GCT 2012 Helmut Wolf Keynote on Emerging Markets


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3rd Annual Executing Global Clinical Trials, Sept 2012 Helmut Wolf, MD, Novartis - Keynote on Emerging Markets

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  • Regulations governing clinical research in West have become more an more complex, placing a greater burden on investigators in terms of compliance, documentation and training.
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  • China has overtaken India in terms of share of new clinical trials. A ratio of 1:1 China:India in number of new trials in 2008 has been transformed into a 2:1 ratio in 2011. While China has expanded its clinical trial bases in the past 5 years, unpredictable regulations in India and slow approval timelines appear to have significantly hurt India's sector. in 2008, 246 in 2009, 254 in 2010 and 169 in 2011 trial approval timelines in India had gone up from about three-four months to close to nine months, while China had reduced its timelines "drastically" from 12 months, with South Korea paring these down to just 30 days from six to nine months. India's current $400 million clinical trial market is still considerably less than the forecasts of more than $1 billion by 2010 Check medpace article for specific stuff on how China is more attractive. China slated to be 2 nd biggest clinical trial market by 2020. Global players (CROs) doubled their presence in 2011 – mostly through acquisitions. Also issues with sample export limited no of countries in which you want ot put central labs Ditto Malaysia - can talk about NVS work there with gvt – get stuff form the article and also pictures and supporting trial timeline improvement, raising standards etc. Some countries have a CT requirement for registration – sometimes more flexible than others (e.g. Orphan, life-saving drugs)
  • The critical properties of a medicine that make it less likely to be sensitive to ethnic factors include nonsystemic mode of action, linear PK, a flat PD (effect-concentration) curve for both efficacy and safety in the range of the recommended dosage and dose regimen (this may mean that the medicine is well-tolerated), wide therapeutic range (again, possibly an indicator of good tolerability), minimal metabolism, high bioavailability thus less susceptibility to dietary absorption effects, low potential for protein binding, little potential for interactions, and little potential for inappropriate use.[1] The critical properties of a medicine that make it more likely to be sensitive to ethnic factors include nonlinear PK, steep PD curve, narrow therapeutic range, high metabolism, genetic polymorphism, administration as a prodrug with the potential for ethnically variable enzymatic conversion, high intersubject variability, low bioavailability, high likelihood of use in a setting of multiple comedications, and high potential for inappropriate use . As mentioned above, the third and final step as per ICH-E5 is to judge the requirement of bridging study (if needed) based on medicine's sensitivity to ethnic factors and on likelihood that extrinsic ethnic factors could affect the medicine's safety, efficacy, and dose-response. A “bridging” study, as its name implies, is designed to allow one to bridge from the original region's (foreign) data in the original population to the new region. ICH-E5 define bridging study as a study performed in the new region to provide PD or clinical data on efficacy, safety, dosage, and dose regimen in the new region that will allow extrapolation of the foreign clinical data to the population in the new region.[1,4,6–8] Generally, for medicines characterized as insensitive to ethnic factors, the type of bridging study needed (if needed) will depend upon experience with the drug class and upon the likelihood that extrinsic ethnic factors (including design and conduct of clinical trials) could affect the medicine's safety, efficacy, and dose-response.[1] A bridging study may not be needed in two conditions, first, if medicine is ethnically insensitive and extrinsic factors such as medical practice and conduct of trials are similar in each region, or medicine is ethnically sensitive but the two regions are ethnically similar and there is sufficient experience with pharmacologically related compounds in the two regions [Table 2].[1]
  • The classic definition of Health transition or epidemiologic transition is �A characteristic shift in the disease pattern of a population as mortality falls during the demographic transition: acute, infectious diseases are reduced, while chronic, degenerative diseases increase in prominence, causing a gradual shift in the age pattern of mortality from younger to older ages. In general, Epidemiologic transitions (in general), Any major shift in patterns of disease or causes of death that affects the level and character of mortality in a population. Life expectancy has risen from below 30-35 to almost 70 years during the industrial era. Three major factors have contributed to this increase: Improved living standards public health & medical care. All are important, though to varying degrees in different eras. The second half of the 20th century witnessed major health transitions in the world, propelled by socio-economic and technological changes that profoundly altered life expectancy and ways of living, while creating an unprecedented human capacity to use science to prolong and enhance life. The most globally pervasive change among these health transitions has been the rising burden of non-communicable diseases (NCDs). Epidemics of NCDs are presently emerging, or accelerating, in most developing countries1. Cardiovascular diseases (CVDs), cancers, diabetes, neuropsychiatric ailments and other chronic diseases are becoming major contributors to the burden of disease, even as infections and nutritional deficiencies are receding as leading contributors to death and disability. In many emerging markets in this transition, they now suffer from a “double burden of disease”. This is an “Asian issue” currently - Latam largely transitioned to NCD and SSA still driven by infectious diseases.
