Dr. Anita Joshi gave a lecture on moving a new drug or biologic candidate from pre-clinical testing to market. She described the multi-step process, including pre-clinical testing in test tubes and animals to determine safety, efficacy, and pharmacokinetics. Successful candidates then undergo clinical trials in three phases with humans to further evaluate these factors before regulatory review and potential marketing approval. The overall process takes an estimated 12 years and costs $5-8 million on average, with many candidates failing to reach later stages or approval.
Preclinical trials involve testing potential new drugs on animals before human testing to determine if they are safe and effective. This process involves several key steps: 1) Researchers identify a biological target related to a disease through basic research. 2) They develop a bioassay using cells or animals to test drug effects. 3) Potential drug compounds are screened in the bioassay to see if they act on the target. 4) Effective and toxic doses are established to find a safe range. If successful, 5) approval is sought from the FDA to begin clinical trials in humans.
Drug development involves basic research to identify drug targets and applied research to develop treatments. Preclinical trials test drug safety and efficacy in animals prior to human trials. They involve pharmacokinetic, pharmacodynamic and toxicology studies in two animal species. This provides data on effective and toxic doses, screens the drug's activity, and identifies formulation. Preclinical trials help determine if a drug warrants further development or should be terminated. They aim to predict potential human adverse effects and provide guidance for initial human clinical trials. However, extrapolating animal data to humans has limitations due to interspecies differences.
This document provides guidelines for safety pharmacology and toxicology studies for pharmaceutical products. It outlines the objectives and types of studies recommended at different stages of clinical development, including safety pharmacology core battery studies, follow-up studies, reproductive and developmental toxicity studies, and human studies. Test systems, dose levels, durations, endpoints, and good laboratory practice standards are discussed for each type of nonclinical study.
New drug development is a highly complex, costly, and time-consuming process that can take over 10 years. It involves synthesis of new chemical entities, preclinical studies in animals and cells to evaluate safety and efficacy, followed by clinical trials in humans in 4 phases to further assess safety and efficacy. If clinical trials are successful, regulatory approval must be obtained before the drug can be marketed. The overall goal is to bring new treatments to patients while ensuring safety and effectiveness through a rigorous scientific process.
The document summarizes the process of drug discovery and development. It involves several long steps: understanding the disease, finding a biological target, discovering a lead compound through screening or nature, conducting preclinical testing on animals, and then clinical trials in three phases with humans to test safety and efficacy before the FDA decides whether to approve the drug. The entire process from discovery to approval takes an average of 10-15 years and costs $1-2 billion. Drugs also have different categories depending on how they are regulated and prescribed.
The document discusses the drug development process from discovery to approval. It covers key stages including discovery research, preclinical testing, clinical trials, regulatory review and approval, and product launch. Key aspects addressed are screening compounds for drug candidates, assessing safety and efficacy in animal and human studies, developing formulations, and engaging regulatory agencies for approval to market a new drug. The overall goal is to discover, develop and launch new pharmaceutical products that treat diseases and conditions.
Preclinical drug discovery and developmentsamthamby79
This document provides an overview of preclinical drug discovery and development processes. It discusses rational drug design, screening approaches, molecular modification of lead compounds, pharmacokinetic and toxicology studies in animal models, and regulatory requirements for data on a drug's primary pharmacology, secondary effects, and interactions prior to clinical trials. The goal of preclinical research is to obtain sufficient safety and efficacy data on new chemical entities to justify testing in humans.
The document outlines the general process for preclinical drug development, including the goals of preclinical studies to determine a product's safety profile and limit risks to human subjects. It describes how flowcharts are used to logically assess risks and guide decision making around transitioning from preclinical to clinical trials. The key areas of preclinical investigation are mentioned, along with the importance of clinical observations and signs of toxicity in interpreting safety data from minimal acute toxicity tests in animals.
Preclinical trials involve testing potential new drugs on animals before human testing to determine if they are safe and effective. This process involves several key steps: 1) Researchers identify a biological target related to a disease through basic research. 2) They develop a bioassay using cells or animals to test drug effects. 3) Potential drug compounds are screened in the bioassay to see if they act on the target. 4) Effective and toxic doses are established to find a safe range. If successful, 5) approval is sought from the FDA to begin clinical trials in humans.
Drug development involves basic research to identify drug targets and applied research to develop treatments. Preclinical trials test drug safety and efficacy in animals prior to human trials. They involve pharmacokinetic, pharmacodynamic and toxicology studies in two animal species. This provides data on effective and toxic doses, screens the drug's activity, and identifies formulation. Preclinical trials help determine if a drug warrants further development or should be terminated. They aim to predict potential human adverse effects and provide guidance for initial human clinical trials. However, extrapolating animal data to humans has limitations due to interspecies differences.
This document provides guidelines for safety pharmacology and toxicology studies for pharmaceutical products. It outlines the objectives and types of studies recommended at different stages of clinical development, including safety pharmacology core battery studies, follow-up studies, reproductive and developmental toxicity studies, and human studies. Test systems, dose levels, durations, endpoints, and good laboratory practice standards are discussed for each type of nonclinical study.
New drug development is a highly complex, costly, and time-consuming process that can take over 10 years. It involves synthesis of new chemical entities, preclinical studies in animals and cells to evaluate safety and efficacy, followed by clinical trials in humans in 4 phases to further assess safety and efficacy. If clinical trials are successful, regulatory approval must be obtained before the drug can be marketed. The overall goal is to bring new treatments to patients while ensuring safety and effectiveness through a rigorous scientific process.
The document summarizes the process of drug discovery and development. It involves several long steps: understanding the disease, finding a biological target, discovering a lead compound through screening or nature, conducting preclinical testing on animals, and then clinical trials in three phases with humans to test safety and efficacy before the FDA decides whether to approve the drug. The entire process from discovery to approval takes an average of 10-15 years and costs $1-2 billion. Drugs also have different categories depending on how they are regulated and prescribed.
The document discusses the drug development process from discovery to approval. It covers key stages including discovery research, preclinical testing, clinical trials, regulatory review and approval, and product launch. Key aspects addressed are screening compounds for drug candidates, assessing safety and efficacy in animal and human studies, developing formulations, and engaging regulatory agencies for approval to market a new drug. The overall goal is to discover, develop and launch new pharmaceutical products that treat diseases and conditions.
Preclinical drug discovery and developmentsamthamby79
This document provides an overview of preclinical drug discovery and development processes. It discusses rational drug design, screening approaches, molecular modification of lead compounds, pharmacokinetic and toxicology studies in animal models, and regulatory requirements for data on a drug's primary pharmacology, secondary effects, and interactions prior to clinical trials. The goal of preclinical research is to obtain sufficient safety and efficacy data on new chemical entities to justify testing in humans.
