I thought it may be useful to circulate to my network a summary of some of the key messages that have arisen out of four recent One Nucleus events that have taken place of late for your perusal. The summaries relate to the following

14th April 2016 One Nucleus Leadership Breakfast with Penningtons Manches 

Title: Clinical Trials: Minimising Liability and Maximising Intellectual Property

The breakfast had good representation from the drug development value chain including which led to interesting discussions and wide coverage of the topic. The key messages are captured in the May 2016 ON Insight paper that followed.

 22nd June 2016 M11 Health Enterprise Forum, hosted by Harlow Council

Title: The Smoke and Mirrors Of Risk Assessment

Framed by speakers from Public Health England and BioReliance, the session discussed how safety of new chemical or biological entities are assessed, interpreted and communicated.

The speaker presentations will be available HERE in due course:

Looking at the modified mosquito scenario:

• The PHEIC has declared a number of emergencies in the not too distant past such as Swine Flu (2009), Polio and Ebola (2014) and Zika (2016). This last one was confirmed even before the CDC had confirmed the link to microcephaly.
• A historical example of not communicating the risks and benefits well enough to the media can be seen when a journalist reporting from India essentially led to Mrs Gandhi cancelling a programme to introduce modified Culex mosquitoes, which were a biting nuisance around Delhi and a vector of Filariasis in other parts of India.
• Risk posed by Anopheles mosquitoes was also underestimated in the 1960’s due to the faith in DDT’s ability to eradicate malaria, a disease we are still battling after 55 years.
• Did regulators, public servants and journalists truly understand what was proposed and was the enemy (disease spreading mosquito species) underestimated?
• Looking more in depth at the risks versus benefits, we have to appreciate there are different types of modified mosquito technologies: (i) transgenic vs paratransgenic vs mutant mosquitoes; (ii) self-propagating compared to self-limiting; (iii) release of non-biting males versus biting females in certain cases.
• Noted that depending on the disease and which species of mosquito carry it, we cannot assume it is a night time problem or can always solved by mosquito net, or solely by getting rid of breeding sites. For example, just two female Aedes mosquitoes emerging a day in an apartment block of a large city could be sufficient to spread Chikungunya, Dengue, Zika, etc. and it is worth noting these mosquitoes bite during the day.

Looking at the pre-clinical assessment of toxicology:

• BioReliance perform a battery of tests for clients across multiple sectors to check if a new chemical entity is a potential carcinogenic risk.
• 80% of NCEs fail, but that doesn’t mean that product cannot be developed and used, it is an assessment. The tests are designed to give positives that triggers further study
• Different industries though have different regulations, so this can determine the impact of an NCE failing a test
• Notable example of late is the assessment of e-cigarettes and the regulation around adding flavours. Terminology of an added flavour must not make the product more harmful may be interpreted as suggesting there is an underlying risk inherent within that product. But little or no regulation of that sector allows progression of that and next generation products.
• Latterly, far from establishing simple thresholds of predicted toxicity from the tests, there is a new concept called ‘Point of Departure’ and defining this in a context of predictive toxicology provides yet more complication.

In summary:

• Perception of risk is a multi-factorial phenomenon and influenced by one’s feeling of responsibility to protect others. A ‘do no harm’ approach can prevail and hinder uptake of innovative solutions, and maintaining ‘status quo’ may not be the best option.
• Regulation in different industrial sectors leads to inconsistencies in how substances are assessed.
• Communication of the risks and benefits of a new product is key to progress. Poor communication between innovators and policymakers (or those that influence policymakers such as media) can lead to a no win scenario for companies, Governments, healthcare providers or ultimately patients.
• Degrees of risk is a challenging concept to communicate to a lay audience, so translation of that technical concept into simple guidance is key.
• As technologies to assess risk have progressed, the sophistication with which we can measure degrees of risk increases, but perhaps our ability to communicate has not.

