E-drug: WHO practical advice on de-listing of ARVs
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Dear all,
On 1 September WHO issued an information sheet with updated information
on the recent de-listings of five ARVs from the list of prequalified
products. The document also presents practical advice for regulatory
agencies, national programmes, prescribers and patients and describes
the next steps WHO will take. The statement is given below.
With best regards,
Dr Hans V. Hogerzeil
Director a.i.
Department of Essential Drugs and Medicines Policy
WHO Geneva
hogerzeilh@who.int
Removal of Antiretroviral Products from the WHO List of Prequalified
Medicines Information and Guidance for Regulatory Bodies, National AIDS
Programmes, Doctors and Patients
1 September 2004
Department of Essential Drugs and Medicines Policy; Department of
HIV/AIDS
WHO continues to receive many questions on the recent de-listing of five
medicines from its list of prequalified products. Given the importance
of these medicines for patients and for international efforts to scale
up treatment, WHO offers below some clearer explanations for the
decision to delist the products concerned, and advice for regulatory
bodies, national AIDS programme managers, prescribers and patients on
what can be done as a response to this at country level.
WHAT HAS HAPPENED?
In May and July 2004, WHO ran a series of inspections of contract
research organizations and/or laboratories (hereafter: CROs) as part of
its ongoing monitoring of prequalified medicines. The CROs had been
contracted by manufacturers to carry out tests to prove the
bioequivalence of medicines submitted for prequalification, in
accordance with WHO requirements. Bioequivalence tests are clinical
trials conducted in healthy volunteers to find out if the concentration
of a generic medicine in the blood of a patient is equivalent to that of
the originator product. Originally, the data (results) presented to WHO
by the manufacturers did prove
bioequivalence.
During the inspections, one CRO was found to be compliant with
international guidance on Good Clinical Practice and Good Laboratory
Practice in doing these studies. However, two other CROs were not found
compliant because of serious discrepancies between the original results
compiled by the CROs and the results presented to WHO by the
manufacturers.
1. Confirmation of two AIDS medicines' bioequivalence
The CRO which had conducted bioequivalence studies for a triple
fixed-dose combination in two different strengths was found compliant.
These products (one prequalified in December 2003, the other at the same
time as the CRO
inspection) are therefore proven to be bioequivalent and can be used as
alternatives to two of the recently removed medicines. These are:
* lamivudine 150mg plus stavudine 40 mg and nevirapine 200 mg tablet
(Cipla) already on the list
* lamivudine 150mg plus stavudine 30 mg and nevirapine 200 mg tablet
(Cipla) recently added
2. Five HIV/AIDS medicines were removed from the list for lack of proof
of bioequivalence
For five medicines, WHO could no longer accept the report on the
bioequivalence studies provided by the manufacturers. Since proof of
bioequivalence is a condition for prequalification, and in view of the
serious nature of the CROs' non-compliance, two of the products
concerned were removed from the list on 27 May and three others on 4
August. The five products are:
* Lamivudine150mg plus stavudine 30mg and nevirapine 200mg tablet
(Ranbaxy Laboratories Ltd, Dewas, India, Al strip of 10 or 60 in box)
* Lamivudine150mg plus stavudine 40mg and nevirapine 200mg tablet
(Ranbaxy Laboratories Ltd, Dewas, India, Al strip of 10 or 60 in box)
* Lamivudine 150mg plus zidovudine 300mg tablet (Ranbaxy Laboratories
Ltd, Dewas, India, Blister pack of 60 or 100)
* Lamivudine 150mg tablet (Cipla Ltd, Kurkumbh, India, blister pack of
10)
* Lamivudine 150mg plus zidovudine 300mg tablet (Cipla Ltd, Vikhroli,
India, blister pack of 10).
WHAT DOES THE REMOVAL OF THE FIVE MEDICINES MEAN?
WHO is not a supranational regulatory authority. The list of WHO
prequalified products includes medicines which have been evaluated and
approved for procurement by United Nations organizations. That list does
not have any legal status at national level. In countries, the full
responsibility for authorizing marketing and use of medicinal products
in public health programmes rests with the national drug regulatory
authority. The standards used by WHO for prequalification are more
stringent than those applied by many countries. For example, not all
countries legally require in vivo bioequivalence studies (small clinical
trials conducted in healthy
volunteers) for generic drugs; nor do they have stringent requirements
for the quality of active pharmaceutical ingredients.