The document outlines the general process for preclinical drug development, including the goals of preclinical studies to determine a product's safety profile and limit risks to human subjects. It describes how flowcharts are used to logically assess risks and guide decision making around transitioning from preclinical to clinical trials. The key areas of preclinical investigation are mentioned, along with the importance of clinical observations and signs of toxicity in interpreting safety data from minimal acute toxicity tests in animals.
The pre-clinical trial process involves testing new drugs on animal and cell bioassays before human testing to determine if they are safe and effective. It begins with basic research to identify a drug target related to a disease. Researchers then develop a bioassay and screen drug candidates to find ones that act on the target as intended without toxicity. Effective and toxic doses are established, and approval is sought from the FDA to begin clinical trials on humans by filing an Investigational New Drug application. The goal of pre-clinical trials is to apply findings from basic research on biochemical pathways and identify promising drug candidates ready for initial human testing.
The document summarizes the stages of drug development from discovery through clinical trials and regulatory approval. It describes 10 main stages: 1) discovery and development, 2) preclinical research, 3) investigational new drug application, 4) clinical research including 3 phases of trials, 5) FDA review and approval, and 6) post-market safety monitoring. Preclinical research involves testing for safety and efficacy in animal and lab models. If promising, the drug enters clinical trials with humans starting with small Phase 1 safety studies, then Phase 2 dosing studies, and larger Phase 3 trials to confirm efficacy before the FDA reviews the final application for approval. The overall process takes around 10-15 years from discovery to patients.
This document discusses the process of new drug evaluation, which involves 3 phases - drug discovery, preclinical testing, and clinical trials. In the drug discovery phase, candidate molecules are selected. Preclinical testing involves animal studies to evaluate safety. Clinical trials with human subjects are then conducted in 3 phases to evaluate efficacy, safety, and adverse effects. The clinical trials process is highly regulated to ensure safety and data integrity. If successful, a New Drug Application is filed with regulatory authorities for approval to market the new drug.
The document discusses various approaches to drug discovery, including pharmacological, toxicological, and preclinical trials. It describes the components of pharmacological evaluation including selectivity testing, pharmacological profiling in vitro and in vivo, and safety pharmacology testing of major organ systems like central nervous system, cardiovascular, and respiratory systems. The goal of preclinical trials is to determine if a new drug works and is safe to test in humans using animal models and evaluating its pharmacological effects, toxicity, and safety pharmacologically.
Preclinical studies are conducted before human trials to assess pharmacological and toxicological effects. Both in vitro and in vivo studies characterize these effects. Preclinical testing aims to detect toxicity, understand hazards, establish dose responses, and assess distribution, metabolism, and carcinogenicity. It involves short and long term animal studies in two species, as well as safety pharmacology, toxicology, developmental and reproductive toxicity testing, and genetic and carcinogenicity studies. The steps of preclinical trials include identifying a drug target, developing a bioassay, screening compounds, establishing effective and toxic doses, and filing for investigational new drug approval.
Phase 1 clinical trials are the first studies conducted in humans of a new drug or treatment. They aim to determine the drug's safety and tolerability, identify the maximum tolerated dose, and understand the drug's pharmacokinetics. Phase 1 trials typically involve small groups of healthy volunteers or patients and start with low doses that are gradually increased. The results of phase 1 trials provide information needed to design subsequent phase 2 and 3 trials to further evaluate efficacy.
Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by serendipitous discovery, as with penicillin. More recently, chemical libraries of synthetic small molecules, natural products or extracts were screened in intact cells or whole organisms to identify substances that had a desirable therapeutic effect in a process known as classical pharmacology. After sequencing of the human genome allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to use high throughput screening of large compounds libraries against isolated biological targets which are hypothesized to be disease-modifying in a process known as reverse pharmacology. Hits from these screens are then tested in cells and then in animals for efficacy
Drug development process and clinical trial for UGsSameerKhasbage
This document summarizes the process of drug development from discovery through clinical trials and approval. It discusses the main goals and requirements of each phase of clinical trials: Phase I focuses on safety and dosing in healthy volunteers, Phase II evaluates efficacy and side effects in patients, Phase III tests efficacy versus existing treatments in hundreds to thousands of patients, and Phase IV monitors long-term safety and efficacy after approval and marketing. The overall process from discovery to approval takes 10-15 years and costs over $2 billion on average.
This document provides guidelines for safety pharmacology studies for human pharmaceuticals. It defines safety pharmacology as studies investigating potential undesirable pharmacological effects on physiological functions. The guidelines describe a core battery of studies on the central nervous, cardiovascular and respiratory systems to be conducted prior to first human administration. Follow up and supplemental studies may be warranted based on properties, class effects or safety concerns. The timing of studies in relation to clinical development is outlined.
Drug development involves preclinical and clinical phases. Preclinical development can take 1-5 years and involves in vitro and in vivo studies to determine pharmacological efficacy, safety, and first human dose. Clinical development has four phases. Phase I studies a drug's safety on 50-100 healthy volunteers. Phase II assesses efficacy on 100-400 patients. Phase III verifies efficacy and safety on 500-2000 patients across sites. Phase IV monitors safety post-marketing through physician reporting. The goal is to determine a drug's pharmacological properties, safety, and efficacy to support regulatory approval and post-market surveillance.
The document discusses the process of drug development from discovery through clinical trials and regulatory approval. It begins with an overview of the iterative process involving biology, animal testing, and medicinal chemistry. It then outlines the typical 5 steps in drug development according to the FDA: discovery/screening, pre-clinical research including in vitro and in vivo testing, clinical research consisting of Phase I-III trials, FDA review, and post-marketing monitoring. The document provides details on each stage of development including pre-clinical and clinical research requirements and processes.
safety pharmacology is the branch of pharmacology specializing in detecting and investigating potential undesirable pharmacodynamic effects of a new chemical on physiological functions .
the content of this presentation is as follows
- introduction
- definition
- history
- ICH - guidelines
- refrences
Preclinical Toxicity Studies-Tool of Drug Discoverydynajolly
As per WHO “Drug is any substance or product that is used or is intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient”. Hence the prime objective of using any substance as a drug is that it must be beneficial for the humans. A large number of compounds are synthesized every year but they cannot be directly used in humans as drugs because no one knows or can predict the possible harmful effects of these compounds in humans. That is why to explore the complete pharmacological profile of these compounds and to ensure complete human safety they are first tested on animals before clinical use. Preclinical Studies thus can be defined as “Testing the newly discovered compound in animals with the objective of gaining information regarding the various aspects of the compound with respect to the biological systems so that the same can be extrapolated for the use of that compound in humans”. As the evaluation progresses undesirable compounds gets rejected at each step, so that only a few out of thousands reach the stage when administration to the humans is considered.
