Understanding TB Regimen Change: The Country Introduction Study

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Understanding TB Regimen ChangeThe Country
Introduction Study

• William Wells, Niranjan Konduri, Cynthia Chen,
  David Lee, Heather Ignatius, and Nina Schwalbe
• Global Alliance for TB Drug Development, New
  York, NY USA
• Management Sciences for Health, Arlington VA,
  USA
• March 23, 2009
• Partners Forum, Rio de Janeiro

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Study aims and methods

• Aims
• Understand
• The past history of major TB regimen changes in
  the 22 highest burden countries for TB (HBCs)
• The process, major players, and key procedural
  success factors for adoption, introduction and
  implementation of a new TB regimen in these
  countries
• The challenges and considerations that will
  require more focused in-country preparatory work
  prior to launch
• Prioritize future launch and access activities.
• Methods
• Selected 17 key factors, structured around the
  Retooling Taskforces Framework, that affect the
  various steps of regimen change.
• Devised questionnaires based on these key
  factors.
• Completed 165 interviews in 21 countries
  (4-10/country).

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Defining the current treatment landscape
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Regimens are moving towards a single WHO standard

• First-line regimens are
• 2HRZE/4HR with daily dosing in 15/22 HBCs
  (including transition countries China from
  intermittent and Kenya and Ethiopia from 8
  months)
• 2HRZE/6HE in 4/22 countries (Afghanistan,
  Nigeria, Pakistan, Uganda)
• 2SHRZ/6HE in Vietnam
• 2HRZE/S / 4HR in Russian Federation
• 2HRZE/4HR with intermittent dosing in India and
  China (in transition)
• Intermittent (3 days a week) is used in China
  (transition), India, Indonesia (continuation
  phase only) and Russian Federation (one option in
  continuation phase only)
• Where known, Daily is being standardized.
• It means 7 days a week (13 countries) or 6 days a
  week (2 countries).
• E.g., South Africa recently changed from 5 to 7
  days.
• So concerns about fitting a new regimen into 5 vs
  6 vs 7-day dosing may be diminishing.

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Current use of FDCs by NTPs is widespread and
complex

• FDC usage can be complex (2 different FDCs in
  some countries 6-16 in others).
• Integrating a new drug into this system will take
  time.

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Does the public sector use only the
NTP-recommended regimen?

• Most physicians in the public sector use the
  NTP-recommended regimen. However, there are
  exceptions
• Adding drugs to ensure a cure. E.g., addition
  of a FQ in the intensive phase or a third drug in
  the continuation phase. This is a response to
  Increasing resistance inadequate DST.
• Using a new regimen despite a lack of NTP
  endorsement. This can occur if regimen change is
  delayed too long.

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Experience with regimen change
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The private sector early adopters?

• Regimen change should occur first in the public
  sector (54/59 responses), yet new regimens may be
  used first in the private or non-NTP sector
• FDC adoption in Philippines
• RHZE intensive, HR continuation and FDC adoption
  in Vietnam
• Daily continuation phase in Bangladesh
• 8- to 6-month change in Vietnam, Kenya and Uganda
• Regimen change may spread between public and
  private, as many public sector physicians operate
  a private practice in the afternoon.
• The private sector may sometimes oppose a regimen
  change. This allows them to use the better
  regimen to attract more patients (Kenya and
  China).

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Most public sector regimen changes take 3-4 years

• Stakeholders described 37 first-line, public
  sector regimen changes in the 22 HBCs.
• Across 27 regimen changes, it took an average of
• 1.4 years for a decision and
• 2.3 years for implementation.
• Delays (1 year for each issue) can arise while
• accessing money (for training and drugs) from a
  long-range budget plan
• registering in a NEML
• negotiating tech transfer
• negotiating procurement and
• using up old stocks of drugs.
• 14 FDC introductions, 4 8- to 6-month changes,
  2 combined changes, and 17 additional changes

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Evidence can drive rapid change

• FDCs were recommended in 1999, but there are
  complications in using this as a reference date
• In different regions, different FDCs of
  sufficient quality became available at different
  times.
• In interviews, it was not always clear which FDC
  was being discussed.
• For 5/7 high HIV AFRO HBCs, the adoption decision
  for 8- to 6-months came an average of
• 2.6 years after the initial WHO recommendation
  (in 2003), but that recommendation was for low
  HIV settings only.
• Less than a year after the final WHO
  recommendation (in 2005, for all settings, after
  the Union trial showed superiority).
• The Union Study A results were published the
  year before, in October 2004, in Lancet 364
  124451.

