Cochrane, together with a range of other civil society organisations, has written to a group of medicines agencies in Europe asking that they take action to ensure trial transparency.
Despite an EU legislation requiring that results from clinical trials be published on the EU Clinical Trials Register within 12 months of a study ending, this information has not been shared for almost 30% of applicable trials.
The letter calls on the Heads of Medicines Agencies (HMA), a body of national regulators in Europe, to take action to address this serious issue and gives recommendations on how to improve the situation. This includes relatively simple steps like writing to the clinical trial sponsors whose results are overdue to remind them of their obligation to share a summary of their findings.
Dr Karla Soares-Weiser, Editor in Chief of The Cochrane Library and Acting CEO of Cochrane, said:
“Cochrane strongly supports efforts to ensure that data from all clinical trials are available and encourages HMA to take action on these recommendations. Without access to reliable information from all clinical trials, the evidence base on which to make judgements is incomplete – this limits the scientific community’s ability to learn from research findings and can lead to patients being harmed.”
Specifications: Full Time, 40hr/week
Location: Flexible location - ideally US-based but open to international candidates.
Application Closing Date: TBD
The Cochrane Neonatal Managing Editor (ME) ensures the efficient and effective operation of the editorial base and manages the editorial process for systematic reviews. This involves supporting and providing specialized editorial and technical support to review authors, editors, and associate editors. The ME works in conjunction with the coordinating editor to strategize the direction and priorities of Cochrane Neonatal and acts as a liaison with international guideline developers, such as the WHO, and performs executive and innovative functions within Cochrane. Currently, members of the Cochrane Neonatal editorial team can be found in Canada, Colombia, the United Kingdom, Australia, Malaysia, and the United States. Cochrane Neonatal consists of over 1000 review authors from 45 countries around the world.
The World Health Organization (WHO) and International Coalition of Medicines Regulatory Authorities (ICMRA) have issued a joint statement calling on the pharmaceutical industry to increase transparency and access to clinical data for all new medicines and vaccines.
Dr Karla Soares-Weiser, Editor in Chief of The Cochrane Library and Acting CEO of Cochrane, said:
“Cochrane is an advocate for greater clinical trial transparency and supports the statement issued by WHO and ICMRA calling on the pharmaceutical industry to provide wider access to research data for new medicines.
COVID-19 has highlighted the importance of timely access to detailed clinical trial data for building public trust and for assessing the quality of studies. Sharing this information has clear benefits to public health and research integrity.
When trial results are not published, or are overly redacted, the ability to make truly evidence-informed decisions about healthcare is jeopardised. This puts people at risk of harm and contributes to research waste.”
Featured Review: The impact of medications with anticholinergic effects on future problems with memory and thinking
In this recently published Cochrane review, the author team explored whether taking a certain type of medication could make older people more likely to develop dementia.
Discussing the review, Terry Quinn, senior author, said: "Almost every week we see a newspaper headline describing something new that allegedly causes or protects against dementia. These features attract attention as we all want to protect our brain health, but there is often little science behind the headlines.
There has been a lot of recent interest around whether certain prescribed medications can cause dementia. A class of medication frequently implicated in causing dementia are the ‘anticholinergics’. Medications with anticholinergic effects are commonly prescribed for conditions like hayfever, asthma, and urinary problems.
In this review we collated all the published evidence around anticholinergic prescribing and future risk of dementia. We found that taking anticholinergic medication long-term is associated with an increased risk of future dementia, and the more anticholinergic medications taken, the bigger the risk.
Reviews that look at whether a factor can predict future health require a different approach to the standard systematic review. These prognosis reviews are a relatively new method for Cochrane but are incredibly important for the dementia field.
So, should people taking anticholinergic medications be worried? At the individual level, the risk of dementia was small and many of the included studies had issues that weakened the credibility of the results. However, older adults taking anticholinergic medications may wish to discuss with their healthcare provider whether their anticholinergic medications are still needed."
What was the aim of this review?
Medicines can be classified by their ability to block the action of a chemical signalling system in the body called the cholinergic system. Medicines that do this are said to have anticholinergic effects. There are various measurement scales to quantify the effects of anticholinergic medicines. The overall anticholinergic effect caused by all the anticholinergic medications a person is taking is referred to as 'anticholinergic burden.'
We aimed to investigate if older people who have no problems with memory or thinking are more likely to develop dementia when prescribed anticholinergic medicines than people who are not prescribed these medicines.
Anticholinergic burden ratings can vary with the scale used because different scales score medicines in different ways. Therefore, we also wanted to know if any particular anticholinergic burden measurement scale was more strongly associated with increased risk of dementia than other scales.
There may be a link between anticholinergic medicine use and future risk of dementia. However, there are limitations in the published evidence, and we cannot say definitively if dementia is caused by the anticholinergic medicines themselves or by other factors. There were too few studies to allow us to compare the various anticholinergic measurement tools.
What was studied in the review?
There are more than 40 million older people worldwide living with dementia. These numbers are expected to rise to over 100 million by 2050 and at present there are very limited treatment options available. Therefore, it is important to identify factors that may increase the risk of dementia.
Because the cholinergic system in the brain plays an important role in learning and memory, there are theoretical reasons to believe that medications with anticholinergic effects could cause future dementia. Research has suggested that these medications may have unintended effects on memory and thinking, potentially resulting in dementia. If this is the case, one way to reduce the numbers of older people who develop dementia may be to avoid prescribing these medicines. Many commonly used medications have anticholinergic effects, for example medications for hay fever, insomnia (difficulty getting to sleep or staying asleep for long enough to feel refreshed), and depression.
In this review, the author team investigated the link between anticholinergic medicines, as measured by various measurement scales, and future dementia.