Pharmacovigilance and Pharmacoepidemiology journal accepts articles from different disciplines as below but not constrained to only these Pharmacovigilance signal, Pharmacovigilance data management, Design and development of drug, Principles of pharmacology, Quality system and pharmacovigilance, Pharmacovigilance softwares, Drug regulatory activities, Drug reactions and diagnosis, Reporting systems, Clinical trials and pharmacovigilance, Marketing surveillance, Pharmacovigilance ethics and regulations, Biomarkers and pharmacology , Concepts and trends in pharmacovigilance, Pharmaceutical medicines, Drug delivery systems, Statistics and data management.
The document outlines the 5 step drug development process: 1) discovery and development, 2) preclinical research, 3) clinical research consisting of 4 phases, 4) FDA drug review, and 5) post-market safety monitoring. It provides details on each step, including discovery methods, preclinical toxicity testing in animals, clinical trial design, and FDA requirements and oversight at each phase of development. The overall process takes an average of 10-15 years from discovery to approval due to the extensive testing required to demonstrate safety and efficacy.
Drug development - Background informationXplore Health
This guide provides background information on the drug development process including the different phases and the ethical, legal and social aspects associated.
This document outlines the new drug development process (NDDP), including drug discovery through screening, preclinical and clinical evaluation, regulatory approval from bodies like the FDA, and ethical guidelines. It describes the stages of clinical trials from Phase I through III that assess safety, efficacy and side effects in increasing numbers of participants. The goal of the NDDP is to develop new drugs to meet unmet medical needs and obtain regulatory approval to market the drug. Ethical standards like informed consent and minimizing risk to participants are required.
Toxicological Approach to Drug DiscoverySuhas Reddy C
This document outlines the toxicological approach to drug development. It discusses the importance of conducting various toxicity studies at different stages of drug development to ensure safety. These include single dose, repeated dose, fertility, reproductive, developmental and genotoxicity studies in animals. It describes the typical safety program involving staged approach and discusses factors to consider in designing toxicity studies. The goal is to obtain sufficient non-clinical safety data to support clinical trials and assess safety for human use.
The document provides an overview of the drug development process. It discusses the major stages of clinical trials from Phase I to Phase IV that drugs must go through for testing and approval. The goals are to determine safety, efficacy, appropriate dosing, and identify any adverse effects. Rigorous clinical trials with control groups, randomization, and large sample sizes are necessary to provide substantial evidence for approval. The overall process takes an average of about 100 months from initial synthesis to approval.
Preclinical studies, clinical trails and pharmacovigilancekamrudeen samani
The document discusses the various phases of drug development including preclinical, clinical, and post-marketing phases. The preclinical phase involves animal studies to evaluate toxicity, pharmacokinetics, and pharmacodynamics. If promising, the drug enters clinical trials with Phase I studying safety in healthy volunteers, Phase II studying efficacy in patients, and Phase III large scale studies to further confirm safety and efficacy. After approval, Phase IV involves post-marketing surveillance. Pharmacovigilance aims to improve patient safety by monitoring drugs for adverse effects after market entry.
Stages of drug development by Dr Joseph Oyepata Simeon (Ph.D)oyepata
The document outlines the stages of drug development from discovery through clinical trials and FDA approval. It discusses 4 main stages: 1) Discovery and preclinical research involving animal testing, 2) Clinical research consisting of 4 phases starting with small safety trials and increasing in size, 3) Filing an Investigational New Drug Application with the FDA to begin clinical trials, and 4) Final FDA review and potential approval or denial to market the drug. Only about 25-30% of drugs make it through the entire process, which can take 10-15 years and costs over $2 billion on average.
The pre-clinical trial process involves testing new drugs on animal and cell bioassays before human testing to determine if they are safe and effective. It begins with basic research to identify a drug target related to a disease. Researchers then develop a bioassay and screen drug candidates to find ones that act on the target as intended without toxicity. Effective and toxic doses are established, and approval is sought from the FDA to begin clinical trials on humans by filing an Investigational New Drug application. The goal of pre-clinical trials is to apply findings from basic research on biochemical pathways and identify promising drug candidates ready for initial human testing.
The document summarizes the stages of drug development from discovery through clinical trials and regulatory approval. It describes 10 main stages: 1) discovery and development, 2) preclinical research, 3) investigational new drug application, 4) clinical research including 3 phases of trials, 5) FDA review and approval, and 6) post-market safety monitoring. Preclinical research involves testing for safety and efficacy in animal and lab models. If promising, the drug enters clinical trials with humans starting with small Phase 1 safety studies, then Phase 2 dosing studies, and larger Phase 3 trials to confirm efficacy before the FDA reviews the final application for approval. The overall process takes around 10-15 years from discovery to patients.
This document discusses the process of new drug evaluation, which involves 3 phases - drug discovery, preclinical testing, and clinical trials. In the drug discovery phase, candidate molecules are selected. Preclinical testing involves animal studies to evaluate safety. Clinical trials with human subjects are then conducted in 3 phases to evaluate efficacy, safety, and adverse effects. The clinical trials process is highly regulated to ensure safety and data integrity. If successful, a New Drug Application is filed with regulatory authorities for approval to market the new drug.
The document discusses various approaches to drug discovery, including pharmacological, toxicological, and preclinical trials. It describes the components of pharmacological evaluation including selectivity testing, pharmacological profiling in vitro and in vivo, and safety pharmacology testing of major organ systems like central nervous system, cardiovascular, and respiratory systems. The goal of preclinical trials is to determine if a new drug works and is safe to test in humans using animal models and evaluating its pharmacological effects, toxicity, and safety pharmacologically.
Preclinical studies are conducted before human trials to assess pharmacological and toxicological effects. Both in vitro and in vivo studies characterize these effects. Preclinical testing aims to detect toxicity, understand hazards, establish dose responses, and assess distribution, metabolism, and carcinogenicity. It involves short and long term animal studies in two species, as well as safety pharmacology, toxicology, developmental and reproductive toxicity testing, and genetic and carcinogenicity studies. The steps of preclinical trials include identifying a drug target, developing a bioassay, screening compounds, establishing effective and toxic doses, and filing for investigational new drug approval.
Phase 1 clinical trials are the first studies conducted in humans of a new drug or treatment. They aim to determine the drug's safety and tolerability, identify the maximum tolerated dose, and understand the drug's pharmacokinetics. Phase 1 trials typically involve small groups of healthy volunteers or patients and start with low doses that are gradually increased. The results of phase 1 trials provide information needed to design subsequent phase 2 and 3 trials to further evaluate efficacy.
Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by serendipitous discovery, as with penicillin. More recently, chemical libraries of synthetic small molecules, natural products or extracts were screened in intact cells or whole organisms to identify substances that had a desirable therapeutic effect in a process known as classical pharmacology. After sequencing of the human genome allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to use high throughput screening of large compounds libraries against isolated biological targets which are hypothesized to be disease-modifying in a process known as reverse pharmacology. Hits from these screens are then tested in cells and then in animals for efficacy
Drug development process and clinical trial for UGsSameerKhasbage
This document summarizes the process of drug development from discovery through clinical trials and approval. It discusses the main goals and requirements of each phase of clinical trials: Phase I focuses on safety and dosing in healthy volunteers, Phase II evaluates efficacy and side effects in patients, Phase III tests efficacy versus existing treatments in hundreds to thousands of patients, and Phase IV monitors long-term safety and efficacy after approval and marketing. The overall process from discovery to approval takes 10-15 years and costs over $2 billion on average.
