We read with interest the study by Perrier et al on the Relationship between the conflicts of interest and the results of meta-analyses of homoeopathy trials. We want to briefly address issues we see with this paper.
Firstly, the criteria for a study presenting a Conflict of Interest (CoI) include that a single author has a link with any research institution involved in homeopathy research. Translated to other fields of research, Oncology for example, this would mean that cancer studies emanating from Cancer Research institutes would have to be considered as conflicted and therefore unreliable. This is clearly an absurd way of defining CoIs.
More importantly, the authors wrongly report the Odds Ratio (OR) data for the Shang et al paper as being OR = 0.88, CI 0.65-1.19, N=105, this OR corresponds to the N=8 ‘larger high-quality trials’ from that study, not N=105. The OR for N=105 was never published but the OR for the N=21 ‘high-quality trials’ is OR = 0.76; CI: 0.59-0.99, N=21 (Ludtke & Ruttem 2008). Ignoring the meaningless N=1 MAs in Fig 1, we end up with three CoI-free MAs, which all favour homeopathy. And this trend would only be accentuated by using the correct OR for the full N=105 trials. The overall picture painted by the data is thereby very different than reported by the authors. In particular there appears to be no statistical difference between their so-called CoI and CoI-free MAs in Homeopathy.
Gøtzsche and Jørgensen claim that the European Medicines Agency (EMA) mishandled their investigation of the safety of the HPV vaccine regarding serious neurological adverse events from the administration of the HPV vaccine, such as postural orthostatic tachycardia syndrome (POTS) and chronic regional pain syndrome (CRPS). The authors highlight the insufficiency due to poor data analysis, conflicts of interest, poor research into aluminum adjuvants, and bias in analyzing the research 1. We want to discuss several key points on the safety of the HPV vaccine.
Over 270 million doses of HPV vaccines have been administered since 2006. Many regulatory agencies have overseen the safety of the HPV vaccine, including the World Health Organization’s GACVS (Global Advisory Committee on Vaccine Safety) 2. Most regulatory agencies regard the HPV vaccine as safe and effective 3,4. The noted exception in this article is the Uppsala Monitoring Centre which identified safety signals for POTS and CRPS post-HPV vaccination 5.
As of specific note from the paper, the majority of the evidence supporting an association with the HPV vaccine and POTS and CRPS in the article by Gøtzsche and Jørgensen was generated from data in Europe, including Denmark 1. A recent study showed no safety signal generally and specifically commented that the Denmark signal was not identified in their analysis, noting that 1,232,572 girls received the vaccine and 563 unique CRPS diagnoses (6). Concerns about...
Gøtzsche and Jørgensen claim that the European Medicines Agency (EMA) mishandled their investigation of the safety of the HPV vaccine regarding serious neurological adverse events from the administration of the HPV vaccine, such as postural orthostatic tachycardia syndrome (POTS) and chronic regional pain syndrome (CRPS). The authors highlight the insufficiency due to poor data analysis, conflicts of interest, poor research into aluminum adjuvants, and bias in analyzing the research 1. We want to discuss several key points on the safety of the HPV vaccine.
Over 270 million doses of HPV vaccines have been administered since 2006. Many regulatory agencies have overseen the safety of the HPV vaccine, including the World Health Organization’s GACVS (Global Advisory Committee on Vaccine Safety) 2. Most regulatory agencies regard the HPV vaccine as safe and effective 3,4. The noted exception in this article is the Uppsala Monitoring Centre which identified safety signals for POTS and CRPS post-HPV vaccination 5.
As of specific note from the paper, the majority of the evidence supporting an association with the HPV vaccine and POTS and CRPS in the article by Gøtzsche and Jørgensen was generated from data in Europe, including Denmark 1. A recent study showed no safety signal generally and specifically commented that the Denmark signal was not identified in their analysis, noting that 1,232,572 girls received the vaccine and 563 unique CRPS diagnoses (6). Concerns about the media role increased in case count, and most cases were self-resolving and limited 1.
So, the question is how to rectify the disparity of conclusions between Uppsala and other regulatory agencies. Or maybe the discussion is misdirected? Gøtzsche and Jørgensen claim bias and poor scientific rigor in the trial design. An alternative to this hypothesis was noted by Uppsala Monitoring Center when they said variability in diagnosis terms (i.e., the ontology of vaccine adverse events) might not provide a coherent diagnosing paradigm and monitoring approach across clinical, regulatory, and industry entities, which was only alluded to by the authors. The Uppsala manuscript has an excellent analysis focused on adversomics, which is completely missing in the Gøtzsche and Jørgensen paper. The adversomics is THE important part of the Uppsala manuscript.
During COVID-19, numerous tools were developed and used to assess vaccine responses for safety and efficacy. These tools could potentially identify people who have adverse events after vaccination. Immunogenomics, transcriptomics, epitope mapping, machine learning, etc., are available and could be used to identify the safety profile of all vaccines 6. We strongly advocate that with these current technologies, risk factors for POTS and CRPS could be identified (> GRADE 3 SAEs (Serious Adverse Event)) through the study of existing and future cases. We strongly advocate developing diagnostic criteria for POTS and CRPS by Brighton Collaboration, including consistent GRADE analysis and ontology. Regulatory agencies could require monitoring using these tools in serious adverse events cases for any vaccine to improve vaccine safety for rare SAEs. Instead of asking whether HPV is safe, maybe we should ask how high-risk patients can be identified pre-vaccination. The COVID-19 analysis suggests we could identify potential risk factors that lead to adverse events to adjuvants and the vaccine in general. We advocate for these approaches through regulatory requirements, including improved phase IV trials, active monitoring, and proper analysis.
1. Gøtzsche PC, Jørgensen KJ. EMA’s mishandling of an investigation into suspected serious neurological harms of HPV vaccines. BMJ Evid-Based Med. 2022;27(1):7-10. doi:10.1136/bmjebm-2020-111470
2. HPV Vaccine Safety, WHO. Accessed June 23, 2023. https://www.who.int/groups/global-advisory-committee-on-vaccine-safety/t...
