Procurement of internationally quality assured (IQA) second-line drugs (SLDs): past, present, future

12 November 2012

Dr Kaspars Lunte

Team Leader MDR-TB medicines supply, GDF

An initiative of the Stop TB Partnership (2001), hosted in WHO and managed by the Stop TB Partnership secretariat

The mandate of GDF included: • expanding access to quality-assured first-line drugs (FLD)

and diagnostics; and second-line TB drugs (SLD) for GLC approved projects,

• contributing to the development of sustainable procurement and supply management for countries in need

GDF began supplying FLDs in 2001, and in 2008

added regular supply of SLDs, pediatric TB medicines and diagnostics, and is major source

for GeneXpert today

What is the Global Drug Facility?

GDF Facts

• GDF operates without a fee, therefore it is primarily a donor-supported organization (USAID)

• GDF is an agency for placing planned orders

• Has successfully catalyzed rapid DOTS expansion

• Has developed the market for FLDs (Fixed dose combinations and patient kits)

• Substantially increased the number of quality-assured MDR-TB second-line drugs (SLDs) available for procurement through GDF from 11 in 2008, to 32 in end 2011

• Conducts international bidding regularly to achieve competitive, transparent, sustainable for SLDs, pricing

• Has aligned quality assurance policy with the Global Fund

• Provides technical assistance in drug management during periodic in-country monitoring visits

GDF is the largest supplier of anti-TB Products on the public market

In just over 10 years GDF procured :

• 22 M FLD Patient treatments

• 92 398 SLD patient treatments (x 4 in 4 years)

• Orders with a total value of 685 M USD

GDF Model

Client Stop TB Partnership/ Global Drug Facility Procurement

Agents

Manufacturers (pre-qualified)

Quality Control Freight

Forwarders

Business Volume 2011 (US$, ex works)

GeneXpert $6,489,297 New Diagnostics

$6,405,667 FLD $56,511,227

SLD $85,291,452

Countries where we work (2001-2011)

WHO Region Number of Countries

AFRO 39

EMRO 17

AMRO 5

SEARO 10

WPRO 13

EURO 17

Total 101

All are low income countries if receiving grants (is GDF criteria) and low to low-middle income countries if NTP orders by direct procurement

GDF Market and Health Impact - 2012

• Pool of suppliers of IQA medicines established for FLDs and great progress for SLDs

• Predictable quantification, but needs some improvement

• Stabilized access to IQA medicines in WHO -recommended formulations/regimens

• Price per treatment reduced for FLDs and contained for SLDs (with price decrease for some important SLDs)

GDF Market and Health Impact – 2012 (cont)

• Suppliers of non-IQA FLDs pushed out of global market

• New suppliers introduced for SLDs

• FLDs formulations standardized (and available globally)

– FDC to avoid monotherapy

– Packaging for easy dose administration

– Patient kits

• New products promoted

– Kits, pediatrics, diagnostic kits

• Monitoring of use and performance

• Technical assistance

TB Drug Supply Chain Management Cycle

Source 2002-2012 Live report: http://gva1swamphion/sree/Reports?op=vs&path=/WHO_HQ_Reports/G1/PROD/INT/Shared/GDF+Market+share+-+Live+report+Rev+1-May+30+2012&userid=GDF_ro&password=gdfread1

GDF is the largest public sector supplier of quality assured SLD patient treatments

SLD Patient Treatments Supplied Running Total 2002-2012

GDF calculations are based on the recommended length of injectable drug use. The 2011 update of the WHO’s guidelines for MDR-TB treatment recommends to prolong use of injectable drugs from six to eight months. However, the current calculation algorithm for the 2012 is based on the 6 months regimen and may need to be revisited based on the evidence (treatment regimens reported by the countries) in 2013

SLD Patient treatments supplied p.a.

