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Dear All,

Welcome to this week-long expert panel discussion on managing second line anti-TB drugs (SLD). Starting today, we invite you to ask questions and share your experiences on this topic with our group of panelists led by Dr. Masoud Dara, Team Leader of the Tuberculosis Programme in the Division of Communicable Diseases, Health Security & Environment at WHO Europe, and GHDonline Moderator:

- Dr Lucica Ditiu, Executive secretary StopTB Partnership
- Dr Kaspars Lunte, Team Leader MDR TB supply WHO-Global Drug Facility
- Dr Ernesto Jaramillo, WHO HQ, policy guidance and palliative care

Portfolio Manager of the Global Fund Mrs. Sandra Irbe will also join the discussion.

Feel free to answer some of these initial questions:

- What issues do you face with the supply of SLD? Are there big time lags between order and delivery for example?
- Have you been affected by price increases of SLD and what is the impact on your work?
- How are you funding drug procurement for MDR-TB?
- What does the cancellation of Round 11 mean to you, your program, and for the population you care for?
- Are you applying to the TFM and if so how do you prioritize funding request?

We look forward to the conversation and please invite colleagues to join. Thank you.

Attached resources:

Link leads to: http://www.stoptb.org/gdf/drugsupply/psmtools.asp

Link leads to: http://erc.msh.org/toolkit/toolkitfiles/file/TB-Primary-Level-Guide-April-2008_final-English.pdf

Link leads to: http://www.theglobalfund.org/en/application/

 
Vadim Testov
Replied at 2:11 AM, 20 Feb 2012

In 2007-2008 Russian GLC approved projects faced with a fair number of problems on initial stage SLD procurement through GLC mechanism. It took 24 months to negotiate, sign the first contract with IDA, to make an order and to effect the delivery (incl. 22 months from the date of prepayment to the date of delivery).The latest contracts took 8-9 months only.
Problems with processing of first contracts:
- limited quantity of IDA suppliers;
- lack of Russian registration for SLD offered by IDA suppliers;
-complicated system of Russian drug import in humanitarian/technical aid (GF requirement);
-miscommunication among participating national and international partners at early stages of program implementation.
These factors were not taken into account while preparation of application to GF Round 4 and program planning.

Masoud Dara, MD
Replied at 2:42 AM, 20 Feb 2012

Dear MDR-TB community and colleagues,

We have now an excellent opportunity to discuss the critical issues that concerns many countries. Most countries have moved or are moving from project to programmatic approach to prevention and control of M/XDR-TB and yet there are many challenges, particularly in management of second line drugs.

I would like to welcome our panelists and members to this week's online discussion. and thank you Vadim for already starting discussion with providing some feedback.

Does your country have enough quality assured second line drugs, if not what are the problems? If you have no problem with procurement and supply of drugs, which measures was taken to reach this stage? Which actions do(es) you or your institutions take to ensure availablity of resources and rational use of medicines? What are the key challenges and suggested next steps from your point of view? What do GDF and GFATM offer?

Please share your thoughts, expriences and views?
Thank you and best regards,
Masoud

Dr Kaspars Lunte
Replied at 7:23 AM, 20 Feb 2012

Dear Vadim,
first of all thank you that you appreciate improvements in cooperation with GDF and its procurement agent!
This is what we in GDF do strive continuously towards: improving the process, starting with speed of replies and ending with shortening the leadtimes as much as possible (but standard leadtimes are standard anyway)

However you are rising very important issue about the in/country registrations. This indeed is crucial as more and more countries seem to switch to mandatory registration instead of one time importation waivers.

Is there any opportunity at the country level to assist the manufacturers? Is the country willing to fasttrack the registration for WHO PreQualified products?

Some important questions for consideration!

Best regards
Kaspars

Lucica Ditiu
Replied at 12:11 PM, 20 Feb 2012

Dear all,
welcome to this Forum and we hope that this will generate a lot of interest and discussions on MDR TB and DR TB , access to proper diagnosis and care for all the people suffering because of it.
In this difficult financial environment, with a GF Round 11 cancelled, with a strict Transitional Funding Mechanism from the GF, with less donors interested in financing public health and even fewer interested in TB - how do we make our voice heard and make the point that DR TB and MDR TB is an atrocity, a crime that we should speak up about?

What should we do in order to make sure that the decision makers in countries are aware of what TB and DR TB means, how cost efficient is to ensure the proper treatment of sensitive TB before we create DR TB, which costs us so much in terms of financial costs but more than that, in terms of suffering costs?
We in the Stop TB Partnership Secretariat decided that PEOPLE - especially people affected and suffering because of TB should be on the first place. All our actions should be linked to delivering for them and for ensuring their proper access to treatment and care, no stigma attached. Are we delivering in this direction? What can we do more and how?

2015 is around the corner and achieving the MDGs will be a challenge. We need to start thinking beyond 2015 and with this in mind, we need to make sure our actions are relevant today.
We, however, need to have the inputs of people working at the grassroot level and, most and foremost, we need to have the input and support of the people suffering because TB and DR TB.
This Forum will help us to have this.

Sandeep Saluja
Replied at 5:12 PM, 20 Feb 2012

One of the major problems in clinical practice is to decide how far to rely on drug susceptibility reports in planning a regimen.May I please seek your expert guidance on the matter?

Sergey Strashuk
Replied at 11:27 AM, 21 Feb 2012

Dear colleagues,
First of all I would like to thank you for opening of the discussion on such important issues. Ukraine is in process of GF Round 9 implementation and on the stage of contract preparation with IDA. We started our activities from 2011 and faced a lot of problems that are in many aspects similar to those that Vadim described in his message.
The main problem is lack of drugs from eligible suppliers registered in Ukraine (especially for kanamycin and capreomycin). The process of registration is rather complicated in Ukraine and eligible producers are not willing to register their products here. We tried to solve the problem and encourage our Ukrainian suppliers to pass the prequalification procedure. They managed to obtain GMP certificate but while preparing the dossier for prequalification they collided another problem - impossibility to get the reference products for Kanamycin as far as the existing eligible producers simply refused to give the products.
The only option left for Ukraine was to get the permission for one-time waiver. Only when all other resources had been used after 9 months process of negotiations we obtained the permission from Ministry of Health (MoH) of Ukraine.
Another problem is that manufacturers lose their eligibility status too often and it put the realization of project under threat. We applied to MoH regarding one time waiver several times and each time we had some changes in the list of medicines or eligible manufacturers.
Ukraine authorities are ready to fasttrack the registration for WHO PreQualified products but they can not force producers to register the drugs. Ukrainian suppliers are ready to start prequalification procedure but they need more assistance from international organizations in the process of dossier preparation or probably some changes in this procedure.

Thank you.

Masoud Dara, MD
Replied at 11:45 AM, 22 Feb 2012

Dear Sandeep,

Thank you for your excellent question. The result of the meta-analysis conducted recently and published in the WHO Guidelines for programmatic management of drug resistant TB 2011 update mentions: Use of drugs to which the strain was reportedly susceptible showed a marginal benefit when compared with their use regardless of susceptibility patterns. The metanalysis included 32 studies with more than 9000 treatment episodes.
Choice of drug would thus depend on the DST of the strain isolated from the patient or close contacts with MDR-TB, previous use of the drug in the patient, and the frequency of its use or
documented background drug resistance in the setting. In applying this observation to
clinical practice, it is important to underline the uncertainties around the reproducibility
and reliability of DST of pyrazinamide (and ethambutol), as well as the secondline
drugs other than the parenteral agents and the fluoroquinolones.

We also need to hear from our lab experts in our community on the reproducibility and reliability of DST.

All the best,
Masoud

Masoud Dara, MD
Replied at 12:09 PM, 22 Feb 2012

Dear colleagues,

Sergey is pointing to a very important problem, we have been discussing this with the health authorities in Ukraine and it is sad to see the problem still exists. Meanwhile the patients are waiting for treatment. Dear Andre and Kaspars, what do you think as drug management experts?

All the best,
Masoud

Sophie Beauvais
Replied at 2:48 PM, 22 Feb 2012

Dear All,

Many thanks to those who have participated so far. Here's a recap, please continue posting questions and sharing your experiences with GDF and second line drugs before the end of the week for discussion with our experts.

On the question of how far does one rely on drug susceptibility reports in planning a regimen, Dr. Masoud Dara commented today that: “The result of the meta-analysis conducted recently and published in the WHO Guidelines for programmatic management of drug resistant TB 2011 update mentions: Use of drugs to which the strain was reportedly susceptible showed a marginal benefit when compared with their use regardless of susceptibility patterns. The metanalysis included 32 studies with more than 9000 treatment episodes. Choice of drug would thus depend on the DST of the strain isolated from the patient or close contacts with MDR-TB, previous use of the drug in the patient, and the frequency of its use or documented background drug resistance in the setting. In applying this observation to clinical practice, it is important to underline the uncertainties around the reproducibility and reliability of DST of pyrazinamide (and ethambutol), as well as the secondline drugs other than the parenteral agents and the fluoroquinolones.”

Dr. Dara also asked the following questions:
- Does your country have enough quality assured second line drugs, if not what are the problems?
- If you have no problem with procurement and supply of drugs, which measures were taken to reach this stage?
- Which actions do(es) you or your institutions take to ensure availability of resources and rational use of medicines?
- What are the key challenges and suggested next steps from your point of view? What do GDF and GFATM offer?

Participants thus far have responded by identifying the following issues:
- Process too long
- Lack of suppliers registered in-country
- Complicated registration process for suppliers: they need assistance
- Complicated drug import system
- Miscommunication

What can be done/is done to address these?

We've heard from members in Russia and Ukraine: Vadim Testov shared that in Russia “It took 24 months to negotiate, sign the first contract with IDA, to make an order and to effect the delivery (incl. 22 months from the date of prepayment to the date of delivery).The latest contracts took 8-9 months only.” He also raised issues with limited number of IDA suppliers, lack of Russian registration of SLD, complicated drug import system, and miscommunication. Sergey Strashuk in Ukraine pointed to the same issues, noting that finding in-country suppliers for kanamycin and capreomycin is especially difficult, and that manufacturers lose their eligibility status too often which threatens the work of many.

Dr. Lunte of the GDF said that speed of replies and lead times are among the first things to improve. He also noted that countries are moving away from one-time waivers in favor of in-country registrations. But that process is complicated. “Is there any opportunity at the country level to assist the manufacturers? Is the country willing to fast-track the registration for WHO PreQualified products?” he asks.

What is the situation in your country? Thank you in advance, Sophie

Sandra Irbe
Replied at 3:48 PM, 22 Feb 2012

Dear colleagues

From the point of view of implementation of the Global Fund grants I would like to emphasize the need of advance planning of procurement and submission of the drug order early in advance in order to account for the long delivery time.

For countries that have been importing drugs with one-time humanitarian waivers and that are likely to transition to government funding for TB drugs in nearest future it is important to ensure that state procurement regulations do not impede procurement of quality assured pharmaceuticals on international market. If changes in the legislation need to be made and I think that TB is to be considered as worth the exceptions to the current procurement rules, these legislation changes have to be initiated with immediate effect. The GF grants could provide resources for legal assistance in pushing for these changes. I am sure that WHO also has consultants who are well versed in the legislation matters.

Sandra Irbe
(Message sent from a portable device)

Sandeep Saluja
Replied at 3:56 AM, 23 Feb 2012

Very often in clinical practice,decisions on choice and duration of drug therapy are based on purely clinical and circumstantial evidence.Lab support may not be there and as mentioned has limitations.
It may be a good idea to have a clinical forum(with somewhat restricted access),just to discuss actual clinical cases arising out of suspected or proven drug resistance.Would someone or some organisation like to initiate it?

Francoise NYWAGI LOUIS
Replied at 4:39 AM, 23 Feb 2012

Thanks Sandeep; I feel the idea of a clinical forum is excellent. Why not having it within the GHD frame. I am for an open forum, since anyone can learn, even if not his/ her specialization! I have learnt a lot here on HEPA filters and UVGI lights!
What do others think?
Cheers
Francoise

Natalie Lorent
Replied at 4:45 AM, 23 Feb 2012

I strongly support the idea. I have submitted clinical cases to this forum and always had very considerative and helpful replies. It may even create more evidence on this difficult topic…

Natalie

Olivera Bojovic
Replied at 5:40 AM, 23 Feb 2012

Dear Lucika,
Since Montenegro has a small number of MDR patients (around 2-3 per year), it is very difficult (and expensive) to provide a continuous supply of quality first and second line drugs. For the first line drugs, pharmaceutical companies do not show interest in applying to the tenders announced by the Government, while for the second line drugs, the companies are not interested in shipping such a small quantities of drugs (a previous supplier was from India but he has notified that they will do the drugs shipping only if we there is a big order from region). We have learnt that there might be some procedural changes in applying for GLC. We have tried to find out from them whether there is going to be a shorter, more simple version of application for countries with small number of patients, or would they have to pay smaller annual fee but unfortunately their representatives could not have been specific in replying to these questions.

Mary Nnankya
Replied at 5:42 AM, 23 Feb 2012

I would very much agree with Francoise, a forum ristricted to clinicians only would limit valuable experties from Lab support which is indispensable in order to "get it right". Since we have this online GDH facility why not make the most it by starting the discussion. Mary

Philippe Creach
Replied at 5:54 AM, 23 Feb 2012

Dear All,

Did you consider regional procurement of SLD ? Balkans, Southern Caucasus, Central Asia... ?