3. HPV Dashboard. Accessed June 23, 2023. https://www.who.int/teams/immunization-vaccines-and-biologicals/diseases...(HPV)/hpv-clearing-house/hpv-dashboard
4. Bonanni P, Bechini A, Donato R, et al. Human papilloma virus vaccination: impact and recommendations across the world. Ther Adv Vaccines. 2015;3(1):3-12. doi:10.1177/2051013614557476
5. Chandler RE. Safety Concerns with HPV Vaccines Continue to Linger: Are Current Vaccine Pharmacovigilance Practices Sufficient? Drug Saf. 2017;40(12):1167-1170. doi:10.1007/s40264-017-0593-3
6. Cotugno N, Ruggiero A, Santilli V, et al. OMIC Technologies and Vaccine Development: From the Identification of Vulnerable Individuals to the Formulation of Invulnerable Vaccines. J Immunol Res. 2019;2019:e8732191. doi:10.1155/2019/8732191
It is misleading (as stated in “what this study adds”) to described this trial as placebo controlled. Although dummy capsules were used to blind participants to which combination of curcumin or omeprazole they were receiving, no group received placebo only. One interpretation of the findings therefore remains that they are due to a placebo effect. It is unfortunate that this misrepresentation of the study design has already been picked up by a UK National newspaper (Guardian 12 September)
we are writing in response to the article titled " How methodological pitfalls have created widespread misunderstanding about long COVID”(1).
We agree with the authors, that the existing epidemiological research on long COVID has suffered from overly broad case definitions and a striking absence of control groups, which may have led in an overestimation of risk.
It is important to acknowledge that Long- and Post-COVID syndrome are heterogeneous conditions, likely comprising different pathomechanistic groups such as autoimmunity, mitochondrial dysfunction, and virus persistence (2). This complexity, coupled with the lack of routine biomarkers, makes it difficult to accurately define and study this condition. Høeg et al et al. therefore raise some relevant points regarding the challenges faced in studying Long- and Post-COVID syndrome, particularly the need for properly matched control groups and internationally-established diagnostic criteria. Regarding the latter, the authors of the article themselves fail to use definitions accurately, particularly in distinguishing between the now consented WHO definitions of Long-COVID and Post-COVID (WHO/2019-nCoV/Post_COVID-19_condition/Clinical_case_definition/2021.1).
It is true, that initial studies depicted a high prevalence of Post-COVID syndrome (PCS). However, more recent population-based studies present a different perspective. In assessing the clinical picture, the primary focus isn...
we are writing in response to the article titled " How methodological pitfalls have created widespread misunderstanding about long COVID”(1).
We agree with the authors, that the existing epidemiological research on long COVID has suffered from overly broad case definitions and a striking absence of control groups, which may have led in an overestimation of risk.
It is important to acknowledge that Long- and Post-COVID syndrome are heterogeneous conditions, likely comprising different pathomechanistic groups such as autoimmunity, mitochondrial dysfunction, and virus persistence (2). This complexity, coupled with the lack of routine biomarkers, makes it difficult to accurately define and study this condition. Høeg et al et al. therefore raise some relevant points regarding the challenges faced in studying Long- and Post-COVID syndrome, particularly the need for properly matched control groups and internationally-established diagnostic criteria. Regarding the latter, the authors of the article themselves fail to use definitions accurately, particularly in distinguishing between the now consented WHO definitions of Long-COVID and Post-COVID (WHO/2019-nCoV/Post_COVID-19_condition/Clinical_case_definition/2021.1).
It is true, that initial studies depicted a high prevalence of Post-COVID syndrome (PCS). However, more recent population-based studies present a different perspective. In assessing the clinical picture, the primary focus isn't merely on the presence of symptoms but on the symptom-related reduction in quality of life. Our own study reveals that only 20% of symptomatic patients experience a significant reduction in their quality of life, indicating suffering from Post-COVID syndrome. This suggests a prevalence of Post-COVID syndrome at 5-6% for the entire population (3). The risk of developing Post-COVID syndrome after infection with currently circulating variants is notably lower than in patients from the initial waves of the infection (3). This aspect should be emphasized as part of a critical analysis of the issue, the authors can be expected to go into this in more depth and thus contribute to a more objective discussion. A systematic meta-analysis that considers different data collection times after infection and the method of symptom recording (self-reported versus documented through examinations) would have been more beneficial. This approach would provide a more comprehensive view rather than highlighting individual studies, thus avoiding polarized statements.
Furthermore, Høeg et al. suggest the inclusion of infection-negative control groups in future research. While this may be ideal, it is not realistic in the current state of the pandemic, which is now in its third year and has reached an endemic stage (Rahman et al., 2021). Additionally, the absence of antibodies does not exclude the presence of infection, as demonstrated in the Conan study, where half of the patients with PCR-confirmed infection had no detectable antibodies six weeks later (4).
Despite methodological limitations pointed out by Høeg et al. that apply to Post-COVID studies, it is crucial to recognize that Post-COVID syndrome is a relevant and frequent condition that requires further investigation in order to optimized diagnostic criteria and identify pathomechanism related biomarkers that may help to assign patients to appropriate randomized treatment studies according to the underlying mechanism. The findings regarding immune dysregulation described by A. Iwaski's working group are indeed promising and offer encouragement to many individuals affected by this condition (5). It is essential to continue studying and addressing post-COVID conditions to provide appropriate care and support for those affected.
Sincerely,
Mathias W. Pletz, MD and Andreas Stallmach, MD
Bibliography
1. Høeg TB, Ladhani S, Prasad V. How methodological pitfalls have created widespread misunderstanding about long COVID. BMJ Evid Based Med. 2023 Sep 25;
2. Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023 Mar;21(3):133–46.
3. Giszas B, Trommer S, Schüßler N, Rodewald A, Besteher B, Bleidorn J, et al. Post-COVID-19 condition is not only a question of persistent symptoms: structured screening including health-related quality of life reveals two separate clusters of post-COVID. Infection. 2023 Apr;51(2):365–77.
