Trials and evidence in Trials and evidence in relation to health policy: The relation to health policy: The case of tuberculosis in Nepal case of tuberculosis in Nepal

and Indiaand India

Ian HarperIan Harper

RifampicinRifampicin

Overview of presentationOverview of presentation

• Rifampicin, and its history in TB Rifampicin, and its history in TB controlcontrol

• RegulationRegulation– DOTSDOTS– Procurement for NTPsProcurement for NTPs

• Relations between the private sector Relations between the private sector and NTP (India and Nepal)and NTP (India and Nepal)

• ConclusionConclusion

Summary of TB treatment in Summary of TB treatment in the pharmaceutical erathe pharmaceutical era

• Monotherapy doesn’t work, and treatment has Monotherapy doesn’t work, and treatment has to be a combination of chemotherapy agentsto be a combination of chemotherapy agents

• The discovery and production of rifampicin key The discovery and production of rifampicin key in bringing TB out of the sanitorium and the in bringing TB out of the sanitorium and the development of ambulatory treatment. development of ambulatory treatment.

• Length of treatment means the question of Length of treatment means the question of adherence is crucialadherence is crucial

Drugs currently used for TB treatmentDrugs currently used for TB treatment

FIRST LINE DRUGSFIRST LINE DRUGS• Isoniazid (H)Isoniazid (H)• Rifampicin (R)Rifampicin (R)• Ethambutol (E)Ethambutol (E)• Pyrazinamide (Z)Pyrazinamide (Z)• Streptomycin (S)Streptomycin (S)

SECOND LINE DRUGSSECOND LINE DRUGS• Kanamycin (KM)Kanamycin (KM)• Amikacin (AMK)Amikacin (AMK)• Capreomycin (CM)Capreomycin (CM)• Quinolones (FQ) – Cipro, Ofx, Gfz, MfxQuinolones (FQ) – Cipro, Ofx, Gfz, Mfx• Ethionamide or Prothionamide (Thiamides)Ethionamide or Prothionamide (Thiamides)• Cycloserine (CS) or Terizdone (Tzd). Cycloserine (CS) or Terizdone (Tzd). • Para-aminosalicylic Acid (PAS)Para-aminosalicylic Acid (PAS)

Current Treatment Current Treatment recommendations (first line)recommendations (first line)

• Treatment based on the idea of a “intensive Treatment based on the idea of a “intensive phase” (IP) and then “continuation phase” phase” (IP) and then “continuation phase” (CP)(CP)

• At least two bacteriacidal drugs in the IP. At least two bacteriacidal drugs in the IP. Adding pyrazinamide decreases overall Adding pyrazinamide decreases overall treatment to 6 monthstreatment to 6 months

• CP mops up residual bacilli and results in less CP mops up residual bacilli and results in less likelihood of relapselikelihood of relapse

Drug ResistanceDrug Resistance

• MDR defined as resistance to at least MDR defined as resistance to at least rifampicin and isoniazidrifampicin and isoniazid

• Rifampicin key to the debate, and Rifampicin key to the debate, and has to be “protected” (including):has to be “protected” (including):– Limit availability to national regimesLimit availability to national regimes– Make it only available in FDCsMake it only available in FDCs– Observation of patients taking drugsObservation of patients taking drugs

India and Nepal’s national India and Nepal’s national regimesregimes

• India has an intermittently administered India has an intermittently administered regime (3x per week)regime (3x per week)

• Nepal has daily therapy (and till 4 months ago) Nepal has daily therapy (and till 4 months ago) had no rifampicin in the continuation phasehad no rifampicin in the continuation phase

• Each has three categories of treatment (i, ii, iii)Each has three categories of treatment (i, ii, iii)

• Each must have a “directly observed” Each must have a “directly observed” component (rephrased in 2006 as “patient component (rephrased in 2006 as “patient support”)support”)

Why intermittent therapy? Why intermittent therapy? (India)(India)

• DOT seen as an absolute must for DOT seen as an absolute must for rifampicin based combinationsrifampicin based combinations

• Logic is that it is therefore easier on Logic is that it is therefore easier on the patients to have this only three the patients to have this only three times per week, rather than dailytimes per week, rather than daily

• CostCost

Evidence base?Evidence base?

