European Biotechnology News Special 5/2012 - Contract Research

European Biotechnology News Science & Industry

May 2012

II Contract Research SPECIAL 33_EBSIN5_12_Special_Titel_tg.indd 33

26.04.2012 12:02:57 Uhr

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Nº 5 | Volume 11 | 2012

Euro|Biotech|News

35

Special: coNtract reSearch Editorial

Europe’s CROs must rise to the challenge Stefano Marini, MD, MFPM, President of EUCROF (European CRO Federation), Rome

at a fundamental level, each of us is aware that the world is changing, and that it is changing rapidly. Politics, the economy, the pharmaceutical industry and – as a result – Cros are changing shape as they try to adapt to new scenarios in this new century. the pharmaceutical industry is caught between government needs to contain expenses on drug reimbursement and patent expiry on a huge number of blockbuster drugs. that struggle, however, means that resources available for the development of new drugs are also limited.

Paradoxically, this critical situation could favour the CRO industry for several reasons.

Pharmaceutical companies desperately need to reduce costs, and recently I came across a perfectly fitting opinion issued by Pfizer’s Stuart Sowder: “We’re entering the third wave. The first was doing it all alone.

The second was doing it with a partner. The third wave is trying to do it all together: government, non-government, and patient advocacy groups, all working together.” The CRO scenario has been reshaped: – both large and medium-sized pharma companies have moved to strategic relationships such as functional services and alliances, mainly with the largest global CROs; – these relationships require full customisation of the CRO team for each client. Since this is not scaleable and incurs higher costs, that poses a challenge to a CRO’s profitability; – small and medium-sized local CROs are looking for joint ventures and alliances with equivalent-size CROs to deliver services with full geographical coverage, and are also seeking to scale-up.

That means proposing stable strategic relationships to medium-sized and large pharma participants – no easy task;

35_EBSIN5_12_Special_Marini_tg.indd 35

President of EUCroF (European Cro Federation) Stefano Marini is also the founder and managing director of dimensione ricerca, an italian contract research organisation. His specialities are psychiatry and endocrinology, and he has nearly three decades of experience in pharmaceutical industry research, mainly managing clinical trials. Marini has also spent more than six years at the University of rome as an investigator, where he gained experience with clinical trials in neuropsychiatry and endocrinology. He was with Janssen italy for over eight years, where he was responsible for CNS r&d. He is also the author of more than 95 scientific articles, and author or co-author of over 170 clinical and pharmacotoxicological expert reports for marketing authorisations.

– other small and medium-size local CROs are looking for clients within the smaller pharmaceutical industry, especially

in biotech. In this they may succeed, because clients need to optimise costs, and need highly-customised services for clinical trials limited in size. This fits well with the capacity of niche, high-quality CROs – which are abundant in Europe.

To better understand these trends, I found the results of an accurate assessment performed by H. Glass and P. Miller very helpful. They recently analysed how CROs are used, and to what degree (Centre for Medicine Research database).

only single functions outsourced The results show that CRO usage, while substantial, might be significantly less than what is considered common knowledge. A third of studies are still done by sponsor companies using internal resources. However, this doesn’t mean that the remaining two-thirds are fully outsourced. Frequently only single functions are outsourced. The primary services that are commonly used include: on-site monitoring, data management, biometrics, patient enrolment, and report writing. Focusing only on the first two services – and stratifying by major, medium and small sponsor companies – we learn that on-site monitoring is used in 24%, 60% and 70% of trials, whereas data management is used in 32%, 49% and 59% respectively. These data are quite surprising, and indicate that attitudes towards outsourcing are more favourable in smaller than in larger pharmaceutical companies.

However, this also means that there is great potential for growth when it comes to outsourcing. By the way, this is in line with other qualified opinions, which also express an optimistic view on the potential increase of CRO business in the near future.

European CROs should pay attention to these indicators, and design strategies to target clients more effectively . As Europe’s CRO representative, EUCROF should additionally play an active role in working together with regulatory bodies, the industry, academia, and patient associations to overcome procedural obstacles that can delay study starts. This collaboration is key to increasing Europe’s attractiveness as a “must-be” location for conducting clinical trials.

