Report on Technical Update
of the Essential Medicines Library

Katharine Jones, Anna Ridge, Derval Harte, Effective Health Care Research Programme, Liverpool School of Tropical Medicine, U.K.

July 2006

Background

The World Health Organization (WHO) is linking policy to best available evidence. Between May and July 2006 we carried out a technical update of the Essential Medicines Library(EMLib) on

Under a grant from WHOwe collaborated with Sue Hill from the Medicines Policy and Standards Departmentto identify high quality, recent evidence relevant to the selection and use of the 298 medicines in the library (vaccines excluded from update), and to checkthe on-line profilefor each medicine as follows:

  • Section
  • Formulation
  • Anatomical Therapeutic Chemical (ATC) classificationcode
  • Drug status
  • Disease/Indication
  • Rationale for use
  • Guidelines

Methods

See Annex 1. Methods were drafted following an exploratory visit to Geneva in May. During the project we encountered several issues as detailed below.

Issues identified

Section

Some inconsistenciesin section existed between the EMLib and the WHO Model list as the library is yet to be updated in line with the changes made between the 13th and 14th editions of the Model list.

Formulation

A significant number of WHO formulationswere not listed in any of the three international formulariesconsulted. For some medicines formulations which appeared more appropriate in view of the recommended dosage schedule were not included in the library.See Annex 2 for full details.

ATC code

Some drugs had no code listed on the ATC website e.g. aluminium diacetate.

Some codes were incorrect e.g. The cephalosporins such as ceftriaxone EMLib J01DA13 ATC code website J01DD04.

Combination drugs were a particular problem with few codes listed on the ATC website e.g.Mifepristone-misoprostol codes only available for each component drug.

Drug status

This section was cross checked with the “Comparative table of core and complementary medicines on the WHO Essential Medicines List from 1977- 2005” As with several WHO documents consulted during the project this spreadsheet contained a key using numbers and letters but no explanation of what these stood for. Some drugs featured on both the core and complementary list for different indications.

Disease/Indication

The WHO applications website and technical reports provide information on the selection and use of drugs on the model list.

a)Applications

Searching for applications was time consuming due to the complexity of the search required for each medicine as detailed in Annex 3. Several documents published on this site contained tables with no clear headings and abbreviations we were unable to interpret.

b)Technical reports

Most technical reports on the WHO website are scanned documents on which Microsoft Office is unable to search. Each report is over 60 pages long and so hand searching was not an option. Using “PDF creator” we were able toconvert these files into word documents and search electronically. The main component of most the reports was a reproduction of the model list with only the last tenth of the document provided any useful informationon the selection and use of specific drugs. Technical reports published since the introduction of the application process in 2002 were notably more informative.

For some drugs we were unable to find any documentation to support the selection and use of a drug for the indications stated on the EMLib. This was a particular problem for antibiotics included in the library, many of which had multiple indicationswith some no longer clinically relevant. Following discussion with Sue Hill we restricted the indications for this group of drugs to the most important clinical conditions and drafted a generic statement for all antibiotics “for use in the treatment of infections with susceptible organisms including…(important clinical conditions). Local antimicrobial resistance patterns need to be taken into account”

Rationale for use

This section was generally used to state the date added to the list and whether a medicine had a square box used to indicate similar clinical performance within a pharmacological class. Where a square box was added we listed comparable alternatives if these were stated in the relevant technical report.

WHO guidelines

We searched four databases for WHO global guidelines relevant to the selection and use of each drug as detailed below. Where no WHO guideline was available we searched a national guideline clearing house. This was by far the most time consuming element of the update due to issues with both guideline documents and databases as summarised below and in Annex 4.

1. Documents

  • No title or explanation regarding the context of the document for some pdfs
  • No publication date available in some WHO documents
  • Page indexing system for some hard copy documents was inadequate for our needs e.g. Guidelines for the treatment of malaria

2. Databases

a) WHO Library and Information Networks for Knowledge Database (WHOLIS)

  • Search engine lacked sufficient sensitivity for our requirements.
  • Ability to order and restrict results by publication date greatly reduced time taken to identify most relevant reference.
  • Labelling of references good and included publication date

b) WHO website

  • Search engine lacked sufficient specificity for our requirements
  • High number of results and inability to order or restrict by publication date or relevance made identifying relevant results for some drugs impractical.
  • Labelling of references unclear and often missing publication date necessitating inspection of full document to establish relevance.
  • Some full documents did not include publication date.

