licensing a new drug Flashcards
What molecular biology, in vitro studies & computer technology cannot do
• Integrated response
– molecule to man
• Reveal the unexpected
– secondary actions, selectivity. Doesn’t remove the risks
• Determine the therapeutic index- know the dose that you are taking into the clinical trail
• Assess importance of multiple mediators- seeing multiple effects
• Determine pharmacokinetics- hw drug is absorbed ,metabolised and excreted
• Assess safety & toxicology
• Set clinical dose range- need to know the dose you are treating with
what is meant by pharmacodynamics
• Is the study of the biochemical and physiological effects of drugs.
• Specifically those actions for which the drug was designed effect
• Information obtained includes:
– Lead optimization- make it as selective and as potent as possible
• Improve target specificity
• Improve target selectivity
– Efficacious dose range and therapeutic window
– Specificity
• Investigation of off target events
what is meant by pharmacokinetics
what happens to the drug after it has been administered?
• Is the determination of the fate of substances administered externally to a living organism. Need to monitor the patient depending on where the drug can affect more than one organ
– Absorption
– Distribution
– Metabolism
– Excretion
what is meant by absorption?
• The process by which drug proceeds from the site of administration to the site of measurement in the body i.e. blood stream. Need to know whether or not you may need to make a pro drug to form the active form.
• Varies due to administration
– IV drug is immediate and complete
– Oral drug delayed and incomplete. Goes through first pass metabolism so the dose will be lower than when it is first administered
• Relies on passage through membranes to reach the blood
what is meant by distribution?
• Determined by
– Partitioning across various membranes- does it cross the Blood Brain Barrier
– Binding to tissue components- does it bind to receptors or outside cells
– Binding to blood components- plasma protein binding
– Physiological volumes- the volumes of liquid in the tissue
what is meant by metabolism?
• Determined by the liver (mainly)
– Location of metabolism enzymes e.g. liver or kidney
– 1st pass metabolism
– Induction of drug metabolizing enzymes-can inhibit drug metabolizing enzymes
– Development of pro-drug
what is meant by elimination?
• Either by excretion unchanged or drug metabolites excreted
• Drug metabolism is usually associated with a chemical modification of the drug with the overall goal of getting rid of the drug, typically enzyme driven
• Excretion is the main process by which the body eliminates unwanted substances
– Most common route biliary or renal
– Other routes include lung, skin, etc need to know eg if it is ecreted whe breathing out
what is meant by toxicology?
• Concerned with the adverse effects of chemicals on living organisms.
what is
Toxicological profile
- Single dose toxicity
- Repeat dose toxicity
- Genotoxicity- works in the genome
- Carcinogenicity
- Reproductive and developmental toxicity
- Local tolerance
- Environmental issues
Molecular mechanisms of toxicity
• Allergic response
– Can lead to anaphylactic shock e.g. penacillin
– Deplete blood cell types e.g. sulfonamides can cause neutropenia
• Receptor, ion channel and enzyme mediated
– Animal toxins can block ion channels
• Biochemical pathways
– Inhibition of mitochondrial function
• Organ-directed toxicity
– Hepatotoxicity e.g. paracetamol affects liver depletes glutathione
– Nephrotoxicity
• Changing glomerular filtration rate e.g. ramapril increases it
• Chronic nephritis e.g. paracetamol
• Mutagenesis and carcinogenesis- drugs that can cause cancer and affect DNA
• Teratogenicity e.g. thalidomide (R-enatiomer sedative, S-enantiomer teratogen) affects the unborn fetus
what are the 2 testing methods?
• Preliminary toxicity testing
– Maximum non-toxic dose given for 28 days to 2 species before tissue damage assessment- see what possible damge there could be for long term use.
– LD50 test-the dose of drug which kills 50% of treated animals within a specified short amount of time
what does single dose studies/ acute toxicity studies entail?
- Effect of single dose- most important stage as it determines the next stage
- Carried out on two different animal species
- Effects of dose observed for 14 days with any mortality recorded.
- Morphological, biochemical, pathological and histological changes are investigated
Repeated dose studies/sub-actue or chronic studies
• Two mammalian species
• Long duration of studies (30-180 days)
• Dose is dependent on dose escalating studies
– High dose 10x the maximum clinical dose
– Low dose 2x clinical dose
– Medium dose midway between low and high dose
• Drug administered by clinical route
• Parameters monitored include
– Behavioral
– Physiological- does it affect breathing heart rate/ tachycardia
– Biochemical- liver, kidney
– Histological- look at every organ in the body
what is local toxicity studies?