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Nº 5 | Volume 11 | 2012

Euro|Biotech|News

Special: coNtract reSearch Intro

Outsourcing to CROs: a growing market outsourcing preclinical or clinical development to Contract research organisations (Cros) can save pharma and biotech companies a lot of time. According to the tufts Center for the Study of Drug Development, clinical trials conducted by Cros are conducted 30% more quickly than those performed in-house – saving an average 4-5 months. And reducing time-to-market results translates into increased revenue potential.

Global CRO revenues totalling about a20bn in 2010 represented a third of total pharma and biotech R&D spending, says the Tufts Center, and the field is going to continue to grow. Global R&D outsourcing is expected to soar from US$28bn this year to US$35bn in 2015, according to figures from ICON Clinical Research. In the face of rising development costs and patents that are running out, Big Pharma and bio­ pharma companies are looking to emerg­ ing markets and costsaving outsourcing initiatives with CROs to drive growth.

As a consequence, the global CRO mar­ ket is ballooning at about 9% annually on average, but at very different region­ al rates. Currently the biggest emerg­

ing clinical trial market is in Asia, where all of the top 10 CROs have established study sites in India, China or South Ko­ rea to complement their traditional sites in North America and Europe. Addition­ ally, eastern European countries can of­ fer treatment­naïve patients at a lower per­patient cost than in western Europe, and are contributing to the globalisation of clinical trials.

Not long ago, traditional sites seemed secure, with approximately 53% of clini­ cal trials being performed in the US, 24% in Europe, and 23% in Asia, Latin America, Africa and Australia, according to to clini­ caltrials.gov. But cost and time pressures have driven further globalisation. Analysts

Cro market growth by phase. Source: www.clinuity.com

36_EBSIN5_12_Special-intro_tg.indd 36

of Insight Consulting Inc. estimate that it would take approximately 5.8 years to fully enrol all currently open Phase III cancer trials if only US locations were used, as compared to 1.9 years using both US and global trial sites (see p. 38).

While BRIC countries (Brazil, Russia, India and China) are often considered the engine of future growth for the pharma­ ceutical industry, a CRO market in Cen­ tral and Eastern Europe is emerging for other reasons. Although they aren’t rapid­ ly­growing markets, these countries can offer the advanced technologies, infra­ structure and know­how required to de­ velop complex emerging molecules such as biosimilars or biobetters. Several bio­ logics – including blockbusters like Her­ ceptin, Remicade and Rituxan – will go off­ patent by 2015, representing sales worth US$63bn. Accordingly, the market for bio­ similars is expected to grow quickly, with Europe at the forefront because of its reg­ ulatory framework for biosimilar medici­ nal products (see p. 42).

a huge market opportunity While CROs are interested in creating robust alliances with drug developers, a recent study commissioned by ICON re­ commends biopharmaceutical enterprises adopt flexible partnerships to stay ahead of the market (see p. 40). The in­depth analy­ ses, which are based on interviews with 11 of the top 20 pharma companies that out­ source services to CROs, provide insights into successful collaboration models.

Confronted with emerging markets in Asia, European regulators such as the Heads of Medicines Agencies (HMA) have already taken action (see p. 41). With­ in three years, its Clinical Trials Facili­ tation Group (CTFG) has established the so­called Voluntary Harmonisation Pro­ cedure (VHP), which has cut the time lag from application to start of a multinational clinical trial from a year to just 82 days.

Meanwhile EUCROF, the European CRO federation, warns that CROs have to opti­ mise their services in a globalised market in which outsourcing plays a less prom­ inent role than appears at first glimpse (see p. 35).

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n g & PR rketi fo Ma h in N R r c e t o W i B

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Nº 5 | Volume 11 | 2012

Euro|Biotech|News

Special: coNtract reSearch BIOlOgICS

The globalization of clinical trials John J. Lewis, Association of Clinical Research Organizations, Washington, US

“globalization” is a term that many people find threatening, for a variety of different reasons. But in the area of clinical trials and drug development, globalization should be embraced as a means for making new treatments and therapies available to patients sooner – in many cases, much sooner.

In large measure, the globalization of clinical trials has been driven by clinical research organizations, which now essentially comprise the global infrastructure for drug development. The Association of Clinical Research Organizations counts amongst its membership the eight largest CROs in the world. Each year, these companies conduct upwards of 11,000 clinical trials involving two million participants in 115 countries.