4. Weis S, Scherag A, Baier M, Kiehntopf M, Kamradt T, Kolanos S, et al. Antibody response using six different serological assays in a completely PCR-tested community after a coronavirus disease 2019 outbreak-the CoNAN study. Clin Microbiol Infect. 2021 Mar;27(3):470.e1-470.e9.
5. Klein J, Wood J, Jaycox J, Dhodapkar RM, Lu P, Gehlhausen JR, et al. Distinguishing features of Long COVID identified through immune profiling. Nature. 2023 Sep 25;
With great interest I read the original research article “Curcumin and proton pump inhibitors for functional dyspepsia: a randomised, double blind controlled trial” by Kongkam et al. While the authors suggest that the study demonstrates that the efficacy of curcumin for functional dyspepsia is comparable to that of omeprazole, I want to point out some deficiencies and discrepancies of the study reporting that cast doubt on this conclusion.
Firstly, it is not clear what hypothesis was tested and what specific study results the conclusion is based on. The main outcomes are vaguely specified as functional dyspepsia symptoms. As the equivalence design is mentioned, the reference to improvement of 2 points in the SODA score between the treatment group should probably be interpreted as the equivalence margin set for the study. The results of nine pairwise comparisons are provided in Table 3. For three of them 95% confidence intervals include the equivalence margin, thus clearly demonstrating non-equivalency. For example, for pain intensity in curcumin only vs omeprazole only arms the 95% CI is −1.16 (−2.95 to 0.64), which demonstrates that curcumin is not non-inferior to omeprazole.
To add to the issue of unclear study question and selective post hoc interpretation of outcomes, it should be mentioned that the study was not registered prospectively. The TCTR registration (TCTR20221208003) is post factum. Also the authors do not properly explain...
With great interest I read the original research article “Curcumin and proton pump inhibitors for functional dyspepsia: a randomised, double blind controlled trial” by Kongkam et al. While the authors suggest that the study demonstrates that the efficacy of curcumin for functional dyspepsia is comparable to that of omeprazole, I want to point out some deficiencies and discrepancies of the study reporting that cast doubt on this conclusion.
Firstly, it is not clear what hypothesis was tested and what specific study results the conclusion is based on. The main outcomes are vaguely specified as functional dyspepsia symptoms. As the equivalence design is mentioned, the reference to improvement of 2 points in the SODA score between the treatment group should probably be interpreted as the equivalence margin set for the study. The results of nine pairwise comparisons are provided in Table 3. For three of them 95% confidence intervals include the equivalence margin, thus clearly demonstrating non-equivalency. For example, for pain intensity in curcumin only vs omeprazole only arms the 95% CI is −1.16 (−2.95 to 0.64), which demonstrates that curcumin is not non-inferior to omeprazole.
To add to the issue of unclear study question and selective post hoc interpretation of outcomes, it should be mentioned that the study was not registered prospectively. The TCTR registration (TCTR20221208003) is post factum. Also the authors do not properly explain why of the two outcome measurement tools used at baseline (SODA and SF-LDQ) the latter was then dropped with no clear explanation given.
Secondly, the attrition seems to be systematically different in the groups. In curcumin plus omeprazole group loss to follow-up was 14, in curcumin only arm 17 and omeprazole only arm 1, while the numbers of subjects who withdrew consent were 2, 2 and 18 respectively. This difference is not very likely to arise by chance alone. No exaplanation is given.
There are some other inconsistencies in the article but I will leave it to the attentive reader to interpret.
On October, 10 I contacted the corresponding author asking to comment on some of the above and requested the study data for re-analysis. As of today my email remains unanswered.
I read this scoping review with great interest. In linguistics there is a term for the phenomenon that a word can have the capacity to have multiple related meanings in different contexts. This term is polysemy. In the context of defining "Evidence-based medicine". If we want to understand each other, it proved successful to define the words we use .Sackett et al. in their seminal article about" EBM what it is and what it isn't" also defined what they mean by "evidence", namely: "By best available external clinical evidence we mean clinically relevant research,often from the basic sciences of medicine, but especially from patient centred clinical research into the accuracy and precision of diagnostic tests (including the clinical examination), the power of prognostic markers, and the efficacy and safety of therapeutic, rehabilitative, and preventive regimens."
Doesn't this render it irrelevant for the context of EBM if others define differently in other contexts? A bigger problem arises when the term evidence is misunderstood or even misused within the context of EBM. This problem might be approached by better teaching of the meaning originally meant. Evidence to my knowledge (as a non-english native speaker) is a juridical term and thus different to proof or fact. Juridically only the sum of evidence is leading to a court decision. And, this decision can be wrong especially if new evidence arises.
The article by Alastair Munro and colleagues (to which this is a rapid response) is of great value and importance, as we can now see, since this article was published, that there has been considerable discussion and interrogation by the COVID inquiry (https://covid19.public-inquiry.uk/), about whether the closure of schools, ordered on 18th March 2020 by Boris Johnson's government, and put into effect two days later on 20th March, was ever necessary.
The rationale for the closure of schools was that it was imperative that the transmission rate of the COVID-19 pandemic, then rapidly spreading in the UK, was brought down at pace. Only three days later, a full, mandated, "lock down" was imposed. This was in the context of a suite of increasingly draconian measures to impose Non-Pharmaceutical Interventions (NPIs) on an increasingly fretful population - on March 12th, 16th, 20th and 23rd.
The question we pose of the authors of the current paper under discussion is a simple one. What is the actual, real world, evidence that the 'R' value fell as a result of the closure of schools? Is there any real-world, UK-based, 2020 information we can use to answer this question. This question cannot remotely be answered by reference to other countries, or, to mathematical models. The impact of school closures must also be analysed independently of all of the other contemporaneous NPIs.
