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REPORT TO: CIAT and all Latin America FROM: Iván Allende (Paraguay) Jaime Argueta (El Salvador) Lourdes Kusunoki ( Peru ) SUBJECT: World CAB 3 Meeting DATE: London , July13-14, 2006 Access to second line antiretroviral regimens Financed by the International Treatment Preparedness Coalition in cooperation with HIV i-Base List of participants: Mohamed Amin India . Jaime Argueta El Salvador. Iryna Borushek Ukraine Robert Carr Jamaica Simons Collins UK Polly Clayden UK Ivan Allende Paraguay . Roman Dudnik Russia . Lourdes Kusunoki Fuero Peru . Gregg Gonsalves South Africa . Loon Henminflun India . Bob Huff USA . Bertrand Kampoer Cameroon . Paul Kasonkomona Zambia . Svilen Konov UK . Anna Koshykova Translator Othman Mellouk Morocco. Lydia Mungherera Uganda. Bob Munk USA. Lilian Mworeko Uganda. Ethel Pengel Suriname. Lawan Sarovat Thailand . Igor Sobolek Estonia . Liudmila Untura Moldova. Win Vandevelde Portugal. Koen Van Rompay USA. Tomislav Vurusic Croatia. World CAB 3 - 13th to 15th July 2006 – London Access to second-line antiretroviral regimens. Sponsored by the International Treatment Preparedness Coalition in co-operation with HIV i-Base AGENDA Wednesday 12th July. Delegates Arrive Thursday 13th July 08.00 – 10.00 Delegates Pre-Meeting 10.00 – 12.00 Meeting with representatives from Gilead Sciences. (Coffee/Tea will be served at 11.00) 12.00 – 13.00 Lunch (provided by conference venue) 13.00 – 16.00 Meeting with Gilead Sciences (continued) 16.00 – 16.15 Tea/Coffee 16.15 – 18.00 Delegates debriefing and planning meeting. Friday 14th July 08.00 – 10.00 Delegates Pre-Meeting 10.00 – 13.00 Meeting with representatives from Abbott Laboratories. (Coffee/Tea will be served at 11.00) 13.00 – 14.00 Lunch (provided by conference venue) 14.00 – 17.00 Delegates debriefing and planning meeting. Tea/Coffee will be served at 16.00 19.30 WorldCAB group dinner. Saturday 15th 09.30 – 12.00 WorldCAB planning meeting. (Future meetings, WorldCAB structure, membership and other topics.) 12.00 – 13.00 Lunch (provided by conference venue) Agenda Thursday, July 13 Introduction - Participants introduction. - Historical background on generic and patent drugs. Delegates pre-meeting Topics to be discussed with GILEAD Science. • Present GILEAD Science World CAB arguments for opposition to patent. • Ask for an explanation about delays on regulatory approval in more than 80% of less developed countries. • Ask about expedite registry in the countries (or consider drafting of local patent rights) • Request price review for all medium income countries and consider a formula based on prices for less developed countries (and x price in LDC = price for medium income countries) • Expedite submission of the new FDC to WHO pre-qualifying program. • Have all products ready for submission for consideration of essential drugs list to WHO. • If they are proposing or if they offered voluntary licenses, to which companies and in what terms. • How will they meet the demand of active pharmaceutical ingredients (APIs) for their licenses, if WHO lists TDF as a component of first line regimens. • Regulations for approval, clinical trials, price and patent status for the use of TDF for Hepatitis B treatment. • Current research for identifying renal toxicity in resource poor settings. • Development status of the integrase inhibitor. Meeting with GILEAD Science. Norbert Bischofberger Amy Flood. * History of Tenofovir. Tenofovir is an excellent option for persons with failure to AZT, 3TC or D4T. * Pricing policy: Gilead has developed a pricing policy according to 4 groups of countries: - Countries benefited by Gilead Access Program or low income countries: 97 countries, Morocco among them (they consider adding 2 countries due to their high potential for generics production, India and Thailand to their initial list). - Medium-low income countries (L-MIC): Latin America is included here. - Medium-high income countries (H-MIC): Brazil , Lebanon and Oman are included here, but they seem to have flexibility for discussion of the list. - High income countries: USA , Western Europe . One of the questions was the price for low income countries. Answer: Viread $17/month and Truvada $26.24/month. Low MIC: $ 30 and $45 respectively. High MIC: Price based on the countries economical situation, epidemiological situation and their payment capacity. * Registry: Gilead is a small laboratory present in 12 industrialized countries. No presence in developing countries. Gilead awarded ALAMO in South Africa a voluntary license for generic products making. ALAMO’s option is troublesome, because it’s a laboratory which also works with big companies. Alamo received also a voluntary license from GSK for Combivir among others. Gilead took many years to produce an ARV and above all to patent them. Registry and distribution of these products in Sub-Saharan Africa is endangered. At present time, Gilead is negotiating with Merck for registry and distribution in the rest of the countries (North Africa, Asia, Latin America and other medium income countries and Morocco ). * Registry progress: Currently, files have been released in 54 of the 97 countries included in the access program initiative. Viread has only been registered in 13 countries and Truvada in 8. They recognize their desperation for registering them in the rest of the countries. They expect to have the registry in most of these countries by year’s end, although there are a lot of problems to achieve this. * Voluntary licenses: Gilead is now negotiating with 5 generic drug producing laboratories in India (Hetero, Ranbaxy and Cipla among them) for voluntary licenses granting, including technology transfer. They expect these agreements to be continuously