  • Globally prevalent. Highest prevalence in Asia – so makes sense to do all the studies there right – its cheaper, quicker etc.!
  • You can probably expand on this slide a bit from your thoughts on the Harvard MRCT project.
  • Regulations governing clinical research in West have become more an more complex, placing a greater burden on investigators in terms of compliance, documentation and training, Poverty, socio-economic inequalities and corruption Alleged exploitation of developing countries in relation to cost advantages and/or through testing drugs in local populations, the outcomes of which would benefit patients mostly in Western countries Standards of care frequently different from those applied in Western countries Alleged lenient regulatory requirements in some host countries Questionable effectiveness of local enforcement mechanisms by some Ethics Committees Inadequate protection of research participants including unethical use of placebo, inadequate patient information regarding the research proposal and lack of provision of care after trial completion Changes to local product patent regime which are perceived as possibly denying affordable drugs targeting major epidemics or life-threatening indications to millions of people. Basic healthcare, health insurance and adequate infrastructures are not widely available Ethical review of research may be sub-optimal Traditions of biomedical research and of human and patient rights are not well-established Experienced and GCP trained healthcare personnel may be in short supply .
  • Anecdotes : Termites ate a pile of CRFs in a study in Brazil: With SARS in China , the patients were not able to go back to the sites for their hospital visits as the hospitals were closed. We had to arrange makeshift clinics in hotels where the doctors could perform the patients assessments and the study could continue. THE QA inspectors will tell you to have fire and waterproof cabinets...........but if a hurricane hits you may need a local team as dedicated as this guy to rescue your data. Or, of course EDC could be your lifeline here!!
  • GCT 2012 Helmut Wolf Keynote on Emerging Markets

    1. 1. Conducting Global Clinical Trials in Emerging Markets Dr. Helmut Wolf, Regional Medical Director, Group Emerging Markets, Novartis AG.
    2. 2. Many Pharma Companies are rushing to place their studies in Emerging Markets
    3. 3. Are there still opportunities for further globalisation? • Are we galloping happily to the promised land in a race for profits and patients? • Or do we need a reality check?
    4. 4. To realise the benefits of further globalisation........... • How can we avoid rushing like lemmings and really realise the benefits of development in Emerging markets? • We need the – Right Medicine – Right Disease – Right countries!
    6. 6. Offshoring vs. “Global” Development • Offshoring: • Primarily driven by cost savings – investigator fees but also speed of recruitment • Tropical Diseases: • Development mainly in poorest markets e.g. Sub Saharan Africa / Myanmar for novel Anti-Malarials • Global Development : • Developing drugs where the patients are to ensure Emerging Market unmet medical needs appropriately represented in our development programmes...... - As a Global Company with presence in over 100 countries worldwide Novartis does all of these but aspires to the latter as a general principle of drug development...........