• Route of administration dependent so for example
– Dermal toxicity studies- the dose is going to be highest at the point of administration
• Local signs (oedema, erythema)
• Histological studies
– Rectal tolerance studies- the dose is going to be highest at the point of administration so look for any signs of pain
• Signs of pain, blood or mucus
• Histological studies
– Parenteral drugs
• For IV, IM, SC, ID
• Sites of injection examined grossly and microscopically
Allergenicity/Hypersensitivity toxicological studies
• Guinea pig maximization test- skin on the ears is the same as the human skin
– Evaulation of erythema and oedema
– Determination of maximum non-irritant or minimum irritant dose
• Local lymph node assay
– Drug given on mouse ear skin
– 5 days treatment followed by auricular lymph node dissection
– Increase in tritiated-thymidine used for evaluation. Taken up by cells that are divining so it shows that there is an inflammatory reaction as the lymph node cells are dividing
Carcinogenicity/Oncogenicity studies
- Life-time bioassays
- Drug used for >6 months or frequent intermittent use for chronic diseases
- Chemical structure of drug indicates carcinogenic potential
- Therapeutic class of drugs which have produced positive carcinogenicity
what are the clinical signs of toxicity?
• Respiratory
– Dyspnea, abdominal breathing, gasping, cyanosis
• Motor activity
– Loss of righting reflex, ataxia, tremors
• Reflexes
– Pinneal, light, righting
• Ocular signs
– Lacrimation, miosis, iritis
• Cardio-vascular signs
– Bradycardia, tachycardia, vasodilation
• Autonomic signs
– Para/sympathomimetic actions or blockers
• Other signs
– Salivation, piloerection, GIT signs (emesis, diuresis)
what is Preliminary toxicity testing
NOAEL (no observed adverse effects level)
Highest concentration that does not a toxic response
LOAEL- lowest observed adverse effects level
Lowest concentration that produces a toxic response
what is the use for NOAEL ?
• Determine NOAEL
• Convert NOAEL to a human equivalent dose (HED)
– Adjust for anticipated exposure in humans
– Adjust for interspecies difference in affinity and potency
• Apply a >10 fold safety factor
how do you calculate
• Convert NOALs to HED based on body surface area
– Assumes there is a 1:1 relation between species when normalized to body surface area (BSA)
• HED (mg/kg)=NOAL (mg/kg) x Animal Km/Human Km
• Km=Body weight (kg)/BSA (m2)
– E.g. Human Km=37 (60 kg), mouse Km=3 (0.02 kg), Rat Km=6 (0.15 kg)
how do you calculate the therapeutic index?
The ratio of the dose of the drug that produces an unwanted
(toxic) effect to that producing a wanted (therapeutic) effect
= LD50 / ED50
Target related safety
• Tissue distribution
– If the target is highly expressed in organs other than those intended for therapeutic modulation
• KO animals
– Phenotypes observed in genetically manipulated animals are valuable in identifying potential issues
• siRNA approach
– Silencing the target in specific organs can identify toxicities
– Confirm the role of the target in a toxicological outcome
• Inactive enantiomers
– Inactive structure is a mirror image of the active isomer the potential for chemistry-related toxicity is equivalent
– Determines that the target is the cause of the toxicity
what are the Chemistry related safety
• Chemical series
– Identify structural features associated with adverse effects
• Metabolites
– Is the drug metabolized into a chemical that causes adverse effects
• Isomers
– Does the drug have an isomer, does it show same activity/toxicity
• Impurities
– During the synthetic pathway what impurities are formed, what % remain in final formulation, do they cause any adverse effects
how to Identify physiological parameters for clinical monitoring of potential adverse effects
- Adverse effects in animals for specific organs
- Tissue expression of the target
- Target itself e.g. receptor found in autonomic nervous system
what are the Hazard integration and risk assessment
• Regarding patient safety – Co-morbidities – Co-medications – Age • Risk-benefit – Effect of drug on symptoms, disabilities and prognosis balanced against unwanted effects
what is meant by scientific study?
• Seeks to establish facts
– Things known to have occurred or be true (OED)
• Contributes to knowledge
• Confirms, adds to or establishes theory
– a conceptual framework that explains existing observations and predicts new ones
- Should be controlled so as to be free of bias
- Should be designed on a scale that the results can be statistically evaluated
Detailed scientific studies
• Are expensive to conduct • Require specialised skilled operators to – Design – Analyse – Interpret the data
Do all scientific studies provide evidence for clinical practice?
- Animal studies
- In- vitro studies
what is meant by Epidemiology
- Study of how often diseases occur in different groups of people and why
- Used to plan and evaluate strategies to prevent illness and as a guide to the management of patients
- Relate primarily to groups of people
- Epidemiology is the method used to find the causes of health outcomes and diseases in populations. In epidemiology, the patient is the community and individuals are viewed collectively. By definition, epidemiology is the study (scientific, systematic, and data-driven) of the distribution (frequency, pattern) and determinants (causes, risk factors) of health-related states and events (not just diseases) in specified populations (neighborhood, school, city, state, country, global). It is also the application of this study to the control of health problems
list the different types of clinical studies?
- Qualitative research
- Focus groups
- Individual interviews
- Observational studies
- Case studies
- Cohort studies
- Cross-sectional studies
- Experimental studies
- Clinical trials
what is meant by qualitative research?
• Collecting and analysing non-numerical data • Understanding – Concepts – Opinions – Experiences • Gather in-depth insights into problems • Generate new ideas for research
what is meant by observational studies?