About a third of this activity is in the biotech sector. ACRO members have contributed to

the development of all of the 20 top-selling drugs in the world, as well as about 90% of the new drugs approved in Europe and the United States each year.

This experience provides CROs with a unique perspective, but also places a huge responsibility – to ensure that research is conducted to the highest standards of quality and ethical consideration for the participants. ACRO has undertaken research to examine the quality and ethics of global trials, but before we get to

these findings, let’s look at the underlying driver of globalization: population.

A quick review of clinicaltrials.gov, the US–based centralized reporting hub for clinical trials activity, shows approximately 9,300 active, industry-sponsored, interventional trials being conducted worldwide.

Currently, about 54% of these trials are being conducted in the United States. This has been a relatively consistent number – about half of trials take place in the US, 25% in Europe and 25% in Asia, Latin America and elsewhere.

But the US population is only 313 million, while the European Union states collectively have a population of some 500 million. Yet the estimated world population is seven billion people! The US and the EU together therefore represent less than 12% of the world’s population, but are supporting 75% or more of its clinical trials. This is neither efficient nor sustainable.

This is one reason why so much attention is being paid to countries such as China (1.3 billion) and India (1.2 billion). Still, these countries comprise, respectively, only 3.3% and 2.8% of current clinical trial activity, though many reports would have you believe the share is much higher. Let’s also keep in mind that the biopharmaceutical industry is global, and that drugs are marketed globally, so there are other reasons

Comparison: estimated time to enroll all open Phase III cancer studies in US only versus globally. Source: ACRO and VOI Consulting US Statistics

Figure

Source/Calculation

global Statistics

Figure

Source/Calculation

A Total Cancer Incidence in US

1,437,180

American Cancer Soc. 2008 (A)

A Total Global Cancer Incidence

10,862,496

Globocan 2002 (L)

A Participation Rate in US

5%

Industry Statistics (B)

A Global Participation Rate

5%

Conservative Estimate (M)

A Total Annual Patients Willing to Enroll

71,859

A x B (C)

A Total Annual Patients Willing to Enroll

543,125

L x M (N)

A Number of Phase III Cancer Studies in US

481

Clinicaltrials.gov (D)

A Number of Phase III Cancer Studies Globally

1,218

Clinicaltrials.gov (0)

A Patients Willing to Enroll Per Study

149

C/D (E)

A Patients Willing to Enroll Per Study

446

N/O (P)

A Percent Excluded due to Screening Factors

20%

Industry Statistics (F)

A Percent Excluded due to Screening Factors

20%

Industry Statistics (Q)

A Patients Willing and Able to Enroll Per Study

120

E x (1 - F) (G)

A Patients Willing and Able to Enroll Per Study

357

P x (1 - Q) (R)

A Average Patients in a Phase III Cancer Drug Trial

691

VOI Consulting (H)

A Average Patients in a Phase III Cancer Drug Trial

691

VOI Consulting (S)

A Years Necessary to Fully Enroll all Phase III Cancer Trials with US Patients

5.8

H/G

A Years Necessary to Fully Enroll all Phase III Cancer Trials with Global Patients

1.9

S/R

A Difference between US-only and global Trials

38-39_EBSIN5_12_Special_ACRO_tg.indd 38

3.8 years

25.04.2012 18:03:57 Uhr

Nº 5 | Volume 11 | 2012

Global clinical development. Source: ClinicalTrials.gov, as of 24/4/2012. Active, industry-sponsored, interventional clinical trials Country A United States

# Active Trials

% Global Activity

5,085

54.4

A United Kingdom

878

9.4

A France

948

10.1

1,234

13.2

A Japan

382

4.1

A Brazil

397

4.2

A Russian Federation

443

4.7

A India

261

2.8

A China

313

3.3

A Korea

551

5.9

9,344

---

A Germany

A Global Total

to conduct clinical trials in “local” markets. Further, for a variety of reasons, the evolving market of biosimilars necessitates access to a global population for development purposes.