    7. 7. • Globalisation of Clinical trials should be a “win-win” also benefitting the local population • Research subjects in Global trials should be treated appropriately in all countries in which a company operates – no “dual standards” for ethics etc. • Conduct of study must be such that trial results are accurate and valid (GCP / ICH not negotiable in ANY country) • For studies for Global registrations, the data should be extrapolatable to other settings - In this case must have right drug, right disease and right patient population! Some Principles for Global Development:
    8. 8. Benefits of globalisation of clinical development are not just for Sponsors • Potential to contribute to economic development in many regions and improve accessibility of drugs and devices to their populations. – Faster study completion brings successful medicines to patients sooner – Access for patients to innovative medicines that could be years away from commercial supply. – Investment in local community medical and scientific infrastructure and capability building.
    9. 9. What are the benefits for Sponsors: • Bringing new medicines to a global population in a timely and efficient manner: – Cost-savings (may be half of the USA or less) – Accelerated recruitment times to enable sooner global filing – Improved regulatory access if local patients in studies (eg Korea,Vn) – Less complex and burdensome hospital environment
    10. 10. External context Benefits of shift to Emerging markets Drivers for globalization of clinical development for Sponsors  Margin pressure for pharma companies  Limited market growth and restricted patient access in developed markets  Opportunities in developing nations • Highest market growth rates • Access to (naive) patients • Increasing clinical infrastructure growth  Competitive intensity increasing – competitors also entering developing nations  Substantial cost savings: • Cost per patient may be one fifth of that in the USA  Accelerating Clinical Development • Large pool of potential new patients • Simpler and cheaper regulatory environment  Evidence base in new regions • Globally relevant evidence base - bringing drugs to patients that need them globally • Relationships forged with KOLs globally Strategic Imperative  Clinical operations excellence in all geographic regions more critical than ever  Emphasis on quality, speed, and costs  Global patient access and commercialisation in line with most Pharma Company strategy
    11. 11. Cost of delay – Operational costs 11 • Average trial cost per month: – Phase II = $160,833 – Phase III = $1,083,333 • Average Operational cost of delay per trial is from: • $160,833 to $1,083,333 • per Month ..! “Every second of delay in a clinical trial costs Bristol-Myers Squibb $17……” President of Bristol Myers Squibb in 2001 Cost of delay – Loss of eventual sales
    12. 12. Key Factors influencing Investigator fees
    13. 13. Investigator fees vary widely per region
    14. 14. • Huge patient populations • Patients see trials as opportunity • Large % of drug naïve patients • Centralized medical centers • Physicians eager • Less competition for investigators Quality QualityRecruitment Why is recruitment so fast? • NVS Experience: • In a recent audit, average no. of patients per site for a key study in US was 6, in EU 5 and in China 30!
    15. 15. Quality can be managed in Emerging Markets
    16. 16. Need to keep up to date with trends • Its a dynamic environment, particularly in Asia • China has overtaken India in terms of share of new clinical trials and is projected to be world’s No.2 clinical trial market by 2012 • Ratio of 1:1 China: India in number of new trials in 2008 has been transformed into a 2:1 ratio in 2011 • Significant reductions in trial approval timelines seen in China ( down from 1 year to 6-9 months), South Korea ( from 9 months to 30 days) and Malaysia (from 9 months to 3-4 months) . • Be aware of increasing requirements for local patients for registration • China, Korea and new legislation in Vietnam..... • Sample Export continues to be an issue. • Can site a central lab in the country if cannot export samples (China) but ad hoc regulations on this can cause problems – Russia few years ago.