What were the main results of the review?
Review authors found 25 studies, including 968,428 people aged 50 years or more. Despite the relatively large number of studies, differences in design and methods only allowed authors to combine a few of them in analyses. They found that there is a consistent link between use of anticholinergic medicines and risk of future dementia. They cannot say if these medicines play a causal role; however, if they do, taking these medicines could potentially double a person's risk of dementia.
Of the anticholinergic measurement scales available, the author team could assess one commonly used tool – the 'Anticholinergic Cognitive Burden scale.' If this scale identified someone as having high anticholinergic burden, the risk of future dementia was more than two times higher than for someone with no anticholinergic burden.
The evidence included in this review was of a low quality overall and may have exaggerated the strength of the association between anticholinergic medicines and dementia. For example, anticholinergic medicines may be prescribed for the early symptoms of dementia. This would give a strong link but would not imply that the medicine caused the memory problems. Similarly, there is a risk that studies are only published when they show an association between anticholinergic medicines and future dementia. It may be that the only way to truly establish if anticholinergic medications are associated with future dementia would be to conduct a study where some people have their anticholinergic medications stopped or changed to an alternative and others continue their usual medications.
How up to date was this review?
The authors searched for studies published up to 24 March 2021.
In this author interview, lead authors Nick Meader and Andrew Moriarity tell us about this recently published Cochrane review, how they worked with a patient advisory group, and how they rose to the challenge of this being their first prognostic review, and the first of this type for Cochrane Common Mental Disorders.
Nick Meader: According to the World Health Organization (WHO), depression is the leading cause of disability worldwide and, during the pandemic, depression symptoms have increased in many countries.
We have effective treatments for depression (like antidepressants and cognitive behavioural therapy). So, a substantial number of people will no longer have symptoms of depression. But about half of those who improve will later experience a relapse or recurrence (become unwell again after an initial improvement). For most of these, relapse or recurrence occurs within a year of an improvement in symptoms.
We wanted to investigate whether there are methods to help identify which people are more likely to experience a relapse or recurrence.
Andrew Moriarty: As a GP, I routinely see the personal impacts of relapse and recurrence of depression. We want to provide strategies to prevent relapse for all patients, but in reality there are all sorts of reasons why this might not happen. Reasons might include resource availability, knowledge of health care professionals, or patient preferences, among others. So until we achieve optimal on-going depression management for all, at least if we can accurately and reliably identify those at higher risk, interventions could be more effectively targeted at those who need them most.
Researchers have started to try find ways to more accurately predict relapse and recurrence by developing prognostic models. Prognostic models combine information from several prognostic factors (also known as predictors) to provide individualised risk predictions. In practice, this would usually involve a healthcare professional entering the values for a number of different predictors – a patient’s age or details of their medical history, for example – and being provided with a risk prediction score for that patient as an output. It is essential for these risk predictions to be reliable, as otherwise wrong clinical decisions could be made based on a person’s predicted risk. This review aimed to identify all prognostic models developed to identify relapse or recurrence of depression.
What did you find out?
AM: We identified ten different prognostic models. These models had been developed across different settings (primary care, secondary care and community settings) with a whole range of different predictors included. Some of these were fairly established predictors (for example, history of previous relapse) and some were less common (such as blood test markers or results of psychological assessments). Only four of the models had undergone ‘external validation’, which means testing of their accuracy and reliability by making predictions in new groups of people and settings.
Some of the models appeared to be potentially good at predicting, but ten out of eleven studies had a high risk of bias, meaning that we need to be careful about how much we can trust the results due to concerns of methodology or gaps in information reported. At present, existing models are unlikely to reliably predict an individual’s risk of relapse or recurrence. There is a need for better quality prognostic model studies for relapse and recurrence of depression.
NM: For me, the surprising finding from our review was how little we can conclude from current research. This partly reflects that research is at an early stage, so we found only 11 studies. It’s also the case that methods are rapidly developing. So with these developments future studies will likely help us to be more confident in their findings.
Many of the studies had significant limitations. For example, studies often did not include enough people in their research. Another key problem was that only 4 studies provided an external validation of their prediction model. If you develop a prediction model from a particular group of people it may work very well on predicting relapse for these people. But what we really want to know is if the model works equally well if we use it to predict relapse in depression for a different group of people.
Without external validation, it is very difficult to know how well the model will apply when used in real life settings. This is a common limitation in prognostic modelling studies and we need more of these types of studies in the future.
As a GP, what do you find most interesting about this study?
AM: Most people who seek help for depression are seen in primary care by GPs. Like most GPs, I feel very comfortable discussing options with people with depression and reaching shared decisions about care. The guidance and evidence is reasonably clear, with room for patient choice. The guidance around what should be offered to people once they have improved, to prevent a relapse, is much less clear. Information on how to identify people who are at higher risk is minimal and there are no evidence-based tools in practice to assist with this.
It’s interesting to me that there have been several efforts to develop prediction tools. It seems to me that such a tool would be very useful in primary care to be used by GPs. However, to be used successfully, a prediction tool must be practical and simple to implement in the real world. It would also need to avoid requiring GPs to spend time gathering a significant amount of extra information. Even if we could be more certain about how well the models identified in this review predict relapse, a lot of the predictors included in the models would not be available to GPs. The potential trade-offs between usability and accuracy are critical for me to consider as a GP. The rest of my fellowship is going to explore this further, and I am going to talk to people with a history of depression and GPs about the results.
I understand you worked with a patient advisory group. How were they involved and what did you take away from their involvement?
