the reality of clinical trials in latin america€¦ · the cost of oncology medicines increased at...

The reality of Clinical Trials in Latin America

Christian Rolfo, MD, PhD, MBA, Dr.h.c.Professor of Medicine

Director of Thoracic Medical OncologyDirector of Early Clinical Trials

Marlene and Steward Greenebaum Comprehensive Cancer Center

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Current Landscape in Cancer:Contribution of Clinical Research

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New Treatment and Trial Paradigm

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Number of Treatment Options over Time for Selected Tumors (1996-2016)

Global Oncology Trends 2017: Advances, Complexity, and Cost. QuintilesIMS Institute. June 2017.

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The cancer treatment landscape has been transformed since 2011

Global Oncology Trends 2017. IQVIA report. https://www.iqvia.com/institute/reports/global-oncology-trends-2017-advances-complexity-and-cost

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New drugs have significantly increased chances of survival

CancerNew therapies have contributed to significant declines in cancer death rates around the world since its peak in 1991. Today, 2 out of 3 people diagnosed with cancer survive at least 5 years1.

Percent Decline in Cancer Mortality Rates Since 1991 1991 to 2011 - All Cancers2

Source: Health Advances analysis; 1PhRMA 2016 Prescription Medicines: Costs in Context; 2WHO Mortality Database (accessed February 2016).

Australia

South KoreaJapanCanada

Mexico

-8%-21% -22%

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Global clinical/Translational studies and trials by indication (%)

Global cancer research by type of study (%)

Liga D. Clinical Trails Conferences 2018.

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Oncology projected to be the biggest therapeutic area of the global pharma market in 2016

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Total global costs of oncology and supportive care therapies increased to $113 billion in 2016 at a rate of 11.6%

Global Oncology Trends 2017. IQVIA report. https://www.iqvia.com/institute/reports/global-oncology-trends-2017-advances-complexity-and-cost

The cost of oncology medicines increased at a compound annual growth rate (CAGR) of 11.0% since 2011, while the cost of supportive care treatments increased at CAGR of 2.0% in 2016.

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Dohll D. Pharmacoepidemiology and Clinical Research Congress 2017.

Global clinical/Biomedical cancer research investment growth in billions

CARG 44%/6.5 years

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WELCOME TO A GOLDEN AGE OF CANCER DRUG DEVELOPMENT!!

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The Traditional Drug Development Paradigm

Courtesy of David Hong

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The Current Drug Development Paradigm

Courtesy of David Hong

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Trial duration and average enrollment have declined highlighting shifts in trial design and target indication size

Trial Duration and Patient Enrollment in Phase III Trials (1997–2016)

Clinicaltrials.gov, Feb 2017; QuintilesIMS Institute, Mar 2017

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The era of Immunotherapy

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Immuno-Oncology PD-1 and PD-L1 Inhibitor Uptake

U.S. FDA, QuintilesIMS, National Sales Perspectives, Feb 2017; QuintilesIMS Institute, Apr 2017

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Next Generation Immuno-Oncology MoAs in Development

PD1/PDL-1 inhibitors have seen the greatest development across many of the existing tumor types

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Combinations of immuno- oncology products will increase the height of these waves.

Global Oncology Trends Report 2015. Report by the IMS Institute for Healthcare Informatics

The present /near future for IO treatments

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Pharmaceutical R&D expenditure in Europe, USA and Japan (millions of national currency units*), 1990–2015

European Federation of Pharmacautical Industries and Association Report 2016

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hRMA, Annual Membership Survey 2016

Allocation of R & D investements by function (%)

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Pharmaceutical industry Research and Development in Europe

The cost of researching and developing a new chemical or biological entity

was estimated at € 1,926 million ($ 2,558 million in year 2013) in 2016

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Industry-Sponsored clinical trials in Europe

Note:Represents all clinical trials Phase 0 through Phase 4 that registered with Clinicaltrials.gov in 2015.

Source: Health Advances analysis; Clinicaltrials.gov (accessed February 2016).

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Decline of Clinical Trials in Central and Eastern Europe: Fluctuation or Trend?