*Data extracted 16/10/2012 +37% increase vs full year 2011

0

5,000

10,000

15,000

20,000

25,000

30,000

2007 2008 2009 2010 2011 2012*

3,494

9,303 10,990

12,420

19,605

26,859

GDF calculations are based on the recommended length of injectable drug use. The 2011 update of the WHO’s guidelines for MDR-TB treatment recommends to prolong use of injectable drugs from six to eight months. However, the current calculation algorithm for the 2012 is based on the 6 months regimen and may need to be revisited based on the evidence (treatment regimens reported by the countries) in 2013

Market shaping role of GDF: experience and future actions responding to

increased SLDs demand

12 November 2012

Dr Kaspars Lunte Team Leader MDR-TB medicines supply, GDF

Pricing examples, USD

GDF Product Code 2010 2011 2012

Am-500/2-(V)-1/(A)-1 amp 1.46 1.22 1.06

Cm-1-(V)-1 vial 3.21* 8.00 5.47

Eto-250-(B)-1 tabl 0.10 0.09 0.07

Lfx-250-(B)-1 tabl 0.06 0.05 0.05

Mfx-400-(B)-5 - 1 tabl 4.38 1.70 1.68

Mfx-400-(B)-70 - 1 tabl 1.00 1.00

PAS-(H)-(S)-30 - 1 sachet 1.88 1.57 1.54

Cs- 250 -(B)-1 caps 0.66 0.59 0.59

Km-1-(V)-1 vial 2.80 2.58 2.58

USD pricelist information: 2010 January 2011 Feb 2012 actual prices

*- concessional price, Eli Lilly

QA and supplier engagement

17

• Global Drug Facility (GDF) –ensuring, via contracted

agents/suppliers, delivery of QA drugs to countries/programs and proactive identification of new potential suppliers.

• Promoting Quality of Medicines Program of USP- USAIDs funded PQM is assisting GDF in its efforts to increase the availability of good quality second-line anti-TB medicines at an affordable price.

• WHO Prequalification Programme (WHO PQ) –

Responsible for prequalification of products and APIs to ensure that products meet international standards of quality before they are procured. Stringent NDRAs also have an important role

Manufacturers Engagement: Roles of Key Players - 1

18

• Programs and Governments – Responsible for planning patient enrolment and treatment; forecasting drug needs; communicating forecasts and delivery schedules to GDF; coordinating with financing mechanisms to ensure payment in advance of supply; facilitating timely registration and importation of drugs; properly managing drugs received.

• Donors and financing mechanisms (governmental and

non-governmental) – Responsible for approving and overseeing expenditures; releasing funds upon demand; advocating with other key actors to eliminate bottlenecks to ensure the greatest possible impact. Defining which QA standards apply to drugs procured with their funds.

• Manufacturers of finished products and APIs: Product

sourcing; receipt of orders for drugs; timely delivery at negotiated or competitively determined prices.

Manufacturers Engagement: Roles of Key Players - 2

GDF Quality Assurance Policy - 1

WHO Report: A Model Quality Assurance System for Procurement Agencies, 2007 http://apps.who.int/medicinedocs/documents/s14866e/s14866e.pdf

• Report recommends that pharmaceutical procurement is restricted to only approved suppliers to ensure that drugs of acceptable quality are procured

• This is reflected in the GDF QA policy implemented June 2010, in full harmonisation with Global Fund QA policy

http://www.stoptb.org/gdf/drugsupply/quality_sourcing_process.asp

GDF Quality Assurance Policy - 2 Prequalification criteria for manufacturers and medicines:

Finished Pharmaceutical Product (FPP) is authorized by the relevant national Medicines Regulatory Authority (NMRA) in the country of use;

AND

1. Product is pre-qualified by WHO under the WHO PQP; OR

2. Product is approved by an SRA; OR

3. Product is found acceptable through a quality risk/benefit assessment process involving an Expert Review Panel (ERP). Time limited approval for 12 months pending WHO PQP or SRA approval

