The early career researcher’s toolkit: translating tissue engineering, regenerative medicine and cell therapy products Qasim A. Rafiq*† 1,2 , Ilida Ortega* 3 , Stuart I. Jenkins* 4 , Samantha L. Wilson* 5 , Asha K. Patel* 6,7 , Amanda Barnes* 8 , Christopher F. Adams* 4 , Derfogail Delcassian* 9,10 and David Smith* 1,11 1 Centre for Biological Engineering, Wolfson School of Mechanical and Manufacturing Engineering, Loughborough University, Leicestershire, LE11 3TU, United Kingdom. 2 Aston Medical Research Institute, School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, United Kingdom. 3 Bioengineering and Health Technologies Group, The School of Clinical Dentistry, University of Sheffield, S10 2TA, United Kingdom. 4 Institute for Science and Technology in Medicine, Keele University, Staffordshire, ST5 5BG, United Kingdom. 5 Academic Ophthalmology, Division of Clincial Neuroscience, Queen’s Medical Centre Campus, University of Nottingham, NG7 2UH, United Kingdom. 6 Wolfson Centre for Stem Cells, Tissue Engineering and Modeling, University of Nottingham, Nottingham, NG7 2RD, United Kingdom. 7 David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States. 8 Biomedical Tissue Research Group, University of York, YO10 5DD, United Kingdom. 9 Department of Materials, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom. 10 Drug Delivery and Tissue Engineering, Centre for Biological Sciences, School of Pharmacy, University of Nottingham, NG7 2UH, United Kingdom. 11 PCT, a Caladrius company, 4 Pearl Court, Suite C, Allendale, NJ 07401, United States. * All authors contributed equally to this work. †Author for correspondence. (Tel: +44-121 204 4895; E-mail: [email protected])
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The early career researcher’s toolkit: translating tissue
engineering, regenerative medicine and cell therapy products
Qasim A. Rafiq*†1,2, Ilida Ortega*3, Stuart I. Jenkins*4, Samantha L. Wilson*5, Asha K.
Patel*6,7, Amanda Barnes*8, Christopher F. Adams*4, Derfogail Delcassian*9,10 and
David Smith*1,11
1Centre for Biological Engineering, Wolfson School of Mechanical and Manufacturing Engineering, Loughborough
University, Leicestershire, LE11 3TU, United Kingdom.
2Aston Medical Research Institute, School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, B4
7ET, United Kingdom.
3Bioengineering and Health Technologies Group, The School of Clinical Dentistry, University of Sheffield, S10 2TA, United
Kingdom.
4Institute for Science and Technology in Medicine, Keele University, Staffordshire, ST5 5BG, United Kingdom.
5Academic Ophthalmology, Division of Clincial Neuroscience, Queen’s Medical Centre Campus, University of Nottingham,
NG7 2UH, United Kingdom.
6Wolfson Centre for Stem Cells, Tissue Engineering and Modeling, University of Nottingham, Nottingham, NG7 2RD, United
Kingdom.
7David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
02139, United States.
8Biomedical Tissue Research Group, University of York, YO10 5DD, United Kingdom.
9Department of Materials, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom.
10Drug Delivery and Tissue Engineering, Centre for Biological Sciences, School of Pharmacy, University of Nottingham, NG7
2UH, United Kingdom.
11 PCT, a Caladrius company, 4 Pearl Court, Suite C, Allendale, NJ 07401, United States.
* All authors contributed equally to this work.
†Author for correspondence. (Tel: +44-121 204 4895; E-mail: [email protected])
Successful project management (described in Section 1) should allow ECRs to identify, liaise
and engage with appropriate bodies to develop a translational pathway. This may involve
forming a ‘spin out’ or joint venture, which allows the inventor to retain some control over IP
commercialization. Alternatively, IP can be sold or licenced to third parties through technology
licencing agreements; however, the inventor’s involvement usually ends here. Building a
personal network with those in relevant fields will enable both the development of one’s
reputation and allow for the identification of collaborators who can aid translation. Forming
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collaborations with those experienced in scale up, automation or other manufacturing issues
can help accelerate the transition to market. Importantly, national and international consortia
facilitating translation from research concept to commercialisation through collaborations are
becoming more common, providing straightforward access to a range of expertise [58, 59].
6.3 Leverage funding
Funding will be required throughout stages of the translation process (Figure 3). Research
councils and charities commonly fund proof-of-concept research, but have varying eligibility
regarding funds for later stage commercialisation such as Phase I through Phase III trials [60].
Instead, alternative funding sources such as business angels, key opinion leaders or
commercialisation seed funding schemes can be accessed for support (Table 3). Eligibility
criteria for these highly competitive schemes vary, often requiring matched funding from an
industrial collaborator (which can be limited to small/medium enterprises, SMEs), but funders
may offer additional support during the application process and post-award. Preparing bids is
time-consuming, so try to get early notice via automated notifications/alerts (e.g. Google alerts,
mailing lists) and leverage collaborators’ knowledge of funding trends and requirements to
save both time and money.
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Conclusion
Having strategically designed the concept with clinical relevance, manufacturing and
regulatory hurdles in mind, validated the scientific worth, protected the idea, and sourced
appropriate funding and collaborators, translation into a commercial product is feasible.