The article by Alastair Munro and colleagues (to which this is a rapid response) is of great value and importance, as we can now see, since this article was published, that there has been considerable discussion and interrogation by the COVID inquiry (https://covid19.public-inquiry.uk/), about whether the closure of schools, ordered on 18th March 2020 by Boris Johnson's government, and put into effect two days later on 20th March, was ever necessary.
The rationale for the closure of schools was that it was imperative that the transmission rate of the COVID-19 pandemic, then rapidly spreading in the UK, was brought down at pace. Only three days later, a full, mandated, "lock down" was imposed. This was in the context of a suite of increasingly draconian measures to impose Non-Pharmaceutical Interventions (NPIs) on an increasingly fretful population - on March 12th, 16th, 20th and 23rd.
The question we pose of the authors of the current paper under discussion is a simple one. What is the actual, real world, evidence that the 'R' value fell as a result of the closure of schools? Is there any real-world, UK-based, 2020 information we can use to answer this question. This question cannot remotely be answered by reference to other countries, or, to mathematical models. The impact of school closures must also be analysed independently of all of the other contemporaneous NPIs.
If the opportunity to test the hypothesis that schools were an important source of inter-generational COVID viral spread were not to have been taken, this would be a tragic lost piece of knowledge which could otherwise have informed the best approach to take for future pandemics in the UK. It is our belief that school closures were a part of the pandemic influenza planning, which it now seems was the only pandemic-related planning that had ever occurred in the UK. COVID-19 as we all well know was much less likely to harm children than pandemic influenza. So the medical benefits to children from school closures would have been minimal, possibly nil, while the societal harms caused by school closures were very significant and long-lasting.
In our paper ( https://doi.org/10.18103/mra.v11i11.4652) we made a comparison with Sweden, where the withdrawal of in-person education for children aged 15 or less was avoided (except for when teachers were unwell and absent). There is much less evidence of educational and psychological damage to children in Sweden (though detailed formal comparisons are naturally very difficult to conduct in retrospect).
The authors carefully and professionally detail in their work the significant and long-lasting harms that school closures brought to children in the UK. These impacts are still being felt today, late in 2023. It is important to glean whether the sacrifices that children were forced to make in 2020 and 2021 actually resulted in any net societal gain, which most likely would be seen in the segment of the population aged over 60 (in which around 90% of hospitalisation and deaths occurred).
Health & healthcare is a human rights issue. Persons with intellectual disabilities use disproportionately more health care resources than the population without intellectual disabilities. In spite of this, they experience poorer health outcomes and they and their carers are significantly less satisfied with the quality of care provided to them by a variety of healthcare personnel. This can include doctors, pharmacists, nurses and other personnel.
The right to health contains freedoms. These freedoms include the right to be free from non-consensual medical treatment, such as medical experiments and research or forced sterilization, and to be free from torture and other cruel, inhuman or degrading treatment or punishment.
The right to health also contains entitlements. These entitlements include among others: The right to a system of health protection providing equality of opportunity for everyone to enjoy the highest attainable level of health; The right to prevention, treatment and control of diseases; Equal and timely access to basic health services; The provision of health-related education and information; Equal and timely access to basic health services etc.
Human rights are interdependent, indivisible and interrelated. This means that violating the right to health may often impair the enjoyment of other human rights, such as the rights to education or work, and vice versa. Persons with disabilities face various challenges to the enjoy...
Health & healthcare is a human rights issue. Persons with intellectual disabilities use disproportionately more health care resources than the population without intellectual disabilities. In spite of this, they experience poorer health outcomes and they and their carers are significantly less satisfied with the quality of care provided to them by a variety of healthcare personnel. This can include doctors, pharmacists, nurses and other personnel.
The right to health contains freedoms. These freedoms include the right to be free from non-consensual medical treatment, such as medical experiments and research or forced sterilization, and to be free from torture and other cruel, inhuman or degrading treatment or punishment.
The right to health also contains entitlements. These entitlements include among others: The right to a system of health protection providing equality of opportunity for everyone to enjoy the highest attainable level of health; The right to prevention, treatment and control of diseases; Equal and timely access to basic health services; The provision of health-related education and information; Equal and timely access to basic health services etc.
Human rights are interdependent, indivisible and interrelated. This means that violating the right to health may often impair the enjoyment of other human rights, such as the rights to education or work, and vice versa. Persons with disabilities face various challenges to the enjoyment of their right to health. Non-discrimination and equality are fundamental human rights principles and critical components of the right to health in this population group.
Healthcare professionals such as doctors, pharmacists and nurses and others should be mindful of the clinical effects associated with intellectual disabilities and how the individual patient's health and access to equitable healthcare is challenged and/or adversely affected. They must also take the time to understand the overall impact the condition has on the patient's life and on their carers and support network. Person centred care involves asking the right questions and listening carefully to patients with intellectual disability and their carers describing their unique challenges and experiences e.g. how to administer often complex medication regimens safely.
The right to health is a fundamental part of our human rights and of our understanding of a life with dignity. Regardless of our age, gender, socio-economic or ethnic background, ability/disability level our health is our most basic and essential asset. Improving health care providers' ( doctors, pharmacists, nurses and others) knowledge of intellectual disabilities and ability to provide culturally competent person centred care can limit the health disparities experienced by this disadvantaged population i.e. help ‘close the gap’.
Culturally competent doctors, pharmacists, nurses are important in eliminating health disparities experienced by people of all populations, including those with intellectual disabilities. Specialist pharmacists must be included in any multidisciplinary clinic as medication use is the main therapeutic intervention in the population with intellectual disabilities. Multidisciplinary teams with knowledge, expertise and experience provide ‘reasonable accommodations’ to the person with intellectual disability and equitable access to healthcare. The population with intellectual disabilities have a right to equitable access to healthcare leading to equal outcomes with the general population.
To: Juan VA Franco, MD
Editor-in-Chief
British Medical Journal, Evidence-Based Medicine
Dear Editor:
The study on cutaneous melanoma overdiagnosis attempts to tackle an important issue. However, we wish to address several methodological concerns that may warrant a critical evaluation of its conclusions.
