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[e-drug] Capetown Declaration on TB Drug Development


  • From: Wilbert Bannenberg <WilbertBannenberg@compuserve.com>
  • Date: Mon, 21 Feb 2000 16:35:16 -0500 (EST)

E-drug: Capetown Declaration on TB Drug Development
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Dear E-druggers

More than 120 TB and public health experts, government and industry
representatives, researchers and donors attended an
intensive 2-day workshop to discuss TB Drug Development in Capetown, South
Africa, 6-8 February 2000.

Reason to meet was the urgent need for new TB drugs to ensure shorter TB
treatments and to fight the increasing resistance of Mycobacterium
Tuberculosis against rifampicin and INH (called Multiple Drug Resistant
Tuberculosis or MDR-TB).
The existing basic TB drugs are already 20-30 years old, and few new TB
drugs have reached the market in recent years.
The pharmaceutical industry seems reluctant to develop drugs for a market
where most of the people are poor, and where developing countries,
institutional buyers and TB Agencies demand low prices.

At this meeting, WHO and TB experts described the need for new TB drugs,
researchers presented promising state of the art research methods and
findings, drug companies explained the difficulties of drug development and
mixed panels discussed the pharmaco-economics of the TB drug market, which
is predicted to be USD 700 million for treating 10,000,000 TB patients
worldwide by 2008. The size of this market should enable the development of
at least 1-2 new drugs, was the opinion.

Quinolones (eg moxifloxacin, gatifloxacin), oxazolidinones (developed and
dropped by Dupont in the 1970's), nitroimidazopyrans (eg PA-824) and newer
rifamycins (rifabutin, rifapentin, rifalazil) were discussed as candidate
TB drugs. PA-824, a nitroimidazopyran, was tipped as a very promising TB
drug, but unfortunately the company involved had decided to "shelve" it as
it had limited development resources and feared the "uncertainties of the
TB market". Most drug companies rate the TB market as "high risk, low
return".

Drug companies pointed out that Drug Regulatory Authorities are now much
stricter than in the 1950's. They quoted an example of the FDA which
recently withdrew the quinolone trovafloxacin from the US market as it had
2% acute toxicity. But streptomycin, still an important TB drug for
resistant strains, has an acute toxicity of 14%!

Drug companies also seem to be reluctant to let quinolones be used for TB
treatment, as quinolones often develop serious adverse drug events in
longterm treatments, so as not to spoil the much more lucrative 'short
term' antibiotics market.

In the eyes of many, orphan drug legislation has not really worked. We need
a combination of "push and pull". A guaranteed off-take or market would be
a strong incentive for the industry.

"Corporate awareness", however, seems to be on the increase, and recent
debates around TRIPS, AIDS drugs and the Nobel Prize for MSF have changed
mind-sets in industry circles. Some companies have specific TB projects,
such as Glaxo's "Action TB" and SKB's "SB Tropicals", others are
considering "donating" the licensing rights of economically less viable 2nd
line TB drugs to public bodies.

Whatever the lower price of TB drugs or even free donations, many public
health people warned that low cost of TB drugs is no guarantee for solving
the TB problem, as managerial problems in many mid-level countries have
only achieved 50-60% cure rates. Poor patient compliance after the first 2
months increases the risk of drug resistance. DOTS is presented as "the
answer" by WHO but not research findings support that.

James Orbinsky of MSF summarized the way forward for the Alliance if it is
to be succesfull:
- there needs to be equity of access to TB treatment;
- the product of the Alliance must be a "public good";
- cost of future TB treatment must remain affordable (USD 30-50)
- promote a rational market for generic manufacturers, and
- the R&D must be focused on the "south".

No easy answers are ahead, and it will require strong international
political will to ensure the funds needed to develop the so much needed new
TB drugs, as it was clear to all that "the market had failed, and would not
resolve the problem".

The Rockefeller Foundation will collate the presentations in a publication.
The meeting discussed a draft "Capetown Declaration on TB Drug Development"
which is reproduced below and speaks for itself.

When detailed summaries become available, we will present them to the
E-drug community.

kind regards

Wilbert Bannenberg
E-drug moderator
Email: WilbertBannenberg@compuserve.com

-----

Working Alliance for TB Drug Development Declaration

Cape Town, South Africa, February 8th, 2000

The Working Alliance for TB Drug Development, a group of interested
organizations, meeting in Cape Town, this Eighth day of February in the
year Two Thousand,

Expressing the need to accelerate the development of new drugs to shorten
the treatment of tuberculosis (TB) and facilitate its control in the
poorest countries,

Hereby makes the following declaration:

I
The increasing TB burden is a blot on the consciousness of human kind. One
third of the world's population, 2 billion people, are infected with M.
tuberculosis. Today, there are 16 million patients with active TB, and
every year there are 8 million new cases, and 2 million deaths; one third
of all HIV-positive people die with TB;

II
TB is a marker of social inequity and a serious impediment to economic
development. As poverty fuels TB, so does TB fuel poverty. Globally, TB is
a leading killer of young adults. TB is also a major cause of death in
women of childbearing age. Although, 95% of this burden falls in poor
countries (in India alone, TB kills one person every minute), TB is a
global problem that knows no borders;

III
TB treatment is one of the most cost-effective health interventions and
DOTS (Directly Observed Therapy, Short Course) is currently the best
strategy to deliver it. As one person with TB can infect many others, early
diagnosis and treatment are an effective preventive strategy, together with
the treatment of latent infection. Such interventions are also an efficient
intervention to extend and improve the lives of HIV-positive people.

