TB-
A Global Emergency
- Every second, someone in the world is newly infected
with TB.
- TB kills 8,000 people a day - that is 2-3 million
people each year. It kills more people than either
AIDS or malaria. In fact, TB is the biggest killer
of young people and adults in the world today.
- 200 million people world wide, or 10% of those infected,
will develop active TB and would then be able to infect
others for 3 decades.
Sandoz and Tuberculosis
Inspite of millions of people loosing their lives to
Tuberculosis, it remains one of the most neglected diseases
by pharmaceutical companies due to lack of commercial
potential. But Sandoz which is a part of Novartis group
has taken TB eradication as a challenge. The association
of Sandoz and TB started way back in 1960s where erstwhile
CIBA * and Lepetit were conducting research on Rifampicin.
Innovator of Rifampicin
In early 60’s CIBA* and Lepetit did the pioneering
research and development work for Rifampicin. Discovery
of rifampicin revolutionized the treatment of TB and
till date is the most essential drug for TB treatment.
Prix Galien Award
For this research and development of Rifampicin the
“ Prix Galien for Pharmaceutica” was awarded
to CIBA and Lepetit by the French journal Pharmacie
Mondiale
* CIBA- Erstwhile CIBA
Giegy and Sandoz merged to form Novartis
Mission- A TB free world
Sandoz and Novartis have taken TB Eradication as a challenge
and are striving to achieve this goal through various
initiatives and actions.
Leading Global Player in
anti-TB formulations
Globally Sandoz is one of the major manufacturers of
anti-TB medicines and has 5 state of the art manufacturing
facilities in South Africa, Bangladesh, Egypt, Pakistan
and India dedicated to it. These plants are approved
by local regulatory authorities’ as well international
agencies like European Union, US- FDA, ICH (International
Conference on Harmonization) and WHO.
Beside being the leader in finished dosage forms of
TB medicines, Sandoz is also backward integrated for
the manufacturing of the key anti-TB API – Rifampicin
at Mahad (India)
Partner of WHO for drug
supply
Sandoz Fixed dose combinations conform to the WHO treatment
guidelines and are in the WHO model list of essential
drugs. Sandoz is one of the prequalified manufacturers
approved by WHO and two of our products are mentioned
on the white list. The world class anti-TB formulations
are supplied to various agencies like WHO, IAPSO, UNDP
etc.
Novartis Initiatives with
GDF and WHO in TB Eradication
Novartis Donation Programme:
Being a Socially Responsible Corporate Citizen, in
December 2003, Novartis signed a Memorandum of Understanding
with WHO committing itself to donate the gold standard
anti-TB formulations to WHO for the treatment of Half
a million patients over a five- year period starting
from 2004.
Global TB Alliance for
TB:
Novartis (India) Limited is one of the signatories
to the “Global TB Alliance for TB Drug Development”
which is working towards the development of new drug
that is expected to be available by 2010.
Novartis Institute of Tropical
Diseases:
Novartis has started Novartis Institute of Tropical Diseases
(NITD) at Singapore where the research activities are
being carried out for drugs on tropical diseases like
Malaria, Dengue, and TB etc.
Sandoz Initiative in India-
JEET:
India has the largest number of patients in the world
Although effective treatment is available, lack of awareness
and misconceptions about the disease, late / improper
diagnosis, limited accessibility to diagnostic facilities,
Incorrect treatment by doctors, Patients’ non-compliance
to treatment, and socio-economic factors are major hurdles
in eradicating TB.
As leaders in the fight against TB, Sandoz believes
it has the capacity and the ability to make a positive
difference. JEET is a joint effort to eradicate tuberculosis-
a combined effort of patients, public , Sandoz and society.
Through various actions under JEET, Sandoz endeavors
to create awareness on tuberculosis and at the same
time control the spread.
Milestones:
1960
Rifampicin was jointly developed with Lepetit
The
Discovery of Rifampicin (pdf)
1968
Rimactan® the first rifampicin indicated in tuberculosis.
Rimactan® was integral part of various international
studies which paved the way for modern short-course
chemotherapy in tuberculosis.
1968 ongoing
Introduction of various
anti-tuberculosis drugs mainly in developing countries,
tailored to the specific needs of the patients: PZA-Ciba®
(Pyrazinamide), Rimactazid® (FDC of Rifampicin +
Isoniazid), Ebutol® (Ethambutol), and many more.
