Download Review of `square boxes`

Agenda Item 8: Review of ‘square boxes’
Text and tables prepared by Dr Sue Hill and reviewed by Dr Leo Offerhaus
Background
In the 2002 Model List there are 113 medicines that are marked with a ‘square box’. The current
statement in the preamble to the Model List regarding the use of a ‘square box’ is:
“The square box symbol indicates that a listed medicine should be seen as a
representative example from a group of clinically equivalent medicines with wide
experience of use, within a pharmacological class. The medicines listed on the Model List
would generally be the least costly therapeutic equivalent within the group. National lists
should not use a similar symbol and should be specific in their final selection, which
would depend on local availability and price.”
In the Expert Committee meeting in 2002 it was considered that there was some confusion and
inconsistency about the way this symbol has been used. For example, neostigmine is listed with a
square box yet there is no pharmacological equivalent; several different corticosteroids are on the
list and some are marked with boxes for some purposes while others are not; in some instances
adrenaline (epinephrine) is marked with a box yet there is no pharmacological or therapeutic
equivalent.
The purpose of this review is therefore to consider the medicines currently marked with square
boxes and to make recommendations about changes needed. In doing so, it is first necessary to
redefine the meaning of the square box symbol.
Equivalence and interchangeability
When considering medicines, there are three possible ways of defining ‘equivalence’ and
‘interchangeability’.
The first definition is based on the active chemical compound. This definition is generic
equivalence and interchangeability, where products that contain the same chemical compound are
interchangeable, e.g. all oral products that contain 20mg fluoxetine. Generic substitution is
assumed to be acceptable for the Model List as the list is constructed by chemical compound, not
brand.
It is recommended that for the Model EML, square boxes should not be used to indicate
substances for which there are known to be multiple suppliers of acceptable generic products.
Whilst this may be useful information, a different ‘tagging’ system should be used so as to avoid
confusion.
The second level of interchangeability is at the level of pharmacological class, eg ACE inhibitors.
There are a number of papers describing the debate about ‘class effects’ of medicines and
whether efficacy and safety can be assumed to be interchangeable throughout a class of drugs. It
is fair to say that the debate has not been concluded. There is some evidence that efficacy can be
assumed across a class of drugs if equipotent doses of the drugs can be established, but that safety
can not necessarily be generalised in the same way. From a policy point of view, it can be useful
to define pharmacological groups that are deemed to be equivalent on the basis of the best
comparative evidence and then to set prices accordingly.
It is recommended that for the Model List the ‘square box’ symbol should be used primarily to
indicate equivalence on the basis of pharmacological class. The listed medicine should be the
example of the class for which there is the best evidence for effectiveness and safety. In some
cases, this may be the first medicine that is licensed for marketing; in other instances,
subsequently licensed compounds may be safer or more effective. Where there is no difference in
terms of efficacy and safety data, the listed medicine should be the one that is generally available
at the lowest price (based on international drug price information sources).
The third possible definition of equivalence and interchangeability is based on therapeutic
indication. Determining therapeutic equivalence is complex. An example would be to suggest that
all classes of drugs used to treat hypertension are therapeutically interchangeable, a suggestion
that has been hotly debated. Defining ‘therapeutic groups’ of medicines for specific indications
requires comprehensive reviews of the clinical data on comparative effectiveness and safety, and
can be the subject of considerable controversy.
It is recommended that the Model List use the ‘square box’ to suggest therapeutic equivalence
and interchangeability but only where this recommendation is made on the basis of reviews of
efficacy and safety and is consistent with standard treatment guidelines for the indication (e.g.
hypertension).
Methods used in this review
As noted in the introduction, the Model List currently has ‘boxed’ medicines that indicate
equivalence according to any of the three definitions described above. This is confusing and
inconsistent. There are also examples of ‘boxed’ medicines where there is no equivalent in
chemical, pharmacological or therapeutic terms – eg aminophylline and ethanol.
For this review, therefore, the approach that has been taken has been to use ‘boxes’ on the basis
of a combination of the second and third definitions of interchangeability. There must be an
alternative available in the same pharmacological class (mandatory criterion) and where evidence
exists, therapeutic interchangeability has been considered as the second criterion.
