Globalisation of industry-sponsored clinical trials Ramón López

Who is Ramón López?

8yrs as General Practitioner in Barcelona

26yrs in Pharma Industry (Clinical Research, Medical and Regulatory Affairs)

+19 countries (EU, US, Asia and Africa)

TT-173 contains modified version of recombinant human tissue factor (rhTF).

Propiedades generales TT-173

Clinical Development

• Phase I: Tooth Extraction √

• Phase II: Skin Graft √

• Phase II/III: Knee Arthroplasty Recruiting

• Phase II/III: Liver Resection Planned • The proposed indication is “adjunct to hemostasis for use

in surgery when control of bleeding by standard surgical techniques (such as suture, ligature or cautery) is ineffective or impractical”

Goals

1.R&D data overview

2.Registration – Map of all Clinical trials

3.Globalization of clinical trial

4.Working in the developing world (India)

5.Conclusions

35.7%

47.6%

16.7%

Breakdown of total health expenditure in Europe

In-patient care (hospital)

Out-patient care and others

Pharmaceuticals & other medical non-durables

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Health Expenditure in Europe

7

16.7% of total health expenditure in Europe was spent on pharmaceuticals and other medical non durables, being a very stable indicator through the years.

R

14

18 Feasibility of Labco Quality Diagnostics as Centralized Clinical Research Laboratory 18 18

Registration

• The World Health Organization (WHO) has established an International Clinical Trials Registry (ICTRP).

• EU Clinical Trials Register

• The U.S. Clinical Trial Registry – ClinicalTrials.gov

• Local Registry (AEMPS)

Map of All Studies on ClinicalTrials.gov

Study and Intervention Type (as of October 13, 2016)

Number of Registered Studies and

Percentage of Total

Number of Studies With

Posted Results and

Percentage of Total***

Total

227,798 22,811

Interventional 182,869 (80%)

21,307 (93%)

Type of Intervention*

Drug or biologic

112,068 17,236

Behavioral, other

53,159 3,472

Surgical procedure

19,815 1,101

Device** 21,003 2,423

Observational 43,893 (19%) 1,504 (6%)

Expanded Access 364 N/A

Costs and Benefits of Conducting Clinical Trials in North America

Costs • Difficulties recruiting patients (up

to 30% of investigators are unable to recruit enough patients for a trial

• Low patient retention • High labour costs • High compensation for patients • High patient and investigator

travel costs • Expensive drugs (for comparator

studies) • High development and packaging

costs for both the drug under investigation and the comparator drug / placebo

Benefits • Experienced investigators • Established, centralised research

facilities and hospitals • FDA requirements fulfilled by

clinical trails conducted in the US • Established CROs • Genetically varied population • Wide range of drugs available (for

comparison) • High level of technological

development (which facilitates • adaptive trails, information

collection and transference)

Costs and Benefits of Conducting Clinical Trials in CEE Countries

• Benefits

• Strong doctor-patient connection

• Cheaper overall costs

• High patient recruitment rate

• High patient retention

• Increasing presence of CROs and increasing openness to the pharmaceutical industry

• Good medical infrastructure

• Costs / Obstacles

• Import restrictions on test and comparator drugs

• Trials approvals may be slow

• Ethics concerns may delay EMEA acceptance

• Language barriers

Benefits and Concerns with Running Clinical Trials in India • Benefits

• Large treatment-naïve population

• Centralised hospitals

• Well-trained medical staff, including doctors and support staff

• Staff familiar with the procedures of large pharmaceutical companies many trained in the West

• Local drug production facilities, for making both the test drug and comparator drugs / placebos

• A genetically diverse population

• Lower staff and drug development costs

• Large, centralised cities

• High interest in conducting clinical trials

• Trials can be shorter than those in other regions

• High patient retention

• Easier patient recruitment

• Low regulatory hurdles

• Concerns • Not enough research personnel to meet

demands (30,000-person shortage reported)

• Population may not fully understand risks of clinical trials

• Potential concerns about informed consent

• Concerns about whether patients can access treatment after trial completion

• Concerns about compensation levels being too low

• Potentially important differences between the genetics of trials patients and intended consumers

• Potential questions about adequate numbers of ethics oversight personnel

• Somewhat erratic regulatory infrastructure

Costs and Benefits of Conducting Clinical Trials in China

Benefits

• Large treatment-naïve population • Drug production facilities available • Lower personnel costs • Lower drugs costs (in general) • Higher rate of recruitment • Higher rate of patient retention

Costs /Problems

• Large percentage of the population has no access to clinics or hospitals

• Concerns about ethics and oversight possibly being inadequate

• Language barriers • Importing drugs can be difficult • Government regulations can be time-

consuming and expensive • Questions about medical

infrastructure • High rate of traditional medicines use

may complicate trials outcomes • Questions about genetics and

relevance of study data to regions where the drug would be sold

Phase I, II, III and IV Trial Characteristics

• Phase I and IV trials have the lowest number of sites per trial (3 and 3.7, respectively). Phase III trials have the highest number of sites per trial (42.5), and Phase II trials have (17) sites per trial.

