either explicitly or implicitly excluded older patients; we also noted a trend towards increasing proportion of these trials over time. Only one trial (0.3%) enrolled solely patients aged 65 and older. CONCLUSION: Older adults are commonly excluded from RCTs in RA based on both age limits and other eligibility criteria. This seriously limits the evidence base for the treatment of older patients in clinical practice. Given the growing prevalence of RA in older adults, relevant RCTs should be more inclusive to them.

Eligibility criteria in clinical trials in breast cancer: a cohort study.

BACKGROUND: Breast cancer (BC) is the most common cancer type in women. The purpose of this study was to assess the eligibility criteria in recent clinical trials in BC, especially those that can limit the enrollment of older patients as well as those with comorbidities and poor performance status. METHODS: Data on clinical trials in BC were extracted from ClinicalTrials.gov. Co-primary outcomes were proportions of trials with different types of the eligibility criteria. Associations between trial characteristics and the presence of certain types of these criteria (binary variable) were determined with univariate and multivariate logistic regression. RESULTS: Our analysis included 522 trials of systemic anticancer treatments started between 2020 and 2022. Upper age limits, strict exclusion criteria pertaining to comorbidities, and those referring to inadequate performance status of the patient were used in 204 (39%), 404 (77%), and 360 (69%) trials, respectively. Overall, 493 trials (94%) had at least one of these criteria. The odds of the presence of each type of the exclusion criteria were significantly associated with investigational site location and trial phase. We also showed that the odds of the upper age limits and the exclusion criteria involving the performance status were significantly higher in the cohort of recent trials compared with cohort of 309 trials started between 2010 and 2012 (39% vs 19% and 69% vs 46%, respectively; p < 0.001 for univariate and multivariate analysis in both comparisons). The proportion of trials with strict exclusion criteria was comparable between the two cohorts (p > 0.05). Only three of recent trials (1%) enrolled solely patients aged 65 or 70 and older. CONCLUSIONS: Many recent clinical trials in BC exclude large groups of patients, especially older adults, individuals with different comorbidities, and those with poor performance status. Careful modification of some of the eligibility criteria in these trials should be considered to allow investigators to assess the benefits and harms of investigational treatments in participants with characteristics typically encountered in clinical practice.

Conflicts of interest in oncology expanded access studies.

Expanded access is a treatment use of investigational drugs, biologicals or medical devices outside of clinical trials. The purpose of our study was to assess self-reported conflicts of interest (COIs) in oncology expanded access studies. One hundred fifty-eight oncology expanded access studies published from 2013 through 2020 were included. The pharmaceutical industry funded either completely or in part 94 studies (59.49%). The authors disclosed mostly financial COIs, while the number of the reported nonfinancial conflicts was relatively small (3528 and 57 COIs, respectively). The number of articles in which at least one author had a financial COI was 118 (74.68%). The most common financial COI types included advisory board membership/consulting (1471 COIs; 41.7%), followed by honoraria (570 COIs; 16.16%) and research funding (441 COIs; 12.5%). Logistic regression was performed to identify predictors of disclosing financial COIs and positive study's conclusions. On univariate analysis, financial COIs were more likely to occur in studies with at least one center located in the United States (odds ratio [OR], 5.62; 95% confidence interval [CI], 1.57-35.98; P = .02). We also found that positive conclusions about the studied treatments were less likely in studies without industry funding (OR, 0.26; CI, 0.08-0.77; P = .01). Most of the research on COIs in oncology performed to date focused on other types of studies, especially clinical trials. To our knowledge, our study is the first to evaluate COIs in oncology expanded access studies.

Public availability of results of ClinicalTrials.gov-registered expanded access studies.

