World Health Organization How WHO ensures the quality How WHO ensures the quality of of antiretrovirals antiretrovirals and other essential medicines and other essential medicines Geneva University Hospital, 7 September 2004 Geneva University Hospital, 7 September 2004 Dr Dr Lembit Lembit R R ä ä go go Quality Assurance and Safety: medicines Quality Assurance and Safety: medicines World Health Organization World Health Organization Geneva Geneva Switzerland Switzerland E E - - mail:[email protected]mail:[email protected]
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World Health Organization
How WHO ensures the quality How WHO ensures the quality of of antiretroviralsantiretrovirals
and other essential medicinesand other essential medicines
Geneva University Hospital, 7 September 2004 Geneva University Hospital, 7 September 2004
Dr Dr LembitLembit RRäägogoQuality Assurance and Safety: medicinesQuality Assurance and Safety: medicines
World Health OrganizationWorld Health OrganizationGenevaGeneva
What is a problem?What is a problem?What is a problem?
♦ A lot of generic manufacturers have started to produce ARVs, including FDCs, but compliance with international requirements for quality, safety and efficacy varies
♦♦ A lot of generic manufacturers have A lot of generic manufacturers have started to produce started to produce ARVsARVs, including , including FDCsFDCs, but compliance with , but compliance with international requirements for quality, international requirements for quality, safety and efficacy varies safety and efficacy varies
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Counterfeit ARVs, including FDCsreality
Counterfeit Counterfeit ARVsARVs, including , including FDCsFDCsrealityreality
♦ WHO distributed in 2003 Rapid Alert about Ginovir3D which was found not to contain the three actives on label in amounts suggested
♦♦ WHO distributed in 2003 Rapid Alert about WHO distributed in 2003 Rapid Alert about GinovirGinovir3D which was found not to contain the three actives 3D which was found not to contain the three actives on label in amounts suggestedon label in amounts suggested
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Looking back (I)Looking back (I)Looking back (I)♦ Maloprim (pyrimethamine + dapsone) was
developed as a malaria prophylactic agent with activity against parasites which had become resistant to pyrimethamine alone in the early 1960’s.
♦ In 1969 Co-trimoxazole (Bactrim or Septrin ) was launched as an FDC antibiotic which resulted from the cross licensing of components by Wellcome (now GSK) and Roche. The compound was the top anti-bacterial of its time (grossing more than $5 billion in sales.)
♦♦ MaloprimMaloprim (pyrimethamine + dapsone) was (pyrimethamine + dapsone) was developed as a malaria prophylactic agent developed as a malaria prophylactic agent with activity against parasites which had with activity against parasites which had become resistant to pyrimethamine alone in become resistant to pyrimethamine alone in the early 1960the early 1960’’s. s.
♦♦ In 1969 CoIn 1969 Co--trimoxazole (Bactrim or trimoxazole (Bactrim or SeptrinSeptrin ) ) was launched as an FDC antibiotic which was launched as an FDC antibiotic which resulted from the cross licensing of resulted from the cross licensing of components by components by WellcomeWellcome (now GSK) and (now GSK) and Roche. The compound was the top antiRoche. The compound was the top anti--bacterial of its time (grossing more than $5 bacterial of its time (grossing more than $5 billion in sales.)billion in sales.)
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Looking back (II)Looking back (II)Looking back (II)
♦ In the 1960s the pendulum began to swing away from Fixed Dose Combinations (FDCs).
– The FDA was mandated to review the effectiveness of drugs approved between 1938 and 1962 in the Drug Efficacy Study Implementation (DESI) program. Some medicines were withdrawn and new FDCs facing a difficulties to pass registration.
♦♦ In the 1960s the pendulum began to In the 1960s the pendulum began to swing away from Fixed Dose swing away from Fixed Dose Combinations (Combinations (FDCsFDCs). ).
–– The FDA was mandated to review the effectiveness The FDA was mandated to review the effectiveness of drugs approved between 1938 and 1962 in the of drugs approved between 1938 and 1962 in the Drug Efficacy Study Implementation (DESI) Drug Efficacy Study Implementation (DESI) program. Some medicines were withdrawn and new program. Some medicines were withdrawn and new FDCsFDCs facing a difficulties to pass registration.facing a difficulties to pass registration.