First, one key study assumption is that the overdiagnosis of melanoma is due to over-screening by clinicians, including dermatologists. However, whether the patients were actually screened by clinicians is unknowable with the current study design. Thus, the lack of direct evidence to support this key assumption limits the study's capacity to attribute melanoma diagnoses to the prevalence of screening.
Second, the study's ecological methodology does not sufficiently account for variables that could affect melanoma diagnosis and mortality rate over time, such as advancements in diagnostic technologies, treatments, public awareness, and healthcare access, all factors that dermatologists have worked to improve over time. These factors could independently influence trends in melanoma incidence and mortality. This limitation is critical as it underlines the difficulty in drawing definitive conclusions from the ecological data presented.
Thirdly, the choice to manually input annual data from the SEER program into the DevCan software, deviating from the standard 3-year data aggregatio...
To: Juan VA Franco, MD
Editor-in-Chief
British Medical Journal, Evidence-Based Medicine
Dear Editor:
The study on cutaneous melanoma overdiagnosis attempts to tackle an important issue. However, we wish to address several methodological concerns that may warrant a critical evaluation of its conclusions.
First, one key study assumption is that the overdiagnosis of melanoma is due to over-screening by clinicians, including dermatologists. However, whether the patients were actually screened by clinicians is unknowable with the current study design. Thus, the lack of direct evidence to support this key assumption limits the study's capacity to attribute melanoma diagnoses to the prevalence of screening.
Second, the study's ecological methodology does not sufficiently account for variables that could affect melanoma diagnosis and mortality rate over time, such as advancements in diagnostic technologies, treatments, public awareness, and healthcare access, all factors that dermatologists have worked to improve over time. These factors could independently influence trends in melanoma incidence and mortality. This limitation is critical as it underlines the difficulty in drawing definitive conclusions from the ecological data presented.
Thirdly, the choice to manually input annual data from the SEER program into the DevCan software, deviating from the standard 3-year data aggregation, raises concerns about the accuracy and reliability of the findings. Such a departure from standardized methods without a robust justification may introduce bias or artifacts into the analysis. Furthermore, this approach complicates the interpretation of trends over time, as it may attribute undue significance to annual fluctuations that could be mere artifacts of random variation rather than indicative of meaningful trends.
In light of these concerns, we urge a cautious interpretation of the study's conclusions regarding the overdiagnosis of cutaneous melanoma. It is essential for future research in this area to address these methodological issues and be inclusive of all racial and ethnic groups, ensuring a more robust and reliable basis for understanding rate of melanoma diagnosis.
Sincerely,
Anna McNay M.D.
President
Melissa Shive M.D., M.P.H.
President Elect
On behalf of the California Society of Dermatology and Dermatologic Surgery (CalDerm)
As French Nuclear Medicine representatives, we read with great interest the article by Le Guludec et al. entitled: Rapid access to innovative medicinal products while ensuring relevant health technology assessment: Position of the French National Authority for Health. In this interesting and important position paper from the French Independent Health Technology body (HTAb) called “Haute Autorité de Santé” (HAS), the authors state that its recommendations derive from consultations with academics. Although we understand that accessibility to innovative drugs used for Positron Emission Tomography (PET) could be considered as a very ancillary issue by the HAS board that authored the paper, these PET imaging molecules are still considered as medicinal products from a regulatory standpoint and should be evaluated as such.
We regret that, to our knowledge, none of the academic members of the French Nuclear Medicine Society (SFMN) board were given the opportunity to draw attention to some of the specific features of the drugs commonly used in nuclear medicine by answering the questionnaire sent to the panelists (cf supplemental material). Indeed, we would clearly have answered “Yes” to the following questions:
- Are there specific methodological issues for Health Technology Assessment you wish to bring to our attention?
- Do you identify methodological issues relative to the assessment of innovative drugs in specific therapeutic areas?
We would also have be...
As French Nuclear Medicine representatives, we read with great interest the article by Le Guludec et al. entitled: Rapid access to innovative medicinal products while ensuring relevant health technology assessment: Position of the French National Authority for Health. In this interesting and important position paper from the French Independent Health Technology body (HTAb) called “Haute Autorité de Santé” (HAS), the authors state that its recommendations derive from consultations with academics. Although we understand that accessibility to innovative drugs used for Positron Emission Tomography (PET) could be considered as a very ancillary issue by the HAS board that authored the paper, these PET imaging molecules are still considered as medicinal products from a regulatory standpoint and should be evaluated as such.
We regret that, to our knowledge, none of the academic members of the French Nuclear Medicine Society (SFMN) board were given the opportunity to draw attention to some of the specific features of the drugs commonly used in nuclear medicine by answering the questionnaire sent to the panelists (cf supplemental material). Indeed, we would clearly have answered “Yes” to the following questions:
- Are there specific methodological issues for Health Technology Assessment you wish to bring to our attention?
- Do you identify methodological issues relative to the assessment of innovative drugs in specific therapeutic areas?
We would also have been grateful to have been given the chance to present the opinion of the SFMN regarding the following two key questions and the SWAT analysis proposed by the HAS:
- what could be useful clinical trial designs or methodological specificities to accelerate the access to innovative drugs?
- how the HAS could modify its methodology for Health Technology Assessment?
In addition to the opinion of the SFMN, we would like to bring to the authors’ and your readers’ attention the Pipame (1) and the Court of Auditors reports (2) , which stressed many years ago that access to medical imaging innovations is of tremendous importance for patients. They both concluded that overcoming ‘administrative’ hurdles regarding evaluation and reimbursement could facilitate access for patients and give a boost to French small-to-medium size enterprises (SMEs) by reducing the time to market. Indeed, it is common knowledge that until recently, French patients had to go abroad to get access to PET imaging for prostate cancer or Neuro-Endocrine Tumors (NETs), and that contributions to innovations by French SMEs in this domain are still few and far between.