AM: An excellent patient advisory group has been involved in this project from the early days of applying for funding. They have kept us focussed on asking the right questions and thinking about how best to use the results. The patient advisory group also read and commented on our Plain Language Summary to ensure that the review is accessible to a lay audience and will continue to advise us on how to disseminate the results more widely. An early realisation for me in discussing this with the group was that, while the subject of prognosis and prognostic modelling is quite technical, the real world implications are potentially very tangible and would have a direct effect on patients. The discussion has been lively and the questions raised were: do such models exist? If so, do they work? And if they work, why are they not being used?
This review has not definitively answered the question of whether relapse prediction is possible, but has put us in stronger position to begin to address these questions. Some of the studies suggest it might be possible to develop a reliable tool and report potentially good predictive accuracy, but weaknesses in the methodology mean we can’t fully trust the results. It might be that we can’t predict relapse, in which case we should make sure that we are doing our best to prevent it from occurring. Our patient advisory group will continue to point us in the right direction.
This is one of the first prognosis reviews on this topic (and the first for Cochrane Common Mental Disorders). Methodologically, how did you find working on this?
I feel really lucky to have worked on one of the first Cochrane Prognosis reviews and it was particularly good fun working on the first for the Cochrane Common Mental Disorders group. Nick and I attended the Cochrane Prognosis Reviews course in Utrecht back in 2019, which was great and introduced us to the different way of thinking required for these reviews. We were also fortunate to get lots of help and support from the Cochrane Prognosis Methods Group, and collaborators in the Centre for Prognosis Research at Keele. For example, we have used the novel PROBAST tool for risk of bias assessment, which I think has worked really well in providing an objective way to assess the quality of each study.
Literature searching is trickier than for most interventions reviews as the prognostic model studies tend to be less consistently labelled. However, again there is a huge amount of work going on to improve methodological standards of prognosis research and we have been lucky to have guidance on searching for prognostic modelling studies available to us. I hope our review can be helpful to other authors considering undertaking a Cochrane Prognosis Review.
NM: I enjoyed the challenge of reviewing prognostic models. I’ve learnt a lot from this process – we went on a great course at the University of Utrecht. Applying these skills in our review has been very satisfying.
In many ways the methods are just an extension of those we use in more traditional reviews. But I’ve found it really fun grappling with the challenges of prognostic modelling studies which can be quite different from those faced in clinical trials.
I’ve also enjoyed working with Andrew on this, as he has the mind of a clinician and also a researcher. So as researchers, we often approach the question in a similar way, but we also have complementary skills (he’s a GP and I’m a statistician) so it’s worked well.
What research is needed in the future?
NM: I think this is an exciting area of research where the evidence is beginning to accumulate. There are probably two main areas of need in future studies.
First, I think we are seeing an improvement in methods over time in this area. We’d like to see future studies building on these improvements. For example, by planning to study enough people so that we can draw more confident conclusions about how well the model predicts relapse. We’d also like to see more external validations of these models.
Secondly, there is also a need for further work on identifying what are the key factors for predicting depression relapse. We hope to address some of the research needs in an upcoming study which Andrew is leading on as part of his Doctoral fellowship.
AM: Speaking from a clinical perspective, the important thing for me is that we find a way to improve outcomes and quality of life for patients. Part of that might involve improving the ability to predict relapse. If we find that we can reliably predict relapse, we also have to then be able to do something to prevent it. We’re likely to need to refine and develop existing interventions into something scalable that can be implemented into practice. In addition to the work we have planned attempting to improve risk prediction, Nick and I are going to work together with some of the wider team on a follow-up Cochrane review of interventions for preventing relapse in primary care – I’m looking forward to it!
This review forms part of Andrew’s National Institute for Health Research (NIHR) Doctoral Research Fellowship, which investigates relapse and recurrence of depression. It was a collaboration between colleagues at the University of York, the Hull York Medical School and Keele University.
The Basement Science is a podcast hosted by science students who share their excitement about science and science communication. They have conversations with scientists and other guests with the aim of making complicated ideas understandable to non-scientists, while showing why science matters.
They are speaking to members of Cochrane over three episodes:Episode 1 - Cochrane Reviews in times of COVID-19 with Dr John Lavis
Tomàs Garnier & Lea Urpa interview Dr. John Lavis. John is a member of the Cochrane editorial board, member of the Cochrane knowledge-translation advisory group, and founder and director of the McMaster Health Forum, which hosts COVID-END. John speaks about what we know about COVID-19 so far, the importance of evidence synthesis and Living Systematic Reviews, how the media covers science, and Cochrane's Plain Language Summaries, translation work, and how Cochrane works with patients and careers.
Next up in the series of podcasts with the Science Basement:
- Episode 2 - How scientists collect and filter information: What are systematic reviews and how they are made – with Cochrane author Fiona Stewart.
- Episode 3 - How can the audience filter information: How can non-scientists make a sense of all the information available – with Jack Nunn, member of Cochrane's Consumer Network Executive and part of our Cochrane Advocacy Advisory group.
Featured Review: Combination fixed-dose beta agonist and steroid inhaler as required for adults or children with mild asthma
Cochrane Airways works with authors (typically clinicians and researchers) to produce systematic reviews on chronic obstructive pulmonary disease (COPD), bronchiectasis and other lung diseases, and asthma.
We asked Dr Timothy Hinks, one of the Cochrane Review authors, about the findings of this recent review.
For those with mild asthma, there are different types of inhaler. What’s the difference?