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Looking back (III)Looking back (III)Looking back (III)♦ WHO Expert Committee maintained the
1978 position until 2002 ♦ In 2002 the position changed to following:
♦ "Most essential medicines should be formulated as single compounds. Fixed dose combination products are selected only when the combination has a proven advantage over single compounds administered separately in therapeutic effect, safety, adherence or in delaying the development of drug resistance in malaria, tuberculosis and HIV/AIDS.
♦♦ WHO Expert Committee maintained the WHO Expert Committee maintained the 1978 position until 2002 1978 position until 2002
♦♦ In 2002 the position changed to following:In 2002 the position changed to following:
♦♦ "Most essential medicines should be formulated as "Most essential medicines should be formulated as single compounds. Fixed dose combination products single compounds. Fixed dose combination products are selected only when the combination has a are selected only when the combination has a proven advantage over single compounds proven advantage over single compounds administered separately in therapeutic effect, safety, administered separately in therapeutic effect, safety, adherence or in delaying the development of drug adherence or in delaying the development of drug resistance in malaria, tuberculosis and HIV/AIDS.resistance in malaria, tuberculosis and HIV/AIDS.
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Background for antiretroviralsBackground for antiretrovirals♦ HAART improves considerably morbidity and
mortality in developed world (see next slide)♦ HAART improves morbidity and mortality
also in developing world (Marins R et.al. AIDS 2003;17:1675)
♦ Improving access to drugs in the developing world through numerous programs including WHO’s 3 by 5 program, Global Fund mechanisms etc.
♦ Simplification of treatment important to help rapid scale-up of treatment programs
♦ Use of FDC’s crucial for simplifying treatment
♦ HAART improves considerably morbidity and mortality in developed world (see next slide)
♦ HAART improves morbidity and mortality also in developing world (Marins R et.al. AIDS 2003;17:1675)
♦ Improving access to drugs in the developing world through numerous programs including WHO’s 3 by 5 program, Global Fund mechanisms etc.
♦ Simplification of treatment important to help rapid scale-up of treatment programs
♦ Use of FDC’s crucial for simplifying treatment
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Before and after HAARTBefore and after HAARTBefore and after HAART
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Traditional HAARTTraditional HAARTTraditional HAART♦ Pill burden, difficult schedules, potential bad
compliance and difficult supply management♦♦ Pill burden, difficult schedules, potential bad Pill burden, difficult schedules, potential bad
compliance and difficult supply managementcompliance and difficult supply management
♦♦ Positive experience Positive experience with other diseaseswith other diseases
♦♦ Program managementProgram management♦♦ CheaperCheaper
DisadvantagesDisadvantages♦♦ LeadLead--in dose may not in dose may not
be followedbe followed♦♦ Difficult to use when Difficult to use when
dose adjustments are dose adjustments are needed ( e.g. renal needed ( e.g. renal failure)failure)
♦♦ ADRsADRs to one to one component: stop the component: stop the FDCFDC
♦♦ Pediatric formulations?Pediatric formulations?
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The need for flexibility vs the need for simple robust treatment schemes needs balancingThe need for flexibility The need for flexibility vsvs the need for simple the need for simple robust treatment schemes needs balancingrobust treatment schemes needs balancing
Problems with FDCs:
– In spite of advantages most likely one
size does NOT fit all but may fit most in
mass treatment programs.
– The need for the availability of various
individual drugs and formulations will
not disappear
Problems with FDProblems with FDCs:Cs:
–– In spite of advantages most likely one In spite of advantages most likely one
size does NOT fit all but may fit most in size does NOT fit all but may fit most in
mass treatment programs.mass treatment programs.
–– The need for the availability of various The need for the availability of various
individual drugs and formulations will individual drugs and formulations will
not disappear not disappear
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The need for dosing flexibility: pediatricsThe need for dosing flexibility: The need for dosing flexibility: pediatricspediatrics
♦ The need for multiple formulations of the same drug applies even more to pediatrics:
– weight-based dosing needed for most
antiretrovirals until adolescence – linear
proportional decrease of doses of all components
may not be always the case; In addition: relative
lack pediatric PK studies; lack of studies with
combinations in pediatric populations
– need for liquid formulations in infants;
♦♦ The need for multiple formulations of the The need for multiple formulations of the same drug applies even more to pediatrics:same drug applies even more to pediatrics:
–– weightweight--based dosing needed for most based dosing needed for most
antiretroviralsantiretrovirals until adolescence until adolescence –– linear linear
proportional decrease of doses of all components proportional decrease of doses of all components
may not be always the case; In addition: relative may not be always the case; In addition: relative
lack pediatric PK studies; lack of studies with lack pediatric PK studies; lack of studies with
combinations in pediatric populationscombinations in pediatric populations
–– need for liquid formulations in infants;need for liquid formulations in infants;
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FDA Approved Fixed Dose Combinations from originatorsFDA Approved Fixed Dose Combinations FDA Approved Fixed Dose Combinations from originatorsfrom originators
♦♦ Evidence based treatment outcome claimed. But based on Evidence based treatment outcome claimed. But based on what exactly?what exactly?
