Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
81 Cards in this Set
- Front
- Back
|
What makes a molecule a potential drug - factors to consider |
Legal - Patentability Physico- chemistry issues Lipinskis rule of 5 Formulation (Log P) Solubility Ionisation potential pKA BCS Biological issues Routes of Administration, metabolism/transport issues Receptor activity and selectivity Chemical issues: synthesis and stability |
|
|
Why do some molecules fail before pre-clinical development |
Safety issues Lack of human clinical affect Some failed due to pharmaceutical formulation issues Bio availability is sub optimal Too costly Design and selection processes in efficient |
|
|
Receptor activity and selectivity |
What is the target receptor? Agonist Antagonist What is the Emax / EC50/ IC50? Potential dose- Concentration needed at the receptor - Specificity is the Efficacy of drug to treat that disease and also side effects
|
|
|
What is a dirty drug |
A drug that acts on many receptors and causes lots of side effects for example haloperidol |
|
|
Biological issues for potential drug |
Route of administration Biological barrier Biological environment – fluid volume, fluid movement, pH, enzymes |
|
|
Oral route of absorption |
Trans cellular route: passive diffusion (non-ionized and in aqueous solution) Trans cellular route: Active transporter utilization – Drug needs to resemble natural molecule Paracellular route: tight junctions Drug needs to be very small and very hydrophilic Lipid absorption via micelles/ bile salts Lipophilic drug Particulate absorption via G AL T: gut associated Lymphatic tissue Drug targets the immune system |
|
|
Metabolism and transport issues |
Cytochrome P450 1st pass metabolism in the liver Cytochrome P450 3A4 enzyme in the Intestine P – glycoprotein efflux transporter - PGP bouncer Drug interactions can induce or inhibit |
|
|
Physico chemical issues |
Ionisation potential – PKa Henderson hasselbach equation PH equals PKSK + log (A-)/(HA) Affects Oral absorption |
|
|
Balance between aqueous and lipid (cell membrane) solubility to move between the biological membrane Brick dust does not dissolve in any solvent Greaseball is very lipophilic and very hydrophobic |
Balance between aqueous and lipid (cell membrane) solubility to move between the biological membrane Brick dust does not dissolve in any solvent Greaseball is very lipophilic and very hydrophobic |
|
|
Bio pharmaceutics classification system |
Class one high s and p Class 2 low s and high p Class 3 high s and low p Class 4 low and low Dependent on how many stomach volumes require us to achieve clinical days – patient dependent on stomach size |
|
|
Li Pinsky’s rule of five |
Predicts if the drug is likely to be biologically absolved Four rules, Molecular weight less than 500 Dalton’s Log P less than five H-bomb donors less than five Hbond acceptors is less than 10 |
|
|
Solid state characteristics |
Ideally the drug is a solid, stable crystalline material with nice spherical particles around 200 µm in diameter Consider melting point, stability, mixing and flow |
|
|
The fewer numbers of steps in the synthetic route, the better to maximize the yield Consider processing conditions – temperature/pressure/solvents Cost of materials Retro synthesis analysis |
The fewer numbers of steps in the synthetic route, the better to maximize the yield Consider processing conditions – temperature/pressure/solvents Cost of materials Retro synthesis analysis |
|
|
Stability |
Stability of the bulk drug Although tends to be is quite quickly Drug products needs a shelflife of 2 to 3 years Typical bulk drug specifications: More than 99% of designated molecule Specified maximum levels of related compounds and degredates Typical Drug product specifications: 95 to 105% of stated level of active drug content, specified maximum levels of the degredates Stability issues include formulation, processing and packaging problems |
|
|
Legal issues patentability |
Patent time is 20 is from first registration, development time is around 10 years that for a limited time for recuperation of costs and trial money into next development Competitors work in Same therapeutic area
|
|
|
Toxicology |
Toxicology is the study of the adverse effects of chemical, physical or biological agent on living organisms and the environment. |
|
|
The purpose of toxicology tests |
Objective of toxicology tests: 1.Hazard/risk assessment 2.Determine safe levels of exposure to natural and man-made chemicals 3.Contribute to the development of therapeutic agents Preclinical toxicology tests are required to prove new drugs are safe prior to first administration to humans in clinical trials and also before later clinical trials |