• Friedman (2004) in a review suggests that Friedman (2004) in a review suggests that intermittent therapy is as good as daily, intermittent therapy is as good as daily, and that animal model experiments and that animal model experiments suggest there is an increase in efficacy of suggest there is an increase in efficacy of HRZ, and is “perhaps slightly more HRZ, and is “perhaps slightly more effective than the daily regime” effective than the daily regime”

• Cochrane (2005) argue no evidence to Cochrane (2005) argue no evidence to support assertions that IR is better than support assertions that IR is better than daily (need more research)daily (need more research)

Why eight month regime? Why eight month regime? (Nepal)(Nepal)• WHO and IUATLD don’t like rifampicin WHO and IUATLD don’t like rifampicin

through whole regime (“protect the through whole regime (“protect the rifampicin”)rifampicin”)

• Less likely to get rifampicin resistance Less likely to get rifampicin resistance should patients relapseshould patients relapse

• Claims of less DOT burden on the patient Claims of less DOT burden on the patient (two months rather than six)(two months rather than six)

• CostCost

• (NB Nepal’s regime changed in Dec 2008 to (NB Nepal’s regime changed in Dec 2008 to rifampicin based in the continuation phase)rifampicin based in the continuation phase)

MethodsMethods

• Interviews with prescribers (chest Interviews with prescribers (chest physicians and GPs)physicians and GPs)

• Interviews and visits to DOTS clinics, Interviews and visits to DOTS clinics, and government officialsand government officials

• Interviews with retailers etc.Interviews with retailers etc.• Interviews with company Interviews with company

representativesrepresentatives

(Nepal, West Bengal, Delhi and UP)(Nepal, West Bengal, Delhi and UP)

Perceptions of the regime and Perceptions of the regime and DOTS (prescribers)DOTS (prescribers)Very inconvenient for patientsVery inconvenient for patients

Too cumbersome and rigid in implementation Too cumbersome and rigid in implementation (e.g. not good for migrants) (e.g. not good for migrants)

DOTS only for poor patients, and not the bestDOTS only for poor patients, and not the best

Intermittent regime based on costs, not science: Intermittent regime based on costs, not science: India is a “poor” countryIndia is a “poor” country

Not enough dosage flexibilityNot enough dosage flexibility

Category 2 is adding one drug to a “failing Category 2 is adding one drug to a “failing regime” and contradicts WHO’s own policyregime” and contradicts WHO’s own policy

DOTS policy based on “irrational optimism”DOTS policy based on “irrational optimism”

Don’t know MDR levels, regime may be wrong Don’t know MDR levels, regime may be wrong and feeding further resistance (India)and feeding further resistance (India)

Free drugs a bad idea- people don’t take it Free drugs a bad idea- people don’t take it seriouslyseriously

Perception that the WHO and the NTP don’t Perception that the WHO and the NTP don’t listen to their concerns and take them listen to their concerns and take them seriouslyseriously

Why private sector better? Why private sector better? (self perceptions)(self perceptions)

• Flexibility on dose and weight schedulesFlexibility on dose and weight schedules• Regime too shortRegime too short• Easier on patients (no DOT), “why go the Easier on patients (no DOT), “why go the

clinic when you could go to work”?clinic when you could go to work”?• AccountabilityAccountability• Poor performance and quality of the Poor performance and quality of the

government system; lack of trustgovernment system; lack of trust• Trust in certain company products (Lupin Trust in certain company products (Lupin

in particular)in particular)

In Nepal…In Nepal…

• Widespread resistance to the Widespread resistance to the national regime because no national regime because no rifampicin in the CPrifampicin in the CP

• Greater flexibility for patientsGreater flexibility for patients

• Distrust of the claims made by the Distrust of the claims made by the NTPNTP

Differences between Nepal and Differences between Nepal and IndiaIndia• ScaleScale• DOTS in Nepal much more widely knownDOTS in Nepal much more widely known• Nepal: Reports of decreased sales of TB drugs from Nepal: Reports of decreased sales of TB drugs from

retailers (e.g. where there are well functioning DOTS retailers (e.g. where there are well functioning DOTS clinics)clinics)

• Major Indian TB drug producers dominate the Nepal Major Indian TB drug producers dominate the Nepal market (Lupin, MacLeods, Concept, Cadilla)market (Lupin, MacLeods, Concept, Cadilla)

• As such rifampicin now mainly available as either As such rifampicin now mainly available as either FDCs or is “strip” packsFDCs or is “strip” packs

• Complaints by prescribers of lack of availability of Complaints by prescribers of lack of availability of uncombined rifampicin on the market (eg Paediatric uncombined rifampicin on the market (eg Paediatric formulations) formulations)

• Criticisms of each regime are technical and specific Criticisms of each regime are technical and specific to eachto each

Discussion pointsDiscussion points• Don’t ignore the perceptions of private Don’t ignore the perceptions of private

practitioners, becausepractitioners, because– They confirm the lack of flexibility of DOTS and They confirm the lack of flexibility of DOTS and

its failure to respond to patient needsits failure to respond to patient needs– They adapt to patient demandsThey adapt to patient demands

– BUT variability of treatments a problemBUT variability of treatments a problem– Never sure what the financial incentives areNever sure what the financial incentives are

• DOTS must be more flexible AND consistent DOTS must be more flexible AND consistent