♦♦ In case of TRIZIVIR In case of TRIZIVIR …… based on bioequivalence studies based on bioequivalence studies FDC FDC vsvs individual drugs. NO "real" clinical studies with individual drugs. NO "real" clinical studies with FDC as such! FDC as such!
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A number of generic products availableA number of generic products availableA number of generic products available
♦ By today there is more than 20 generic manufacturers in Asia, Latin America, also starting in Africa …
♦ A lot of generic products including FDCs
♦ … and few meet international criteria for quality, safety and efficacy…
♦♦ By today there is more than 20 generic By today there is more than 20 generic manufacturers in Asia, Latin America, manufacturers in Asia, Latin America, also starting in Africa also starting in Africa ……
♦♦ A lot of generic products including A lot of generic products including FDCsFDCs
♦♦ …… and few meet international criteria and few meet international criteria for quality, safety and efficacyfor quality, safety and efficacy……
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FDCs from generic manufacturers (1)FDCsFDCs from generic manufacturers (1)from generic manufacturers (1)
What to do ensure quality, safety and efficacy of antiretrovirals?What to do ensure quality, safety and What to do ensure quality, safety and efficacy of efficacy of antiretroviralsantiretrovirals??
♦ Discussions within UN organizations 2000♦ It was decided in 2001 to start
prequalification project to ensure that UN family and international donor money is not spent on drugs that do not meet quality, safety and efficacy criteria
♦ Important to save "magic pills"
♦♦ Discussions within UN organizations 2000Discussions within UN organizations 2000♦♦ It was decided in 2001 to start It was decided in 2001 to start
prequalification project to ensure that UN prequalification project to ensure that UN family and international donor money is not family and international donor money is not spent on drugs that do not meet quality, spent on drugs that do not meet quality, safety and efficacy criteriasafety and efficacy criteria
♦♦ Important to save "magic pills"Important to save "magic pills"
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Prequalification of HIV/AIDS Drugs Prequalification of HIV/AIDS Drugs -- UN UN joint activityjoint activity
Partners*Partners*–– UNAIDSUNAIDS–– UNICEFUNICEF–– UNFPAUNFPA–– WHOWHO–– With the support of World BankWith the support of World Bank
WHO roleWHO role–– Technical assistance based on Technical assistance based on WHO norms and WHO norms and
standards, plus ICH and other standards, where standards, plus ICH and other standards, where applicable applicable
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Prequalification basic principlesPrequalification basic principles♦♦ VoluntaryVoluntary for participating manufacturers for participating manufacturers ♦♦ LegitimateLegitimate -- General procedure and standards General procedure and standards
approved through WHO Expert Committee systemapproved through WHO Expert Committee system♦♦ Widely discussedWidely discussed in many in many forafora
–– FIP Congress, Nice 2002FIP Congress, Nice 2002–– Supported by ICDRA in 2002 and 2004, representing Supported by ICDRA in 2002 and 2004, representing
more than 100 national drug regulatory authoritiesmore than 100 national drug regulatory authorities♦♦ TransparentTransparent (all information available on the web site (all information available on the web site
http://http://www.who.intwww.who.int/medicines//medicines/))♦♦ OpenOpen to both innovators and to both innovators and multisourcemultisource/generic /generic
manufacturersmanufacturers♦♦ No costNo cost for applicants so farfor applicants so far
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Prequalification: quality generics or not? Prequalification: quality generics or not?
♦♦ FDA requirements for generic drugs FDA requirements for generic drugs ((www.fda.gov/cder/ogdwww.fda.gov/cder/ogd))
A generic drugs must: A generic drugs must: 1. contain the same active ingredients as the innovator 1. contain the same active ingredients as the innovator
drugs as the innovator drugdrugs as the innovator drug2. be identical in strength, dosage form, and route of 2. be identical in strength, dosage form, and route of
administrationadministration3. have the same use indications 3. have the same use indications 4. be bio4. be bio--equivalentequivalent5. meet the same batch requirements for identity, strength, 5. meet the same batch requirements for identity, strength,
purity and qualitypurity and quality6. be manufactured under the same strict standards of 6. be manufactured under the same strict standards of
GMP required for innovator products.GMP required for innovator products.