This document provides guidelines for safety pharmacology studies for human pharmaceuticals. It defines safety pharmacology as studies investigating potential undesirable pharmacological effects on physiological functions. The guidelines describe a core battery of studies on the central nervous, cardiovascular and respiratory systems to be conducted prior to first human administration. Follow up and supplemental studies may be warranted based on properties, class effects or safety concerns. The timing of studies in relation to clinical development is outlined.
Drug development involves preclinical and clinical phases. Preclinical development can take 1-5 years and involves in vitro and in vivo studies to determine pharmacological efficacy, safety, and first human dose. Clinical development has four phases. Phase I studies a drug's safety on 50-100 healthy volunteers. Phase II assesses efficacy on 100-400 patients. Phase III verifies efficacy and safety on 500-2000 patients across sites. Phase IV monitors safety post-marketing through physician reporting. The goal is to determine a drug's pharmacological properties, safety, and efficacy to support regulatory approval and post-market surveillance.
The document discusses the process of drug development from discovery through clinical trials and regulatory approval. It begins with an overview of the iterative process involving biology, animal testing, and medicinal chemistry. It then outlines the typical 5 steps in drug development according to the FDA: discovery/screening, pre-clinical research including in vitro and in vivo testing, clinical research consisting of Phase I-III trials, FDA review, and post-marketing monitoring. The document provides details on each stage of development including pre-clinical and clinical research requirements and processes.
safety pharmacology is the branch of pharmacology specializing in detecting and investigating potential undesirable pharmacodynamic effects of a new chemical on physiological functions .
the content of this presentation is as follows
- introduction
- definition
- history
- ICH - guidelines
- refrences
Preclinical Toxicity Studies-Tool of Drug Discoverydynajolly
As per WHO “Drug is any substance or product that is used or is intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient”. Hence the prime objective of using any substance as a drug is that it must be beneficial for the humans. A large number of compounds are synthesized every year but they cannot be directly used in humans as drugs because no one knows or can predict the possible harmful effects of these compounds in humans. That is why to explore the complete pharmacological profile of these compounds and to ensure complete human safety they are first tested on animals before clinical use. Preclinical Studies thus can be defined as “Testing the newly discovered compound in animals with the objective of gaining information regarding the various aspects of the compound with respect to the biological systems so that the same can be extrapolated for the use of that compound in humans”. As the evaluation progresses undesirable compounds gets rejected at each step, so that only a few out of thousands reach the stage when administration to the humans is considered.
Pharmacovigilance and Pharmacoepidemiology journal accepts articles from different disciplines as below but not constrained to only these Pharmacovigilance signal, Pharmacovigilance data management, Design and development of drug, Principles of pharmacology, Quality system and pharmacovigilance, Pharmacovigilance softwares, Drug regulatory activities, Drug reactions and diagnosis, Reporting systems, Clinical trials and pharmacovigilance, Marketing surveillance, Pharmacovigilance ethics and regulations, Biomarkers and pharmacology , Concepts and trends in pharmacovigilance, Pharmaceutical medicines, Drug delivery systems, Statistics and data management.
The document outlines the 5 step drug development process: 1) discovery and development, 2) preclinical research, 3) clinical research consisting of 4 phases, 4) FDA drug review, and 5) post-market safety monitoring. It provides details on each step, including discovery methods, preclinical toxicity testing in animals, clinical trial design, and FDA requirements and oversight at each phase of development. The overall process takes an average of 10-15 years from discovery to approval due to the extensive testing required to demonstrate safety and efficacy.
Drug development - Background informationXplore Health
This guide provides background information on the drug development process including the different phases and the ethical, legal and social aspects associated.
This document outlines the new drug development process (NDDP), including drug discovery through screening, preclinical and clinical evaluation, regulatory approval from bodies like the FDA, and ethical guidelines. It describes the stages of clinical trials from Phase I through III that assess safety, efficacy and side effects in increasing numbers of participants. The goal of the NDDP is to develop new drugs to meet unmet medical needs and obtain regulatory approval to market the drug. Ethical standards like informed consent and minimizing risk to participants are required.
Toxicological Approach to Drug DiscoverySuhas Reddy C
This document outlines the toxicological approach to drug development. It discusses the importance of conducting various toxicity studies at different stages of drug development to ensure safety. These include single dose, repeated dose, fertility, reproductive, developmental and genotoxicity studies in animals. It describes the typical safety program involving staged approach and discusses factors to consider in designing toxicity studies. The goal is to obtain sufficient non-clinical safety data to support clinical trials and assess safety for human use.
The document provides an overview of the drug development process. It discusses the major stages of clinical trials from Phase I to Phase IV that drugs must go through for testing and approval. The goals are to determine safety, efficacy, appropriate dosing, and identify any adverse effects. Rigorous clinical trials with control groups, randomization, and large sample sizes are necessary to provide substantial evidence for approval. The overall process takes an average of about 100 months from initial synthesis to approval.
Preclinical studies, clinical trails and pharmacovigilancekamrudeen samani
The document discusses the various phases of drug development including preclinical, clinical, and post-marketing phases. The preclinical phase involves animal studies to evaluate toxicity, pharmacokinetics, and pharmacodynamics. If promising, the drug enters clinical trials with Phase I studying safety in healthy volunteers, Phase II studying efficacy in patients, and Phase III large scale studies to further confirm safety and efficacy. After approval, Phase IV involves post-marketing surveillance. Pharmacovigilance aims to improve patient safety by monitoring drugs for adverse effects after market entry.
Stages of drug development by Dr Joseph Oyepata Simeon (Ph.D)oyepata
The document outlines the stages of drug development from discovery through clinical trials and FDA approval. It discusses 4 main stages: 1) Discovery and preclinical research involving animal testing, 2) Clinical research consisting of 4 phases starting with small safety trials and increasing in size, 3) Filing an Investigational New Drug Application with the FDA to begin clinical trials, and 4) Final FDA review and potential approval or denial to market the drug. Only about 25-30% of drugs make it through the entire process, which can take 10-15 years and costs over $2 billion on average.
Phase 1 clinical trials are the first studies done in humans of a new drug or treatment. They aim to determine the drug's safety and side effects, identify the maximum tolerated dose, and understand how the body processes the drug through pharmacokinetic evaluation. Phase 1 trials typically involve small groups of healthy volunteers or patients and start with low doses that are gradually increased. The results of phase 1 trials provide information needed to design subsequent clinical trial phases that further evaluate efficacy.
