Overview of Drug Development
Mark Chang, John Balser, Jim Roach, Robin Bliss in Innovative Strategies, Statistical Solutions and Simulations for Modern Clinical Trials, 2019
Traditionally, Phase I trials are the first stage of testing in human subjects. Normally, a small (6–60) group of healthy volunteers will be selected with the exception of some special diseases such as oncology and HIV in which these studies may be conducted in patients with the disease under evaluation. The objectives of the phase trials are to assess/explore the safety, tolerability, pharmacokinetics, and pharmacodynamics of a drug. These trials are often conducted in an inpatient clinic, where the subject can be closely monitored. The subject who receives the drug is usually observed until a minimum of five half-lives of the drug have passed. A Phase I trial is often a dose escalation study to determine the appropriate dose for therapeutic use. If the drug is intended to be used for multiple dose, then phase I trials will usually include a single ascending dose (SAD) study followed by a multiple ascending dose (MAD) trial.
Role of Biomarkers in Clinical Development of Cancer Therapies
Sherry X. Yang, Janet E. Dancey in Handbook of Therapeutic Biomarkers in Cancer, 2021
The goals of phase I trials are to evaluate the pharmacokinetics and safety of the agent and to make recommendations for the dose that will be used in phase II efficacy evaluation. For a drug to reliable test the hypothesis of the target, it is essential to ensure that the drug hits the intended target, and that the selected dose is optimal for efficacy and tolerability. The traditional models based on PK and toxicities have worked well for cytotoxic chemotherapies, whose target toxicities on proliferative tissues (bone marrow suppression or diarrhea) often follow a similar dose-effect relationship as in tumor cells. Some MTAs are also associated specific and quantifiable target-related toxicities (e.g., skin rash after EGFR inhibition), and these adverse events are useful indicators of the target effects. For other MTAs, the target effects on host tissues can be low or nonspecific, in which case, measurements of molecular changes in tumor tissues before and after drug exposure would be critical to verifying the target engagement and estimating the required dose for efficacy. Although PK and safety endpoints should remain the primary objectives of phase I trials, PD markers can provide important ancillary information when properly used and interpreted. Various PD markers have been used in modern day early clinical trials (Table 3.2).
Bayesian Statistics in Drug Development
Harry Yang, Steven J. Novick in Bayesian Analysis with R for Drug Development, 2019
The primary objective of a Phase I study is to determine the safety profile and to study the pharmacokinetic property of the drug. For drugs with moderate toxicity, the trial is normally carried out using healthy male volunteers. However, for cytotoxic agents, Phase I trials are usually conducted in the target patient populations to minimize unnecessary exposures of the drugs in healthy volunteers. Dose-escalation designs may be used (see Chapter 5). They typically begin with a low dose of the drug predicted from the animal studies and progressively escalate to higher doses if the drug is well tolerated. A range of doses is explored, and the maximum tolerated dose is determined. The study also collects pharmacodynamic and pharmacokinetic data to address important questions such as side effects, therapeutic effects, and ADME. The knowledge garnered from this stage of development, including the safe dosing range, is used to guide the next phase of clinical development.
Neither the Harm Principle nor the Best Interest Standard Should Be Applied to Pediatric Research
Published in The American Journal of Bioethics, 2018
Marcin Waligora, Karolina Strzebonska, Mateusz T. Wasylewski
Phase I trials in oncology aim to establish safety, the maximum tolerated dose, and preliminary efficacy of tested drugs. Participants have exhausted standard therapeutic treatments. An average risk of severe (grade 3) and life-threatening or disabling (grade 4) drug-related adverse events (AE) for pediatric participants of phase 1 clinical trials in oncology is 1.32 per person (on average every participant experiences at least one of grade 3/4 AEs). Around 1 in 50 children die from drug-related AEs (grade 5). Approximately 1 in 10 children experiences surrogate objective response (i.e., tumor shrinkage), which will not necessarily translate into real-life benefit such as survival rate or quality of life (Waligora et al. 2018). Classifying those trials as “potentially beneficial” and offering “minimal risk” in light of systematic findings on the risk and benefit can be misleading. Thus, we argue that neither the best interest standard nor the harm principle is an appropriate concept for the ethical framework for these trials. We propose a secure child standard complemented by additional safeguards instead (Piasecki, Waligora, and Dranseika 2015; Shah 2013).
“Paid to Endure”: Paid Research Participation, Passivity, and the Goods of Work
Published in The American Journal of Bioethics, 2019
As these quotes highlight, research participation appears to be an unusually passive way of making a living. Most workers are paid to produce or achieve something. This may involve tasks that are unpleasant, demeaning, or intrusive on their privacy. But what is experienced as unpleasant, demeaning, or intrusive is usually integral to something workers do. Participation in phase I trials seems different. Subjects’ main tasks are to ingest substances (investigational drugs, active controls, or placebos), undergo tests (e.g., blood pressure, electrocardiograms) and physical interventions (e.g., blood draws, lumbar punctures), provide samples of bodily material (e.g., urine, feces), comply with strict routines regarding, for example, diet and resting, and, in most cases, agree to temporary confinement to a research facility. In other words, they are not paid to produce or achieve anything, but to submit to the actions of others.
The Exploitation of Professional “Guinea Pigs” in the Gig Economy: The Difficult Road From Consent to Justice
Published in The American Journal of Bioethics, 2019
While Millum and Garnett are not explicitly considering professional guinea pigs in their recommendations, this framework could easily be adapted to their situation. It’s worth considering acceptable alternatives—but there might not be any, regarding the participation of professional guinea pigs in phase I trial research. That’s the point of conducting phase I trials in the first place. While some have recommended computerized modeling to move from preclinical studies to later phases of drug development, where the drugs would be tested for safety and efficacy, this does not seem feasible. We have suggested lowering the number of phase I me-too drug trials, which would limit risks for participants while ensuring potential outcomes and would also eliminate professionalization by relying on altruistic participation for a reduced number of potentially lifesaving drugs. The powerful pharmaceutical lobby would no doubt fight to the teeth any restriction or incentive to limit me-too drug trials (Angell 2004). And while for bioethicists the altruistically motivated might constitute the preferred subject group, as they would be simultaneously informed, rational, and oriented toward the social good, we know that blood and organ donation and other instances of altruism do not fare well beyond the limited windows of an emergency or a particular mobilizing event.
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