There are two main types of inhaled medications for asthma. ‘Relievers’ treat just the symptoms by relaxing the constricted airways, these medicines are ‘beta-agonists’, some of which are fast-acting (FABA) and provide symptom relief within 5-10 minutes. ‘Preventers’ are inhaled corticosteroids, which treat the underlying inflammation causing asthma. Inhaled steroids are very effective in reducing severe attacks of asthma and asthma deaths, but they need to be taken for several days at a time before people begin to feel the effects. Both medications are important and helpful. These different types of medicines were originally given in two separate inhaler devices and someone with asthma needed to use two different inhalers. This caused a problem that many people depended too much on the reliever inhalers because they provide rapidly relief of symptoms, but this can lead some people not to take as much of the preventer inhalers as needed to effectively treat the underlying problem, increasing the risk of severe asthma attacks, and hospitalisation or death.
In recent years inhalers have become available which contain both the beta-agonist and the inhaled corticosteroids in a single device. Combination inhalers have proved very effective in moderate and severe asthma, but till now it was not known whether they might be the best way to treat people with mild asthma – who make up the majority of people who suffer from asthma.
Tell us more about this review; why did you think it was important to do it?
We looked at the use of combination inhalers in mild asthma using a strategy where the inhaler is only used when people experience symptoms. We compared this with two current approaches to treatment: just using a reliever when needed, or using a reliever when needed on top of regular daily use of a preventer. We chose to do this study now because several recent large clinical trials have reported in the last 3 years which directly addressed this question. Consequently several national and international guidelines are being revised to reflect the findings of the study. We aimed to provide an objective, global review of the available evidence to inform decision makers, clinicians and people with asthma.
What did the review find?
We found that combination inhalers used as-needed reduced severe exacerbations requiring tablet steroids and rates of emergency admission to hospital with asthma symptoms when compared with reliever-only treatment.
Combination inhalers used as-needed were as effective as daily preventative steroid inhalers. People using combination inhalers as-required had lower rates of hospital admission and overall used a lower total inhaled steroid dose.
What’s the core message for clinicians and patients?
These findings suggest that as-required use of combination inhalers is an effective and safe approach to the treatment of mild asthma, and could reduce the number of severe asthma attacks. This is important as asthma is a major cause of time off work, economic costs, and chronic ill health and it remains a largely preventable cause of death for 400,000 people per year globally. This approach also simplifies treatment regimes and could reduce contradictory or ambiguous messages to people with asthma. It would support adoption of this strategy in current guidelines. However cost frequently limits the availability of these inhalers in many low and middle income countries, who rely heavily on reliever therapies or tablet steroids instead. We need further pragmatic studies and healthcare cost assessments in such countries to support equitable access to affordable quality-assured asthma medicines.
Featured Review: Paying for performance to improve the delivery of healthcare services in low- and middle-income countries
A recently published review from Cochrane Effective Practice and Organisation of Care (EPOC) Group looks at the effects of ‘pay for performance’ strategies on the delivery of healthcare services in low- and middle-income countries.
Karin Diaconu, first author of this review, notes, "There is growing interest in paying for performance as a strategy for aligning the work of health providers and healthcare organizations with public health goals. The volume of schemes implementing paying for performance has increased over the last decade and so has the number of studies on the effectiveness of these strategies in low- and middle-income countries.
This review brings this evidence together and asks how successful schemes are in improving health care and health. The review notes that paying for performance may have some positive effects: it may lead to increased uptake of some health services, better quality of care, and improve the availability of resources as well as improving autonomy of involved healthcare organisations."
Pay for performance strategies may have both positive and negative effects on the health services they target. These strategies may also have positive effects on other health services that are not directly targeted and may have no unintended negative effects on these services. However, most of this evidence is of low certainty and we need more, well-conducted studies on this topic.
What is ‘pay for performance’?
In a 'pay for performance' approach, people are given money or other rewards if they carry out a particular task or meet a particular target. This strategy is usually directed at health workers or healthcare organizations. The health workers or healthcare organizations are rewarded if they offer particular services or deliver care that is of a certain quality, or if their patients use particular services and achieve better health as a result.
Planners use these strategies to target specific health problems and services that need improvement. But it is also possible that pay for performance strategies have positive or negative effects, including on other services that are not specifically targeted. For instance, these strategies could lead health workers to improve the quality of the other services they deliver. But it could also lead them to avoid services that do not give extra payment. To find out more, the review authors assessed the effects of paying for performance on both targeted and untargeted services. This included looking for any unintended effects of the strategies.
What are the main results of the review?
The review included 59 relevant studies. Most were from sub-Saharan Africa and Asia. Most of the pay for performance schemes in the studies were funded by national Ministries of Health, also with support of the World Bank.
Forty-nine studies compared health facilities that used pay for performance strategies to health facilities who were doing business as usual. Seventeen studies compared health facilities that used pay for performance strategies to facilities that used other strategies. In most of these studies, health facilities using pay for performance strategies were compared to facilities who were given the same amount of funds but without a pay for performance element.
The effects of paying for performance compared to business as usual
For health services that are specifically targeted, pay for performance strategies:
- may improve health outcomes, may improve service quality and probably increase the availability of health workers, medicines and well-functioning infrastructure and equipment
- but may have both positive and negative effects on the delivery and use of health services
For health services that are untargeted, pay for performance strategies:
- probably improve some health outcomes
- may improve the delivery, use and quality of some health services but may make little or no difference to others
- may have few or no unintended effects
- we don’t know what the effects of pay for performance are on the availability of medicines and other resources because the evidence was of very low certainty
The effects of paying for performance compared to other strategies
For health outcomes and services that are specifically targeted, pay for performance strategies:
- may improve service quality
- may make little or no difference to health outcomes
- may have mixed effects on the delivery and use of health services and on the availability of equipment and medicines, including both positive and negative effects
For health outcomes and services that are untargeted, pay for performance strategies:
- may make little or no difference to health outcomes and to the delivery and use of health services
- we don’t know what the effects of pay for performance are on service quality, on the availability of resources, and on unintended effects because the evidence was missing or of very low certainty
How up to date is this review?