c) WHO Health Topics site

  • Clear categorisation by disease indication made search easy
  • Very few documents available via this site

d) Google

  • Search engine sufficiently sensitive
  • Results appeared to generally be ordered by relevance allowing rapid identification of the most relevant document.
  • For some drugs using this search engine was the fastest and most consistent method of identifying relevant guidelines.
  • References generally clearly labelled although some missing publication date

e) Guideline Clearing House

  • Search engine sufficiently sensitive and specific
  • Labelling of results clear
  • Guidelines produced by institutions in the U.K., U.S.A. and Australia so may not be relevant to low and middle income countries

Evidence

We were able to identify a relevant Cochrane reviewfor the majority of drugs on the list using the Centre for Reviews and Dissemination Database (see Annex 5 for those drugs without a review). For those medicines without a Cochrane review we quoted other forms of randomised evidence where available.

Library presentation

At present references in the on-line version of the library are not labelled or divided according to type i.e. technical reports, WHO guideline, Cochrane review etc.

Time taken

Total of 540hrs for three people to complete technical update of profiles for all medicines (does not exploratory visit to Geneva)

Summary

Accessibility of information

WHO documents

  • No publication date stated in some WHO publications
  • No internal key available in several WHO reference documents
  • Page indexing for hard copies of some guidelines did not meet our needs

WHO website

  • Scanned technical reports made electronic searching impossible
  • Searching for applications was complex and time consuming
  • WHOILS search engine lacked sensitivity although ordering and labelling of results allowed rapid identification of the most relevant document.
  • WHO website search engine lacked specificity and lack of capacity to order or restrict results pluspoor labelling of references made identifying the most relevant document time consuming.

EMLib

  • The profile of most medicines in the library now includes a reference to a relevant Cochrane review.

Proposals for change

  • Improvement in search engine capacity, labelling of search results and indexing of WHO documents would greatly increase the accessibility of information.
  • An on-line inventory of WHO guidelines would be useful.
  • An alternative reference source for WHO formulationsis required.
  • Division and labelling of library references by document type would be helpful.
  • Qualitative research to gain feedback from users of the library would be informative.

Report on Technical Updateof the Essential Medicines Library -- page 1

ANNEX 1

Methods for technical update of the Essential Medicines Library

Background

The task is to identify reliable, up-to-date evidence relevant to each of medicines included in the library on and check the entry for each medicine as follows:

  • Section
  • Formulation
  • Anatomical Therapeutic Chemical (ATC) classification code
  • Drug status
  • Disease/Indication
  • Rationale for use
  • Guidelines

In our experience updating the library by drug sections rather than in alphabetical order is more efficient as there is documentation overlap between drugs within each section.A separate word file for each drug profile with comments inserted allows queries to be flagged.

1. Section

Check correct by using edit and search function on "14th Model" list pdf and use NEXT function to locate all mentions of drug.

2. Formulation

Search any of the on-line international formularies below to cross check the WHO formulation:-

BNF

Australian Medicines Handbook (subscription only)

MIMS Asia

If not in any of the above try searching Google!

NB Martindale: The complete drug reference contains no details on formulation.

Injectable formulations should only be on the list if absolutely necessary. Please flag if you think an injectable formulation is surplus to requirements.

Please keep a list of any drugs not listed in the BNF or MIM, or where there are discrepancies between the listing in the WHO formulary and the references.

3. ATC code

Cross check with ATC codes website Please flag if the code is unclear or appears incorrect for the indication.

4. Drug status

Check core/complimentary status from “Comparative table of core and complementary medicines on the WHO Essential Medicines List from 1977- 2005” spreadsheet. The default status for all drugs is core and drugs should only be moved to the complimentary list with good reason (special equipment required etc.). Please flag any drugs whose status appears incorrect. Where a square box has been added please state the year when this occurred and any comparable alternatives as specified in the technical reports so that countries can choose the drug they can get hold of the cheapest and easiest.

5. Disease/Indication

Search WHO applications and technical reports as below.

For drugs with multiple indications chose the most important 2 or 3 and only search and include evidence relevant to these conditions.

For antibiotics include a generic statement “for use in the treatment of infections with susceptible organisms including…. Local antimicrobial resistance patterns need to be taken into account”.