6th July 2016 BioWednesday, hosted by LBIC, sponsored by Penningtons Manches, Hamilton and Bio-Analysis Centre

Title: Academic – Industry Collaboration: A 2-Way Validation Before Investing in Development

The panel discussion focussed around the factors that contribute to the reproducibility, or lack of, in early stage research findings. The key points addressed were as follows: 

• Experimental Design – the rigour required for effective design of experiments in order to provide a robust output can be lacking in research labs. This is likely due to a combination of factors that includes the appropriate teaching of experimental design, lack of resource/time for senior academic group leaders to spend in the lab supervising their charges due to other pressures and a lack of thorough understanding of statistics
• Statistics – statisticians are much more involved in the industry-based research than in academic labs where often it the use of a formula by a researcher to achieve ‘significance’ that assists in getting a paper published perhaps, yet is that statistical relevance actually meaningful – eg “Is the correct test system being used for the question being asked?” and “are all variables being suitably controlled for?” may be questions not addressed by reviewers. Statisticians play a much more integral role in the industry labs and that enhances the experimental design quality.
• Publication and Peer Review – The bias of journals to publish positive rather than negative results hinders knowledge sharing and allowing others to learn from a third party’s experiments (not mistakes, just negative results). It is accepted that peer review is not perfect for reasons that include securing the right reviewers, the time reviewers have  and sometimes the lack of popularity if a reviewer if they ask to see raw data to check the provisional paper’s findings. Even with seeing the raw data however, the reviewer (or supervisor of a student) can still be uncertain of some impactful factors, such as was the temperature sufficiently controlled when doing the study. There isn’t a better system to peer review that is obvious however.
• Teaching Best Practice – Whether industry should be more involved in teaching experimental design to academic researchers and would this enhance the reproducibility of the research findings is one question perhaps. There may be inherent limitations that include: (i) resource related in that whether industry would support such training by its R&D staff which may be indirectly rather than directly beneficial; (ii) would academic researchers welcome it when their focus is on securing publications (in the current system) often meaning submitting to other journals if the first one says no and hence content with their ‘statistical significance’ findings; and (iii) where in the process should experimental design training begin and who should pay for it
• Third Party Validation – It has been mooted in a number of quarters that third party validation of results should become a requirement before publication or subsequent grant funding to the programme under question. Whilst contract research labs would welcome such a role and business for sure, it again comes back to who would pay and who would select the appropriate third party to do the study. You may run into the same issues of potential bias or conflict of interest seen in the current peer review process
• Co-Working – Perhaps the transfer of rigour from industry to academia and the reverse flow of knowledge and insight in disease pathologies from academia to industry is best achieved through collaboration and even co-location of researchers such as the GSK-Crick Institute’ MedImmune-CRUK and Janssen-University of Edinburgh collaborations where at the very earliest stages experiments are geared to answer questions industry feel are relevant, academia get access to industry resources to answer those questions and, above all, collective learning occurs between experts in the field. Perhaps such initiatives are the mechanism to address the reproducibility of early stage research findings
• Translation – The closing thought I left with was how do we reconcile not just reproducibility but then the ability to translate those findings into advances in treatment. ‘Translatability’ vs ‘Reproducibility’ which perhaps is a reflection that the experimental design needs to ensure that the appropriate questions are being addressed in the correct models and then delivered in a robust manner that builds confidence to take the findings forward.

13th July 2016 One Nucleus Leadership Seminar with TranScrip

Title: Evolving Risk Management Requirements in Early Development

Supervision of early phase studies is critical and is more than ever to ‘front of mind’ for regulators and investors. Focus on safety in such studies will initiate closer scrutiny of sponsors – particularly small, start-up entities whose infrastructure and personnel may fall short of the oversight requirements of the major regulatory agencies. Outsourcing to a CRO is often a preferred option to ensure studies follow protocols. CROs are well aware of regulatory changes, but sponsors have the ultimate responsibility and should know how to meet regulatory standards. The event offered a good review and insights to what is changing in this area, and provided guidance as to how small companies can be ready – without breaking the bank. The key messages are captured in the July 2016 ON Insight paper that followed.