[e-drug] detailed communication re new WHO EDL

[andy@healthlink.org.za]

E-DRUG: detailed communication re new WHO EDL
--------------------------------------------------------------
[from our sister list DRUGINFO in South Africa. Thanks, Andy,
for that review! WB]

Hi all

The summary of recommendations from the newly named Expert Committee on
the Selection and Use of Essential Medicines can be accessed at
http://www.who.int/medicines/organization/par/edl/expertrecommend.shtml
- some of the changes include:

* a broader recommendation regarding the inclusion of combination
products - "Most essential medicines should be formulated as single
compounds. Fixed dose combination products are selected only when the
combination has a proven advantage in therapeutic effect, safety,
adherence or in delaying the development of drug resistance in malaria,
tuberculosis and HIV/AIDS."

* setting priorities for review, including this: "The section on
antihypertensive drugs should be reviewed as soon as the new WHO/ISH
treatment guidelines are available. In the light of this review other
medicines on the Model List such as reserpine, methyldopa, hydralazine
and nifedipine should also be reviewed. "

* changing the presentation of the list - "in addition to its usual
presentation the printed version of the Model Lists should also be
presented in the 5-level Anatomical Therapeutic Chemical (ATC)
classification."

The 12th Model EDL, which "contains 325 active substances which include
12 ARVs and over 60 other essential medicines for HIV-related care,
including drugs against opportunistic infections", is presented in three
parts:
-the core EDL can be accessed at
http://www.who.int/medicines/organization/par/edl/edl2002core.doc,
- a complementary list ("The complementary list presents essential
medicines for priority diseases which are efficacious, safe and
cost-effective but not necessarily affordable, or for which specialised
health care facilities or services may be needed") at
http://www.who.int/medicines/organization/par/edl/edl2002complement.doc,
and
- a separate listing of the antivirals (also in the core list) at
http://www.who.int/medicines/organization/par/edl/edl2002antivirals.doc

In addition, the EBM web site also has these extensive notes (in full
below, with links to the sources added) that accompany the decisions.
Altogether a most impressive and timeous set of documentation.