Best wishes,

Philippe Creac'h

Paul Nunn
Replied at 6:21 AM, 23 Feb 2012

Many thanks for the interesting inputs to date, but nobody has yet mentioned the price of the drugs, which we see as one of the main bottlenecks for wider availability of treatment for MDR-TB. Is this perceived as a barrier at country level? As the Global Fund resources shrivel (at least for now), will it be seen as a greater barrier? The average price for a regimen provided through the GDF to India is nearly $6000 and these will be internationally quality assured (IQA) drugs, assured through "strict" national drug regulatory agencies, through the WHO Prequalification system, or recommended by the ERP Committee of the Global Fund. However, the same chemical entities are obtained by India through their tendering process for around $2400. These latter drugs are approved by the Indian drug control authority using their "Schedule M". Why does this enormous cost difference exist? What can be done to reduce it?
We have seen that the speed of delivery of SLDs through GDF has improved noticeably in recent years. There are still problems of lack of availability because of events (mainly) outside GDF's control, such as contamination of the single supplier API (kanamycin), and the tsunami and subsequent reduction in electricity supplies in Japan (also kanamycin). These kinds of obstacles show, however, that there is a need to widen the number (and geographical distribution?) of API suppliers, as well as of manufacturers of the finished pharmaceutical product. Thus, what we are now seeing in WHO with respect to the delays that occur in delivery of SLDs is that the bulk of the delays are at country level (eg failure to make the order) or at the Global Fund (eg failure to ensure the funds are available).

Dr. Daniela Cirillo, MD, PhD
Replied at 7:08 AM, 23 Feb 2012

Regional procurement can be an important strategy for Country with a small number of cases per year. The balkan region is a very good example
Daniela Maria Cirillo, MD PhD
Head of Emerging Pathogens Unit
WHO Collaborating centre for integrated laboratory strengthening on
tuberculosis and other emerging infections
San Raffaele Scientific Institute
San Gabriele Building
Via Olgettina 58
20132 Milano , Italy
Ph +390226437947
Assistant Mrs G Graziano

Paul Nunn
Replied at 9:42 AM, 23 Feb 2012

In response to Olivera Bojovic's posting:
For accessing SLDs within the NEW GLOBAL FRAMEWORK TO SUPPORT SCALE UP TO UNIVERSAL ACCESS TO QUALITY MANAGEMENT OF MDR-TB a separate application to the GLC is no longer needed. Please fill in the procurement request form (can be downloaded from http://www.who.int/tb/challenges/mdr/greenlightcommittee/procurement_form_201... )
and submit it directly to the Global Drug Facility at and to Argimiro Garcia at with copy to . You will be provided with a quote and once you agree and payments are made, you will be informed about the lead-time for the delivery of the drugs to your country.

For countries with low MDR TB burden using Global Fund funds for the procurement of SLDs through GDF and accessing technical assistance services through the GLC framework a reduced Cost-Sharing-Element of 25,000 USD per year can be expected. For countries with just a handful of patients, this amount has bee negotiated down still further in the past.

Please also note that in July of last year a regional GLC was set up to support the implementation of MDR TB management and provide technical assistance if and when needed. Please feel free to contact the regional GLC/Europe at any time at . Please note that GLC/Europe is encouraging countries to develop and update existing National M/XDR-TB response plans and align them with Regional Action Plan to Prevent and Combat M/XDR TB in WHO European region, 2011 – 2015 http://www.euro.who.int/__data/assets/pdf_file/0014/152015/e95786.pdf .

All information can also be accessed at http://www.who.int/tb/challenges/mdr/greenlightcommittee/en/ , http://www.stoptb.org/gdf/ and http://www.euro.who.int/en/what-we-do/health-topics/communicable-diseases/tub... .

We hope this is helpful. Should you have any further questions, please do not hesitate to contact us at: .

With best regards,
Susanne Carai
On behalf of the gGLC secretariat
and
Ogtay Gozalov
On behalf of GLC/Europe secretariat

Dr Kaspars Lunte
Replied at 9:53 AM, 23 Feb 2012

Dear all, very happy about active sharing of ideas and thoughts!
With this message I would like to highlight paragraph from Sandras message:
"For countries that have been importing drugs with one-time humanitarian waivers and that are likely to transition to government funding for TB drugs in nearest future it is important to ensure that state procurement regulations do not impede procurement of quality assured pharmaceuticals on international market. If changes in the legislation need to be made and I think that TB is to be considered as worth the exceptions to the current procurement rules, these legislation changes have to be initiated with immediate effect. The GF grants could provide resources for legal assistance in pushing for these changes."

Can anybody share experiences of using GF grant to push for so much needed legislation change?
That would be very interesting and important.

Thanks
Kaspars

Alberto Colorado
Replied at 3:44 PM, 23 Feb 2012

Dear acTBistas. Thank you for this great discussion on SLDs. Could you please talk about the global deficit of quality assured kanamycine? Thank you. Alberto

Dr Shanta Ghatak
Replied at 8:12 PM, 23 Feb 2012

Dear colleagues
All said and done , SLD storage and procurement processes are hardly
timely/efficient . Patients wait and die before even treatment intiations
and now this discrepancy of the payment structure for the laboratory
technicians and the SUPERVISORY CADREs has cretaed havoc for the TB program
all over India. ALL have been put under the same payment structure? Silence
over this issue is inexcusable.
How long will this inefficiency help the hapless TB patients?
Understanding the ground work and allocating resources for these helping
hands would have definitely have a positive impact .
And in India - central and north east : the reality is different. Work
ethics and accessibility should be considered as most important. Blanket
regimens and rough data analysis to be done by third party if possible?
Thanks

Tine Demeulenaere
Replied at 2:40 AM, 24 Feb 2012

worldwide: finding Clofazimine and Gatifloxacin for the Bangladesh is often a problem: recurrent for Clof, and worsening for Gati. Producers in India and one in Bangladesh have stopped producing the latter.

Tine Demeulenaere
Replied at 2:41 AM, 24 Feb 2012

sorry, I meant the Bangladesh regimen, not just the country...

Lucica Ditiu
Replied at 2:48 AM, 24 Feb 2012

On the Clofazimine - we are trying - from geneva, I mean - to contact Novartis and see what is possible related to availability and costs. This is and will remain a difficult matter.

Dr Kaspars Lunte
Replied at 2:52 AM, 24 Feb 2012

Dear Alberto,

Let me kindly clarify on your posting:

For GDF, there is no shortage of kanamycin 1g injectable.

What is often perceived as shortage basically is problem in planning at the program level.

Unfortunately there are many cases when program is approaching GDF with last minute requests for kanamycin and the standard leadtime (4-6 months for all products) is not considered.

This then causes our reply that the product is not immediately available as we order fresh product from the approved manufacturer to guarantee most fresh product. For the SLDs the shelf life is just 24 months after the product is manufactured.

Hope this clarifies the situation and I can really urge to approach GDF better sooner than later: we would then be able to accomodate programs requests and even agree about split delieveries to guarantee best shelf life of the quality products we procure.

Best regards
Kaspars Lunte

Dr Kaspars Lunte
Team Leader MDR TB supply WHO-GDF
------------------------
Sent from my BB Terminal

Dr Kaspars Lunte
Replied at 3:21 AM, 24 Feb 2012

Dear all,

Would like to support Pauls message on the crucial importance of diversifying the risks to ensure uninterrupted supply of SLDs.

Just let me start with clarification on the treatment costs per patient: it first of all depends on the regimen chosen: some countries prefer to use capreomycin instead of cheaper injectable, are willing to use more expensive PAS product etc. This contributes to higher treatment cost per patient. But, of course, for that there is clear justification.

On the lower end though, the regimen of quality medicines procured via GDF could be as low as less then 3000 USD per patient.

Also, if need exists to compare cost per patient treatment, this can be done only if «apples are compared with apples»: the regimens using only QA quality medicines, approved by WHO PQP or Stringent DRAs, so comparison with India schedule M would not be really valid.

Now, coming back to diversification of risks, GDF is constantly looking to widen the number and/or geographies of our suppliers. This is also contributing to positive pricing dynamics.
Also to note that diverse quality approved API sources are of crucial importance.

We in GDF cooperate with our colleagues in WHO Prequalification program and provide link for eligible TB manufacturers for free technical assistance from Promoting Quality of Medicines program of US Pharmacopeia.

This serves the purpose to ensure we have larger pool of approved suppliers of both, API and finished product suppliers for the foreseeable future.

Just to indicate practical example: I am writing these lines while driving back to Shanghai from meeting with potential manufacturing partner in Zhejiang province.

This concludes series of important meetings of this week with selected SLD manufacturers in China, and the potential is big here.

Also, next week GDF will present its business opportunities is South Korea in dedicated meeting called by PQM: more that 100 participants confirmed their attendance already!

With best regards,
Kaspars Lunte

Dr Kaspars Lunte
Team Leader MDR TB supply WHO-GDF
------------------------
Sent from my BB Terminal

Liana Kasyan
Replied at 3:24 AM, 24 Feb 2012

Dear MDR-TB community and colleagues,

I would like to answer on above mentioned questions.

1.The time lag between the order and delivery is generally 6 months which is considered before the order.
2.At this moment we have no any problem relate to price increases. Because the price increase for the SLD was considered while the budget calculations were made.
3. The MDR-TB drugs procurement is funded by the Global Fund and is procured through IDA.
4. The Round 11 was targeted in: financing performance incentives for doctors/nurses and patients/family for successful completion of each new sputum smear positive pulmonary TB case (500 cases yearly); financing targeted activities of prevention and treatment of TB at migrants, women and pediatric groups of population in Armenia. So we may have funding shortages to complete these activities.
5. At this moment we are not planning to apply for the TFM.

Thank you in advance for comments.
Liana Kasyan
WHO CO in Armenia.

1.

tony wilson
Replied at 4:37 AM, 24 Feb 2012

But here in Uganda we have no available drugs for MDR-TB treatment despite
the number of patients. No prizes for guessing whether the delay is at
country level or Global Fund level. Tony Wilson

grania brigden
Replied at 4:38 AM, 24 Feb 2012

I agree the cost of quality assured SLD is a major factor in limiting scale up of DRTB programmes. In “DR-TB drugs under the microscope” the prices of the quality assured drugs procured by GDF are shown along with access issues that affect each drug. It also shows that the three main contributors to the high cost of DR TB regimen are Capreomycin, Cycloserine and PAS.

As diagnostics improve and countries commit to scaling up their DR-TB programmes there needs to be discussions to ensure that the trend of rising drug prices is reversed. There are many possible ways to achieve this from greater transparency behind the costs, considering drug costs when deciding a regime ( for example not using PAS and Cycloserine), consolidating the market in quality assured drugs to pooled procurement among countries in regions. There also needs to better forecasting so that manufacturers can predict and plan for what is hopefully going to be an expanding market.

I have found this discussion very interesting. There is definately a need to work to find a way to stop drug costs being a barrier to scale up.

Thanks,

Dr Grania Brigden
TB advisor
Médecins Sans Frontières- Access Campaign
Geneva, Switzerland

www.msfaccess.org

Attached resource:

Salem Barghout
Replied at 9:26 AM, 24 Feb 2012

Dear Kaspars and MDR Colleagues:

I have been reading through these very interested and lively discussions re. the very hot topic of SLD. Please allow me to share my personal views on this topic from my experience in EMR and especially in Pakistan. Although some countries might prefer to use Capreomycin however, at least in our area, injectables are selected based on the clinical history, previous use of SLD, DST pattern and drug availability. For more than a year, Capreomycin has not been available through GDF and we had to use Amikacin instead although, in many cases such as XDR, Capreomycin would have been the drug of choice but unfortunately it was not available yet. All of this is to say that personal preference plays, at least in our region, a very little role in treatment selection and the cost of treatment regimen per patient, using QA SLD through GDF, has been anywhere between US$ 5-6 Thousands.
The other issue, which is the long lead time from the time of pre-payment until SLD delivery, must be urgently addressed and shortened knowing that this problem has not been getting any better. I realize that there are many factors effecting this condition and many of them are probably beyond GDF's responsibilities but I am taking this opportunity to call upon the Global community to work together in order to bring this matter to a reasonable time, say 2-3 months at the maximum. May be I'm dreaming but that's ok to have some good dreams.

Regards,

Salem Barghout


Salem Barghout, MD
MO/MDR-TB/WHO-Pak
Cell: + 92 300 8599580
WHO GPN: 62481
E.Mail:

Jennifer Furin
Replied at 10:06 AM, 24 Feb 2012

Dear Colleagues:
Thank you for participating in this panel, which brings together many of the leaders in TB and MDR-TB control. I would ask if members of the panel could please comment on the status of pediatric second-line antituberculous drugs. Currently, the only second-line agent available in a pediatric form is PAS with the Lucane PAS pediatric dosing spoon. As the panel knows, there are tens of thousands of children in need of MDR-TB therapy. Programs currently treating children have to manipulate the tablets and capsules intended for adults. This leads to inaccurate dosing of these medications in children. I recognize that developing pediatric formulations of medications can be difficult and costly. However, reasonable modifications to the adult tablets (i.e. scoring the tablets for division into quarters) could be rapidly implemented and improve pediatric MDR-TB care.
Children with drug-resistant TB are not being offered appropriate or timely therapy and this leads to excess morbidity and mortality from the disease. When HIV treatment was scaled up, pediatric formulations of ART were available and contributed to saving tens of thousands of children's lives. I would appreciate a comment from the expert panel on what is being done to develop and make available pediatric-friendly formulations of second-line anitutberculous agents.
Thank you,
Jennifer Furin, MD., PhD
Case Western Reserve University
TB Research Unit

Masoud Dara, MD
Replied at 10:23 AM, 24 Feb 2012

Thanks Tine for your feedback. Which countries are using Bangladesh regimen at this level?
It seems that our advocacy for bringing/keeping the price down has worked against further expansion of production by pharmaceutical companies.
All the best,
Masoud

Philippe Creach
Replied at 10:45 AM, 24 Feb 2012

Dear Salem,

I hope that you are not dreaming since an average lead time of 6 months to deliver SLD is, somehow, astonishing. I can not imagine, in any private company, such a lead time for a product much in demand and need. If I would go to a private pharmacy for aspirin and the pharmacist would answer me that he needs to start the production, I would be astonished as well.