The review authors included studies that had been published up to April 2018.
Featured review: Poly ADP‐Ribose Polymerase (PARP) inhibitors for locally advanced or metastatic breast cancer
Location: Flexible location (remote working) – contract type dependent on location.
Specifications: Permanent employment if successful applicant based in UK, Germany or Denmark. Rolling annual contract (consultant) in other locations.
Hours: Full-time or minimum 25 hours per week (flexible working considered).
Salary: £30,000 (pro-rated for part-time).
Application Closing Date: Tuesday 11 May (Midnight GMT).
This role is an exciting opportunity to use your communication and problem-solving skills to make a difference in the field of health care research.
As Community Support Officer you will be joining Cochrane’s Community Support team. We are the first point of contact for the international Cochrane community. We provide a timely and coordinated support service to Cochrane editorial teams and review authors, and handle enquiries from members of the public about Cochrane’s work. We resolve queries covering a broad range of areas including Cochrane Account login, Cochrane review software, the editorial process, training and volunteering.
Community Support sits within the People Services department in Cochrane’s Central Executive. The department provides all people-focused services within Cochrane, including inclusive learning programmes, human resources, consumer engagement and a wide range of internal and public-facing support services.
We are looking for a self-motivated and highly organised individual who is able to work effectively and collaboratively as part of a remote team. Experience in providing user support to authors and editors using Editorial Manager would be an asset; however training can be provided. The successful candidate will also have:
- Experience in providing technical support, including excellent communication skills.
- Proactive and flexible approach to learning new systems to provide the best possible user support.
- Excellent English-language communication skills (both verbal and written).
- Experience in communicating technical content, tailoring standard communications to individual requirements, and working with people from a variety of cultural and linguistic backgrounds.
- Attention to detail to ensure that community members always receive accurate information.
- Experience in working collaboratively within complex organisations, including diverse and geographically-dispersed staff, collaborator and stakeholder groups across different time zones.
- Self-motivated and results-oriented, with excellent organisation and time management skills, including the ability to work to deadlines as part of an interdependent team working remotely.
- Openness to continuous professional development and training.
Cochrane is a global, independent network of health practitioners, researchers, patient advocates and others, responding to the challenge of making vast amounts of research evidence useful for informing decisions about health. We do this by synthesizing research findings to produce the best available evidence on what can work, what might harm and where more research is needed. Our work is recognised as the international gold standard for high quality, trusted information.
For further information on the role and how to apply, please click here. The supporting statement should indicate why you are applying for the post, and how far you meet the requirements, using specific examples. Note that we will assess applications as they are received, and therefore may fill the post before the deadline.
- Deadline for applications: Tuesday 11 May (12 midnight GMT).
- Interviews to be held on: Tuesday 25 May (times to be confirmed).
Antidepressants are widely used for depression and anxiety. Guidelines recommend that an antidepressant should be continued for at least six months after people start to feel better, and for at least two years if they have had two or more periods of depression. Many people take antidepressants for much longer. Ellen Van Leeuwen and Mark Horowitz, authors of a recently published Cochrane review on approaches for discontinuing antidepressant use, answer some questions about the findings of the review.
Tell us about this Cochrane Review, why did you think it was important to do it?
Ellen: The rise in long-term antidepressant use is a major concern. For example, in the UK, nearly half of people using antidepressant (8% of the total population, approximately 3.7 million people) have been taking them for more than two years. Antidepressants that, despite initially being appropriate, are not discontinued after the recommended duration can lead to unnecessary harm and costs.
Mark: Antidepressants can put people at risk of adverse events such as sleep disturbance, weight gain, sexual dysfunction and gastrointestinal bleeding, as well as feeling emotionally numb and what they described as feeling “addicted,” because they cannot easily stop the medication. This is because people’s brains physically adapt to antidepressants after long-term use (called physical dependence). They may also impair patients’ autonomy to deal with problems in their life without medication. Guidelines recommend that antidepressants should be taken up to 6 to 12 months after improvement and 2 years after improvement in people at risk for relapse.
Ellen: As a GP I see many patients struggling with coming off antidepressants that they have been taking long-term. However, I was surprised that there wasn’t a Cochrane review on discontinuing long-term antidepressants, so I started this review. We included all studies comparing approaches for discontinuation with continuation of antidepressants (or usual care) for people who are prescribed antidepressants for depression or anxiety for at least six months.
What can people learn about discontinuation from antidepressants from this evidence?
Ellen: Honestly, the evidence in this area is very problematic. It is not possible to make any firm conclusions about the effects and safety of the approaches for discontinuation studied to date. There were only a few studies with a focus on successful antidepressant discontinuation rate.
The main problem is that studies did not distinguish between symptoms of relapse of depression and symptoms of withdrawal after discontinuation.
Mark: Yes, withdrawal symptoms can include insomnia, low mood, anxiety, changes to appetite, and these symptoms will be recorded on the depression scales used to detect relapse, so they might inflate the rate of relapse recorded in groups that stop antidepressants.
Additionally, most tapering regimes were limited to four weeks or less, in contrast to NICE guidelines recommending tapering over four weeks or more. In fact, there is now increasing recognition that antidepressants might need to be tapered over months or longer than a year to very low doses for long-term users.
Ellen: For me, it was disappointing that the large group of people taking antidepressants in the community (i.e. those with only one or no prior episode of depression) have been under-researched. Most published studies focus on people with recurrent depression. Another finding was that we found very low certainty evidence that high intensity psychotherapy such as mindfulness based cognitive therapy (MB-CT) and cognitive behavioural therapy (CBT) may support people to come off antidepressants. But none of the studies included more scalable and accessible psychological approaches such as online support.