Although navigating through the translational landscape may seem daunting, we suggest that
ECRs can increase their chances of success by tactically planning their research to address
these common pitfalls early, minimising the chances of having to reiterate a design step later
on in the commercialisation process.
Future perspective
Clinical and commercial failures in recent years have reinforced the need for the translation of
TERM therapies. The industry is therefore entering a critical phase which can no longer rely
on potential, but is expected to deliver efficacious, cost-effective products. Whilst this presents
a significant challenge, the TERM industry is ideally positioned to capitalise on recent clinical
success (e.g. T-cell immunotherapy) amidst a backdrop of renewed government/state
investment (e.g. Cell Therapy Catapult, Centre for Commercialization of Regenerative
Medicine). What imbues the greatest confidence of success, however, is the emergence of a
generation of highly trained, committed, translationally-focussed ECRs.
Although faced with an uncertain regulatory/reimbursement landscape and complex
scientific/technical obstacles, global recognition of the importance of translation will ensure
that translational ECRs are given the appropriate authority to play a central role in the
realisation of TERM therapies. We believe translational ECRs will rise to the challenge,
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learning from mistakes of the past, adopting best practices from closely aligned industries and
developing innovative solutions to TERM-specific issues in a pre-competitive environment.
Executive summary
As translational ECRs in TERM, we have come to realise that the process of translation can be
intricate, exceptionally resource consuming and prone to hidden obstacles. We have therefore
compiled ‘tips and tricks’, based on our own experience and research that facilitate translation
and will improve the chances of successful product development.
Manage the research effectively
Utilise project management tools and divide the research into work packages with clear
milestones and deliverables. Effective research management also includes day-to-day
planning, mapping out the experimental process and identifying high risk areas and
ways of mitigating these.
Ensure the data are scientifically robust
Experiments in TERM are resource heavy. Take time and care in planning experiments
and implement systematic methods such as Design of Experiments. Source raw
materials carefully and ensure that the principles of any technology, assay or technique
are well understood to ensure maximum output of reliable and robust data.
Ensure the work has clinical relevance
To increase chances of clinical and commercial success, research should be aligned
with appropriate clinical pull, and where possible developed as platform technologies.
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In addition, many current assays are unreliable, or unsuitable for testing TERM
therapies, but these shortcomings provide rich opportunities for the development of
new, TERM-relevant models with genuine predictive utility.
Understand the regulations
Identify early on in the research programme the regulatory classification of the potential
product to provide a framework of standards which can be referred to. Build compliance
of regulatory standards into the process, and when necessary, be prepared to engage
and inform the regulator.
Understand the implications for manufacture
Relevant functional metrics, with associated tolerances, need to be identified and
quantified to improve process and product understanding. The pursuit of consistency in
manufacture is paramount and efforts must be made to avoid or minimise sources of
variation. Scalability should be considered from the outset with a focus not only on the
technical challenges but also cost of goods and supply chain issues associated with
scaled production.
Commercialise the research
IP protection is generally necessary to demonstrate commercial value. Effective
partnerships and collaborations will accelerate commercialisation and de-risk the
venture for potential investors and funders to invest. Develop an effective funding
strategy, stratifying funding sources if necessary and leveraging funds from one source
with another.
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Acknowledgements
The authors would like to thank Professors David Williams (Loughborough University, UK)
and John Fisher (University of Leeds, UK) for their guidance and direction in the preparation
of this manuscript.
Financial & competing interests disclosure
The authors would like to acknowledge the support of the Engineering and Physical Sciences
Research Council for the funding of the Engineering, Tissue Engineering and Regenerative
Medicine (E-TERM) Landscape Fellowship programme, which involves a partnership of
Loughborough, Leeds, Sheffield, Keele, Nottingham and York Universities. All authors, with
the exception of Dr David Smith are current E-TERM Fellows or E-TERM alumni. Dr David
Smith is a Biomedical Engineer at PCT (a Caladrius Company). The authors have no other
relevant affiliations or financial involvement with any organization or entity with a financial
interest in or financial conflict with the subject matter discussed in the manuscript apart from
those disclosed. No writing assistance was utilized in the production of this manuscript.
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Reference annotations
* Lowenstein PR, Castro MG. Uncertainty in the translation of preclinical experiments to clinical trials.
Why do most phase iii clinical trials fail? Curr. Gene Ther. 9(5), 368-374 (2009).
An easily-digestible survey of why clinical failures occur, with an important rallying call for ‘preclinical
robustness’.
* Weinstein MC, Torrance G, Mcguire A. Qalys: The basics. Value Health 12, S5-S9 (2009).
A review of the concept of quality-adjusted life year, its evolution and the proposal of alternative
conceptual models for measuring health and cost-effectiveness.
* Varga OE, Hansen AK, Sandoe P, Olsson IA. Validating animal models for preclinical research: A
scientific and ethical discussion. Alternatives to laboratory animals : ATLA 38(3), 245-248 (2010).
A comprehensive overview of the urgent need for, and a proposed route towards, preclinical model
validation.
* Bravery CA, Carmen J, Fong T et al. Potency assay development for cellular therapy products: An
ISCT review of the requirements and experiences in the industry. Cytotherapy 15(1), 9-19 (2013).
A comprehensive review of the requirements for defining and measuring the quality of cellular products,