In this blog post, we examine the IND application process and give insight on how to reach IND readiness faster with the InVivo Biosystems preclinical development platform.
Key Points
- In order to advance a compound to clinical trials, the Investigational New Drug (IND) application must be approved by the FDA.
- Our top recommendation for a seamless IND application process is to arrive well prepared to a pre-IND meeting with the FDA.
- In the pre-IND meeting and IND application as a whole, Preclinical Support is a key foundational piece which is expanded upon in this blog below.
- Presenting strong Preclinical Support in the pre-IND meeting can result in the FDA offering a fast-track approval process, which saves an extensive amount of money and time in the drug development process.
- The proprietary RapidGen™ platform offered exclusively by InVivo Biosystems executes preclinical discovery and development 2-3x faster than traditional in vivo methods for a broad range of novel and repurposed therapeutics.
The Investigational New Drug (IND) Process:
The Investigational New Drug (IND) process is a regulatory pathway followed by pharmaceutical companies to obtain permission from regulatory authorities, such as the Unites States Food and Drug Administration (FDA), to conduct clinical trials with a new drug or biologic in humans. The FDA is responsible for regulating all pharmaceutical drugs that are available on the market in the United States, but at what point do they become involved? The Investigational New Drug (IND) application is the point at which a potential new drug enters the regulatory system, and IND approval is necessary before a drug can be administered as part of a clinical trial.
The first step of completing an IND is the pre-IND meeting, which is an optional but heavily recommended step drug manufacturers should be prepared to have towards the end of the preclinical development process. In this article we will discuss the key aspects needed for an IND application, and how alternative animal models lower the cost and timeline associated with clinical drug development.
Drug Discovery:
Drug development is a complex process that includes several stages, such as target identification, lead identification, lead optimization, preclinical development, and clinical trials [Figure 1]. On average, bringing drugs to market takes between seven to ten years and requires an investment of approximately one billion dollars per drug.
Traditionally, the drug discovery stage heavily depended on research and development in a laboratory setting. With recent in silico methods emerging and showing to be a reliable technology, computational methods are now a foundation for drug discovery (Mahalmani, V. et al., 2022). Machine learning algorithms have enabled preliminary testing of thousands of compounds to evaluate their ability to specifically interact with the disease target. Numerous AI SmartLibraries are now readily available, listing anywhere from a handful to hundreds of potential drug candidates for any given disease. Target and lead identification are the core pillars in drug discovery efforts, with in silico methods primarily aiding in the target identification step.
Figure 1. New Drug Development and Review Process
Preclinical Development:
The drug discovery phase is followed by the pre-clinical development phase. In the pre-clinical development phase, lead compounds are tested in vitro and/or in vivo.
The key components within preclinical development, prior to clinical trials are:
- Lead optimization
- Compound efficacy testing
- Mechanism of Action (MoA)
- Safety assessment (toxicity, oxidative stress, etc.)
There are a variety of assays which collectively come into play when optimizing a drug lead and assessing the safety of a novel or repurposed therapeutic. At InVivo Biosystems, our RapidGen™ platform is a customizable end-to-end preclinical drug discovery route providing transgenic in vivo models and validated phenotypic assays, including but not limited to:
- Mechanism of action studies
- Compound efficacy testing
- Neurotoxicity (CNS) testing
- Aging and longevity assays
- Global gene expression studies
- Immunotoxicology/Immunology assessments
- Cardiovascular safety assessments
- Oxidative stress (ROS exposure) assays
- And more!
In addition to having strong data supporting preclinical development efforts, effective communication between the pharmaceutical company and the FDA is also a critical aspect of the drug development process. The first required point of contact between the two parties is the Investigational New Drug (IND) Application which the manufacturer or potential marketer submits when they have a drug compound that is ready to enter clinical trials (U.S. FDA, 2022). Prior to submitting the application, pharmaceutical companies have the option to request a pre-IND meeting with FDA staff to discuss the manufacturer’s IND application. Our top recommendation is for pharmaceutical companies to take advantage of the pre-IND meeting.
Pre-IND Meeting:
This pre-IND meeting, although not required, is incredibly valuable as it lets the pharmaceutical company gain feedback and guidance on their IND application which helps avoid an application being considered deficient and being put on clinical hold. Beyond ensuring that the IND application has the necessary components, the pre-IND meeting can shorten the approval time later on, as FDA staff will be familiar with the research and proposed clinical study. But what is needed for this pre-IND meeting, and the IND application itself?
It is important to enter into the pre-IND meeting with:
- Preclinical Support
- Chemistry, Manufacturing, and Control (CMC) plans
- Detailed clinical trial design
- Showcased compliance with outlined Good Clinical Practices (GCPs)
- Selection of dosage information, determined by preclinical toxicity analyses
Based on this pre-IND discussion, the FDA can recommend ways to bring the drug to market faster by offering an accelerated track designation. See our white paper to learn about how to fast track a novel or repurposed therapeutic by utilizing the FDA’s expedited tracks.
Download our Whitepaper
How to Achieve Strong Preclinical Support:
One of the most commonly asked questions about the IND application is what qualifies as good preclinical support, as manufacturers often find themselves toeing a line between trying to lower the notoriously high cost of drug development, while obtaining sufficient quality data to showcase the pharmacological benefit of their compounds. This is where alternative animal models such as zebrafish and C. elegans can be hugely advantageous, as they offer whole organism testing that is both fast and cost effective.
