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
A AT GGA AT C G TA TA A CCA AG G GTT TCC ACA GCC TGA GCC G AT AT C G TA AG G GA A CAC CGA GCC CAA AGC ACC TA A AGT GTT
T G A CAC ACG T TC GCC C C A T C A C G A TA A A A C GA A ACC GA A TCA GCC T T G CA A GGC CAC CAG AC T GGA ACA AGA TCC STudieS & ConSulTinG T T C G TA T T A A C T A G A ConferenCeS AAG G A G CTC CTG GCG GTG TCA BookST C T C G C C A TA A ACG G A A A C G G G T G A C T V & VideoA C T C C G C A TA G G C T C A A A AC G C A CorporATe puBliShinG C A G C T T A C C AGA T G C inTerneT C T C C G C A C G G T T T C C A C A GCC T G A MAGAzineSG A T T C G T C T C A ACC CA A GGA G T T e V enT MAnAGeMenT T A A AC GCC CAG TCC AT T CAC GCT G T T CCC GGA G G C AAA G C A C A T C C A GGC GCA T G T T GA CAC G C T AGA CA A ACA T C T G T T C T C A AG GA A TGA A C T A C G T C C T G C AT G
G AT A A G G A A G T T AT G G A A GGA C A A T TA C C C G AT T G G AGT CA A GA A G C T T TC GAC TA G C A C A C G T G C G G A A C G AAA G C T T A T T G G A A G T G C G C A TA C C A A T G C AT G C A C G AT C AT T C T A A C C C T T A T AT C C C C T T G A C C GGC C G G A AT C A G T G A C G A C C G T G T C G T T G G C T T A A A G C T TA G G G G A AT C C A A C C GAC A G A C A T T T G C G A G C T A G A ACG T G T G C C G AT C A A G A A T G C T T T G G A GA A C T A A C A T C T A AG AT C T T G G G A G G C A C T T C C A AT G G A AT C G T A TA A G C C G A T AT C G TA AG G T G A C T C A G T ACG T C A TA G C A A G TA C TA C T G C G C G A A C T T GCG TCG ACG CAC CA A T G C AGA GAG TCA TA A GAC GCA T G C A C A G C C AG G A C T C T T AGA GA A TGG GAC ACG TGC A AT C A G C C T G A T TA G C A C W e C r e AT e k n o W l e d G e ! CGA T G T GCC T T G ACC TCG T T G CGA T T G GGA AGA A A A
CCT AAA TGC ACA CCG GGA AGC TTT ACA GCC AT T TA A A AG AGA GAG CCA CAA ACT ACG ACC GCA TGC CAC CAG TGG ACG CTC
BIOCOM AG | Lützowstraße 33–36 | 10785 Berlin | Germany www.biocom.de | Tel. +49 (0)30 264921-0 | Fax +49 (0)30 264921-11
BIOCOM_EA_en_210x275.indd 11 34_EBSIN5_12_BIOCOM.indd
25.04.2012 18:01:47 13:56:21 Uhr
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. B
25.04.2012 18:02:00 Uhr
36
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). B
27.04.2012 13:34:13 Uhr
n g & PR rketi fo Ma h in N R r c e t o W i B
,
ce
N Ex a h
rs
d I n te r n a t i o n al l an a n s and Confe Fai tio i ti o n re n ib
s Te c
hno
log y Tran
s fe
io is of B tech Bu lys s a ience in N ine An nd Sc RW s a
r
ps
,
s
Su
pp
or t-u t of ar B i o te c h St Co ach ing ing & Financ
P ro m o t i o n of Yo s ung Ac a d e mic
bio.nrw.de Busyness for Biotech. North Rhine-Westphalia’s biotechnology cluster BIO.NRW is a central catalyst for the sustainable development of the state’s biotechnology sector. It activates cooperation between business, research, investors, and policymakers.
phone: +49-211-385469-9200 • E-Mail: bio.nrw@bio.nrw.de
37_EBSIN5_12_BIONRW.indd 1
25.04.2012 18:02:42 Uhr
38
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. B
38-39_EBSIN5_12_Special_ACRO_tg.indd 39
26.04.2012 12:04:23 Uhr
40
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. B
25.04.2012 18:08:31 Uhr
Nº 5 | Volume 11 | 2012
Euro|Biotech|News
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.
Dedicated to Biomanufacturing Expertise Experience Excellence
Europe_biotech_news_185x120_281011.indd 1
41_EBSIN5_12_Special_PEI_tg.indd 41
To learn how our experience and expertise fit your needs for Expertise
protein, virus, DNA, live cells and biosimilars production, Experience Excellence
please visit www.cobrabio.com
28/10/2011 16:06
25.04.2012 18:21:53 Uhr
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.
Join the European Biotechnology Network! The European Biotechnology Network is dedicated to facilitating co-operation between professionals in biotechnology and the life sciences all over Europe. The network is run by the European Biotechnology Foundation, a non-profit organisation based in Brussels. Do you want to know more about the advantages of a (free) membership? Just have a look at our website: www.european-biotechnology.net
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
42-43_EBSIN5_12_Special_Covance_tg.indd 42
27.04.2012 13:35:10 Uhr
Nº 5 | Volume 11 | 2012
Euro|Biotech|News
43
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
FGK Clinical Research GmbH is a full service contract research organization offering the complete range of clinical development and consulting services to biotechnology, medical device and pharmaceutical companies.
You need full commitment – for best results – in every phase. FGK Clinical Research GmbH The Clinical Trial Optimizer FGK Clinical Research GmbH Heimeranstrasse 35 80339 Munich Germany 42-43_EBSIN5_12_Special_Covance_tg.indd 43
Dr. med. Edgar J. Fenzl T | +49 (0) 89 893 119-22 M | +49 (0) 172-673 8556 E | edgar.fenzl@fgk-cro.com
fgk-cro.com
Dipl.-Stat. Martin Krauss T | +49 (0) 89 893 119-25 M | +49 (0) 173-581 4683 E | martin.krauss@fgk-cro.com 26.04.2012 12:06:15 Uhr