Nuclear medicine uses radiolabeled drugs for targeted irradiation to treat malignant diseases. The SFMN is grateful to the Ministry of Health for allowing our patients to access molecular radiotherapy rapidly and for compassionate use. Even though it does not meet the HAS definition of targeted therapies stricto sensu, molecular radionuclide therapy is by nature a targeted therapy whose indications rely indisputably on PET imaging companion markers, hence the concept of ‘theranostics’. However, most radiolabeled drugs are used for diagnostic purposes, and the number of new PET procedures per year is sky-rocketing. (https://www.cnp-mn.fr/wp-content/uploads/2023/01/2021_Enquete-Nationale-... )
We would particularly like to stress that blinded randomized controlled trials (RCT), which are claimed to be the cornerstone of drug efficacy and toxicity assessment, are not relevant for assessing molecular imaging drugs for reasons of practicality and cost-effectiveness. In our opinion, the lack of appropriate key performance indicators for PET drugs has for many years been the white elephant in the HAS medical imaging room.
We were reassured to read that the HAS acknowledges that conditions may exist that make conducting RCT unreasonable. However, assessing the performance of medical imaging has nothing to do with any hypothetical deductive approaches deemed to benefit from this RCT exemption. PET imaging has entered an era of continuous progress in which mathematics and physics are giving rise to reliable metrics such as spatial resolution, detection sensitivity, and dosimetry. Thanks to histopathologic verification, it is possible to calculate diagnostic performance and likelihood ratios (LR) even in small cohorts. Not using these assessments, which are based on evidence that has a high level of certainty, has led to bizarre ranking decisions (added medical value; i.e Amélioration du Service Medical Rendu: ASMR V). In turn, this has led to French patients being hindered in their access to PET procedures that are performed daily in neighboring countries.
For example, take the ‘clinical case’ of 68Ga edotreotide, a radiopharmaceutical thought to be innovative in France while being used in standard practice elsewhere for the staging and follow up of NETs. The HAS concluded that 68Ga edotreotide has high clinical value (Service Médical Rendu ; SMR ) but that its ASMR is poor (Amelioration du service medical rendu ASMR rank = V) https://www.has sante.fr/portail/jcms/c_2758095/fr/iasotoc 05042017 avis ct15806) because of the lack of a clinically relevant comparator. Therefore, the HAS considered that somatostatin receptor scintigraphy with 111InOctreotide should be considered as the relevant comparator, even though it is no longer in use in many countries because of its notoriously poor performance. Therefore, the HAS recommended using 111InOctreotide upfront. Almost the same is happening regarding the use of 68GaPSMA for prostate cancer.
However,…
- Patient irradiation was not taken into consideration: 111In Octreotide delivered a 2.4-higher dose to the patient than 68Gaedotreotide, so complying with the HAS recommendation raised an ethical issue.
- 111In Octreotide scintigraphy requires patients to come twice to the hospital, so do we need any prospective evaluation to conclude that a 2-day procedure (historical comparator) is more expensive than a single-day procedure, whatever the impact on patient management?
- The likelihood ratio is about 12 and 6 for 68Gaédotréotide and 111InOctrotide, respectively (i.e. the risk of a false negative is 2-fold higher for a NET patient undergoing 111InOctrotide scintigraphy). Again the clinical benefit can be directly derived from these metrics.
The added clinical value was also considered poor because of the lack of evidence on patient management. This is a substantial methodological shift far beyond comparing diagnostic accuracy with a relevant comparator. This implies a much more ambitious methodology with the risk of an expensive trial. Considering the time spent to initiate, conduct and analyze such an RCT, it is more likely that the treatment used would be considered obsolete by the time of publication, if any. Moreover, the cost effectiveness of such an approach remains questionable. Numm et al estimate that for a cost of 100US$, profitability is reached at around 1 million doses per year (3; 4). Such a massive use of PET tracers costing more than 1000 US$ is simply not sustainable. Based on the De Massi (5, 6) et al and Numm (3; 4) et al analysis of the radiopharmaceutical market, it is very unlikely that an SME could spend around 200 M US$ in developing a PET drug, especially since PET procedures are reimbursed independently (at least in France) of the cost of the molecule, whatever its ASMR.
However, some years ago the HAS came up with an interesting alternative (HAS NOTE DE CADRAGE Place de la technique du ganglion sentinelle dans la stratégie diagnostique de l’envahissement ganglionnaire d’un cancer du sein à un stade précoce sept 2011 www.has-sante.fr). Considering that the predictive values of a test can be easily derived from the LR and the pretest probabilities (6) (i.e. prevalence, TNM stage), the HAS demonstrated that cost-effectiveness studies can be used to determine the value of sentinel node scintigraphy for breast cancer surgery. Therefore, the same methodology could be easily applied to pragmatic trials or real-world cohorts of PET patients. The SFMN has created a real-registry that provides more reliable data than the PMSI, as it also includes outpatients and more detailed data than that collected in early or compassionate use programs. The theragnostic market is expected to grow from 4BUS$ in 2013 to 14BUS$ in 2025 : Richard Zimmerman, Oncidium Foundation
We agree with the HAS that one should avoid overusing the term ‘innovation’ when discussing any drug candidate. However, nuclear medicine has come a long way since 2007 when Adrian Nunn pointed out the fact the approval of radiopharmaceuticals was at an all-time low, with all the major radiopharmaceutical agents in use having been approved over 10 years before. Recent successes such as the Food and Drug Administration approval of Lutathera and NETSPOT have resulted in an increasing number of pharmaceutical companies pursing theragnostics, with further impetus provided by the purchase of Advanced Accelerator Applications by Novartis for 3.9 billion and Endocyte, Inc for 2.1 billion (8).
Times are changing; it’s time to rethink matters collectively in the quest to discover a more efficient and agile way to assess medical imaging innovations.
We remain at the disposal of the HAS to continue this discussion.
Référence
1. Pôle interministériel de Prospective et d'Anticipation des Mutations économiques (PIPAME)http://competitivite.gouv.fr/documents/commun/Documentation_poles/etudes...