I guess that we have clear estimates now on the number of patients in need of SLD thanks to the GLC, DRS...So, the forecasting of needs should not be an issue. It seems that we did not move much from the approach at the very beginning of the GLC: the exact number of pills started on procurement according to the exact number of patients in a GLC application.

I was reading in this forum that the Global Fund was cited as a bottleneck as it fails to deliver the needed financial resources. Well, this is surprising as it is the main funding party.

To come back to lead time, it is so long in some instances that it has prompted countries to request refund before replacing the same order not to be at odd with its national legislation. This is inefficient.

Sorry for being intense on this topic but the approach should be reviewed.

Best wishes,

Philippe Creac'h

Alberto Colorado
Replied at 7:50 PM, 24 Feb 2012

Thank you Kaspars, unfortunately patients suffer because of the lack of timely requisition of SLD by some TB programs among other administrative issues. To prevent this unnecessary pain, in Latin America, we are trying to scale-up the engagement of the civil society role and have citizen monitors of TB care and programs.
Best regards,
Alberto Colorado
Patient Advocate
International Public Health Consultant
Advocates for Health International
San Diego, California. USA

Tel: (619) 460-6630
Google tel: (619) 609-7058
Skype: acTBistas
Twitter: acTBistas
Youtube: http://bit.ly/lK3D0A

Alberto Colorado
Replied at 8:20 PM, 24 Feb 2012

Dear acTBistas,
People are following this discussion on my social media platforms. Today, I received this question from Chile. "What innovative actions from a social perspective can be used for treatment compliance of MDRTB patients?" any response from the panel?
Alberto Colorado
Patient Advocate
International Public Health Consultant
Advocates for Health International
San Diego, California. USA

Tel: (619) 460-6630
Google tel: (619) 609-7058
Skype: acTBistas
Twitter: acTBistas
Youtube: http://bit.ly/lK3D0A

Alberto Colorado
Replied at 8:58 PM, 24 Feb 2012

Dear acTBistas, could you please comment about SLD side effects, sequels of MDRTB and the psychosocial impact on MDRTB and XDRTB patients? What health policies are you developing to support TB programs and address these sometimes deadly issues?

Thank you.

Alberto Colorado
Patient Advocate
International Public Health Consultant
Advocates for Health International
San Diego, California. USA

Tel: (619) 460-6630
Google tel: (619) 609-7058
Skype: acTBistas
Twitter: acTBistas
Youtube: http://bit.ly/lK3D0A

Dr Kaspars Lunte
Replied at 9:46 PM, 24 Feb 2012

Dear Philippe, dear all,

The lead time of 6 months is not astonishing, it is reality unfortunately. And there are many elements which contribute to this:

1. The order process will start when the payment arrives to the account of our procurement agent. I have seen many times the delays for this, both due to delays from the program or from the Global Fund. I fully understand that the relevant delays are caused by important internal factors, but this is where the delays start before the order can be placed.

2. GDF consolidates the orders for the deliveries to have 1-2 shipments for the particular project for all medicines, to save the transportation costs: the preferred shipment mode is airfreight and this might be quite costly. The consolidated shipments are also easier for importation procedures at country level: however, we have seen weeks and in some cases even months when the goods were held at the border before importation has been fully granted. In any case, there would be no sense to deliver each of the product separately as soon as they are arriving to our consolidation warehouse or are manufactured: the treatment is possible only when ALL medicines are received. So, in this case the longest delivery time of the particular product concerned for the regimen directs the shipment date of whole shipment.

3. Shipment itself is relatively quick - air freight 1 week and sea freight app.6-8 weeks. Pre shipment inspection can take 1 - 2 weeks.

4. Manufacturing itself - minimum 8-10 weeks. However, for TB specific products it could take much longer if API is not immediately available and needs to be ordered (and here this process takes long, as the fresh API order needs to be placed, manufactured and shipped to SLD manufacturer. In some cases, for the API only sea shipment is possible due to regulations) Here also we need to account for the time when the manufactured product is sent from manufacturer to our warehouse for consolidation of the medicines together for the shipment to the program.

So if you read all this, I believe, you will agree that the process is objectively long and the unexpected delays can happen on any stage of this complex process.

Add to all above that sometimes countries don't consider the minimum order quantities for production. This causes additional delay as we need to receive another order from another project to put them together to create order with minimum order quantity ,and is hard to predict, when such will be received.

Add to this countries requirement to receive absolutely most possible fresh shelf life for the SLD products ( 24 months maximum shelflife for SLDs) and sometimes longer time to convince the countries that the slightly shorter shelf life is also OK and the products could be consumed throughout all the duration of the shelflife, as indicated on the packaging.

And we cannot unfortunately compare made on order specific MDR TB medicines with aspirin on the pharmacy shelf. Aspirin in OTC product and will always be available as it is widely required. And even then you could receive it with the remaining shelf life of 8 months for example...

Hope this explains the complexity around SLDs and the leadtimes.

GDF is working with our partners to improve the leadtimes and we have seen some good progress already, as much as it depends from in house process.

But many elements unfortunately is out of GDF control.

Best regards,

Kaspars Lunte

Masoud Dara, MD
Replied at 5:52 AM, 25 Feb 2012

Dear Alberto,

Thank you very much for bringing the Latin perspective. Adherence to treatment is a major problem in many settings. Treatment is lengthy and patients often experience several adverse events. In addition to the health system interventions, including ensuring well trained, motivated and supportive health care staff to administer appropriate treatment regimen with good communication skills and measures to prevent, monitor and manage the adverse events, different programmes use multiple measure to improve treatment adherence. Social mobilization to decrease stigma and provide a supportive environment is essential. Social support in terms of food incentives, support to the patients and his/her family and enablers (e.g. reimbursement of transport costs to health care facility) have proven to play important role. Peer support, "treatment accompagnant", involving community leaders and psychosocial support and addressing drug or alcohol use are also used to improve treatment adherence. For your information there is a sister community on GHD online under "Adherence & Retention". I would encourage colleagues to share their experience through both communities.

Thank you and all the best,
Masoud

Dr Masoud Dara
Programme Manager / Medical Officer
Tuberculosis and M/XDR-TB Programme
Division of Communicable Diseases, Health Security & Environment
Tel: +45 3917 1717 (direct number 1378)
Fax: +45 3917 1818
E-mail:

8 Scherfigsvej, DK-2100 Copenhagen, Denmark
http://www.euro.who.int


-----Original Message-----
From: GHDonline (Alberto Colorado) [mailto:]
Sent: 25 February 2012 02:21
To: Dara, Masoud (DCE-TBM)
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right

Alberto Colorado replied to the discussion "Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment & Prevention community.

Reply contents:
"Dear acTBistas,
People are following this discussion on my social media platforms. Today, I received this question from Chile. "What innovative actions from a social perspective can be used for treatment compliance of MDRTB patients?" any response from the panel?
Alberto Colorado
Patient Advocate
International Public Health Consultant
Advocates for Health International
San Diego, California. USA

Tel: (619) 460-6630
Google tel: (619) 609-7058
Skype: acTBistas
Twitter: acTBistas
Youtube: http://bit.ly/lK3D0A"

--
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Sandeep Saluja
Replied at 6:48 AM, 25 Feb 2012

I am happy many of my esteemed colleagues concur with the idea of a clinical forum.Would the GHD like to get the ball rolling?

Masoud Dara, MD
Replied at 6:51 AM, 25 Feb 2012

Thank you very much Kaspars for your very informative response shedding light on the key problems causing longer lead time for second line drugs procurement and supply.

From experience, I know at least in two settings where the second line drugs (SLD) were for very long time stocked for the costume clearance. On at least one another setting, the SLDs needs of several years were ordered at once, leading to some of the drugs expiring. Many of these problem are due to lack of/poor planning. National authorities often do not have a sound national MDR-TB/TB response plan with an up-to-date forecasting. In WHO European Region and with USAID financial support, we are helping countries improve their national MDR-TB response plans. I am pretty sure other Regions and countries are doing the same. It would be good to hear from the members on their experiences in SLD forecasting and planning.

All the best,
Masoud

Dr Masoud Dara
Programme Manager / Medical Officer
Tuberculosis and M/XDR-TB Programme
Division of Communicable Diseases, Health Security & Environment
Tel: +45 3917 1717 (direct number 1378)
Fax: +45 3917 1818
E-mail:

8 Scherfigsvej, DK-2100 Copenhagen, Denmark
http://www.euro.who.int



-----Original Message-----
From: GHDonline (Dr Kaspars Lunte) [mailto:]
Sent: 25 February 2012 03:47
To: Dara, Masoud (DCE-TBM)
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right

Dr Kaspars Lunte replied to the discussion "Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment & Prevention community.

Reply contents:
"Dear Philippe, dear all,

The lead time of 6 months is not astonishing, it is reality
unfortunately.
And there are many elements which contribute to this:

1. The order process will start when the payment arrives to the account
of our procurement agent. I have seen many times the delays for this,
both due to delays from the program or from the Global Fund. I fully
understand that the relevant delays are caused by important internal
factors, but this is where the delays start before the order can be
placed.

2. GDF consolidates the orders for the deliveries to have 1-2 shipments
for the particular project for all medicines, to save the transportation
costs: the preferred shipment mode is airfreight and this might be quite
costly. The consolidated shipments are also easier for importation
procedures at country level: however, we have seen weeks and in some
cases even months when the goods were held at the border before
importation has been fully granted.
In any case, there would be no sense to deliver each of the product
separately as soon as they are arriving to our consolidation warehouse
or are manufactured: the treatment is possible only when ALL medicines
are received.
So, in this case the longest delivery time of the particular product
concerned for the regimen directs the shipment date of whole shipment.

3. Shipment itself is relatively quick - air freight 1 week and sea
freight app.6-8 weeks. Pre shipment inspection can take 1 - 2 weeks.

4. Manufacturing itself - minimum 8-10 weeks. However, for TB specific
products it could take much longer if API is not immediately available
and needs to be ordered (and here this process takes long, as the fresh
API order needs to be placed, manufactured and shipped to SLD
manufacturer. In some cases, for the API only sea shipment is possible
due to regulations)
Here also we need to account for the time when the manufactured product
is sent from manufacturer to our warehouse for consolidation of the
medicines together for the shipment to the program.

So if you read all this, I believe, you will agree that the process is
objectively long and the unexpected delays can happen on any stage of
this complex process.

Add to all above that sometimes countries don't consider the minimum
order quantities for production. This causes additional delay as we need
to receive another order from another project to put them together to
create order with minimum order quantity ,and is hard to predict, when
such will be received.

Add to this countries requirement to receive absolutely most possible
fresh shelf life for the SLD products ( 24 months maximum shelflife for
SLDs) and sometimes longer time to convince the countries that the
slightly shorter shelf life is also OK and the products could be
consumed throughout all the duration of the shelflife, as indicated on
the packaging.

And we cannot unfortunately compare made on order specific MDR TB
medicines with aspirin on the pharmacy shelf. Aspirin in OTC product and
will always be available as it is widely required. And even then you
could receive it with the remaining shelf life of 8 months for
example...

Hope this explains the complexity around SLDs and the leadtimes.

GDF is working with our partners to improve the leadtimes and we have
seen some good progress already, as much as it depends from in house
process.

But many elements unfortunately is out of GDF control.

Best regards,

Kaspars Lunte


-----Original Message-----
From: GHDonline (Philippe Creach) [mailto:]
Sent: Friday, February 24, 2012 4:47 PM
To: Lunte, Kaspars
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right

Philippe Creach replied to the discussion "Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB
Treatment & Prevention community.

Reply contents:
"Dear Salem,

I hope that you are not dreaming since an average lead time of 6 months
to deliver SLD is, somehow, astonishing. I can not imagine, in any
private company, such a lead time for a product much in demand and need.
If I would go to a private pharmacy for aspirin and the pharmacist would
answer me that he needs to start the production, I would be astonished
as well.

I guess that we have clear estimates now on the number of patients in
need of SLD thanks to the GLC, DRS...So, the forecasting of needs should
not be an issue. It seems that we did not move much from the approach at
the very beginning of the GLC: the exact number of pills started on
procurement according to the exact number of patients in a GLC
application.

I was reading in this forum that the Global Fund was cited as a
bottleneck as it fails to deliver the needed financial resources. Well,
this is surprising as it is the main funding party.

To come back to lead time, it is so long in some instances that it has
prompted countries to request refund before replacing the same order not
to be at odd with its national legislation. This is inefficient.

Sorry for being intense on this topic but the approach should be
reviewed.

Best wishes,

Philippe Creac'h

-----Original Message-----
From: GHDonline (Salem Barghout) [mailto:]
Sent: Friday, 24 February 2012 3:26 PM
To: Philippe Creac'H
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right

Salem Barghout replied to the discussion "Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB
Treatment & Prevention community.

Reply contents:
"Dear Kaspars and MDR Colleagues:

I have been reading through these very interested and lively discussions
re. the very hot topic of SLD. Please allow me to share my personal
views on this topic from my experience in EMR and especially in
Pakistan. Although some countries might prefer to use Capreomycin
however, at least in our area, injectables are selected based on the
clinical history, previous use of SLD, DST pattern and drug
availability. For more than a year, Capreomycin has not been available
through GDF and we had to use Amikacin instead although, in many cases
such as XDR, Capreomycin would have been the drug of choice but
unfortunately it was not available yet. All of this is to say that
personal preference plays, at least in our region, a very little role in
treatment selection and the cost of treatment regimen per patient, using
QA SLD through GDF, has been anywhere between US$ 5-6 Thousands.
The other issue, which is the long lead time from the time of
pre-payment until SLD delivery, must be urgently addressed and shortened
knowing that this problem has not been getting any better. I realize
that there are many factors effecting this condition and many of them
are probably beyond GDF's responsibilities but I am taking this
opportunity to call upon the Global community to work together in order
to bring this matter to a reasonable time, say 2-3 months at the
maximum. May be I'm dreaming but that's ok to have some good dreams.