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Some regimen changes occur in parallel, some
serially, and there are challenges

• Multiple regimen changes are often introduced at
  once
• 8 to 6 FDCs in Cambodia and Mozambique
• E, altered HZ dose, altered FDC in Brazil
• FDCs and deinstitutionalization in Brazil
• FDC, dosage and schedule changes in Indonesia.
• But serial changes also occur. Within 5 years,
  Bangladesh implemented 3 changes, first to an EH
  FDC, then to an RH FDC, then to a different RH
  FDC.
• Regimen changes come with challenges
• Require significant resources in training and
  logistics
• Can highlight weaknesses in pharmaceutical
  management.
• Phase-outs are often poorly or not managed (clear
  examples in 5 HBCs) with large stocks of drugs
  destroyed.

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Decision-making procedures

• There is a continuum all the way from
• Permanent committees through ad hoc committees to
  unilateral decisions
• Reliance on WHO recommendation to robust internal
  debate.
• It is not clear what evidence is required by
  decision-making bodies.
• In general, stakeholders put more emphasis on
  programmatic concerns and logistics, rather than
  clinical evidence.
• Because evidence was sometimes lacking in the
  past, some countries demonstrated
• A suspicion of efforts at global standardization
  and
• A tradition of decision-making via expert opinion
  rather than evidence.
• Sometimes there is no barrier to change, but just
  the lack of a local champion.

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Some countries generate their own evidence to
support regimen change

• Local investigators conduct trials that are
  closer to field conditions.
• Studies to support past regimen change were
  conducted by research organizations in at least 9
  HBCs (Bangladesh, Brazil, China, India, Kenya,
  Philippines, Russian Federation, South Africa,
  Vietnam).
• Local clinical data would be required for
  adoption in 5 HBCs (BRCS Indonesia), and
  possibly in another 5 HBCs.

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Looking forward to future regimen changes
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Ease of funding a new regimen vs. donor dependence

• More stakeholders in donor-dependent countries
  believe that accessing funds for a new, more
  expensive regimen would be easy (chi squared
  0.005, n57).
• But financing solutions must be in place when a
  new regimen is considered. If not, HBCs may
  reject a new regimen on cost grounds alone.

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Questions for future regimen change

• Which questions are best answered with local
  research?
• How should decision makers (global and local)
  balance the costs, risks, and benefits of regimen
  change?
• How should the TB community approach the
  possibility of serial change?

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Summary

• Current treatment regimens are converging to a
  single standard. This makes comparisons to new
  regimens easier.
• FDC usage is widespread.
• The private or non-NTP sector has sometimes led
  regimen change.
• Timelines of public sector regimen change are
  acceptable, but delays can occur.
• Decision-making procedures are variable. Many
  require local evidence.
• Funding solutions need to be in place for new
  regimens.

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Many thanks to all who contributed to the study

• Data collection and review Additional reviewers
• Dr. Rashidi Mohammed MSH, Kabul,
  Afghanistan Andy Barraclough, MSH
• Dr. Azad Chowdhury Consultant, Dhaka,
  Bangladesh Gabriel Daniel, MSH
• Dr. Joel Keravec MSH, Rio de Janeiro,
  Brazil Vimal Dias, MSH
• Valerie Chambard Consultant, Phnom Penh,
  Cambodia Ned Heltzer, MSH
• Sharri Hollist MSH, Arlington, VA Tom Moore,
  MSH
• Gabriel Bukasa MSH, Kinshasa-Gombe, DR
  Congo Gavin Steel, MSH
• Edmealem Ejigu MSH, Addis Ababa, Ethiopia
  Pedro Suarez, MSH
• Dr. Nirmal Gurbani Consultant, Rajasthan,
  India Hugo Vrakking, MSH
• Dr. Sri Suryawati Consultant, Yogyakarta,
  Indonesia Andre Zagorski, MSH
• Andy Barraclough MSH, Banglamung, Thailand
• Dr. Samuel Kinyanjui MSH, Nairobi, Kenya
• Dr. Grace Kahenya MSH, Lusaka, Zambia
• Andy Marsden MSH, Ferney-Voltaire, France
• Dr. John Wong Consultant, Manila, Philippines
• Dr. Serge Bosisov Consultant, Moscow, Russia
• Dr. Shabir Banoo MSH, Johannesburg, South
  Africa
• Dr. Sauwakon Ratanawijitrasin Consultant,
  Bangkok, Thailand

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Questions?
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Draft recommendations

• RTF and Stop TB to produce guidance on what
  countries can do to prepare for regimen change.
• Endemic countries to define procedures for
  considering future regimen change, if they have
  not already done so.

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What evidence is needed?

• What types of local data are required for
  adoption of a new regimen? From most to least
  frequently mentioned
• Cost-effectiveness data
• Proof of easier logistics
• Resistance studies
• Proof of increased compliance
• Adoption in high income countries
• Proof of equal or lower cost
• Shorter time to sputum conversion
• Proof of greater efficacy

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What were the positive influences for past
decisions (8 to 6 and FDCs)?