Quality and ethics In 2010, ACRO commissioned a research study to look at the question of whether research in “emerging” or “developing” regions was of the same quality as that in “mature” regions like the US, western Europe or Japan. An analysis of 25 Phase II and Phase III trials involving more than 65,000 participants in fact found that there were no statistically significant differences between or among countries or regions. In the analysis, ‘quality’ was measured using a standard method of errors per CRF and errors that led to database changes, although data from China was insufficient to make any firm conclusion.

We have shared these findings with both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), as the reliability of data from “foreign” or “third-country” clinical trials is an issue high on their regulatory agendas. In fact, the EMA in April published its final reflection paper on ethical and good clinical practice (GCP) aspects of clinical trials conducted outside the EU or the European Economic Area, entering into force on 1 May 2012. ACRO is largely supportive of the EMA’s approach to ensuring adherence to ethical standards and GCPs globally and encourages harmonization of these standards with other regulators around the world In this regard, ACRO is currently in the midst of a follow-up study examining ethical issues in multi-regional trials using metrics such as protocol deviations, SAE reporting, site audit findings and enrollment goals. We expect to report these results later this year.

From an earlier research project, we know that high-quality, ethical research conducted globally can, for instance, reduce the time required for a Phase III cancer trial from nearly six years if conducted in only the US to less than two years if conducted globally.

Translation: a new cancer drug for patients four years sooner. This is not just the promise, but the reality of globalization.

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Nº 5 | Volume 11 | 2012

Euro|Biotech|News

Special: coNtract reSearch Nimble PaRTNeRShiPS iN The PhaRma iNduSTRy

Structuring CRO relationships Charley Beever, Matthew Le Merle, Tara Churik, Booz & Company and James McSweeney, PhD., ICON Clinical Research

in today’s complex and highly-competitive business environment, the world’s leading pharmaceutical companies, including biotech firms, are scrutinising their research and development capabilities as they search for ways to extract more value. in order to succeed in an evolving marketplace, they will need to build effective partnerships with clinical research organizations (CROs). a pharmaceutical company’s CRO relationships should reflect its business strategy, including its views on which clinical development capabilities can be outsourced and which should remain in-house.

In collaboration with ICON, a global provider of outsourced development services to the pharmaceutical, biotechnology and medical device industries, Booz & Company conducted qualitative research to understand how pharmaceutical companies currently engage with their CRO partners, and the extent to which their strategies are aligned with the structure of their CRO partnerships. We completed 20 structured interviews with senior executives at the vice president or senior director level in 11 of the top 20 pharmaceutical companies.

Our findings suggest that most pharmaceutical companies do not take a topdown, strategic approach to CRO partnerships. Many have announced “strategic

CRO partnerships”, but specific strategic objectives need to be better defined. In addition, the design and structure of CRO relationships, and associated capabilities, need to be aligned with the strategic rationale for outsourcing and sources of value within the organisations. For example, several companies declared that clinical trial monitoring is not a core capability and would be fully outsourced. However, they have not always determined how to outsource in a way that enables them to maintain desired relationships with key clinicians at clinical trial sites.

The relationships between drug companies and CROs vary based on three key business considerations:

Pharmaceutical-CRO relationship models Qualified Talent Supplier

Preferred Capacity Partner

Preferred Capability Partner

Strategic Partner

People

Discrete Services

Functional Capability

Long-term results

A Are any functions completely outsourced (globally)?

No

No

Yes

Yes

A What is the time frame of the agreement?

Short/Medium

Medium

Medium

Long

No

No

Limited

Yes

Characteristic A What does the CRO relationship deliver?

A Is there any expectation of innovation?

40_EBSIN5_12_Special_Icon_tg.indd 40

1. The work the CRO will perform: Will it add more flexible capacity to the firm’s own organisation, or will it provide capabilities that are not available internally?

2. The model used to deliver additional capacity or new capabilities: As a service?

Through individuals? A combination of the two?

3. The relationship structure: Is it a standard contract, a sophisticated strategic alliance, or something in-between?

Taking these into account, four pharmaceutical-CRO relationship models emerge (see Table): – Qualified talent supplier: CROs provide pharmaceutical companies with temporary employees with specific skills to expand capacity or enhance capabilities (including assistance with protocol design, monitoring of trial sites, analysis of findings, and production of study reports).

