EBioMedicine 7 (2016) 4–6

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EBioMedicine

journal homepage: www.ebiomedicine.com

In Focus

The Need for Predictive, Prognostic, Objective and Complementary

Anne-C. Bay-Jensen a, Yves Henrotin b,c, Morten Karsdal a,d, Ali Mobasheri e,f,g,h,i,⁎,1
a
Rheumatology, Biomarkers and Research, Nordic Bioscience, Herlev, Denmark
b
Bone and Cartilage Research Unit, Arthropôle Liège, University of Liège, Institute of Pathology, Liège, Belgium
c
Physical Therapy and Rehabilitation Department, Princess Paola Hospital, Marche-en-Famenne, Belgium
d
Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, United Kingdom
e
Department of Cancer and Inflammation Research, University of Southern Denmark, Copenhagen, Denmark
f
Arthritis Research UK Centre for Sport, Exercise and Osteoarthritis, Queen's Medical Centre, Nottingham, United Kingdom
g
Center of Excellence in Genomic Medicine Research (CEGMR), King Fahd Medical Research Center (KFMRC), King Abdul Aziz University, Jeddah, Saudi Arabia
h
Arthritis Research UK Pain Centre, Queen's Medical Centre, Nottingham, United Kingdom
i
Medical Research Council and Arthritis Research UK Centre for Musculoskeletal Ageing Research, Queen's Medical Centre, Nottingham, United Kingdom

Osteoarthritis (OA) has traditionally been viewed as a non- and characterization of the individual patient will adversely influence
inflammatory arthropathy and has not been considered a ‘serious dis- healthcare management and the recruitment of the right patient co-
ease’. However, this view has radically changed in recent years, due to horts for the testing of drugs in clinical trials. There is a medical need
the complexity and heterogeneity of the patient populations, spiralling for objective, precise and accurate in vitro diagnostic devices for clinical
socio-economical costs and long-term impact on the quality of life of af- trial enrichment (Kraus et al., 2015; Karsdal et al., 2013).
fected individuals. There is an acute need for objective and non-invasive
diagnostic biomarkers in OA, markers that can stratify patient subtypes
and thereby direct therapeutic treatments at an earlier disease stage 2. What Is the Medical Need for Biomarkers?
(read personal health care (PHC)) (Conaghan, 2013). Increased interest
in the development of new diagnostic and prognostic tests for early The lack of approved DMOADs in OA drags a long tail of failed clinical
forms of OA may incorporate the use of blood-based biomarkers; how- drug trials. Recently the US Food and Drug Administration (FDA), the
ever, both research and regulated development and approval are still European Medicines Agency (EMA) and other regulatory agencies
needed to reach a diagnostically important significant point where a have published guidelines on how biomarkers should be defined. Differ-
given biomarker will benefit the clinical management of the patient. ent groups and public-private partnerships have proposed different
models for classifying OA biomarkers for clinical use (Bauer et al.,
2006; Kraus et al., 2011; Bay-Jensen et al., 2016a,b). There is a general
1. The OA Biomarker Landscape Today consensus on the medical need for biomarker development which
may be summarized as seven key points:
There are currently no disease-modifying osteoarthritis drugs
(DMOAD) available for treatment of OA patients (Mobasheri, 2013;
1. Translational biomarkers, which allow better characterization of a
Qvist et al., 2008). This may be due to the heterogeneity of the OA pop- drug in preclinical development, ensuring of selection of the most
ulation, where the origin and driver of disease progression is often poor-
viable projects
ly understood. The main treatment options for OA presently are pain
relief, physical therapy and nutritional supplements (nutraceuticals). 2. Early identification of efficacy of intervention; Go/no-go decision-
However, none of these can halt or reverse disease progression. In addi- making already in phase 1b/2a studies, which normally do not
tion, diagnosis is often subjective, due to the lack of objective, precise include efficacy measures.
and accurate diagnostic devices. Thus the limited clinical diagnosis 3. Phase II and Phase III trial enrichment; reduction in study size, and a
particular OA phenotype tailored for a selective interventions, which
⁎ Corresponding author at: Faculty of Health and Medical Sciences, University of Surrey, will recuse length of the clinical study to allow more efficient and less
Guildford, Surrey GU2 7XH, United Kingdom. costly trials
E-mail addresses: [email protected] (A.-C. Bay-Jensen), [email protected] 4. Identification of patients who are fast progressors and as such in
(Y. Henrotin), [email protected] (M. Karsdal), [email protected]
(A. Mobasheri).
greatest need of treatment.
1
The authors are members of the D-BOARDhttp://www.d-board.eu/dboard/index.aspx 5. Identification of super responders to a specific treatment; patients
and APPROACHhttp://www.approachproject.eu European Commission funded consortia. with high efficacy and low safety concerns