While drug development has traditionally been conducted on rodent models, recently, the FDA has signaled a desire to adopt a safer and more ethical approach that promotes the utilization of alternative models and in silico methods. The FDA Modernization Act 2.0 removed the rodent testing requirement in the preclinical stage of drug development. While speaking in support of the law, Senator Rand Paul explained the goal of the new legislation, saying that it aimed to “accelerate innovation and get safer, more effective drugs to market more quickly by cutting red tape that is not supported by current science (Paul, 2023).”
The FDA Modernization Act 3.0 has been introduced in the White House as of February 29th, 2024. The new bill, once enacted, will legislatively establish alternative models such as the zebrafish and C. elegans as encouraged models to utilize in preclinical development.
The FDA doesn’t require any particular model system, mouse models are just the de facto standard, but this is to our industry’s detriment, because not only are rodents expensive, they aren’t always the best way to model.
The Alternative Model Advantage:
Here at InVivo Biosystems, we partner with pharmaceutical and biotech companies to generate the comprehensive science-based evidence of safety and efficacy that is needed for the IND application. One of our current pharmaceutical clients explained why they chose to reach out to us, and what they see as the benefit to employing alternative animal models to the drug development process – saying that companies such as theirs face both internal company pressure and external public pressure to transition towards a way of testing that is more effective. After all, currently, only around 10% of drugs that enter human clinical trials ultimately receive approval, which goes to show that the current system is not working (Sun, Gao, Hu & Zhou, 2022).
Working with InVivo Biosystems gave us the information [we needed] to better improve our and optimize our compounds to the final clinical candidate stage
Podcast: Pioneering the Next Generation of Drug Discovery
Zebrafish have also been directly compared to mice as a fast, affordable, and reliable alternative to rodent models for research. Zebrafish not only reach maturity faster than mice (90 days versus 4-7 weeks), but InVivo Biosystems has licensed gene editing solutions which execute precise gene edits in zebrafish at record speed, with licensed multiplex CRISPR capabilities providing our customers with unbeatable high throughput indications in preclinical development.
Beyond having the advantages of lower cost, accelerating a project’s timeline and being a reliable alternative to rodents, the zebrafish and C. elegans models may help improve the current high drug failure rate. This is because, alternative animal models can help to identify potential adverse effects of a drug candidate which may not be evident in traditional mammalian models. For instance, some drugs induce immunological reactions and toxic effects on humans’ cardiovascular systems which are not observable in rodents (Lee, Hwang & Kim, 2017). Likewise, neurological diseases such as Alzheimer’s and Parkinson’s are not well modeled in rodents, as mouse models do not fully recapitulate the pathological features seen in Alzheimer’s disease and the current Parkinson’s models are limited in their inability to reproduce the selective vulnerability of dopaminergic neurons that are seen in humans (Dawson & Ko, 2013).
Conclusion:
The IND application is a regulatory requirement for pharmaceutical companies seeking to enter clinical trials with a novel or repurposed drug in the USA. Here, we have given a brief overview of the key components in preclinical discovery and development leading up to the IND application and stated the importance of holding a pre-IND meeting with the FDA. Recent legislative measures have motivated researchers to explore alternative animal models for studying diseases traditionally studied in rodents. The novel in vivo models and technologies offered within the RapidGen™ platform are revolutionizing drug development, as the models not only exhibit closer resemblance to human diseases than rodents in certain cases but the platform as a whole also offers a 2-3x faster and more cost-effective route to generate the comprehensive data package necessary for an IND application.
References:
- U.S. Food and Drug Administration (2/22/22). Small Business and Industry Assistance: Frequently Asked Questions – Pre-Investigational New Drug (IND). Retrieved May 28, 2024, from https://www.fda.gov/drugs/cder-small-business-industry-assistance-sbia/small-business-and-industry-assistance-frequently-asked-questions-pre-investigational-new-drug-ind
- U.S. Food and Drug Administration. (2/28/22). Investigational New Drug (IND) Application. https://www.fda.gov/drugs/types-applications/investigational-new-drug-ind-application
- Paul, S. (2023). Dr. Paul’s Bipartisan FDA Modernization Act 2.0 to End Animal Testing Mandates Included in 2022 Year-end Legislation, Dr Rand Paul, US Senator, Kentucky. https://www.paul.senate.gov/news/dr-pauls-bipartisan-fda-modernization-act-20-end-animal-testing-mandates-included-2022-year
- Dawson, T. M., & Ko, H. S. (2013). Alzheimer’s disease: emerging concepts and therapeutic targets. Journal of neurochemistry, 127(3), 454-461. doi: 10.1111/jnc.12194
- Lee, E. J., Hwang, Y. H., & Kim, H. R. (2017). Non-clinical safety evaluation of therapeutic monoclonal antibodies: current status and future directions. Journal of pharmaceutical investigation, 47(4), 287-296. doi: 10.1007/s40005-017-0323-x.
- Sun, D., Gao, W., Hu, H., & Zhou, S. (2022). Why 90% of clinical drug development fails and how to improve it?. Acta pharmaceutica Sinica. B, 12(7), 3049–3062. https://doi.org/10.1016/j.apsb.2022.02.002
- Mahalmani V, Sinha S, Prakash A, Medhi B. Translational research: Bridging the gap between preclinical and clinical research. Indian J Pharmacol. 2022 Nov-Dec;54(6):393-396. doi: 10.4103/ijp.ijp_860_22. PMID: 36722550; PMCID: PMC10043823.