State any information found and flag any inconsistencies between statements in these documents and available evidence. Any important contra-indications should be included in this section but not prescribing information as this is outside the remit of the site.

6. Rationale for use

If no available evidence then just state the date added to the list. For drugs which are known to be widely misused it may be appropriate to quote the evidence.

7. Date added

Check this in the“Comparative table of core and complementary medicines on the WHO Essential Medicines List from 1977- 2005” spreadsheet.

8. Applications

Search for applications from 12th, 13th and 14th expert committee agendas via the applications website listed below using the search process described in annex 3. If the application contains relevant information then no need to quote anything else. If no relevant information available in any of the application documents but the drug is listed then still quote relevant document but flag that it is not a useful reference.

9. Technical reports

Check spreadsheet for year drug added to Essential Drug list.

Search Technical reports from year added to list using find and edit from Technical reports word files as those on website are scanned documents and therefore edit and find function does not work. Be careful to click on the main text of the word document before using the edit and find function as otherwise the function will only search the text box highlighted.

Only quote the report in which the drug was added or any where there was a change in the status of the drug or relevant information is available.

TRS and corresponding years listed below:

Report on Technical Updateof the Essential Medicines Library -- page 1

TR 722 – 1985

TR 770 – 1988

TR 796 – 1990

TR 825 – 1992

TR 850 – 1995

TR 867 – 1997

TR 882 - 1998

TR 895 – 2000

TR 914 – 2003

TR 920 – 2004

TR 933 – 2005

Report on Technical Updateof the Essential Medicines Library -- page 1

NB draft technical report 933 is available as a pdf via the applications website under 14th expert committee and unedited expert committee report.

10. WHO guidelines

For each drug please use the following search strategy

a) WHOILS

Use the search strategy:-

“drug name” +/- “guideline/s”

“drug group” +/- “guideline/s”

“disease” +/- “guideline/s”

For drugs with multiple indications only search and include evidence relevant to the most important 2 or 3 indications as specified in Disease/Indication section.

b) Search the main WHO website using the same search strategy as in a)

c) Search the health topic site using the same search strategy as in a)

c) Search google using same search strategy as in a) but also including the phrase “World Health Organization”

d) Search anywhere else you can think of!

Please insert a comment detailing which method led you to the guideline and any info which you think may be useful feedback.

11. Other guidelines

If no WHO Guideline found search guideline clearing house and list as a hyperlink.

12. Evidence

Search the Database of Abstracts of Reviews of Effectiveness via the link below for relevant evidence. If a Cochrane review is available this is sufficient. Keep a list of drugs with no Cochrane review and quote other evidence where available. Include all reviews whether supportive or not but insert comment if not supportive.

