Tuberculosis

Leena Menghaney Access Campaign, June 2013

TB drugs & MSF

- Intellectual Property
- Quality of TB drugs - Irrational prescription of TB/antibiotics - Indiscriminate sale of antibiotics (pharmacies) - Stimulating production of old medicines - Stimulating production of pediatric formulations - Off label use - Compassionate Use - regulation of private sector DR TB/new drugs - Clinical trials of new combinations

Issues raised by MSF projects in India field experience Failure to diagnose DR TB Quality of TB medicines in public sector (DOTS) but also private sector (retail) The kind of prescriptions they see from the private sector The indiscriminate sale of antibiotics in India

Pushed from Pillar to Post: Getting treatment for drugresistant TB in Mumbai: Shantis story Shanti, an HIV positive woman living in Mumbai, was finally diagnosed with multidrug resistant tuberculosis in MSF and put on treatment. But it was too late. She passed away this May. Shanti was first put on a six month TB treatment course in 2007. After her health did not improve, Shanti went out and paid for an X-ray test herself to test for TB. This led to her being given another six month treatment course. But Shanti continued not to respond to the treatment she was given. When she asked to be put on yet a third round of treatment, the doctor refused saying further treatment could damage her kidneys. She switched to another doctor who was happy to prescribe another TB treatment course for a further eight months. Yet again, Shantis health failed to improve and she underwent further tests at a major hospital in the city that through more accurate tests, explained that she was resistant to the drugs she was being given to treat it. She was told in the hospital that her form of TB was incurable and that, in any case, the medicines she needed would be far too expensive for her to afford. She started her treatment for DR-TB with MSF in 2011.

diagnosis

Drug Resistance TB Public Health Emergency?

TB drugs in India
Public Sector First line procurement of domestically registered drugs DR TB drugs WHO prequalified as funders are GFATM/GDF In times of stock out each state government asked to buy locally Private sector Reliance on domestic FDA (registered under Drugs & Cosmetic Act)

MSF accepts products that are:

WHO pre-qualified products Registered in Highly Regulated Countries through the NDRA (National Drug Regulatory Authorities) Qualified through the MSF Qualification Scheme and accepted by the general Directors and the Medical directors

Product Assessment: Key Indicators

National Drug Regulatory Authority - reliability Stability of the finished products Finished Product (FP) analytical reference standards Active Pharmaceutical Ingredient (API) Quality Assurance (QA) Sample (dosage form + packaging + labelling) Manufacturing site level of GMP compliance Therapeutic equivalence (if needed)

National programme TB approach to quality

Domestic registration (Indian FDA) If there is a doubt about the quality get them tested at governments' laboratories Central Drugs Testing Laboratory (CDTL) or Regional Drugs Testing Laboratory (RDTL)

Tamil Nadu Medical Services Corporation Ltd., (TNMSC) Quality Control

Every Batch of Drugs and Medicines supplied is kept under Quarantine is tested at initial supply stage through Empanelled Laboratories. Random samples are drawn from every Warehouse where the Batch has been supplied. Batch wise Drug sample de-coding is done through strict confidential system. De-coded samples are sent for quality checking randomly to any of the Empanelled Laboratories which are located throughout the Country. On receipt of Quality Passed certificate from the Empanelled Laboratories that batch is Released for distribution of Drugs to Government Hospitals. During the shelf life of Drugs, random samples are periodically drawn from Warehouse and quality is checked to ensure that Drug is of Standard Quality up till date of expiry.

Substandards- The issues

Under concentration of active ingredient Over concentration of active ingredient Wrong active ingredient No active ingredient Dissolution failure Irregular filling of vials Mislabelling (not of brands, but paracetamol labelled as cotrimoxazole) Contamination Packaging problems Poor stability

Recommendation
Identify the problem Insist on the standards (API source, bioequivalence rather than WHO prequalification) Request testing by quality control labs under the Drugs & Cosmetic Act Put in the agenda of the pharmacist team

PROPOSED ACTION Conduct a systematic randomized trial of TB drug quality using international and national lab to examine chemical composition. Step: Explore the required methodology, scale and estimated time and cost to undertake such a study. Methodology: 1- Determine the presence and relative concentration of the active pharmaceutical ingredient (API), and whether it met internationally acceptable standards: run semi-quantitative Thin-layer Chromatography (CTL) on each sample. 2- Determine appropriate solubility of tablets: Conduct Disintegration tests. (see if samples disintegrated in water at 37C in <30 min. Scale: Sampling should be representative. Need to test at least 50 treatment packs of each medicine coming from different batches. Time: depending on sampling collection. Tests can be done within one week. Cost: Minilab 5265 Euros (Price including Ref.standards ANTI-TB and transport and packing costs up to Delhi) Conclusion/comments: Full-scale pharmacopoeial testing is expensive and out the scope for this study. This methodology it is the most accessible and basic one, but still with the appropriate scientific support. Suggested by WHO in case of weak quality control system at country national level. http://www.who.int/medicines/areas/quality_safety/quality_assurance/control/en/ Anyway, to be able to put weight on the study, a significant number of samples must be tested and the same should be done by a recognized organization. Therefore, I would suggest strategically that either we try WHO India to run this king of study or we could associate with Global Pharma Health Fund,Giessen, Germany -www.gphf.org to run the tests for us. Additional information in case we want or need to do further testing, with other methodologies: here the WHO Prequalified Quality Control Laboratories based in India: http://apps.who.int/prequal/lists/pq_qclabslist.pdf Vimta Labs Limited SGS India Pvt. Ltd. (Life Science Services)