ERP process Interim approval of 12 months under the following conditions:

1. FPP manufactured at an approved site

– Inspected by WHO PQP

– Inspected by an SRA

– Inspected by inspectors of a regulatory authority participating in the Pharmaceutical Inspection Cooperation Scheme

2. Product approval is pending – i.e. dossiers have been accepted for assessment by WHO PQ or SRA

• Objective: adherence with principles of public procurement 1. Best value for money 2. Fairness, integrity and transparency 3. Effective international competition 4. Interest of the organisation

• Evaluation of the tender and awards based on: • Price • Delivery Time • Technical compliance: Quality assurance status, Minimum batch quantity,

Production capacity, Product registration, Shelf life

• Market share allocation* – 65%/35% in case of primary/secondary supplier – 60%/25%/15% in case of primary/secondary/tertiary supplier

*allocation is indicative only, and the actual allocation might deviate due to importation requirements, client preferences, registration status and other factors as deemed necessary by GDF or its clients.

Bidding and LTAs

Importance of additional suppliers

When the number of suppliers increase, total manufacturing capacities increase, also increasing competition between manufacturers, thus impacting positively prices of medicines for the entire TB community

GDF has significantly increased the number of suppliers thus production capacity and access: especially in fragile SLD market

From 2008 GDF SLD demand has quadrupled. Key IQA products manufacturers have increased from 6 to 10 resulting in increased production capacity & prices decrease

Source live report: 2007-2012 http://gva1swamphion/sree/Reports?op=vs&path=/WHO_HQ_Reports/G1/PROD/INT/Shared/GDF+EXW_Order_placed_Report_per_product_count_suppliers&userid=GDF_ro&password=gdfread1

SLD product demand vs. No of Suppliers

Note: Partial data for 2012

GDF Added Value

• Pooled procurement for GDF customers: GDF is able to aggregate demand for anti-TB products for more timely & simplified procurement

• Pricing: GDF conducts international bidding for Procurement Agent (PA) services and for medicines (via PA) regularly in order to achieve competitive, transparent pricing. New SLD bidding due November 19, 2012

• Quantification & Forecasting: GDF assists client countries in identifying their drug needs

• Quality assurance policy aligned with the Global Fund • Technical Assistance & monitoring: periodic monitoring

of GDF clients and identification of their PSM challenges

Is GDF ready to respond to scale-up needs?

GDF is ready to double its SLD business

We are ready today:

– To double its number of patient treatments to 50 000 on short notice : 3 to 6 months

and

– Can deliver treatments for all global cases to be enrolled by 2015 as per Global TB report 2012

If funding ensured and no delays in payment from projects/donors to procurement agent for the medicines

Capacity analysis of SLD manufacturers, September 2012

29

• GDF has updated the available information on existing and potential manufacturers capacities of selected SLDs

• The SLDs studied were based on following criteria:

– Only MDR-TB specific products (no widely available products such as fluorquinolones (i.e. levofloxacin), used for other indications were studied)

– 4 SLDs contribute to 80% of a standard regimen and the costs of it (PAS products combined (sodium and acid formulations), cycloserine, kanamycin and capreomycin)

• Questionnaires were sent to 9 eligible and high potential future manufacturers of these 4 SLDs on 12/09/2012.

• GDF continues engagement work with more potential suppliers.

• No of treatments required for each of the 4 major SLDs (for total 50 000 treatments) was estimated based on their respective share in the regimens as provided by GDF to our clients

Introduction

100% of manufacturers provided the information within deadline

Important comments received:

• The manufacturers don't see the scale up materializing in their orders yet

• Order consolidation via stockpile is seen to be key for regular order placement and reaching the minimum order quantity (MOQ)

• Additional scale up steps are possible such as introduction of additional shift, re-planning of manufacturing lines, this can be done on short notice

• Increase even further of the manufacturing capacity is possible via obtaining new/larger/higher capacity machinery.