• 66% of clinical trials are conducted in North America, Western Europe and Australia.

• However, other regions have arisen in recent years

Novak et al, Applied Clinical Trials Jun 16, 2014

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Best Countries For Oncology Clinical ResearchChina remains the top country overall, but Russia, Ukraine, Poland, and Romania rank close behind.North America and Western Europe rank third and fourth respectively, while the Middle East and Africa perform the worst with the lowest regional scores.

All these countries have relatively strong infrastructures for Oncology, but really outperformed other countries with their strong recruitment rates and access to patients.

The scenario can change...

(excluding Japan from the analysis)KMR Group Data, Applied Clinical Trials 02 December 2016

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2015 Availability of New Oncology Medicines Launched 2010-2014

IMS Health, MIDAS, Q4 2015, IMS Institute for Healthcare Informatics, May 2016

Canada

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2015 Availability of Oncology Medicines Launched 2010-2014 within the EU and Eastern Europe

IMS Health, MIDAS, Q4 2015, IMS Institute for Healthcare Informatics, May 2016

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Cancer Clinical Trials 04/04/2019: 17212 Studies

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CT ́s of cancer through the Years

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Pantents Granted

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What type of Clinical Research?

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Trials Sponsorship in Emerging Regions

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Regulatory aspects of Clinical Trials in LATAM

Investigator Support Pharma Support

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Time to regulatory authority approval according to geographical (A) and economic (B) regions.

Metzger-Filho O et al. The Oncologist 2013;;18:134-140

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Analysis of Regional Timelines Time to regulatory authority (RA) approval, defined as the

time interval between protocol submission by the sponsor to the RA and its approval

Metzger-Filho O et al. The Oncologist 2013;;18:134-140

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Efficiency Gain From A Thoughtful Scientific/Regulatory Strategy

Unoptimized Strategy

Phase I

Phase II

Phase III

Preclinical

Toxicology

Patent

lifeRegulatory

Filing

Phase III

Phase II

Phase I

Preclinical

Toxicology

Discovery

Time (Years)

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Efficiency Gain From A Thoughtful Scientific/Regulatory Strategy

Time (Years)

Patent

lifeRegulatory

Filing

Phase I

Phase III

Preclinical

Toxicology

Phase II

Discovery

Accelerated Approval

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SCIENTIFIC PRODUCTION OF LATAM: IT’S POSIBLE??

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The Globalization of Clinical Investigators

Percent of total

Tufts CSDD 2015

20155th

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Despite myriad problems in many countries, pockets of excellence thrive in South American science.

• Science in Brazil and many other countries in South America has come a long way since the dark days of the dictatorships just a generation ago.

• In Argentina, the number of science doctorates jumped nearly ten fold between 2000 and 2010

• Peruvian scientists tripled the tally of articles they produced over the same period; and science funding is climbing in most countries.

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Distribution and trends of hematology and oncology research in Latin America: A decade of uncertainty

Acevedo A, et al. Cancer. 2014 Apr 15;120(8):1237-45.

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Country Ranking according

to full-text

publications

Total abstracts

presented

Later publication of

abstract

as a full-text report†

Time to full-text

publication

in years

n % Median (range)

Brazil 1 1008 212 (21) 2 (0-7)

Mexico 2 279 54 (19.4) 1 (0-8)

Argentina 3 387 43 (11.1) 1 (0-7)

Chile 4 50 11 (22) 1 (0-3)

Peru 5 122 10 (8.2) 0.5 (0-3)

Cuba 6 27 9 (33.3) 2 (0-3)

Venezuela 7 25 6 (24) 1.5 (1-4)

Uruguay 8 32 3 (9.4) 0 (0-7)

Colombia 9 25 3 (12) 0.5 (0-1)

Costa Rica 10 4 2 (50) 3.5 (2-5)

Panama N/A 5 0 N/A

Total 1972 353 (17.9) 1 (0-8)Acevedo A, et al. Cancer. 2014 Apr 15;120(8):1237-45.

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All LATAM countries

Brasil

Argentina

México

Acevedo A, et al. Cancer. 2014 Apr 15;120(8):1237-45.

