Decisions on WHO’s essential medicines need more scrutinyBMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g4798 (Published 31 July 2014) Cite this as: BMJ 2014;349:g4798
All rapid responses
We are extremely grateful to Magrini and colleagues for reacting to our article on WHO’s essential medicines process (1). As strong supporters of the WHO’s role, we are pleased to know that some of the issues raised in our article (2) reflect internal discussions at WHO on how to strengthen the process for selection of medicines for the WHO list of essential medicines (EML).
Here we take advantage of their comment to clarify three issues.
(1) Magrini and colleagues pointed out that “those reviewing the applications are aware of the potential conflicts of interest”, but the issue we raised is that potential conflicts of interest are not publicly available. The same applies to members of the WHO expert committee: as noted by Welch (3), WHO does not publicly report how these are selected and whether they have potential conflicts.
(2) We agree with Magrini and colleagues that GRADE does not always apply, but the issue we raised is that when it is possible to apply a tool such as GRADE, it should be applied. In our article we showed that of 14 applications where GRADE was possible, only one used it.
(3) One of the most relevant aspects with GRADE is that it forces to summarize the evidence for each comparison and outcome of interest. It is therefore surprising to know that specifying comparators and outcomes of interest “would be a major change of focus” for WHO. We believe that making decisions on which medicines should be included in the WHO list must take into consideration how a medicine compares with others with respect to critical and important outcome measures. Thus, specifying comparators and outcomes would be of paramount relevance for the selection process.
We agree with Magrini and colleagues that the whole process can be strengthened. More interaction between the WHO Secretariat, applicants and international experts would be welcome. As part of this interaction, WHO and member states should set up a medium- and long-term strategic plan for the list.
1. Magrini N, Robertson J, de Joncheere K, Bero L. BMJ 2014;349:g4798. http://dx.doi.org/10.1136/bmj.g4798
2. Barbui C, Purgato M. Decisions on WHO's essential medicines need more scrutiny. BMJ 2014;349:g4798. http://www.bmj.com/content/bmj/349/bmj.g4798.
3. Welch C. BMJ 2014;349:g4798. http://dx.doi.org/10.1136/bmj.g4798
Competing interests: No competing interests
We appreciate the paper by Barbui and Purgato reflecting on the processes for selection of antidepressant and antipsychotic medicines for the World Health Organization’s Model List of Essential Medicines List (WHO Model EML) and welcome their suggestions on how these decision-making processes could be improved.1 Some of the issues raised reflect internal discussions at WHO on how to strengthen the process.
As noted by Barbui and Purgato, the reforms implemented in 2001 substantially changed the way the Expert Committee reviews submissions.2 A requirement for systematic evidence synthesis and appraisal was introduced, along with the assessment of comparative cost and cost-effectiveness. In addition, the WHO made its processes for receiving and reviewing applications transparent, with all submitted data and reviews publicly available and opportunities for interested parties to comment.
It is unclear why Barbui and Purgato are concerned that “WHO does not report information on potential conflicts of interests of applicants”. The process of submitting an application is open to all parties, including medicine manufacturers, and the applicant must be disclosed. Thus, those reviewing the application are aware of the potential conflicts of interest. While the current procedures do not prohibit applications from applicants with conflicts of interests, there are rigorous procedures in place to assess and manage any potential conflicts of interests of Committee members.
Barbui and Purgato raise three major issues regarding the EML processes: the quality of the evidence in the submissions considered by the Committee; the transparency of the decision-making process and the criteria used in making the judgments; and the discord between Expert Committee decisions and the recommendations of individual WHO Departments.
The authors suggest that the use of GRADE is new to the EML process. One of the earliest applications using GRADE assessments of the quality of evidence was for the addition of lamotrigine, submitted to the Committee in 2009.3 It has been requested that “where appropriate [this] evidence of comparative effectiveness and safety should be presented in tabular form using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) tables”.4 This has been done to a variable extent in the submissions received, also depending on the nature of the application. However, a GRADE approach is not always appropriate, for example for evaluating pharmacokinetic data, as was done when assessing the doses and dosage forms needed for the first-line treatment of tuberculosis in children; or there may be existing high quality systematic reviews that have not applied this methodology.