    17. 17. CHOOSE THE RIGHT MEDICINE To serve our patients properly in emerging markets we need to understand how medicines behave in different climates and in different patients
    18. 18. Ethnic Sensitivity Assessment • The ICH-E5 guideline provides a general framework for evaluating the potential impact of ethnic factors on the acceptability of foreign clinical data, with the underlying objective of minimizing duplication of clinical data, and it also describes the requirement of bridging studies for extrapolation of foreign clinical data to a new region. • The ICH-E5 guideline basically suggests a three-step process for judging the acceptability of foreign clinical data. The first step is assessment of completeness of clinical data package of the medicine and if clinical data package is found to be complete, then second step is to assess the product's sensitivity to ethnic factors and third and final step is to judge the requirement of bridging study based on medicine's sensitivity to intrinsic ethnic factors and on likelihood that extrinsic ethnic factors could affect the medicine's safety, efficacy, and dose-response
    19. 19. Extrinsic Factors Intrinsic factors Factors in Ethnic Sensitivity Assessment (ICH E5)  Factors associated with environment and culture in which a person resides. These factors tend to be less genetically, more culturally, and behaviorally determined • Environment (eg sunlight, pollution) • Culture • Medical practice • Socio-economic factors • Language • Disease definition and diagnostics • Therapeutic approach • Drug compliance • Diet • Exercise/ Lifestyle  Factors that help to define and identify a subpopulation and may influence the ability to extrapolate • Gender • Race • Age • Height / weight • Renal, cardiac, hepatic function • Genetic polymorphisms in metabolising enzymes • ADME • Smoking/ Alcohol use. • Co-morbidities All these may affect ADME, safety and efficacy of a medicine in different patients
    20. 20.  Nonsystemic mode of action  Linear PK  Flat PD curve • For both efficacy and safety in the range of recommended dosage (may mean generally well tolerated)  Wide therapeutic range  Minimal metabolism  High Bioavailability • Thus less susceptible to food effects  Low potential for Protein Binding  Little potential for Interactions  Little Potential for inappropriate use. Not Likely to be sensitive to ethnic factors Likely to be sensitive to Ethnic factors Drug susceptibility to Ethnic sensitivity:  Non-Linear PK  Steep PD Curve  Narrow therapeutic range  High metabolism  Genetic Polymorphism  Prodrug • Potential for ethnically variable enzymatic conversion  High Intersubject variability  Low bioavailability  High use in setting with multiple co- medications  Consider also traditional remedies  High Potential for Inappropriate use. Evaluate and decide if bridging study, global study or local study needed!
    21. 21. • Even if a medicine is deemed Ethnically Insensitive (preferably done in phase 1 so dose finding can be done in multiple populations if needed) there are logistical considerations for use in Emerging Markets • Cold Chain: – May be difficult to ensure in markets with poorer infrastructure. – Increasing issue with rise in biologics in trials – Care needed once sites beyond primary cities. • Tropical Countries: – Even if refrigeration not needed drug substance or product may not be stable under WHO Climate Zone IV conditions of heat and humidity. – Implications for safety and efficacy variability in global studies and registration potential even for local studies. Physico-Chemical Properties of drug
    22. 22. CHOOSE THE RIGHT DISEASE Hepatitis C as an example
    23. 23. Purpose of Development? • Is this for Global Development or for a disease endemic only in emerging markets? • It does not make sense to run Malaria studies in Boston but does it make sense to run diabetes, hepatitis or other “global disease” studies globally for registration in the USA/ Europe?
    24. 24. Global disease burden is shifting • With Economic Development Emerging markets classically undergo an “Epidemiological Transition” from early mortality , driven by infection to later mortality driven by Cardiovascular and metabolic diseases (Omran 1970’s) • This is generally associated with a transition to “Western” Lifestyles and many emerging markets now suffer from a “double burden of disease” – particularly in Asia.
    25. 25. Drug Development for “global diseases” • FDA accepts “foreign” data – as long as it is relevant to the practice of Medicine in the USA......... – Even if the epidemiology seems to be the similar, is the disease really similar enough to be able to run a global study? – Are there local disease variants? – Is the response to medication uniform globally? – What about at the genotypic level as we move towards personalised Medicine.........? • None of these are deal breakers for global development but we do need to understand the disease we are dealing with.
    26. 26. Hepatitis C is a global disease • A “simple” disease to use as an example – Seemingly not multifactorial; caused by the Hepatitis C Virus – Global epidemiology with many patients in “cheaper” markets (< 2% prevalence in USA, 14% Egypt) – Global standard of care as comparator ( IFN/ Ribavirin) – “Ideal” candidate for a global study?
