1. These are two different clinical development stage of Any New Chemical Entity (NCE) or New Biological Entity (NBE).
Once Potential lead molecule identified in discovery phase including pre-clinical studies like pharmacology (in-vitro and in-vivo), toxicology and pharmacokinetic studies. If the molecule found to be promiscuous then it will enter in clinical phase and first-in-man study can be started based on pre-clinical data.
Phase 0 clinical study
Phase-0 is also called as Microdosing study (Before Phase-I study) in which the dose of drug would be 100th times less than pharmacologically active dose (based on animal pharmacodynamic study data) with maximum dose of <100 micrograms. The necessity of Phase 0 or Microdosing study arises because many lead molecules fail in Phase-I studies due to various reason like poor pharmacokinetic profile, safety issues etc. The ADME characterization can be predicted at early stage with safe dose administration.
To overcome failure, this new concept can help to identify even better clinical candidate at early stage which save time and cost. One of the major costs saving factor is toxicological studies, safety pharmacological studies at pre-clinical stage. The requirement of toxicity testing is also minimal (14 days exposure to one mammalian species of both sexes and route of administration should be similar as intended in human the duration also depend on exposure to human as mentioned in guidance of exploratory studies by USFDA) because microdose studies involve only single exposure to microgram quantity.
However, the administered dose is in microgram so it is difficult to detect smaller quantity with most commonly using LC-MS. It require very high sensitive mass spectroscopy. There are few laboratories which provide bio-analytical services. They use AMS (Accelerator Mass Spectrometer) to detect even pico and famto gram quantity with high specificity. Many imaging techniques like PET are also used to see targeted delivery and molecular level pharmacodynamic effects.
Proof of Concept Study
Proof of Concept study is generally called as Phase-II studies which perform after successful completion of Phase-I (First In Man) based on safety and PK profile of molecule. The proof of efficacy and safety is evaluated in Phase-II with enrollment of targeted patient population. The sample size would be generally in range of 50 to few hundreds (based on Statistical parameter with consideration to primary and secondary end point). Before starting to Phase-II, we would require extensive safety data from pre-clinical studies including, acute, sub-acute, genotoxicity, and reproductive toxicity studies data with Phase-I Clinical study reports with risk and benefit analysis.
A Discussion
Regarding the sensitivity of analytical methods to be used when the objective is to detect traces of ingredients or measuring small quantities (pico and fento), the electrochemical detectors are I think more convenient as the price is still reasonable. Also regarding the PoC, they start at the time the safety studies end, which means it can be Phase Ib or Phase IIa where sometimes less than 50 subjects can be considered.
A phase zero study uses a pharmacologically inactive level of compound to allow clinical studies without the typical required nonclinical safety assessment. A proof of concept study follows the initial safety assessment in humans at near pharmacologic doses after complete nonclinical safety testing, and if done correctly, defines the developability and usability of that compound as a therapeutic.
A phase zero study uses a pharmacologically inactive level of compound to allow clinical studies without the typical required nonclinical safety assessment. A proof of concept study follows the initial safety assessment in humans at near pharmacologic doses after complete nonclinical safety testing, and if done correctly, defines the developability and usability of that compound as a therapeutic.
In April 2005, the FDA released a draft guidance for Exploratory IND studies that clarifies preclinical and clinical approaches when planning exploratory studies in humans. This process is available to the industry enabling a faster, more cost-effective path to early clinical development.
The guidance applies to early phase 1 clinical studies of investigational new drug and biological products that assess feasibility for further development of the drug or biological product. Therefore, the primary application of an Exploratory IND study is Micro-dosing or Phase 0 Clinical Trials.
The Phase 0 is a relatively a new concept; one or more drug candidates are taken into humans at micro doses in order to obtain early ADME and PK information, then the data are used as part of the decision to select which of the micro-dosed drugs has the appropriate PK parameters to take further. This screening allows ensuring that drugs do not have to be dropped later down the development pathway because of inappropriate metabolism. Micro-dosing studies allow to select the best lead compound supported by clinical data, save time and money, lead candidate(s) selected in months not years, cost-effective approach to adding value drug pipeline.
A micro-dose is defined as less than 1/100th of the dose calculated to yield a pharmacological effect of a test substance and a maximum dose of <100 micrograms. The micro-dosing studies are designed not to induce pharmacological effects, the potential risk to human subjects is very limited. Therefore, these studies can be initiated with less preclinical safety data, help reduce the number of human subjects needed and require fewer resources for selecting promising drugs candidates for further development. The duration of dosing is expected to be limited (e.g., 4 to 7 days).
The proof of Concept (PoC) study is aimed to demonstrate the clinical efficacy with a small number of patients. It may be defined as the earliest stage in the drug development process at which potential GO/NO GO decision criteria are: Safety, Tolerability, Bioavailability/PK, PD, Biopharmaceutics, Duration of action; Relationship Dose / PD, Efficacy,
Patient acceptability , Commercial viability... Therefore PoC is multi objectives but focused on attributes that, if not addressed, represent a threat to the success of the project in crucial areas such as safety, efficacy, pharmaceutics, commercial and regulatory issues. As the published in the Applied Clinical Trials Journal, the role of the regulatory affairs scientists is expected to change.
Tools for PoC include biomarkers, targeted populations, PK/PD modeling, simulation, and adaptive study designs. Challenges to the success of PoCs include a shortage of skilled personnel, failure to integrate multiple disciplines and information, and the demand made by organizations for weighting the decisions.
