Introduction

This week’s article is about the third and final phase in clinical trials, Phase III. Over the last two weeks, we covered Phase I and II, which gathered information about the safety of the drug on humans and the efficacy of the targeted illness or condition. The sample size had increased to about 100 to 300 patients with detailed inclusion and exclusion criteria to provide as much data as possible before Phase III. Throughout Phase II complications occur both with and without human intervention. Common reasons for failure are lack of study design and insufficient efficacy. Many companies are rushing to adopt their own AI/ML programs into Phase II in various methods from data filtering to predictions of trials. Once the drug’s data can confirm the efficacy and safety levels set by the lead scientist(s), the drug is advanced to Phase III, where the sample size ranges from 300 to 3,000 patients. This is one of the few stages where AI is not heavily implemented, but hopefully, in the future, there will be. Some drugs that are entering or undergoing Phase II are AL002 and LXE408. With the help of AI/ML and other technologies, we hope these drugs advance to Phase III.

Information about Phase III

Phase III is the final and largest phase in the drug development pipeline clinical trials. As mentioned above the sample size can range from 300 to 3,000 patients and once again the inclusion and exclusion criteria list is more definitive. This change in criteria happens from the change in goals from Phase II to Phase III and with the judgment of the lead scientist a goal for the study will be set. Given that safety and efficacy have been confirmed in previous stages, the goal of a Phase III clinical trial is to compare the drug candidate against the current medication used for the condition. This phase can take from one to four years. Throughout this trial, scientists will also gather valuable information about the drug’s safety and efficacy in hopes that the scientists gather enough data to submit to the FDA review team in hopes of getting their approval for market release. Within the sample size, patients will be split up into a control group and a study group. The control group takes the standard treatment while the study group takes the candidate. The control group can vary from placebo, no treatment, or active control depending on the state of treatment. The study group is the group that takes the treatment being tested. In some cases, the clinical trials have sub-groups to explore specific factors or variations within the study. The general inclusion and exclusion criteria target demographics, medical history, current health status, allergies, concurrent treatment and conditions, and pregnancy status. With the help of the AI/ML programs, they begin searching for possible patients for the trial in hopes of getting at least 300.

As an example of the inclusion and exclusion criteria for Phase III, we can see Metronomic Capecitabine as Adjuvant Therapy in Stage III Gastric Cancer: a Multicentre, Open-label, Parallel-group, Randomised, Controlled, Phase 3 Trial. The inclusion criteria include an age range of 18 to 80, diagnosed with primary adenocarcinoma of gastric cancer and staged III by pathological evidence, R0 gastrectomy with D2 lymphadenectomy, ECOG (ECOG score standard) performance status of 0 or 1 and expected to survive more than 6 months, and no contraindications, including normal peripheral blood routine, liver and kidney function and electrocardiogram (WBC≥3.5 x 109 /L, NEU≥1.2 x 109 /L, PLT≥90 x 109 /L and HGB≥80g/L). The exclusion criteria include history of chemotherapy, radiotherapy, immunotherapy or targeted therapy, multiple primary tumors, suffering from other serious diseases, including cardiovascular, respiratory, kidney, or liver disease, complicated by poorly controlled hypertension, diabetes, mental disorders or diseases, unavailable for R0 resection and D2 lymph node dissection, and patients with stage IV gastric cancer. Although the criteria list is shorter compared to previous phases, the criteria is much more detailed making it harder to find patients to fill the participant pool. In this clinical trial, there are two groups: the standard therapy group and the experimental group. The experimental group has the treatment of the metronomic capecitabine group (dose of 500 mg/m2 body surface area twice daily for one year). The standard therapy group has treatment of standard adjuvant chemotherapy. Throughout the trial, the FDA will also be checking for Good Clinical Practice (GCP). After the trial is finished, a folder is made with all the data from the previous stages in the drug development pipeline with the New Drug Application (NDA) and turned into the FDA review team for approval to release into the market. After the FDA review team receives the NDA and data they have three possible options: rejection, clinical hold, or approval. This process can take up to 10 months to complete.