2. Cours des comptes L’imagerie médicale –mai 2016 Cour des comptes -www.ccomptes.fr-@Courdescomptes
3. Nunn A D The Cost of Bringing a Radiopharmaceutical to the Patient’s Bedside J. Nucl Med 2007;48 : 169
4. Nunn A D The cost of developing imaging agents for routine clinical use Invest Radiol 2006; 41 : 206 2012
5. DiMasi, J.A., R.W. Hansen, et H.G. Grabowski (2003), The price of innovation: New estimates of Drug Development Costs, Journal of Health Economics 22, 151-185.
6. DiMasi, J.A., R.W., Hansen, H.G. Grabowski, et L. Lasagna (1991), Cost of innovation in the pharmaceutical industry, Journal of Health Economics 10, 107-142.
7. Fagan. Letter: Nomogram for Bayes theorem N Engl J Med 1975; 293:25
8. Cathy S. Cutler, PhD Economics of New Molecular Targeted Personalized Radiopharmaceuticals Semin Nucl Med 2019 49:450-457
We read with interest the study by Perrier et al on the Relationship between the conflicts of interest and the results of meta-analyses of homoeopathy trials. We want to briefly address issues we see with this paper.
Firstly, the criteria for a study presenting a Conflict of Interest (CoI) include that a single author has a link with any research institution involved in homeopathy research. Translated to other fields of research, Oncology for example, this would mean that cancer studies emanating from Cancer Research institutes would have to be considered as conflicted and therefore unreliable. This is clearly an absurd way of defining CoIs.
More importantly, the authors wrongly report the Odds Ratio (OR) data for the Shang et al paper as being OR = 0.88, CI 0.65-1.19, N=105, this OR corresponds to the N=8 ‘larger high-quality trials’ from that study, not N=105. The OR for N=105 was never published but the OR for the N=21 ‘high-quality trials’ is OR = 0.76; CI: 0.59-0.99, N=21 (Ludtke & Ruttem 2008). Ignoring the meaningless N=1 MAs in Fig 1, we end up with three CoI-free MAs, which all favour homeopathy. And this trend would only be accentuated by using the correct OR for the full N=105 trials. The overall picture painted by the data is thereby very different than reported by the authors. In particular there appears to be no statistical difference between their so-called CoI and CoI-free MAs in Homeopathy.
Gøtzsche and Jørgensen claim that the European Medicines Agency (EMA) mishandled their investigation of the safety of the HPV vaccine regarding serious neurological adverse events from the administration of the HPV vaccine, such as postural orthostatic tachycardia syndrome (POTS) and chronic regional pain syndrome (CRPS). The authors highlight the insufficiency due to poor data analysis, conflicts of interest, poor research into aluminum adjuvants, and bias in analyzing the research 1. We want to discuss several key points on the safety of the HPV vaccine.
Show MoreOver 270 million doses of HPV vaccines have been administered since 2006. Many regulatory agencies have overseen the safety of the HPV vaccine, including the World Health Organization’s GACVS (Global Advisory Committee on Vaccine Safety) 2. Most regulatory agencies regard the HPV vaccine as safe and effective 3,4. The noted exception in this article is the Uppsala Monitoring Centre which identified safety signals for POTS and CRPS post-HPV vaccination 5.
As of specific note from the paper, the majority of the evidence supporting an association with the HPV vaccine and POTS and CRPS in the article by Gøtzsche and Jørgensen was generated from data in Europe, including Denmark 1. A recent study showed no safety signal generally and specifically commented that the Denmark signal was not identified in their analysis, noting that 1,232,572 girls received the vaccine and 563 unique CRPS diagnoses (6). Concerns about...
It is misleading (as stated in “what this study adds”) to described this trial as placebo controlled. Although dummy capsules were used to blind participants to which combination of curcumin or omeprazole they were receiving, no group received placebo only. One interpretation of the findings therefore remains that they are due to a placebo effect. It is unfortunate that this misrepresentation of the study design has already been picked up by a UK National newspaper (Guardian 12 September)
Dear Editor,
we are writing in response to the article titled " How methodological pitfalls have created widespread misunderstanding about long COVID”(1).
We agree with the authors, that the existing epidemiological research on long COVID has suffered from overly broad case definitions and a striking absence of control groups, which may have led in an overestimation of risk.
Show MoreIt is important to acknowledge that Long- and Post-COVID syndrome are heterogeneous conditions, likely comprising different pathomechanistic groups such as autoimmunity, mitochondrial dysfunction, and virus persistence (2). This complexity, coupled with the lack of routine biomarkers, makes it difficult to accurately define and study this condition. Høeg et al et al. therefore raise some relevant points regarding the challenges faced in studying Long- and Post-COVID syndrome, particularly the need for properly matched control groups and internationally-established diagnostic criteria. Regarding the latter, the authors of the article themselves fail to use definitions accurately, particularly in distinguishing between the now consented WHO definitions of Long-COVID and Post-COVID (WHO/2019-nCoV/Post_COVID-19_condition/Clinical_case_definition/2021.1).
It is true, that initial studies depicted a high prevalence of Post-COVID syndrome (PCS). However, more recent population-based studies present a different perspective. In assessing the clinical picture, the primary focus isn...
Dear Editor,
With great interest I read the original research article “Curcumin and proton pump inhibitors for functional dyspepsia: a randomised, double blind controlled trial” by Kongkam et al. While the authors suggest that the study demonstrates that the efficacy of curcumin for functional dyspepsia is comparable to that of omeprazole, I want to point out some deficiencies and discrepancies of the study reporting that cast doubt on this conclusion.
Firstly, it is not clear what hypothesis was tested and what specific study results the conclusion is based on. The main outcomes are vaguely specified as functional dyspepsia symptoms. As the equivalence design is mentioned, the reference to improvement of 2 points in the SODA score between the treatment group should probably be interpreted as the equivalence margin set for the study. The results of nine pairwise comparisons are provided in Table 3. For three of them 95% confidence intervals include the equivalence margin, thus clearly demonstrating non-equivalency. For example, for pain intensity in curcumin only vs omeprazole only arms the 95% CI is −1.16 (−2.95 to 0.64), which demonstrates that curcumin is not non-inferior to omeprazole.