Although in this case Barbui and Purgato argue for strengthening evidentiary requirements, others have complained that the “lengthy, exhaustive process for applying for a listing can be discouraging [as] each component requires a separate detailed, complex application.”5 A balance must be reached between the perfect and the good.
To date, Expert Committee decision-making has been reported in the Technical Report Series (TRS), a formal requirement of WHO Expert Committees. WHO has been discussing ways of improving the quality of this reporting and the proposed approach of a more structured template has merit.
Consistency between EML decisions and WHO clinical guidelines issued by other WHO departments is highly desirable. As noted by the authors, after standardizing the application format and review process of the EML in 2001, formal guideline development processes were adopted by WHO in 2007.6 Where it exists, high quality evidence generated for guideline development has also been used for EML applications (see for example the applications for antiretrovirals).7
Barbui and Purgato have also suggested that WHO should specify comparators and outcomes of interest. However, this would be a major change of focus and more in line with regulatory activities than with selecting medicines for an essential medicines list.
The accompanying commentary by Millard et al. raises issues about the quality of available evidence and the influence of “vested interests” and “expert opinion” on the decisions taken by the Expert Committee.8 The authors argue that these components had more influence than available evidence on the decision to include misoprostol on the EML for prevention of postpartum haemorrhage (PPH) where oxytocin is not available or cannot be safely used. However, misoprostol was added for this purpose to the list in 2011 after the publication of an additional well conducted placebo-controlled trial in a community setting by Mobeen and colleagues, showing relative risks for prevention of moderate and severe PPH of 0.76 (95% CI 0.59–0.97) and 0.57 (95% CI 0.27–1.22), respectively.9 The Expert Committee (and the Cochrane Reviews that were included in the application) assessed the risks of bias of all available evidence and came to a different conclusion compared to the review referenced by Millard et al.10
The way forward
More interaction between the WHO Secretariat and applicants can ensure that the minimum standards for applications are met; this requires adequate resources for both WHO and applicants. Alignment between WHO guidelines and the EML has been the basic principle of the selection process, and WHO is working towards achieving better harmonisation of guideline development and consideration by the Expert Committee.
Assessing cost-effectiveness at a global level presents many challenges, however meaningful ways to include cost considerations in the selection processes for the Model List are needed. The methods of WHO CHOICE (CHOosing Interventions that are Cost-Effective) are being used to facilitate country-level cost-effectiveness assessments and are being applied to topics such as trastuzumab for breast cancer.11
WHO has a role in supporting countries in the evidence-based selection of medicines for national EMLs and in the implementation of these lists to guide medicines procurement and medicines use in practice. The Model EML is a key innovation and achievement in WHO history.12 In 2012, more than 120 countries reporting having national EMLs; others have adapted their EML or used similar evidence-based decision-making to choose medicines for medicines reimbursement lists. The importance of the Model EML was recognised in this year’s World Health Assembly resolution on access to medicines.13
The selection processes for EML medicines are not perfect. Yet the process in place is largely transparent and tries to strike a fair balance between methodological rigour, timeliness and other critical considerations including public health need and equity of access.
Kees de Joncheere
Essential Medicines List Secretariat,
Essential Medicines and Health Products Department,
World Health Organization, Geneva
Chair of WHO Expert Committees on the Selection and Use of Essential Medicines in 2011 and 2013
Medicines Use and Health Outcomes,
Faculty of Pharmacy and Charles Perkins Centre,
The University of Sydney
1. Barbui C, Purgato M. Decisions on WHO's essential medicines need more scrutiny. BMJ 2014;349:g4798. http://www.bmj.com/content/bmj/349/bmj.g4798.
2. World Health Organization. WHO medicines strategy. Revised procedure for updating WHO’s Model List of Essential Drugs. http://www.who.int/selection_medicines/committees/subcommittee/2/eeb1098...
3. Review of the available evidence on lamotrigine for epilepsy for the WHO Model List of Essential medicines (2009). http://www.who.int/selection_medicines/committees/expert/17/application/...