• The number of participants/subjects per trial is, as expected, lowest for Phase I trials with an average of 47.3 subjects per trial, while Phase II trials average 165.4 subjects/trial, and Phase III trials 632.8 subjects/trial. Phase II and III trials together account for 77.4 percent of all trial participants

Sites per continent Phase II-III from 2006 onwards

• Continent Sites(n) Sites(%) North America 327.501 46,4 Europe 168.747 23,9 East Europe 87.241 12,4 Asia 64.568 9,1 L. America 28.011 3,9 Oceania 14.609 2,0 Africa 6.853 0,9 Middle East 6.673 0,9

Ranking between Countries

1. US 301.622 42,8%

2. Germany 39.238 5,5%

3. Japan 25.573 3,6%

4. France 25.441 3,6%

5. Canada 25.429 3,6%

6. Spain 21.147 3,0%

7. UK 19.541 2,7%

• 138 New Caledonia

• 137 American Samoa

• 136 Nepal

• 135 Mongolia

• 134 Trinidad – Tobago

• 133 Sudan

• 132 Madagascar

Factors contributes to the industry’s interest in conducting clinical trials in a wider range of countries

• The higher availability of emerging-region patients with the relevant disease profile who are willing to participate in clinical trials

• The availability of qualified investigators and infrastructure

• Commercial potential for the product

• Cost-reduction opportunities

• Ethical and regulatory environment

• Potentially faster clinical trials

# Region Population

(2016) Yearly

Change Net

Change Density (P/Km²)

Area (Km²)

Migrants (net)

Fert. Rate

Med. Age

Urban Pop %

World Share

1 Asia 4,436,224,473 0.98 % 42,928,459 143 31,022,549 -1,256,133 2.2 30 48.7 % 59.7 %

2 Africa 1,216,129,815 2.53 % 29,951,533 41 29,661,703 -579,959 4.71 19 40.2 % 16.4 %

3 Europe 738,849,002 0.06 % 406,932 33 22,121,228 824,644 1.6 42 74.3 % 9.9 %

4 Latin America and the Caribbean

641,029,306 1.05 % 6,642,739 32 20,158,154 -414,767 2.15 29 79.5 % 8.6 %

5 Northern America

360,529,324 0.75 % 2,691,288 19 18,680,276 1,235,878 1.86 38 82.6 % 4.9 %

6 Oceania 39,901,355 1.45 % 570,225 5 8,489,650 190,337 2.42 33 70.8 % 0.5 %

World Population by Region 2016

TOP 20 LARGEST COUNTRIES BY POPULATION (LIVE)

• 1 China 1,384,207,253 • 2 India 1,331,553,668 • 3 U.S.A. 324,824,176 • 4 Indonesia 261,491,242 • 5 Brazil 210,085,719 • 6 Pakistan 194,010,129 • 7 Nigeria 188,444,528 • 8 Bangladesh 163,488,643 • 9 Russia 143,434,717 • 10 Mexico 129,119,402 • 11 Japan 126,249,038 • 12 Philippines 102,719,006 • 13 Ethiopia 102,602,271 • 14 Vietnam 94,744,614 • 15 Egypt 93,952,481 • 16 Germany 80,680,497 • 17 D.R. Congo 80,472,890 • 18 Iran 80,324,858 • 19 Turkey 79,910,584 • 20 Thailand 68,202,767

Cost per trial or rather per subject

• The cost per trial or rather per subject is highly dependent on the therapeutic area and partially on the cost of living in the country where the trial is conducted.

• The cost estimation is based with 12 subjects and the total cost per subject is $52,000 USD, including internal cost of the sponsor (25 percent), CRO cost (50 percent) and study site cost (25 percent).

ICH Mision

• Harmonisation for pharmaceutical product registration through the development of ICH Tripartite Guidelines.

• Benefits to both regulatory authorities and the pharmaceutical industry with beneficial impact for the protection of public health:

– preventing duplication of clinical trials in humans

– minimising the use of animal testing

– streamlining the regulatory assessment process for new drug applications;

– reducing the development times and resources for drug development.

The purpose of this guideline is to describe general principles for the planning and design of MRCTs with the aim of increasing the acceptability of MRCTs in global regulatory submissions

The objective of this ICH GCP Guideline is to provide a unified standard for the European Union (EU), Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions. Australia, Canada, the Nordic countries, Brazil, Switzeland and South of Korea

What is the ICH Addendum Proposing?

• Harmonization

• Investigator Responsabilities - Adequate resources - Records and reports

• Sponsor-Quality Management

• Sponsor: - Contract Research Organizations - Trial Management, Data Handling and Record Keeping - Monitoring

• Essential Documents/(e)TMF

The purpose of this guidance is to facilitate the registration of medicines among ICH regions by recommending a framework for evaluating the impact of ethnic factors upon a medicine’s effect

Challenges for Global Clinical Trials

• Results from trials conducted in other countries may not be generalizable to the U.S. population.