The document outlines the key stages of the drug development process:
1) Discovery, where potential drug candidates are identified through research. 2) Preclinical testing to evaluate safety and efficacy in animal studies. 3) Clinical trials involving human subjects in 3 phases to further assess safety and effectiveness. 4) Regulatory review and approval by agencies like the FDA if the drug is found safe and effective for its intended use. The entire process is lengthy and rigorous, aimed at bringing only beneficial treatments to market.
Preclinical studies are conducted before human trials to assess pharmacological and toxicological effects. Both in vitro and in vivo studies characterize these effects. Preclinical testing aims to detect toxicity, understand hazards, establish dose responses, and assess distribution, metabolism, and carcinogenicity. It involves short and long term animal studies in two species, as well as safety pharmacology, toxicology, developmental and reproductive toxicity testing, and genetic and carcinogenicity studies. The steps of preclinical trials include identifying a drug target, developing a bioassay, screening compounds, establishing effective and toxic doses, and filing for investigational new drug approval.
New Drug Discovery And Development (part-2)swatisejwani
The document discusses the steps involved in preclinical trials for new drug development. Preclinical trials involve laboratory and animal testing to evaluate safety and efficacy before human testing. Key steps include: identifying a drug target and developing a bioassay; screening the drug in the bioassay; establishing effective and toxic doses; filing for Investigational New Drug approval with the FDA; and conducting various studies like toxicity, pharmacokinetic, and animal model testing under Good Laboratory Practice standards. The goal of preclinical trials is to obtain sufficient safety and efficacy data to justify moving a drug into clinical trials with human subjects.
This phase 1 clinical trial protocol aims to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of a new investigational bronchodilator drug, CF-021, in healthy adult volunteers. The study is a randomized, open-label, single ascending oral dose trial. It will enroll approximately 30 subjects in sequential dose cohorts to determine the maximum tolerated dose of CF-021. Safety monitoring, pharmacokinetic profiling and bronchodilator effects will be assessed after single oral doses. The study aims to establish a safe clinical dosing range to enable further evaluation of CF-021 in phase 2 trials for chronic obstructive pulmonary disease.
The document discusses the process of drug discovery and development. It has 5 main stages: drug discovery, pre-clinical testing, clinical trials (phases I-III), regulatory approval, and post-marketing surveillance. Drug discovery involves screening compounds for pharmacological activity through random testing, serendipitous findings, or rational drug design. Pre-clinical testing involves extensive animal studies to evaluate safety, efficacy, and adverse effects. Clinical trials in humans have 3 phases to further assess these factors before regulatory approval and marketing of the drug. Post-approval monitoring continues to study long-term safety and efficacy.
To accomplish a desired systemic effect, drug molecules must reach the systemic circulation after extravascular administration. The percent of the taken dose that reaches intact to the systemic circulation is called “bioavailability, BA”. Absolute Bioavailability compares the BA of the active drug in systemic circulation following non-intravenous administration
This document discusses the process of generating safety data during drug development. It describes the three main phases - drug discovery, preclinical, and clinical trial phases. The preclinical phase involves pharmacodynamics, pharmacokinetic, and toxicological studies in animals over 1.5-2 years. These studies evaluate absorption, distribution, metabolism, excretion, toxicity, and help establish a safety profile before human trials. The clinical trial phase involves 4 phases to test safety and efficacy in humans. After approval, phase 4 surveillance continues to monitor performance and adverse effects through periodic safety reports.
PHAR2202 Drug Design And Analytical Methods.docxwrite5
This document provides an overview of non-clinical studies conducted for a new drug called QMU1221 to treat transient liver disease in adult women. It finds that while some preliminary studies like toxicity testing were conducted on rats and dogs, many crucial non-clinical studies required by regulators were not fully carried out due to a tight budget. This includes insufficient general toxicology, reproductive toxicology, and ADME studies. Further long-term testing is needed in multiple species to fully characterize the drug's toxicity profile, support later phases of clinical trials, and satisfy regulatory expectations.
New drug development involves a series of pre-clinical and clinical trials. In pre-clinical trials, new chemical compounds are screened in vitro and tested in animal models to assess pharmacology, toxicity, and effectiveness. If a compound shows promise, it enters clinical trials with humans. Clinical trials have four phases - Phase I tests safety in a small group, Phase II explores efficacy in a larger group, Phase III tests efficacy in a larger patient population, and Phase IV monitors long-term safety and efficacy after market approval. The drug development process aims to establish that a new drug is safe and effective for its intended use through rigorous multi-stage testing.
This document discusses safety testing of pharmaceuticals. It covers the importance of safety testing to establish storage conditions and ensure stability. The major steps discussed are preclinical research in cells and animals, preclinical safety assessment testing in two animal species, clinical trials in humans proceeding from phase 1 to 4, and post-marketing surveillance. Toxicological studies evaluate toxicity, effects, and target organs while biocompatibility studies examine the interaction between drugs and tissues. Regulatory authorities like the FDA oversee safety testing to help safe products reach the market.
Pre-clinical screening involves testing potential new drugs in animal models before human trials to evaluate safety and efficacy. This includes pharmacological screening to determine mechanism of action and dose response, as well as toxicological testing to identify adverse effects and calculate safe starting doses for clinical trials. Studies progress from molecular and cellular assays to whole animal experiments. Acute and repeated dose toxicity tests are followed by sub-chronic and chronic studies to identify long-term effects. These pre-clinical studies aim to generate data required to deem a new compound safe enough for initial human testing.
clinical and preclinical approaches to drug discovery.Here we mainly deals with preclinical approaches, ie. Pharmacological approach and toxicological approach
This document provides guidelines for safety pharmacology studies for human pharmaceuticals from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The guidelines discuss the objectives, scope, general principles, test systems, experimental design, dose levels/concentrations, duration of studies, and studies on metabolites for safety pharmacology evaluations. The goal is to help protect clinical trial participants and patients by identifying potential adverse effects of pharmaceuticals early in development.
This document provides information about types of experimental studies and clinical trials. It discusses randomized controlled trials as the best way to test new treatments. The key steps in a RCT are described including developing a protocol, obtaining informed consent, randomization of participants, intervention, follow up, and assessment. Sources of bias in clinical trials and different trial designs such as parallel groups and cross-over designs are also summarized.
DRUG DISCOVERY & DEVELOPMENT PROCESS, it's a detail description about how drug is made available in market it's development and discovery of drug The Hole Study is given in This Topic.
ABDOMINAL TRAUMA in pediatrics part one.drhasanrajab
Abdominal trauma in pediatrics refers to injuries or damage to the abdominal organs in children. It can occur due to various causes such as falls, motor vehicle accidents, sports-related injuries, and physical abuse. Children are more vulnerable to abdominal trauma due to their unique anatomical and physiological characteristics. Signs and symptoms include abdominal pain, tenderness, distension, vomiting, and signs of shock. Diagnosis involves physical examination, imaging studies, and laboratory tests. Management depends on the severity and may involve conservative treatment or surgical intervention. Prevention is crucial in reducing the incidence of abdominal trauma in children.