regards
Andy
~~~

http://www.who.int/medicines/organization/par/edl/expertnotes.shtml
12th Expert Committee on the Selection and Use of Essential Medicines
Meeting, 15-19 April 2002

** Notes on the inclusion of new items on the Model List

Antiretroviral drugs

The Expert Committee reviewed written submissions containing
information on 12 anti-retroviral drugs from the HIV/AIDS Department of
the World Health Organisation for inclusion on the Model List. All of
the proposed drugs are included as antiretroviral drug combinations
recommended in the new WHO treatment guidelines for antiretroviral
treatment in resource-poor settings2.

The written submissions comprised summaries of the evidence related to
the clinical benefits, adverse effects, practical details of treatment,
and comparisons with other members of their drug class. The clinical
evidence had been assembled from comprehensive literature reviews for
each drug and drug combination, several of which were conducted by staff
working for the Cochrane Collaboration. The submissions also provided a
summary of background information on the public health impact of HIV
infection world-wide, the overall impact of anti-retroviral therapy on
the course of illness in HIV-infected subjects, the value of surrogate
markers as measures of treatment response, and a summary of the
experience and impacts of delivering anti-retroviral therapy in
resource-limited settings3.

The meeting commenced with a series of oral presentations from staff in
the HIV/AIDS and EDM departments of the WHO. These presentations
included summaries of the submitted written material, a history of the
development of WHO guidelines for use of ARVs in resource-limited
settings, and a description of the experiences of the use of ARVs in
some developing countries. The logic behind the selection of first line
and alternative regimens, and the development of appropriate criteria
for case selection and minimum standards for monitoring treatment
response and toxicity were of particular interest and concern to the
Expert Committee.

Having considered the data, the expert committee agreed that there was
substantial evidence supporting the claims of efficacy for ARV
combinations comprising at least three drugs. Typically, these
combinations include two nucleoside reverse transcriptase inhibitors
(NRTIs) in combination with either a non-nucleoside reverse
transcriptase inhibitors (NNRTI), or a third NRTI, or a protease
inhibitor. It was considered that there was convincing evidence from
meta-analyses of randomized clinical trials, and from large well
conducted cohort studies, that combination ARV treatment reduces
mortality substantially. The committee accepted the validity of
surrogate markers (CD4 cell counts and viral load estimates), which have
been used in the majority of clinical trials of these agents. The
survival gains were not off-set by severe adverse effects; consequently,
effective treatment leads to large absolute reductions in mortality, and
restoration of a worthwhile quality of life. However, highly active
anti-retroviral therapy is not a cure for the disease and long-term
suppressive therapy is necessary.

There were a number of issues of general concern to the Committee.
These were the need for listing of what was seen to be a large number of
drugs, the safety and efficacy of therapy when delivered with the
minimal levels of laboratory monitoring advocated in the WHO treatment
guidelines, the advantages and disadvantages of fixed dose combinations
and the specific toxicity of certain agents (see consideration of
specific drug classes for the latter).

The issue of the number of drugs proposed for listing was addressed by
staff from the HIV/AIDS department of the WHO. While accepting that
there were many circumstances in medicine where one essential drug may
substitute easily for other members of a class, thus allowing the
placement of a single agent on the Model List (with appropriate advice
about substitution), this was not possible with HIV treatment. Effective
therapy requires commencement of three drugs simultaneously, and
alternative regimens are necessary to meet specific requirements at
start-up, to substitute for first-line regimens in the case of toxicity,
or to replace failing regimens. The committee considered various
approaches to the listing of these agents but agreed finally that if
they were to be listed, all drugs recommended should be included in the
Model List.

The availability of adequate laboratory monitoring of anti-retroviral
therapy was a particular concern of several members of the committee.
The new WHO ARV guidelines appear to allow a low level of monitoring,
which can be provided at basically equipped health facilities. This
raises questions about the safety of ARV therapy, the failure to
recognize drug toxicity and failure of regimens, which may in turn lead
to viral resistance. It was noted that there have not been large field
studies demonstrating the efficacy and safety of ARV therapy provided
under such circumstances. Discussion and debate on these issues was
extensive. In the end, there was a consensus within the Expert Committee
that the treatment guidelines regarding case selection and monitoring
should be accepted. However, it was recommended by the Committee that:
the issues discussed should be reviewed at its next meeting, that
suitable footnotes should be added to specific drugs in the Model List,
and that relevant organizations should be strongly encouraged to fund
field trials of low level monitoring of ARV treatments.

The Committee also supported the proposal that CD4 count laboratory
facilities be made more widely available and encouraged the Global Fund
to support the provision of such services.

There was also discussion regarding the advantages and disadvantages of
fixed dose combinations of ARV drugs. The principal advantage is the
improved adherence with treatment due to simplifications of regimens.
This in turn should result in higher levels of efficacy and lower rates
of viral resistance. The main disadvantages are inflexibility in dosing,
and doubts about the pharmaceutical quality of fixed-dose combination
products that are produced in the absence of strict regulatory and
quality standards. Generally, the Committee favoured the increased
availability of assured quality fixed dose combination products,
incorporating suitable doses of appropriate drug combinations. It was
noted that, at present, only a limited number of such combinations are
available internationally. However, there is likely to be increased
availability of fixed dose combinations in future from a range of
manufacturers and it is hoped that relevant products will quickly be
tested under the WHO's prequalification program.

Following these discussions the Expert Committee moved onto a
consideration of the ARV drugs proposed for listing by the HIV/AIDS
Department of the WHO.

In considering each application the Committee considered the
following:
- Applications for each medicine, some of which had been available on
the WHO web site
- Additional written material from external stakeholders
- Oral presentations (also provided in hard copy) by staff from WHO and
UNAIDS.