When deciding on the best course of action, national authorities,
programmes, prescribers and patients should take the following
considerations into account:
* These products may or may not be bioequivalent;
* Interruption of ARV treatment constitutes a serious risk for the
individual and may have negative implications from a public health
perspective.
PRACTICAL IMPLICATIONS FOR NATIONAL DRUG REGULATORY AUTHORITIES
Additional explanation
The five products have been removed because proof of bioequivalence is
missing as a result of non-compliance with good clinical and laboratory
practices. However, they do meet other quality specifications, such as
the active pharmaceutical ingredient purity, stability, and manufacture
in compliance with Good Manufacturing Practices in a state-of-the-art
pharmaceutical plant.
Recommended action
Many national drug regulatory authorities do not require bioequivalence
data to admit generic drugs into their markets. In this case there is no
legal obligation to withdraw marketing authorization for the five drugs
that were removed. In countries where bioequivalence is required, the
national drug regulatory authority should consider one or more of the
following actions:
(1) Request a confidential copy of the inspection report(s) from WHO;
(2) Temporarily waive its requirement of bioequivalence for these
products as an emergency measure, requesting that the manufactures
submit data on new bioequivalence studies within four months (if these
deadlines are not met, consider withdrawing marketing authorization);
(3) Do not release the products in stock for use until further evidence
from new bioequivalence studies becomes available;
(4) Withdraw marketing authorization for the products;
(5) Provide detailed information and advice to programme managers,
prescribers and patients on the best ways to manage the situation
without compromising the goals of treatment programmes.
PRACTICAL IMPLICATIONS FOR PROGRAMME MANAGERS
Additional explanation
In countries where bioequivalence data are not required by the national
drug regulatory authority there is no legal need to withdraw the
products; and even in countries where these data are required, the
authorities may
(temporarily) decide not to withdraw them (see above). In all cases, a
careful balance must be sought between the risks associated with the
lack of proof of bioequivalence in these products and the individual and
public health risk of interrupting treatment should no alternative
medicines be found.
In general, switching to similar antiretrovirals (ARVs) from
alternative, prequalified suppliers would be the most appropriate
response, if and when such products are available. (see Annex 1 below)
However, switching to non-prequalified ARVs is not advised since not
only has their bioequivalence not been confirmed, but, in addition,
other quality aspects have not been verified by WHO.
Recommended action
(1) Consult with the national drug regulatory authority to establish the
best course of action.
(2) Prepare and implement a communication strategy addressed to
prescribers and patients.
(3) Take the necessary measures to switch to alternative prequalified
products (listed in Annex 1 below). In this regard, the following
actions are recommended in specific situations:
(a) The procurement of de-listed drugs is considered, but they have not
yet been ordered. De-listed products should not be ordered. Instead,
other prequalified products should be ordered unless the de-listed
medicines are reinstated on WHO's list of prequalified products.
b) De-listed drugs have been ordered to continue or scale up treatment
programmes. De-listed drugs that have been ordered, but not received,
should not be accepted. In this case, alternative prequalified products
should be ordered instead. However, if alternative suppliers are not
immediately available and the non-acceptance of the ordered products
could lead to an inability to continue or to start treating patients,
the risk of withholding treatment is higher than that of providing
medicines whose bioequivalence is not proven but which have, otherwise,
been prequalified. In this case it would be justified to accept and use
the de-listed products. For follow-up orders, only prequalified products
should be used.
PRACTICAL IMPLICATIONS FOR PRESCRIBERS AND PATIENTS
In principle, patients should discontinue using de-listed medicines and
switch to other prequalified products (see Annex 1). However, in many
cases it will be difficult to find alternative prequalified products
immediately. In this situation it is recommended that patients continue
to use de-listed products, as the risk of interrupting treatment is
higher than that of taking medicines whose bioequivalence is not proven
but which have otherwise been prequalified. A switch to non-prequalified
products is not recommended as their quality has not been documented by
WHO.
The patient should be informed that there is no reason to believe
continued use of the de-listed products is dangerous, and that
suspending the treatment or switching to alternative ARVs whose quality
has not been assured is far riskier.
NEXT STEPS
Next steps by the manufacturers
The manufacturers have indicated that they will resubmit the products in
question to a different laboratory for new bioequivalence studies. If
and when those products and the laboratory meet the specified
requirements, WHO will reinstate them in its list of prequalified
medicines.
Next steps by WHO
* WHO will make available to national drug regulatory authorities,
upon request and under confidential cover, the inspection reports on the
de-listed products.