8 Surprising Reasons To Meditate 40 Minutes A Day That Can Change Your Life.pptxHolistified Wellness
We’re talking about Vedic Meditation, a form of meditation that has been around for at least 5,000 years. Back then, the people who lived in the Indus Valley, now known as India and Pakistan, practised meditation as a fundamental part of daily life. This knowledge that has given us yoga and Ayurveda, was known as Veda, hence the name Vedic. And though there are some written records, the practice has been passed down verbally from generation to generation.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of the physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Histololgy of Female Reproductive System.pptxAyeshaZaid1
Dive into an in-depth exploration of the histological structure of female reproductive system with this comprehensive lecture. Presented by Dr. Ayesha Irfan, Assistant Professor of Anatomy, this presentation covers the Gross anatomy and functional histology of the female reproductive organs. Ideal for students, educators, and anyone interested in medical science, this lecture provides clear explanations, detailed diagrams, and valuable insights into female reproductive system. Enhance your knowledge and understanding of this essential aspect of human biology.
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
Promoting Wellbeing - Applied Social Psychology - Psychology SuperNotesPsychoTech Services
A proprietary approach developed by bringing together the best of learning theories from Psychology, design principles from the world of visualization, and pedagogical methods from over a decade of training experience, that enables you to: Learn better, faster!
Muktapishti is a traditional Ayurvedic preparation made from Shoditha Mukta (Purified Pearl), is believed to help regulate thyroid function and reduce symptoms of hyperthyroidism due to its cooling and balancing properties. Clinical evidence on its efficacy remains limited, necessitating further research to validate its therapeutic benefits.
TEST BANK For Community Health Nursing A Canadian Perspective, 5th Edition by...Donc Test
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From the test tube to the market
1. From the test tube… into
the market
Dr. Anita Joshi
Garware College, Pune – lecture for
Post graduate students
02/04/10
2. 05/29/13 Dr. Anita Joshi 2
New drug/ biologic
Candidate drug
5 batches
Pre-clinical testing IND Clinical trials NDADCGI
Candidate biologic
IBSC RCGM Pre-clinical testing Clinical trialsDCGI
MANUFACTURING AND
MARKETING
LICENSE
DCGI
In vitro
characterisation
3. 05/29/13 Dr. Anita Joshi 3
Pre-clinical testing
Done after In-vitro testing – characterization of
the molecule and safety perspectives – “risk”
Objective: preliminary efficacy, toxicity and
mechanism of action and pharmacokinetics of the
drug under investigation
In-vivo testing- rodent / non-rodent because a
drug may affect different species in different
ways
Done in GLP environments only, Schedule Y
A drug that successfully completes this phase
only has a 20% chance to make it to market
4. 05/29/13 Dr. Anita Joshi 4
Toxicological testing
The study of the adverse effects of
chemical, physical or biological agents on
living organisms and the ecosystem
Advantages-
chemical exposure can be precisely controlled
environmental conditions can be well-
controlled
virtually any type of toxic effect can be
evaluated
the mechanism by which toxicity occurs can be
studied
5. 05/29/13 Dr. Anita Joshi 5
In vivo testing
How much of the drug is absorbed into the
blood?
How is the drug broken down in the body?
What is the toxicity of the drug and its
breakdown products?
How quickly does the body excrete the drug
and its breakdown products?
Safe route for administration, safe dosage,
safe schedule
6. 05/29/13 Dr. Anita Joshi 6
In vivo testing critical parameters
Choice of animal – mice, rats, guinea pigs,
rabbits etc (Sprague Dawley rats, Wistar rats,
Swiss albino mice, New Zealand white rabbits,
monkeys, dogs)
Age of the animals
Gender
Dosage and route
Duration
7. 05/29/13 Dr. Anita Joshi 7
Efficacy
In case of a vaccine, the efficacy would be
defined by the potency of a vaccine
Immunogenecity studies – antibodies
generated in response to vaccine
Challenge tests
Safety tests
8. 05/29/13 Dr. Anita Joshi 8
Different types of toxicity tests
Most commonly used tests are
Acute Toxicity
Subacute toxicity
Subchronic Toxicity
Chronic Toxicity
9. 05/29/13 Dr. Anita Joshi 9
Acute Toxicity
Adverse effects of a substance after a
single dose or brief exposure
Observation period- 14 days
3 doses recommended- dose response
curve
Small grp of animals- 5 of each sex / dose
Exposures: fractionated dose or single
dose over 24hrs for oral and 4 hrs for
inhalation studies
LD50 calculated
10. 05/29/13 Dr. Anita Joshi 10
Sub acute and sub chronic
(repeated dose)
Repeated exposure for several weeks or several months
Two distinct situations need to be considered:
Prolonged exposure to a substance
Prolonged internal exposure because a substance
remains in the body for a long time
3 dose levels + control group; 2 different animal sps
10 of each sex per dose level
Observation 30 days for sub acute
Observation 90 days for sub chronic
Observed each day for signs of toxicity: weight change,
appetite, signs of disease or abnormal behavior.
Evaluation of effects and histopathology is conducted on all
animals.
This is outlined in ISO 10993-11.
11. 05/29/13 Dr. Anita Joshi 11
Chronic toxicity
Determines toxicity from exposure for a
substantial portion of a subject's life
Extend over a longer period of time and
involve larger groups of animals.
Two sps of animals
20 animals of each sex / dose level
3 dose levels
12-24 months
12. 05/29/13 Dr. Anita Joshi 12
Other toxicity tests
Reproductive toxicity – reproductive organs,
conception, birth
Developmental toxicity - embryotoxicity
Dermal toxicity
Occular toxicity – Draize test
Genotoxicity – Ames test, cell line based tests
Neurotoxicity
Carcinogenecity
In vitro testing
13. 05/29/13 Dr. Anita Joshi 13
Good Laboratory Practices
GLP - (guidelines are like GMP) for
laboratory and pre-clinical (i.e., animal)
studies
Defined in 21 CFR 58.
All about control and documentation/
implementation for the lab
14. 05/29/13 Dr. Anita Joshi 14
GLP
Requirement for a Study Director
Requirement for a Quality Assurance unit
Responsible for maintaining a Master Schedule Sheet of
all studies conducted
Responsible for inspecting the study during its conduct
Determine no deviations
Review final report for accuracy
Maintain records
Facilities designed to
Permit segregation necessary to ensure study integrity
including:
Areas for preparation of test and control articles
Routine and specialized analytical procedures
Separation of animal species and their proper
maintenance
Animals in different studies
Quarantine of new animals
15. 05/29/13 Dr. Anita Joshi 15
GLP
Equipment must be inspected, cleaned, and maintained,
including calibration
Reagents appropriately labeled
Test and control articles characterized for identity, strength
(potency), purity, and composition
Manufacturing of test article documented
Stability determined before or during study according to
written SOPs
SOPs for routine procedures (listed examples in 21 CFR
58.81)
Study protocol detailing specific study
Results recorded and raw data documented
Records (including raw data) maintained for specified time
periods
Final report written documenting procedures, results,
statistical analyses
16. 05/29/13 Dr. Anita Joshi 16
Pharmacokinetics
Pharmacokinetics describes how the
body affects a specific drug after
administration.