• Investments to be justified via firm order commitments from GDF (Olainfarm, Vianex)

General feedback

Assumptions • All suppliers mentioned will become/stay eligible • No new manufacturers by 2015 (opposite scenario

much more likely) • GF directs all their SLD grants via GDF • Full funding and in-country capacity to treat is

ensured • No API supply interruptions • No registration bottlenecks in countries • GDF can justify and commit to future orders to

increase the existing capacity even further (especially for PAS products)

Source: Global tuberculosis control: WHO report 2012

Global estimations 2012

Expected cases to be enrolled

Kanamycin Capacity in patient treatments, all potential suppliers vs current GDF deliveries vs global cases expected to be enrolled

0

10,000

20,000

30,000

40,000

50,000

60,000

70,000

GDFdeliveries

Capacity GDFdeliveries

Capacity GDFforecast

Globalreport

Capacity Globalreport

Capacity Globalreport

Capacity

2011 2012 2013 2014 2015

Macleods

Panpharma

Meiji

40% of 50 000 treatments contain kanamycin

Capreomycin Capacity in patient treatments, all potential suppliers vs current GDF deliveries vs global cases expected to be enrolled

0

10,000

20,000

30,000

40,000

50,000

60,000

70,000

80,000

90,000

GDFdeliveries

Capacity GDFdeliveries

Capacity GDFforecast

Globalreport

Capacity Globalreport

Capacity Globalreport

Capacity

2011 2012 2013 2014 2015

Macleods

Hisun DP

Aspen

Akorn -IN

Vianex

Akorn -US

Lilly

50% of 50 000 treatments contain capreomycin

Capacity in patient treatments, all potential suppliers vs current GDF deliveries vs global cases expected to be enrolled

Cycloserine

-

10,000

20,000

30,000

40,000

50,000

60,000

70,000

80,000

90,000

GDFdeliveries

Capacity GDFdeliveries

Capacity GDFforecast

Globalreport

Capacity Globalreport

Capacity Globalreport

Capacity

2011 2012 2013 2014 2015

Dong A

Biocom

Aspen

TCC

Macleods

100% of 50 000 treatments contain cycloserine

Capacity in patient treatments, all potential suppliers vs current GDF deliveries vs global cases expected to be enrolled

PAS sodium and acid formulations

0

10000

20000

30000

40000

50000

60000

GDFdeliveries

Capacity GDFdeliveries

Capacity GDFforecast

Globalreport

Capacity Globalreport

Capacity Globalreport

Capacity

2011 2012 2013 2014 2015

Macleods

Jacobus

Olainfarm

70% of 50 000 treatments contain PAS

GDF initiatives

1. SLD is a small market

2. Little incentive for manufacturers to enter the IQA SLD Market

38

MDR-TB Public health problem of access

Demand Side Half a million people are estimated to have MDR-TB today, with little progress in diagnosing and treating them

The complexity of treating MDR-TB has limited rapid scale up and thus demand:

Diagnosis is technically challenging, time consuming and relatively expensive: many countries fail to diagnose and enroll cases planned for their GF projects

Treatment must be tailored to individual drug resistance profile, treatment lasts 2 years and can cause debilitating side effects

Drug intake is very complex: 4-5 drugs have to be taken every day for 24 months, with one injectable to be used daily for 6-8 months

Drugs are expensive and countries have insufficient funding to procure IQA SLDs from GDF

MDR-TB expansion is slower than expected

1. SLD is a small market

Public market for IQA SLDs estimated for 2013, is just $150-170 million (GDF projections)

SLD orders are often small in scale and unpredictable – sometimes come to GDF as emergency requests due to in-country capacity problems

Manufacturing of API is limited to very few sites (monopoly)

Combined global demand for IQA SLD is below the “comfort” level required for efficient and profitable manufacturing (full batch and continuous)