Regards,

Salem Barghout


Salem Barghout, MD
MO/MDR-TB/WHO-Pak
Cell: + 92 300 8599580
WHO GPN: 62481
E.Mail:


-----Original Message-----
From: GHDonline (Dr Kaspars Lunte) [mailto:]
Sent: Friday, February 24, 2012 1:21 PM
To: Salem Barghout
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right

Dr Kaspars Lunte replied to the discussion "Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB
Treatment & Prevention community.

Reply contents:
"Dear all,

Would like to support Pauls message on the crucial importance of
diversifying the risks to ensure uninterrupted supply of SLDs.

Just let me start with clarification on the treatment costs per patient:
it first of all depends on the regimen chosen: some countries prefer to
use capreomycin instead of cheaper injectable, are willing to use more
expensive PAS product etc. This contributes to higher treatment cost per
patient. But, of course, for that there is clear justification.

On the lower end though, the regimen of quality medicines procured via
GDF could be as low as less then 3000 USD per patient.

Also, if need exists to compare cost per patient treatment, this can be
done only if <apples are compared with apples>: the regimens using only
QA quality medicines, approved by WHO PQP or Stringent DRAs, so
comparison with India schedule M would not be really valid.

Now, coming back to diversification of risks, GDF is constantly looking
to widen the number and/or geographies of our suppliers. This is also
contributing to positive pricing dynamics.
Also to note that diverse quality approved API sources are of crucial
importance.

We in GDF cooperate with our colleagues in WHO Prequalification program
and provide link for eligible TB manufacturers for free technical
assistance from Promoting Quality of Medicines program of US
Pharmacopeia.

This serves the purpose to ensure we have larger pool of approved
suppliers of both, API and finished product suppliers for the
foreseeable future.

Just to indicate practical example: I am writing these lines while
driving back to Shanghai from meeting with potential manufacturing
partner in Zhejiang province.

This concludes series of important meetings of this week with selected
SLD manufacturers in China, and the potential is big here.

Also, next week GDF will present its business opportunities is South
Korea in dedicated meeting called by PQM: more that 100 participants
confirmed their attendance already!

With best regards,
Kaspars Lunte

Dr Kaspars Lunte
Team Leader MDR TB supply WHO-GDF
------------------------
Sent from my BB Terminal

----- Original Message -----
From: GHDonline (Paul Nunn) <>
To: Lunte, Kaspars
Sent: Thu Feb 23 12:22:16 2012
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right

Paul Nunn replied to the discussion "Expert Panel Feb. 20-24: Management
of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment
& Prevention community.

Reply contents:
"Many thanks for the interesting inputs to date, but nobody has yet
mentioned the price of the drugs, which we see as one of the main
bottlenecks for wider availability of treatment for MDR-TB. Is this
perceived as a barrier at country level? As the Global Fund resources
shrivel (at least for now), will it be seen as a greater barrier? The
average price for a regimen provided through the GDF to India is nearly
$6000 and these will be internationally quality assured (IQA) drugs,
assured through "strict" national drug regulatory agencies, through the
WHO Prequalification system, or recommended by the ERP Committee of the
Global Fund. However, the same chemical entities are obtained by India
through their tendering process for around $2400. These latter drugs
are approved by the Indian drug control authority using their "Schedule
M". Why does this enormous cost difference exist? What can be done to
reduce it?
We have seen that the speed of delivery of SLDs through GDF has improved
noticeably in recent years. There are still problems of lack of
availability because of events (mainly) outside GDF's control, such as
contamination of the single supplier API (kanamycin), and the tsunami
and subsequent reduction in electricity supplies in Japan (also
kanamycin). These kinds of obstacles show, however, that there is a
need to widen the number (and geographical distribution?) of API
suppliers, as well as of manufacturers of the finished pharmaceutical
product. Thus, what we are now seeing in WHO with respect to the delays
that occur in delivery of SLDs is that the bulk of the delays are at
country level (eg failure to make the order) or at the Global Fund (eg
failure to ensure the funds are available)."

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Watch the Global Fund's inspiring 10 Years of Impact
video<http://www.theglobalfund.org/en/mediacenter/videos/The_Global_Fund
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Dr Kaspars Lunte
Replied at 7:26 AM, 25 Feb 2012

Dear Masoud,

Cannot agree more!

It would be great if some countries could share with us their experiences on proper planning and most frequent bottlenecks!

With best regards,

Dr Kaspars Lunte
Team Leader MDR TB supply WHO-GDF
------------------------
Sent from my BB Terminal

Masoud Dara, MD
Replied at 7:53 AM, 25 Feb 2012

Dear Sandeep,

A subgroup of GHD online community can certainly accommodate this.

Since patient information is anonymous, I suggest we continue open discussion on cases colleagues need consultation.

All the best,
Masoud

----- Original Message -----
From: GHDonline (Sandeep Saluja) [mailto:]
Sent: Saturday, February 25, 2012 12:48 PM
To: Dara, Masoud (DCE-TBM)
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right

Sandeep Saluja replied to the discussion "Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment & Prevention community.

Reply contents:
"I am happy many of my esteemed colleagues concur with the idea of a clinical forum.Would the GHD like to get the ball rolling?"

--
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Sandra Irbe
Replied at 12:41 PM, 25 Feb 2012

Dear Kaspars

Thank you for outlining all the steps leading to the long delivery times of 2nd line drugs. At the Global Fund we should think how to accelerate the payment and ordering processes. Often times, the grant negotiations take long because of lack of clarity around other issues but 2nd line drugs. Also, the first disbursements are subject to the fulfilment by the country, of certain conditions - also not related to the 2nd line drug order. In those cases, we should be flexible enough to allow for payments and orders of those drugs as part of a separate grant agreement.

We hope that with the current restructuring and refocusing of the Global Fund we will become more flexible and reduce bureaucracies affecting a timely delivery of drugs.

Kind regards

Sandra
(Message sent from a portable device)

----- Original Message -----
From: GHDonline (Dr Kaspars Lunte) [mailto:]
Sent: Saturday, February 25, 2012 03:48 AM
To: Sandra Irbe
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right

Dr Kaspars Lunte replied to the discussion "Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment & Prevention community.

Reply contents:
"Dear Philippe, dear all,

The lead time of 6 months is not astonishing, it is reality
unfortunately.
And there are many elements which contribute to this:

1. The order process will start when the payment arrives to the account
of our procurement agent. I have seen many times the delays for this,
both due to delays from the program or from the Global Fund. I fully
understand that the relevant delays are caused by important internal
factors, but this is where the delays start before the order can be
placed.

2. GDF consolidates the orders for the deliveries to have 1-2 shipments
for the particular project for all medicines, to save the transportation
costs: the preferred shipment mode is airfreight and this might be quite
costly. The consolidated shipments are also easier for importation
procedures at country level: however, we have seen weeks and in some
cases even months when the goods were held at the border before
importation has been fully granted.
In any case, there would be no sense to deliver each of the product
separately as soon as they are arriving to our consolidation warehouse
or are manufactured: the treatment is possible only when ALL medicines
are received.
So, in this case the longest delivery time of the particular product
concerned for the regimen directs the shipment date of whole shipment.

3. Shipment itself is relatively quick - air freight 1 week and sea
freight app.6-8 weeks. Pre shipment inspection can take 1 - 2 weeks.

4. Manufacturing itself - minimum 8-10 weeks. However, for TB specific
products it could take much longer if API is not immediately available
and needs to be ordered (and here this process takes long, as the fresh
API order needs to be placed, manufactured and shipped to SLD
manufacturer. In some cases, for the API only sea shipment is possible
due to regulations)
Here also we need to account for the time when the manufactured product
is sent from manufacturer to our warehouse for consolidation of the
medicines together for the shipment to the program.

So if you read all this, I believe, you will agree that the process is
objectively long and the unexpected delays can happen on any stage of
this complex process.

Add to all above that sometimes countries don't consider the minimum
order quantities for production. This causes additional delay as we need
to receive another order from another project to put them together to
create order with minimum order quantity ,and is hard to predict, when
such will be received.

Add to this countries requirement to receive absolutely most possible
fresh shelf life for the SLD products ( 24 months maximum shelflife for
SLDs) and sometimes longer time to convince the countries that the
slightly shorter shelf life is also OK and the products could be
consumed throughout all the duration of the shelflife, as indicated on
the packaging.

And we cannot unfortunately compare made on order specific MDR TB
medicines with aspirin on the pharmacy shelf. Aspirin in OTC product and
will always be available as it is widely required. And even then you
could receive it with the remaining shelf life of 8 months for
example...

Hope this explains the complexity around SLDs and the leadtimes.

GDF is working with our partners to improve the leadtimes and we have
seen some good progress already, as much as it depends from in house
process.

But many elements unfortunately is out of GDF control.

Best regards,

Kaspars Lunte


-----Original Message-----
From: GHDonline (Philippe Creach) [mailto:]
Sent: Friday, February 24, 2012 4:47 PM
To: Lunte, Kaspars
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right

Philippe Creach replied to the discussion "Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB
Treatment & Prevention community.

Reply contents:
"Dear Salem,

I hope that you are not dreaming since an average lead time of 6 months
to deliver SLD is, somehow, astonishing. I can not imagine, in any
private company, such a lead time for a product much in demand and need.
If I would go to a private pharmacy for aspirin and the pharmacist would
answer me that he needs to start the production, I would be astonished
as well.

I guess that we have clear estimates now on the number of patients in
need of SLD thanks to the GLC, DRS...So, the forecasting of needs should
not be an issue. It seems that we did not move much from the approach at
the very beginning of the GLC: the exact number of pills started on
procurement according to the exact number of patients in a GLC
application.

I was reading in this forum that the Global Fund was cited as a
bottleneck as it fails to deliver the needed financial resources. Well,
this is surprising as it is the main funding party.

To come back to lead time, it is so long in some instances that it has
prompted countries to request refund before replacing the same order not
to be at odd with its national legislation. This is inefficient.

Sorry for being intense on this topic but the approach should be
reviewed.

Best wishes,

Philippe Creac'h

-----Original Message-----
From: GHDonline (Salem Barghout) [mailto:]
Sent: Friday, 24 February 2012 3:26 PM
To: Philippe Creac'H
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right

Salem Barghout replied to the discussion "Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB
Treatment & Prevention community.

Reply contents:
"Dear Kaspars and MDR Colleagues:

I have been reading through these very interested and lively discussions
re. the very hot topic of SLD. Please allow me to share my personal
views on this topic from my experience in EMR and especially in
Pakistan. Although some countries might prefer to use Capreomycin
however, at least in our area, injectables are selected based on the
clinical history, previous use of SLD, DST pattern and drug
availability. For more than a year, Capreomycin has not been available
through GDF and we had to use Amikacin instead although, in many cases
such as XDR, Capreomycin would have been the drug of choice but
unfortunately it was not available yet. All of this is to say that
personal preference plays, at least in our region, a very little role in
treatment selection and the cost of treatment regimen per patient, using
QA SLD through GDF, has been anywhere between US$ 5-6 Thousands.
The other issue, which is the long lead time from the time of
pre-payment until SLD delivery, must be urgently addressed and shortened
knowing that this problem has not been getting any better. I realize
that there are many factors effecting this condition and many of them
are probably beyond GDF's responsibilities but I am taking this
opportunity to call upon the Global community to work together in order
to bring this matter to a reasonable time, say 2-3 months at the
maximum. May be I'm dreaming but that's ok to have some good dreams.

Regards,

Salem Barghout


Salem Barghout, MD
MO/MDR-TB/WHO-Pak
Cell: + 92 300 8599580
WHO GPN: 62481
E.Mail:


-----Original Message-----
From: GHDonline (Dr Kaspars Lunte) [mailto:]
Sent: Friday, February 24, 2012 1:21 PM
To: Salem Barghout
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right

Dr Kaspars Lunte replied to the discussion "Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB
Treatment & Prevention community.

Reply contents:
"Dear all,

Would like to support Pauls message on the crucial importance of
diversifying the risks to ensure uninterrupted supply of SLDs.

Just let me start with clarification on the treatment costs per patient:
it first of all depends on the regimen chosen: some countries prefer to
use capreomycin instead of cheaper injectable, are willing to use more
expensive PAS product etc. This contributes to higher treatment cost per
patient. But, of course, for that there is clear justification.

On the lower end though, the regimen of quality medicines procured via
GDF could be as low as less then 3000 USD per patient.

Also, if need exists to compare cost per patient treatment, this can be
done only if <apples are compared with apples>: the regimens using only
QA quality medicines, approved by WHO PQP or Stringent DRAs, so
comparison with India schedule M would not be really valid.

Now, coming back to diversification of risks, GDF is constantly looking
to widen the number and/or geographies of our suppliers. This is also
contributing to positive pricing dynamics.
Also to note that diverse quality approved API sources are of crucial
importance.

We in GDF cooperate with our colleagues in WHO Prequalification program
and provide link for eligible TB manufacturers for free technical
assistance from Promoting Quality of Medicines program of US
Pharmacopeia.

This serves the purpose to ensure we have larger pool of approved
suppliers of both, API and finished product suppliers for the
foreseeable future.

Just to indicate practical example: I am writing these lines while
driving back to Shanghai from meeting with potential manufacturing
partner in Zhejiang province.

This concludes series of important meetings of this week with selected
SLD manufacturers in China, and the potential is big here.

Also, next week GDF will present its business opportunities is South
Korea in dedicated meeting called by PQM: more that 100 participants
confirmed their attendance already!

With best regards,
Kaspars Lunte

Dr Kaspars Lunte
Team Leader MDR TB supply WHO-GDF
------------------------
Sent from my BB Terminal

----- Original Message -----
From: GHDonline (Paul Nunn) <>
To: Lunte, Kaspars
Sent: Thu Feb 23 12:22:16 2012
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right

Paul Nunn replied to the discussion "Expert Panel Feb. 20-24: Management
of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment
& Prevention community.

