Phase 0 Trials and FDA and EMEA Standards′ Impact on Drug Development

Kurt Naber^*
*Correspondence: Kurt Naber, Department of Urology, Pediatric Urology and Andrology, Ludwig-Maximilians-University, 35392 Giessen, Germany, Email:

Keywords

Actionability • PharmGKB • Pharmacodynamic

Introduction

Regulatory agencies like the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), the Chinese National Medical Products Administration (NMPA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) play a crucial role in advancing the development of new therapeutic drugs. The partnership between pharmaceutical sponsors and regulators is essential in order to discuss and align expectations for the generation of evidence, facilitate innovative development strategies and ultimately ensure the timely availability of new treatments for patients worldwide. These and other regulatory agencies contribute to the harmonization of global regulatory requirements through bilateral collaborations and active membership in the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). The International Committee for Harmonization (ICH)'s goal is to ensure that safe, effective and high-quality drugs are developed and included in the most resource-effective manner. The recently adopted ICH E17 guideline on General principles for planning and designing multiregional clinical trials, whose principles have the potential to expedite worldwide access to novel therapeutic drugs [1,2], serves as an excellent illustration of this.

Description

The CPIC guidelines and the FDA Table of Pharmacogenetic Associations don't agree very much. Only 5 of the 126 drugs in either source had the same gene-drug association and dosage recommendation and the FDA table does not include many of the medications in the CPIC guidelines. In addition, there is no correlation between the drug classifications in particular sections of the FDA table and the CPIC-assigned or provisionally assigned clinical actionability levels. The Pharmacogenomics Knowledge Base (PharmGKB) typically has high levels of clinical annotation for drugs mentioned in CPIC guidelines. The PharmGKB clinical annotation levels frequently are unassigned or at a lower level for medications that are listed in the FDA table but not in the CPIC guidelines. The FDA's access to PGx data that is not included in the published literature or the fact that PGx classifications are based on criteria other than clinical actionability [3] could be the cause of these variations.

Phase 0 clinical trials are the ones that take place prior to the standard dose escalation, safety and tolerance studies. A novel compound should only be administered to a small number of healthy volunteers or patients in these first-in-human trials for a brief period of time at a lower dose than in Phase I. In phase 0 clinical trials, there is no therapeutic or diagnostic purpose for the volunteer; They should, at least theoretically, enable researchers to quickly ascertain whether a novel compound has the appropriate pharmacokinetic and pharmacodynamic profiles in humans. Phase 0 trials will not be used to determine whether a candidate drug has a positive effect on the targeted disease; instead, the conventional dose escalation, safety and tolerance studies will continue to be carried out. However, due to the lower risk of toxicity, the smaller number of humans treated and the lower doses, the Phase 0 strategy would necessitate fewer preclinical in vitro and in vivo studies than a typical Phase I trial. Prior to Phase I testing, potential drugs may be eliminated through Phase 0 clinical studies, thereby reducing costs and time and increasing drug development efficiency.

Contingency tables were used to conduct a statistical analysis of the dichotomized (bivariate) variables. The diagnostic values of the various proposals were determined by looking at the connections between exposure, confounder and diagnostic outcome. Youden's J-index, positive and negative likelihood ratios (+ LR and LR), diagnostic odds ratio (DOR) and positive and negative predictive values (PPV and NPV, respectively) were all calculated. The evaluation of the area under the bend (AUC) was carried out using ROC bend examination. Using Pearson's item second connection coefficient, the strength of the relationship between openness and a positive demonstrative result was estimated.

During the comparative analyses, the normality and homoscedasticity of the distributions were evaluated using dot charts and Q–Q plots, respectively. To compare independent, homoscedastic and normally distributed variables, the Student's two-sided t test was used. Independent variables with heteroscedastic distributions that are normally distributed were subjected to the two-sided modified t test. Non-parametric tests were used when parametric tests were deemed insufficient. A p value of less than 0.05 was considered significant. This study's findings suggest that FDA condom label indications may influence MSM condom use. In a public web-based example, the majority of MSM (69%) predicted that the FDA name sign of condoms for butt-centric sex would increase their likelihood of using condoms [4].

It was more likely that respondents from demographic groups with a higher risk of HIV transmission, such as younger Black and Latino individuals1, would anticipate an increase in their user count. Despite the fact that condoms are not explicitly labeled as being indicated for anal sex, this study provides evidence that the FDA should be provided with sufficient data to enable an explicit determination. The MSM uses condoms for a number of reasons, including personal preference (like how they fit in or feel), interpersonal (like family) and policy (like the lack of access to appropriate sexual health education among youth who identify as lesbian, gay, or transgender). Given that structural sexual stigma is linked to a decreased utilization of HIV prevention methods, it will be crucial to maximize access to and utilization of HIV prevention services. The three guidelines agree that it is necessary to demonstrate an effect on functional outcome in the prodromal AD stage (where subtle functional impairment is present) in order to confirm the clinical significance of changes on neuropsychological measures. However, they also acknowledge that the current functional decline measures may not be able to detect the specific and subtle functional changes at the prodromal AD stage. Even though the FDA and CHMP encourage the creation of new measures, their guidelines also point to the possibility of measuring only the specific functional domains that are known to be impaired in the early stages of cognitive impairment [5].

Conclusion

It is clear that regulators and sponsors will need to interact in order to agree on the design of the pivotal clinical trials in order to demonstrate that a new drug's effect is clinically significant for patients. If approved in the future, drugs that target the predementia stages of AD should shed light on how clinical meaningfulness is evaluated and whether this evaluation is affected by whether the treatment is claimed to be symptomatic or disease-modifying.

References

1. Stranges, Saverio, Joan M. Dorn, Francesco P. Cappuccio and Richard P. Donahue, et al. "A population-based study of reduced sleep duration and hypertension: The strongest association may be in premenopausal women." Int J Hypertens 28 (2010): 896-902.

Google Scholar, Crossref, Indexed at

2. Cappuccio, Francesco P., Saverio Stranges, Ngianga-Bakwin Kandala and Michelle A. Miller, et al. "Gender-specific associations of short sleep duration with prevalent and incident hypertension: The Whitehall II Study." J Hypertens 50 (2007): 693-700.

Google Scholar, Crossref, Indexed at

3. Bergsagel, P. Leif, Marta Chesi, Elena Nardini and Leslie A. Brents, et al. "Promiscuous translocations into immunoglobulin heavy chain switch regions in multiple myeloma." Proc Natl Acad Sci 93 (1996): 13931-13936.

Google Scholar, Crossref, Indexed at

4. Desrosiers, Ronald, Karen Friderici and Fritz Rottman. "Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells." Proc Natl Acad Sci 71(1974): 3971-3975.

Google Scholar, Crossref, Indexed at

5. Dai, Dongjun, Hanying Wang, Liyuan Zhu and Hongchuan Jin, et al. "N6-methyladenosine links RNA metabolism to cancer progression." Cell Death Dis 9 (2018): 1-13.

Google Scholar, Crossref, Indexed at