What did we learn from Tamiflu?BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m626 (Published 19 February 2020) Cite this as: BMJ 2020;368:m626
All rapid responses
Owen Dyer highlights many of the challenges researchers face in accessing and making use of clinical study reports (CSRs) to assess healthcare interventions. The feature is of great interest to those involved in Cochrane and brings into stark focus the fundamental role CSRs can play in the completeness and trustworthiness of systematic reviews.
Like The BMJ, Cochrane has long been a passionate supporter of the AllTrials initiative and advocates for full, open-access CSRs. Examples include an open letter written in response to the FDA’s Public Comment Request on the Clinical Data Summary Report Pilot, and a statement in support of the EMA’s clinical study report transparency policy following the recent legal challenge. Campaigning for access to CSRs will continue to be a key focus of Cochrane's advocacy work and the organisation is in discussion with multiple data sharing platforms to facilitate access, including Vivli and the EMA. We would like to respond to the statement that Cochrane reviewers have “not embraced clinical study reports” by outlining a range of initiatives that are underway to help Cochrane authors decide when to include CSRs, and to support them in doing so.
Shortly after the Cochrane Review of Tamiflu was published, Cochrane funded a project to identify when to use CSRs in Cochrane Reviews. The project involved two of the review's authors, Thomas Jefferson and Peter Doshi, who are correctly posited in Dyer’s article as trailblazers in the campaign to improve access. The report was subsequently published in The BMJ and identified 18 criteria to guide when to adopt this approach. Based on the results of the project, the Cochrane Scientific Committee acknowledged that CSRs were likely to be of huge importance for some, but not all, Cochrane reviews and recommended that their use be optional while the necessary methods tools and guidance for authors and editorial teams were put in place.
In May 2019, Cochrane hosted a consultation meeting with clinical researchers, methodologists and Cochrane editors to discuss the future of searching for, assessing and incorporating data from CSRs into Cochrane Reviews where it would be appropriate to do so. A post about this meeting, including the slides and minutes, was subsequently made available on the Cochrane Methods website. Challenges and obstacles for Cochrane Review Groups were discussed in detail by those with experience dealing with CSRs, which led to the identification of five priority areas for further work and formation of a CSR Working Group. It is important to note that Dyer's reference to the 2018 survey finding that 83% of Cochrane authors had not considered using CSRs was sent to all Cochrane authors, and does not account for Jefferson and Doshi's criteria for assessing whether it is appropriate to do so. The survey also investigated barriers to accessing and using CSRs and those who responded (which included both authors who had or had not considered using CSRs) highlighted many of the same challenges identified in the Cochrane consultation meeting (limited access, time and resources required, and a lack of guidance).
An update on progress was given in November 2019 as part of the Virtual Cochrane Colloquium 2019 and the recently formed CSR Working Group have since developed a draft starter pack to help Cochrane Groups to support author teams wanting to include CSRs in their reviews. The starter pack brings together available guidance, training, tools and support and identifies gaps where resources need to be developed. Cochrane is supporting the teams producing five ongoing Cochrane Reviews in their use of CSRs to identify the issues first-hand and help concentrate efforts to support their use more widely. There is ongoing research in Cochrane looking at risk of bias assessments for journal articles and CSRs which will further contribute to understanding the usability of CSRs within Cochrane Reviews.
Cochrane fully supports the use of CSRs in systematic reviews and is undertaking all of the initiatives described to alleviate the challenges they pose for Cochrane Review Groups and volunteer author teams. We hope that as the infrastructure and guidance develops that more Cochrane Review Groups will feel confident and supported to use CSRs within their reviews when it is relevant to the research question.
 BMJ 2020;368:m626 doi: 10.1136/bmj.m626
Competing interests: Both authors are employed by Cochrane as members of the Editorial and Methods Department
Excellent article! Pharmaceutical agents may be of considerable value, and robust research is always needed. Much modern pharmacology is derived from origins in herbalism - it is thought that in 1945 over 75% of a GP's prescriptions were herbal.
So is there anything to learn around alternatives to Tamiflu in the treatment of influenza, as well as the standard advice of supportive approaches of hot fluids, keeping warm, additional vitamin C to support the immune system (humans, as opposed to other mammals, do not make their own) and nourishing food?
A 2015 study head to head of Echinacea, a well known herbal immune stimulant, against oseltamivir in the treatment of influenza showed that Echinacea in the form of a proprietary preparation was as effective as Oseltamivir, with similar rates of recovery. This was seen in those diagnosed clinically during peaks of influenza infection, and also in those with infections confirmed virologically. The Echinacea outperformed the oseltamivir in terms of complications and safety. Echinacea is of course an over the counter medicine, not a prescription one, so could be available at the earliest onset of symptoms, as an important factor in the treatment of influenza.
The advice to use echinacea is not widely known in medical circles. It is not known why this is so, when echinacea is an effective and inexpensive over-the-counter resource. The herbal medicine industry do not have the same marketing abilities or resources as a major pharmaceutical company, nor is echinacea patented, thus is less profitable. Medical students learn nothing about echinacea in pharmacology or therapeutics, so there may be an unconscious system bias against such approaches, even if valuable and cost effective.
Wise use of resources and helping people to self-care may become drivers to embrace such evidence based approaches.
1 Raus K, School R, Pleschka S. Klein P, Fisher P. Echinaforce [proprietary name] versus Oselatmivir in influenza: a randomised, double-blind, double-dummy, multicenter, non-inferiority clinical trial, Current Therapeutic Research 2015 https://www.ncbi.nlm.nih.gov/pubmed/26265958
Competing interests: No competing interests
TAMIFLU & INFLUENZA VACCINES: MORE HARM THAN GOOD?