AIMS: Expanded access is the use of investigational treatments outside of clinical trials. Results of expanded access studies provide insights into how investigational treatments work in real-world settings. The objective of this study was to evaluate public availability of results of expanded access studies. METHODS: Eligible expanded access studies were identified in ClinicalTrials.gov (CT.gov). Publications matching records of individual studies were searched for in Medline and Embase. In addition, we assessed whether results of the included studies were publicly available from other sources including CT.gov, sponsor web sites and conference proceedings. RESULTS: After median time of 49.5 (interquartile range, 36.7-64.7) months from study completion, the results of 69 out of the 152 included studies (45.39%) were publicly available, either as a journal publication (53 studies; 34.87%) or from other source (16 studies; 10.52%). The percentage of studies whose results were available as a journal publication after 12, 24, 36 and 48 months from study completion was 13.2, 21.1, 33.1 and 35.7%, respectively. The percentage of studies whose results were publicly available from any source (including journal publications) at 12, 24, 36 and 48 months were 19.1, 29.6, 43.2 and 47.5%, respectively. CONCLUSION: Results of a considerable proportion of expanded access studies are not publicly available. In view of the growing importance of real-world data, sponsors and principal investigators of those studies should always consider making their findings public.

ClinicalTrials.gov as a Source of Information About Expanded Access Programs: Cohort Study.

BACKGROUND: ClinicalTrials.gov (CT.gov) is the most comprehensive internet-based register of different types of clinical studies. Expanded access is the use of unapproved drugs, biologics, or medical devices outside of clinical trials. One of the key problems in expanded access is the availability to both health care providers and patients of information about unapproved treatments. OBJECTIVE: We aimed to evaluate CT.gov as a potential source of information about expanded access programs. METHODS: We assessed the completeness of information in the records of 228 expanded access programs registered with CT.gov from February 2017 through May 2020. Moreover, we examined what percentage of published expanded access studies has been registered with CT.gov. Logistic regression (univariate and multivariate) and mediation analyses were used to identify the predictors of the absence of some information and a study's nonregistration. RESULTS: We found that some important data were missing from the records of many programs. Information that was missing most often included a detailed study description, facility information, central contact person, and eligibility criteria (55.3%, 54.0%, 41.7%, and 17.5% of the programs, respectively). Multivariate analysis showed that information about central contact person was more likely to be missing from records of studies registered in 2017 (adjusted OR 21.93; 95% CI 4.42-172.29; P<.001). This finding was confirmed by mediation analysis (P=.02). Furthermore, 14% of the programs were registered retrospectively. We also showed that only 33 of 77 (42.9%) expanded access studies performed in the United States and published from 2014 through 2019 were registered with CT.gov. However, multivariate logistic regression analysis showed no significant association between any of the variables related to the studies and the odds of study nonregistration (P>.01). CONCLUSIONS: Currently, CT.gov is a quite fragmentary source of data on expanded access programs. This problem is important because CT.gov is the only publicly available primary source of information about specific programs. We suggest the actions that should be taken by different stakeholders to fully exploit this register as a source of information about expanded access.

Phage therapy: Current status and perspectives.

The spread of antimicrobial resistant bacterial pathogens combined with the lack of new drug classes in the antibiotic pipeline causes a resurgence of the use of bacterial viruses (phages) to treat bacterial infections (phage therapy [PT]). There has been a substantial increase in patients subjected to this experimental therapy and emergence of new PT centers in Europe and the United States paralleled by one clinical trial completed in accord with good medical practice (GMP) requirements and a few others underway. What is more, evidence has been accumulating to suggest that phages can also exert anti-inflammatory and immunomodulatory action which opens new pathways for the development of novel targets for PT. Here we present the status quo of the PT, recent regulatory, and clinical developments as well as new perspectives for its wider application in clinical medicine.

Legal regulations, ethical guidelines and recent policies to increase transparency of clinical trials.

