european biotechnology news special 5/2012 - contract research

EuropeanBiotechnology

Science & Industry NewsMay 2012

SPECIAL

II Contract Research

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Euro|Biotech|NewsNº 5 | Volume 11 | 2012 35

Special: coNtract reSearch

Paradoxically, this critical situation could fa-vour 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: gov-ernment, non-government, and patient ad-vocacy groups, all working together.” The CRO scenario has been reshaped:– both large and medium-sized pharma

companies have moved to strategic re-lationships such as functional services and alliances, mainly with the largest global CROs;

– these relationships require full cus-tomisation of the CRO team for each client. Since this is not scaleable and incurs higher costs, that poses a chal-lenge to a CRO’s profitability;

– small and medium-sized local CROs are looking for joint ventures and allianc-es with equivalent-size CROs to deliver services with full geographical cover-age, and are also seeking to scale-up. That means proposing stable strate-gic relationships to medium-sized and large pharma participants – no easy task;

Editorial

Europe’s CROs must rise to the challengeStefano 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 centu-ry. the pharmaceutical industry is caught between government needs to contain ex-penses 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.

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

in bio tech. In this they may succeed, be-cause clients need to optimise costs, and need highly-customised services for clini-cal 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 per-formed by H. Glass and P. Miller very help-ful. They recently analysed how CROs are used, and to what degree (Centre for Med-icine 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. How-ever, 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 manage-ment, 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 surpris-ing, and indicate that attitudes towards out-sourcing 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 out-sourcing. By the way, this is in line with oth-er 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 strate-gies 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 asso-ciations to overcome procedural obstacles that can delay study starts. This collabo-ration is key to increasing Europe’s attrac-tiveness as a “must-be” location for con-ducting clinical trials. B

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.

35_EBSIN5_12_Special_Marini_tg.indd 35 25.04.2012 18:02:00 Uhr

36 Euro|Biotech|News Nº 5 | Volume 11 | 2012


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 biopharma companies are looking to emerging markets and cost saving outsourcing initiatives with CROs to drive growth.

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

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 Cent-er 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.

ing clinical trial market is in Asia, where all of the top 10 CROs have established study sites in India, China or South Korea to complement their traditional sites in North America and Europe. Additionally, eastern European countries can offer 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 clinical trials being performed in the US, 24% in Europe, and 23% in Asia, Latin America, Africa and Australia, according to to clinicaltrials.gov. But cost and time pressures have driven further globalisation. Analysts

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 pharmaceutical industry, a CRO market in Central and Eastern Europe is emerging for other reasons. Although they aren’t rapidlygrowing markets, these countries can offer the advanced technologies, infrastructure and knowhow required to develop complex emerging molecules such as biosimilars or biobetters. Several biologics – including blockbusters like Herceptin, Remicade and Rituxan – will go offpatent by 2015, representing sales worth US$63bn. Accordingly, the market for biosimilars is expected to grow quickly, with Europe at the forefront because of its regulatory framework for biosimilar medicinal 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 recommends biopharmaceutical enterprises adopt flexible partnerships to stay ahead of the market (see p. 40). The indepth analyses, which are based on interviews with 11 of the top 20 pharma companies that outsource 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). Within three years, its Clinical Trials Facilitation Group (CTFG) has established the socalled Voluntary Harmonisation Procedure (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 optimise their services in a globalised market in which outsourcing plays a less prominent role than appears at first glimpse (see p. 35).� BCro market growth by phase. Source: www.clinuity.com

36_EBSIN5_12_Special-intro_tg.indd 36 27.04.2012 13:34:13 Uhr

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

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 differ-ent 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 clin-ical trials has been driven by clinical re-search organizations, which now essen-tially comprise the global infrastructure for drug development. The Association of Clini-cal Research Organizations counts amongst its membership the eight largest CROs in the world. Each year, these companies con-duct upwards of 11,000 clinical trials involv-ing 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 re-search is conducted to the highest stand-ards of quality and ethical consideration for the partici pants. ACRO has undertak-en 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 approximate-ly 9,300 active, industry-sponsored, inter-ventional trials being conducted worldwide. Currently, about 54% of these trials are be-ing 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 togeth-er 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 atten-tion is being paid to countries such as Chi-na (1.3 billion) and India (1.2 billion). Still, these countries comprise, respectively, only 3.3% and 2.8% of current clinical trial ac-tivity, 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 mar-keted globally, so there are other reasons

