Lecture 13 - Drug development of a small molecule drug Flashcards
What occurred with elixir sulfanilamide?
- contained diethylene glycol, killing 107 people, mainly children
- the federal food, drug and cosmetic was passed by congress a year later
What occurred with sulfathiazole tablets?
- tainted with the sedative Phenobarbital, caused 300 deaths
- numerous control deficiencies in the plant and serious irregularities in the firms attempt to recall the drug
What occurred with thalidomide?
sleeping pill caused severe birth defect of arms and legs in Western Europe
What occurred regarding the thalidomide disaster (1960s)?
- 1954 first synthesized
- 1957 launched sleeping tablet ‘Contergan’ onto market
- Sold in over 40 countries under license
- US has not given licensing approval
- caused birth defects in 10,000- 20,000 babies
- 1961 withdrawn from most markets
Describe the process of drug development
- Basic research target selection
- Pre -clinical research
- Phase 1
- Phase 2
- Phase 3
- Regulatory review
What targets are involved in target selection?
- receptors
- enzymes
- transport proteins
What is involved in lead finding?
automated screens against libraries
What is involved in target selection?
Drug targets are, with few exceptions, functional proteins (e.g. receptors, enzymes, transport proteins)
There are usually identified from bio-science research
What is the process of lead finding?
When the biochemical target has been decided and the feasibility of the project has been assessed, the next step is to find the LEAD COMPOUNDS. The usual approach involves cloning the target protein - normally the human form, because the sequence variation among species is often associated with pharmacological differences, and it is essential to optimize for activity in humans. An assay system must then be developed, allowing functional activity of the target protein to be measured. This could be a cell-free enzyme assay, a membrane-binding assay or a cellular response assay.
What are the 3 steps in drug development?
Lead –> Preclinical development –> clinical development
What occurred in 1920 regarding animal toxicology and small molecules?
experiment to determine dose that would cause 50% death rate in mice and labelled it the median lethal dose (LD50)
What is the 3R initiative?
- reduce
- refine
- replace
aim to reduce animal use
Describe the effect of small molecules on rodents & non-rodents
For small molecules, the nonclinical safety studies need to be conducted in both a rodent model and a non-rodent model with the assurance that major human metabolites and the parent molecule are present and, therefore, qualified by at least one both of the nonclinical safety species
What is the default rodent used?
rat
What is the default non-rodent used?
beagle
What are the 3 dose groups?
- Low (no toxicology)
- Intermediate
- High (toxicology expected in target organ)
What is clinical pathology?
- haematology/clinical chemistry
- kidney and liver function
- coagulation
What is pathology?
- large organ toxicity
What is histopathology?
study of the structural manifestation of disease at the light microscopic level. It is largely a descriptive and interpretive science. The trained and experienced toxicologic pathologist must be able to distinguish normal variation and spontaneous disease processes from the changes resulting from the administration of a test article. Histopathology results are one of the most important parts of the nonclinical safety assessment process
What is the goal of toxicologic pathology?
In toxicologic pathology, the goal is to determine if the test article produces changes through a comparison of treated animals with control animal data (both concurrent and historical controls). It is important, therefore, that microscopic observations be recorded in a consistent, objective manner that readily allows tabulation (put in a table) and comparison of group effects. In this setting, the use of descriptive, rather than diagnostic terminology is preferred
What are the goals of non-clinical safety evaluations regarding toxicity?
- on/off target
- reversibility
What are the goals of non-clinical safety evaluations regarding toxicokinetics?
- relate toxicity to exposure
- max non-toxic dose/min affective dose
- dose selection for first in human
- identification of specific monitoring requirements
What is the purpose of preliminary toxicological testing?
to eliminate genotoxicity and to determine the maximum non-toxic dose of the drug (usually when given daily for 28 days, and tested in 2 species). As well as being checked regularly for weight loss and other gross changes, the animals treated are examined minutely postmortem as the end of the experiment to look for histological and biochemical evidence of tissue damage.
What does pharmacokinetic testing include?
includes studies on absorption, metabolism, distribution and elimination (ADME studies) in laboratory animals.
Chemical and pharmaceutical development to assess the feasibility of large-scale synthesis and purification, to assess the stability of the compound under various conditions and to develop a formulation suitable for clinical studies
What is the safety pharmacology of the CNS?
- motor activity
- behaviour
- coordination
- sensory/motor
- reflexes
- body temperature
What is the safety pharmacology of respiratory system?
- respiratory rate
- tidal volume
- O2 saturation
What is the safety pharmacology of cardiovascular?
- blood pressure & heart rate
- ECG
- repolarization (APD)
- hERG assay
- conduction
What do the regulatory agencies provide?
the regulatory agencies provide the general principles and recommendations for safety pharmacology studies, which are studies that investigate the potential undesirable effects on physiological functions in relation to the exposure in the clinical therapeutic range and above. The core battery of safety pharmacology studies consist of the assessment of effects on the CARDIOVASCULAR system, the CNS and the RESPIRATORY system. This needs to be completed prior to FIH (first-in human) clinical trials.
What are the 3 areas assessed in safety pharmacology studies?
Cardiovascular system, the CNS and the respiratory system
What do safety pharmacology core battery studies investigate?
investigate the potential undesirable effects on physiological functions
What conclusions must be made before human trials?