– preferred capacity partner: Flexible and responsive CROs offer services (such as trial monitoring and study data management) that the pharmaceutical company also retains internally, in order to expand capacity as needed during periods of peak demand.

– preferred capability partner: CROs provide capabilities (such as clinical site monitoring) that the pharmaceutical company considers non-core and does not choose to build internally.

– Strategic partner: The pharmaceutical company structures a long-term relationship with a CRO to jointly deliver overall development results (such as successful clinical trials in a particular therapeutic area) with the expectation that the partnership will result in improvements in quality, cost and speed.

To choose the most effective partnership structure, pharmaceutical companies need to first assess their internal capabilities to identify those areas where they already excel or where they want to make additional investments. These capability choices will form the basis of a coherent CRO partnership strategy. This “new nimble” approach allows pharmaceutical companies to stay ahead of changing market dynamics, differentiate themselves, and generate value at every point in their organisations.

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25.04.2012 18:08:31 Uhr

Nº 5 | Volume 11 | 2012

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41

SPECIAL: CONTRACT RESEARCH REGULATORY AUTHORITIES

Outcome of Voluntary Harmonisation Procedure for clinical trials in Europe The Voluntary Harmonisation Procedure (VHP), which began in 2009, enables applicants to process authorisations of clinical trials in several European countries simultaneously. In April, members of the Clinical Trials Facilitation Group (CTFG) of the Heads of Medicines Agencies (HMA) reported some success (NATURE REVIEWS DRUG DISCOVERY, doi:10.1038/nrd3202-c2).

The time that elapses before a multinational clinical trial is authorised in all participating EU countries could be reduced from a year to less than three months.

Until recently, biotech and pharma companies planning to conduct a clinical trial needed national authorisations for every single trial. Multinational trials, which

are carried out in more than 10 countries, had to undergo the entire procedure of validation, assessment, grounds for non-acceptance/reply, and authorisation/rejection.

Benefit for companies Under the auspices of the German regulatory authority Paul-Ehrlich-Institut, the CTFG developed the VHP. In 2011, the average period required until authorisation for a multinational clinical trial was obtained amounted to just 82 days. The actual harmonisation procedure, on the other hand, takes only 50 days on average. Applicants are required to apply

for authorisation in the individual countries in which the study is to be conducted within 20 days following a favourable opinion. The deadline for such cases is now just ten days, which is feasible since all of the pertinent scientific questions have already been answered in the new harmonised procedure. Within three years, the time period required for obtaining an authorisation of multinational clinical trials could be reduced from 124 days in the first year to currently 82 days. That is partially thanks to the fact that the VHP has already undergone several revisions – an advantage of this procedure, which requires no change in the law, and which allows useful changes to be implemented on a short-term basis.

The number of applications is also currently on the rise. In 2009, 26 applications were made. In 2011, this figure had more than tripled to 85, and that number is increasing. Altogether, 170 applications have been made so far. 

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European Biotechnology

Nº 5 | Volume 11 | 2012

Net work

BIologICS

Biosimilar properties that impact CRO work Werner Frings, Covance Laboratories GmbH, Münster, Germany

generic drugs are considered identical to the original drug, and therefore are generally designated as therapeutically interchangeable. But biopharmaceuticals typically carry different and/or multiple post-translational modifications that can be related to the expression system, as well as to downstream processing and formulation.

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These modifications can have an influence on pharmacokinetics, efficacy (pharmacodynamics, PD), and eventually even toxicity. That means more preclinical and clinical testing is required before biosimilar marketing authorisation. However, because biopharmaceuticals have only been on the market for a few decades, experts still have little experience in biosimilar development. Consequently, no ICH consensus document has been issued. The European Medical Agency (EMA) finalised first guidance in 2005, and is currently working on a revision, while the FDA recently issued a draft guideline.

Different therapeutic proteins can have isoforms, and larger molecules often carry more and different modifications than smaller peptides. For example, a monoclonal antibody could theoretically have up to 108 possible states [Kozlowski and Swann,

Adv. Drug Deliv. Rev. 58 (2006), 707-722].

Therefore more detailed guidelines have been published by the EMA for selected biopharmaceuticals.