http://dx.doi.org/10.1016/j.ebiom.2016.05.004
2352-3964/© 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 A.-C. Bay-Jensen et al. / EBioMedicine 7 (2016) 4–6 5

6. Biomarkers of disease activity; as OA is not a stabile disease, there is a (LDT) (Sarata and Johnson, 2014), which is a type of in vitro diagnostic
need for devices for identification with high disease activity and test that is designed, manufactured and used within a single laboratory.
potential progression
7. Easy accessible monitoring devices – point of care; post marketing 4. How Do We Move Forward?
patient care and personalized medicine
Different approaches, techniques and better-stratified patient
Although there are clear overlaps in the above, it is clear that no samples are needed to move biomarker development towards qualifica-
single biomarker will be the answer for all. tion, which means that new partners need to come together and
collaborate. For example development of a novel blood-based and
3. Message From the Regulators cartilage-derived protein biomarker requires application of advanced
analytical techniques such as proteomics and mass spectrometry,
The public attention to biomarkers is increasing, recently further whereas development of the biomarker assay requires knowhow of
emphasized by the “white house” initiate focusing on quantifiable biochemical and immunological assessment platforms. Furthermore,
tools for patient election and monitoring.2 On the regulatory side, the testing, validation and qualification requires access to high quality
FDA issued a position document describing the need and road ahead clinical samples from several independent retrospective or prospective
for personalized medicine “FDA: Paving the Way for Personalized cohorts. In the end a commercialisation plan needs to be established
Medicine”,3 which later resulted in new guidelines to faster biomarker to push forwards and finance the qualification of biomarkers. Thus it is
tool development by the guidelines “Identifying Potential Biomarkers most likely that no single entity, public or private, will be able to
for Qualification and Describing Contexts of Use To Address Areas complete these development steps alone. There is a need for
Important to Drug Development”,4 which are in addition to the i) Formation of public-private partnerships to develop, test, validate
standard guidelines for in vitro companion diagnostic device. This has and qualify biomarkers for use in clinical trial and patient management,
led to the discussion on prospective-retrospective biomarker analysis ii) Design of clinical studies that stratify patients and investigate trends
for regulatory consideration, by the white paper from the industry and characteristics of specific OA cohorts and study populations, and iii)
pharmacogenomics working group (Patterson et al., 2011). This will Collaboration between biotech and pharmaceutical companies to
greatly assist precision medicine and PHC by guiding the discussion on support the commercialization of biomarkers.
how to implement a “prospective-retrospective biomarker analysis”. In summary, a great deal of collaborative work needs to be done in
The prospective-retrospective biomarker analysis approach is this area to develop more predictive, prognostic, objective and comple-
developed to “rescue” failed phase III trials. Qualified biomarkers are mentary biomarkers for OA management and DMOAD development.
to be measured in certified, high-quality laboratories and analyzed
using predefined statistical analysis plans to test hypotheses related to Conflict of Interest Statement
retrospective analysis of technically and biologically validated
biomarkers. The authors wrote this paper within the scope of their research
According to the FDA, a prognostic in vitro diagnostic biomarker positions. The authors declare no conflict of interests.
would need a 510 K or de novo approval (class II device), whereas a
predictive biomarker would need ldt pre-market approval (PMA, class
Competing Interests
III device). The main separating factor is that a prognostic biomarker
provides you with an estimate for progression, whereas a predictive
The authors declare no competing interests.
biomarker would be used to decide the exact treatment regimen for
