This article was originally published online on Jan. 27, 2021.
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Accelerated drug development timelines must accommodate all crucial elements of nonclinical safety studies.
While the process for developing human therapeutics is long, complex, and requires considerable resources, in urgent situations such as COVID-19, the pace of development can move much faster. Steps that ordinarily take years were completed in months. Whether for a cardiac drug or a COVID-19 drug, the development process must show that the drug has an effect on the disease it is being used to treat and is safe for human use.
Safety testing must be a priority during the discovery, nonclinical phase, and clinical phases of drug development (Figure 1). While some nonclinical safety, or toxicology, testing is performed during the discovery phase, the majority of the toxicology testing occurs during the nonclinical phase and concurrently with the clinical phase. The goal of the toxicology testing is to determine, using animal models, if a potential new drug is safe to use in humans and to identify compounds that could potentially cause more harm than good.
The endpoint of the nonclinical phase for US drug candidates—the investigational new drug (IND) submission—features a summary of the toxicology work performed to support the administration of the potential new drug to humans in a Phase I clinical trial.
During the nonclinical phase, the following four types of studies generate data for the IND application:
Once the studies are conducted, the data are assessed to estimate a safe starting dose for the Phase I clinical trials. Once a positive risk assessment determines an appropriate dose for Phase I clinical trials and any adverse effects are identified in animal toxicology studies, the drug development company files an IND application. If FDA reviewers agree with the assessment of the potential new drug, the Phase I clinical trials in humans can be initiated. An unfavorable toxicity profile at the nonclinical stage of drug development is a common reason why a compound fails and does not progress in the drug development process.
This article was originally published online on Jan. 27, 2021.
As drug candidates progress through clinical trial phases, sponsors must continue toxicology testing and data collection for a new drug application (NDA), mindful of the requirements of different global regulatory authorities where submissions may be planned.
While the potential new drug is administered to people during the clinical phases of development, the safety testing of the compound in nonclinical animal models must continue for the same duration as the clinical study. For example, if the duration of treatment of patients in a clinical trial is months, nonclinical safety studies, typically three to nine months in duration, will be conducted to cover the time patients will be treated. The typical nonclinical toxicology studies conducted during the clinical phase of development include the following:
Extensive data reviews are conducted to determine the drug candidate’s efficacy and safety, and if the data point to a favorable risk-benefit assessment, the company will submit an NDA to FDA or similar application to other regulatory authorities for market approval.
While nonclinical animal toxicology studies follow accepted designs, the following crucial points must be considered:
The majority of nonclinical toxicology studies must be conducted according to good laboratory practices (GLPs) and include a robust quality management and documentation system that ensures the validity, integrity, and reliability of the nonclinical safety data submitted for regulatory evaluation and approval.
Rapid advancement of the availability of drugs that treat serious diseases and unmet medical needs are in everyone’s interest, especially when the drugs are the first available treatment or if the drug has advantages over existing treatments. FDA’s approaches to speed development—priority review, breakthrough therapy, accelerated approval, and fast track—have proven successful in bringing treatments, especially for unmet and orphan designations, to market quickly.
The COVID-19 pandemic has offered the public a glimpse of how drug and vaccine development can be accelerated during a public health emergency. The scientific response to COVID-19 has been unprecedented, from both clinical and nonclinical contributors. The global research community—which includes government labs, academic researchers, contract research organizations (CROs), and biotech and pharmaceutical companies—is racing to find solutions, and regulatory agencies are helping to accelerate these vaccines and treatments.
In 2020, FDA launched the Coronavirus Treatment Acceleration Program (CTAP) (1), an emergency program designed to speed up the regulatory processes for SARS-CoV-2 research without compromising safety. A notable change in CTAP is that it now consolidates the typical pre-IND meeting request and package development process into a single step to save time. The pre-IND meeting request will be expedited and prioritized based upon the completeness of the submission and scientific merit.
For drug developers, outsourcing the nonclinical toxicology work to a CRO can have a positive impact on the pace of research during the pandemic. Online scheduling of studies, accelerated reporting, remote study monitoring, and live streaming of key events allow studies to progress faster than before. This versatility has been extremely helpful to pharma companies as they race to find therapies and treatments in record time.
Nonclinical toxicology is an important component in the drug development process and ensures that safe drugs are made available to people. A sound nonclinical toxicology program should address all regulatory authority concerns and ensure that time and resources are properly used.
Rapid research and development efforts in 2020 demonstrated that bio/pharma companies must be positioned to move swiftly through the drug development process with unwavering commitment and oversight to ensure the compounds slated for the clinic are safe. The combined efforts of pharmaceutical companies, governments, and CROs were instrumental in reducing the development timeline from a decade or more to one year for some R&D programs. Time will tell what impact the current pandemic has on the overall approval for all therapeutics for all diseases outside of a global pandemic, but regardless of what these changes bring, safety will always be a priority.
Charles River scientists Steven Bulera, PhD, DABT; Rebecca Walker Comba, PhD; and Sam Chuang, PhD contributed to this article.
1. FDA, “Coronavirus Treatment Acceleration Program (CTAP),” www.fda.gov, accessed Jan. 12, 2021.
Shannon Parisotto, MBA, is the corporate senior vice president of Charles River Laboratories.
Vol. 34, No. 3
When citing this article, please refer to it as S. Parisotto, "Toxicology: Ensuring Drugs are Safe for People," BioPharm International 34 (3) 2021.