Timely and accurate dissemination of outcomes is essential to accomplish main benefits of scientific research including clinical trials. Clinical trial results can be disseminated in two main ways: by publication in a peer-reviewed journal and by posting on a publicly available clinical trial register. The credibility of the literature on clinical trials is significantly diminished because a high percentage of trials is not published. While current legal regulations both in the European Union (EU) and the USA impose a duty to submit summary results of clinical trials to a respective register (EU Clinical Trial Register and ClinicalTrials.gov, respectively), the compliance with this requirement has been generally inadequate. Trial outcomes can be also made accessible by data sharing. However, in spite of the wide promotion of this idea, the access of investigators to participant-level datasets remains limited. The main objective of this review is to discuss current legal regulations, international standards, ethical guidelines and recent policies pertaining to dissemination of clinical trial results.

Ethics framework for treatment use of investigational drugs.

BACKGROUND: Expanded access is the use of investigational drugs (IDs) outside of clinical trials. Generally it is performed in patients with serious and life-threatening diseases who cannot be treated satisfactorily with authorized drugs. Legal regulations of expanded access to IDs have been introduced among others in the USA, the European Union (EU), Canada and Australia. In addition, in the USA an alternative to expanded access is treatment under the Right-to-Try law. However, the treatment use of IDs is inherently associated with a number of ethically relevant problems. MAIN TEXT: The objective of this article is to present a coherent framework made up of eight requirements which have to be met for any treatment use of an ID to be ethical. These include a justified need for the use of an ID, no threat to clinical development of the ID, adequate scientific evidence to support the treatment, patient's benefit as the primary goal of the use of an ID, informed decision of a patient, fair access of patients to IDs, independent review, as well as the dissemination of treatment results. CONCLUSIONS: While this framework is essentially consistent with the legal regulations of expanded access of the USA, the EU, Canada and Australia, it is substantially wider in scope because it addresses some important issues that are not covered by the regulations. Overall, the framework that we developed minimizes the risks and threats, and maximizes potential benefits to each of the four key stakeholders involved in the treatment use of IDs including patients, doctors, drug manufacturers, and society at large.

Ethics codes and use of new and innovative drugs.

Treatment with new and/or innovative drugs with uncertain safety and efficacy profile is associated with substantial ethical concerns. The main objective of this paper is to present guidance on the use of such drugs contained in: (i) major international codes and guidelines pertaining to medical ethics and biomedical research; (ii) national codes of medical ethics and professional conduct of the USA, Canada, Australia, New Zealand, the UK, Ireland, France and Germany. Out of the four international codes and guidelines analysed, only the Declaration of Helsinki addresses the question of the use of unproven drugs. Among national codes, only two (USA and New Zealand) explicitly allow for use of new or innovative drugs. Moreover, treatment with unproven drugs seems to be permissible under the French code, though this is not stated explicitly. The remaining codes do not contain any articles on the use of new and innovative drugs. An update of existing articles, as well as the addition of new guidelines to the codes, should be considered in view of the rapid pace of development and introduction to clinical practice of new drugs. This work is relevant to innovative off-label applications of approved drugs and expanded access to investigational drugs.

Inhibitory Effects of Bacteriophage Preparations on Adenoviral Replication.

BACKGROUND/AIMS: Bacteriophages (phages) are viruses of bacteria. Escherichia coli phage (T4) can potentially interfere with adsorption of HAdV-5 to cellular integrins by its KGD motif, while staphylococcal A5/80 phage does not possess this structure. The objective of this study was to investigate the effects of T4 and A5/80 phage preparations on type 5 human adenovirus (HAdV-5) DNA synthesis and the expression of HAdV-5 genes. METHODS: Experiments were performed on the A549 cell line. HAdV-5 DNA synthesis was investigated with real-time PCR. Expression of HAdV-5 early (DBP) and late (hexon) genes was determined by quantitative real-time PCR in preincubation and coincubation experiments. RESULTS: While both phage preparations significantly reduced the expression of HAdV-5 genes, synthesis of HAdV-5 DNA was inhibited only by T4. CONCLUSION: Phage preparations show promise as novel antiviral agents. However, further studies are required to investigate their antiviral effects.