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2 0 2 | N AT U R E | VO L 5 1 0 | 1 2 J U N E 2 0 1 4

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HOW TO OVERCOME THIS SITUATION??

Becaming more attractive for Clinical Trials!

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Recruitment potentialRegion Number

Studies analyzed

# of recruited subjects

% recruited patients

Patients per million citizens

LATAM 161 23.341 7.5% 46

USA 181 40.433 12.9% 133

Australasia 185 9.653 3.1% 140

UK 173 16.873 5.4% 276

Canada 191 14.695 4.7% 442

Leem Recherche, Clinique Internationale Enquete 2010.

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Value of Inter-Institutional clinical projects

• Improved access of patients and professionals to the local and international experts/knowledge

• Increased communication and hence learning among all participants (community of practice)

• May identify problems that are specific to populations, regions or institutions

J Clin Epidemiol. 2012;65(5):482-7.

If you are trying to start cancer research in Latin America:1. Do outcome research (real clinical scenarios)2. Design population based data bases3. Increase effective networking 4. Use mentorship5. Use operative data management 6. Improve medical writing 7. Protect time to be creative 5t

h ESO-E

lass i

n Clin

ical O

The survey was completed by 6931 members of the public, over 75% of whom

reported having no or less than good knowledge of medicines R&D.

What the public knows and wants to know about medicines research and development: a survey of the general public in six European countries

Parsons S, et al. BMJ Open 2015;5:e006420.

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Patient Enrollment in Oncology Phase I Clinical Trials

Van Der Biessen D. et al, The Oncologist 2013;18:323–329

• 44% of all patients who were in-

formed about a specific phase I trial

eventually participated.

• Reasons for both participation and non

participation were diverse.

• Patient participation rates could be

improved by forming an experienced

and dedicated study team.

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Fashion

Business

More and more ‘’market and regulatory oriented’’ and

less patients directed or based on unmet need in

diseases or settings!

Current strategy of clinical research is dominated by:

Modified from A. Awada

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YES NO

• Several new anticancer agents reached clinical practice

• Often improvement in PFS but rarely in survival

•Redundancy in the development of agents

•Many competitive trials in the same setting

•Few studies looking to a therapeutic strategy

•Few studies in unmet need clinical settings•More and more biomarkers studies butlimited validated biomarkers for clinical use

Still a huge gap between clinical research & the need in clinical

practice

Does the current design of oncology trials meet the need of patients?

Courtesy of A. Awada

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Regulation of the European Parliament and of The Council on Clinical Trials on Medicinal Products for Human Use, repealing Directive 2001/20/EC

• The scope of the Regulation is extensive, with several primary components

• covered in the core text and multiple appendices, including:

• Authorization procedures

• Start of trial, suspension or temporary holds, early termination

• Protection of subjects, informed consent

• Conduct of trials

• Safety reporting

• IMP manufacturing, labeling and import

• Insurance

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Genotype driven

Basket trialsTest the effect of one or more drugs on one or more single mutation in a variety of cancer types

UmbrellaTest the impact of different drugsin different mutations in a single type of cancer

New designs

Adaptative trialbased on modifying parameters of a clinical trial evaluating a treatment according to outcomes in participants

N of 1Assessing the administration of an investigational agent over a short period of time

Windows of opportunity

Assessing the administration of an investigational agent over a short period of time

Selected new designs in drug development

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Partnership and Funding

People LabsCash Consumables

Source: Health Advances analysis; 1IMI website; 2EFPIA 2014 Annual Report.

€1,638BILLION

€1,425EFPIA direct and indirect

member companies

€213Other sectors

€3,276

€1,638BILLION

€3,276BILLION2014-2024

€1,638From Horizon 2020

PRIVATE IN KINDCONTRIBUTION

PRIVATEPARTNERS

PUBLICPARTNERS

PUBLIC

CASH for grants for PUBLIC PARTNERS

PRIVATE PARTICIPATION

Biopharmaceutical Innovation

IMI 2 Partnership and Funding Overview2

The Innovative Medicines Initiative

(IMI) is the world's largest public-private partnership

IMI supports collaborative research projects and builds networks of industrial and academic experts in order to boost pharmaceutical innovation in Europe.