First line - alternate day regimen (co-blisters) Anshu Prakash, the joint secretary at the Ministry of Health & Family Welfare, which oversees the Central TB Division, told The Wall Street Journal earlier this month that India had solved the shortages of adult dosages by letting states purchase the medicines themselves from private suppliers. But the states could not buy the childrens medicines, according to another government TB official who refused to be identified, because private suppliers offer mainly daily dosages that differ from the governments treatment plan, which is designed around alternate-day dosages.

Treatment protocol public sector fatal confusion

Treatment Protocol private sector

There are 48 different FDC dosage combinations and 22 different single drug formulations in India - of the 4 first line drugs Private sector treatment is often inappropriate: in one study in India, 100 private doctors prescribed 80 different regimens

December 2011
Reporting on the cases of patients resistant to 1st and 2nd line TB drugs in India in the Clinical Infectious Diseases Journal The study team focus on how DR develops in TB infected individuals due to poor treatment management, "the vast majority of these unfortunate patients seek care from private physicians in a desperate attempt to find a cure for their tuberculosis. The majority of these prescriptions were inappropriate and would only have served to further amplify resistance."

New Drugs on the horizon

TMC 207 (Bedaquiline) Delamanid (OPC-67683) Should be strictly regulated Access from government hospitals a must (access is key) NEWS Pharma cos seek retail opening for swine flu drug May 6, 2009 | Nina Mehta & Khomba Singh , ET Bureau MUMBAI/NEW DELHI: Indian pharmaceutical companies that manufacture oseltamivir, the generic version of tamiflu, are pushing the government into allowing them to sell the drug in the retail market, industry sources told ET. The current directive from the government restricts companies from making the drug available in the open market through chemists and pharmacies that are either standalone or part of a private hospital. "We can sell only to government hospitals or directly to the government.

Recommendation
MSF should advocate for daily FDCs Study the large number of formulations in the mkt and look at policy recommendations DR TB drugs - directive from the govt to restrict companies from making the drug available in the open market through chemists and pharmacies that are either standalone or part of a private hospital. New Drugs have to be made available only through public sector

Stimulating production of child friendly doses of 1st line TB drugs

Dr Soumya Swaminathan, Scientist at the National Institute for Research in Tuberculosis, Chennai, It is unfortunate that there are hardly any child friendly formulations of the existing drugs available for Drug Sensitive TB in the market. For second line drugs we have nothingno childrens formulation-- and that is where the pharmaceutical companies really have to do something. http://www.citizen-news.org/2012/11/has-childhood-tb-come-of-age.html Treatment of children with TB has long been hampered by the lack of paediatric Appropriate drug formulations. This year the World Health Organisation (WHO) added Recommended fixed-dose combinations for treating children with drug-sensitive TB onto the Expression of Interest list for manufacturers to submit products for evaluation for prequalification i.e. this should encourage drug manufacturers to produce paediatric TB drug formulations.

Patents and local production

Patent No patent

One producer

Multiple producers

No competition

Competition

High prices of imported medicines

Low prices of locally produced medicine

Linezolid (TB): R264 per tablet or R8,460 per patient per month. R676 per tablet for use in the private sector and by NGOs. The product patent set to expire in 2014. An additional patent on the crystalline form of the medicine was granted in 2002. Will it block generic entry after 2014 - until 2021?) Generic versions in India as low as R10 per tablet.

TMC 207 (Bedaquiline), an experimental diarylquinoline (Johnson & Johnson (Janssen Pharmaceutica, Tibotec)

Patent

India

Status Granted Pat No. 236811

Details Granted 27/11/09, opposition deadline passed, but there are grounds for a s3d challenge Good case for an oppositon Method of use patent, good case for a s3(i) opposition

Free base (substituted (derivative) 220/DELNP/ quinoline compounds) 2005 Fumarate salt and enantiomer of free 1220/MUM base NP/2009 Treatment of MDRTB using TMC207 6315/DELNP free base /2006 509/DELNP/ 2007 New use of TMC207- sterilising 5213/DELNP properties effective in killing dormant /2007 latent mycrobacteria for TB and used to treat latent TB Process for isolating TMC 207 9746/DELNP (alpha/bromo enatiomer form) /2009

unlike original patent for TMC 207 i.e granted patent no. 236811 which is used to treat MDR-TB