Manufacturers must make significant investments, especially for QA certifications and in-country registration requirements. Supplier prequalification requires 18 - 24 months or longer

For most manufacturers, SLDs are just a small fraction of their total sales, which makes MDR-TB much less attractive

2. Little incentive for manufacturers to enter the IQA SLD Market

39

MDR-TB Public health problem of access

Supply Side

Expected impact

GDF worked with technical partners to develop following initiatives:

(1) Global Strategic Stockpile

(2) Flexible Procurement Fund

Greatly reduce lead times (from 4-6 months to 4-6 weeks) Avoid unnecessary drug stockouts Maintain quality and supplier base for the FLD and SLD market Sustain, then further reduce prices, gradually Contribute to better global forecast of FLDs and SLDs – with partners

s

40

Two New Initiatives

2 New initiatives

With Donor Support – to a New Paradigm

41

GDF would build on the

existing stockpile for SLDs

Flexibly manage supply

of FLDs and SLDs Stabilize

SLD market (e.g. APIs and

prices)

Larger stockpile would

require at least 300 000

FLD and up to 16 000 SLD

patient treatments

FPF would mitigate funding delays on the demand side

Ensure procurement volume commitment to suppliers Increase availability of medicines

Reduce threat of stockouts

Promote efficiency of the reordering process

Bridging gaps caused by funding delays from donors and clients

“production to order”

to a

“production to stock”

paradigm

allowing building of

stocks in anticipation of

firm orders with

significantly lower lead

times

The Global Strategic Stockpile (GSS)

The Flexible Procurement Fund (FPF):

GDF manufacturers will shift from a

42

1. Public Health Impact - in one year’s time:

– Increased number of countries served via the GSS and FPF

– Reduced risk of supply interruptions

– Reduced lead times for standard orders

– Growth in the IQA SLD market based on increased orders placed

2. Sustainable Market Impact – in three years’ time.

– Reduction in the cost of overall SLD treatment regimens over 3 years vs. 2011 costs, due to a reduction of the inefficiency, demand risk and monopoly premiums currently built into SLD prices

– Increased market share for GDF, allowing pooled procurement to function at its best

– Increased number of IQA suppliers available in the market

Expected Impact of the Paradigm Shift

Registration of medicines in countries:

– Problem: registration requirement and stringency differs by country:

• No registration required: (e.g. Mexico, Afghanistan); importation through waiver: (e.g. China); full registration (e.g. Russia, Kenya)

• Increasing trend is towards full registration; and harmonization among countries is rare

• Some requirements mean a large investment of resources (financial and time) compared with size of sales; cost of registration can range from a few hundred dollars to more than 10 000 USD per product (e.g. Russia)

– Solution: Entity to be identified, which would incentivize manufacturers to enter smaller countries by: covering registration fees, translation services

Additional Needed interventions

Conclusion

Live Report 2008-2012: http://gva1swamphion/sree/Reports?op=vs&path=/WHO_HQ_Reports/G1/PROD/INT/Shared/Survey_Report_Rev1&userid=GDF_ro&password=gdfread1

From 2008, 130 Feedback surveys were received from GDF customers – as a systemic control of GDF quality of service and performance (ISO 9001)

GDF service is highly rated by its customers

GDF is the one-stop solution for quality assured anti-TB products

GDF can respond to the current scale up plans for MDR-TB

Thank you!

Back up

TB-specific medicines in the regimen contributing to 80% of the costs

Item Form Dose

Units per patient course, average

=Units*days*months

Proportion in the drug group

Share of treatments required for total 50 000

treatments

Injectable

Amikacin ampoules/vials 500 mg 416 10% 5,000

Capreomycin vials 1 g 208 50% 25,000

Kanamycin ampoules/vials 1 g 208 40% 20,000

Oral bacteriostatics

Cycloserine capsules 250 mg 1560 100% 50,000

PAS products combined sachets 4 g 1040 70% 35,000