Conducting Global Clinical Trials in Emerging Markets

Dr. Helmut Wolf, Regional Medical Director, Group Emerging

Markets,Novartis AG.

Many Pharma Companies are rushing to place their studies

in Emerging Markets

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?

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!

WHY THE RUSH TO EMERGING MARKETS?

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...........

• 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:

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.

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

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

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

Key Factors influencing Investigator fees

Investigator fees vary widely per region

• 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!

Quality can be managed inEmerging Markets

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.

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

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

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

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!

• 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

CHOOSE THE RIGHT DISEASE

Hepatitis C as an example

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?

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.

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.

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?

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?

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

CHOOSE THE RIGHT COUNTRY

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

Ethical issues are now a major consideration

“A major concern is the ethical oversight of research involving human subjects”

NEJM 360;8, 2009

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.

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

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

Risk Mitigation: Internal(complete mitigation should be

possible)Risk Possible Impact MitigationNew 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

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)

• 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?

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 assumptions3 RoW countries with NVS presence – Africa, Middle East, South East Asia

Source: CIA, OECD, The Economist, Chinese Embassy, internal estimates

920 –1,120

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

Decision tree for detailed analysis

Knock-out factors

• Is the local geopolitical environment stable?

• Are GCP / ICH principles in place and enforced?

• Is the transport, IT, communication infrastructure adequate?

Patient access

• Is the country population > 10 mio?

• Is there a functioning Health Care system? (diagnosis, referals, treatment)

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?

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?

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?

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.

20072010

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)

PotentialFootprint 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

41

1<1

21

64

53

21

53

11

China 50 ( 65 )67

India 13 ( 19 )285

East Asia* Sing. 8 (20) / Thailand 21 (25)2572<*

43

FOOTPRINT SHIFTDELIVERY

DEMANDTrial Allocation Board

SUPPLYBuild 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 throughRegional Clin Ops

Integrated, Accelerated training fornew recruits

Personnel exchange schemes tofoster knowledge transfer

Regular country visits

Regional meetings

Footprint shift requires balancing resource build-up with

the trial requirements

Areas to be covered with markets

to which footprint will shift Ca

pabi

litie

sEn

viro

n-m

ent

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?

Pote

ntia

l be

nefit

s/ri

sks 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

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

Novartis Case study – “ Clinical Trial Enabler project”, partnering

with Malaysian Government“ Curing and Caring in Malaysia”

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

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

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)

Despite the planning and risk mitigation there can be some

surprises!

What do these pictures have to do with Clinical Research in Emerging Markets?

Be prepared for the unexpected !

Be aware of potential obstacles to data collection and the safety & integrity of the data themselves

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!