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 3.8 years

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Nº 5 | Volume 11 | 2012

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 ques-tion of whether research in “emerging” or “developing” regions was of the same quality as that in “mature” regions like the US, west-ern Europe or Japan. An analysis of 25 Phase II and Phase III tri-als 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 data-base 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 prac-tice (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 en-rollment goals. We expect to report these results later this year. From an earlier research project, we know that high-quality, ethi-cal research conducted globally can, for instance, reduce the time required for a Phase III cancer trial from nearly six years if con-ducted 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. B

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

Country # Active Trials % Global Activity

A United States 5,085 54.4

A United Kingdom 878 9.4

A France 948 10.1

A Germany 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

A Global Total 9,344 ---

38-39_EBSIN5_12_Special_ACRO_tg.indd 39 26.04.2012 12:04:23 Uhr



Pharmaceutical-CRO relationship models

Characteristic Qualified Talent Supplier

Preferred Capacity Partner

Preferred Capa-bility Partner

Strategic Partner

A What does the CRO relationship deliver?

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

A Is there any ex pect-ation of innovation?

No No Limited Yes

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 or-der to succeed in an evolving marketplace, they will need to build effective partner-ships with clinical research organizations (CROs). a pharmaceutical company’s CRO relation ships should reflect its business strategy, including its views on which clini-cal development capabilities can be outsourced and which should remain in-house.

In collaboration with ICON, a global pro-vider of outsourced development services to the pharmaceutical, biotechnology and medical device industries, Booz & Com-pany conducted qualitative research to un-derstand how pharmaceutical companies currently engage with their CRO partners, and the extent to which their strategies are aligned with the structure of their CRO part-nerships. We completed 20 structured in-terviews with senior executives at the vice president or senior director level in 11 of the top 20 pharmaceutical companies.

Our findings suggest that most phar-maceutical companies do not take a top-down, strategic approach to CRO partner-ships. 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 ra-tionale for outsourcing and sources of val-ue 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 com-panies and CROs vary based on three key business considerations:

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

2. The model used to deliver additional ca-pacity or new capabilities: As a service? Through individuals? A combination of the two?

3. The relationship structure: Is it a stand-ard contract, a sophisticated strategic al-liance, or something in-between?

Taking these into account, four pharma-ceutical-CRO relationship models emerge (see Table):– Qualified talent supplier: CROs provide

pharmaceutical companies with tem-porary employees with specific skills to expand capacity or enhance capa-bilities (including assistance with pro-tocol 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 or-der to expand capacity as needed dur-ing periods of peak demand.

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

– Strategic partner: The pharmaceutical company structures a long-term re-lationship 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 im-provements 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 ex-cel or where they want to make additional investments. These capability choices will form the basis of a coherent CRO partner-ship strategy. This “new nimble” approach allows pharmaceutical companies to stay ahead of changing market dynamics, dif-ferentiate themselves, and generate value at every point in their organisations. B

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SPECIAL: CONTRACT RESEARCH

REGULATORY AUTHORITIES

Outcome of Voluntary Harmonisation Procedure for clinical trials in EuropeThe Voluntary Harmonisation Procedure (VHP), which began in 2009, enables ap-plicants to process authorisations of clin-ical 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 multina-tional clinical trial is authorised in all par-ticipating EU countries could be reduced from a year to less than three months.

Until recently, biotech and pharma com-panies planning to conduct a clinical trial needed national authorisations for eve-ry single trial. Multinational trials, which

are carried out in more than 10 coun-tries, had to undergo the entire proce-dure of validation, assessment, grounds for non-acceptance/reply, and authorisa-tion/rejection.

Benefit for companies

Under the auspices of the German reg-ulatory authority Paul-Ehrlich-Institut, the CTFG developed the VHP. In 2011, the average period required until authorisa-tion 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 aver-age. Applicants are required to apply

for authorisation in the individual coun-tries in which the study is to be conduct-ed within 20 days following a favoura-ble opinion. The deadline for such cas-es is now just ten days, which is feasible since all of the pertinent scientifi c ques-tions have already been answered in the new harmonised procedure. Within three years, the time period required for ob-taining an authorisation of multination-al clinical trials could be reduced from 124 days in the fi rst year to currently 82 days. That is partially thanks to the fact that the VHP has already undergone sev-eral revisions – an advantage of this pro-cedure, 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 cur-rently on the rise. In 2009, 26 applications were made. In 2011, this fi gure had more than tripled to 85, and that number is in-creasing. Altogether, 170 applications have been made so far.