    27. 27. But the Epidemiology is not uniform at the viral genotype level: • Genotypes of the Virus differ around the world and these have different response rates to treatment (no overlap in genotype between USA and Egypt.....) • Before you design a study need to know which genotypes you want to include in your development programme – Are you just “offshoring” data generation or do you want to develop a data package that can be for truly global registration?
    28. 28. Nor at the level of response to therapy which may depend on the human genotype: • So even if you are simply offshoring and looking for patients infected with the same genotypes as are found in the USA you need to look deeper. • Response to Rx differs due to differences in the molecular genotype type of the patients for IL28B. Allelle frequencies vary between ethnic groups. • Have to select patients at the genotypic level (personalized medicine if reliable diagnostic is available !) or take this increased variability into account in study design and statistical plan. Patients with favourable C/C genotype have 2 to 3 times Sustained Viral Response in HCV genotype 1 infected patients treated with IFN/Ribavirin . Clark et al. Am J Gastroenterol 2011 106:38-45
    30. 30. Are there still opportunities for further globalisation? • Globalisation & Ethics is a hot topic • Risk Mitigation : Common pitfalls and how to avoid ? • So how does Novartis decide where to go? • Partnering with local Governments and communities, a case study
    31. 31. Ethical issues are now a major consideration “A major concern is the ethical oversight of research involving human subjects” NEJM 360;8, 2009
    32. 32. Some Key Ethical topics to consider: • Investigator standards & certification – do we need a uniform standard for all Ix or will it depend on drug, protocol etc.  What is really important, what are the minimum criteria and is it the same for a malaria site as a oncology site.......? • Informed Consent – Use of picture books & community involvement. • Protocol ethics section – Including justification of placebo if standard of care is much higher in “Western” markets. • Site selection – Don’t just look for patient numbers but ability to meet ethical standards • IRB standards – Must be independent and adequately trained – Use of central IRB if local IRB not available or not needed per regulations ( eg phase IV studies) •  Risk- benefit to the study – May be only chance for community to access innovative medicines. – Need for continuing supply of medication to trial participants until launch / reimbursement through extension protocols , individual patient supply etc.
    33. 33. Are there still opportunities for further globalisation? • Globalisation & Ethics is a hot topic • Risk Mitigation: Common pitfalls and how to avoid? • So how does Novartis decide where to go? • Partnering with local Governments and communities, a case study
    34. 34. External Internal Risks in Globalisation of Clinical Development  Limited ethical oversight; • IRBs not adequate • Poor understanding of informed consent • Role of placebo? • Patient compensation  Inadequate Investigator experience • Data quality • Limited clinical infrastructure  Regs structured for domestic markets • Inadequate support or control  Is the data generalisable to the West? • Social ecology & genetic makeup of population  Hiring of new staff in target countries • Poor quality monitors • Inadequate medical advisor / regulatory/ drug safety support • Poor site management and poor data  Under-serving developed markets • Data “ not relevant “ leads to large post approval commitments or NDA rejection • Relationships lost with Western KOLs • Inadequate local data to secure reimbursement in key markets  Logistics • Delayed study start up times • Sample shipment to labs as cost driver Clear Understanding and Risk mitigation plans needed
    35. 35. Risk Mitigation: Internal (complete mitigation should be possible) Risk Possible Impact Mitigation New monitors in Target Countries  Low Quality work  Poor productivity  Recruitment of both experienced monitors and college graduates  Extensive training & in-country mentoring program  Co-visits  Intra-region personnel exchange to promote learning Insufficient Local Medical Advisors  Poor site management  Sub-optimal KOL handling  Low quality trial procedure  Tight coordination with medical Department  Build-up of local and regional medical resources Drug safety, DRA or CQA resources & capabilities not aligned with Clin Ops  Unmanaged safety or quality issues  Unsuitable data. Delayed trial approval or submission  Tight coordination with Drug safety  Complete audit program for all Target Countries  Coordinated resource allocation Underserve existing developed markets (US,EU) by decreasing trial activity  Negative impact on market access  Increase productivity in EU/US to maintain trial volume  Refine trial allocation process to ensure “right trial in right place” Logistics Issues. Less experienced Logistics infrastructure in Target Countries  Delayed drug / sample shipments  Increased bureaucracy  Restrict expansion to major cities with good infrastructure  Inclusion of logistics in study start-up times