We, recognizing the above, draw attention to the following challenges and
opportunities:

IV
After a decade of global efforts under the World Health Organization's
(WHO) leadership, DOTS coverage expanded significantly. Despite this public
health achievement, less than half of patients are detected by the health
care system. Of those patients who are found to have the disease, nearly
half can not complete therapy, thus ensuring ongoing transmission and the
emergence of multi-drug resistance (MDR-TB);

V
Implementation of TB control remains a challenge. Treatment duration of at
least 6 months requires infrastructure and managerial skills often
insufficient in the very areas most affected by TB. In settings where TB
control is weak, compliance with treatment drops dramatically after 2
months. Furthermore, a quarter of all TB patients will go without therapy
in the year 2000 due to geographic, financial and other programmatic
barriers;

VI
To scale up DOTS implementation we need both more effective use of existing
tools and new products. No new drugs to fight TB have been introduced in
decades. BCG was developed in the early 20th century but its effectiveness
is limited and, despite widespread use, it has not stopped the epidemic.
Substantial efforts are currently underway to develop an effective vaccine
but it may take another 20 years before it becomes available. During that
time 50 million people will die from TB;

VII
In the 1960s and 1970s, the duration of TB chemotherapy was shortened from
24 to 6 months after the introduction of novel drugs. Further shortening TB
treatment would be another revolution in endemic countries, potentially
leading to improved compliance and cure rates, decreased program costs, and
expanded DOTS coverage, making sustainable TB control a reality. New drugs
should also help overcome MDR-TB, and more efficient treatment of persons
with latent TB infection could be instrumental in eliminating TB in many
countries;

VIII
The recent sequencing of the Mycobacterium tuberculosis genome and the
biotechnology revolution offer solid opportunities for TB drug development.
New compounds are needed, but TB drugs could emerge as derivatives of
current TB drugs or from other antibiotics. The effort should bear fruit
within this decade;

IX
A new drug need not necessarily be a substantial financial burden on a
country's health budget. For example, shortening treatment to 1 or 2 months
would free up the cost of drugs of the remaining 4 to 7 months. There are
other potential savings in drug delivery costs, plus the economic, social
and humanitarian benefits of improved TB control;

X
Approximately 10 million patients are treated for TB every year. At an
average drug-cost of $50 per treatment, annual drug sales are considerable.
A company introducing a new drug could share a substantial portion of that
market. Furthermore, drug development costs would be shared by the public
sector (drug screening and clinical trials.) Need and consensus would
expedite drug registration, and market penetration should occur fast and
without costly marketing.

We commit ourselves to accelerate the development of new TB drugs to
improve the prevention and treatment of the disease. In coming months we
will:

1. Work in concert with the goals for TB control as outlined by the Stop TB
Initiative, a global partnership coordinated by the World Health
Organization which recognizes the need for new tools as part of a
comprehensive approach to fight TB.

2. Lay out a Scientific Blueprint for TB Drug Development that brings
technical consensus by existing institutions and clarifies priorities for
academic research and coordinated funding over the next 5 to 10 years;

3. Put together a Report on the Pharmaco-economics of TB Drug Development
that clarifies the size and characteristics of TB drug markets, the cost,
current investment and gaps in research and development, and the social and
financial returns of a new TB treatment by the year 2010 taking into
account the evolving epidemics of HIV and MDR-TB;

4. Design the Road Map for Advocacy for the Development of New TB Drugs to
bring about support and resources for this initiative, and to ensure its
products reach all patients.

5. Develop a dedicated Global Alliance for TB Drug Development during Year
2000, with partners from academia, industry, major agencies,
non-governmental organizations, and donors the world around. Acknowledging
a variety of efforts and institutional missions, this partnership will
provide leadership, raise funds, advocate, and coordinate efforts in
various sectors and settings to improve health equity by developing and
delivering a simple and affordable TB treatment in endemic countries this
decade.

This declaration reflects the spirit of participants in the meeting of Cape
Town on TB Drug Development, February 6-8, 2000. The meeting was convened
by the Rockefeller Foundation, hosted by the Medical Research Council of
South Africa, and co-sponsored by the Stop TB Initiative (WHO, WB, CDC,
KNCV, ATS, ALA, IUATLD, JICA, TDR, et al.), the U.S. National Institutes of
Health, the Bill and Melinda Gates Foundation, the Wellcome Trust, and the
U.K. Department of International Development. The document was prepared by
Ariel Pablos-Mendez with input from participants in the Working Alliance
for TB Drug Development and other scientist and field workers participating
in the meeting..

Comments and requests for background papers can be sent to:

Ariel Pablos-Mendez,
Associate Director, Health Equity
Rockefeller Foundation
420 Fifth Avenue
New York NY 10018
USA
Tel +1-212-8528348
Fax +1-212-8528279
Email: apablos-mendez@rockfound.org

[note from the moderator: The Working Alliance for TB Drug Development
consists of: Rockefeller Foundation, the Stop TB Initiative (= WHO,
Worldbank, KNCV, ATS, IUATLD etc), The Bill and Melinda Gates Foundation,
the UNDP/World Bank/WHO Special Programme for Research and Training in
Tropical Diseases (TDR), the US National Institute of Health (NIH), the
Wellcome Trust, Pharmaceutical Industry, UK Department for International
Development (DFID), US Centre for Disease Control and Prevention (CDC),
South African Medical Research Council (MRC), the Sequella Foundation and
others.]
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