To add to the issue of unclear study question and selective post hoc interpretation of outcomes, it should be mentioned that the study was not registered prospectively. The TCTR registration (TCTR20221208003) is post factum. Also the authors do not properly explain...
Show MoreI read this scoping review with great interest. In linguistics there is a term for the phenomenon that a word can have the capacity to have multiple related meanings in different contexts. This term is polysemy. In the context of defining "Evidence-based medicine". If we want to understand each other, it proved successful to define the words we use .Sackett et al. in their seminal article about" EBM what it is and what it isn't" also defined what they mean by "evidence", namely: "By best available external clinical evidence we mean clinically relevant research,often from the basic sciences of medicine, but especially from patient centred clinical research into the accuracy and precision of diagnostic tests (including the clinical examination), the power of prognostic markers, and the efficacy and safety of therapeutic, rehabilitative, and preventive regimens."
Doesn't this render it irrelevant for the context of EBM if others define differently in other contexts? A bigger problem arises when the term evidence is misunderstood or even misused within the context of EBM. This problem might be approached by better teaching of the meaning originally meant. Evidence to my knowledge (as a non-english native speaker) is a juridical term and thus different to proof or fact. Juridically only the sum of evidence is leading to a court decision. And, this decision can be wrong especially if new evidence arises.
The article by Alastair Munro and colleagues (to which this is a rapid response) is of great value and importance, as we can now see, since this article was published, that there has been considerable discussion and interrogation by the COVID inquiry (https://covid19.public-inquiry.uk/), about whether the closure of schools, ordered on 18th March 2020 by Boris Johnson's government, and put into effect two days later on 20th March, was ever necessary.
The rationale for the closure of schools was that it was imperative that the transmission rate of the COVID-19 pandemic, then rapidly spreading in the UK, was brought down at pace. Only three days later, a full, mandated, "lock down" was imposed. This was in the context of a suite of increasingly draconian measures to impose Non-Pharmaceutical Interventions (NPIs) on an increasingly fretful population - on March 12th, 16th, 20th and 23rd.
The question we pose of the authors of the current paper under discussion is a simple one. What is the actual, real world, evidence that the 'R' value fell as a result of the closure of schools? Is there any real-world, UK-based, 2020 information we can use to answer this question. This question cannot remotely be answered by reference to other countries, or, to mathematical models. The impact of school closures must also be analysed independently of all of the other contemporaneous NPIs.
If the o...
Show MoreHealth & healthcare is a human rights issue. Persons with intellectual disabilities use disproportionately more health care resources than the population without intellectual disabilities. In spite of this, they experience poorer health outcomes and they and their carers are significantly less satisfied with the quality of care provided to them by a variety of healthcare personnel. This can include doctors, pharmacists, nurses and other personnel.
The right to health contains freedoms. These freedoms include the right to be free from non-consensual medical treatment, such as medical experiments and research or forced sterilization, and to be free from torture and other cruel, inhuman or degrading treatment or punishment.
The right to health also contains entitlements. These entitlements include among others: The right to a system of health protection providing equality of opportunity for everyone to enjoy the highest attainable level of health; The right to prevention, treatment and control of diseases; Equal and timely access to basic health services; The provision of health-related education and information; Equal and timely access to basic health services etc.
Human rights are interdependent, indivisible and interrelated. This means that violating the right to health may often impair the enjoyment of other human rights, such as the rights to education or work, and vice versa. Persons with disabilities face various challenges to the enjoy...
Show MoreFebruary 28, 2024
To: Juan VA Franco, MD
Editor-in-Chief
British Medical Journal, Evidence-Based Medicine
Dear Editor:
The study on cutaneous melanoma overdiagnosis attempts to tackle an important issue. However, we wish to address several methodological concerns that may warrant a critical evaluation of its conclusions.
First, one key study assumption is that the overdiagnosis of melanoma is due to over-screening by clinicians, including dermatologists. However, whether the patients were actually screened by clinicians is unknowable with the current study design. Thus, the lack of direct evidence to support this key assumption limits the study's capacity to attribute melanoma diagnoses to the prevalence of screening.
Second, the study's ecological methodology does not sufficiently account for variables that could affect melanoma diagnosis and mortality rate over time, such as advancements in diagnostic technologies, treatments, public awareness, and healthcare access, all factors that dermatologists have worked to improve over time. These factors could independently influence trends in melanoma incidence and mortality. This limitation is critical as it underlines the difficulty in drawing definitive conclusions from the ecological data presented.
Thirdly, the choice to manually input annual data from the SEER program into the DevCan software, deviating from the standard 3-year data aggregatio...
Show MoreAs French Nuclear Medicine representatives, we read with great interest the article by Le Guludec et al. entitled: Rapid access to innovative medicinal products while ensuring relevant health technology assessment: Position of the French National Authority for Health. In this interesting and important position paper from the French Independent Health Technology body (HTAb) called “Haute Autorité de Santé” (HAS), the authors state that its recommendations derive from consultations with academics. Although we understand that accessibility to innovative drugs used for Positron Emission Tomography (PET) could be considered as a very ancillary issue by the HAS board that authored the paper, these PET imaging molecules are still considered as medicinal products from a regulatory standpoint and should be evaluated as such.
Show MoreWe regret that, to our knowledge, none of the academic members of the French Nuclear Medicine Society (SFMN) board were given the opportunity to draw attention to some of the specific features of the drugs commonly used in nuclear medicine by answering the questionnaire sent to the panelists (cf supplemental material). Indeed, we would clearly have answered “Yes” to the following questions:
- Are there specific methodological issues for Health Technology Assessment you wish to bring to our attention?
- Do you identify methodological issues relative to the assessment of innovative drugs in specific therapeutic areas?
We would also have be...
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