And what can people learn about continuation of long-term antidepressant use?
Ellen: Based on the limitations we have mentioned, we cannot make any conclusion about this, as we were not confident in the evidence we found. We certainly need more de-prescribing studies investigating the harms and the benefits of discontinuation before we can make any conclusion.
Mark: Yes, it is very difficult to interpret existing studies that suggest continuation of antidepressants because they are based on discontinuation studies in which half of the patients are stopped – often abruptly or in a few days – compared to a group that continues their antidepressants. This means we can’t be sure whether the group who stopped got worse because of withdrawal symptoms or genuine relapse. To provide clearer evidence on this, future studies should distinguish carefully between relapse and withdrawal symptoms and follow emerging guidance to use taper schemes of many weeks or months (or longer for long-term users) down to very low doses before stopping. Such studies would give us a clearer idea of the ability of antidepressants to prevent relapse.
Ellen: Additionally, there is an urgent need to include wider representation of patient populations. For example, those people with one or no prior episodes of depression, those with anxiety disorders, and older people including those who take multiple medications (polypharmacy) and those who are frail. Most antidepressants are prescribed by GPs. This review reinforces the call for more research in the primary care setting, particularly for people with low risk of relapse and those for whom there is uncertainty about the benefit of antidepressant treatment.
What is the core message for clinician’s and patients?
Ellen: Overall there remain many uncertainties. However, this review aids clinicians in openly discussing with their patient and with family/carers (as appropriate) the potential benefits and harms of continuing or discontinuing antidepressants including withdrawal.
Mark: Doctors and patients should be aware that withdrawal symptoms from antidepressants are common and can be mistaken for relapse of the underlying condition. Although evidence found in this review is sparse, experiencing withdrawal symptoms is not a sign that the patient needs the antidepressant, but rather a sign that they might need to taper more gradually and down to lower doses before stopping.
What will happen next? Are you planning an update or any subsequent reviews on a linked topic?
Ellen: Celebrating with my team that we made it! No, I am currently working on a PhD of which the review is part of it which I want to defend in 2021. However, I’m continuing further research in the field of long-term antidepressants. One of the recommendations of our review is a further review comparing different discontinuation strategies.
Mark: At the moment there are a few studies happening around the world looking at discontinuing antidepressants, such as the REDUCE trial in the UK, some including somewhat slower tapers than the studies found in this review, going down to lower doses, and so an update to this review may be necessary in the future.
Dear Community Colleagues,
Last week, we informed you of the news that Mark Wilson was stepping down from his role as Chief Executive Officer (CEO) after eight years of outstanding service.
Today, we want to provide you with an update of the Governing Board's plans during this transition period for organizational leadership.
Our Editor in Chief, Karla Soares-Weiser, will be Cochrane’s Acting CEO; Toby Lasserson will be stepping up to Acting Editor in Chief; and Chris Champion, Head of People Services, will take on additional management responsibilities for finance, governance, and strategy. These arrangements will be effective until 24th May 2021.
Toby Lasserson, Karla Soares-Weiser, Chris Champion
We have begun the process of recruiting an interim CEO. More details on an appointment will follow shortly. In the meantime, the Board will work with Karla and the Senior Management Team to ensure continuity as the organization delivers its priorities for this year.
We understand that this is a time of change for Cochrane and we are committed to providing regular updates and information regarding our plans.
With our grateful thanks and best wishes,
Catherine Marshall and Tracey Howe
Co-Chairs on behalf of Cochrane’s Governing Board
- Visit an online Community Message-board where members, supporters and Group staff can leave their personal best wishes for Mark.
Closing date: 28 April 2021
Location: remote (home-working)
The Cochrane Pain, Palliative and Supportive Care (Cochrane PaPaS) Review Group is looking for an experienced Systematic Reviewer to undertake high quality, priority Cochrane systematic reviews for publication in the Cochrane Library.
The focus of PaPaS is studies of interventions for acute pain, chronic pain, headache and migraine, palliative care for those with life-limiting disease or illness, and supportive care of patients and significant others living with serious illness.
The candidate will work with a multidisciplinary team to undertake new priority reviews, or update existing reviews, often as lead author and Contact Person. The candidate will be expected to adhere to editorial procedures and timelines, liaise with co-authors and members of the CRG, and respond to peer review and editorial feedback. The candidate must also ensure all output meets Cochrane standards and expectations, for example the Cochrane Handbook for Systematic Reviews of Interventions, and Methodological Expectations of Cochrane Intervention Reviews (MECIR).
The ideal applicant will be educated with a first degree in a related field (e.g. medical sciences, biology, statistics) and will have a higher degree relevant to the research area or equivalent qualifications. The candidate will have an understanding and working knowledge of scientific and medical terminology and clinical trials methodology, experience in writing Cochrane systematic reviews, and the ability to interpret and communicate complex information.
The PaPaS CRG is funded by the National Institute of Health Research (NIHR) in the United Kingdom as part of the Research and Development programme, and hosted by the Oxford University Hospitals (OUH) NHS Foundation Trust.
Liverpool School of Tropical Medicine’s Centre for Evidence Synthesis in Global Health has led developments in systematic reviews in tropical medicine and international health. In the 1990s, staff contributed to setting up Cochrane, and established the Cochrane Infectious Diseases Group (CIDG). This is now recognised as one of Cochrane’s premier groups, with over 150 Cochrane reviews and 600 authors, and is well-linked with the World Health Organization.
Two job positions are currently being advertised with the Centre (Research Assistant and Clinical Research Associate in evidence synthesis). A further position is advertised with the University of Liverpool (Research Assistant/Postdoctoral Research Associate in medical statistics).