Owen Dyer reminds us that we have spent billions on a drug that possibly does more harm than good. (BMJ 2020;368:m626—February 19) The same thing can be said about influenza vaccines.
We hear so much about the vital importance of flu shots that it will come as a nasty surprise to learn that they increase the risk of illness from noninfluenza virus infections such as rhinoviruses, coronaviruses, RS viruses, parainfluenza viruses, adenoviruses, HMP viruses and enteroviruses. This has been shown in at least two studies that have received little attention from public health authorities: A prospective case-control study in healthy young Australian children found that seasonal flu shots doubled their risk of illness from noninfluenza virus infections (unadjusted OR 2.13, CI 1.20—3.79). Overall, the vaccine increased the risk of virus-associated acute respiratory illness, including influenza, by 73% (OR 1.73, CI 0.99—3.03). (Table 2 in Kelly et al, Pediatr Infect Dis J 2011;30:107)….A randomized placebo-controlled trial in Hong Kong children found that flu shots increased the risk of noninfluenza viral ARIs fivefold (OR 4.91,CI 1.04—8.14) and, including influenza, tripled the overall viral ARI risk (OR 3.17, CI 1.04—9.83). (Table 3 in Cowling et al, Clin Infect Dis 2012;54:1778)…..To my knowledge, the foregoing risk figures have not been explicitly published anywhere. They will not be found in the abstracts of the articles, so you have to go to the tables and look at the numbers themselves.
What is going on? We are told year after year that influenza vaccines are 60% effective…30% effective…45% effective…etc. Does this mean that they prevent a significant proportion of all viral respiratory infections? No, these reports are based on non-randomized surveys known as “test-negative case-control studies”; they look only at influenza infections and make no attempt to look at the other 200-plus respiratory viruses. Furthermore, they make no attempt to look at any vaccine adverse effects such as seizures, narcolepsy, Guillain-Barre’ syndrome, or oculorespiratory syndrome.
How can influenza vaccines increase the risk of other infections? There are at least two possible mechanisms: first, influenza vaccines probably alter our immune systems non-specifically to increase susceptibility to other infections; this has been observed with DTP and other vaccines. (Benn et al, Trends in Immunology, May 2013) Secondly, there is the phenomenon of “viral interference” in which a virus infection stimulates the innate immune system to provide temporary and non-specific protection against other viruses. By preventing influenza infection a vaccine could prevent this unexpected but positive side effect. The Cowling study discusses this possibility in some detail. A recent study of virus population dynamics found, at least, that influenza A prevented subsequent rhinovirus infections, and influenza B prevented adenovirus infections. (Nickbakhsh et al, PNAS, 12 Nov 2019)
In the US seasonal influenza vaccines are now recommend every year for the entire population (excepting infants before 6 months of age). It is important to realize that this policy was instituted without acquiring safety and effectiveness data from randomized controlled trials. When routine vaccination for healthy young children was being contemplated some experts in pediatrics and infectious disease issued warnings. Kenneth McIntosh called for the performance of multi-center randomized trials over several seasons before such a policy was instituted. In explicit language he worried about adverse effects, and the possibility that the risks of annual vaccination would outweigh the benefits. (Editorial, NEJM 2000;342:275) Twenty years later we must ask, “What harm is done by annual influenza vaccines? Where is the balance between risks and benefits?”
One of the imponderables is the effect of seasonal influenza vaccines on population immunity. Individuals who recover from influenza can have broad and long-lasting protection against an array of influenza viruses. First infections in young children can provide this, a phenomenon known as “imprinting”; this is subverted by childhood vaccination. Furthermore, the protection in adults who still carry the imprint from childhood may be subverted by the seasonal flu vaccine. This was seen in middle-aged adults during the 2018/19 influenza A(H3N2) epidemic in Canada; vaccine recipients suffered a nearly fivefold risk of illness from a drifted strain of A(H3N2), compared with unvaccinated individuals (OR 4.67, CI 1.85--11.82). (Skowronski et al, EuroSurveillance, 14 Nov 2019)……What are we doing to population immunity with wide annual distribution of seasonal flu vaccines? Are our annual epidemics getting milder or more severe? What effect will years of seasonal influenza vaccines have on the next pandemic? Remember the 2009 swine flu pandemic? The risk of severe pH1N1 illness in Quebec increased progressively according to the number of seasonal flu shots received in previous years and was more than threefold in individuals who had received five vaccinations in five years, compared with unvaccinated individuals (adjusted OR 3.24, CI 1.97—5.34). (Table 5 in Skowronski et al, PLoS Medicine, April 2010)
In the US a regular feature of publicity urging annual flu shots are mathematical estimates of deaths caused by influenza, provided by the CDC. Since the 2010-11 season these estimates have ranged between 12,000 and 79,000 US deaths each season. The numbers are far in excess of actual cases documented in death certificates or by surveillance networks reporting on laboratory test-positive cases. While we wait for better numbers, it is not merely academic to ask what we would find if we focused as intensively on other respiratory viruses as we do on influenza. If influenza vaccines increase the overall risk of viral ARIs, as they do in the studies discussed above, would they also increase the overall number of ARI deaths? Tamiflu and influenza vaccines: more harm than good?
ALLAN S. CUNNINGHAM 23 February 2020
Competing interests: No competing interests