How prequalification is done?How prequalification is done?How prequalification is done?
♦ By competent national regulators and inspectors exactly as the best regulatory agencies do it:
– Thorough assessment of documentation provided for quality, safety and efficacy
– Inspections of all manufacturing sites– Inspection of API manufacturers (if not inspected
by others like EU inspectors or US FDA) planned – Inspections of CROs where BE studies are done– QC lab testing– Follow-up surveillance of supplies
♦♦ By competent national regulators and By competent national regulators and inspectors exactly as the best regulatory inspectors exactly as the best regulatory agencies do it:agencies do it:
–– Thorough assessment of documentation Thorough assessment of documentation provided for quality, safety and efficacyprovided for quality, safety and efficacy
–– Inspections of all manufacturing sitesInspections of all manufacturing sites–– Inspection of API manufacturers (if not inspected Inspection of API manufacturers (if not inspected
by others like EU inspectors or US FDA) planned by others like EU inspectors or US FDA) planned –– Inspections of Inspections of CROsCROs where BE studies are donewhere BE studies are done–– QC lab testingQC lab testing–– FollowFollow--up surveillance of suppliesup surveillance of supplies
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Recent events: 28 November 2003Recent events: 28 November 2003Recent events: 28 November 2003
♦ WHO prequalified in addition to single products and double generic FDCs(lamivudine+zidovudine) first generic triple FDCs first from Cipla, and then from Ranbaxy:
♦ Stavudine/ Lamivudine/ Nevirapine40/150/200
♦ Stavudine/ Lamivudine/ Nevirapine30/150/200
♦♦ WHO WHO prequalifiedprequalified in addition to single in addition to single products and double generic products and double generic FDCsFDCs((lamivudine+zidovudinelamivudine+zidovudine) ) first generic triple first generic triple FDCsFDCs first first from from CiplaCipla, and then from , and then from RanbaxyRanbaxy::
Why it was different and caused concerns?Why it was different and caused Why it was different and caused concerns?concerns?
♦ The first triple FDC for which originator FDC did not exist
♦♦ The first triple FDC for which originator The first triple FDC for which originator FDC did not existFDC did not exist
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Does existence of originator FDC is a regulatory must?Does existence of originator FDC is a Does existence of originator FDC is a regulatory must?regulatory must?
♦ Originator FDCs approved also based on bioequivalnce (BE) studies against single components – TRIZIVIR case by FDA and EMEA
♦ Key – is there clinical evidence that combination as such is safe and effective?
♦ If yes, scientifically appropriate BE studies in healthy volunteers is enough
♦ Naturally all stringent quality requirements have to be met as well
♦♦ Originator Originator FDCsFDCs approved also based on approved also based on bioequivalncebioequivalnce (BE) studies against single (BE) studies against single components components –– TRIZIVIR case by FDA and TRIZIVIR case by FDA and EMEAEMEA
♦♦ Key Key –– is there clinical evidence that is there clinical evidence that combination as such is safe and effective?combination as such is safe and effective?