• Geographically dispersed populations may have genetic differences that cause them to respond differently to drugs

• In developing countries, where research involving human subjects is complicated by factors such as lack of education, poverty, and low health care standards

• Some diseases may go untreated or undertreated in developing countries, making it easier to find trial participants whose outcomes will not be complicated by prior medications.

• Investigators in developing countries tend to be less well-versed in these guidelines and less experienced, which can be a barrier to obtaining trial data and publishing results

• There is a lack of transparency with regard to clinical research in many developing countries.

• Participants may not fully understand the trial process or their role • They may feel compelled to participate by the promise of financial compensation or

access to health care that might otherwise be outside their reach • Conducting trials in other countries can also be ethically challenging • Finally, there are regional idiosyncrasies -- differences of language, both spoken and

unspoken, working patterns, culture and religion

Regional idiosyncrasies

WORKING IN THE DEVELOPING WORLD

• Know the local Regulatory requirements

• Prioritize relationship management

• Plan for local infrastructure

• Help partners develop

• Consider the culture

• Provide the standards and processes

• Create contingency plans

Conclusions

• Search Information

• Select local partner

• Site and Investigator Selection. They have sufficient knowledge, expertise and infrastructure to conduct a clinical trial in accordance with Good Clinical Practice

• Informed Consent: adapted to local needs

• Ethnic and population (genetic) differences.

• Knowledge the local Regulatory requirements

• Create contingency plan

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Globalization - Ethical & Business Considerations in Clinical Research

• Global trials speed drug development - the globalized trials can reduce

development time by half while lowering costs and maintaining quality and safety.

• Research quality standards must be met worldwide - The trials in

emerging countries, such as China and India, are subject to the same standards as those conducted in the U.S. and Western Europe.

• Clinical research improves local economies - Clinical research offers huge advantages for host countries, including an influx of advanced equipment, trained personnel and high-paying jobs.

• Emerging market equals growth market - CRO activity in Central European countries, South Korea and Taiwan is very robust, medical infrastructures are advanced and capabilities are just about on par with Western Europe.

some of the challenges facing clinical trial

• The Changing Regulatory Environment

• Differing Customs Requirements

• Infrastructure Issues

• Technology/Data Management

• Regional Idiosyncrasies

• Differing Quality Standards

Why clinical trials are and should be done globally, including the developing world

• Global pharmaceutical companies are doing increasing

number of trials at sites in the developing world, in addition to sites in wealthy countries.

• to continue ensuring that the design, oversight, and execution of the studies are fully addressed and meet both legal and ethical standards

• must meet international standards, including the ICH Guideline for Good Clinical Practice (International Conference on Harmonization 1996) and the principles in the Declaration of Helsinki (2008).

Globalization of industry-sponsored clinical trials

• the quality of the data collected in emerging regions • how representative the test results are for the target

population of the medicinal products tested, i.e., in the U.S. and in Europe, respectively

• to accelerate the completion of the clinical development test programs in compliance with local and international regulations and guidelines.

• it was demonstrated that emerging regions are doing at least as well as established regions with regard to FDA clinical investigator inspections

• Countries with large populations, good track records and efficient infrastructure are the winners

Factors driving this geographical shift

• Significant cost savings are possible, particularly in developing countries

• Shorter timelines, due largely to faster recruitment • Conducting trials in other countries allows drug sponsors to access

more commercial markets for the drug they are testing • Conduct standards and intellectual property protection have

improved in foreign countries, making these sites more attractive than they have been in the past.

• A key driver of this improvement has been the widespread adoption of the ICH Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice (ICH-GCP) guidelines

• The regulatory environment in wealthy countries, including the United States, has become increasingly burdensome to drug sponsors

WORKING IN THE DEVELOPING WORLD

• Consider the culture: Communication is more than mere words, and communicating effectively can achieve superior results. Research local customs and communication styles before plunging in and demonstrate respect at all times.

• Provide the standards and processes: Establish high global standards, sharing SOPs and best practices to help staff and partners achieve and maintain them.

• Maintain visibility of the supply chain. • Create contingency plans: Contingency planning is a

goodrule for life. Confirm everything, anticipate what could go wrong, and identify options -- every time.

• To inexperience in conducting trials and differing quality standards, there are wide spread differences from country to country in Customs knowledge, experience and laws.

• Many developing countries are also evolving Regulatory requirements about the conduct of clinical trials and protection of research subjects.

• Other challenges include the need to manage logistics complicated by countries with limited infrastructure, especially outside major cities. The transportation of the samples need presents additional logistical challenges.

• -- that add another layer of complexity.

WORKING IN THE DEVELOPING WORLD

• Know the local requirements: Establish a knowledge database reflecting regulatory requirements, real-life experience and intelligence gathering -- and keep it current with information and insights from local staff.

• Prioritize relationship management: Cultivate and maintain relationships with regulatory authorities and local partners, who can help navigate issues that arise.

• Plan for local infrastructure: Allocate extra time for infrastructure-challenged locations, particularly during inclement weather, and consult local partners who know the geography.

• Help partners develop: Training and education are investments in people, performance and the pride of doing a job properly. Personnel who feel like they’re part of the team usually act the part.