From patient uncertainty to WHO policy in two years:
One GP’s experience of completing a Cochrane Review
by Greg Irving
Identifying uncertainties in UK general practice
In March 2010, during a routine Monday morning GP surgery, a patient told me in passing that he was going to India for his summer holidays that year. I dutifully offered to arrange the appropriate travel vaccinations for him. I emphasised that hepatitis A was the most common vaccine-preventable virus acquired during travel and that it was particularly important that he be covered for this. In reply, he asked me two simple questions that would take me on a journey of discovery resulting in several important changes to the World Health Organization’s (WHO) hepatitis A vaccination policy: “Does it work?’ and “Is it safe?”
To my surprise, I could find very little high-quality evidence addressing the outcomes of interest to my patient – does the vaccine actually prevent clinical hepatitis A from occurring, and is it safe? Instead, much of the existing literature was related to proxy outcomes such as antibody production. I turned to The Cochrane Library but could find no systematic review on the topic. It was at this point when I spoke with a local GP and Cochrane Review author, John Holden, who suggested we collaborate and produce the systematic review ourselves. We registered the review with the Cochrane Hepatobiliary Group in Copenhagen, Denmark, led by Christian Gluud.1
Data rising in the East
Given the widespread use of the live attenuated vaccine in China, we suspected there may be a number of randomised trials published in Chinese literature relevant to our review. We invited a Chinese colleague, Rongrong Yang, then a PhD student working at the University of Peking, to join the Review Group and conduct a search of the Chinese literature. We soon began to identify a large number of trials that would otherwise not have been identified had we restricted our search to the usual Western medical databases. Some of the trials we identified were huge and included over half a million participants. 2, 3
We presented our preliminary findings at the 2011 WONCA conference in Warsaw, Poland in a session chaired by Domhnall MacAuley, editor of the BMJ, who later wrote in his BMJ blog about the incredible potential for Chinese research powered by the sheer scale of their population.4, 5 BBC Radio 4 presenter, Geoff Watts, then invited me to contribute to a BMJ feature article titled, “Data rising from the East,” who picked up on the fact that, although we had identified many Chinese studies in our review, few were of high methodological quality.6
Changing WHO policy
I was contacted by Steven Wiersma of the WHO’s Health Security and Environment cluster and was invited to present our findings in Geneva to inform the hepatitis A Strategic Advisory Group of Experts hepatitis A working group. Our contribution not only strengthened several existing recommendations when measured against the GRADE criteria, but also identified a number of gaps in our existing knowledge and raised questions that required further investigation.7-9 These included a need for more evidence exploring the use of single-dose inactivated/live attenuated hepatitis A vaccines, a need for high-quality evidence exploring the efficacy and safety of the live attenuated vaccine and a review of the evidence exploring the long-term protection that required further investigation. Indeed, we later published a joint paper addressing this very question.10
The review itself was published on 13 July 2012, two years after the patient first asked. This appears to be the second largest vaccine-related Cochrane Review to date in terms of number of participants included.11 On the 14th day of the Cochrane Review being published, an unknown member of the public had faithfully taken the key findings of our review and made the decision to receive the hepatitis A vaccine; a wonderful example of how social media can bring high-quality evidence into the public domain.12 More recently, we have been invited to contribute to the Brighton Collaboration on vaccine safety and will undoubtedly continue to work with the WHO in the future as the review is updated in coming years.
For me, undertaking a Cochrane Review has been an education in itself in terms of the knowledge, skills and attitudes I have developed. The impact of the review has gone far beyond simply producing the review itself. I have worked collaboratively with researchers and policy-makers across the world. I can now confidently say to my patients: yes, the inactivated hepatitis A vaccine works and it is safe. Perhaps, more importantly, many others around the world can confidently do the same. I would argue that it is of vital importance that more clinicians are encouraged to take an active role in undertaking Cochrane Reviews.
I would like to thank Sir Iain Chalmers for encouraging me to share my experience with a wider audience in the hope that it may inspire others to follow suit.
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References
1. Gluud C, Nikolova D, Klingenberg S. Cochrane Hepato-biliary Group. Secondary Cochrane Hepato-biliary Group 2012. http://ctu.rh.dk/chbg.
2. Xu Z WX, Li R, Meng Z, Zhang Y, Gong J, et al. Immunogenicity and efficacy of two live attenuated hepatitis A vaccines (H(2) strains and LA-1 strains). Zhonghua Yi Xue Za Zhi 2002;82(10):678-81
3. Li Y, Wu, H., Xu, T.,. Observation of Immunogenicity and Epidemiological Efficacy Assessment of Attenuated Live Hepatitis A Vaccine. Chinese journal of public health 2000;16(8):737-38
4. Irving G. Holden J, Pope D, Yang R. Systematic review of the protective efficacy of hepatitis A vaccines. 17th Wonce Europe conference 2011; Warsaw.
5. MacAuley D. 17th Wonca Europe Conference, Warsaw. Secondary 17th WONCA Europe Conference, Warsaw 2011. http://blogs.bmj.com/bmj/2011/09/16/domhnall-macauley-17th-wonca-europe-conference-warsaw/.
6. Watts G. Data rising from the East. BMJ 2011;343
7. Wiersma S, Irving G, Ott J, Holden J. WHO GRADE tables: Full dose inactivated hepatitis A vaccine. Secondary WHO GRADE tables: Full dose inactivated hepatitis A vaccine 1992. http://www.who.int/immunization/sage/2_GRADETables1a_d_EfficSafety_14Oct_nov11.pdf.
8. World Health Organization. Evidence based recommendations for use of hepatitis A vaccines in immunization services: Background paper for SAGE discussions. Secondary Evidence based recommendations for use of hepatitis A vaccines in immunization services: Background paper for SAGE discussions 2011. http://www.who.int/immunization/sage/meetings/2012/april/1_HepABackground_17Oct_final2_nov11.pdf.
9. World Health Organization. Meeting of the Strategic advisory group of experts on immunization, april 2012 – conclusions and recommendations. Weekly epidemiological record 2011;21(87):201-16
10. Ott J, Irving G, Wiersma S. Long-term protective effects of hepatitis A vaccines. A systematic review. Vaccine 2012
11. Irving GJ, Holden J, Yang R, Pope D. Hepatitis A immunisation in persons not previously exposed to hepatitis A. The Cochrane Library 2012
12. Wikipedia. Hepatitis A vaccines. Secondary Hepatitis A vaccines 2011. http://en.wikipedia.org/wiki/Hepatitis_A_vaccine.