♦♦ If yes, scientifically appropriate BE studies in If yes, scientifically appropriate BE studies in healthy volunteers is enoughhealthy volunteers is enough
♦♦ Naturally all stringent quality requirements Naturally all stringent quality requirements have to be met as well have to be met as well
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Clinical evidence for triple combination approved by WHOClinical evidence for triple Clinical evidence for triple combination approved by WHOcombination approved by WHO
1. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN StudyF van Leth, P Phanuphak, K Ruxrungtham et al. Lancet 2004; 363: 1253–63
Remark: Prove of efficacy and safety of the combination but not FDC as such. See next slide for FDC safety and efficacy, plus MSF data presented in Bangkok July 2004 AIDS Conference
1. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN StudyF van Leth, P Phanuphak, K Ruxrungtham et al. Lancet 2004; 363: 1253–63
Remark: Prove of efficacy and safety of the combination but not FDC as such. See next slide for FDC safety and efficacy, plus MSF data presented in Bangkok July 2004 AIDS Conference
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WHO/HQ, Geneva 15-17 December 2003 WHO/HQ, Geneva 15WHO/HQ, Geneva 15--17 December 2003 17 December 2003
FIXED DOSE COMBINATIONS FOR HIV/AIDS, TUBERCULOSIS, AND MALARIA
Current status and future challenges from clinical, regulatory, intellectual property, and production
FIXED DOSE COMBINATIONS FOR HIV/AIDS, FIXED DOSE COMBINATIONS FOR HIV/AIDS, TUBERCULOSIS, AND MALARIATUBERCULOSIS, AND MALARIA
Current status and future challenges from clinical, Current status and future challenges from clinical, regulatory, intellectual property, and production regulatory, intellectual property, and production
perspectivesperspectives
Materials and presentations:Materials and presentations:
♦ Some parties felt that during the meeting there was not enough time to deal with regulatory aspects of FDCsduring WHO December 2004 meeting
♦ A new initiative took shape in early 2004…
♦♦ Some parties felt that during the Some parties felt that during the meeting there was not enough time to meeting there was not enough time to deal with regulatory aspects of deal with regulatory aspects of FDCsFDCsduring WHO December 2004 meeting during WHO December 2004 meeting
♦♦ A new initiative took shape in early A new initiative took shape in early 20042004……
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Botswana ConferenceBotswana ConferenceBotswana ConferenceConference on Fixed-Dose Combination (FDC) Drug
Products--Scientific and Technical Issues related to Safety, Quality and Effectiveness
Gaborone, BotswanaMarch 29-30, 2004
Cosponsored by:Southern African Development Community (SADC)
World Health Organization (WHO)United Nations Joint Program on HIV/AIDS (UNAIDS)
U.S. Department of Health and Human Services (HHS)
Conference on FixedConference on Fixed--Dose Combination (FDC) Drug Dose Combination (FDC) Drug ProductsProducts----Scientific and Technical Issues related to Scientific and Technical Issues related to
Safety, Quality and EffectivenessSafety, Quality and EffectivenessGaboroneGaborone, Botswana, BotswanaMarch 29March 29--30, 2004 30, 2004
Cosponsored by:Cosponsored by:Southern African Development Community (SADC) Southern African Development Community (SADC)
World Health Organization (WHO)World Health Organization (WHO)United Nations Joint Program on HIV/AIDS (UNAIDS)United Nations Joint Program on HIV/AIDS (UNAIDS)
U.S. Department of Health and Human Services (HHS)U.S. Department of Health and Human Services (HHS)
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Purpose of ConferencePurpose of Conference♦♦ To develop principles document on FDCsTo develop principles document on FDCs♦♦ Provide points to consider when developing, Provide points to consider when developing,
evaluating and/or considering combinations for evaluating and/or considering combinations for use in programs using FDCs for treatment of use in programs using FDCs for treatment of HIV/AIDS, TB and Malaria and their associated HIV/AIDS, TB and Malaria and their associated diseases.diseases.
♦♦ Document focuses on aspects of efficacy, Document focuses on aspects of efficacy, safety and quality of FDCssafety and quality of FDCs
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Conference AttendeesConference Attendees♦♦ Government officialsGovernment officials♦♦ Representatives from drug regulatory agencies Representatives from drug regulatory agencies
(23 countries)(23 countries)♦♦ ResearchResearch--based and generic Rx industrybased and generic Rx industry♦♦ Public health leadersPublic health leaders♦♦ Health care providersHealth care providers♦♦ Advocacy groups Advocacy groups
–– Including persons living with HIV/AIDSIncluding persons living with HIV/AIDS♦♦ Academia Academia ♦♦ NonNon--governmental organizations (NGOs)governmental organizations (NGOs)
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How to structure regulatory approach to FDCs?How to structure regulatory approach How to structure regulatory approach to to FDCsFDCs??
♦ Discussing the first draft of Botswana document the 4 scenario approach to was suggested
– DRAFT April 22, 2004– Final version expected September 2004
♦♦ Discussing the first draft of Botswana Discussing the first draft of Botswana document the 4 scenario approach to document the 4 scenario approach to was suggestedwas suggested
–– DRAFT April 22, 2004DRAFT April 22, 2004–– Final version expected September 2004Final version expected September 2004
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Scenario 1Scenario 1Scenario 1♦ A new FDC product developed as a
generic bioequivalent to an existing FDC (originator product)
♦♦ A new FDC product developed as a A new FDC product developed as a generic bioequivalent to an existing generic bioequivalent to an existing FDC (originator product)FDC (originator product)
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Scenario 2Scenario 2Scenario 2
♦ A new FDC product developed by combining active components that are already well studied and for which the simultaneous use of all the individual active components in a multidrug regimen has been well characterised as safe and effective.