For informal inquiries regarding the two LSTM posts, please contact: email@example.com
- Full-time, fixed-term appointment for 1 year. Based in Liverpool
- Full details are available here: Research Assistant | LSTM (lstmed.ac.uk)
- Closing date: 28 April 2021
Based in Liverpool, an exciting opportunity has arisen for a Research Assistant to join the team of 11 staff to contribute to public health and clinical Cochrane reviews relevant to COVID-19. CIDG work closely with the Central Cochrane Editorial Unit in prioritising and completing relevant reviews. We have published reviews in public health measures including quarantine, diagnostic tests, and treatments. We are currently working with a variety of teams worldwide on COVID-19 relevant reviews and review updates, including diagnostic COVID-19 reviews with the international team organised from the University of Birmingham.
The successful candidate will have a Master degree that includes training in interpreting quantitative data; ideally you will also hold a postgraduate qualification in epidemiology or related quantitative topic. You will have experience in biomedical or social science research in low and middle-income countries, and have the ability to critically appraise medical literature at postgraduate level. A PhD is desirable.
You need clear evidence of critical insight into priority policy questions in international health relevant to infectious diseases, and experience in diagnostic test research is desirable. If you have authored a Cochrane review, have experience of using GRADE, or have a track record in published research, it will be an added advantage to your application.
Clinical Research Associate
- Full-time, fixed-term appointment for up to 18-months. Based in Liverpool
- Full details are available here: Research Associate | LSTM (lstmed.ac.uk)
- Closing date: 28 April 2021
Based in Liverpool, an exciting opportunity has arisen for a Research Associate to join the team of 11 staff to contribute to the broad programme of research and development in READ-It. We are currently working on Cochrane effects reviews in COVID-19, malaria drug treatment, malaria vector control and TB and malaria diagnostics; and a variety of qualitive evidence synthesis reviews in neglected tropical diseases and TB. There are also methodological projects related to Cochrane review methods that there may be opportunities to be part of. We aim for a mixed portfolio to provide a broad exposure to evidence-informed science.
The successful candidate will have an MBBS and an appropriate postgraduate qualification. You will have experience and confidence in critically appraising medical literature at postgraduate level and demonstrate evidence of a critical insight into priority policy questions in international health in infectious diseases relevant to low- and middle-income countries. Excellent skills in writing in plain English are important to the post.
The post holder will demonstrate experience of working in a multi-disciplinary team with the ability to work collaboratively as well as independently. We want people who have an enthusiastic approach to work and possess excellent attention to detail. Strong communication, time and organisational skills are pivotal as you will be responsible for ensuring effective communication flow within the project team. If you have authored a Cochrane review, have experience of using GRADE, have a track record in published research or possess a PhD in a relevant field, it will be an added advantage to your application. You will also contribute to the postgraduate teaching programme in critical appraisal and evidence synthesis.
Research Assistant / Postdoctoral Research Associate
University of Liverpool - Department of Health Data Sciences
- Full-time, fixed-term appointment for 1 year. Based in Liverpool
- Full details are available here: Research Assistant / Postdoctoral Research Associate (Grade 6/7) at University of Liverpool (jobs.ac.uk)
- Closing date: 16 April 2021
This is a post for a medical statistician with an interest in systematic reviews and network meta-analysis to support the work of the Liverpool Reviews and Implementation Group (LRiG), Cochrane Infectious Diseases Group and evidence synthesis research at the Department of Health Data Science.
You will have a Master’s degree in Statistics or a related field, an ability to manage quantitative data as well as advanced computing skills. Proven experience in the development and critical appraisal of indirect treatment comparisons and network meta-analysis is required and you will be able to use statistical software packages. You must be organised, conscientious and able to work both independently and within a research team.Thursday, April 8, 2021 Category: Jobs
Wednesday 7 April marks World Health Day, a day organised by the World Health Organization (WHO) to highlight a particular global health issue. This year, it aims to spotlight health equity.
Health equity is the absence of avoidable and unfair differences in health. The COVID-19 pandemic and its uneven impacts worldwide has brought attention to long-standing inequities in living and working conditions which affect people’s health outcomes.
This World Health Day, WHO is calling on leaders to address these inequities, to monitor them, and to ensure people have access to quality health care.
Cochrane is committed to promoting the consideration of health equity in evidence synthesis and has been working on this in several ways.
Health equity in the Cochrane Handbook
The Cochrane Handbook for Systematic Reviews of Interventions has a full chapter dedicated to incorporating health equity in evidence synthesis.
Health equity in methods
Equity has its own standard in the Methodological Expectations of Cochrane Intervention Reviews (MECIR), the overarching standards which guide the conduct and reporting of Cochrane Intervention Reviews. The Campbell and Cochrane Equity Methods Group is also developing an equity checklist.
Cochrane Interactive Learning health equity module
There is a module of the Cochrane Interactive Learning course on health equity in systematic reviews. In it, users can learn about health equity and how and when health equity can be incorporated in all steps of the systematic review process. The module also addresses how health equity should be considered in planning aspects of knowledge translation.
Cochrane Review Group Networks’ health equity priority setting
Cochrane Review Group Networks are currently piloting an approach to incorporating health equity considerations in priority setting for the update of reviews. Eve Tomlinson, Network Support Fellow for the Cochrane Cancer Network, presented an update on this project at last week’s monthly Join the Conversation webinar. Watch the recording below.
Vaccine equity declaration
In March 2021, Cochrane also signed WHO’s Vaccine Equity Declaration, which calls for a more equitable distribution of vaccines for COVID-19.
