It is difficult to say with precision when drug development came under tighter regulatory control, but the foundation began in Great Britain in 1540, with the Apothecary Wares, Drugs and Stuff’s Act (Rago and Santoso, 2008). In modern times, the U.S. Food & Drug Administration (FDA) introduced the Pure Food and Drugs Act in 1906, and the World Health Organization (WHO) was established in 1960, quickly followed by the Organization for Economic Co-operation and Development (OECD) in 1961.

It was in the 1990s that key regulatory guidelines to support non-clinical safety assessment (Toxicology, DMPK and Safety Pharmacology) started to be put in place. Prior to that, the FDA, the European Medicines Agency (EMA), and Japanese regulatory bodies had developed some guidance to support Reproductive Toxicology, triggered by the thalidomide catastrophe, but little else. In an attempt to harmonize across the key pharmaceutical markets of the time, the International Conference on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) was established involving the U.S., Europe, and Japan. It provided a forum to discuss scientific and technical aspects of drug registration, with the aim to support registration in a resource-efficient manner and ensure the development of safe, effective and high-quality medicines.

The guidelines were welcomed by the pharmaceutical industry to help navigate the regulatory arena and 30 years later, remain an invaluable support. However, with the passing of time and a changing industry, there are gaps, misinterpretations and misunderstandings, which can lead to confusion and inefficiencies in the drug development process. To circumnavigate the guidelines, it’s useful to consider them both a blessing and a curse, which may help lead to a smoother regulatory pathway.

A blessing: providing standards for better program design
When the first ICH guidelines were established, the majority of drugs were small molecules, which were developed by large, established pharmaceutical companies. Biologicals were a twinkle in researchers’ eyes and the biotech industry didn’t yet exist. The guidelines provided a sense of reassurance, helping to understand regulatory agencies’ legal and regulatory expectations, and hopefully leading to better designed programs to support market approval.

Today, multiple guidelines exist, produced at the national, regional and international level, and offer a wide range of guidance on many drug development topics, including both general guidance about what studies to conduct and when, as well as consideration of specific study designs and the quality standards. The ICH guidelines provide the most comprehensive guide covering many aspects from preclinical up to new drug approval. For example: ICH M3 provides an overview of non-clinical and clinical development whilst others are more specific, such as: ICHS7a,b; ICH S4; ICH S1. As the industry innovates, further guidelines are being developed and updated. One of the latest ICH guidelines being updated is the carcinogenicity guideline, ICH S1.

The guidelines also now support Replacement, Reduction and Refinement (3R’s) initiatives—aimed at improving animal welfare and reducing animal numbers in regulatory and investigatory research—demonstrating changing regulatory expectations. In fact, when the original ICH reproductive toxicology guidelines were introduced in the 1960s, which reportedly supported the use of tens of thousands of models, there was an overall reduction in the number of research models requested (Chapman et al., 2013 on designing studies to reduce animal use).

Clearly, guidelines provide a great support structure for the drug development process. But, when do they go from a blessing to a curse?

A curse: guidance does not replace skilled practitioners
Guidelines provide an opportunity to learn the steps in how to develop a drug. They are available to anyone, and like a cookbook, tell you the recipes and what ingredients you need. However, just as a cookbook doesn’t suddenly make everyone a Michelin-star chef, neither do guidelines make everyone a successful drug developer. This wasn’t a major consideration in the 1990s, as drugs were developed mainly by large experienced pharmaceutical companies.

Today, the industry has changed. Large pharmaceutical companies are increasingly moving towards outsourcing research and development, and virtual biotechs, startups and patient advocates are jumping into drug development to fill unmet gaps in the pipelines. Unfortunately, the latter often lack experienced toxicologists to properly design and execute safety assessment research. Examples show that a lack of experience, inappropriate interpretation of the guidelines or, in extreme cases, refusal to even consider them, can be detrimental to the delivery of a successful program in a timely manner. They often lead to poorly designed studies and worse, the closure of companies.

These stories of failure are less widely shared than the breakout successes, but the end result is clear: ignoring or misinterpreting guidelines results in less efficient plans, with a loss of both time and money.

Interpretation, language and experience
Interpretation is key and is influenced by many factors, including individual and company experience, perception, language and its nuances. Some may interpret the guidelines as ‘de facto’, using them as a tick list to follow in a linear manner. However, rarely does drug development follow a linear path, and is usually not black and white, but that’s difficult to capture in generic guidelines.

Understanding the nuances within drug development and the science, is key. In trying to be general and cover multiple situations, guidelines often include words such as ‘should be’ and ‘may be’. These words are nuanced to give flexibility, but can be misleading, even for a native speaker. As a global industry, English is not the first language of many, yet it remains the predominant language in which guidance documents are originally authored.

An independent opinion from a member of the Medicines and Healthcare products Regulatory Agency (MHRA) suggested: “regulatory guidelines are like the modern map of the London Underground. They don’t completely represent the ‘real’ world and there’s almost always more than one way to reach an objective. The recommended route may not be the one you should follow, particularly if there is a good scientific rationale not to.” (3NR 2018). It’s a good way to view the guidelines. However, be aware, regulatory authorities can differ in their laws and expectations, including at the level of an individual reviewer, and that will add a layer of complexity.