♦ The dosage regimen of the components given individually in a multidrug regimen and the dosage regimen of the FDC are the same.
♦♦ A new FDC product developed by combining A new FDC product developed by combining active components that are already well active components that are already well studied and for which the simultaneous use studied and for which the simultaneous use of all the individual active components in a of all the individual active components in a multidrug regimen has been well multidrug regimen has been well characterised as safe and effective. characterised as safe and effective.
♦♦ The dosage regimen of the components The dosage regimen of the components given individually in a multidrug regimen and given individually in a multidrug regimen and the dosage regimen of the FDC are the the dosage regimen of the FDC are the same.same.
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Scenario 3Scenario 3Scenario 3♦ A new FDC product is developed from
individual components that have a well-characterised safety and efficacy profile on their own, but the efficacy and safety of their simultaneous use in a multidrug regimen is not well established;
♦ or when two or more well-characterised individual components from an established multidrug regimen are combined using a novel dosing regimen.
♦♦ A new FDC product is developed from A new FDC product is developed from individual components that have a wellindividual components that have a well--characterised safety and efficacy profile on characterised safety and efficacy profile on their own, but the efficacy and safety of their their own, but the efficacy and safety of their simultaneous use in a multidrug regimen is simultaneous use in a multidrug regimen is not well established; not well established;
♦♦ or when two or more wellor when two or more well--characterised characterised individual components from an established individual components from an established multidrug regimen are combined using a multidrug regimen are combined using a novel dosing regimen.novel dosing regimen.
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Senario 4SenarioSenario 44
♦ The FDC is developed by incorporating one or more new molecular entities.
♦♦ The FDC is developed by incorporating The FDC is developed by incorporating one or more one or more newnew molecular entities. molecular entities.
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Scientific DisciplinesScientific Disciplines♦♦ The document details the information to be The document details the information to be
provided for each scenario in the following areas:provided for each scenario in the following areas:–– MicrobiologyMicrobiology–– ToxicologyToxicology–– Clinical safety and efficacyClinical safety and efficacy
•• Bioequivalence studyBioequivalence study•• Pharmacokinetic and pharmacodynamic studiesPharmacokinetic and pharmacodynamic studies•• Clinical study designClinical study design
♦ Risk/benefit assessments for FDCs may have to take into consideration the differences in anticipated patient populations, and decision making may vary between the different national drug regulatory authorities (DRAFT April 22, 2004).
♦♦ Risk/benefit assessments for Risk/benefit assessments for FDCsFDCs may may have to take into consideration the have to take into consideration the differences in anticipated patient differences in anticipated patient populations, and decision making may vary populations, and decision making may vary between the different national drug between the different national drug regulatory authorities (DRAFT April 22, regulatory authorities (DRAFT April 22, 2004).2004).
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Not Stand Alone DocumentNot Stand Alone Document♦♦ Document not exhaustive on the topics Document not exhaustive on the topics
discusseddiscussed♦♦ Document should be used in conjunction with Document should be used in conjunction with
existing national and international regulatory existing national and international regulatory guidelines on the specific topics in the areas of guidelines on the specific topics in the areas of quality, safety and efficacy.quality, safety and efficacy.
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ExpectationsExpectations♦♦ It is hoped that this document will facilitate and It is hoped that this document will facilitate and
promote the development of FDCs, by both promote the development of FDCs, by both innovator and generic for the treatment of innovator and generic for the treatment of HIV/AIDS, TB, malaria and their associated HIV/AIDS, TB, malaria and their associated infectious diseases.infectious diseases.