- evidence of pharmacological activity
- maximum non-toxic dose
- adverse effects on target organs
- relationship of effects to dose and exposure
- differences observed in different species
- evaluation of risk in humans
How is pathology data part of the nonclinical safety data set?
Pathology data from nonclinical toxicology studies, consisting of both clinical pathology endpoints and light microscopic evaluations, compose an essential part of the nonclinical safety data set that supports both clinical development and subsequent new drug applications and approval.
What does toxicologic pathology encompass?
It encompasses the study of changes in tissue morphology that help define potential safety risk to humans. The interpretation of these pathology data, in addition to other nonclinical data forms the basis for judgement about the safety of the product. Therefore, the scientific generation and interpretation of pathology data must be unimpeachable.
What % of registered studies are found in the US vs non-US?
US - 31%
non-US - 53%
Approximately how many registered studies have there been up to April 2023?
450,000
What is phase 1?
the first stage of clinical testing and is often also referred to as First in Man, or First in Human
What is the main aim of phase 1?
The main aim is to test if the drug is safe in humans and to check for signs of any potentially:
- dangerous effects
- tolerability
- pharmacokinetic properties
What are the dangerous effects?
e.g. on cardiovascular, respiratory, hepatic or renal function
What is tolerability?
does the drug produce any unpleasant symptoms, e.g. headache, nausea, drowsiness
What are pharmacokinetic properties?
Is the drug well absorbed? What is the time course of the plasma concentration? Is there of cumulation or non-linear kinetics?
How are Phase 1 studies?
usually performed on a small group (normally 20-80) of normal healthy volunteers. These groups are usually divided into smaller groups called cohorts. The first cohort received a very low dose of the drug and this dose is then adjusted for the subsequent cohorts. The dose is increased until the most useful or best tolerated dose level is found
What else may Phase 1 studies test for?
Pharmacodynamic effects in volunteers, which is the effect of the drug on the body. This is often done by lab tests to find out if the drug is hitting the target of changes the level of a protein
What occurs in Phase II?
Performed on groups of patients (normally 100-300 are designed to test for efficacy in the clinical situation, and if this is confirmed, to establish the dose to be used in the dose to be used in the definitive phase III study. Often such studies will cover several distinct clinical disorders (e.g. anaemia, rheumatoid arthritis) to identify the possible therapeutic indications for the new compound and the dose required.
When the new drug targets are being studied, it is not until these Phase II trials are completed that the team finds out whether or not its initial hypothesis was correct, and lack of the expected efficacy is a common reason for failure.
Describe what happens during Phase IIa
Exploratory (non-pivotal) study that has a clinical efficacy. Pharmacodynamics or biological activity as primary endpoint, conducted in patients or healthy volunteers
- proof of concept, efficacy or mechanism
- mechanistic studies
- dose range exploration
- pilot studies
Describe what happens during Phase IIb
Definite dose range finding in patients with efficacy as primary endpoint.
Exceptionally, Phase II studies can be used as pivotal trials, if the drug is intended to treat life-threatening or severely-debilitating illnesses as in oncology indications
- define dose finding studies
- extension studies of Phase IIb studies
What occurs in Phase III?
- 1000+ patients
- Definitive results
- Multi centre
- Multi national
- application for marketing
Phase III studies are the efinitive double-blind, randomized trials, commonly performed as multi-centre trials on thousands of patients, aimed at comparing the new drug with commonly used alternatives. These are extremely costly, difficult to organise and often take years to complete, particularly if the treatment is designed to retard the progression of a chronic disease. It is not uncommon for a drug that seemed highly effective in the limited patient groups tested in phase II to look much less impressive under the more rigorous conditions of Phase III trials
What occurs during Phase IIIa trials?
A pivotal study that is a trial designed & executed to get statistically significant evidence of efficacy and safety as required by Has for DNA/sNDA approval
It also includes studies with the aim to include into the label as well as post-marketing commitments
- pivotal studies (vs placebo/comparator)
- long term safety studies for registration
- post marketing study commitments
What does a pivotal study refer to?
A pivotal trial refers to a clinical trial or study intended to provide evidence for a drug marketing approval - e.g by the US FDA. Phase III trials are assumed to be pivotal so the phrase is often used for the rare pivotal phase II trials
What is the definition of a pivotal study?
typically a Phase 3 study which presents the data required by a regulatory agency to decide whether or not to approve a drug. A pivotal study will generally be well-controlled, randomized, or adequate size, and whenever possible, double-blind
What occurs in Phase IIIb?
A study started prior to approval and whose primary intention is support of publications rather than registration or label changes
The results are not intended to be included in the submission dossier
- studies intended to support publication, claims, or prepare launch, which start before approval but are not intended for regulatory submissions
What occurs in Phase IV?
- Post marketing surveillance
- Detect rare or long-term adverse effects
Phase IV studies comprise the obligatory post marketing surveillance designed to detect any rare or long-term adverse effects resulting from the use of the drug in a clinical setting in many thousands of patients. Such events may necessitate limiting the use of the drug to particular patient groups, or even withdrawal of the drug
What are examples of withdrawn drugs?
- Sibutramine
- Propoxyphene
- Drotrecogin alfa
- Rimonabant
- Hydromorphone