Bacteriophages targeting intestinal epithelial cells: a potential novel form of immunotherapy.

In addition to their established role as a physical barrier to invading pathogens and other harmful agents, intestinal epithelial cells (IEC) are actively involved in local immune reactions. In the past years, evidence has accumulated suggesting the role of IEC in the immunopathology of intestinal inflammatory disorders (IBD). Recent advances in research on bacteriophages strongly suggest that-in addition to their established antibacterial activity-they have immunomodulating properties that are potentially useful in the clinic. We suggest that these immunomodulating phage activities targeting IEC may open novel treatment perspectives in disorders of the alimentary tract, particularly IBD.

Increased serum levels of progranulin (PGRN) in patients with haemophilic arthropathy.

Haemophilia A and B are rarely occurring X chromosome-linked congenital coagulation disorders dominated by spontaneous joint bleedings and chronic synovitis, leading to development of haemophilic arthropathy (HA). Progranulin (PGRN) is a growth factor with anti-inflammatory and immunomodulatory properties. PGRN is an important molecule in the pathogenesis of osteoarthritis (OA) and rheumatological disorders. This study was aimed at investigating the potential role of PGRN in the mechanisms underlying the pathogenesis of HA. The serum levels of PGRN were measured by enzyme-linked immunosorbent assay (ELISA) in patients with end-stage knee joint HA (n = 20) and end-stage primary knee joint OA (n = 20) who met the inclusion and exclusion criteria. The clinical and radiological assessment of disease severity was evaluated by the Knee Society Score (KSS) and Kellgren-Lawrence scale. Median PGRN levels in HA patients was 349.1 ng/mL (232.8-415.6 ng/mL) and in OA patients 148.3 ng/mL (112.1-275.3 ng/mL) with statistically significant differences between both groups (P < 0.015). Further analysis revealed no correlation between PGRN levels and any of the patient demographics and clinical parameters. This study demonstrates increased PGRN serum levels in patients with HA and provides new insights into the mechanisms underlying the pathogenesis of HA indicating a new potential target for therapeutic intervention.

Ethics review in compassionate use.

BACKGROUND: Compassionate use is the use of unapproved drugs outside of clinical trials. So far, compassionate use regulations have been introduced in the US, Canada, many European countries, Australia and Brazil, and treatment on a compassionate use basis may be performed in Japan and China. However, there are important differences between relevant regulations in individual countries, particularly that approval by a research ethics committee (institutional review board) is a requirement for compassionate use in some countries (e.g. the US, Spain, and Italy), but not in others (e.g. Canada, the UK, France, and Germany). DISCUSSION: The main objective of this article is to present aspects of compassionate use that are important for the discussion of the role of research ethics committees in the review of compassionate use. These aspects include the nature of compassionate use, potential risks to patients associated with the use of drugs with unproven safety and efficacy, informed consent, physicians' qualifications, and patient selection criteria. Our analysis indicates that the arguments for mandatory review substantially outweigh the arguments to the contrary. CONCLUSIONS: Approval by a research ethics committee should be obligatory for compassionate use. The principal argument against mandatory ethical review of compassionate use is that it is primarily a kind of treatment rather than biomedical research. Nonetheless, compassionate use is different from standard clinical care and should be subject to review by research ethics committees. First, in practice, compassionate use often involves significant research aspects. Second, it is based on unapproved drugs with unproven safety and efficacy. Obtaining informed consent from patients seeking access to unapproved drugs on a compassionate use basis may also be difficult. Other important problems include the qualifications of the physician who is to perform treatment, and patient selection criteria.

Mesenchymal Stem Cells from Human Amniotic Membrane and Umbilical Cord Can Diminish Immunological Response in an in vitro Allograft Model.