Legality and interpretation
Guidelines are guidelines but their aim is also to provide a regulatory legal position, often with an end goal in mind: market approval, license and label. Consideration of statutory regulatory laws adds a layer of complexity in their interpretation, particularly when in the early development phase. ICHQ3A impurity guidelines is a good example: the guidelines are written for license and do not provide clarity on early developmental needs.

It is therefore an important consideration when interpreting guidelines that the program specifics, the product, indication and business plan are understood and in place in advance. A Target Product Profile is perhaps one of the most useful key tools to put in place early on. Limited experience in how to do this may increase the risk of a misinformed decision, which leads to a less efficient program (time/cost). The challenge is the fear of failure. This often drives us to err on the side of caution with the aim of avoiding a theoretical risk of regulatory rejection. This approach means that the tendency is to do more rather than less, despite the additional work potentially being irrelevant or worse, misleading.

Of course, the consequence of rejection by a regulatory agency is no small issue, also adding time and money to any development program or license application. However, misinterpreting or rigidly following the guidance without full understanding, may have consequences on budget, time and the 3R’s, albeit that these aspects may be less quantifiable at the time.

Talking to experts, specifically experienced toxicologists, can help in interpretation of the guidelines and help put together the most appropriate plan. Again, approaching the authorities for an early discussion may be advisable. Different agencies have different processes, some are easier than others, so that will also have to be considered in your approach. The FDA actively encourages pre-IND meetings, with written guidance and relatively easy access, which includes meeting by telephone to enable global participation and cut down travel.

Advancing science
Science is moving at an ever-increasing rate. Today, there are increasingly complex lists of available drug products, including antibodies, oligos, CAR-T cells, etc. The list and, inventiveness within the industry, appears endless. How do the guidelines keep up with the science, and what happens when science leaps ahead?

Generating guidelines and keeping them updated is resource-intensive, particularly where harmonization is required within the context of the ever-changing pharmaceutical environment. There are some guidelines that do not yet exist e.g. ICH vaccine guidelines, therapeutic vaccines, oligonucleotides, stem cells and advancing technologies, like CRISPR/Cas9. These new technologies create exciting medical advances, but also invite challenges in understanding their toxicological risks.

In addition to creating new guidelines to cover these new classes of medicine, there is also a need to update some older guidelines to capture changes in technology or thinking and thus ensure a smooth efficient process and patient safety. In cases that are less straightforward or where there is a lack of guidelines, talking to experienced experts can be key, as well as considering engaging early on with the relevant agency. 

Expanding markets and regulatory bodies
Another challenge is differences in regulatory agencies. Guidelines cannot realistically address every single situation faced by drug developers. Today, with new and emerging markets, it is not clear how these new agencies are working and whether they will buy into the ICH guidelines.

The Chinese FDA, perhaps the most advanced, has shown some alignment with the USA FDA. However, for others it’s less clear. It is unclear how this will evolve with the globalization of markets or whether the ICH will expand its membership. Tackling this individually at a company level is difficult. It is something to be taken up collectively, either from the regulatory side or perhaps with the support of the industry with organizations such as ICH itself.

Even with harmonized guidelines, there can still be differences between authorities that result in studies being requested by one authority and not by another. These differences add to the complexity of drug development, particularly when targeting a global market and challenge the spirit of the 3R’s. International harmonization helps reduce cost and time in developing a drug which in turn helps patients on a global scale and we need to see more of this.

Every individual involved in drug development can help support the 3R’s. This can be further supported by continued international harmonization and the support of the regulatory authorities.

Conclusion
With the acceleration of drug discoveries and innovative treatment strategies, there’s a need to balance regulatory guidelines, which help minimize undue patient risk without impeding cutting edge medicines progressing into the clinic. Toxicology in drug development provides the initial safety assessment and requires both science and artful thinking. Having a regulatory base means that certain steps may be dictated by what is needed to get your drug into a clinical trial or onto the market: but understanding of the rationale and with the question of “when along the chain?” is critical.
There’s more to non-clinical safety assessment than ticking a box, and that is rarely found stated in any guideline. What needs to be considered further is:

1. Interactions between the international agencies;
2. Increased input from industry players other than large pharma’s in the update of guidelines; and
3. Including toxicologists early in discovery, as part of a multidisciplinary team, along with DMPK, CMC (chemistry, manufacturing and controls) and clinical specialists, all who can help to develop the most appropriate plan and provide guidance when to actively engage in discussions with an appropriate agency.

As we move toward an increasingly globalized world, with a focus on next-generation solutions in drug development, regulatory agencies will have to evolve to account for the rapidly changing industry, and the industry will likewise have to evolve in their adherence to, and interpretation of, regulatory guidances. 

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Sarah Gould, PhD, is a senior principle scientific advisor at Charles River with more than 20 years of experience in biotech, pharma and as a consultant. She has a proven track record of delivering toxicology and safety pharmacology programs, individual studies and regulatory documents (IND, IMPD, CTD) for both small and large molecules (proteins, peptides, mAbs, virus vectors) along the development pipeline and has supported over 100 submissions. Sarah has interacted with various health authorities, including FDA, EMA, PMDA, as well as individual European authorities and emerging markets.