♦♦ The document specifically encourages the The document specifically encourages the development of pediatric formulations of FDCdevelopment of pediatric formulations of FDC
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Status of DocumentStatus of Document♦♦ Was posted on the web for commentsWas posted on the web for comments
–– http://www.globalhealth.gov/fdc.shtmlhttp://www.globalhealth.gov/fdc.shtml–– Comment period Comment period April22 April22 -- May 10, 2004May 10, 2004
♦♦ Comments received are being evaluated Comments received are being evaluated for incorporation into the documentfor incorporation into the document
♦♦ Final document will be posted for use by Final document will be posted for use by interested partiesinterested parties
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US FDA initiative, May 2004US FDA initiative, May 2004US FDA initiative, May 2004Guidance for Industry
Fixed Dose Combination andCo-Packaged Drug Products for
Treatment of HIVDRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
U.S. Department of Health and Human ServicesFood and Drug Administration
Center for Drug Evaluation and Research (CDER)May 2004
V. CLINICAL CONSIDERATIONS V. CLINICAL CONSIDERATIONS
♦ For many potential FDCs or co-packaged products (e.g., those in Attachment B), FDA believes adequate clinical studies confirming safety and efficacy of the combination have already been conducted, obviating the need for new clinical studies.
– Applicants for FDC or co-packaged products may provide clinical efficacy and safety information by one or more of the following mechanisms …
♦♦ For many potential For many potential FDCsFDCs or coor co--packaged products packaged products (e.g., those in Attachment B), (e.g., those in Attachment B), FDA believes FDA believes adequate clinical studies confirming safety and adequate clinical studies confirming safety and efficacy of the combination have already been efficacy of the combination have already been conducted,conducted, obviating the need for new clinical obviating the need for new clinical studies. studies.
–– Applicants for FDC or coApplicants for FDC or co--packaged products may packaged products may provide clinical efficacy and safety information by one provide clinical efficacy and safety information by one or more of the following mechanisms or more of the following mechanisms ……
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FIFTY-SEVENTH WORLD HEALTH ASSEMBLY, Geneva 22 May 2004FIFTY-SEVENTH WORLD HEALTH ASSEMBLY, Geneva 22 May 2004
♦ Agenda item 12.1: Scaling up treatment and care within a coordinated and comprehensive response to HIV/AIDS
♦ Requested Director General ♦ (3) to take measures to improve access of developing
countries to pharmaceutical and diagnostic products to diagnose, treat and manage HIV/AIDS, including by strengthening WHO’s prequalification project;
♦ (4) to ensure that the prequalification review process and the results of inspection and assessment reports of the listed products, aside from proprietary and confidential information, are made publicly available;
♦ Agenda item 12.1: Scaling up treatment and care within a coordinated and comprehensive response to HIV/AIDS
♦ Requested Director General ♦ (3) to take measures to improve access of developing
countries to pharmaceutical and diagnostic products to diagnose, treat and manage HIV/AIDS, including by strengthening WHO’s prequalification project;
♦ (4) to ensure that the prequalification review process and the results of inspection and assessment reports of the listed products, aside from proprietary and confidential information, are made publicly available;
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What has happened since then?What has happened since then?What has happened since then?
♦ Several countries up-scaling their treatment programs
♦ Removal of some products from prequalified list
♦ WHO draft guideline for FDCsdeveloped
♦ Good progress but still huge unfinished agenda
♦♦ Several countries upSeveral countries up--scaling their scaling their treatment programstreatment programs
♦♦ Removal of some products from Removal of some products from prequalifiedprequalified listlist
♦♦ WHO draft guideline for WHO draft guideline for FDCsFDCsdevelopeddeveloped
♦♦ Good progress but still huge unfinished Good progress but still huge unfinished agendaagenda
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Why WHO prequalification is such a big issue?Why WHO prequalification is such a big issue?Why WHO prequalification is such a big issue?
♦ Different parties very different interests♦ Why everybody talks about ARVs
quality but not much about TB drugs or antimalarials
♦ ARVs – this where the patents exist, TB and antimalarials – Big Pharma has no patents …
♦♦ Different parties very different interestsDifferent parties very different interests♦♦ Why everybody talks about Why everybody talks about ARVsARVs
quality but not much about TB drugs or quality but not much about TB drugs or antimalarialsantimalarials
♦♦ ARVsARVs –– this where the patents exist, this where the patents exist, TB and TB and antimalarialsantimalarials –– Big Big PharmaPharma has has no patents no patents ……
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Instead of conclusion: When all elephants start to co-operate and go into the same direction?
Instead of conclusion: When all elephants Instead of conclusion: When all elephants start to costart to co--operate and go into the same operate and go into the same direction?direction?
♦ Last year millions died from a drug problem. They could not get any (Medecins Sans Frontiers).
♦♦ Last year millions died from a drug problem. Last year millions died from a drug problem. They could not get any (They could not get any (MedecinsMedecins Sans Sans FrontiersFrontiers).).