BACKGROUND/AIM: Mesenchymal stem cells (MSCs) are gaining rising interest in gynecology and obstetrics. MSCs immunomodulatory properties are suitable enough to reduce perinatal morbidity caused by inflammation in premature neonates. The aim of this study was to evaluate and compare the ability to inhibit allo-activated lymphocytes proliferation by MSCs derived from different sources: amniotic membrane (AM), umbilical cord (UC) and adipose tissue (AT). METHODS: MSCs were isolated from AM (n = 7) and UC (n = 6) and AT (n = 6) of healthy women. Cells were characterized by flow cytometry and differentiation assay. To evaluate the potential of fetal and adult MSCs to diminish immunological response, mixed lymphocytes reaction (MLR) was performed. RESULTS: Amnion and UC-derived cells displayed typical MSCs characteristics. Addition of MSCs to MLR significantly inhibited the proliferation of stimulated lymphocytes. The effect was observed regardless of the MSCs type used (p < 0.01 in all groups). Comparative analysis revealed no significant differences in this action between tested MSCs types. Additionally, no type of MSCs significantly stimulated allogeneic lymphocytes. CONCLUSION: The results prove the immunosuppressive capacities of fetal-derived MSCs in vitro. In the future, they may be potentially used to treat premature newborn as well as in immunomodulation in post-transplant therapy.

Exclusion of older patients from randomized clinical trials in Parkinson's disease.

Prevalence of Parkinson's disease (PD) increases with age. The purpose of this study was to evaluate the eligibility criteria in randomized clinical trials (RCTs) in PD, especially those limiting the enrollment of older adults. We examined RCTs of pharmacological and non-pharmacological anti-parkinsonian interventions registered with ClinicalTrials.gov and started from 2013 through 2022. Primary outcome was proportion of RCTs with an upper age limit of 85 years of age or less. Secondary outcome was proportion of RCTs with other exclusion criteria. Associations between trial characteristics and the presence of the age limits were determined using logistic regression. Our study included 420 RCTs. Two hundred thirty-nine (57%) of these had an upper age limit of 85 years of age or less. Proportion of these trials significantly increased over time. The odds of the presence of an upper age limit were significantly associated with the investigational site location, phase, and timeframe for the primary endpoint assessment. Three hundred fifty-six (85%) trials had other eligibility criteria limiting the enrollment of older patients; these often (n = 285; 68%) included cognitive impairment. Overall, 386 (92%) RCTs either explicitly excluded older adults or had criteria indirectly limiting their enrollment. Underrepresentation of older patients in clinical trials in PD considerably reduces the generalizability of their results. Some eligibility criteria should be modified to enable the investigators to assess the benefits and harms of new therapeutic interventions in older adults. This problem is important in view of rapidly growing number of older patients with PD.

Placebo-controlled randomized clinical trials of antidepressants for major depressive disorder: Analysis of ClinicalTrials.gov, 2008-2022.

The purpose of this study was to analyze the key aspects of the design of contemporary placebo-controlled randomized clinical trials (RCTs) of antidepressants enrolling patients with major depressive disorder (MDD) aged 18 years or older, especially the outcome measures and the eligibility criteria. The study included 122 RCTs registered with ClinicalTrials.gov and started from 2008 through 2022. Most RCTs assessed only clinical remission, with proportion of trials with outcome measures related to functional remission being rather low (n = 34; 28 %). Clinical remission was mostly evaluated in acute phase of depression, and only 7 (6 %) trials assessed the prevention of relapse. Proportion of trials utilizing self-report questionnaires that provide important information complementary to clinician-rated scales was moderate (n = 66; 54 %). Another problem in included RCTs was common use of stringent eligibility criteria. For instance, minimal symtpom severity required for the patient's inclusion was listed in 104 RCTs (85 %), and 41 RCTs (34 %) excluded patients based on comorbid anxiety disorders. Most RCTs (n = 103; 84 %) excluded older patients, and only 6 (5 %) trials were dedicated exclusively to them. To ensure optimal development of clinical pharmacotherapy of MDD, the investigators should consider modification of some of the key aspects of the design of RCTs of antidepressants.