1998
Development of Fixed Dose
Combinations - FDCs - conform to WHO guidelines &
part of the essential drug list:
The bioavailability of Rifampicin is proven by the
MRC (Medical Research Council, Pretoria, South Africa)
one of the 2 WHO approved laboratories.
MRC Document: Rimstar® 4-FDC (pdf)
MRC
Document: Rimcure® 3-FDC (pdf)
MRC
Document: Rimactazid® 150/75 (pdf)
2003
Opening of the Novartis
Institute for Tropical Diseases in Singapore.
Novartis
Institute for Tropical Diseases
NITD
Inaugural Symposium: Dengue Fever & Tuberculosis
(pdf)
2005
RIMSTAR 4- FDC Clinical trial
Novartis and Sandoz have a long association with Tuberculosis.
As part of its ongoing commitment to TB, Sandoz initiated
clinical trial with its fixed dose anti-TB drug- RIMSTAR
4- FDC in 2002 in 5 countries. The main objective of
this trial was to compare the efficacy; safety and acceptability
of Rimstar 4- FDC with individual drugs/ combipack in
patients with newly diagnosed smear positive pulmonary
tuberculosis.
This was the first ever multinational, multi-centric
and multiethnic controlled clinical trial for 4 drug
fixed dose combination for the treatment of TB and this
step is a major milestone in the treatment of TB.
FDCs in the treatment of
Tuberculosis
Short-course chemotherapy are highly efficacious in
treating tuberculosis (TB). However, the length (>/=6
months) and complexity (three or four different drugs)
of the treatment makes adherence difficult. Erratic
treatment not only fails to cure patients but also creates
chronically contagious cases, who may excrete drug-resistant
TB bacteria. The Directly Observed Treatment Short-course
(DOTS) strategy recommended by WHO provides a comprehensive
organizational and infrastructural framework for the
rational use of diagnosis, drug supply, as well as case
and programme management services, in TB control. WHO
and other organizations recommend fixed-dose combination
formulations (FDCs) as a further step to facilitate
the optimal drug treatment of TB. Using FDCs in TB control
will simplify the doctor's prescription and patient's
drug intake, as well as the drug supply management of
the programme. By preventing monotherapy and facilitating
the ingestion of adequate doses of the constituent anti-TB
drugs, FDCs are expected to help prevent the emergence
of drug resistance.
Need for Rimstar Clinical
Trial
Although the advantages of Fixed Dose Combinations
for TB treatment are well known, practical experience
with 4-FDCs is still very limited. Anticipating this
need gap, Sandoz initiated a multinational, multicentric
clinical trial in high TB prevalent tropical countries
like India, Pakistan, Thailand, Philippines and Egypt
from 2002. Sandoz believes that the results of this
trial will be helpful for expanding the knowledge base
of benefits regarding the 4-FDCs in practical tuberculosis
control.
Salient Features of Rimstar
Trial
- The first multinational, multiethnic trial to document
the FDCs as tools for the unification and simplification
of tuberculosis treatment
- Aimed at comparing the efficacy, safety and acceptability
of two short-course regimens in patients with newly
diagnosed smear positive pulmonary tuberculosis
- Randomised Controlled trial in 30 centers across
5 countries with 1300 patients
Trial Methodology
High quality controls associated
with good clinical trial practices
Standardization of protocol
ensuring:
- Practical feasibility in five different countries
- Comparability of data for statistical analysis
- Overall high trial standard
Compliance with International
Standards
- ICH / GCP Standard
- WHO Recommendations on 4-FDC trials (Geneva 2001)
- WHO Guidelines for National Programmes
- Novartis Standard Operating
- Procedures (SOPs)
- National Tuberculosis Opinion Leaders/Major TB Institutions/
National TB Control Programmes
Based on WHO advocacy of
sputum smear microscopy
WHO advocates sputum smear microscopy for diagnosis
of tuberculosis as well as monitoring of patients with
smear positive pulmonary tuberculosis. Treatment success
evaluated by sputum smear microscopy forms the basis
of the study endpoints.
Study endpoints
Primary endpoint
Sputum smear conversion
rate at 6 months.
Secondary endpoints
- Sputum smear conversion rate at 2 months
- Sputum smear conversion rate at 4 months
- Sputum smears at 9 months
- Sputum smears at 12 months
- Relapse rate at 12 months
- Frequency and type of adverse reactions
- Patient compliance
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