individual patients, and would therefore have a significant impact on
the patient's life. A predictive biomarker will often become a companion Funding Sources
diagnostic.5 In addition, the recent “drug development tool (DDT) box”
guidelines are also allowing for regulatory assessment of tools to assist A-C B-J and MK are employees of Nordic Bioscience. The authors are
in clinical drug development, such as the fibrinogen enrichment of members of the D-BOARD Consortium funded by European Commission
patients in COPD clinical studies with a more severe outcome (fast Framework 7 programme (EU FP7; HEALTH.2012.2.4.5-2, project
progressors), which is now classified as a DDT. number 305815, Novel Diagnostics and Biomarkers for Early Identifica-
No biomarkers have yet been qualified as biomarkers for OA, tion of Chronic Inflammatory Joint Diseases). AM is co-ordinator of the
however several biomarkers have been developed targeting cartilage D-BOARD Consortium and member of the Arthritis Research UK Centre
degradation and formation (e.g. CTX-II, ARGS, PIIANP), joint for Sport, Exercise, and Osteoarthritis, funded by Arthritis Research UK
inflammation (e.g. C3M, Col2-NO2), bone remodelling (e.g. alpha (Grant Reference: 20194). AM has received funding from the Deanship
CTX\\I, osteocalcin) as well as inflammation and metabolic factors of Scientific Research (DSR), King Abdulaziz University (grant no. 1-
(Bay-Jensen et al., 2016a,b). The scientists and clinicians working in 141/1434 HiCi). The authors are also members of the Applied Public-
the biomarker field cannot expect a “one size fits all” solution for OA. Private Research enabling OsteoArthritis Clinical Headway (AP-
Consequently it is important to test and validate a biomarker to a specif- PROACH) Consortium6, a 5-year project funded by the European
ic hypothesis. This can be done under the laboratory-developed test Commission's Innovative Medicines Initiative (IMI). APPROACH is a
public-private partnership directed towards osteoarthritis biomarker
2
The White house, 2015. Precision Medicine Initiative | The White House [WWW Doc- development through the establishment of a heavily phenotyped and
ument]. White house. URL https://www.whitehouse.gov/precision-medicine (accessed comprehensively analyzed longitudinal cohort. The research leading
2.5.16). to these results has received partial support from the Innovative
3
FDA, 2013. Paving the Way for Personalized Medicine [WWW Document]. URL http://
Medicines Initiative (IMI) Joint Undertaking under grant agreement
www.fda.gov/downloads/ScienceResearch/SpecialTopics/PersonalizedMedicine/
UCM372421.pdf (accessed 2.5.16).
no. 115770, resources of which are composed of financial contribution
4
FDA, 2015. Identifying Potential Biomarkers for Qualification and Describing Contexts from the European Union's Seventh Framework programme (FP7/
of Use To Address Areas Important to Drug Development; Request for Comments [WWW 2007-2013) and EFPIA companies' in kind contribution. YH is the
Document]. FDA. URL https://www.federalregister.gov/articles/2015/02/13/2015-02976/ Founder, Chairman of the Board, and President at Artialis SA (http://
identifying-potential-biomarkers-for-qualification-and-describing-contexts-of-use-to-
www.artialis.com). He is also the founder and the Chairman of the
address-areas (accessed 2.5.16)
5
FDA, 2014. In Vitro Companion Diagnostic Devices. Guidance for Industry and Food
6
and Drug Administration Staff. http://www.approachproject.eu
6 A.-C. Bay-Jensen et al. / EBioMedicine 7 (2016) 4–6

Board of the spin-off company of the University of Liège Synolyne Karsdal, M.A., Christiansen, C., Ladel, C., Henriksen, K., VB, K., AC, B.-J., 2013. Osteoarthritis —
a case for personalized health care? Osteoarthr. Cartil.
Pharma SA (http://synolyne-pharma.com), a company developing Kraus, V.B., Blanco, F.J., Englund, M., Karsdal, M.A., Lohmander, L.S., 2015. Call for
medical device for the joint viscosupplementation and tissue repair. standardized definitions of osteoarthritis and risk stratification for clinical trials and
clinical use. Osteoarthr. Cartil.
Kraus, V.B., Burnett, B., Coindreau, J., Cottrell, S., Eyre, D., Gendreau, M., Gardiner, J.,
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