Exclusion of older adults from clinical trials in cancer-related pain.

Pain is one of the most common symptoms in cancer patients including older adults. The objective of this study was to evaluate the enrollment criteria that can limit the inclusion of older adults in clinical trials concerning cancer-related pain (CRP). The study included 356 trials registered with ClinicalTrials.gov. Our primary outcome measures were the proportion of trials that excluded patients based on upper age limits (80 years of age or less), strict organ-specific exclusion criteria, broad and imprecise criteria, and inadequate performance score. One hundred and twenty-six trials (35.4%) had upper age limits. Strict exclusion criteria were used in 95 (26.7%) trials. Broad and imprecise exclusion criteria were listed in 57 (16.2%) trials. Low performance score was used as an exclusion criterion in 4 trials (1.1%). Overall, in 241 trials (67.7%) there was either an upper age limit or at least one strict or broad and imprecise exclusion criterion, or a criterion involving the performance status. The odds of excluding older adults were significantly higher in certain neoplasm types, study objectives, intervention types, and center locations. In conclusion, considerable proportion of recent clinical trials concerning CRP either explicitly exclude older adults or create high risk of such exclusion which substantially limits the evidence base for the treatment of such patients in clinical practice. Sponsors and investigators should consider careful modification of the enrollment criteria to improve the inclusion of older individuals who make up the major proportion of cancer patients population.

Ethics codes and medical decision making.

OBJECTIVE: The objective of this study is to analyze guidance about medical decision making contained in ethics codes. The primary question we address is which of the main decision-making models - informed decision making (IDM), shared decision making (SDM), or paternalism - is promoted by these codes. METHODS: We manually searched codes of medical ethics for guidance on medical decision making. Our analysis focused on the major international code, the World Medical Association International Code of Medical Ethics (ICME), and national codes of the US, Canada, Australia, New Zealand, the UK, Ireland, Germany, France and Norway. RESULTS: The ICME does not promote any specific model of medical decision making. 10 of the 11 analyzed national codes contain guidance about IDM, while only four refer to SDM. Some codes contain articles which are imprecise with regard to the question of medical decision making. CONCLUSIONS: All of the analyzed national codes should be updated or amended. In particular, given the great importance of SDM in medicine, codes which do not contain relevant guidance should be updated. PRACTICE IMPLICATIONS: Relevant amendments introduced to ethics codes could contribute to promoting of adequate standards of medical decision making (especially those regarding SDM) among doctors.

Prophylactic effect of bacteriophages on mice subjected to chemotherapy-induced immunosuppression and bone marrow transplant upon infection with Staphylococcus aureus.

Due to the increased resistance of bacteria to antibiotics, phage therapy may be an alternative to treat or prevent suppurative infections in immunocompromised patients. The authors' recent studies indicated that such an approach is particularly beneficial in immunosuppressed mice. A5/L bacteriophages, specific for the Staphylococcus aureus strain L, were tested for their ability to protect CBA mice subjected to myeloablative (busulfan) and immunosuppressive (cyclophosphamide) conditioning followed by a syngeneic bone marrow transplantation (BMT) and infected with a sublethal or lethal dose of bacteria. The application of phages to immunocompromised mice given BMT led to a significant (>90%) reduction in bacterial load in the spleen and liver. Moreover, 72% of such mice attained long-term survival versus 8.2% survival of mice not treated with phages. Analysis of leukocyte number and blood cell type composition revealed that phage application increased the leukocyte numbers and neutrophil content in the circulating blood. Moreover, phage application led to an increased content of the myelocytic cell lineage in the bone marrow. The protective effects of phages in immunosuppressed mice are both direct (bacteriolytic) and indirect (by stimulation of myelopoiesis). The results suggest a potential benefit of phage therapy in immunocompromised patients subjected to bone marrow transplant procedures.