• Researchers observe the effect of something on a population
– Disease
– Risk factor
– Diagnostic test
– Treatment or intervention
• Is not experimental
– Do not try to change who is or isn’t affected
what is meant by Cross-sectional studies
- Measure the frequency of a disease or condition in a defined population at a given time
- A census of occurrence of characteristic(s)
what entails in a case study?
• Medical history of one (or small group of) patient
• No control group
– Anecdotal evidence
what is meant by case study control?
• Compares patients who have a condition with a group who do not have that condition
• Looks retrospectively at risk factors that may impact on the condition
– Also known as retrospective studies
what are the advantages and disadvantages of case control studies?
- Good for studying rare conditions
- Relatively quick to set up
- Can look at multiple risk factors
- Clinical records may be inconsistent
- May rely on memory (recall bias)
what is meant by cohort studies
- Observational studies of subjects with a specific disease or characteristic
- May be compared to a control group
- Usually over a long time period
what is meant by prospective and retrospective studies?
n a retrospective cohort study, the group of interest already has the disease/outcome. In a prospective cohort study, the group does not have the disease/outcome, although some participants usually have high risk factors.
what is meant by experimental studies?
- Introduce an intervention
* Study the effects on the treated population
what are the different categories of a clinical trail?
- Specified condition
- Specified treatment
- Test and control group
- Measure the outcomes
what is meant by randomised controlled trails
- Population of patients chosen
- Divided into 2 groups
- Trial group compared with control group
what is meant by Meta-analysis of RCTs
- A type of systematic review that focuses on the numerical results
- Aim is to combine the results to produce an estimate of the overall effect size
- Data from several trials are pooled and averaged to estimate the overall effect
- No new raw data collected
list in order the hierarchy of evidence
- Systematic review / meta analysis
- Randomised control trials
- Cohort studies
- Case control studies
- Case series /reports
what do clinical trials test for?
• Administration of new substances with therapeutic potential to people under controlled conditions for the purpose of determining – Efficacy – Bioavailability – Safety – Tolerability – Acceptability
what does the The Medicines for Human Use (Clinical Trials) Regulations 2004 say?
- Good Clinical Practice
- Good Manufacturing Practice
- Regulatory inspection and enforcement
- Protection of incapacitated adults
- Protection of minors
- Pharmacovigilance arrangements
what does ICH guidelines – good clinical practice
- Risks and potential benefits must be assessed before trials are started
- Interests of the individual study subject must take precedence over those of science or society
- All trial subjects must give consent
- Trials must be scientifically sound
- Trials must have a clear protocol
- Trials must be approved by a properly constituted ethics committee
- Only properly qualified staff may be involved (including physicians to provide care if needed)
- Should be adequate preclinical testing of the product
- Product should be of adequate quality (as defined in ICH guidelines for medicines)
- Trial subjects privacy and confidentiality must be respected and assured
- Data must be recorded, handled and stored in a way that allows accurate reporting, interpretation and verification
what are the 4 clinical development phases?
phase 1: First administration and safety evaluation in man – usually healthy volunteers
phase 2: Early exploratory and dose-finding studies in patients
phase 3: Large scale studies in patients
phase 4: Post-marketing safety monitoring
what are some considerations of clinical trials
• Most Phase I volunteers are men – Women of reproductive age? – In EU, only post-menopausal or surgically sterilised women can participate • Genetic polymorphisms – Fast or slow metabolisers – Accumulation of drug in slow metabolisers – Consider the target population – Where is the drug to be marketed?
what does phase 1a single dose trials entail?
• 4-8 cohorts of 6-8 participants
• Escalating dose from one cohort to the next
• Maximum tolerated dose determined
– Before safety / tolerability issues arise
– For low toxicity drugs, the highest practicable dose
• Establishes pharmacokinetic parameters
– Cmax:Peak drug / metabolite concentration
– Tmax: Time to peak drug / metabolite concentration
– AUC: to infinity and to specified time
• Establishes bioavailability and total exposure
– T1/2: rate of elimination
– VD: Volume of distribution
– MRT: Mean residence time
• – average time the drug remains in the body after administration
what does phase 1b
- Similar participants to Phase Ia
- Escalating repeat-dose
- Establishes ‘steady state’ dosing requirements
what does phase iia trails entail?
what does phase iib trails entail?
what does phase iii trails entail?
why do trails fail?
• Insufficient biological activity • Unacceptable toxicity • Problems in the design of the trial – Measurement criteria (endpoint) – Patient selection – Sample size – duration • Problems in the execution of the trial – Randomisation of patients – Analysis of data
what does phase iv trails entail
what is the yellow card scheme?
- Reports made by patients and health professionals
- Assessed at the MHRA – medics, pharmacists and other scientists
- If a new side effect is identified, information is considered in the context of the overall side effect profile for the medicine, and how the side effect profile compares with other medicines used to treat the same condition.
- The MHRA takes action to ensure that medicines are used in a way that minimizes risk, while maximizing patient benefit