Pharmacokinetic properties of drugs may
be affected by elements such as the site of
administration and the concentration in
which the drug is administered.
These may affect the absorption rate.
17. 05/29/13 Dr. Anita Joshi 17
Pharmacokinetics
ADME measures the extent and rate of
Absorption, Distribution, Metabolism and
Excretion.
recent understanding about the drug-body
interactions brought about the inclusion of new
term Liberation. Now LADME.
Liberation- release of drug from the formulation.
Absorption -a substance entering the body.
Distribution - dispersion or dissemination of
substances throughout the fluids and tissues of
the body.
Metabolism- irreversible transformation of parent
compounds into daughter metabolites.
Excretion- elimination of the substances from the
body. In rare cases, some drugs irreversibly
accumulate in a tissue in the body.
18. 05/29/13 Dr. Anita Joshi 18
Pharmacodynamics
Study of the physiological effects of drugs on the
body or on microorganisms or parasites within or
on the body
Mechanisms of drug action and the relationship
between drug concentration and effect
There are 5 main drug actions:
depressing
stimulating
cytotoxicity
irritation
replacing substances
19. 05/29/13 Dr. Anita Joshi 19
Desired activity
The desired activity of a drug is mainly due to
one of the following:
Cellular membrane disruption
Chemical reaction
Interaction with enzyme proteins
Interaction with structural proteins
Interaction with carrier proteins
Interaction with ion channels
Ligand binding to receptors:
Hormone receptors
Neuromodulator receptors
Neurotransmitter receptors
20. 05/29/13 Dr. Anita Joshi 20
Undesirable effects of drugs
Increased probability of cell mutation
(carcinogenic activity)
A multitude of simultaneous assorted
actions which may be deleterious
Interaction (additive, multiplicative, or
metabolic)
Induced physiological damage, or
abnormal chronic conditions
21. 05/29/13 Dr. Anita Joshi 21
Clinical trials
Once the pre clinical trials are complete the data
is submitted to DCGI for approvals for a clinical
trial.
Research study to answer specific questions
about vaccines or new therapies or new ways of
using known treatments.
Safety and efficacy of drugs in humans
GCP – ensure safety of subjects, protection of
human rights, reliability of results and
maintenance of scientific quality
22. 05/29/13 Dr. Anita Joshi 22
The roadmap of a trial
In accordance with the GCPs ICH guidelines, Schedule Y,
Helsinki Declaration
Sponsor approaches CRO
Feasibility check
Investigators appointed
Protocol is designed
Ethics Committee approvals
Recruiting the volunteers – eligibility criteria set
Informed Consent forms
Starting the trials
Audits by sponsor
Completion of trials
Submission of data
23. 05/29/13 Dr. Anita Joshi 23
Experimental design of a trial
Randomized
Blind- The subjects involved in the study
do not know which study treatment they
receive.
Double-blind- the researchers also do not
know which treatment is being given to
any given subject to prevent biases
Placebo-controlled: The use of a placebo
(fake treatment) allows the researchers to
isolate the effect of the study treatment.
24. 05/29/13 Dr. Anita Joshi 24
Phase 1 trials
First stage of testing in humans
Done in a small group of healthy
volunteers (20 -100)
Objective: to assess the safety,
tolerability, pharmacodynamics,
pharmacokinetics of a drug
Single ascending dose studies
Multiple ascending dose studies
25. 05/29/13 Dr. Anita Joshi 25
Phase II trials
Typically done on larger groups – 100-300
Patients are enrolled for this phase
Phase II studies are sometimes divided into
Phase IIA and Phase IIB.
Phase IIA is specifically designed to assess dosing
requirements (how much drug should be given).
Phase IIB is specifically designed to study efficacy (how
well the drug works at the prescribed dose(s)).
When the development process for a new drug
fails, this usually occurs during Phase II trials
when the drug is discovered not to work as
planned, or to have toxic effects.
26. 05/29/13 Dr. Anita Joshi 26
Phase III trials
Much larger group 300-3000
Multi centric trials
Gold standard
gather additional information about
effectiveness and safety
evaluate overall benefit-risk relationship of
the drug
provide the basis for the precautionary
information that accompanies the drug
27. 05/29/13 Dr. Anita Joshi 27
The CTD
Drug has proved satisfactory after Phase III trials
•Trial results are usually combined into a large document containing
•a comprehensive description of the methods
•results of human and animal studies
•manufacturing procedures
•formulation details
•shelf life.
Regulatory Authorities for review- DCGI
Most drugs undergoing Phase III clinical trials can be marketed
under FDA norms with proper recommendations and guidelines
If any adverse effects are reported
the drugs need to be recalled immediately
28. 05/29/13 Dr. Anita Joshi 28
Phase IV- Post Marketing Surveillance Trial
Safety surveillance (pharmacovigilance)
Ongoing technical support of a drug after it receives permission to
be sold.
Required by regulatory authorities
May be undertaken for finding a new market for the drug
Study interactions with other drugs, or on certain new population
groups such as pregnant women
Rare or long-term adverse effects over a much larger patient
population and longer time period than was possible during the
Phase I-III clinical trials.
Harmful effects if discovered - drug being no longer sold, or
restricted to certain uses
Recent examples involve cerivastatin (brand names Baycol and
Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).