Reply contents:
"Many thanks for the interesting inputs to date, but nobody has yet
mentioned the price of the drugs, which we see as one of the main
bottlenecks for wider availability of treatment for MDR-TB. Is this
perceived as a barrier at country level? As the Global Fund resources
shrivel (at least for now), will it be seen as a greater barrier? The
average price for a regimen provided through the GDF to India is nearly
$6000 and these will be internationally quality assured (IQA) drugs,
assured through "strict" national drug regulatory agencies, through the
WHO Prequalification system, or recommended by the ERP Committee of the
Global Fund. However, the same chemical entities are obtained by India
through their tendering process for around $2400. These latter drugs
are approved by the Indian drug control authority using their "Schedule
M". Why does this enormous cost difference exist? What can be done to
reduce it?
We have seen that the speed of delivery of SLDs through GDF has improved
noticeably in recent years. There are still problems of lack of
availability because of events (mainly) outside GDF's control, such as
contamination of the single supplier API (kanamycin), and the tsunami
and subsequent reduction in electricity supplies in Japan (also
kanamycin). These kinds of obstacles show, however, that there is a
need to widen the number (and geographical distribution?) of API
suppliers, as well as of manufacturers of the finished pharmaceutical
product. Thus, what we are now seeing in WHO with respect to the delays
that occur in delivery of SLDs is that the bulk of the delays are at
country level (eg failure to make the order) or at the Global Fund (eg
failure to ensure the funds are available)."

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-------------------------------------------------------------
The Global Fund has contributed to dramatic health gains over the past
decade
Watch the Global Fund's inspiring 10 Years of Impact
video<http://www.theglobalfund.org/en/mediacenter/videos/The_Global_Fund
_10_Years_of_Impact/>"

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Alberto Colorado
Replied at 3:03 AM, 26 Feb 2012

Dear Masoud, thank you for your response. You are absolutely right that there is social and economical ways to keep patients on treatment. Unfortunately, in Latin America is very limited in certain areas like rural, poor communities, indigenous communities. migrants, and other groups of the most at risk populations. Let's keep this conversation open, fortunately, there is also a good civil society movement in Latin America that not only helping on treatment adherence but as monitors of TB program performance.
Best regards.
Alberto

Masoud Dara, MD
Replied at 4:03 AM, 26 Feb 2012

Thank you Sandra,

Dear colleagues,

Although our panel discussion is over, however we feel there are still questions and need for further discussion on management of second line drugs. Please feel free to continue posting your questions and comments at least till Monday 27th Feb COB GMT.

Together with other moderators and Sophie we will decide on how to proceed. One option could be to continue as featured discussion.

All the best,
Masoud

Lucica Ditiu
Replied at 5:20 AM, 26 Feb 2012

Hi,

I am not sure how this functions anymore as we passed the deadline, however, if there is anyway in which we can continue this discussionhs this would be great.
I read with a lot of care all the comments and the more I look into this problem, the more I realize that if we want real scale up, a lot alot of efforts are needed as we seems challenged from different places: from the access to all seconde line drugs, in time, good quality, affordable prices to the huge challenge of the capacity in countries to diagnose and manage the case,s to retain the cases in treatment,m to advocate for funding and..... the fundingt itself.
Discusasions that we have for a long time and, from what I get, we did not advance that much....
So, it will be extremelly appropriate to have this discussion going on, one way or another.

Thank you, Masoud

Lucica

________________________________

From: GHDonline (Masoud Dara, MD) [mailto:]
Sent: Sun 26/02/2012 10:07 AM
To: Ditiu, Lucica
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right



Masoud Dara, MD replied to the discussion "Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment & Prevention community.

Reply contents:
"Thank you Sandra,

Dear colleagues,

Although our panel discussion is over, however we feel there are still questions and need for further discussion on management of second line drugs. Please feel free to continue posting your questions and comments at least till Monday 27th Feb COB GMT.

Together with other moderators and Sophie we will decide on how to proceed. One option could be to continue as featured discussion.

All the best,
Masoud

----- Original Message -----
From: GHDonline (Sandra Irbe) [mailto:]
Sent: Saturday, February 25, 2012 06:41 PM
To: Dara, Masoud (DCE-TBM)
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right

Sandra Irbe replied to the discussion "Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment & Prevention community.

Reply contents:
"Dear Kaspars

Thank you for outlining all the steps leading to the long delivery times of 2nd line drugs. At the Global Fund we should think how to accelerate the payment and ordering processes. Often times, the grant negotiations take long because of lack of clarity around other issues but 2nd line drugs. Also, the first disbursements are subject to the fulfilment by the country, of certain conditions - also not related to the 2nd line drug order. In those cases, we should be flexible enough to allow for payments and orders of those drugs as part of a separate grant agreement.

We hope that with the current restructuring and refocusing of the Global Fund we will become more flexible and reduce bureaucracies affecting a timely delivery of drugs.

Kind regards

Sandra
(Message sent from a portable device)

----- Original Message -----
From: GHDonline (Dr Kaspars Lunte) [mailto:]
Sent: Saturday, February 25, 2012 03:48 AM
To: Sandra Irbe
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right

Dr Kaspars Lunte replied to the discussion "Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment & Prevention community.

Reply contents:
"Dear Philippe, dear all,

The lead time of 6 months is not astonishing, it is reality
unfortunately.
And there are many elements which contribute to this:

1. The order process will start when the payment arrives to the account
of our procurement agent. I have seen many times the delays for this,
both due to delays from the program or from the Global Fund. I fully
understand that the relevant delays are caused by important internal
factors, but this is where the delays start before the order can be
placed.

2. GDF consolidates the orders for the deliveries to have 1-2 shipments
for the particular project for all medicines, to save the transportation
costs: the preferred shipment mode is airfreight and this might be quite
costly. The consolidated shipments are also easier for importation
procedures at country level: however, we have seen weeks and in some
cases even months when the goods were held at the border before
importation has been fully granted.
In any case, there would be no sense to deliver each of the product
separately as soon as they are arriving to our consolidation warehouse
or are manufactured: the treatment is possible only when ALL medicines
are received.
So, in this case the longest delivery time of the particular product
concerned for the regimen directs the shipment date of whole shipment.

3. Shipment itself is relatively quick - air freight 1 week and sea
freight app.6-8 weeks. Pre shipment inspection can take 1 - 2 weeks.

4. Manufacturing itself - minimum 8-10 weeks. However, for TB specific
products it could take much longer if API is not immediately available
and needs to be ordered (and here this process takes long, as the fresh
API order needs to be placed, manufactured and shipped to SLD
manufacturer. In some cases, for the API only sea shipment is possible
due to regulations)
Here also we need to account for the time when the manufactured product
is sent from manufacturer to our warehouse for consolidation of the
medicines together for the shipment to the program.

So if you read all this, I believe, you will agree that the process is
objectively long and the unexpected delays can happen on any stage of
this complex process.

Add to all above that sometimes countries don't consider the minimum
order quantities for production. This causes additional delay as we need
to receive another order from another project to put them together to
create order with minimum order quantity ,and is hard to predict, when
such will be received.

Add to this countries requirement to receive absolutely most possible
fresh shelf life for the SLD products ( 24 months maximum shelflife for
SLDs) and sometimes longer time to convince the countries that the
slightly shorter shelf life is also OK and the products could be
consumed throughout all the duration of the shelflife, as indicated on
the packaging.

And we cannot unfortunately compare made on order specific MDR TB
medicines with aspirin on the pharmacy shelf. Aspirin in OTC product and
will always be available as it is widely required. And even then you
could receive it with the remaining shelf life of 8 months for
example...

Hope this explains the complexity around SLDs and the leadtimes.

GDF is working with our partners to improve the leadtimes and we have
seen some good progress already, as much as it depends from in house
process.

But many elements unfortunately is out of GDF control.

Best regards,

Kaspars Lunte


-----Original Message-----
From: GHDonline (Philippe Creach) [mailto:]
Sent: Friday, February 24, 2012 4:47 PM
To: Lunte, Kaspars
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right

Philippe Creach replied to the discussion "Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB
Treatment & Prevention community.

Reply contents:
"Dear Salem,

I hope that you are not dreaming since an average lead time of 6 months
to deliver SLD is, somehow, astonishing. I can not imagine, in any
private company, such a lead time for a product much in demand and need.
If I would go to a private pharmacy for aspirin and the pharmacist would
answer me that he needs to start the production, I would be astonished
as well.

I guess that we have clear estimates now on the number of patients in
need of SLD thanks to the GLC, DRS...So, the forecasting of needs should
not be an issue. It seems that we did not move much from the approach at
the very beginning of the GLC: the exact number of pills started on
procurement according to the exact number of patients in a GLC
application.

I was reading in this forum that the Global Fund was cited as a
bottleneck as it fails to deliver the needed financial resources. Well,
this is surprising as it is the main funding party.

To come back to lead time, it is so long in some instances that it has
prompted countries to request refund before replacing the same order not
to be at odd with its national legislation. This is inefficient.

Sorry for being intense on this topic but the approach should be
reviewed.

Best wishes,

Philippe Creac'h

-----Original Message-----
From: GHDonline (Salem Barghout) [mailto:]
Sent: Friday, 24 February 2012 3:26 PM
To: Philippe Creac'H
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right

Salem Barghout replied to the discussion "Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB
Treatment & Prevention community.

Reply contents:
"Dear Kaspars and MDR Colleagues:

I have been reading through these very interested and lively discussions
re. the very hot topic of SLD. Please allow me to share my personal
views on this topic from my experience in EMR and especially in
Pakistan. Although some countries might prefer to use Capreomycin
however, at least in our area, injectables are selected based on the
clinical history, previous use of SLD, DST pattern and drug
availability. For more than a year, Capreomycin has not been available
through GDF and we had to use Amikacin instead although, in many cases
such as XDR, Capreomycin would have been the drug of choice but
unfortunately it was not available yet. All of this is to say that
personal preference plays, at least in our region, a very little role in
treatment selection and the cost of treatment regimen per patient, using
QA SLD through GDF, has been anywhere between US$ 5-6 Thousands.
The other issue, which is the long lead time from the time of
pre-payment until SLD delivery, must be urgently addressed and shortened
knowing that this problem has not been getting any better. I realize
that there are many factors effecting this condition and many of them
are probably beyond GDF's responsibilities but I am taking this
opportunity to call upon the Global community to work together in order
to bring this matter to a reasonable time, say 2-3 months at the
maximum. May be I'm dreaming but that's ok to have some good dreams.

Regards,

Salem Barghout


Salem Barghout, MD
MO/MDR-TB/WHO-Pak
Cell: + 92 300 8599580
WHO GPN: 62481
E.Mail:


-----Original Message-----
From: GHDonline (Dr Kaspars Lunte) [mailto:]
Sent: Friday, February 24, 2012 1:21 PM
To: Salem Barghout
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right

Dr Kaspars Lunte replied to the discussion "Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB
Treatment & Prevention community.

Reply contents:
"Dear all,

Would like to support Pauls message on the crucial importance of
diversifying the risks to ensure uninterrupted supply of SLDs.

Just let me start with clarification on the treatment costs per patient:
it first of all depends on the regimen chosen: some countries prefer to
use capreomycin instead of cheaper injectable, are willing to use more
expensive PAS product etc. This contributes to higher treatment cost per
patient. But, of course, for that there is clear justification.

On the lower end though, the regimen of quality medicines procured via
GDF could be as low as less then 3000 USD per patient.

Also, if need exists to compare cost per patient treatment, this can be
done only if <apples are compared with apples>: the regimens using only
QA quality medicines, approved by WHO PQP or Stringent DRAs, so
comparison with India schedule M would not be really valid.

Now, coming back to diversification of risks, GDF is constantly looking
to widen the number and/or geographies of our suppliers. This is also
contributing to positive pricing dynamics.
Also to note that diverse quality approved API sources are of crucial
importance.

We in GDF cooperate with our colleagues in WHO Prequalification program
and provide link for eligible TB manufacturers for free technical
assistance from Promoting Quality of Medicines program of US
Pharmacopeia.

This serves the purpose to ensure we have larger pool of approved
suppliers of both, API and finished product suppliers for the
foreseeable future.

Just to indicate practical example: I am writing these lines while
driving back to Shanghai from meeting with potential manufacturing
partner in Zhejiang province.

This concludes series of important meetings of this week with selected
SLD manufacturers in China, and the potential is big here.

Also, next week GDF will present its business opportunities is South
Korea in dedicated meeting called by PQM: more that 100 participants
confirmed their attendance already!

With best regards,
Kaspars Lunte

Dr Kaspars Lunte
Team Leader MDR TB supply WHO-GDF
------------------------
Sent from my BB Terminal

----- Original Message -----
From: GHDonline (Paul Nunn) <>
To: Lunte, Kaspars
Sent: Thu Feb 23 12:22:16 2012
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right

Paul Nunn replied to the discussion "Expert Panel Feb. 20-24: Management
of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment
& Prevention community.

Reply contents:
"Many thanks for the interesting inputs to date, but nobody has yet
mentioned the price of the drugs, which we see as one of the main
bottlenecks for wider availability of treatment for MDR-TB. Is this
perceived as a barrier at country level? As the Global Fund resources
shrivel (at least for now), will it be seen as a greater barrier? The
average price for a regimen provided through the GDF to India is nearly
$6000 and these will be internationally quality assured (IQA) drugs,
assured through "strict" national drug regulatory agencies, through the
WHO Prequalification system, or recommended by the ERP Committee of the
Global Fund. However, the same chemical entities are obtained by India
through their tendering process for around $2400. These latter drugs
are approved by the Indian drug control authority using their "Schedule
M". Why does this enormous cost difference exist? What can be done to
reduce it?
We have seen that the speed of delivery of SLDs through GDF has improved
noticeably in recent years. There are still problems of lack of
availability because of events (mainly) outside GDF's control, such as
contamination of the single supplier API (kanamycin), and the tsunami
and subsequent reduction in electricity supplies in Japan (also
kanamycin). These kinds of obstacles show, however, that there is a
need to widen the number (and geographical distribution?) of API
suppliers, as well as of manufacturers of the finished pharmaceutical
product. Thus, what we are now seeing in WHO with respect to the delays
that occur in delivery of SLDs is that the bulk of the delays are at
country level (eg failure to make the order) or at the Global Fund (eg
failure to ensure the funds are available)."