    36. 36. Risk Possible Impact Mitigation Low numbers and generally less experienced sites  Competition for best sites  Delayed recruitment  Unsuitable data  Work independently and with Industry bodies on training / education. E.g. in India work with an SMO to increase nr of sites  Restrict to major sites / major cities  Perform monitoring in-house only (not CRO)  Match new sites with experienced monitors Informed Consent process not as per GCP  Trial data unusable  Patient selected from literate demographic  Monitor and investigator training Ethics Committees inexperienced or irregular  Trial data unusable  Training in GCP and Novartis Integrity programs  Professional site selection process Regulatory requirements not in line with US/EU norms. E.g.  Insistence on comparator studies  Bureaucratic trial approval procedures  Data not suitable for Global Development programs  Patients may not be accessible within Project timeframes  Concerted efforts of local DRA, market access, medical to streamline trial approval procedures  Balance evolving FDA trial design requirements with Clin Ops country capabilities and local Health Authority practice  Improve internal clinical planning (LEAN) Risk Mitigation: Internal (complete mitigation should be possible)
    37. 37. • Globalisation & Ethics is a hot topic • Risk Mitigation : Common pitfalls and how to avoid ? • So how does Novartis decide where to go? • Partnering with local Governments and communities, a case study Are there still opportunities for further globalisation?
    38. 38. Economic growth in targeted countries is increasing the potential patient pool U.S. Europe (G5) Japan China RoW3 Patient Access1 (millions) 2007 20202 250 340 300 310 120 120 150-250 750-1,000 100 250 1,770 – 2,020 1 Covered by insurance (gov’t or private) 2 Projections based on population growth, external estimates, internal assumptions 3 RoW countries with NVS presence – Africa, Middle East, South East Asia  Source: CIA, OECD, The Economist, Chinese Embassy, internal estimates 920 – 1,120
    39. 39. Basic principles for target country selection • Target country must offer sustainable opportunity of — Patient access advantage (disease prevalence, regulatory environment, medical practice) and / or — Cost advantage • Evidence that Novartis quality standards can be maintained despite fast increase of local staff, number of sites and patient contribution • Target countries should be growth markets that are commercially relevant for Novartis • Target countries for increased clinical trial activity must be prepared to launch pipeline candidate
    40. 40. Decision tree for detailed analysis
    41. 41. Knock-out factors • Is the local geopolitical environment stable? • Are GCP / ICH principles in place and enforced? • Is the transport, IT, communication infrastructure adequate?
    42. 42. Patient access • Is the country population > 10 mio? • Is there a functioning Health Care system? (diagnosis, referals, treatment)
    43. 43. Site access • Does your country currently have > 20 sites involved in MNC sponsored Clinical Trials? • Is there capacity for further growth in Trial activities? • Do the sites meet Novartis standards? • Is the ratio of physicians per capita adequate?
    44. 44. Business environment • Do customs and excise regulations allow for smooth timely import of investigational product and equipment? • Is the export of human tissue samples allowed? • Do local tax regulations support clinical trials? • Is there adequate data privacy protection? • Are there adequate facilities for drug & samples supply, transport, storage and destruction? • Is there adequate medical infrastructure to perform specialised tests (CT, MRI)? • Are there institutions which provide GCP training? • Are there certified translators in the country for study documentation? • Are there local or Global CROs operating in your country? • If „no“ are their CROs in neighbouring countries which can operate in your country? • Is there a talent pool of trained and experienced CRAs in your country?
    45. 45. Novartis factors • Is Novartis represented in the country? • Are DRA, Pharmacovigilance, Medical established in the CPO? • Does Novartis intend to market the drug in this country? • Can we comply with Novartis Policy for emerging markets?
