Interview with Simon Hoffman, Regulatory Consultant. 

On the 29th of September 2022, the U.S. Senate unanimously passed Bill S. 5002, the “FDA Modernization Act 2.0.” with the headline of removing the requirement of in vivo studies in favor of cell-based assays and computer models. This signaled clear intent from the FDA to address the growing need for better pre-clinical models for drug discovery, to close the translational gap, and to reduce the 90% drug attrition rate. 

And the Biopharma industry responded almost immediately. Our market research has indicated that 75% of respondents are increasing iPSC investment in 2023, while 34% are actively reducing their in vivo model usage. Over half of our respondents cited the Act as a key driver behind the industry transition. 

From patients demanding more effective and safer drugs to Biopharma looking to de-risk their development programs, this was big news and opened the gates to investing in better models of human disease in vitro and in silico. 

But beyond the punchline, what does it mean to the Regulatory undertaking of pharmaceutical companies? What does it change? 

We caught up with Simon Hoffman, Principle Quality Assurance & Regulatory Consultant to hear what he thought of the FDA Modernization Act 2.0 and how it will impact drug discovery. 

Q Thanks for your time, Simon. Let’s start at the top: what is the FDA Modernization Act 2.0? 

This bill authorizes the use of certain alternatives to animal testing, including cell-based assays and computer models, to obtain an exemption from the Food and Drug Administration to investigate the safety and effectiveness of a drug.  

The bill has been passed by the Senate to end animal testing mandates. 

Q What does the Act change?  

In straightforward terms, the act removes the necessity to utilize animal studies to prove the safety and efficacy of a medicinal substance. However, it should duly be noted that the act effectively details an alternative, not a complete replacement. It effectively allows certain animal testing alternatives, including cell-based assays and computer models. It is not mandating that animal testing will, or indeed necessarily should, be replaced – it is more effectively ending the mandating of animal testing.  

However, it is probably just as vital to note what the act does not change. It is still an absolute necessity to objectively verify the safety and efficacy of medicinal products to the same statistically proven degree. I therefore cannot stress enough, from a safety and efficacy perspective, the act is by no means a “shortcut”.  

Indeed, based on many years of experience and monitoring the approach to FDA inspections, the introduction of a new guidance document or bill often leads to enhanced scrutiny and assertion of regulatory requirements – the FDA are often under the microscope themselves. Add this to the recent publicity of the Covid-19 pandemic, and the whole world literally hanging on daily updates relating to clinical trials and the like, the scrutiny is only like to increase, which goes hand-in-hand with increasing standards and demands. 

Q What does it mean to pharmaceutical companies in terms of changing their processes? 

There are numerous implications and considerations for pharmaceutical companies and change is, realistically, inevitable; those who embrace the change will thrive. Put simply, in an increasingly socially aware and ethical world (not to mention an increasingly socially connected world), there will likely only be increasing pressure to utilize any, if not ALL, potential alternatives to animal testing.  

It has been justified for decades, if not centuries, that animal testing is a “necessary evil” in the launch of lifesaving treatments. Put in blunt terms, the welfare of mankind has been put before the welfare of the animal kingdom. Thus, if there is ANY alternative to animal testing available, there is an increasing, ethical, cultural, and political pressure to utilize it. The day when the majority will consider the “necessary evil” justification as completely unacceptable is possibly, if not, probably closer than we think – this is increasingly not just the position of radical groups such as the ALF.  

It should also be noted that 20 years ago, I only had to field ethically challenging questions relating to clinical trials on an isolated, rare basis, mostly from people within the healthcare industry; in this new social media-obsessed and, supposedly socially conscious world, I am facing daily questions on the ethics of clinical trials and indeed bio-pharma treatments on a daily (and sometimes hourly) basis.  

Pharmaceutical companies also need to be thinking of implementing processes that will permit the determination/selection, implementation, and validation of alternative methods. It will also have to be duly considered that they may be “pioneers” who are using certain methods for the first time, or at least part of the initial pioneering groups. The level of scrutiny of the justification for method utilization will be significantly high, particularly when considering the aforementioned increased FDA sensitivity and inevitable political awareness and pressure. It is also worth noting that animal testing methods have been around for centuries and some of the more recent alternatives are both new and, indeed, incredibly complex. 