• Why favor new regimens in the past (8 to 6, and
  FDCs)?
• Global WHO recommendation (24 in 14 countries)
• Country-level WHO recommendation (12 in 10
  countries)
• Free drugs from GDF (7 in 7 countries for FDCs) ?
• Increased efficacy (5 in 5 countries) ?
• Union evidence (5 in 5 countries)
• Compliance (3 in 2 countries)
• Lower cost (3 in 3 countries) ?
• Easier logistics (3 in 3 countries for FDCs) ?

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Regulatory approval and Procurement

• HBC regulatory authorities are less demanding
  than NTPs only 4-5 (China, India, Nigeria,
  Vietnam, and perhaps Kenya) require local
  clinical data .
• 14/22 have a fast track mechanism for TB drugs,
  but the rules are often unclear and seemingly
  influenced by politics.
• In many HBCs, political support from the NTP is
  needed to get prompt regulatory attention.
• Most HBC NTPs require a drug to be WHO
  prequalified and on the NEML for public
  procurement (14/22 and 13-15/22, respectively).
• But there is significant confusion over both of
  these requirements and over the details of the
  NEML process.
• Average time for listing on the NEML 1.6 years.
  There are some interim measures.

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The impact of local manufacturing is difficult to
predict

• 13 HBCs currently produce TB drugs locally.
• Local production of TB drugs is required in
  Brazil and encouraged in at least 12 other HBCs.
• Tech transfer is time-consuming (FDCs in Brazil,
  Indonesia).
• Supply of drugs can end up as an unstable
  balancing act. In some countries
• Government funds can be used only for locally
  manufactured drugs and
• Donor funds can be used only for WHO prequalified
  or ICH-approved drugs, which are often imports.
• Local manufacturers may resist entry of a foreign
  drug company with a new TB drug. But answers on
  these questions were understandably cautious.

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Define issues for users (Value Proposition Study)
Demand Forecast (Moxi Demand Forecast)
Choose WHERE and understand HOW (Country
Introduction Study)
Understand Existing Market (Market Study)

• Devise local launch
• strategy
• Stakeholder and partner
• mapping and engagement
• Document resources for operational research,
  financing, TA, retraining

Manufacturing Strategy
Market Access Strategy
IP agreements
Pricing Strategy
Consumer marketing
Regulatory Strategy
Support local decision-making (cost-benefit)
Engage funding and procurement agencies
Engage guideline- setting agencies (WHO and
others)
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Size of private sector

• The private sector is estimated to treat
• 30-80 of the TB cases in India, Indonesia,
  Pakistan, Nigeria, Afghanistan, Cambodia, and
  Philippines
• 8-30 in Myanmar, DR Congo, UR Tanzania,
  Bangladesh, and Thailand
• 5 or less in Kenya, South Africa, Mozambique,
  Ethiopia, Brazil, Zimbabwe, Uganda and Russian
  Federation
• Uknown percentages in Vietnam and China
• Other sectors are neither NTP nor private
  e.g., the public hospitals outside of the NCTB in
  China the NGO sectors in Nigeria and Cambodia.

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Impact of a new regimen can be defined in
different ways

• HBCs are the 22 countries that contain the most
  TB cases (making up gt80 of the global burden).
• But HBC rank by burden is more predictive of a
  countrys population than of its TB incidence
  rate (per 100,000 population).
• India and China are
• 1 and 2 for burden (24 and 18 of worldwide
  prevalence)
• 17 and 21 for incidence rate amongst the 22
  HBCs
• 61 and 80 for incidence rate worldwide
• Among HBCs, Cambodia, Mozambique and Zimbabwe are
  the opposite low burden but high incidence rate.
• Some non-HBCs have reasonable size and high
  incidence rate. If burden and incidence rankings
  are averaged, the top entries include Zambia
  (7), Côte dIvoire (9), Malawi (14), and
  Rwanda (16).

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Major factors affecting launch strategy (1/2)
Decision-making issues and process

• Issues considered in the decision
• Current regimen
• Current use of FDCs
• NTP funding from donors
• HIV prevalence
• MDR-TB prevalence and treatment
• Fluoroquinolone availability, usage and
  resistance
• Quality of the decision-making process
• Past experiences with regimen change
• Timing and mechanisms available for regimen
  change
• Capacity for conducting bridging and
  effectiveness studies

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Major factors affecting launch strategy
(2/2)Introduction, Implementation, and Impact

• Introduction
• Regulatory capacity
• Political stability and corruption
• Implementation
• Current and past TB control performance
• Local production of TB drugs
• Potential impact
• TB burden ( of global within country)
• Ability to act as regional leader
• Extent of private sector market for TB drugs
• Default and death rates