    46. 46. Novartis policy on clinical trials in emerging markets • Novartis research sponsored projects should be responsive to the health needs of the local population and ultimately benefit them. • The choice of a comparator, i.e. placebo and/or active treatment, must always be well-justified on both scientific and ethical grounds. Also, any arrangements for the continuation of treatment beyond the study, or the reasons for their absence, should ideally be identified before conducting the study and described in the study protocol. They should be included in the informed consent form and discussed with the patient. • Novartis conducts clinical trials only in countries where there is reasonable expectation that the drug tested will be granted marketing authorization and be made available to the residents of the host countries, once proven safe and efficacious.
    47. 47. 2007 2010 Example country assessment * East Asia focus on Singapore, Malaysia, Philippines and Thailand ** E. Europe focus on Hungary, Czech Republic, Slovakia, Romania *** Mexico rebuilding needed after recent setbacks, belief that significant potential exists; start up time data of one trial only Source: Clin Ops Min (Average) startup time (weeks) Potential Footprint shift (percent of total) Russia 32 ( 34 ) Turkey 18 ( 36) E. Europe** 14 ( 25) Baltics 14 ( 26 ) Mexico*** 33 (33) Argentina 22 ( 30 ) Poland 18 ( 23 ) Easier to expand Moderate difficulty Most difficult Patient growth 2008–2010 (percent) 29 110 47 N/A 197 28 58 4 1 1<1 21 64 53 21 53 11 China 50 ( 65 )67 India 13 ( 19 )285 East Asia* Sing. 8 (20) / Thailand 21 (25)257 2<* 43
    48. 48. FOOTPRINT SHIFT DELIVERY DEMAND Trial Allocation Board SUPPLY Build up of Local Execution Capability COMs given explicit Low Cost Country targets Competitive Intelligence to monitor  Patient Profiling  Study start-up times  Site availability  Ongoing competitor trials  Regulatory changes Monthly KPIs to track  Headcount changes  %Pts in LCC  Savings Management mentoring through Regional Clin Ops Integrated, Accelerated training for new recruits Personnel exchange schemes to foster knowledge transfer Regular country visits Regional meetings Footprint shift requires balancing resource build-up with the trial requirements
    49. 49. Areas to be covered with markets to which footprint will shift CapabilitiesEnviron- ment  What will be the impact on regulatory approval timelines for trials with the increased volume?  What are the minimum patient thresholds in the market for approval? - Do they vary across TAs?  How does the increasing trial volume affect the product approval timelines?  what other companies are doing in these markets to be successful? Potential benefits/risks  Is there an opportunity to optimize country footprint for trials?  Will the proposed shift have substantial impact on prescription uptake of physicians?  How can the perceived increased risk to intellectual property from increasing trial volume in the markets be managed?  How can operational risk be managed given the language/cultural differences, infrastructure and regulatory constraints?  Internal - How is current capacity aligned against current trial plans? - What specific skills and capabilities will be required at the country level? - How much time is needed to build up the capacity in the market? - What support should global organization provide in the ramp-up phase? - What demand management changes need to be made upstream ?  External - What is the quality and availability of investigators and patients across TAs and indications? • Are there any special circumstances around prevalence, treatment rates, hospital sites across TAs that need to be considered? - How can we ensure that high quality data is reported from the sites with the increasing volume? - What is current CRO quality and capacity across TAs in the country/region? - What are the capability and capacity of existing Central Labs in the country/region? - Are the supply and logistics scalable to handle the increased volume? • Potential delays in import and custom clearances, transportation issues training of handling staff
    50. 50. Are there still opportunities for further globalisation? • Globalisation & Ethics is a hot topic • Risk Mitigation : Common pitfalls and how to avoid ? • So how does Novartis decide where to go? • Partnering with local Governments and communities: a case study
    51. 51. Novartis Case study – “ Clinical Trial Enabler project”, partnering with Malaysian Government “ Curing and Caring in Malaysia”