Due consideration should also be afforded to the different skill sets required. For instance, somewhat contrasting skill sets are required for animal testing and computer models – one may need more IT experts rather than pharmacologists, molecular biologists, and the like!  

Q Does it change the way Biopharma approaches the Quality aspects of in vitro models?

When considering the reasons outlined above, then yes, diversification and embracing of change is required, put simply, due to the potential diversification of alternative methods. However, the basic premise that all methods utilized must be fully justified or indeed validated still prevails. One must also consider the ever-increasing standards and scrutiny in validation and the need to prove statistically justified and quantified consistency. Even when not considering the computerized model alternative methods, and considering the more traditional in vitro methods, there is still a need to bring in the number crunchers! Numerical quantification is becoming all the more prevalent. Again, the aforementioned method’s complexity adds another challenge! 

Also, on the aforementioned theme of “necessary evil”, in vitro methods are often considered the “lesser of two evils” when compared to in vivo animal studies. This, along with a multitude of other ethical and indeed practical, and financial reasons, will likely lead to an inevitable increase in in vitro method utilization. This effectively is, again, a formula for increased scrutiny and indeed increased standards – put simply, the more people who are practicing, the higher the level of overall expertise! Practical standards and thus regulatory expectations will likely rise, simultaneously hand-in-hand. 

Q Are there Regulatory structures already in place for companies looking to further utilize in vitro or in silico methods? 

There are certainly more direct regulatory structures in place for in vitro methods than for in silico methods. Traditionally (and one may point out that there is insufficient history to utilize said term) “in silico” is a somewhat modern phrase typically to denote experimentation “performed” by computer/computerized means/system and is indeed related to the more widely (at least until now) used biological and pharmacological term in vitro and indeed in vivo.  

The limited history of the “in silico” term is poorly defined and widely contested by diverse researchers all claiming their role in its origin. Ironically, much as the history and claims associated with in silico methods vary somewhat, inconsistencies exist in the regulatory frameworks that are applied, particularly when considering their application. Indeed, as a veteran of dozens of FDA inspections, I have never seen the same approach twice! I also see even the most experienced inspectors and auditors finding their comfortable place regarding regulations to fall back on. Guidance, rather than full-blown codes of federal regulations (CFRs) are filtering in: for instance, in November 2022, the FDA published a new report “Successes and Opportunities in Modelling and Simulation for FDA” but I am still experiencing 21 CFR part 11, and GAMP 5 being cited more than anything in silico specific. At best, it is a growing and far from well-established area. 

Q Does it only apply in the US? Is there an equivalent in the EU and Asia? 

When I first acquired my Home Office License way back in 1996 at Liverpool University, the first lecture I sat through was not conducted by a Veterinary Surgeon, pharmacologist, zoologist, or indeed even a traditional medical professional or scientist, it was a Professor of Philosophy and Ethics who made it very clear that my absolute priority, or indeed the priority of anybody undertaking or having any involvement in animal testing, should be to only utilize animal testing if there is absolutely no alternative and indeed if it really was a “matter of life or death”.  

The next lecture centered around the cornerstone of the Home Office License – “The 3Rs alternatives” – the replacement, reduction, and refinement of animals used in research and testing, and also teaching and exhibition, as first described in 1959 by Dr. William Russell and Dr. Rex Burch. To put it bluntly, Europe has been onto the need to replace animal testing for years. 

However, it has been a slow process in regulating and pushing forward the replacement of animal testing. Indeed, the first directive (note: not regulation) for the protection of animals in the scientific field was eventually adopted nearly 30 years later in 1986 and was replaced by Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes. More recently, Regulation (EU) 2019/1010 introduced a new level of transparency and pushed animal testing replacement more to the forefront of the Biopharmaceutical industry, to help progress towards the eventual replacement of animal use in science. The amendments have been incorporated into the now-consolidated text of the Directive. The 60-year timeframe from first coining the phrase “The 3Rs alternatives” to some actual regulation may be attributed to a lack of suitable alternatives, the need for technological advancement but most of all, bureaucracy and red tape! 