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Shelly Batra, MD
Replied at 2:40 PM, 26 Feb 2012

Thank you, all for the discussion. Once again, adherance is the biggest issue when it comes to MDR-TB. The solution lies in extensive community involvement. My organisation, Operation ASHA, is treating MDR-TB as part of the governments DOTS-Plus program, and has used lessons learnt in DOTs delivery to ensure adherance to MDR regimens.. My DOTS -Plus clinics are established deep in urban slums and rural areas, open early morning and late night, so no patient needs to lose work and wages in order to get the medicines. Counselors or health workers are selected from the community they serve, to carry our education of patients and their families. Essentially, the message is re-inforced on each patient -counselor interaction, that missing doses could lead to terrible consequences.One innovation that has really worked is giving counselors cash incentives to prevent default, and this is right now being studied by MIT-JPAL who are carrying out randomised controlled trails of our incentive based model. Of course, there is no substitute for tender, loving care, and counselors go door to door, meeting with the community, solving health issues, forming the vital link between patients and the public hospitals, and giving OTC medicines to prevent side effects.

MDR treatment is difficult no doubt, but can be done if there is a will, and we must remember that we cannot afford default. There have been horrifying reports in the newspapers about patients in Mumbai suffering from some kind of TB which has no cure, which I presume is XXDR. Now WHO has declared that 58 countries have reported MDR. So the scenario is bleak indeed.

And one last point. According to the WHO, electronic datasets should be used to ensure correct data and analysis. This again is important when we consider that all over the world, TB is under-reported. India's Health Minister declares in Times of India that MCH and other data is fudged. The solution lies in leveraging technology. I am using biometric fingerprint identification to identify every patient, monitor DOTS, prevent fudging of data ( fingerprints cannot be tampered with!), tracking patients who have missed medication, and incentivising counselors for default tracking. The next step is to adapt this basic biometric model to serve MDR-TB patients. I am looking for like-minded people who might be interested in developing technology to the next level.

Alberto Colorado
Replied at 1:23 AM, 27 Feb 2012

Dear acTBistas, Thank you for continuing the conversation. Last Friday, I received questions for the Panel from Dr. Oswaldo Jave, ex NTP Peru until December 2011.
1- Is there a plan to increase the production of Capreomycin?
2- Are you planing to increase Capreomycin manufacturers and suppliers?
3- Are you planning to include Linezolid in your XDRTB guidelines?
4- What can we do to reduce the high cost of Linezolid?
Thank you and remember to comment on the psychological effects and sequels of MDRTB. It seems to me those are the missing links in TB care.
Best regards,
Alberto

Philippe Creach
Replied at 4:19 AM, 27 Feb 2012

Dear All,

This was the meaning of my message: as long as we continue with an inefficient system, all steps of this system, whatever well undertaken it is, will lead to failure. The point is not to improve these steps but to change the system.

The failure came exactly from this "made on order" that is just the continuation of an inefficient way to address SLD procurement. The GLC was reformed because it failed to address the needed scale-up to enrol very large numbers of eligible MDR-TB cases. But the system of procurement remained the same: the name change from GLC to GDF. SLD are still made on order. How can it work ?

In the manufacturing world of today, I do not see much goods made on order, except some luxury cars. For pharmaceuticals, I have none in mind and certainly not for tens of thousands of patients in needs. A bit of creativity would not hurt.

Every business is making a planning of goods to manufacture instead of waiting the order made by the clients.

I understand the difficulties, Kaspar, that you highlighted regarding the numerous steps to go through. But as long as the system is set such, MDR-TB cases, through the GLC/GDF, will remain at a low scale.

Best wishes,

P


-----Original Message-----
From: GHDonline (Dr Kaspars Lunte) [mailto:]
Sent: Saturday, 25 February 2012 3:46 AM
To: Philippe Creac'H
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right

Dr Kaspars Lunte replied to the discussion "Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment & Prevention community.

Reply contents:
"Dear Philippe, dear all,

The lead time of 6 months is not astonishing, it is reality unfortunately.
And there are many elements which contribute to this:

1. The order process will start when the payment arrives to the account of our procurement agent. I have seen many times the delays for this, both due to delays from the program or from the Global Fund. I fully understand that the relevant delays are caused by important internal factors, but this is where the delays start before the order can be placed.

2. GDF consolidates the orders for the deliveries to have 1-2 shipments for the particular project for all medicines, to save the transportation
costs: the preferred shipment mode is airfreight and this might be quite costly. The consolidated shipments are also easier for importation procedures at country level: however, we have seen weeks and in some cases even months when the goods were held at the border before importation has been fully granted.
In any case, there would be no sense to deliver each of the product separately as soon as they are arriving to our consolidation warehouse or are manufactured: the treatment is possible only when ALL medicines are received.
So, in this case the longest delivery time of the particular product concerned for the regimen directs the shipment date of whole shipment.

3. Shipment itself is relatively quick - air freight 1 week and sea freight app.6-8 weeks. Pre shipment inspection can take 1 - 2 weeks.

4. Manufacturing itself - minimum 8-10 weeks. However, for TB specific products it could take much longer if API is not immediately available and needs to be ordered (and here this process takes long, as the fresh API order needs to be placed, manufactured and shipped to SLD manufacturer. In some cases, for the API only sea shipment is possible due to regulations) Here also we need to account for the time when the manufactured product is sent from manufacturer to our warehouse for consolidation of the medicines together for the shipment to the program.

So if you read all this, I believe, you will agree that the process is objectively long and the unexpected delays can happen on any stage of this complex process.

Add to all above that sometimes countries don't consider the minimum order quantities for production. This causes additional delay as we need to receive another order from another project to put them together to create order with minimum order quantity ,and is hard to predict, when such will be received.

Add to this countries requirement to receive absolutely most possible fresh shelf life for the SLD products ( 24 months maximum shelflife for
SLDs) and sometimes longer time to convince the countries that the slightly shorter shelf life is also OK and the products could be consumed throughout all the duration of the shelflife, as indicated on the packaging.

And we cannot unfortunately compare made on order specific MDR TB medicines with aspirin on the pharmacy shelf. Aspirin in OTC product and will always be available as it is widely required. And even then you could receive it with the remaining shelf life of 8 months for example...

Hope this explains the complexity around SLDs and the leadtimes.

GDF is working with our partners to improve the leadtimes and we have seen some good progress already, as much as it depends from in house process.

But many elements unfortunately is out of GDF control.

Best regards,

Kaspars Lunte


-----Original Message-----
From: GHDonline (Philippe Creach) [mailto:]
Sent: Friday, February 24, 2012 4:47 PM
To: Lunte, Kaspars
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right

Philippe Creach replied to the discussion "Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment & Prevention community.

Reply contents:
"Dear Salem,

I hope that you are not dreaming since an average lead time of 6 months to deliver SLD is, somehow, astonishing. I can not imagine, in any private company, such a lead time for a product much in demand and need.
If I would go to a private pharmacy for aspirin and the pharmacist would answer me that he needs to start the production, I would be astonished as well.

I guess that we have clear estimates now on the number of patients in need of SLD thanks to the GLC, DRS...So, the forecasting of needs should not be an issue. It seems that we did not move much from the approach at the very beginning of the GLC: the exact number of pills started on procurement according to the exact number of patients in a GLC application.

I was reading in this forum that the Global Fund was cited as a bottleneck as it fails to deliver the needed financial resources. Well, this is surprising as it is the main funding party.

To come back to lead time, it is so long in some instances that it has prompted countries to request refund before replacing the same order not to be at odd with its national legislation. This is inefficient.

Sorry for being intense on this topic but the approach should be reviewed.

Best wishes,

Philippe Creac'h

-----Original Message-----
From: GHDonline (Salem Barghout) [mailto:]
Sent: Friday, 24 February 2012 3:26 PM
To: Philippe Creac'H
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right

Salem Barghout replied to the discussion "Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment & Prevention community.

Reply contents:
"Dear Kaspars and MDR Colleagues:

I have been reading through these very interested and lively discussions re. the very hot topic of SLD. Please allow me to share my personal views on this topic from my experience in EMR and especially in Pakistan. Although some countries might prefer to use Capreomycin however, at least in our area, injectables are selected based on the clinical history, previous use of SLD, DST pattern and drug availability. For more than a year, Capreomycin has not been available through GDF and we had to use Amikacin instead although, in many cases such as XDR, Capreomycin would have been the drug of choice but unfortunately it was not available yet. All of this is to say that personal preference plays, at least in our region, a very little role in treatment selection and the cost of treatment regimen per patient, using QA SLD through GDF, has been anywhere between US$ 5-6 Thousands.
The other issue, which is the long lead time from the time of pre-payment until SLD delivery, must be urgently addressed and shortened knowing that this problem has not been getting any better. I realize that there are many factors effecting this condition and many of them are probably beyond GDF's responsibilities but I am taking this opportunity to call upon the Global community to work together in order to bring this matter to a reasonable time, say 2-3 months at the maximum. May be I'm dreaming but that's ok to have some good dreams.

Regards,

Salem Barghout


Salem Barghout, MD
MO/MDR-TB/WHO-Pak
Cell: + 92 300 8599580
WHO GPN: 62481
E.Mail:


-----Original Message-----
From: GHDonline (Dr Kaspars Lunte) [mailto:]
Sent: Friday, February 24, 2012 1:21 PM
To: Salem Barghout
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right

Dr Kaspars Lunte replied to the discussion "Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment & Prevention community.

Reply contents:
"Dear all,

Would like to support Pauls message on the crucial importance of diversifying the risks to ensure uninterrupted supply of SLDs.

Just let me start with clarification on the treatment costs per patient:
it first of all depends on the regimen chosen: some countries prefer to use capreomycin instead of cheaper injectable, are willing to use more expensive PAS product etc. This contributes to higher treatment cost per patient. But, of course, for that there is clear justification.

On the lower end though, the regimen of quality medicines procured via GDF could be as low as less then 3000 USD per patient.

Also, if need exists to compare cost per patient treatment, this can be done only if <apples are compared with apples>: the regimens using only QA quality medicines, approved by WHO PQP or Stringent DRAs, so comparison with India schedule M would not be really valid.

Now, coming back to diversification of risks, GDF is constantly looking to widen the number and/or geographies of our suppliers. This is also contributing to positive pricing dynamics.
Also to note that diverse quality approved API sources are of crucial importance.

We in GDF cooperate with our colleagues in WHO Prequalification program and provide link for eligible TB manufacturers for free technical assistance from Promoting Quality of Medicines program of US Pharmacopeia.

This serves the purpose to ensure we have larger pool of approved suppliers of both, API and finished product suppliers for the foreseeable future.

Just to indicate practical example: I am writing these lines while driving back to Shanghai from meeting with potential manufacturing partner in Zhejiang province.

This concludes series of important meetings of this week with selected SLD manufacturers in China, and the potential is big here.

Also, next week GDF will present its business opportunities is South Korea in dedicated meeting called by PQM: more that 100 participants confirmed their attendance already!

With best regards,
Kaspars Lunte

Dr Kaspars Lunte
Team Leader MDR TB supply WHO-GDF
------------------------
Sent from my BB Terminal

----- Original Message -----
From: GHDonline (Paul Nunn) <>
To: Lunte, Kaspars
Sent: Thu Feb 23 12:22:16 2012
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right

Paul Nunn replied to the discussion "Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment & Prevention community.

Reply contents:
"Many thanks for the interesting inputs to date, but nobody has yet mentioned the price of the drugs, which we see as one of the main bottlenecks for wider availability of treatment for MDR-TB. Is this perceived as a barrier at country level? As the Global Fund resources shrivel (at least for now), will it be seen as a greater barrier? The average price for a regimen provided through the GDF to India is nearly
$6000 and these will be internationally quality assured (IQA) drugs, assured through "strict" national drug regulatory agencies, through the WHO Prequalification system, or recommended by the ERP Committee of the Global Fund. However, the same chemical entities are obtained by India through their tendering process for around $2400. These latter drugs are approved by the Indian drug control authority using their "Schedule M". Why does this enormous cost difference exist? What can be done to reduce it?
We have seen that the speed of delivery of SLDs through GDF has improved noticeably in recent years. There are still problems of lack of availability because of events (mainly) outside GDF's control, such as contamination of the single supplier API (kanamycin), and the tsunami and subsequent reduction in electricity supplies in Japan (also kanamycin). These kinds of obstacles show, however, that there is a need to widen the number (and geographical distribution?) of API suppliers, as well as of manufacturers of the finished pharmaceutical product. Thus, what we are now seeing in WHO with respect to the delays that occur in delivery of SLDs is that the bulk of the delays are at country level (eg failure to make the order) or at the Global Fund (eg failure to ensure the funds are available)."

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The Global Fund has contributed to dramatic health gains over the past decade Watch the Global Fund's inspiring 10 Years of Impact video<http://www.theglobalfund.org/en/mediacenter/videos/The_Global_Fund
_10_Years_of_Impact/>"

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The Global Fund has contributed to dramatic health gains over the past decade
Watch the Global Fund’s inspiring 10 Years of Impact video<http://www.theglobalfund.org/en/mediacenter/videos/The_Global_Fund_10_Years_of_Impact/>

Masoud Dara, MD
Replied at 4:45 AM, 27 Feb 2012

Thank you very much Philip for sharing your thoughts. GLC or GDF are not barrier to scale up, There is a wide range of reasons why countries can't/don't scale up and the root problem in most setting is poor planning. We don't want to open the old debate of no treatment is better than poor treatment and amplifying resistance. It is high time for all stakeholders particularly the health authorities, partners and civil society organizations to push from all sides for a careful and timely forecasting, removing barriers for registration/waiver of second line drugs, strengthening programmes not to create more MDR-TB and XDR-TB and "getting it right". It would be useful to learn the reasons why some manufacturers are not producing the second line drugs in the amount needed or in advance of orders. Have there been ever over production of these medicines?