|
|
Preclinical Trials |
At the preclinical stage, the FDA/EMA will generally ask, at a minimum, that sponsors: (1) develop a pharmacological profile of the drug (2) determine the acute toxicity of the drug in at least two species of animals (3) conduct short-term toxicity studies ranging from 2 weeks to 3 months, depending on the proposed duration of use of the substance in the proposed clinical studies. Data to fulfil the requirements; ADME, In vitro toxicity, metabolic stability |
|
|
Preclinical animal studies |
Aim: Identify the pharmacological properties: -PD (mode of action) -PK (metabolism) -Comparative physiology (extrapolation of animal data to humans) Understand the toxicological profile: -Establish a safe initial dose level of the first human exposure -Identify parameters for clinical monitoring of potential adverse effects -Special toxicity (e.g. genotoxicity, carcinogenicity, reproduction toxicity) |
|
|
Why do we need toxicity tests? |
1938 Food, Drug, and Cosmetics Act, giving the FDA power to monitor the safety of new drugs after Sulfanilamide. But more than 100 people died after taking the drug. The drug’s solvent, diethylene glycol, was identified as the reason. |
|
|
Thalidomide |
• Introduced in late 1950’s as a sedative • 200 times the therapeutic dose was not fatal • Prescribed for morning sickness Then: 1960’s - a rare form of congenital malformation – phocomelia was observed in the offspring of some mothers who had taken the drug |
|
|
Toxicokinetics |
Toxicokinetics is the study of what the body does to the drug (relates to Adsorption, Distribution, Metabolism and Excretion) and can predict the concentration of toxin that reaches the site of injury and the resulting damage 1. Absorption via - gastrointestinal tract respiratory tract skin 2. Distribution - Once the toxicant has entered the blood it is distributed around the body (this includes excretory organs) 3. Metabolism - After distribution many chemicals undergo biotransformation - most important site of such reactions is the liver Phase I reactions – oxidation, reduction and hydrolysis Phase II reactions – conjugation reactions |
|
|
Reactions to a toxic compound |
1. Local effects – injury at site of first contact e.g. corrosive materials on the skin, irritant vapours in the respiratory tract 2. Systemic effects – most toxicants have a target organ/organs. Organs particularly susceptible to toxin damage are the liver and kidney 3. Reversible and irreversible effects reversible – disappear when there is no further exposure to the toxicant irreversible – carcinomas, mutations, liver cirrhosis 4. Immediate and delayed effects Single exposure can result in toxic response. However, carcinogenic effects may occur years after the initial exposure 5. Morphological, functional and biochemical effects Morphologic – gross, microscopic changes to the tissues e.g. necrosis functional – usually reversible changes in the functions of target organs 6. Allergic and idiosyncratic reactionsIdiosyncratic reactions - not predictable, not clearly related to dose, occur rarely, maybe fatal. 7. Adverse drug reactions Unwanted or harmful responses occurring at therapeutic doses of a drug. Type A (pharmacological) – predicted based on known pharmacology, common and often dose-related e.g. haemorrhage with warfarin Type B (idiosyncratic) – unrelated to known pharmacology, rare and unpredictable e.g. bone marrow suppression with chloramphenicol |
|
|
Factors which may affect response to a toxicant |
1. sex, hormonal status and pregnancy, inherited susceptibility or resistance factors e.g. Female rat is more susceptible to warfarin and strychnine 2. Age Neonates, very young children and young animals due to relatively greater inhalation volumes, gastro intestinal absorption rate, immature detoxification systems and a smaller excretion rate. examples: morphine – due to a less efficient blood-brain barrier penicillin and tetracycline – excreted more slowly in the young. The elderly - previous drug exposure, increased body stores of some xenobiotics, impaired renal excretion, reduced detoxication. Additionally, there may be altered CYP enzyme activity 3. Dietary habits -Various dietary constituents (e.g. protein and fibre content) as well as the amount of food consumed can greatly influence the gastrointestinal absorption rate of many toxic chemicals 4. Disease stateLiver diseases can result in decreased biotransformation of chemicals Renal disease can affect excretory rate of the toxicant and therefore lead to increased response 5. Environmental factors – in animal studies1. changes in temperature 2. Light and dark cycles 6. Interactions with other drugs/chemicalsToxicity may be enhanced or decreased by the simultaneous or consecutive exposure to another chemical. Drugs can bind to serum proteins and affect the transport, distribution and excretion rate of various toxic chemicals or by the induction/depression of CYP P450 enzymes. Lead to change in quantity or change in intensity of a specific response in a target organ |