In terms of Asia, animal testing ethics and driving forward the replacement of animal testing is very much varied. In terms of ethics in animal experimentation, advanced countries (for instance, Japan and South Korea) have adopted the 3R principles of humane experimental technique first espoused by Russell and Burch in 1959. For instance, in 1985, the 3Rs were translated into 11 basic principles by the Council of International Organizations for Medical Sciences (CIOMS). These items have become international principles that govern animal experimentation. 

China is slowly also coming to the table, with new laws coming into force from circa 2021. Although one can find more evidence of cosmetic animal testing replacement, Biopharma is sure to follow. 

Q Do you expect an increase in investment for in vitro models?

Based on the reasons outlined previously, I expect an exponential increase in investment in in vitro models! In a nutshell, there is an enormous ethical benefit but financial benefit is, realistically, the overriding motivation that will prevail! 

Q How should companies approach patient selection/stratification from a quality perspective? 

The days of using whatever healthy volunteers (or indeed unhealthy volunteers, if for a specific disease) you can and then pulling together a justification based on however many are available are long gone. Sample size justification is now required upfront (and realistically this has long been the case). A much more objective and quantifiable approach based on recognized statistical methods is both expected and indeed scrutinized.   

It should also be fully appreciated that the clinical evaluation is now not simply a one-off project at the outset of a product launch- it is now an ongoing cycle that continues long after the product is fully launched into the clinical and commercial environment. Ongoing post-market surveillance, pharmacovigilance, and risk management continue the “live” continuous clinical evaluation of all Biopharmaceutical products through their entire lifecycle. Again, patient selection and stratification is also subject to exponentially increased regulatory scrutiny and not a simple inspection and audit afterthought or tick box exercise. Inspectors are scrutinizing to the statistically-based Nth degree! 

Q Our cells are manufactured under ISO 9001:2015 procedures – how important is that for linking in with a Biopharma’s quality process? 

Firstly, ISO 9001, and especially the 2015 edition, should not be underestimated or seen as the “easy route” to independently-verified quality. Following the increased requirements and standards pertaining to Risk Management as detailed in the updated 2015 vs 2008 edition of ISO 9001 is the key to success in this regard.  

Taking a step back, ISO 9001 does provide an excellent foundation and framework for a company-especially a healthcare company- to build and enhance its quality management system upon. Applying the principles contained within ISO 9001, Axol’s processes should be fully mapped out and all process outputs of Axol, and relevant client process inputs, fully linked and visually represented i.e., get round the table and map out the entire Axol/client process lifecycle. This will permit a full identification of all the risks of the combined Axol/client processes and full risk scoring, identification of risk mitigation, and ongoing risk-based management of the overall integrated processes and lifecycles. All practical, technical, and compliance/regulatory risks (and indeed any pertinent risks) can be fully identified in a proactive manner. This also permits the means to generate a live, risk-based approach to managing projects through the entire R&D to commercialization lifecycle.  

So, in terms of how important ISO 9001 is for linking in with a Biopharma client’s quality process, the guidance provided in ISO 9001 (when applied according to the principles within) highlights the means to implement what is absolutely vital for linking together suppliers and Biopharma processes. In other words, utilize ISO 9001’s potential rather than simply tick its boxes for certification! 

Q What should Biopharma companies be asking suppliers of human iPSCs in terms of quality and characterization? 

First of all, it should be ensured that the receipt of a human iPSC at a Biopharma company is the first verification of assured quality in the overall supplier/Biopharma lifecycle. This is why the overall process between supplier and Biopharma company should be fully mapped out, understood, mitigated, and fully established. In a nutshell, the process should be fully efficient and not variable and subject to constant issues and breakdown.  

This is in addition to the obvious questions such as: are your characterization methods fully recognized and validated? And if not, what documented justification do you have? Do you have a fully operational and independently verified quality management system? Backed up by certification, licensing, etc., Biopharma companies should be asking: how will you ensure that your processes and supply of iPSC will be fully integrated with our processes and overall lifecycle and indeed quality management system?  

 References and reading 

• https://cn-bio.com/us-fda-modernization-act-2-what-does-it-mean/ 
• https://www.congress.gov/bill/117th-congress/senate-bill/5002 
• https://www.animalfreeresearchuk.org/the-fda-modernisation-act-2-0-what-does-it-mean-and-what-will-follow/ 
• https://www.thepharmaletter.com/article/the-fda-modernization-act-2-0-implications-for-drug-development