E-DRUG: Post Prequalification Rigor at the WHO
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[On 27 May, WHO removed 2 generic ARVs of CIPLA from the list of
pre-qualified products, as an inspection had found that the bio-studies had
not been done under 100% GLP as required. The NY Times came with the story
on 16 June, and interviewed Lembit Rago (head of WHO/QSM, responsible for
the prequalification project. Cipla has withdrawn the products and
resubmitted them to another CRO for another bio-equivalence study. Although
problematic for countries/projects using the LMV 150mg or LMV 150/AZT 300
tablets, other prequalified products are available, and it shows that the
WHO prequalification project is strict as it should be. Industry lobbyists
have tried to misuse this opportunity to attack generic companies and WHO
PQ, but that is not justified. Similar CRO problems have been noted in
Europe and USA. Below an activist perspective, the NY Times article with the
QSM interview, the Cipla response and the original WHO statement. Copied as
fair use. Sorry, long message. WB]
---
Brook Baker, Health Gap at IP-Health
Post Prequalification Rigor at the WHO
Brook K. Baker, Health GAP
June 16, 2004
The New York Times reports today (Altman and McNeil, U.N. Agency Drops 2
Drugs for AIDS Care Worldwide) that two generic antiretrovirals produced by
Cipla of India, namely lamivudine (4TC) 150 mg tablets and the fixed-dose
combination of lamivudine and zidovudine (AZT) have been removed from the
WHO list of prequalified medicines. Cipla had commissioned a Contract
Research Organization (CRO) in India to conducts its bioequivalence test on
these two products, and a subsequent review by the WHO found that the CRO's
documents did not meeting the standards for Good Clinical Practices and
Good Laboratory Practices. Although it is quite likely that Cipla's
products are in fact bioequivalent to their brand name counterparts (one of
them has been separately approved by the FDA), the WHO suspended
prequalification until Cipla resubmits new data, which it intends to do by
the end of July.
Although the U.S. and its think-tank proxies might try to argue that
suspension confirms concerns about the rigor of the WHO Prequalification
Project, the opposite is true. WHO conducted inspections of the
independent testing lab, decertified products when the lab's record-keeping
was substandard, and notified the relevant public via its website. This is
evidence of a global public health agency that takes its mandate seriously.
Similarly, this is not a wholesale indictment of the quality, safety, and
efficacy of Cipla's ARVs or of other Indian generic products, but rather
the importance of dotting every "i" twice when selecting subcontractors for
laboratory services. Cipla has many other products which are still
prequalified at the WHO based on unquestioned bioequivalence studies
analyzed at other labs, including Cipla's WHO-recommended triple-fixed
dose-combination, Triomune. Moreover, one of the products temporarily
suspending, lamivudine, has received tentative approval from the FDA based
on alternative bioequivalence studies conducted in the U.S. Likewise, ARVs
from two other Indian companies, Hetero and Rambaxy, are still on the WHO
list. Thus, generic ARVs can continue to provide standard quality
medicines at the lowest cost and should be procured accordingly
Both of the challenged medicines are still registered by national drug
regulatory agencies in many developing countries and thus may still be
lawfully prescribed for in-country use. Nonetheless, careful health
providers may temporarily suspend product use until the medicines are
re-listed at the WHO, so long as therapeutically equivalent products are
available and patient treatment is not interrupted. Similarly, delisting
does not automatically require a change of medicines for projects receiving
funding from the Global Fund to Fight AIDS, TB, and Malaria, but would do
so as of Jan. 1, 2005.
Although substandard procedures and record-keeping at CROs is regrettable,
it happens in the U.S. as well as at the WHO, and it has affected brandname
as well as generic drugs. The lapse here seems to have been innocent
enough, but in other contexts drug companies developing high-stakes
innovative products have been known to cook the books. Thus, in a
companion article in the Times today, the American Medical Association has
joined other medical groups in calling for dissemination of information
concerning all clinical trials, including those with unfavorable results.
In this regard, GlaxoSmithKline, the world's major producer of proprietary
HIV medicines, has just been sued in New York for having failed to publish
reports on concerning adverse effects in clinical trials, including suicide
among adolescents taking its anti-depressant, paroxetine. Paroxetine
generated $533 million dollars in sales in the first quarter of 2004 alone,
showing just how profitable monopoly-priced, patent-protected can be.
-----
NY Times article
http://www.nytimes.com/2004/06/16/health/16aids.html
June 16, 2004
U.N. Agency Drops 2 Drugs for AIDS Care Worldwide
By LAWRENCE K. ALTMAN and DONALD G. MCNEIL Jr.
he World Health Organization has pulled two generic antiretroviral drugs
from its list of approved H.I.V. drugs that are most often used in poor
countries, saying a routine check found the manufacturer had not proved
that they were biologically equivalent to patented drugs.
It is the first time that W.H.O. has removed any H.I.V. drug from its
list, Lembit Rago, an official of the Geneva-based agency, said yesterday.
Dr. Rago said the problem was found during routine tests that the agency
conducts among drugs it finds acceptable for procurement by United Nations
agencies. But, he said, the problem was not expected to interfere with
W.H.O.'s initiative to treat three million H.I.V.-infected people, mostly
in Africa, by next year.
Cipla, an Indian company that has been in the forefront of getting generic
drugs approved for use in poor countries, made the two generic drugs,
lamivudine, which is also known as 3TC, and zidovudine, which is also
known as AZT.
The action follows the Bush administration's recent announcement of a
significant shift in its AIDS policy to allow the purchase of cheaper
generic drugs for Africa and the Caribbean. Cipla said the situation was
"on the mend" and that it expected its drugs to be put back on the list
within a matter of weeks.