Through the IMI 2, a joint undertaking between the European Union and the pharmaceutical industry association EFPIA, a

€3.3 billion budget for the period 2014-2024 has been established.

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: A New Clinical Research Network

A network of 8 comprehensive cancer centers and 13 university

hospitals and academic centers dedicated to oncology care and

research.

•University Hospital Brussels Belgium

•Institut Jules Bordet Brussels Belgium

•Antwerp University Hospital Belgium

•CHU Ambroise Paré, Mons Belgium

•Saint Elisabeth, Namur Belgium

•Centre Hospitalier de Luxembourg

•Oslo University Hospital Norway

•Erasmus MC Rotterdam Netherlands

•Centre Oscar Lambret, Lille France

•CHU Rouen France

•CHU Strasbourg France

•Hopital Saint Louis Paris France

•Centre Georges-François Leclerc Dijon France

•Institut Claudius Rigaud Toulouse France

•Institut Paoli Calmette Marseille France

•Institut Curie Paris France

•Hopital Paris Saint Joseph France

•Val d’Hebron Madrid Spain

•Istituto Nationale dei Tumori Milan Italy

•American University of Beirut Lebanon

•Anhui Medical University Hospital China

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olacancer.org

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Molecular Tumor Board

Patient case is derived from his doctor

Mol. Pathol PediatGeneticistOncologist Gyneco Thorax

Molecular Tumor BoardReport with therapeutic

proposal

Referral Doctor Discussion

Nav. nurse

New tools like Molecular Tumor Boards

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More infrastructure …..

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Translational Reserach….

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Increasing the Recruitment Startegies

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EXAMPLE OF SUCCESS IN LATAM

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Colombia (24.7%)N 1.939/EGFR+ 479

Argentina (14.4%)N 1.713/EGFR+ 247

Perú (51%)N 300/EGFR+ 200

México (34.3%)N 1.417/EGFR+ 486

Latin America (26%)N 5.738/EGFR+ 1.492

Costa Rica (31.4%)N 102/EGFR+ 32

Panama (27.3%)N 174/EGFR+ 48

Population

- Female 52.6%

- Tobacco exposure 51%

- Adenocarcinoma 95.1%

- K-Ras 7.1% (N 2385/184)

Arrieta O, et al. J Thorac Oncol. 2015 Jan 28. [Epub ahead of print]

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Latin America N= 4,136

Positive 6.09% (252)

Negative 93.91% (3,884)

FISH- ALK in Non-Small Cell Lung Cancer

Colombia

(10/242)

(5/94)

Argentina

(153/2491)

Uruguay

(2/37)

Panama

(5/114)

Mexico

(64/769)

Costa Rica

(13/137)

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Patiño, Cardona, Arrieta, Rolfo et al, in press

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International collaboration in the scientific production (Scopus) on cancer with at least one author affiliated to an institution in Colombia, Quantitative (2013-2017)

Bravo-Linares D, Ruiz-Patiño A, Lucio D, Cardona AF. Unpublished data (ACHO 2018).

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Collaborative networks in the scientific production on cancer (WoS) with at least one researcher affiliated with an institution in Colombia

Bravo-Linares D, Ruiz-Patiño A, Lucio D, Cardona AF. Unpublished data (ACHO 2018).

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Latin America Authorship Network

Patiño, Cardona, Arrieta, Rolfo et al, in press

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This is a Race!

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LATAM Europe Est Asia USA

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▪We are no the worst! We have an incredible potential bur It’s a very competitive world!

▪Strategies to implementation of attractive approaches are needed.

▪Harmonization among all LATAM countries is mandatory

▪Networking and Education are crucial!

▪Advocacy groups are a great resource

Key Messages:

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olacancer.org

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christian.rolfo@umm.edu

Thanks christian.rolfo@umm.edu

@ChristianRolfoThanks to Dr. Andrés Cardona and Dr. Henry Gómez

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the reality of clinical trials in latin america€¦ · the cost of oncology medicines increased at...

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