29. 05/29/13 Dr. Anita Joshi 29
Performance of vaccine
Hemagglutinin inhibition assay (a
laboratory test used to measure the
amount of antibody present in a sample by
determining if the antibody inhibits
influenza virus from attaching to red blood
cells)
Microneutralization assay (a technique
used to determine if the level of antibody
in the sample inhibits the virus from
infecting cells grown in the laboratory)
30. 05/29/13 Dr. Anita Joshi 30
Pipeline of drug development
AstraZeneca (AZN) , Bristol-Myers Squibb Company (BMY) , Eli Lilly and
Company (LLY) , GlaxoSmithKline (GSK) , Merck (MRK) , Pfizer (PFE) ,
Sanofi-Aventis
31. 05/29/13 Dr. Anita Joshi 31
General trends
TIME REJECTION
PRECLINICAL 2-5 YRS 2.5
PHASE I 1-2 YRS 1.5 90%
PHASE II 2-3 YRS 2 50%
PHASE III 2-5 YRS 4 20%
REGULATORY 1-2 YRS 2 10%
ESTIMATED 12
TIME
EST. COSTS 5-8 MILLION USD
Editor's Notes
For example if a person drinks too much alcohol on a regular basis then their health may suffer as a result. The alcohol does not have a long biological half life but it is supplied on a regular basis to the body of the person For example if a person were to ingest radium much of it would be absorbed into the bones where it would exert a harmful effect on a person's health. The radium might cause a disturbance in the blood cell-forming part of the bone (bone marrow)
Reproductive Toxicity Reproductive toxicity testing is intended to determine the effects of substances on gonadal function, conception, birth, and the growth and development of the offspring. The oral route is preferred. Developmental toxicity testing detects the potential for substances to produce embryotoxicity and birth defects Dermal Toxicity Dermal toxicity tests determine the potential for an agent to cause irritation and inflammation of the skin. This may be the result of direct damage to the skin cells by a substance. It may also be an indirect response due to sensitization from prior exposure. Ocular Toxicity Ocular toxicity is determined by applying a test substance for one second to the eyes of 6 test animals, usually rabbits. The eyes are then carefully examined for 72-hours, using a magnifying instrument to detect minor effects. The ocular reaction may occur on the cornea, conjunctiva, or iris. It may be simple irritation that is reversible and quickly disappears or the irritation may be severe and produce corrosion, an irreversible condition. The eye irritation test is commonly known as the "Draize Test." This test has been targeted by animal welfare groups as an inhumane procedure due to pain that may be induced in the eye. The test allows the use of an eye anesthetic in the event pain is evident. The Draize Test is a reliable predictor of human eye response. However, research to develop alternative testing procedures that do not use live animals is underway. While some cell and tissue assays are promising, they have not as yet proved as reliable as the animal test. Genetic Toxicity Genetic toxicity is determined using a wide range of test species including whole animals and plants (e.g., rodents, insects, and corn), microorganisms, and mammalian cells. A large variety of tests have been developed to measure gene mutations, chromosome changes, and DNA activity. The most common gene mutation tests involve:
A fundamental distinction in evidence-based medicine is between observational studies and randomized controlled trials . Types of observational studies in epidemiology such as the cohort study and the case-control study provide less compelling evidence than the randomized controlled trial. In observational studies , the investigators only observe associations (correlations) between the treatments experienced by participants and their health status or diseases. A randomized controlled trial is the study design that can provide the most compelling evidence that the study treatment causes the expected effect on human health. Currently, some Phase II and most Phase III drug trials are designed as randomized, double blind , and placebo -controlled. Randomized: Each study subject is randomly assigned to receive either the study treatment or a placebo. Blind: The subjects involved in the study do not know which study treatment they receive. If the study is double-blind, the researchers also do not know which treatment is being given to any given subject. This 'blinding' is to prevent biases, since if a physician knew which patient was getting the study treatment and which patient was getting the placebo, he/she might be tempted to give the (presumably helpful) study drug to a patient who could more easily benefit from it. In addition, a physician might give extra care to only the patients who receive the placebos to compensate for their ineffectiveness. A form of double-blind study called a "double-dummy" design allows additional insurance against bias or placebo effect. In this kind of study, all patients are given both placebo and active doses in alternating periods of time during the study. Placebo-controlled: The use of a placebo (fake treatment) allows the researchers to isolate the effect of the study treatment. Of note, during the last ten years or so it has become a common practice to conduct "active comparator" studies (also known as "active control" trials). In other words, when a treatment exists that is clearly better than doing nothing for the subject ( i.e. giving them the placebo), the alternate treatment would be a standard-of-care therapy. The study would compare the 'test' treatment to standard-of-care therapy. Although the term "clinical trials" is most commonly associated with the large, randomized studies typical of Phase III, many clinical trials are small. They may be "sponsored" by single physicians or a small group of physicians, and are designed to test simple questions. In the field of rare diseases sometimes the number of patients might be the limiting factor for a clinical trial. Other clinical trials require large numbers of participants (who may be followed over long periods of time), and the trial sponsor is a private company, a government health agency, or an academic research body such as a university.
Phase I trials are the first stage of testing in human subjects. Normally, a small (20-100) group of healthy volunteers will be selected. This phase includes trials designed to assess the safety ( pharmacovigilance ), tolerability, pharmacokinetics, and pharmacodynamics of a drug. These trials are often conducted in an inpatient clinic, where the subject can be observed by full-time staff. The subject who receives the drug is usually observed until several half-lives of the drug have passed. Phase I trials also normally include dose-ranging , also called dose escalation, studies so that the appropriate dose for therapeutic use can be found. The tested range of doses will usually be a fraction of the dose that causes harm in animal testing . Phase I trials most often include healthy volunteers. However, there are some circumstances when real patients are used, such as patients who have terminal cancer or HIV and lack other treatment options. Volunteers are paid an inconvenience fee for their time spent in the volunteer centre. Pay ranges from a small amount of money for a short period of residence, to a larger amount of up to approx $6000 depending on length of participation. There are different kinds of Phase I trials: SAD Single Ascending Dose studies are those in which small groups of subjects are given a single dose of the drug while they are observed and tested for a period of time. If they do not exhibit any adverse side effects, and the pharmacokinetic data is roughly in line with predicted safe values, the dose is escalated, and a new group of subjects is then given a higher dose. This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (at which point the drug is said to have reached the Maximum tolerated dose (MTD). MAD Multiple Ascending Dose studies are conducted to better understand the pharmacokinetics & pharmacodynamics of multiple doses of the drug. In these studies, a group of patients receives multiple low doses of the drug, while samples (of blood, and other fluids) are collected at various time points and analyzed to understand how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level. Food effect A short trial designed to investigate any differences in absorption of the drug by the body, caused by eating before the drug is given. These studies are usually run as a crossover study , with volunteers being given two identical doses of the drug on different occasions; one while fasted, and one after being fed.
Phase III studies are randomized controlled multicenter trials on large patient groups (300–3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment. Because of their size and comparatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions. It is common practice that certain Phase III trials will continue while the regulatory submission is pending at the appropriate regulatory agency. This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. Other reasons for performing trials at this stage include attempts by the sponsor at "label expansion" (to show the drug works for additional types of patients/diseases beyond the original use for which the drug was approved for marketing), to obtain additional safety data, or to support marketing claims for the drug. Studies in this phase are by some companies categorised as "Phase IIIB studies."[19][20] While not required in all cases, it is typically expected that there be at least two successful Phase III trials, demonstrating a drug's safety and efficacy, in order to obtain approval from the appropriate regulatory agencies such as FDA (USA), or the EMEA (European Union), for example. Once a drug has proved satisfactory after Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the "regulatory submission" that is provided for review to the appropriate regulatory authorities[3] in different countries. They will review the submission, and, it is hoped, give the sponsor approval to market the drug. Most drugs undergoing Phase III clinical trials can be marketed under FDA norms with proper recommendations and guidelines, but in case of any adverse effects being reported anywhere, the drugs need to be recalled immediately from the market. While most pharmaceutical companies refrain from this practice, it is not abnormal to see many drugs undergoing Phase III clinical trials in the market.[21]