|
|
Factors in an animal study |
Social dynamics - Sex segregated or male/female mix. Caging - individual or group, microbially sterile Diet Researcher/ Staff - handing? sex of researcher Room - temperature, sound, lighting, odor |
|
|
Animal rights vs animal welfare argument |
Welfare argument #: Using animals is morally right Use animals to benefit ourselves We should not cause unnecessary pain or death Scientists have a moral obligation to treat animals humanely Animal rights argument: Belief that humans and animals have the same legal right Animal rights campaigners believe there is no difference between a rat and sick child. We should not inflict pain or death on animals |
|
|
animal husbandry throughout toxicology studies |
1. Controlled environment: temperature of 22 ±3 °C Adequate ventilation (i.e. 10 changes of air per hour) relative humidity between 30 and 70 % a 12 h light/dark cycle standardised diet and water 2. Healthy young animals should be used: mice - body weight of 15 – 16 g rats - body weight of 150 – 250 g guinea pigs - body weight of 350 – 450 g rabbits - 2 -3 kg |
|
|
Toxicity tests required |
Single dose toxicity (info can often be obtained from other studies) Repeated dose toxicity (S4). Toxicity on reproduction: fertility, teratogenicity, peri/postnatal studies (S5) Genotoxicity (S2) Carcinogenicity (S1) Single dose toxicity (info can often be obtained from other studies) Repeated dose toxicity (S4). Toxicity on reproduction: fertility, teratogenicity, peri/postnatal studies (S5) Genotoxicity (S2) Carcinogenicity (S1) |
|
|
Single dose (acute) studies |
• Define toxicity of the chemical • Single administration of a substance or multiple doses within 24 hours • Observations carried out for approx 14 days after • Identify the target organ • Determine LD50/MTD • Provide information which will determine the dose levels used for chronic studies • Three main types of acute studies: oral, cutaneous and inhalation According to the guidelines the single dose (acute) toxicity for a pharmaceutical should be evaluated in two mammalian species prior to the first human exposure. |
|
|
Choice of animal species |
• Generally 2 species – a rodent and non-rodent dog is most common non-rodent – have the advantage that blood samples can be collected during study without killing the animal • Generally the rat and mouse are selected economical, readily available, easy to handle and lots of toxicological data exists for these animals • Should have similar responses as that expected in humans • Should expose animal by the same route as that expected in humans • Studies are carried out for over 10 % of animals life time 3 months in rodents 1 year in dogs • Equal numbers of females and males in each dose group • A non-rodent may be desirable especially when the rate of metabolism in humans is known to be different from rats and mice Dose levels - At least 3 to allow a clear demonstration of dose-response relationsh |
|
|
Acute oral tests |
• Substance is dissolved in water, or corn oil/appropriate solvents • Solution is administered by gavage (gastric intubation) and animals in control group should receive the same volume of vehicle can give substance in the water or diet (less controlled though) • 2 methods of dosing test substance: 1. Varying the dosing volume 2. Varying the concentration of the dosing solutions (all animals receive the same volume of vehicle) Most guidelines suggest a constant dose volume with the dose volume being as small as possible and not exceeding 10 ml/kg body weight |
|
|
Acute skin tests |
• Commonly performed on rabbits • Hair is removed from a band around the trunk of the animal • Test substance is applied uniformly to approx 10 % of the body surface • Exposure time of 4 -24 h • Skin irritation is assessed according to a scoring system If no test substance related mortality is observed at 2 g/kg testing at higher doses is not necessary |
|
|
Acute inhalation tests |
• Only needed if inhalational exposure is expected to occur Particles with diameters > 100 µm are unlikely to be inhaled Diameters of 10-50 µm are likely to be retained in the nose Diameters < 7 µm can reach the alveoli and regarded as respirable • Exposure duration of 4 - 6 h • Determine the mean lethal concentration (LC50) following a single exposure An inhalational limit of 50 mg/m3 is thought to be acceptable |