All the best,
Masoud

Dr Masoud Dara
Programme Manager / Medical Officer
Tuberculosis and M/XDR-TB Programme
Division of Communicable Diseases, Health Security & Environment
Tel: +45 3917 1717 (direct number 1378)
Fax: +45 3917 1818
E-mail:

8 Scherfigsvej, DK-2100 Copenhagen, Denmark
http://www.euro.who.int



-----Original Message-----
From: GHDonline (Philippe Creach) [mailto:]
Sent: 27 February 2012 10:20
To: Dara, Masoud (DCE-TBM)
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right

Philippe Creach replied to the discussion "Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment & Prevention community.

Reply contents:
"Dear All,

This was the meaning of my message: as long as we continue with an inefficient system, all steps of this system, whatever well undertaken it is, will lead to failure. The point is not to improve these steps but to change the system.

The failure came exactly from this "made on order" that is just the continuation of an inefficient way to address SLD procurement. The GLC was reformed because it failed to address the needed scale-up to enrol very large numbers of eligible MDR-TB cases. But the system of procurement remained the same: the name change from GLC to GDF. SLD are still made on order. How can it work ?

In the manufacturing world of today, I do not see much goods made on order, except some luxury cars. For pharmaceuticals, I have none in mind and certainly not for tens of thousands of patients in needs. A bit of creativity would not hurt.

Every business is making a planning of goods to manufacture instead of waiting the order made by the clients.

I understand the difficulties, Kaspar, that you highlighted regarding the numerous steps to go through. But as long as the system is set such, MDR-TB cases, through the GLC/GDF, will remain at a low scale.

Best wishes,

P


-----Original Message-----
From: GHDonline (Dr Kaspars Lunte) [mailto:]
Sent: Saturday, 25 February 2012 3:46 AM
To: Philippe Creac'H
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right

Dr Kaspars Lunte replied to the discussion "Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment & Prevention community.

Reply contents:
"Dear Philippe, dear all,

The lead time of 6 months is not astonishing, it is reality unfortunately.
And there are many elements which contribute to this:

1. The order process will start when the payment arrives to the account of our procurement agent. I have seen many times the delays for this, both due to delays from the program or from the Global Fund. I fully understand that the relevant delays are caused by important internal factors, but this is where the delays start before the order can be placed.

2. GDF consolidates the orders for the deliveries to have 1-2 shipments for the particular project for all medicines, to save the transportation
costs: the preferred shipment mode is airfreight and this might be quite costly. The consolidated shipments are also easier for importation procedures at country level: however, we have seen weeks and in some cases even months when the goods were held at the border before importation has been fully granted.
In any case, there would be no sense to deliver each of the product separately as soon as they are arriving to our consolidation warehouse or are manufactured: the treatment is possible only when ALL medicines are received.
So, in this case the longest delivery time of the particular product concerned for the regimen directs the shipment date of whole shipment.

3. Shipment itself is relatively quick - air freight 1 week and sea freight app.6-8 weeks. Pre shipment inspection can take 1 - 2 weeks.

4. Manufacturing itself - minimum 8-10 weeks. However, for TB specific products it could take much longer if API is not immediately available and needs to be ordered (and here this process takes long, as the fresh API order needs to be placed, manufactured and shipped to SLD manufacturer. In some cases, for the API only sea shipment is possible due to regulations) Here also we need to account for the time when the manufactured product is sent from manufacturer to our warehouse for consolidation of the medicines together for the shipment to the program.

So if you read all this, I believe, you will agree that the process is objectively long and the unexpected delays can happen on any stage of this complex process.

Add to all above that sometimes countries don't consider the minimum order quantities for production. This causes additional delay as we need to receive another order from another project to put them together to create order with minimum order quantity ,and is hard to predict, when such will be received.

Add to this countries requirement to receive absolutely most possible fresh shelf life for the SLD products ( 24 months maximum shelflife for
SLDs) and sometimes longer time to convince the countries that the slightly shorter shelf life is also OK and the products could be consumed throughout all the duration of the shelflife, as indicated on the packaging.

And we cannot unfortunately compare made on order specific MDR TB medicines with aspirin on the pharmacy shelf. Aspirin in OTC product and will always be available as it is widely required. And even then you could receive it with the remaining shelf life of 8 months for example...

Hope this explains the complexity around SLDs and the leadtimes.

GDF is working with our partners to improve the leadtimes and we have seen some good progress already, as much as it depends from in house process.

But many elements unfortunately is out of GDF control.

Best regards,

Kaspars Lunte


-----Original Message-----
From: GHDonline (Philippe Creach) [mailto:]
Sent: Friday, February 24, 2012 4:47 PM
To: Lunte, Kaspars
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right

Philippe Creach replied to the discussion "Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment & Prevention community.

Reply contents:
"Dear Salem,

I hope that you are not dreaming since an average lead time of 6 months to deliver SLD is, somehow, astonishing. I can not imagine, in any private company, such a lead time for a product much in demand and need.
If I would go to a private pharmacy for aspirin and the pharmacist would answer me that he needs to start the production, I would be astonished as well.

I guess that we have clear estimates now on the number of patients in need of SLD thanks to the GLC, DRS...So, the forecasting of needs should not be an issue. It seems that we did not move much from the approach at the very beginning of the GLC: the exact number of pills started on procurement according to the exact number of patients in a GLC application.

I was reading in this forum that the Global Fund was cited as a bottleneck as it fails to deliver the needed financial resources. Well, this is surprising as it is the main funding party.

To come back to lead time, it is so long in some instances that it has prompted countries to request refund before replacing the same order not to be at odd with its national legislation. This is inefficient.

Sorry for being intense on this topic but the approach should be reviewed.

Best wishes,

Philippe Creac'h

-----Original Message-----
From: GHDonline (Salem Barghout) [mailto:]
Sent: Friday, 24 February 2012 3:26 PM
To: Philippe Creac'H
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right

Salem Barghout replied to the discussion "Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment & Prevention community.

Reply contents:
"Dear Kaspars and MDR Colleagues:

I have been reading through these very interested and lively discussions re. the very hot topic of SLD. Please allow me to share my personal views on this topic from my experience in EMR and especially in Pakistan. Although some countries might prefer to use Capreomycin however, at least in our area, injectables are selected based on the clinical history, previous use of SLD, DST pattern and drug availability. For more than a year, Capreomycin has not been available through GDF and we had to use Amikacin instead although, in many cases such as XDR, Capreomycin would have been the drug of choice but unfortunately it was not available yet. All of this is to say that personal preference plays, at least in our region, a very little role in treatment selection and the cost of treatment regimen per patient, using QA SLD through GDF, has been anywhere between US$ 5-6 Thousands.
The other issue, which is the long lead time from the time of pre-payment until SLD delivery, must be urgently addressed and shortened knowing that this problem has not been getting any better. I realize that there are many factors effecting this condition and many of them are probably beyond GDF's responsibilities but I am taking this opportunity to call upon the Global community to work together in order to bring this matter to a reasonable time, say 2-3 months at the maximum. May be I'm dreaming but that's ok to have some good dreams.

Regards,

Salem Barghout


Salem Barghout, MD
MO/MDR-TB/WHO-Pak
Cell: + 92 300 8599580
WHO GPN: 62481
E.Mail:


-----Original Message-----
From: GHDonline (Dr Kaspars Lunte) [mailto:]
Sent: Friday, February 24, 2012 1:21 PM
To: Salem Barghout
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right

Dr Kaspars Lunte replied to the discussion "Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment & Prevention community.

Reply contents:
"Dear all,

Would like to support Pauls message on the crucial importance of diversifying the risks to ensure uninterrupted supply of SLDs.

Just let me start with clarification on the treatment costs per patient:
it first of all depends on the regimen chosen: some countries prefer to use capreomycin instead of cheaper injectable, are willing to use more expensive PAS product etc. This contributes to higher treatment cost per patient. But, of course, for that there is clear justification.

On the lower end though, the regimen of quality medicines procured via GDF could be as low as less then 3000 USD per patient.

Also, if need exists to compare cost per patient treatment, this can be done only if <apples are compared with apples>: the regimens using only QA quality medicines, approved by WHO PQP or Stringent DRAs, so comparison with India schedule M would not be really valid.

Now, coming back to diversification of risks, GDF is constantly looking to widen the number and/or geographies of our suppliers. This is also contributing to positive pricing dynamics.
Also to note that diverse quality approved API sources are of crucial importance.

We in GDF cooperate with our colleagues in WHO Prequalification program and provide link for eligible TB manufacturers for free technical assistance from Promoting Quality of Medicines program of US Pharmacopeia.

This serves the purpose to ensure we have larger pool of approved suppliers of both, API and finished product suppliers for the foreseeable future.

Just to indicate practical example: I am writing these lines while driving back to Shanghai from meeting with potential manufacturing partner in Zhejiang province.

This concludes series of important meetings of this week with selected SLD manufacturers in China, and the potential is big here.

Also, next week GDF will present its business opportunities is South Korea in dedicated meeting called by PQM: more that 100 participants confirmed their attendance already!

With best regards,
Kaspars Lunte

Dr Kaspars Lunte
Team Leader MDR TB supply WHO-GDF
------------------------
Sent from my BB Terminal

----- Original Message -----
From: GHDonline (Paul Nunn) <>
To: Lunte, Kaspars
Sent: Thu Feb 23 12:22:16 2012
Subject: Re: [MDR-TB Treatment & Prevention] Expert Panel Feb. 20-24:
Management of Second Line anti-TB Drugs: Getting it right

Paul Nunn replied to the discussion "Expert Panel Feb. 20-24: Management of Second Line anti-TB Drugs: Getting it right" in the MDR-TB Treatment & Prevention community.

Reply contents:
"Many thanks for the interesting inputs to date, but nobody has yet mentioned the price of the drugs, which we see as one of the main bottlenecks for wider availability of treatment for MDR-TB. Is this perceived as a barrier at country level? As the Global Fund resources shrivel (at least for now), will it be seen as a greater barrier? The average price for a regimen provided through the GDF to India is nearly
$6000 and these will be internationally quality assured (IQA) drugs, assured through "strict" national drug regulatory agencies, through the WHO Prequalification system, or recommended by the ERP Committee of the Global Fund. However, the same chemical entities are obtained by India through their tendering process for around $2400. These latter drugs are approved by the Indian drug control authority using their "Schedule M". Why does this enormous cost difference exist? What can be done to reduce it?
We have seen that the speed of delivery of SLDs through GDF has improved noticeably in recent years. There are still problems of lack of availability because of events (mainly) outside GDF's control, such as contamination of the single supplier API (kanamycin), and the tsunami and subsequent reduction in electricity supplies in Japan (also kanamycin). These kinds of obstacles show, however, that there is a need to widen the number (and geographical distribution?) of API suppliers, as well as of manufacturers of the finished pharmaceutical product. Thus, what we are now seeing in WHO with respect to the delays that occur in delivery of SLDs is that the bulk of the delays are at country level (eg failure to make the order) or at the Global Fund (eg failure to ensure the funds are available)."

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Dr Kaspars Lunte
Replied at 4:57 AM, 27 Feb 2012

Dear all,

The manufacturers are producing in advance the products, which have
other indications beyond TB, such as Levofloxacin, for example. But
there is another issue with this- short shelf life of 24 months.

Many countries request the most fresh shelf life, and this can be
guaranteed only based on specific order for fresh production.

GDF also has stockpile of some SLDs, to respond to urgent requests as
much as possible. However, this UNITAID funded stockpile project is
ending 2012. We are looking forward to discuss with UNITAID about
expansion of this well working project for the next period.

Hope this clarifies.

My best regards,

Kaspars Lunte

Salmaan Keshavjee, MD, PhD
Replied at 6:36 AM, 27 Feb 2012

Dear all,

I want to echo Philippe’s excellent comments. I had the privilege of being a member of the Green Light Committee for five years (from 2005 until 2010) and the Chair of the committee for three years (2007-2010). I have also been involved in PIH projects in Russia and Lesotho, both of which have faced drug shortages.

At the outset, I want to point out that there is no problem with the supply of second-line anti-TB drugs in general. In fact, they can be purchased in pharmacies in most high-burden countries. There is, however, a shortage in quality-assured second-line anti-TB drugs through our current mechanism. We have to question why.

As early as 2007, we identified a number of important problems with the global mechanism for second-line drug procurement (using the Global Drug Facility (GDF) as its procurement agent):

1. No pooled procurement. Because GDF is housed in the WHO, it is unable to do true pooled procurement. The WHO financial rules require that funds be secured for orders before an order is placed. The result is that orders are only placed as they arrive, and not pooled together in a manner that could secure a commitment from manufacturers to lower the price. Attempts to address this with the creation of a buffer stock have had limited success.

2. No real negotiation with manufacturers over price. It turned out that there was no negotiation team working on determining the “true price” of products, and through this, determining what the lowest originator price could be.

3. Inability to forecast. For a number of years the GDF was unable to provide proper forecasts to manufacturers. Manufacturers don’t enter the market because they cannot trust the forecast data that they receive. New attempts are currently being made to improve this.

There were many other issues (e.g. the WHO prequalification process; the size of local markets for non-prequalified drugs, etc) which I will not go into here.