Once Potential lead molecule identified in discovery phase including pre-clinical studies like pharmacology (in-vitro and in-vivo), toxicology and pharmacokinetic studies. If the molecule found to be promiscuous then it will enter in clinical phase and first-in-man study can be started based on pre-clinical data.
Phase 0 clinical study
Phase-0 is also called as Microdosing study (Before Phase-I study) in which the dose of drug would be 100th times less than pharmacologically active dose (based on animal pharmacodynamic study data) with maximum dose of <100 micrograms. The necessity of Phase 0 or Microdosing study arises because many lead molecules fail in Phase-I studies due to various reason like poor pharmacokinetic profile, safety issues etc. The ADME characterization can be predicted at early stage with safe dose administration.
To overcome failure, this new concept can help to identify even better clinical candidate at early stage which save time and cost. One of the major costs saving factor is toxicological studies, safety pharmacological studies at pre-clinical stage. The requirement of toxicity testing is also minimal (14 days exposure to one mammalian species of both sexes and route of administration should be similar as intended in human the duration also depend on exposure to human as mentioned in guidance of exploratory studies by USFDA) because microdose studies involve only single exposure to microgram quantity.
However, the administered dose is in microgram so it is difficult to detect smaller quantity with most commonly using LC-MS. It require very high sensitive mass spectroscopy. There are few laboratories which provide bio-analytical services. They use AMS (Accelerator Mass Spectrometer) to detect even pico and famto gram quantity with high specificity. Many imaging techniques like PET are also used to see targeted delivery and molecular level pharmacodynamic effects.
Proof of Concept Study
Proof of Concept study is generally called as Phase-II studies which perform after successful completion of Phase-I (First In Man) based on safety and PK profile of molecule. The proof of efficacy and safety is evaluated in Phase-II with enrollment of targeted patient population. The sample size would be generally in range of 50 to few hundreds (based on Statistical parameter with consideration to primary and secondary end point). Before starting to Phase-II, we would require extensive safety data from pre-clinical studies including, acute, sub-acute, genotoxicity, and reproductive toxicity studies data with Phase-I Clinical study reports with risk and benefit analysis.
A Discussion
Regarding the sensitivity of analytical methods to be used when the objective is to detect traces of ingredients or measuring small quantities (pico and fento), the electrochemical detectors are I think more convenient as the price is still reasonable. Also regarding the PoC, they start at the time the safety studies end, which means it can be Phase Ib or Phase IIa where sometimes less than 50 subjects can be considered.
A phase zero study uses a pharmacologically inactive level of compound to allow clinical studies without the typical required nonclinical safety assessment. A proof of concept study follows the initial safety assessment in humans at near pharmacologic doses after complete nonclinical safety testing, and if done correctly, defines the developability and usability of that compound as a therapeutic.
A phase zero study uses a pharmacologically inactive level of compound to allow clinical studies without the typical required nonclinical safety assessment. A proof of concept study follows the initial safety assessment in humans at near pharmacologic doses after complete nonclinical safety testing, and if done correctly, defines the developability and usability of that compound as a therapeutic.
In April 2005, the FDA released a draft guidance for Exploratory IND studies that clarifies preclinical and clinical approaches when planning exploratory studies in humans. This process is available to the industry enabling a faster, more cost-effective path to early clinical development.
The guidance applies to early phase 1 clinical studies of investigational new drug and biological products that assess feasibility for further development of the drug or biological product. Therefore, the primary application of an Exploratory IND study is Micro-dosing or Phase 0 Clinical Trials.
The Phase 0 is a relatively a new concept; one or more drug candidates are taken into humans at micro doses in order to obtain early ADME and PK information, then the data are used as part of the decision to select which of the micro-dosed drugs has the appropriate PK parameters to take further. This screening allows ensuring that drugs do not have to be dropped later down the development pathway because of inappropriate metabolism. Micro-dosing studies allow to select the best lead compound supported by clinical data, save time and money, lead candidate(s) selected in months not years, cost-effective approach to adding value drug pipeline.
A micro-dose is defined as less than 1/100th of the dose calculated to yield a pharmacological effect of a test substance and a maximum dose of <100 micrograms. The micro-dosing studies are designed not to induce pharmacological effects, the potential risk to human subjects is very limited. Therefore, these studies can be initiated with less preclinical safety data, help reduce the number of human subjects needed and require fewer resources for selecting promising drugs candidates for further development. The duration of dosing is expected to be limited (e.g., 4 to 7 days).
The proof of Concept (PoC) study is aimed to demonstrate the clinical efficacy with a small number of patients. It may be defined as the earliest stage in the drug development process at which potential GO/NO GO decision criteria are: Safety, Tolerability, Bioavailability/PK, PD, Biopharmaceutics, Duration of action; Relationship Dose / PD, Efficacy,
Patient acceptability , Commercial viability... Therefore PoC is multi objectives but focused on attributes that, if not addressed, represent a threat to the success of the project in crucial areas such as safety, efficacy, pharmaceutics, commercial and regulatory issues. As the published in the Applied Clinical Trials Journal, the role of the regulatory affairs scientists is expected to change.
Tools for PoC include biomarkers, targeted populations, PK/PD modeling, simulation, and adaptive study designs. Challenges to the success of PoCs include a shortage of skilled personnel, failure to integrate multiple disciplines and information, and the demand made by organizations for weighting the decisions.