reached. However, these laboratories would submit to the very precise conditions and to the obligation of supplying themselves with Gilead’s active ingredients with their Bahamas laboratory. The manufactured products will only be for the 97 countries in the Access initiative. Possible export to medium income countries will be via Merck (including Morocco ). Gilead justifies this situation with the fact that they notably support and above all to certain Brazilian and Eastern Europe markets. Gilead will be in charge of verifying manufacturing practices of Cipla, Hetero and Ranbaxy, because these laboratories are actually disputing Tenofovir’s patent in India and some of them have filed demands in court. As Indian courts have made no representations, it's not probable that they accept these voluntary licenses (there's no personal confidence for the moment, especially with Ranbaxy). * TDF renal toxicity: TDF reduces tubular absorption with an important urinary loss of phosphates, glucose and amino acids. Renal toxicity proved to be stronger in African populations. Toxicity is more important in adults than in children. For Gilead , the toxic one is Adefavir. License has been denied by FDA due to this renal toxicity. TDF (Disoproxil Fumarate) is more soluble and less toxic. A trial on this will be presented at Toronto . At high doses, TDF could cause some osseous abnormalities in menopausic women and notably among young adolescents). Friday, July 14 Meeting with Abbott Delegates pre-meeting Topics to be discussed during the meeting with ABBOTT * Desperate need for a new Kaletra formulation in Africa, Asia and other settings, so the drug can be taken without food and stores without refrigeration. · Even in its old formulation, Kaletra is not available in many places due to lack of registry and/or the price. · Need to know about their pricing policy and where will they seek registry. · Let us know the status on the plans for patents and voluntary licenses, especially in India (not limited to that country). · Development time for a new thermo-stable version of Ritonavir. · Need for a lower RTV booster dose and at a lower price. · Training for health professionals and communities on the properties of the new Kaletra formulation. · Side effects of the new formulation. · Data about Kaletra monotherapy? · Pediatric formulations? · Quick tests (access to quick diagnostic test DETERMINE and pricing policies). ABBOTT Introduction Abbot has simply made available its thermo stable product, which doesn’t need refrigeration. At present time they are considering to market the same product: Aluvia for developing countries. The name difference would enable to avoid medicines to be transported from southern to northern countries where there's no differentiated price and where this version of Kaletra is not necessary. According to Abbott, they had changed their position with a pricing policy due also to pressures by MSF; they had made efforts for developing countries to have the new Kaletra version. Abbott is considering increasing their production capacity in order to notable respond to increasing demand in southern countries for second line treatments. They are now building a factory in Italy with a huge investment. * Registry: Kaletra in tablets (thermo stable version) was accepted in November 2005. Development of this thermo stable version took 7 years. This development is due to a “revolutionary” technology named “Metrex” (fusion expulsion), and consists in dissolving the molecule into a polymer matrix. This accounts for their reluctance to technology transfer. They state that although voluntary licenses are available, without this technology it’s impossible to produce, and they don’t want to transfer this technology due to their high investment in development. Kaletra's international version for developing countries will be named ALUVIA. They want to speed up registry process; this can take about 12-24 months. * Pricing policy: Abbott is inflexible: $500 for Access countries. (They include all Africa ). No price decrease has been announced for medium-low countries. They would agree to discuss inclusion criteria (World Bank criteria: Low MIC or Lower MIC, prevalence, etc). According to them, no manufacturer can produce at a lower price than the estimated cost for low income countries ($500 per person per year). Besides, it’s a very complex process. If they sell at a lower price, there will be loses, it’s their production cost. At the same time they refuse to hand absolute voluntary licenses (as Gilead ’s notice). They are eager to defend their intellectual property rights through to the bitter end. They state that even Norvir, which is no longer protected, has been possibly manufactured by other companies. Although Abbott considers improbable to increase its production capacity at that price, for increasing its production capacity six fold, for example, will multiply by six their loses possibility. * Benefits of the new version (thermo-stable) - Increase in molecule solubility. - Increase in bio-availability. - Storage at regular temperature. - One capsule contains: 200mg lopinavir, 50mg ritonavir (4 tablets instead of 6 capsules) - No refrigeration. - No need to take with food. - Less pharmacokinetic variability. - Potentially less side effects (fewer diarrheas). * Norvir Actually, Abbott is developing a new 100 mg. Norvir thermo-stable version. They are beginning some bio-availability trials in humans and the prototype is being developed for this year. They think it will take more time to develop than Kaletra, but is about the same process. Development of this version would be interesting as this booster could be used with another protease inhibitor produces by generics making companies. They think to have attained