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 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.

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.

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.

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.

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.

The Presence of Bacteriophages in the Human Body: Good, Bad or Neutral?

The presence of bacteriophages (phages) in the human body may impact bacterial microbiota and modulate immunity. The role of phages in human microbiome studies and diseases is poorly understood. However, the correlation between a greater abundance of phages in the gut in ulcerative colitis and diabetes has been suggested. Furthermore, most phages found at different sites in the human body are temperate, so their therapeutic effects and their potential beneficial effects remain unclear. Hence, far, no correlation has been observed between the presence of widespread crAssphage in the human population and human health and diseases. Here, we emphasize the beneficial effects of phage transfer in fecal microbiota transplantation (FMT) in Clostridioides difficile infection. The safety of phage use in gastrointestinal disorders has been demonstrated in clinical studies. The significance of phages in the FMT as well as in gastrointestinal disorders remains to be established. An explanation of the multifaceted role of endogenous phages for the development of phage therapy is required.

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.

Phage Therapy: Towards a Successful Clinical Trial.

While phage therapy carried out as compassionate use (experimental therapy) has recently flourished, providing numerous case reports of supposedly healed patients, clinical trials aiming to formally prove their value in accord with current regulatory requirements have failed. In light of the current issue of increasing antibiotic resistance, the need for a final say regarding the place of phage therapy in modern medicine is evident. We analyze the possible factors that may favor success or lead to the failure of phage therapy: quality of phage preparations, their titer and dosage, as well as external factors that could also contribute to the outcome of phage therapy. Hopefully, better control of these factors may eventually bring about long-awaited positive results.

Sepsis, Phages, and COVID-19.

Phage therapy has emerged as a potential novel treatment of sepsis for which no decisive progress has been achieved thus far. Obviously, phages can help eradicate local bacterial infection and bacteremia that may occur in a syndrome. For example, phages may be helpful in correcting excessive inflammatory responses and aberrant immunity that occur in sepsis. Data from animal studies strongly suggest that phages may indeed be an efficient means of therapy for experimentally induced sepsis. In recent years, a number of reports have appeared describing the successful treatment of patients with sepsis. Moreover, novel data on the anti-viral potential of phages may be interpreted as suggesting that phages could be used as an adjunct therapy in severe COVID-19. Thus, clinical trials assessing the value of phage therapy in sepsis, including viral sepsis, are urgently needed.

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.

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.