Drug-development, dose-selection, rational combinations from bench-to-bedside: are there any lessons worth revisiting?
Year: 2021
Type: article
Abstract: OverviewOne of the most intractable problems in drug development is getting an impartial and accurate evaluation of the agent one is working on, especially since patients are involved in clinical trials.It is particularly acute in the oncology field, where both cause and appropriate treatment of a tumor may partially be rational guesswork.In this situation, patients have a high likelihood of a sub-optimal outcome, notably when they, as profoundly impaired "salvage patients", end up in early clinical trials, receiving modestly characterized agents, which can do great harm if not judiciously used.These factors argue for caution when evaluating an agent, and there are several rules of thumb designed to terminate weak drug candidates as rapidly as possible.This precautionary stance is justified by the high failure rates of drugs in clinical trials.In this review, we argue that certain rules of the drug developmental paradigm are frequently misapplied, resulting in many good agents being discarded, and we provide an example of Hsp90 inhibitors.These "rules" are worth revisiting so that new cancer drugs can be developed and tested in a way that increases the overall success rates in patients. Challenges in cancer drug developmentThe aim of cancer drug development is to kill malignant cells while minimizing the adverse effects on normal cells.But, as the processes and molecules being targeted express in both types of cells to a different extent, this aim is always a balancing act, with extremely few "clean shots" which are not also targets in the patient's normal tissues.The development of a new treatment modality, especially a novel cancer drug, is arduous work and takes years from conception to apparent success (or failure).The process for new drug approval is prolonged, taking 5-15 years with billions of dollars of investment.It is a roller coaster with high attrition, mostly due to clinical efficacy, safety, or commercial concerns.Even when successful, later treatment failure due to the development of eventual drug resistance remains a major challenge, and the majority of patients with inoperable solid tumors still die from them.Bringing a new drug to the market is governed by stringent regulations.Projects can fail at any step of the drug discovery process, particularly during late-stage clinical trials.Despite outsiders' rather glamorous views of drug development, less than 10% of projects make it from Phase I to approval.
Source: Oncotarget
Institution: University of Michigan
Language: English
Subfield: Statistics and Probability
Field: Mathematics
Domain: Physical Sciences
Open Access status: diamond
OpenAlex ID: W3165396245