4. Essential Medicines List (EML) 2015 – Commented application. Information to be included in an application for inclusion, change or deletion of a medicine in the WHO Model List of Essential Medicines. http://www.who.int/selection_medicines/committees/expert/20/Commented_EM...
5. Klein HG. Should blood be an essential medicine? N Engl J Med 2013;368:199-201.
6. Hill S, Pang T. Leading by example: a culture change at WHO. Lancet 2007;369:1842-4.
7. 12th Expert Committee on the Selection and Use of Essential Medicines, 15-19 April 2002. Guide to the submissions for antiretroviral drugs. http://archives.who.int/eml/expcom/expcom12/arvs_submissions.htm
8. Millard C, Brhlikova P, Pollock AM. Commentary: Evidence versus influence in the WHO procedure for approving essential medicines: misoprostol for maternal health. BMJ 2014;349:g4823. http://www.bmj.com/content/349/bmj.g4823
9. Mobeen N, Durocher J, Zuberi NF, Jahan N, Blum J, Wasim S, et al. Administration of misoprostol by trained traditional birth attendants to prevent postpartum haemorrhage in homebirths in Pakistan: a randomised placebo-controlled trial. BJOG 2011;118:353-61.
10. Chu CS, Brhlikova P, Pollock AM. Rethinking WHO guidance: review of evidence for misoprostol use in the prevention of postpartum haemorrhage. J R Soc Med 2012;105:336-47.
11. World Health Organization. CHOosing Interventions that are Cost-Effective (WHO-CHOICE). http://www.who.int/choice/cost-effectiveness/en/
12. World Health Organization. Continuity and Change — Implementing the third WHO Medicines Strategy 2008-2013. WHO Policy Perspectives on Medicines 2010. http://apps.who.int/medicinedocs/documents/s16880e/s16880e.pdf
13. World Health Assembly 2014. Resolution WHA67.22 - Access to Essential Medicines. http://apps.who.int/medicinedocs/documents/s21453en/s21453en.pdf
Competing interests: No competing interests
The World Health Organization (WHO) has been promoting essential drugs for nations since 1997 with the first model list of essential drugs. The list has been updated every two years and the current list is the 18th edition published in 2013. The last updated list for children is the 4th edition in 2013 (1). In India, the concept of essential drug list was first promoted in Tamilnadu state in 1994. Delhi took the lead in developing a comprehensive Drug Policy in 1994 and was the only Indian state to have such a comprehensive policy (2). Now many state governments too have developed standard treatment guidelines (STGs) for use within the state government health facilities. The Armed Forces Medical College (AFMC) has developed STGs for a large number of common conditions (3).
The first National Essential Medical List (NEML) was prepared in 1996 (4). This list was neither implemented for procuring drugs nor were STGs drawn up (5). The first and second revision was published in 2003 and 2011, respectively. However, the Delhi model list is considered to be an example for the other states in India. The Government of National Capital Territory of Delhi along with Delhi Society for Promotion of Rational Use of Drugs (DSPRUD) is providing a lead role of revising the list of essential drugs since 1996, the last being in 2013. It involved widespread participation of doctors from hospitals, dispensaries and health centres. Suggestions received were discussed in eleven sub-committees and finally 406 medicines including 152 for dispensary level were included in the latest list (6).
The NLEM 2011 contains 348 medicines and was prepared by 87 experts. It has been well documented with inputs from experts from various fields in the review committee. A critical appraisal of the list reveals some areas of concern such as inclusion of a nearly anaesthetic agent, such as ether ; non-inclusion pediatric formulations, and errors in the strengths of formulations etc.(7). In addition, some essential drugs listed in the WHO model list and Delhi list are missing from the “essential medicines” list. Several Diabetes, TB, HIV, Cancer drugs are not included in the list. Essential oral anti-diabetic medicines like glimeperide and glicazide do not find a place in the list of essential medicines (8). The list in the DSPRUD for Delhi includes anti-diabetic medicines such as Glimepiride, Sitagliptin, Vildagliptin, Saxagliptin (9).