Phase III Complications

According to the graph above the rate of success for Phase III from 2010 to 2023 averaged about 56% and peaked in 2015 at 81%. The drug must go through tedious testing during each stage previous to Phase III, passing various tests for efficacy and safety while competing against other drug candidates. In 2023, the FDA approved 55 new drugs with a 10.8% approval, which is considered an improvement by IQVIA Healthcare Intelligence. The main reasons for failure during Phase III are lack of efficacy, FDA rejection, costs, study design issues, management, and recruitment. In a GENEDGE article, Arora uses an example of Amylyx Pharmaceuticals' Phase III failure to highlight the failure of drugs in neuroscience. As Phase III is the longest and most expensive trial to conduct, that is just one of the few problems scientists face. He states that trials need to implement exposome markets to measure the life course of environmental factors, widen the approach to more than just symptoms and a molecular profile, and change from measuring quantity to quality over time. The article called for innovative testing methods beyond genetics and phenotyping, prioritizing temporal dynamics and environmental factors to advance CNS drug development.

Ledesma’s LinkedIn article in 2023 about clinical trial budget states that for Phase III studies approved by the FDA, the median cost per patient is $41,117. Multiplying that number with the least amount of patients needed in a Phase III trial (300), the median cost for the smallest Phase III trial would be around $12.3 million. The NIH’s article written in 2022 states the estimated cost per participant was around $16,494. Using this lower number the cost of the small Phase III trial would be around $5 million. When finding the cost of clinical trials, there are several factors such as study size, location, drug type, time, and more, but we are just using the median and smallest number to showcase that even the smallest trials are expensive. These trials are paid for by large companies such as medical corporations, universities, and major hospitals. The costs of clinical trials can be reduced with the help of AI/ML in the future by aiding in patient selection, prediction of trials, and data filtering to help save time. The problem with efficacy can be solved if more data can be provided in previous phases or stages with technological advancements. FDA rejection occurs when the drug does not have enough data or GCP is violated during the clinical trials. As mentioned above, this is the longest phase in clinical trials due to the large sample size, complexity of the trial, and large amounts of data gathered. During Phase III, scientists are looking for any possible reaction to the drug before releasing it into the market to avoid recalls, so testing can be extended depending on the drug and condition being treated.

Adapted from PharmaExcipients. This graphs shows the relationship between specificity/potency (SAR) to Tissue exposure/selectivity (STR).

Current News for Phase III

This week there has been breaking news for two drug candidates, AstraZeneca’s Calquence, Lilly's Tirzepatide, and Sound Pharmaceuticals’ SPI-1005. First, AstraZeneca released high-level findings from their Phase III AMPLIFY study showing the combination regimen of its BTK blocker Calquence and AbbVie and Roche’s Vebckexta improves survival in patients with chronic lymphocytic leukemia. In terms of safety, there were no new signals of concern during the trial and AstraZeneca is waiting on approval to hopefully make Calquence the only second-generation BTK inhibitor available as both a treat-to-progression and fixed-duration treatment. Secondly, Eli Lilly Company announces positive topline results from their SUMMIT Phase III clinical trial evaluating the Tirzepatide injection for treating adults with heart failure with a preserved ejection fraction (HFpEF) and obesity. Tirzepatide is a once-weekly glucose-dependent insulinotropic polypeptide (GIP) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist. As a report of their topline primary endpoint results, Tirzepatide MTD scored 24.8 points in efficacy while placebo scored 15 points. Tirzepatide scored 19.5 points and placebo scored 12.7 points for treatment regimen estimated. The safety profile of Tirzepatide in the SUMMIT trial was consistent with the existing data from previous stages and trials of the drug development pipeline and previous studies, SURMOUNT and SURPASS. Finally, Sound Pharmaceuticals has concluded its Phase III clinical trial on SPI-1005, an investigational anti-inflammatory therapy for treating Meniere’s disease.  The study is currently in the RCT data analysis stage with interim topline results expected to be available this quarter. SPI-1005 contains ebselen, a new chemical entity that is a selen-organic compound that mimics and induces glutathione peroxidase (GPx) activity and is effective in reducing neuroinflammation across the central and peripheral nervous systems.

Phase III is the final step of research and gathering data before submitting the NDA for the FDA team to review and decide whether the drug is market-approved or not. The drug enters this stage with information about its efficacy, safety, and ability to target a specific condition. During this phase, scientists compare the current medication against the drug candidate. The chances for drugs to make it this far in the drug pipeline are slim, but hopefully, with the help of technology, the chances will increase in the future.

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

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• AstraZeneca's Calquence aces Phase III CLL trial, eyes fixed-duration approval. (2024, July 31). BioSpace. Retrieved from https://www.biospace.com/drug-development/astrazenecas-calquence-aces-phase-iii-cll-trial-eyes-fixed-duration-approval

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