    52. 52. Curing & Caring in Malaysia – working with the Government to build clinical research capabilities and bring trials to where the patients are! • Rationale / background – Government of Malaysia drives ambitious Economic Transformation Program • identified clinical research as key priority • funded and established Clinical Research Centers as an enabler to position Malaysia as a preferred destination for conduct of clinical trials • goal of 1000 locally conducted trials by 2020 – Novartis Malaysia has a good reputation in the country • track record of socially responsible business practices • partnering with the Ministry of Health to share treatment costs of life saving high quality medicines to improve patient access – incl Glivec/Tasigna to 485 CML and GIST patients, Exjade to 3000 Thalassemia patients and Lucentis to 400 patients – NVS MY and the government were therefore natural partners for the current Clinical Trial Enabler Project. Key Theme: Innovation with collaboration
    53. 53. Curing & Caring in Malaysia - working with the Government to build clinical research capabilities and bring trials to where the patients are! • Solution / Best Practice overview – Innovative collaboration between the MOH MY and NVS MY is aligned with NVS MY’s 7 pillar strategy • to support the MoH in various areas of capability building, incl. clinical research – The Clinical Trial Enabler workshop aimed to build fundamental clinical research skills with Novartis collaboration by: • Providing Access to research questions, biomedical technologies, industry clinical and scientific expertise and data • Providing an opportunity to influence the research agenda to healthcare areas of mutual interest • Providing opportunities for networking and collaboration within this group, with Novartis associates, and where possible, with other Novartis academic collaborators • Building Clinical Research Capability among local scientists and increase number of clinical trials conducted in Malaysia • Impact – Novartis would contribute to the MOH vision of 1000 clinical trials by 2020 – Novartis would contribute to building capabilities of clinical investigators involved in Novartis trials • Applicability / transportability to other CPOs – Similar programs could be conducted if MOH research infrastructure is developing in the same direction as in Malaysia
    54. 54. Curing & Caring in Malaysia - working with the Government to build clinical research capabilities and bring trials to where the patients are! • Project framework : Based on 4 pillars of content – Pillar 1: Drug Discovery and Development – Pillar 2: Designing & Reporting Clinical Trials • Protocol writing and development, clinical study report, publications • Clinical Trial Regulatory Requirements in Malaysia • Role of CRC (Clinical Research Center) – Pillar 3: Regulatory Framework for Clinical Trials – Pillar 4: Pharmacovigilance and Risk Management • Pharmacovigilance System, Signal Detection, Risk Management Plan, • RMP Commitments Implementation: The Gilenya Story • The inaugural workshop was based on Pillar 1 & 2 – Opening speech delivered by Dr Goh PikPin National Head CRC(Clinical research center MOH) – Enabling clinical research capability: A two way learning process – Drug Discovery overview-from molecule to applications in therapy: from bench to bedside – Study Concept and Design, writing a study protocol – Publication techniques and journal assessment of submissions – CRM: Roles in Clinical research development in Malaysia (delivered by CRM Clinical Research Malaysia Head MOH)
    55. 55. Despite the planning and risk mitigation there can be some surprises! What do these pictures have to do with Clinical Research in Emerging Markets?
    56. 56. Be prepared for the unexpected ! Be aware of potential obstacles to data collection and the safety & integrity of the data themselves
    57. 57. Choose the right molecule  Ethnic Sensitivity Assessment ( ICH E5)  Physico-chemical properties of the drug ( Climate zone / cold chain) Choose the Right Disease  Consider if you are developing a drug for registering in Emerging markets only or for Global Registration?  Make sure you thoroughly understand the disease at the genomic level and account for variability in your study design and statistical plan. Choose the Right Country  Early definition of potential countries and clear principles for making decisions at the trial and program level  Understand the internal and external risks per country and plan to mitigate.  Build Clin Ops and/or external (CRO) infrastructure in target regions to develop investigator relationships and speed average country activation time – well in advance of when your studies should start.  Partner with local Governments and communities  Expect the unexpected & have fun !!! Bring the right drug to the right patient in Emerging Markets and get the patient access and productivity gains!