THE discovery and development of a new medicine through to regulatory approval is one of humankind’s most challenging, expensive and risky enterprises. The full-scale development of a new medicine or vaccine to meet exacting regulatory standards is, with few exceptions, funded and led by the experienced, well-resourced and expert development capabilities of the pharmaceutical and biotechnology industries. Therefore, outside the regulatory agencies and these industries, the know-how and experience to develop new medicines and vaccines (at scale) is limited. This represents a major barrier to success, as revealed by the coronavirus disease 2019 (COVID-19) pandemic, and needs to be addressed to rapidly advance new treatments.
The basic premise underlying drug development and regulation is assessment of the relative risk of adverse events versus benefit of a potential new therapy. This necessitates clinical efficacy being demonstrated in well characterised patient populations, using an optimised dose and dosing regimen (to provide an acceptable therapeutic index/margin), side effects and adverse events being characterised and known as best as practicable, and guidance being provided with respect to contraindications, concomitant medications and comorbidities. This information forms part of the submitted regulatory dossier and it directly informs the regulator-approved prescribing information for the medicine.
In its simplest form, advancing a medicine to regulatory approval can be viewed as a broadly linear process with substantial interdependencies between the discovery, product development, clinical, regulatory and manufacturing sciences. Deep, integrated ecosystems support each of these different sciences and an inherent challenge is orchestration and integration of the learnings and insights from the respective ecosystems. Once completed, this provides a comprehensive characterisation of the potential medicine cross-referenced with the required efficacy, safety and quality standards demanded by regulatory agencies.
Although a reductionist view of medicine development focuses on clinical trials, major findings that have an impact on development regularly emerge during non-clinical safety assessment, clinical pharmacology and the broader developmental studies.
Time and direct cost (ie, not including failures) estimates for the discovery, development and approval of a new, unprecedented medicine (ie, new biological target) are more than 10 years and more than $0.5 billion dollars (being dependent on therapy area) respectively. COVID-19 is a new pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and hence, there were no pre-existing drug discovery or development programs that could be accelerated. Consequently, current therapy development efforts have largely been focused on development of new vaccines, and the repurposing of approved medicines or pivoting of therapeutic candidates already in development. Anything else will simply take too long to provide effective and affordable solutions to the current pandemic.
To repurpose a medicine, speed of response and the generation of quality data are essential attributes of a successful program – and this is optimally achieved via collaborative stewardship between the different ecosystems essential to deliver an approvable product. In the context of public efforts to repurpose medicines for COVID-19, innovations are needed in how studies are designed and conducted; how individuals and teams are involved; how collaborations are established to avoid wasteful duplication of effort; how to access funding at scale; how to share data, experience and clinical findings using consistent and comparable methodologies; and how to chart an agreed pathway for rapid advancement.
This represents a challenge for university-based research groups and not-for-profit research institutes in their quest to repurpose medicines for COVID-19 as it is at odds with an often entrenched “publish or perish” imperative and a “hunter and gatherer” research funding mindset.
Today, there are a plethora of clinical studies, generally occurring in parallel, and with limited stewardship between the ecosystems essential for repurposing a medicine.
For example, of the 687 clinical trials recruiting and completed around the world for SARS-CoV-2, many are single medicine studies, there is duplication of the same or similar dose regimens, study end points cannot be pooled, and there is minimal information on the rationale for dose selection within the study database.
In some studies, combination therapy of two drugs is being assessed – this is an inherently more complex undertaking as it requires identification of the optimal dose of each drug, which could be higher, or lower, than when used alone; the dosing frequency of each drug, or the combined drugs, taking into consideration their differing pharmacokinetic profiles; and the increased risk of interaction between each drug and other medications in the context of existing patient morbidities.
A further consideration when selecting drug products for clinical trials is possible bio(in)equivalence between multisource, generic medicines manufactured in different countries, including counterfeit medicines. If the quality and bioperformance of different products of the same drug are different, this will limit extrapolation to other clinical settings. It would certainly invalidate the compilation of such studies into an overall database to support regulatory approval of a repurposed drug (or drug combination).
Quantitative, translational and clinical pharmacology informs selection of an optimal dose, and dosing regimen, for drugs or drug combinations. In the case of repurposed medicines, the simulations arising from physiologically based pharmacokinetic models to identify optimal dosing regimens are based on the existing (and typically extensive) human data, thereby providing a higher level of confidence compared with new drug candidates and, therefore, an ability to accelerate their development.
The logical and programmatic approaches to repurpose medicines have been challenged by the inherent emotion in the urgent need for effective therapies for COVID-19. Such a need has unfortunately prompted enthusiastic reports in the lay press (that offer unreasonable hope) from preliminary in vitro studies with limited clinical applicability; poorly informed advocacy by high profile, non-medically qualified individuals; inappropriate self-administration of agents leading to serious adverse events and death; and concerns about medicine shortages for chronically ill patients using them in accord with their approved clinical use. Such actions have prompted the US Food and Drug Administration to recently issue a safety communication regarding the use of hydroxychloroquine or chloroquine for treatment of COVID-19.
If the “wrong shortcuts” are taken when selecting a drug and dosing regimen for clinical studies, likely outcomes will range from it being a single point study with limited applicability to one where the lives of study participants are at risk. For example, a recent clinical trial in Brazil evaluating a high dose of chloroquine in combination with azithromycin was halted after a trend towards higher lethality was observed compared with a lower dose regimen.
The step-change needed to rapidly repurpose medicines for COVID-19 will be enhanced through meaningful collaborations and integration of an experienced clinical pharmacology and medicine development mindset into program teams. Drug development is not a local or national activity; it is almost always global to access the necessary skills and capabilities and it is always coordinated.
Recognising the importance of multisectoral partnerships, major consortia for coordinating and speeding development of COVID-19 therapeutics have recently been established, such as the COVID-19 Therapeutics Accelerator and the public–private Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership. A recent shared platform for translational pharmacology supporting COVID-19 therapeutics is a welcome initiative. Pre-competitive collaborations are well established, and successful, within the pharmaceutical industry and they provide a useful model and framework as medicines are repurposed for COVID-19.
Beyond improved collaboration and adoption of the strategies described herein, a major challenge is the redesign of drug development for COVID-19 in a timeframe of months, not years. This will necessitate shared engagement across scientific disciplines within rapid and tightly orchestrated “learn and confirm” cycles to accelerate development of candidate therapeutics.
Finally, we recognise that learnings from the development of a new medicine, or the repurposing an approved medicine for SARS-CoV-2, are equally applicable to responses to future pandemics or advancing medicines for poorly served patient groups where treatments are limited due to market failure. Even under the shadow of COVID-19, it is apparent that countries that embrace competency-based, multisectoral coalitions to prepare and respond to future pandemics will be far better served than those that do not.
Bill Charman is a Sir John Monash Distinguished Professor in the Faculty of Pharmacy and Pharmaceutical Sciences at Monash University, Melbourne, Australia.
Craig Rayner is President of Integrated Drug Development at Certara and Adjunct Associate Professor and Distinguished Alumnus in the Faculty of Pharmacy and Pharmaceutical Sciences at Monash University, Melbourne, Australia.
Mark Sullivan is founder and Managing Director of the not-for-profit biopharmaceutical company Medicines Development for Global Health and an Honorary Professor at the Kirby Institute, University of New South Wales.
The statements or opinions expressed in this article reflect the views of the authors and do not represent the official policy of the AMA, the MJA or InSight+ unless so stated.