progress in dose reduction with this version (50 mg. could be enough). Even Gilead is interested in this version. Abbott has no intention in developing this type of relationships. They confirm Gilead 's interest and that Abbott is encouraging them. They say Gilead only has to use the liquid of their drugs in order to prove the coadjutant effect. Abbott was asked if they were ready to grant Ritonavir rights o granting of some voluntary licenses for another integrase inhibitor booster. They say that Hetero is interested, but it’s tool early for any negotiation. * Pediatric: Thermo-stable pediatric version will soon be produced. There is an issue with achievement of dosing flexibility. * Fixed dose combinations: ¿Is there any interest to team up with other companies for development of fixed dose combinations with Ritonavir as coadjutant? As was the latter case with Gilead , Merck and BMS. They have interest, but nothing has been done. * Use of Kaletra monotherapy: Lopinavir/Ritonavir combination (Kaletra) can be possibly used in monotherapy (biotherapy in fact) in these situations: - Initial therapy - Maintenance therapy: beginning with 3 Arts and upon undetectable VL achievement, use as monotherapy. Some interesting results about these trials will be presented at Toronto . * New thermo-stable version registry (Aluvia): At this time they hope to obtain the Pharmaceutical Product Certificate from the European Union, before starting the process of product registry in developing countries (this certificate will be required by most countries). FOLLOW-UP With ABBOTT: • Another meeting with ABBOTT? With medium income countries? Yes, but we will make the agenda in order to cover other items as: Is $500 the lowest price? We should stand together as a block and not individually. • Check out with Clinton , Cipla, etc, if RTV and RTV/LPN can be produced for less than $500 per year. • Immediate teleconference with Abbott and medium income countries? We need to do our work; collect information about drug prices in and then request a teleconference with ABBOTT. • Drug prices harmonization, do our own analysis and then approach the companies. • Have meetings between CIAT, Global Fund, WHO and UNAIDS. • Don’t let ABBOTT divide activists from low and medium income countries. • Develop a standard political position in medium income countries for all companies. • Take advantage of the Toronto Conference as a platform to lobby about the topic of second line therapies; as well and meetings with WHO, UNAIDS and Global Fund. • Discuss second line therapies with generic drugs manufacturers and the Clinton Foundation. Tasks • Take our agreements to other groups working in second line therapies (WIM and SVILEN) Next 10 days! • Make a written statement for widespread release, containing prices, licenses (SIMON and GREGG) - NOW! • Have a meeting between ABBOTT and medium income countries. (WIM AND BOB MUNK) • Talk to generic drugs companies in BRAZIL , THAILAND and INDIA about the possibility of making drugs at US$500 now or in the future (TAHIR and IVAN) TWO WEEKS! • Demand ABBOTT to override their patent rights in INDIA (TAHIR). • Write to ABBOTT about a price offer. Next Week! • Collect prices and other data from medium income countries (ODILON, LOURDES , IRINA, JAIME) and Africa (OTHMAN AND LYDIA) – Two weeks! • Price negotiations with local ABBOTT representatives (all) - Next Week! • We need to support discussion about new drugs (Simon) from now on. • TIBOTEC prices (ODILON, WIM) – Now! Comments Lourdes Kusunoki From now on, there is a lot to be done. We should focus on priority activities, for the most important thing is the country’s political compromise so they can increase their national budgets for ARVs buying; also to seek commitment by international cooperation agencies for this purpose. Because even if prices drop to their lowest, if there's no budget, second line drugs could not be purchased, and even so if we want to put Kaletra as first line treatment, the scenario will be more complex, for there would not be resources available to begin treatment with NAÏVE patients. It would be important to gather data about PLWHA follow-up in countries offering HAART, and its troubles. What's the status of adherence for these patients; recognizing that adherence and positive prevention are important for this population. Iván Allende The World CAB delegates meeting showed the huge inequalities for drug access in participant countries and the troubles in access to second line drugs, or those needed by persons with HAART failure. Also, there was evidence of low access to follow-up tests with the recommended frequency in order to guide in therapy changes. Difficulty is even higher when we deal with tests that can certify emergence of resistant virus and the sensitivity pattern to ARVs (genotyping and resistance tests). In Latin America and the Caribbean (LAC) possibility of access to recommended and pre-qualified drugs by WHO, is very different and has to deal with national budgets, access to non-reimbursable external funding like the one from the GFTAM, and in some cases contributions from the local civil and private sector (NGOs). Other item to be discussed would be pricing policies from companies producing innovative drugs. Both GILEAD and ABBOTT made reference to country rating by income produced by the World Bank. This rating is far from reality as it does not use the health per capita money numbers set apart by our countries, which is where financing is found for free ARVs national programs. In analyzing this income distribution, it’s more than evident that the World Bank rating is not realist as far as health investment, and distorts companies’ views at pricing time.


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