Metathesiophobia: from preclinical to clinical development

Having worked in early-stage clinical pharmacology for over 30 years, I've found that one of the greatest fears in our field is the transition from preclinical to clinical research. And let's face it, these concerns are well placed and fitting for Halloween. Even experienced professionals can make serious errors, as dramatically illustrated by the cases of TeGenero (TGN1412) and Bial [1][2]. If a regulatory authority considers your goals and understanding to be misplaced, all your hopes and ambitions can come crashing down, followed by loss of funding and inevitable failure – the stuff of nightmares.

Often, investigators who develop an initial concept and conduct the early research feel this clinical challenge most acutely. Being more comfortable in the laboratory, they tend to be less well-informed about how to formulate the right questions for human studies. A common misstep is designing clinical trials on the assumption that the agent is efficacious, assuming they simply need to prove it. However, regulators expect investigations focused on safety in adequately designed, well-controlled studies [3]. Smaller biotechs often lack the regulatory resources to compile the necessary documentation, placing considerable stress on company resources [4].

The good news is that you don't have to navigate this alone. Operating in a global marketplace means the different offerings from various regulatory agencies open opportunities to fit a strategy to your specific development challenges. Even so, many smaller sponsors don't know how to exploit this landscape. For example, they may have misconceptions about obtaining institutional review board (IRB) approval or what's required before submitting an investigational new drug (IND) application [5]. Fear of the unknown often causes hesitation and the adoption of more-conservative strategies. In contrast, the next steps, like creating a formal study protocol, are more reflective of the processes they already follow in the lab. There is certainly no shortage of guides and templates to help write a protocol or contract research organisations (CROs) with the skills to deliver your study.

Strategic Tools to Reduce Uncertainty: Regulatory Pathways and Modelling Approaches

Beyond standard regulatory submissions, sponsors need to be aware of programs designed to exorcise uncertainty and minimise fear. For instance, the FDA’s Expanded Access (sometimes called "compassionate use") pathway, which includes specific initiatives like Project Facilitate (launched in 2019), provides mechanisms for patients with serious or life-threatening conditions to access investigational drugs outside of clinical trials [6]. A cross-sectional study of programs registered up to August 2017 found that expanded access was available for a median of 10 months prior to FDA approval, constituting about 14% of the premarket clinical development period [7]. Understanding these frameworks can alleviate the fear of completely blocking patient access and inform a more nuanced regulatory strategy.

Another powerful tool to combat the fear of translation is Quantitative Systems Pharmacology (QSP) modelling. QSP has emerged as a mature approach to bridge the gap between preclinical findings and human outcomes. Recent advances have empowered developers to gain a deeper understanding of context-dependent pharmacology, guide first-in-human (FIH) dose selection, and design dosing regimens with expanded therapeutic windows [8]. Similarly, Physiologically-Based Pharmacokinetic (PBPK) modelling has been applied increasingly during the discovery stage for early risk assessment, prediction of human dose, and toxicokinetic dose projection [9]. These models are not just theoretical; they are being used to simulate virtual clinical trials and predict responses, as demonstrated in the development of antibody-drug conjugates for HER2+ metastatic breast cancer [10]. Monster killers.

Making the leap into the clinical unknown is necessary if we want to achieve advances in human medicine. History is filled with cases where promising pre-clinical data from mice, dogs, or rats, showing clear potential in cancer or Alzheimer's disease, have failed to translate to the clinic [11][12]. It does not benefit humans to cure cancer in mice; we must use preclinical data to justify moving into humans. Often, the first step is conducting studies in healthy subjects. The critical requirement here is getting your dosing right, clinical pharmacology already has too many horror stories [13]. You need an appropriately calculated dose-escalation strategy, and your efforts will be better rewarded if you incorporate relevant biomarkers and establish appropriate endpoints [14][15].

Practical Execution: Protocol Design, Variability Control, and Team Expertise

Despite the complexity, you should not be intimidated by the required documentation. This is not Frankenstein’s Monster territory. The European Medicines Agency, the UK's Medicines and Healthcare products Regulatory Agency, and the US FDA provide a wealth of information that is straightforward to download and follow [16][17][18]. Resources include overviews of the drug development process, guidance on preclinical work, clinical trials guidance, IRB checklists, and even lists of why first applications are often rejected [19]. Following an example, especially a successful one, certainly helps build confidence when writing your first submission documents.

In many cases, admitting ignorance is the first step to wisdom. Those who approach any trial as if it were routine clinical practice often end up making mistakes. They may run afoul of safety or ethical requirements, changes to regulatory requirements, or fail to collect sufficiently robust data to support their objectives [20]. That's why it's vital to engage a team experienced in running clinical studies, whose expertise complements your own clinical and laboratory knowledge.