The problem was detected during an inspection of an independent laboratory
that Cipla had hired to conduct bioequivalence studies among volunteers
whose blood had been tested after they took the generic drugs. The tests
were devised to determine whether the concentration of the generic drug in
the blood was the same as in its patented counterpart. Dr. Rago did not
provide the name of the company that did the testing.
A review found that the company's documents did not meet the standards
known as good clinical and laboratory practice, Dr. Rago said in a
telephone interview from Washington, where he was attending a meeting.
Despite the inspection's findings, the generic drugs may be bioequivalent
to the patented drugs. But W.H.O. had to remove them because the
documentation was lacking, Dr. Rago said.
Inspections have found similar problems with the bioequivalency of many
drugs in countries in Europe and the United States, Dr. Rago said. He also
said many developing countries do not require bioequivalency testing.
Cipla's chairman, Dr. Yusuf K. Hamied, said the problem was due to
inadequate record keeping in the testing laboratory in Bombay. Dr. Hamied,
reached by telephone in London, said that Cipla's lamivudine has been
tested for bioequivalency in a laboratory in the United States and
approved by the Food and Drug Administration and that he would submit that
data to the health agency.
Dr. Hamied said the testing was done for the American drug agency because
Cipla hopes to sell generic lamivudine when an American patent expires in
2006.
W.H.O. did not issue a news release about the problem after it was
detected in May. Dr. Rago said such an announcement was not necessary
because his agency had informed other United Nations agencies about the
problem and had posted the delisting on its Web site, www.who.int.
GlaxoSmithKline of Britain holds the American patents on lamivudine (3TC)
and zidovudine (AZT).
---
CIPLA response
June 16, 2004
I was asked to post the following statement from Cipla concerning
the media report that two ARV products being withdrawn from the WHO
qualification list.
Cipla was unable to respond last night because the Hudson Institute
began to solicit media after corporate Cipla in Mumbai, India had closed
for the day. Dr. Amar Lulla, Cipla's Managing Director has been
responding to NGOs and UN agencies about the status of the revalidation
of two ARV singles, Lamivudine (3TC) and zidovudine (AZT). *
Here are the facts:
Three years ago, in accordance with regulatory requirements, Cipla
submitted the two above mentioned products to a CRO (Contract Research
Organization) for investigation. The CRO report ... the bio study ...
indicated no problems when compared to the European versions of these
products. In the intervening years, several international regulatory
authorities visited the CRO and from what can be determine found their
procedures were in accordance with international requirements. The CRO
serviced a number of companies.
In a routine and intimate follow-up inquiry by WHO and Cipla, it was
discovered that the necessary back-up documentation at the CRO did not
meet accepted standards.
Cipla immediately and voluntarily withdrew the products and resubmitted
them to another CRO for investigation. In accordance with its
requirements and standards, WHO removed the two products from their
prequalification list until the new data is received and evaluated. This
information was published on the WHO web site leading to a number of
inquiries to Cipla which were expeditiously answered.
Independently, one of the two Cipla products, Lamivudine, using FDA
standards and requirements, was successfully evaluated against the brand
product marketed in the United States. Cipla asked for and received
permission to submit this information to WHO.
There has never been any question with regard to the quality of the two
products or Cipla's facilities.
Cipla conducts approximately thirty or more bioequivalence studies a
year in CROs in India and elsewhere in the world.
What follows is /_not_/ offered in explanation of the current
situation but is noted to provide context:
"While bio studies are monitored at critical time points it is
physically impossible to check every detail either in India or anywhere
else in the world. The CRO in question is certified for GCP and GLP by
various international agencies. From time to time there are instances of
bioequivalence centers not meeting or being inadequate in their
documentation and record keeping. For example, last year a CRO in
Switzerland was found to be inadequate and a number of licenses for a
product were canceled in Europe. /_However, there is no denial that the
responsibility for a biostudy rests with the sponsor, in this case
Cipla."_/
Finally:
Cipla stands by the quality, safety and effectiveness of these two
products and is committed to completing the biostudies in the shortest
time possible and looks forward to having them restored to the WHO
qualification list. Those who doubt WHO's qualification procedures and
follow-through should take heart at this unfortunate development.*
As has been reported, these two WHO qualified products are available
from other sources so no lag in the supply chain exists.*
This clarification came from Dr. Amar Lulla, Managing Director of Cipla
who is available to interested media and other parties at
91-222-307-0385 (Cipla, Mumbai).
Thanks for listening.
---
WHO announcement (http://mednet3.who.int/prequal/hiv/hiv_suppliers.pdf)
15th edition 27 May 2004
H043. Lamivudine 150mg tablet. Cipla Ltd, Kurkumbh, India. Blister 10.
Removed from the list as a result of the outcome of an inspection performed
by the World Health
Organization (WHO) in which compliance with Good Clinical Practices (GCP)
and Good Laboratory
Practices (GLP) was assessed, as well as data verification of the
bioequivalence study at the Contract
Research Organization (CRO) used by the sponsor. Products are subject to
re-assessment when a
complete new data set is presented about the bioequivalence studies.
H060. Lamivudine 150mg plus Zidovudine 300mg tablet. Cipla Ltd, Vikhroli,
India. Blister 10.
Removed from the list as a result of the outcome of an inspection performed
by the World Health
Organization (WHO) in which compliance with Good Clinical Practices (GCP)
and Good Laboratory
Practices (GLP) was assessed, as well as data verification of the
bioequivalence study at the Contract
Research Organization (CRO) used by the sponsor. Products are subject to
re-assessment when a
complete new data set is presented about the bioequivalence studies.
---end
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