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Nº 5 | Volume 11 | 2012

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

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

A Absence of core fucose Enhanced ADCC Okazaki et al., J. Mol. Biol 2004

A A(1-3)-Gal Non human > antigenic -

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 gener-ally 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.

These modifications can have an influence on pharmacokinetics, efficacy (pharmaco-dynamics, PD), and eventually even toxici-ty. That means more preclinical and clinical testing is required before biosimilar market-ing authorisation. However, because bio-pharmaceuticals have only been on the mar-ket for a few decades, experts still have little experience in bio similar development. Con-sequently, 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 car-ry more and different modifications than smaller peptides. For example, a mono-clonal 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 bio-pharmaceuticals.

Testing for chemical and functional sim-ilarity might be practically challenging for the biosimilar companies, or for CROs when work is outsourced. Methods for chemical characterisation of originator and biosimi-lar 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 com-parison, as numbers of animals are limited for practical and ethical reasons. This is of

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References

[1] Guidelineonsimilarbiologicalmedicinalproducts

(CHMP/437/04),andconceptpaperforrevision

(CHMP/BMWP/572643/2011)

[2] Guidelineonsimilarbiologicalmedicinalprod-



particular interestwhennon-humanpri-matesaretheonlypharmacologicallyrele-vantspecies.Theseanimalsarenotinbred,andthusmorefrequentlyshowahighinter-animalvariabilityofPDmarkers,andfew-eranimalsareusedthaninrodentstudies.Dataevaluationcanbemoredifficultwhensomeanimalsdevelopanti-drugantibod-ies,resultinginoutliersthatmighthavetobeexcludedfromdataevaluation.Inafewcases,onemightevensuspectadifferentimmunogenicpotentialofbiosimilarandoriginaldrug,althoughthisusually isnotdetectedinanimalstudiesduetolownum-bers,andbecauseimmunogenicityinani-malsisnotpredictiveforhumans.Eveninclinicalstudies,theimmunogenicpotentialoftencannotbeassessed.WithCROsusu-allyhavingthebestknowledgeabouttheirtestanimals,itisthereforeextremelyim-portantthatthesponsorandCROdiscussthe study design (animal number, doselevel(s),groupallocation,pre-selectionforPDmarker)indetail. A

EU-approved biosimilars (as of May 2011)

Brand name Producer/Distributor

A Omnitrope Sandoz/Sandoz

A Valtropin LGLifeScienc./Biopartners

A FilgastrimHexal Sandoz/Hexal

A Zarzio Sandoz/Sandoz

A Biograstim SICOR/ctArzneimittel

A Ratiograstim SICOR/ratiopharm

A Tevagrastim SICOR/Teva

A Nivestim Hospira/Hospira

A Abseamed Lek,Rentschler/Medice

A EpoetinaHexal Lek,Rentschler/Hexal

A Binocrit Lek,Rentschler/Sandoz

A Retacrit Norbitec/Hospira

A Silapo Norbitec/Stada

uctscontainingbiotechnology-derivedproteins

asactivesubstance:non-clinicalandclinical

issues(EMEA/CHMP/BMWP/42832/2005),

andconceptpaperforrevision(EMA/CHMP/

BMWP/572828/2011)

[3] Guidelineonsimilarbiologicalmedicinalprod-

uctscontainingbiotechnology-derivedproteins

asactivesubstance–qualityissues(EMEA/

CHMP/49348/05),andconceptpaperforrevision

(EMA/CHMP/BWP/617111/2010)

[4] Draftguidelineonsimilarbiologicalmedicinal

productscontainingmonoclonalantibodies(EMA/

CHMP/BMWP/403543/2010)

[5] Guidelineonevaluationofsimilarbiotherapeutic

products(SBPs),WHO2009

[6] ICHtopicS6–Noteforguidanceonpreclini-

calsafetyevaluationofbiotechnology-derived

pharmaceuticals(CPMP/ICH/302/95)

[7] Guidelineontheclinicalinvestigationofthe

pharmacokineticsoftherapeuticproteins(CHMP/

EWP/89249/2004)

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

ComplianceRegulatoryInformation/Guidances/

UCM291128.pdf

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