In doing the review the following principles have been used:
1. For any medicine where there is not at least one other member of its pharmacological class
(listed in standard references Goodman and Gilman, Martindale) in clinical use, it is
recommended that the square box should be removed. Examples are pilocarpine eye drops;
ethanol as a disinfectant, chlorhexidine as a disinfectant, chloroquine as an antimalarial.
2. In some cases a recommendation is made to maintain the square box but to change the listed
medicine. This is done when there is an alternative drug in the class which is either available
as a generic product, or with better evidence for efficacy and safety (using the above
references plus the Cochrane Database of Systematic reviews), or with a more convenient
dosage regimen (and equivalent efficacy and safety data), or which is generally cheaper.
All medicines with a square box in the Model List of 2002 are listed in the attached table. For
each medicine, the following information is given:
(1) A description of the pharmacological class, using standard chemical and therapeutic
descriptive terms based on UK/North American/Australian terminology and references
(2) The indication for which it is currently listed on the Model List, or the section title
(3) Pharmacologically equivalent medicines. Where there are many members of the class, a
selection of commonly available alternatives are listed
(4) Potential therapeutic alternatives, where these exist
(5) Remarks and recommendations by Dr Sue Hill
(6) Remarks and recommendations by a second reviewer, Dr Leo Offerhaus
(7) WHO Secretariat recommendations to keep/change/delete the square box, and on the need for
further review, indicating the estimated scope (update, new, complex review), and the level of
priority (low, medium, high).
The colour codes in the table indicate the following:
Blue: the two reviewers do not (fully) agree
Yellow: recommendation to keep the square box, but list for review
Red: recommendation to delete the box, and/or list the medicine for deletion from the Model List
Observations:
Based on this work, it appears that there are a number of sections of the list that should be
reviewed. These are anaesthetics, dermatological agents, antiseptics and disinfectants, antibiotics,
contrast agents and ophthalmic medicines.
Specific questions that have been identified for possible review include:
(1) Substitution of SSRIs for tricyclic antidepressants
(2) Comparative efficacy and safety of anti-Parkinsonian agents
There are some sections that need further review to resolve inconsistencies. These are
(1) Estrogens and oral contraceptives
(2) Anaphylaxis section –currently has four corticosteroids listed
(3) Corticosteroids as a class – four listed for anaphylaxis, one for asthma, one for topical use
WHO Secretariat recommendation to the Expert Committee
(1) Review and endorse the following adapted description for the use of the square box, for
inclusion in the Annex of the Expert Committee report and the Introduction to the Model
List:
“The square box symbol indicates that a listed medicine should be seen as a
representative example from a group of clinically equivalent medicines within a
pharmacological class. The medicine listed on the Model List would generally be one for
which there is the best evidence for effectiveness and safety in a variety of settings.
When there is no difference in terms efficacy and safety data, the listed medicine is the
one that is generally available at the lowest price. Therapeutic equivalence is only
indicated on the basis of reviews of efficacy and safety and when consistent with WHO
clinical guidelines. National lists should not use a similar symbol and should be specific
in their final selection, which would depend on local availability and price.”
(2) Review and endorse the listed pharmacological and therapeutic alternatives
(3) Review and endorse the proposed changes (keep, change, delete the square box)
(4) Review and endorse the list of questions for review, and assign an order of priority. The
recommendations for review can be summarized as follows:
Priority:
Update of review
High
Amitriptyline
Antihypertensives
Oral estrogens
Simple review
Complex review
Propyliodone
Medium
Ergometrine
Oncology medicines
Polygeline
Ergocalciferol
Fluconazole
Mannitol
Propranolol in migraine
Procainamide
Quinidine
Sulfadiazine
Sulfameth/trimethoprim
Alcuronium
Amidotrizoate
Amoxicillin/clav.acid
Benzyl benzoate
Betamethasone oint
Bupivacaine
Chlorine compound
Radiocontrast media
Low
Chlorphenamine
Promethazine
Amiloride
Biperiden
Calamine lotion
Dextran 70
Ergocalciferol
Iodoxuridine
Podophylline
Senna
Corticosteroids
Antitetanus imm.gl.
Sodium lactate