In general terms, evidence in the applications was described according
to the following classification:
Level 1: Evidence from relevant high quality systematic reviews of
unbiased randomised comparative clinical trials
Level 2: Evidence from at least one relevant unbiased randomised
comparative clinical trial
Level 3: Evidence from relevant controlled observational studies.

There was discussion as to whether listing of these drugs should be on
the core or complementary sections of the Model List. Complementary
listing could be used to signal that experience to date of their use in
resource-poor settings was limited. However, while accepting concerns
about the problems of limited laboratory monitoring, the Committee
considered that core listing was appropriate with the addition of
suitable footnotes. It was felt that complementary listing would be
inconsistent with previous decisions regarding drugs that require
monitoring and the decision might be used inappropriately as an argument
against the wider access to ARV drugs.

It was noted that the most recent draft of the ARV guidelines
recommended the use of total lymphocyte count as a surrogate for CD4
count only for HIV-infected individuals who were, or had been,
symptomatic. It was requested that the permanent copies of the
submissions for ARV drugs be amended to reflect this.

After discussion, the Committee recommended to include the following
medicines on the core list: the nucleoside reverse transcriptase
inhibitors zidovudine (ZDV or AZT), lamivudine (3TC), stavudine (d4T),
didanosine (ddI) and abacavir (ABC); the non-nucleoside reverse
transcriptase inhibitors nevirapine (NVP) and efavirenz (EFV or EFZ);
and the protease inhibitors indinavir (IDV), lopinavir/low dose
ritonavir (LPV/r), nelfinavir (NFV), ritonavir (r), and saquinavir
(SQV).

The committee also requested that the following footnotes be added to
the Model List:

"The antiretroviral drugs do not cure the HIV infection, they only
temporarily suppress viral replication and improve symptoms. They have
various adverse effects and patients receiving these drugs require
careful monitoring by adequately trained health professionals. For these
reasons, continued rigorous promotion of measures to prevent new
infections is essential and the need for this has not been diminished in
any way by the addition of antiretroviral drugs to the Model List.
Adequate resources and trained health professionals are a prerequisite
for the introduction of this class of drugs. Effective therapy requires
commencement of three or four drugs simultaneously, and alternative
regimens are necessary to meet specific requirements at start-up, to
substitute for first-line regimens in the case of toxicity, or to
replace failing regimens. The Committee strongly recommends the use of
three- or four-drug combinations as specifically recommended in the WHO
treatment guidelines. The use of fixed dose preparations for these
combinations is also recommended, with assured pharmaceutical quality
and interchangeability with the single products as approved by the
relevant drug regulatory authority."

"Selection of two or three protease inhibitors from the Model List will
need to be determined by each country after consideration of local
treatment guidelines and experience, as well as the comparative costs of
available products. Ritonavir is used in combination with indinavir,
lopinavir and ritonavir as a booster, and not as a drug in its own
right."

Fixed combination of artemether and lumefantrine

The first application for the inclusion of artemether/lumefantrine in
the WHO Model List of Essential Drugs was reviewed by the Expert
Committee on Essential Drugs in 1999 (WHO, 2000a). The Committee
considered that the combination had the potential to play an important
role in the management of uncomplicated falciparum malaria but that it
was not appropriate at that time to include it in the WHO Model List of
Essential Drugs since (i) there was no data on operational use of the
combination; (ii) the Company proposed two dosage regimens to be used in
non-immune and semi-immune patients which was might lead to confusion;
(iii) there were concerns regarding the degree of compliance that may be
obtained in rural health settings with a drug combination that required
a relatively long and complex treatment regimen (i.e. 6 doses over 60
hrs); and (v) the affordability of the combination for populations in
greatest need.

The Committee then considered the revised application4. The Committee
noted that the prevalence of drug resistant falciparum malaria has
increased so that, in some countries, resistance to all of the available
antimalarial drugs, except artemisinin and its derivatives, exists. For
patients with falciparum malaria resistant to chloroquine, sulfadoxine/
pyrimethamine, mefloquine and quinine, the use of artemisinin and its
derivatives is essential.

The Committee also appreciated the differential pricing arrangement
that has been made with the company, leading to a long-standing
arrangement for a differential price for developing countries (when
compared to developed countries) as well as an agreed price differential
within developing countries between the private sector and the public
and not-for-profit health care systems. The three markets are separated
by different product names and packages.

The Committee noted that the recommendation to use artemisinin
combinations would, in the medium term, require a review of the need to
maintain single artemisinin derivatives on the Model List; but concluded
that it was too early to delete these immediately. In the mean time it
recommended that single artemisinin and its derivatives would be
reserved for severe malaria when there is resistance to quinine.

Despite the absence of detailed clinical data on the use of artemether
and lumefantrine in children below 10 kg and the limited data on use in
pregnancy, the Committee recommended the inclusion of
artemether/lumefantrine on the core list of the Model List of Essential
Drugs, with the following footnote: "Recommended for use in areas with
significant drug resistance and not in pregnancy or in children below 10
kg".

The Committee encouraged the development of more fixed-dose
combinations of artemisinin and long-acting antimalarial medicines for
future comparative review.


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-----

2 Scaling up antiretroviral therapy in resource-limited settings:
guidelines for a public-health approach. Geneva: World Health
Organization, April 2002 (in print) -
http://www.who.int/HIV_AIDS/HIV_AIDS_Care/Executive%20sum-April22v3.pdf

3 See Applications for antiretroviral medicines -
http://www.who.int/medicines/organization/par/edl/arvs_submissions.shtml

4 See Application for artemether + lumefantrine -
http://www.who.int/medicines/organization/par/edl/coartem.doc

 Last update:22-Apr-2002



~~~~~~~~~~~~~~~~~~~
Andy Gray MSc(Pharm) FPS
Senior Lecturer
Dept of Experimental and Clinical Pharmacology
Nelson R Mandela School of Medicine
PBag 7 Congella 4013
South Africa
Tel: +27-31-2604334/4298 Fax: +27-31-2604338
email: graya1@nu.ac.za or andy@healthlink.org.za


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