Introduction

Over the past few weeks, we looked at some of the key critical stages in clinical trials, specifically Phase I-III where human testing is performed to evaluate aspects such as drug efficacy to safety and tolerability at a grand scale. Last week, we discussed how Phase III was crucial to provide more data before the drug is pushed out into the market, with a key emphasis on profiling the drug’s efficacy, safety, and tolerability (with respect to other drugs currently available in the market) as well as doing so with a much larger population (thousands compared to hundreds in the trials before). This week, we will dive into the regulatory considerations during the drug development to market process. Given the number of regulatory and governing bodies necessary to oversee the process, academic institutions and drug companies must adhere to and follow all necessary procedures to ensure that their product can safely enter the market.

Regulatory Considerations as a Whole

During the preclinical research stage, we discussed how the goal is to get preliminary data regarding a promising drug through the usage of in vitro and in vivo studies. While the FDA currently does not regulate preclinical work, most of the compliance aspects are focused to Good Laboratory Practices (GLP) as well as all necessary training and ethical guidelines regarding working with cells or animal models. Assuming all given information is promising for clinical purposes, companies may then push out an Investigational New Drug Application (IND) to obtain approval to start clinical trials in humans. INDs are submitted to the FDA and require a collection of preclinical studies, manufacturing information, and an overview of the clinical trial plans. The FDA reviews the IND within 30 days and if all goes well, the sponsor/individuals overseeing the studies may proceed with clinical trials.

Clinical trials are extensive as evident from our previous articles covering them. They are critical to establish drug safety, efficacy, and dosage in humans while also ensuring that they are more efficacious than other drugs currently available in the market. Not too much needs to be said regarding this aspect other than making sure that sponsors continue to adhere to FDA guidelines, ensure proper patient care throughout the process, and allow the FDA to continue their monitoring of the trial (as well as any other protocol amendments or changes if needed).

Upon successful completion of all three phases (as well as any post-market surveillance), sponsors may then submit a New Drug Application (NDA) or a Biologics License Application (BLA). NDAs would be submitted for standard drugs and are expected to receive a result within 10 months of receiving this application. However, priority review can be given to drugs to have them approved within 6 months, specifically if the drug has significant improvements toward the diagnosis, treatment, or prevention of serious conditions. BLAs, on the other hand, are submitted for biologics (therapies that are isolated from natural sources such as blood). These applications may take up to 2 years to be approved after the completion of Phase III clinical trials, however, sponsors may choose to request a pre-BLA meeting 4 months before applying in hopes of expediting this procedure.

If all information and data provided are up to standard with the FDA, the NDA is then approved and additional post-market surveillance will take place to observe any new side effects that occur. Regulatory agencies will continue to monitor these adverse effects and will require any necessary changes to labels, usage, or even withdrawal of the drug as a whole if necessary.

It is important to note that while the information provided above discusses a lot about the FDA’s process, there are additional considerations that take place in other countries. For example, Europe has the European Medicines Agency that oversees its drug development process and Japan has the Pharmaceuticals and Medical Devices Agency for its process. While similar to the FDA in the US in certain ways, there are some small differences in timing or even monitoring compared to what the FDA does. However, to ensure that drug processes stay somewhat universal between countries, there are harmonization efforts such as the International Council of Harmonisation of Technical Requirements for Pharmaceutics for Human Use (ICH) and Mutual Recognition Agreements (MRAs) to allow the recognition of other country’s inspections and certifications.

Regulatory Considerations for Drug Repurposing

In drug repurposing, the process is slightly different given that new therapeutic approaches are being developed using existing drugs (rather than developing an entirely novel idea). Typically, drug repurposing is much faster and cost-effective. That being said, there are still some regulatory considerations that must be addressed.

For starters, one important aspect to keep note of involves patent considerations. This includes understanding what a prior drug’s patents entails, what indications does it cover, and whether or not a method-of-use patent can be filled to distinguish a clear and obvious difference from the original patent. Additionally considerations need to be taken regarding the patent’s remaining lifespan, as expiration dates do exist with the patents attached to the respective drugs.

Existing data can also be utilized in drug repurposing, including safety information to leverage preclinical trials and efficacy data (assuming the the desired mechanism of action is similar to the new indication of interest). While similarities may exist, sponsors may decide to conduct bridging studies to link existing data to their new indication as well as run new clinical trials (specifically Phase II and Phase III) as the repurposed drug may still have differences for their new purpose.

In terms of necessary documentations and applications, INDs can be amended for the new indication. It is important that these INDs contain new data and plans for additional clinical trials (similar to what was required for original IND application). For NDAs, a supplement DNA (sDNA) can be submitted if the drug is already approved another indication (thus requiring the necessary data to support this new indication). Additionally, depending on the circumstances, expedited programs (such as Breakthrough Therapy) or Orphan Drug Designation (indications for rare diseases that come with incentives) can be applied for.

A key consideration with drug repurposing regulations surrounds its labels and marketing considerations. In cases where the drug is used for new indications, the drug label must include more information regarding said indication as well as dosage, administration, and new side effects. Furthermore, the drug needs to be marketed to reflect what its new approved use is (while adhering to standard FDA policies regarding claims that are being made about the drug). Beyond this, post-market surveillance is relatively similar, watching out for any adverse effects and adapting as needed.

Regulatory Considerations with the Implementation of AI in Drug Development

With the increase of artificial intelligence in drug development, there has been an increase in interest regarding how AI can be regulated. Given that the field is still very novel, there has yet to be seen any real shift towards how AI and machine learning will be regulated within the context of drug development and medicine. However, within 2024, we may start to see some clear evidence of this being a factor.

In March 2024, the FDA announced their recognition and acceptance of AI/MLs inevitably integration into the drug development process. According to their report, over a 100 submission included AI/ML components whether it was during the drug discovery process all the way to post-market survey surveillance. That being said, the FDA is open to the integration of AI/ML as a way of innovating the field while also still adhering to their all safety and efficacy guidelines that they are focused on promoting.

To do so, the FDA’s Center for Drug Evaluation and Research (CDER) has worked closely in collaboration with the Center for Biologics Evaluation and Research (CBER) and Centers for Devices and Radiological Health (CDRH) to develop an initial discussion paper regarding the matter. The document is extensive in understanding the implications, discussing current usages of AI/ML in drug development, clinical research (including recruitment, dose optimization, site selection, etc), post-market surveillance, advanced pharmaceutical management, and even discussing the FDA’s current experience with AI/ML in drug development. While intended specifically for stakeholders, it is evident that the FDA is looking towards relevant considerations to properly implement this new technology while also allowing for feedback towards how this can be improved. The full copy of this discussion paper can be seen attached to this references of this article.

Recent articles hint at a potential full-scale documentation regarding the proper use of AI/ML into drug discovery, expected to come forth by the FDA sometime later this year. With the promise and openness of the FDA to push forth AI/ML, there is promise for this industry to help revolutionize and innovate the drug discovery process to provide more therapeutic options to patients at a faster delivery rate. By the end of this year, we may get to see the full-fledged ability fo AI/ML into this process, with regulatory and governing bodies supporting its integration.

Written and Constructed by Joshua Minami, Christian Chung, and Christopher Korban

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