* As soon as new bioequivalence data of the de-listed products
have
been received WHO will arrange for immediate data assessment and site
inspections, to minimize administrative delays in the potential
re-listing of the products.
* WHO will send a letter to all manufacturers of prequalified
products, asking them to take all necessary measures to ensure that the
data submitted to WHO are correct and complete, and to check that CROs
have followed the appropriate standards.
* As a matter of urgency, WHO will inspect all other CROs which
have
conducted bioequivalence studies for prequalified products, starting
with priority medicines.
* For new applications, WHO will introduce inspections of CROs and
laboratories for compliance with Good Clinical Practice and Good
Laboratory Practice as a prerequisite for prequalification.
* WHO will also start a programme of inspections of manufacturers
of
Active Pharmaceutical Ingredients (raw materials), with an initial focus
on antiretrovirals.
FREQUENTLY ASKED QUESTIONS
How is it possible that these de-listed products had been prequalified
at all?
Up to now the assessment of bioequivalence data (supplied by the
manufacturer) was part of the standard procedure for prequalification;
regular on-site inspection of the CROs where the bioequivalence studies
were done was not. This reflected common practice in many national Drug
Regulatory authorities. On 1 May 2004, European Commission Directive
2001/10/EC came into force, demanding that countries carry out such
inspections. Given WHO's commitment to the highest standards, the EC
Directive prompted inspections of the CROs carrying out bioequivalence
studies (starting with products for priority diseases), which ultimately
led to the de-listing of the above five products.
What does it mean for the other products on the list?
All products on the list have been assessed through: evaluation
of data in the product dossiers on efficacy, safety, quality and
bioequivalence; inspection of manufacturing sites for compliance with
good manufacturing practices; and testing of product samples at
independent laboratories for compliance with product specifications. In
line with the European Directive of 1 May 2004, good clinical and
laboratory practices inspections are now being included in the
requirements. For example, a recent inspection at the CRO which did the
bioequivalence studies for two different strengths of Cipla's triple
combination revealed that good clinical and laboratory practices had
been followed and that these products (one prequalified in December 2003
and the other in August 2004) are therefore bioequivalent with the
originator medicines.
Many national Drug Regulatory authorities do, from time to time,
withdraw a registered product. This does not mean that the original
registration was unjustified, but that the verification system is
rigorous and that the efficacy, safety and quality of registered
products continue to be checked after initial registration.
Further Information
Statements on the removal of products can be found at:
http://www.who.int/mediacentre/news/releases/2004/pr53/en/
http://www.who.int/mediacentre/news/statements/2004/statement_aidsprequa
l/en
More information on the prequalification project, including a full list
of WHO prequalified products, is available at
http://mednet3.who.int/prequal/
Price information is available from WHO at
http://www.who.int/medicines/organization/par/ipc/s&pScreen/S&Pscreen.pd
f
from MSF at http://www.accessmed-msf.org/documents/untanglingtheweb6.pdf
For more information please contact:
For technical and regulatory issues: Andr� van Zyl, Scientist, Tel:
+41 22 7913598, Mobile: +41 79 4755527; email: vanzyla@who.int
For clinical and treatment issues: Jos Perriens, Director AIDS Medicines
and Diagnostics Service, HIV/AIDS Department, tel +41 22 79134456,
Mobile +41 79 2173422; email: perriensj who.int
For media enquiries: Daniela Bagozzi, Communications Officer, Tel.
+41 22 7914544, mobile: +41 79 4755490, email: mailto:bagozzid@who.int
ANNEX 1:
ALTERNATIVE PREQUALIFIED MEDICINES AND SUPPLIERS
* Lamivudine 150 mg plus zidovudine 300 mg tablet (GSK), blister (60),
bottle (60)
* Lamivudine 150 mg plus zidovudine 300 mg tablet (Hetero), blister
(10), bottle (60)
* Lamivudine 150mg plus stavudine 40 mg and nevirapine 200 mg tablet
(CIPLA), bottle (60)
* Lamivudine 150mg plus stavudine 30 mg and nevirapine 200 mg tablet
(CIPLA), bottle (60)
* Lamivudine 150 mg tablet (GSK), 10 mg/ml oral solution (GSK), bottle
(60) and bottle (240 ml), respectively
* Lamivudine 150 mg tablet (Hetero), blister (10), bottle (60)
* Lamivudine 150 mg tablet (Strides), blister (10), bottle (60)
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