The other findings are: commonly used anti-asthmatic medicines like salmeterol and montelukast are not included in the essential medicines list. One of the main concerns is regarding the emergence of Multi-drug resistant tuberculosis (MDR-TB). The World Health Organisation (WHO) model List (EML) includes capreomycin, cycloserine, ethionamide, kanamycin and para-aminosalicylic acid for treatment of multi-drug resistant tuberculosis. These drugs are missing from the NLEM 2011 list. Similarly, while the WHO list mentions 21 vaccines, the NLEM 2011 mentions only nine vaccines (8).
In its present form, the NLEM 2011 needs further discussion and revision in the light of the missing drugs and keeping in view of the requirements under various National Health Programmes as well as the National Formulary of India 2010. The Indian Academy of Paediatrics has come out with a list of essential drugs for children in India. Such a list might be consulted for the paediatric list of essential medicine in the NLEM. Provision should be made to review the NLEM at two yearly intervals.
The efforts made by the Government of India include a policy for pricing of essential medicines (9). The Central Government is negotiating with the pharmaceutical industry to bring down the cost of essential drugs by 25-40% (10). This will make the drugs more affordable in India. A panel of experts has been formed to add more drugs to the list of essential drugs and all of them would come under a price cap (11). The Ministry of Health, Government of India, has a vision to provide 50 essential generic medicines, free of cost, from "birth to death" to all Indians across the nation. The programme will be rolled out in phases, beginning with select hospitals across India, with the objective of reaching every citizen. Once the rollout is complete, everyone will get these 50 medicines – that includes traditional treatments for pain, infection, hypertension, diabetes, among others – complimentary on prescription at public hospitals and dispensaries (12).
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3. Standard Treatment guidelines: Medical management and Costing of selected conditions. India: Armed forces Medical College, Pune in collaboration with MOHFW and WHO country office; 2007.
4. Sharma S, Kh R, Chaudhury RR. Attitude and opinion towards essential
medicine formulary. Indian J Pharmacol 2010;42:150‑2.
5. Better medicines for children in India. World Health Organization. Available
from: http://www.apps.who.int/medicinedocs/documents/s17812en/s17812en.pdf. (accessed on 8th August 2014).
6. http://www.dsprud.org/ (accessed on 8th August 2014).
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way forward. Journal of Postgraduate Medicine 2012;58(1):68-72.
8. Pradhan R. NLEM: Grey area about what are “essential drugs”. http://www.moneylife.in/article/essential-drugs-under-nlem/35320.html (accessed on 8th August 2014).
9. http://www.idma-assn.org/pdf/drug-price-control-order-2013.pdf (accessed on 8th August 2014).
10. http://timesofindia.indiatimes.com/india/Will-try-to-bring-down-drug-pri... (accessed on 8th August 2014).
11. http://timesofindia.indiatimes.com/business/india-business/Govt-may-exte.... (accessed on 8th August 2014).
12. Sharma S. Health min plans to give 50 essential medicines free. Available at
http://www.hindustantimes.com/india-news/50-essential-meds-to-be-given-f... (accessed on 8th August 2014).
Competing interests: No competing interests
Barbui and Purgato  are to be congratulated on their article calling for reforms to both the standard of applications to, and the clarity of reporting of decisions by the WHO expert committee on essential medicines. But they don't go nearly far enough. It isn't just the decisions that need more scrutiny, but the composition of the committee itself.
We are told only that the committee is made up of experts "appointed by the WHO director general" who meet "every two years to review applications with expert assessors and decide which medicines are added or deleted". Just try to find out from the WHO website who the committee members are before a committee meeting (as opposed to when the meeting report is published), let alone their qualifications, fitness for the role, or conflicts of interest. Why is there never a call for nominations to the committee? The list of current members smacks of croneyism, the appointments process is completely opaque, and the decisions lack clarity. Transparency is its own reward; WHO should indeed try leading by example.
1. Barbui C, Purgato M. Analysis Decisions on WHO’s essential medicines need more scrutiny. BMJ 2014;349:g4798
Competing interests: No competing interests