Cochrane community contributes to update to the PRISMA statement. PRISMA is an evidence-based minimum set of items for reporting in systematic reviews and meta-analyses. PRISMA primarily focuses on the reporting of reviews evaluating the effects of interventions, but can also be used as a basis for reporting systematic reviews with objectives other than evaluating interventions (e.g. evaluating aetiology, prevalence, diagnosis or prognosis).
A dedicated global team of methodologists, search specialists, biostatisticians and systematic reviewers have spent the last few years diligently updating PRISMA - the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. First published in 2009, PRISMA was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found.
While this may sound simple, it is anything but. Systematic reviews are complex, using an array of methods from the identification of studies through to the synthesis of results, and careful reporting is required so that users of the review (such as guideline developers, policy makers, healthcare providers and patients) are able to understand what was done and how the findings might apply to them.
The updated open-access PRISMA statement is available online and published in no less than five leading journals - including BMJ, PLOS Medicine, Journal of Clinical Epidemiology, Systematic Reviews and International Journal of Surgery. It represents a major global collaborative effort which was sustained throughout the many challenging months dominated by COVID-19 throughout 2020. The project had strong representation from Monash University's School of Public Health and Preventive Medicine, with co-leads Matthew Page and Joanne McKenzie (and David Moher, Ottawa Hospital Research Institute) and contributors Sue Brennan and Steve McDonald. This representation reflects the calibre of systematic review expertise within the School - with specialisation in methods for bias, statistics, certainty of the evidence (GRADE) and searching.
PRISMA workshop participants, Cochrane Colloquium, Edinburgh 2018
‘This was such a rewarding experience thanks to the enthusiastic input, detailed deliberations and expert contributions from both our local team and fellow researchers around the world,’ lead author Matthew Page explains. ‘The updating process involved lengthy consultation and a comprehensive survey of systematic reviewers, journal editors and methodologists with experience with and interest in the use of the previous iterations of PRISMA.’
‘We obtained a lot of valuable feedback via our initial survey. In addition to answers to more straightforward multiple choice questions, we also collated over 100 pages worth of collective free text comments from respondents who felt really passionately about particular reporting elements, and specified what they thought should or shouldn’t be included in the updated guideline. We had this wealth of feedback to draw on and discuss at our two day workshop at the Cochrane Colloquium in Edinburgh back in 2018, which was fantastic. A healthy degree of consensus emerged from that, followed by much drafting, redrafting and careful considerations around the clarity of language used to update existing and outline new recommendations. This was followed up by piloting with authors to get their feedback and incorporate a final round of changes.’
Joanne McKenzie played a critical role throughout this process, co-facilitating the development meeting and processing the meeting notes, developing the updated guideline structure and overseeing the inclusion of guidance on new statistical developments that have been introduced in the decade since the original PRISMA statement was released.
‘We know systematic reviews are essential for healthcare providers, policy makers, and other decision makers, who would otherwise be confronted by an overwhelming amount of research to guide their decisions,’ Joanne says. ‘We really wanted to make this a practical, accessible and contemporary checklist both for systematic reviewers and for the many different users who depend on them. As such, we included detailed information about why reporting of each item is recommended along with plenty of examples from published reviews.’
‘We’re hopeful that these kinds of changes and additions to PRISMA 2020 will encourage greater uptake of the guideline and lead to more transparent, complete and accurate reporting of systematic reviews around the globe. There are plenty of positives in that for everyone.’
In a study Matthew Page and colleagues conducted on Reporting Characteristics of Systematic Reviews in PLOS Medicine back in 2016, around 29% of authors explicitly reported that they used the PRISMA Statement to guide either the conduct or reporting of their review, and all those who worked on this update are hopeful this number will continue to rise.
‘Looking ahead, we’ll continue to work together to plan and design interventions and software to help with future implementation,’ Joanne concludes. ‘We’re keen to evaluate both the use and usability of PRISMA 2020 in the months and years to come, so while we’re excited about the launch today it’s definitely part of a bigger picture plan to support and encourage more accurate and complete reporting of systematic reviews now and into the future.’
In March 2020, Cochrane Australia convened the National COVID-19 Clinical Evidence Taskforce - bringing together leading health researchers, experts and organisations from across the country.
Since then, over 240 members have worked around the clock to deliver living clinical guidelines and flowcharts for frontline health workers. The guidelines are updated and published online every week, they feature 124 guideline recommendations and have reached more than 180,000 users worldwide.
To learn more about the work of Cochrane Australia and how the Taskforce is continuing to evolve, click here to read a short case story.
Cochrane Austria, together with TranspariMED and Transparency International Austria, has recently published a report on clinical trial transparency in Austria, which provides an update on figures released one year ago.
The report uses data from the EU Trials Tracker to summarise the clinical drug trial reporting rates of the 14 largest sponsors in Austria. Under EU rules, clinical trial sponsors must post summary results to the EU Clinical Trials Register within one year of a study ending, or six months for paediatric trials.
According to the new report, results have now been published for 37% of due clinical trials, compared to just 18%, as cited in 2020.
While this is impressive progress – with some institutions making significant efforts to publish their backlog of results – there is still more work to be done. 233 completed and overdue trials are still awaiting results on the EU registry, and half of the sponsors have made no progress at all.
Barbara Nussbaumer-Streit, co-director of Cochrane Austria, said: “The trend towards better reporting is welcome. However, we should not forget that two thirds of trial results are still missing. This can lead to delays in the development of new and effective therapies, and thereby harms patients.”
Gerald Gartlehner, co-director of Cochrane Austria, said: "Missing clinical trial results can lead to patients receiving ineffective therapies because doctors lack important information."
Cochrane supports clinical trial transparency. We rely on the availability of trial results to produce high quality and relevant systematic reviews. When trial results are left unpublished, it is impossible to make truly evidence-informed decisions about healthcare and people can be put at risk.