Vagary, poor planning, and variability are the demons that come back to haunt you. You must identify robust endpoints and minimise all sources of variability. For instance, in hypertension trials, researchers must ensure consistent patient positioning and a controlled environment. Details like ensuring the subject doesn't cross their legs or has rested beforehand can significantly reduce variability in blood pressure measurement [21]. Devices also need regular calibration throughout the study [22]. Failure to manage these variables will surely bury your study.

This example highlights how trial conduct differs from clinical practice. A trial requires more control to ensure consistent, high-quality data, and this care must be clearly described in the protocol. It's worth grasping the complexity of even the simplest clinical trial. Every team member brings relevant knowledge, statistics, clinical care, monitoring, data management, analysis, etc. The complexity underlines the importance of a well-formed protocol to coordinate your monster squad appropriately [23].

Getting the protocol right is critical. It depends on adopting an iterative process that integrates everyone's expertise and documents everything accurately, so the trial is executed consistently. It then serves as the central document for submission, registration, and for preparing other regulatory and analytical documents like the statistical analysis plan and clinical study report [24]. Undertaking in-depth planning during protocol creation is essential for a successful trial. After all, who needs The Bogey Man?

References

1. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006;355(10):1018-28.
2. Eddleston M, Cohen AF, Webb DJ. Implications of the Bial trial disaster for the early development of drugs. Nat Rev Drug Discov. 2016;15(7):451-2.
3. International Council for Harmonisation. ICH Harmonised Guideline: General considerations for clinical studies E8(R1). Geneva: ICH; 2021.
4. Hwang TJ, Carpenter D, Kesselheim AS. Target population involvement in the design and conduct of clinical trials: a review of current practices. Clin Trials. 2018;15(3):233-42.
5. US Food and Drug Administration. Institutional Review Boards (IRBs) and Protection of Human Subjects [Internet]. Silver Spring (MD): FDA; [cited 2024 May 20].
6. Scepura B, et al. Oncology Expanded Access and FDA's Project Facilitate. Oncologist. 2021 Oct;26(10):e1880-e1882.
7. Puthumana J, et al. Availability of Investigational Medicines Through the US Food and Drug Administration's Expanded Access and Compassionate Use Programs. JAMA Netw Open. 2018;1(4):e181571.
8. Qi T, et al. Development of bispecific T cell engagers: harnessing quantitative systems pharmacology. Trends Pharmacol Sci. 2023 Dec;44(12):880-890.
9. Real-world application of PBPK in drug discovery. Drug Metab Dispos. 2023 Dec 12.
10. Scheuher B, et al. Towards a platform quantitative systems pharmacology (QSP) model for preclinical to clinical translation of antibody drug conjugates (ADCs). J Pharmacokinet Pharmacodyn. 2024 Oct;51(5):429-447.
11. Begley CG, Ellis LM. Drug development: Raise standards for preclinical cancer research. Nature. 2012;483(7391):531-3.
12. Cummings JL, Morstorf T, Zhong K. Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther. 2014;6(4):37.
13. Posner J, Griffin JP. The Role of Clinical Pharmacology in the Development of New Drugs. In: Griffin JP, Posner J, Barker GR, editors. The Textbook of Pharmaceutical Medicine. 7th ed. Oxford: Wiley-Blackwell; 2013. p. 197-215.
14. Le Tourneau C, Lee JJ, Siu LL. Dose escalation methods in phase I cancer clinical trials. J Natl Cancer Inst. 2009;101(10):708-20.
15. Group BDW, Atkinson AJ Jr, Colburn WA, DeGruttola VG, DeMets DL, Downing GJ, et al. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89-95.
16. European Parliament and Council. Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use. Off J Eur Union. 2014;L158:1-76.
17. Medicines and Healthcare products Regulatory Agency. Clinical trials for medicines: apply for authorisation [Internet]. London: MHRA; [cited 2024 May 20].
18. US Food and Drug Administration. Guidance Documents [Internet]. Silver Spring (MD): FDA; [cited 2024 May 20].
19. US Food and Drug Administration. Common Reasons for Refuse to File Decisions [Internet]. Silver Spring (MD): FDA; [cited 2024 May 20].
20. Junod V. The challenges of clinically oriented, investigator-initiated trials. Contemp Clin Trials. 2017;63:62-6.
21. Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, et al. Recommendations for blood pressure measurement in humans and experimental animals: part 1: blood pressure measurement in humans. Circulation. 2005;111(5):697-716.
22. Turner MJ, Speechly C, Bignell N. Sphygmomanometer calibration--why, how and how often? Aust Fam Physician. 2007;36(10):834-8.
23. Farrell B, Kenyon S, Shakur H. Managing clinical trials. Trials. 2010;11:78.
    International Council for Harmonisation. ICH Harmonised Guideline: Guideline for Good Clinical Practice E6(R2). Geneva: ICH; 2016.