For five years we worked on trying to fix this mechanism. Paul Zintl (Chief Operating Officer of PIH) devoted two years and a significant amount of time as the Chair of a Drug Management Subgroup in the MDR-TB Working Group of the Stop TB Partnership. The committee’s efforts to rationalize the system—to push for structural changes in the way GDF handled second-line drugs—were met with a lukewarm response from GDF and its managers. In the end, the Subgroup was disbanded and few of its recommendations were implemented. Many of the committees recommendations were enshrined in an U.S. Insitute of Medicine Report on Barriers to MDR-TB Scale-up.

At the same time, numerous GLC reports from countries—based on on-site evaluations by trained GLC consultants—were indicating that in some cases countries were not able to enroll patients identified with MDR-TB because they did not have enough drugs. Drug supply issues were a major concern of the committee for the entire five years that I was a member. Country after country was found to be facing problems; the blame was usually placed on the country but not the system. In some cases, this was warranted (e.g. when drugs could not be released from customs, etc); in many other cases, it was because the drugs were not yet made by the manufacturer because there had been improper forecasting and not advance purchasing. The committee also worked closely with the GDF to encourage changes, with limited success.

The GLC underwent a massive reform process, which resulted in the Green Light Committee being closed. A new mechanism with a similar brand name (gGLC) emerged. The GDF remained as the sole supplier for GFATM projects. Significant problems remain. These problems are structural (and are not the fault of the people working very hard inside the GDF). There are some clear solutions:

1. PROBLEM: By being housed in a large bureaucratic organization such as the WHO the GDF is operationally limited (e.g. cannot do advance purchases and pooled procurement; does not have the ability to do hard-core negotiations with manufacturers) and cannot operate in a nimble, independent, and innovative fashion.

SOLUTION: The GDF should be spun off into an independent or semi-independent NGO. This won’t solve the demand problem – the fact that not enough MDR-TB patients are on treatment – but it will create a structure that is potentially capable of addressing the problem. An alternative is that a new independent MDR-TB drug facility be created as a multi-institutional partnership of key stakeholders, and GDF can be part of this. GDF has a role and its relationship with the WHO helps some countries get importation waivers. From the discussion thread, it seems that this is not reason enough to keep the current system going.

2. PROBLEM: By being granted an effective monopoly in procurement of MDR-TB drugs by the Global Fund, the GDF has not had to perform at a level expected for an epidemic of this nature.

SOLUTION: the Global Fund Board should remove the effective monopoly that it has granted GDF. It should require that countries purchasing MDR-TB drugs follow Global Fund rules. GDF can be one (of many) procurement options. This will encourage other systems of procurement of MDR-TB drugs to develop. Breaking this effective monopoly should be a priority for countries with a high-burden of MDR-TB, for advocates, for donors, for patients, and for the Global Fund itself (which, along with UNITAID, has paid premium prices for drugs that should not be so expensive).

3. PROBLEM: Drugs have a short shelf-life and need to get to countries as rapidly as possible. A risk needs to be taken for advance purchase.

SOLUTION: Funds should be made available by donors and innovative funders such as UNITAID to create a buffer stock of MDR-TB drugs. This has been attempted through GDF in the past, but should be done through a new and independent entity.

While these suggestions may be surprising to some, they should not be. There is not central agency for the procurement of HIV and Malaria drugs, and the Global Fund has granted no monopoly for procurement to any part. Instead, it has created procurement guidelines that should be followed by countries. For first line TB drugs, the GDF provides less than 15% of the global supply. The rest are purchased by countries themselves.

Philippe’s suggestion that we should be thinking outside the box is correct. We have been working with a system that does not have the capacity to meet our needs. I was initially reluctant to respond to this thread because I know that some colleagues will construe the suggestion that we think outside the box—that we really rethink the GDF’s role in second-line drug procurement—as an attack. It is not. Rather, it is my belief that we should be advocating for patients, and not the continuation of a system that has not been able, to date, to meet the needs of even the small number of patients on treatment. In reading the discussion thread, I became concerned that the voices expressed have not been from the countries most affected by our current system. I think that the reason is that country programs are often scared to complain about their situation for fear that they will lose support from the large international partners, and through them, donors. Those of us that know the data need to make it known that the situation is critical and the current system is one factor that is and will hamper any significant scale-up.

The Global Fund is in a position to change that dynamic. It would be good for patients (and for the Global Fund itself) if it reverses its 2003 decision granting the GLC and the GDF an effective monopoly over global MDR-TB. We should all be advocating strongly for that.

Irina Gelmanova, MD
Replied at 5:32 AM, 28 Feb 2012

Dear colleagues,
Reading the posts I could see several problems with the current system of SLD procurement.
1) The majority of manufacturers seem not to be interested in the prequalification process. As a result, only a limited number of GDF/WHO-approved manufactures are registered within a given country. These countries also have local producers.
2) GDF consistently is unable to procure all necessary SLD on time. Many countries have constant shortages of drugs and cannot put all their patients on treatment. I have never spoken to anybody from a country that has not had a problem with procurement through the GDF mechanism.
3) Some of GDF prices might be higher that SLD prices within countries from local producers. SLD prices significantly increased within the last 10 years. I remember in 2001 we were buying capreomycin for $1 per vial, currently it is $8. I cannot imagine any low income country buying these medications without any external financial support. Even with financial support from Global Fund, we are spending money that could be used to treat other patients. We should be realistic about this.
4) Many countries had long time customs clearance process. TB has been declared as a global emergency in 1993 and MDR-TB after 2006, so senior leadership at the UN need to encourage the senior government officials in countries to let these drugs in.
5) Only a small proportion of all SLD consumed in the world is procured through GDF. In general we would like all countries to use only quality assured medications for TB treatment, so we obviously failed in this prospect.
So, all above indicates a failure of the current system to ensure that EVERY MDR TB patient gets quality assured medications. The medications are too expensive and only a small proportion of SLD have prequalification process.
As we know GF had a requirement to buy medications through GDF. However, if we want countries to cover costs themselves, we have to imagine that they may not be interested in buying meds from GDF. It is likely they will look at the locally registered manufacturers with lower prices.
I am not in the position to say how to improve GDF functioning as it was suggested by some people.
However, from country perspective it would be great to have a rating of different SLD manufacturers present in the country. US Pharmacopeia has this list for first line meds around the world. Why not create the same for second line drugs? That way, people will at least have an idea of the quality of the drugs that they our using. Of course, prequalification process is different from random checking of some batches, and countries can still be recommended to buy stringent quality-assured medications. However, if the country decides to buy meds within the country (and a significant proportion do), at least, they can choose those companies that are rated well by Pharmacopeia (or another organization testing SLD). Published ratings might also stimulate manufacturers to improve the quality of produced medications and motivate them to ask for help with this.
Irina Gelmanova

Sophie Beauvais
Replied at 1:35 PM, 28 Feb 2012

Hi All,

Excellent panel. Here’s a comment from Dr Francoise Nywagi Louis (initially posted on our blog: http://tinyurl.com/6ur29ow):

---

We are working in SA, but also in Botswana and Swaziland; cha;;enges are different in those countries;
1. Projects in Swaziland and Botswana jointly with NTPs say the procurement through GLC is extremely long, forcing the national programs to buy drugs, which comply to the WHO prequalification list, as much as possible.
2. Due to the delay in GLC procurements, the countries have experienced experienced stock outs and were under pressure to find emergency solutions
3. Drug ordering is uneven, sometimes patient based, sometimes consumption based;
4. Identification and reporting of side effects can be a challenge as in spome countries there is no pharmacovigilance system
5. ACTG groups set up a list of severity grading system for side effects ranking and this should also apply to SLD
4. There is need to set up a list of ancillary drugs for side effects, and clear guidelines for management of side effects depending on the severity, and per level of care (includng community
5. Botswana has gone very far in applying to the TFM already
6. In Swaziland they buy SLD through the local procurement, while waiting for the GLC containment, but it is mainly the ART program that is highly affected by the cancellation of GF R11
7. With XpertMTB/Rif and LPA, we expect more cases to be identified, which is good for the community and for the patient him/herself; but on a programmatic side, the forecast of SLD and ancillary drugs should have been done prior to the introduction of those molecular methods of diagnosis; the latter is usually faster than the procurement system (low amounts of SLD produced, single WHO prequalified manufactuirng site, delivery time etc….) and countries might end up diagnosing DRTB patients without having available drugs….

Masoud Dara, MD
Replied at 5:17 PM, 28 Feb 2012

Dear panellists, dear Lucica, Ernesto, Kaspars and Sandra,

Dear community members,

I am writing to thank you for an excellent, interactive and open discussion on "management of second line drugs, getting it right".

We heard colleagues' perspectives from different countries from Latin America to India and from Eastern Europe to the Middle East. We also heard views and suggestions of activists, experts, managers, clinicians, laboratory scientists and community representatives, some revolutionary and some evolutionary, which approach would be more constructive, effective and result-oriented is food for thought and open for discussion, but I think suggestions were useful, and healthy to improve the management of second line drugs. We did not hear much from the health authorities themselves on how they plan to improve management of second line drugs, but I am confident that many of them did read this thread and would reflect. To this end, one take- home message could be that management of TB drugs is not/shall not be considered solely an international affair, it is everybody's business if we want effective TB control and prevent M/X/XXDR-TB development. It is the national authorities' responsibility to ensure quality assured medicines are available, accessible and acceptable for their citizens and that international organizations, donors, NGOs and others may only assist them and not replacing them. Even if there are discussions/disputes on how to assist, in one thing we would all concur and that is that the universal access to quality assured and reasonably priced medicines and their rational use is a human right principle and highly effective public health intervention to break the chain of TB transmission and preventing further development of antimicrobial resistance.

Some concrete suggestions were proposed, but we did not have enough time to discuss them in details, they need to be further discussed within the community and beyond. Therefore I suggest continuing our correspondence in a featured discussion within the MDR-TB GHD online community.

Sandeep, Francois and some others suggested having more discussion on the clinical issues, a sort of online Clinical Pathologic Case Presentation (CPC). We could dedicate a room in this community for this purpose.

Last but least, I would like to thank Sophie for taking on board the suggestion of establishing this panel and her support and guidance.

Thank you everyone and best regards,
Masoud

Lucica Ditiu
Replied at 9:22 PM, 28 Feb 2012

Thank you. This was actually fantastic discussion for us, thank you all!
Lucica

Salem Barghout
Replied at 11:47 PM, 28 Feb 2012

Dear Masoud and Colleagues:

Lots of excellent ideas, opinions, suggestions and challenges have been
exchanged recently through this wonderful forum concerning SLD management.
My only hope is that whatever has been shared and discussed would reach
our friends who have the power to change the situation and make a real
difference. I realize that SLD management is affected by multiple
organizations and its serious and urgent challenges cannot be resolved by
one side. However, the time has come that the global community would get
together and work hand in hand to reverse the situation rather that each
side' trying to defend its position and justify the causes of the problem.
If we want to reach our target that each MDR patient should have a
universal access to treatment by 2015, QA SLD must be made available in a
reasonable lead time, affordable and directly financed through donors (such
as the GF or others) and properly managed.

Regards,

Salem Barghout

--
Salem Barghout, MD
MDR-TB Consultant/ WHO-Pak
Mobile: + 92 300 8599580
E-Mail:

Dr Kaspars Lunte
Replied at 2:05 AM, 29 Feb 2012

Dear Masoud, dear panelists and colleagues,

Indeed, very interesting and hopefully useful discussions!

I fully agree that MDR TB requires efforts at all levels and with all partners.

I would like to stress that Global Drug Facility (GDF) is there to assist programs in the best way possible, so please don't hesitate to approach us with your requests!

With warm regards,
Kaspars Lunte


Dr Kaspars Lunte
Team Leader MDR TB supply WHO-GDF
------------------------
Sent from my BB Terminal

Sophie Beauvais
Replied at 4:13 PM, 29 Feb 2012

Dear All,

On behalf of all of us at Global Health Delivery online, and our founding collaborators at the Brigham and Women's Hospital and at Harvard Medical School, I would like to extend sincere thanks to all participating in this panel discussion on second line anti-TB drugs management. Some clear actionable items and takeaways have been identified (they will soon be referenced in a peer-reviewed Discussion Brief and published in GHDonline). We hope this conversation is only the beginning of an open and constructive dialogue to bring forth change and improve health care delivery for all.

I would also like to extend special thanks to Dr. Masoud Dara for leading the conversation, and for our esteemed colleagues at the WHO, the GDF, the Stop TB Partnership, and the Global Fund, for participating. As Dr. Dara noted, “It [the management of TB drugs] is everybody's business if we want effective TB control and prevent M/X/XXDR-TB development.” World TB Day is less than a month away and you are on the front lines so if you have not yet posted in this discussion, and although the panel has officially ended, you can still make your voice heard.

Best, Sophie

Ravinder Makkar
Replied at 8:26 AM, 13 Jun 2012

Dr Dara, Dr DitiuI, Dr Lunte, Dr Jaramillo,

I read the WHO 2011 TB report with great interest. While the global TB picture is scary, I believe that a great progress has been made towards reducing the burden of TB, thanks to the concerted efforts of WHO and other organizations. In the report, I noted that in China, the number of MDRTB cases in 2010 is reported to be ~63000, whereas the actual number of MDR Tb patients treated in the same year in China is reported to be only ~ 1200 (China country fact sheet, WHO 2011 report). That’s a correct treatment rate of only ~2%!!
Does that mean that the rest of the MDRTB cases (98%!!)in China are left undiagnosed or untreated? If that is the case, then (given the high mortality rates esp in MDRTB), the total number of TB deaths in China should be much higher than what is reported in WHO 2011 report (54000 deaths). Or else, the treated numbers that are reported (2%) are too low. Clearly, there seems to be some disrepancy between the treated MDRTb numbers or the reported Tb mortality numbers.

Another WHO report -[WHO/HTM/TB/2011.3]- quotes that around 10% of MDR TB cases get enrolled in MDR treatment in the high burden countries) Can you shed some light on this?

Thanks,
Dr Ravinder Makkar

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