Report on Technical Updateof the Essential Medicines Library -- page 1

ANNEX 2

Formulation issues

Drug name / Formulation on 14th Model List / Problem with current formulation
Aluminium diacetate / Solution 13 % / Unable to find - BNF and mims Asia
Aluminium hydroxide Formulation / Oral suspension 320 mg/5mL / Not found. A 200mg/ml oral suspension is available
Amidotrizoate / Injection 120-420mg iodine (as sodium or meglumine salt)/mL in 20 mL ampoule / Need to check formulation with manufacturer
Azithromycin / Oral suspension 200 mg/5 mL / Unable to cross reference formulation
Barium sulphate / Aqueous suspension / Unable to find formulation
Biperiden / Injection 5 mg/mL in 1-mL ampoule / Is injection formulation required? Not found in BNF/mims Asia. Review for possible deletion?
Calamine lotion / Lotion / BNF: lotion containing calamine 15% zinc oxide 5% glycerol 5% betonite 3%, sodium citrate 0.5%, liquefied phenol 0.5%, in freshly boiled and cooled purified water
Carbimazapine / Tablets 100mg, 200mg / Suggest review for addition of 400mg formulation, in view of max dose of 1.2g – 2g daily in epilepsy
Charcoal, activated / Powder for oral suspension / No formulation given. Formulations available include 25g and 50g packs
Chloroquine / 100mg tablet and 150mg as phosphate
Injection / Unable to find formulation
Is injection formulation still appropriate for list?
Chlorine base compound / Powder (0.1% available chlorine) for solution / Cannot find formulation
Chloroxylenol / Solution 4.8% / Cannot find formulation
Chlorpromazine / Tablet 100 mg (hydrochloride) / Initial starting dose is 25 mg TID. Should further tablet formulations be added? (10 mg, 25 mg and 50 mg formulations are available)
Clomipramine / Capsules 10 mg, 25 mg / Should 50 mg capsule be included? (upper dosage level for OCD can reach 250 mg)
Coal tar / Solution 5 % / Other concentrations found, but not 5 %
Cyclophoshamide / Tablet 25 mg / 50 mg, 100 mg and 200 mg tablets are available. 25 mg not found
Cycloserine / Capsule or tablet 250 mg / Tablet formulation not found
Daunorubicin / Powder for injection 50 mg / 20 mg found. 50 mg available in liposomal form, but not injection
Diazepam / 5 mg/mL in 2-mL amp. (rectal or IV) / In BNF 5 mg or 10 mg rectal solution
Didanosine (ddl) / Buffered powder for oral solution 100 mg, 167 mg, 250 mg / Unable to find
Diethycarbamazine / Tablet 50 mg, 100 mg / 100 mg tablet not found (only 50 mg and 300 mg)
Enalapril / Tablet 2.5 mg / Starting dose is 5 mg. 2.5 mg formulation no longer appropriate?
Epinephrine (adrenaline) / 1mg (as hydrochloride)/ml in ampoule, Section 12.02.00.00 (for use in cardio-pulmonary resuscitation) which is equivalent to 1/1000 / The IV dose should be 1/10,000 (100mcg/ml).
Incorrect formulation listed. Need to review
Ergocalciferol / Capsule or tablet 1.25 mg (50000 IU), Oral solution 250 micrograms/mL (10000 IU/mL) / Can only find 250 microgram dose as a capsule. No oral solution found
Ergometrine / Injection 200 micrograms in 1-mL amp. / Only formulation found is 500 micrograms
Ethionamide / Tablet 125 mg, 250 mg / Unable to find 125 mg tablet
Flucytosine / Capsule 250mg; infusion 2.5g/250ml / Capsule cannot be found. BNF states that tablet can be ordered on a named patient basis from Bell and Croyden
Fluorouracil / Ointment 5% / Only cream found in BNF/mims Asia
Folic acid / Tablet 1mg, 5mg / Cannot find 1mg tablet
Glutaral / Solution 2%; / Cannot find in any formulary
Heparin sodium / Injection 1,000 IU/ml, 5,000IU/ml, 20,000IU/ml in 1 ml amp / 20,000IU/ml does not appear to be available. Usual formulation available is 25,000IU/ml
Hydrocortisone / Suppository 25mg (acetate); Retention enema (section: 17.03.00.00) / This formulation cannot be found
Idoxuridine / Solution,( eye drops) 0.1%; eye ointment 0.2% / 0.1% eye solution found (Indonesia) Cannot find eye ointment
Indinivir (IDV) / Capsule 200mg, 333mg, 400mg (as sulphate) / Only 200mg and 400mg formulations appear to be available
Insulin (intermediate-acting) / 40IU/ml in 10 ml vial, 100IU/ml in 10 ml vial, (as compound insulin zinc suspension or isophane insulin) / There do not seem to be 40 IU/ml vials
Insulin (soluble) / Injection, 40IU/ml in 10 ml vial, 100IU/ml in 10 ml vial / There do not seem to be 40 IU/ml vials