Testing for chemical and functional similarity might be practically challenging for the biosimilar companies, or for CROs when work is outsourced. Methods for chemical characterisation of originator and biosimilar are often highly complex. This requires a good method transfer, or a specialised CRO with respective expertise. For in-vitro assays, it is crucial that the variability of the test be low enough to allow for detection of mild functional differences, or the number of tests must be raised for a higher statistical power. The variability of useful PD markers in lab animals can impede a perfect comparison, as numbers of animals are limited for practical and ethical reasons. This is of

Some known post-translational modifications that can have an impact on the similarity of proteins. mAb: monoclonal antibody, ADCC: antibody dependent cellular cytotoxicity Modification

Influence on mAb action

Reference

A GlcNAc/Mannose

Ligand for mannose binding > complement activation

Malhotra et al., Nat. Med. 1995

A Sialic acid

Suppression of ADCC (anti-inflammatory activity)

Kaneko et al., Science 2006

European Biotechnology Foundation Rue d‘Egmont 15 B-1000 Bruxelles, Belgique

A Galactose

Placental transport

Kibe et al., J. Clin. Biochem. Nutr. 1996

A Bisecting GlcNAc

Prevents core fucosylation > enhanced ADCC

Umana et al., Nat. Biotech. 1999

Tel: +32 2 50 08 531 Fax +32 2 64 92 989

A Absence of core fucose

Enhanced ADCC

Okazaki et al., J. Mol. Biol 2004

A A(1-3)-Gal

Non human > antigenic

-

info@european-biotechnology.org www.european-biotechnology.net

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Special: coNtract reSearch particular interest when non -human primates are the only pharmacologically relevant species. These animals are not inbred, and thus more frequently show a high interanimal variability of PD markers, and fewer animals are used than in rodent studies.

Data evaluation can be more difficult when some animals develop anti-drug antibodies, resulting in outliers that might have to be excluded from data evaluation. In a few cases, one might even suspect a different immunogenic potential of biosimilar and original drug, although this usually is not detected in animal studies due to low numbers, and because immuno genicity in animals is not predictive for humans. Even in clinical studies, the immunogenic potential often cannot be assessed. With CROs usually having the best knowledge about their test animals, it is therefore extremely important that the sponsor and CRO discuss the study design (animal number, dose level(s), group allocation, pre-selection for PD marker) in detail.

A

EU-approved biosimilars (as of May 2011)

ucts containing biotechnology-derived proteins as active substance: non-clinical and clinical

Brand name

Producer/Distributor

A Omnitrope

Sandoz/Sandoz

A Valtropin

LG Life Scienc./Biopartners

A Filgastrim Hexal

Sandoz/Hexal

A Zarzio

Sandoz/Sandoz

ucts containing biotechnology-derived proteins

A Biograstim

SICOR/ct Arzneimittel

as active substance – quality issues (EMEA/

A Ratiograstim

SICOR/ratiopharm

A Tevagrastim

SICOR/Teva

A Nivestim

Hospira/Hospira

A Abseamed

Lek, Rentschler/Medice

A Epoetin a Hexal

Lek, Rentschler/Hexal

A Binocrit

Lek, Rentschler/Sandoz

A Retacrit

Norbitec/Hospira

A Silapo

Norbitec/Stada

issues (EMEA/CHMP/BMWP/42832/2005), and concept paper for revision (EMA/CHMP/ BMWP/572828/2011) [3] Guideline on similar biological medicinal prod-

CHMP/49348/05), and concept paper for revision (EMA/CHMP/BWP/617111/2010) [4] Draft guideline on similar biological medicinal products containing monoclonal antibodies (EMA/ CHMP/BMWP/403543/2010) [5] Guideline on evaluation of similar biotherapeutic products (SBPs), WHO 2009 [6] ICH topic S6 – Note for guidance on preclinical safety evaluation of biotechnology-derived pharma ceuticals (CPMP/ICH/302/95) [7] Guideline on the clinical investigation of the

References

pharmacokinetics of therapeutic proteins (CHMP/

[1] Guideline on similar biological medicinal products

EWP/89249/2004)

(CHMP/437/04), and concept paper for revision

[8] http://www.fda.gov/downloads/Drugs/Guidance ComplianceRegulatoryInformation/Guidances/

(CHMP/BMWP/572643/2011) [2] Guideline on similar biological medicinal prod-

UCM291128.pdf

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