Iodine / Iodized oil, 1 ml (480 mg iodine) in ampoule (oral or injectable); 0.57 ml (308 mg iodine) in dispenser bottle; capsule 200mg. / These formulations cannot be found (Lugol’s soln available, this is 130mg/ml iodine)
Iohexol / Injection 140-350mg iodine/ml in 5 ml, 10ml and 20ml ampoule / Like other radiocontrast media this formulation cannot be found
Iopanoic acid / Tablet, 500mg / Like other radiocontrast media this formulation cannot be found
Isoniazid + ethambutol / Tablet, 150mg + 400mg / No formulation can be found
Ivermectin / Scored tablet, 3mg, 6mg / No formulation can be found
Levamisole / Tablet 50 mg, 150 mg / Unable to find 150 mg tablet
Lidocaine / Injection for spinal anaesthesia, 5% (hydrochloride) in 2-ml ampoule to be mixed with 7.5% glucose solution / Unable to find
Neomycin sulfate + bacitracin / Ointment 5 mg neomycin sulphate + 500 IU bacitracin zinc/g / Cannot find this formulation.
Neomycin sulfate 3,300 units, bacitracin zinc 250units, l-cysteine 2mg, glycine 10mg, dl-threonine 1mg perg; cream and powder(from BNF + emims)
Nicotinamide / Tablet 50 mg / Unable to cross reference WHO formulation
Nifurtimox / Tablet 30 mg 120 mg 250 mg / Unable to cross reference
WHO formulation
Oxamniquine / Capsule 250 mg, Syrup 250 mg/5 mL / Unable to cross reference WHO formulation
Pentamidine / Tablet 200 mg 300 mg / Unable to find tablet formulation.
Potassium chloride / Powder for oral solution, potassium chloride 1.5g / Unable to find formulation for powder
Potassium ferric hexacyanoferrate
(II) 2H20 (Prussian blue) / Powder for oral administration / Unable to cross reference WHO formulation
Potassium iodide / 1 g/mL (saturated solution) / Unable to find
Praziquantel / Tablet 150 mg / Unable to find
Procaine benzylpenicillin / Injection (powder for solution) 1g vial (1 million IU) 3g vial (3 million IU) / Unable to find
Propranolol / Tablet 20mg, 40mg (Hydrochloride) / BNF/mims Asia - 20 mg tablet not listed. 10 mg is available
Propyliodone / Oily suspension 500-600 mg/mL in 20-mL ampoule / Unable to cross reference formulation
Pyrazinamide / Tablet 400 mg / BNF/mims Asia - 500 mg tablets only. WHO formulary states 500mg not included in model list
Pyridostigmine / Injection 1 mg in 1-mL ampoule / Not found
Rabies immunoglobulin / Injection 150 IU/mL in 2-mL or 10-mL vial / Unable to find
Rifampicin / Capsule or tablet 150 mg, 300 mg / Cannot cross reference tablet formulation
Rifampicin + isoniazid / 60 mg + 30 mg, 150 mg + 75 mg, 60 mg + 60 mg (For intermittent use three times weekly) 150 mg + 150 mg (For intermittent use three times weekly) / Unable to cross reference – BNF and mims Asia
Rifampicin + isoniazid + pyrazinamide / Tablet 60 mg + 30 mg + 150 mg, 150 mg + 150 mg + 150 mg (for intermittent use three times weekly) / Unable to cross reference
Salbutamol / Injection 50 micrograms (as sulfate)/mL in 5-mL ampoule / Hong Kong and Indonesia have a 500 mcg/1 mL in 1-mL amp.
Salicylic acid / Solution 5 % / Unable to cross reference - BNF and mims Asia
Sodium hydrogen carbonate / Injectable solution, 1.4%
isotonic (equivalent to Na+ 167 mmol/l, HCO3- 167 mmol/l) 8.4% solution in 10-ml ampoule (equivalent to Na+ 1000 mmol/l, HCO3-1000 mmol/l) / Unable to cross reference injectable solution 1.4 %isotonic and mmol/l for both formulations
(8.4% solution in 10-ml ampoule is available)
Sodium nitrite / Injection 30 mg/mL in 10-mL ampoule / Cannot cross reference ampoule size.
Sodium thiosulfate / Cutaneous solution 15 % / Unable to cross reference
Stavudine (d4T) / Oral solution (powder for reconstitution) 5 mg/5 mL / BNF and mims Asia have 1mg/1 mL oral solution
Suramin sodium / Powder for injection 1 g in vial / Unable to find formulation
Suxamethonium / Powder for injection (chloride) in vial / Unable to find formulation
Testosterone / Injection (oily) 200 mg (enantate) in 1-mL vial / BNF and mims Asia have 250 mg in 1-mL amp.
Triclabendazole / Tablet 250 mg / Unable to find formulation
Urea / Cream or ointment 10 % / Cannot find ointment formulation
Vancomycin / Powder for injection 250 mg (as hydrochloride) in vial / Unable to find 250 mg formulation. BNF and mims Asia have 500 mg and 1 g formulations
Zinc sulfate / Tablet or syrup in 10 mg per unit dosage form / Are these formulations available yet?

*Resources used for cross referencing included the British National Formulary, mims online (Asia) and the Australian Medicines Handbook