|
|
Dose-response relationships and median lethal dose (LD50) |
LD50 can be defined as the dose of a compound that causes 50 % mortality in a population Dose response curves can be transformed into straight lines by probit analysis and then the lethal dose for any % of the population can be determined (e.g. LD10) BUTSlope of the log dose-response curve is important Steep slope - may indicate a rapid onset of action or faster absorption Flat slope - may have a wider margin of safety. Large increases in dose produce only a small response |
|
|
Maximum Tolerated Dose |
Important a range of doses, including those that cause no adverse effect to those causing life-threatening (but not death) toxicities should be used to calculate MTD Use a limited number of animals, e.g. 3 – 5 rodents per sex per group |
|
|
no observed adverse effect level (NOAEL) |
Maximum dose level that doesn’t induce any sign of toxicity in the most susceptible and appropriate species of animal tested NOAEL in each animal species converted to ‘human equivalent dose’ (HED) - Conversion usually based on body surface area (dose mg/m2) A safety factor of at least 10 is used |
|
|
Repeat dose studies (subchronic/subacute) |
• To determine adverse effects following repeated exposure to a chemical • Lower dose levels than those used for acute studies • Demonstrate whether there is a latency period for the development of toxicity • Are the toxic effects induced reversible? Major end point is not lethality • Pharmacokinetic profile of administering a small daily dose of a substance will be different to that after administering a single large dose • Dose levels should allow for the determination of NOAEL |
|
|
Dose levels |
• Aim is to determine the NOAEL level as well as which organs have the greatest susceptibility to the toxic effects of the chemical • In repeat dose studies the test substance may be incorporated into the diet or drinking water • But food consumption varies from weaning to maturity – need to predict on a weekly basis changes in body weight and food consumption and adjust the substance accordingly |
|
|
Checklist of clinical signs during a toxicity study |
Appearance of the animal1. General bodily condition - overweight, underweight, emaciated,2. Condition of hair coat and underlying skin –ragged and coarse, dull or dry,piloerection, hair thin or bald patches3. Eyes –cloudy or opaque, inflamed membranes with lacrimation or discharge4. Ears – inflamed, colour, discharge, crusting or scabbing, twitching5. Mouth and lips –inflamed, ulcers, excessive salvia, dental abnormalities6. Nose –dry, crusty or inflamed, fresh or dried exudate or serous fluid7. Feet – colour, swelling8. Anus – enlarged inflamed, ulcerated, soiled9. External genitalia – any abnormalities10. Any lesions/tumours/other abnormalities? Behaviour1. Activity – hyperactivity, abnormalsensitivity, lethargy2. Gait- muscular tone, tremor, balance3. Temperament – indifference,nervousness, aggression Functions1. Respiration – rapid, slow, laboured,noisy, gasping2. Salivation – watery or viscous, slight orprofuse, intermittent or persistent3. Urination – frequency, quantity, colour |
|
|
Tests for Toxicology - Haematology |
• Blood can be collected by venepuncturefrom large species and from the retroorbital sinus or tail in rodents (attermination rodents can be bled from theabdominal aorta or inferior vena cava) • Classic haematologic measurements areerythrocyte, leukocyte, haemoglobin,platelet and reticulocyte counts Clinical chemistry• Include fasting blood glucose, serum AST and ALT, total protein, albumin,globulin, blood urea nitrogen, sodium, potassium and calcium• Other tests may be carried out to identify specific target organ effects |
|
|
Tests for Toxicology -Urine analysis |
Easy to perform – animals areplaced in metabolism cages 1. Urine volume – dehydration, diuresis 2. Osmolality – ability of the kidney to concentrate the urine 3. pH – urine has a pH of 4.6 – 8.0 4. Glucose 5. Colour/turbidity – increases when urine becomes saturated (crystals mayindicate kidney stones),red – indicative of haematuria 6. protein |
|
|
Tests for Toxicology - Post Mortem |
1. Complete checklist for signs of toxicity (record on a PM form) 2. Record body weight 3. Take blood for haematology and serum/plasma for clinical chemistry 4. Examination of internal organs – look for any abnormalities (ulcers, lesions,colour, size)5. Remove organs and weighexpressed as a relative weight (g/kg body weight)liver, kidneys, lung, spleen, adrenals, heart, brain, thyroid 6. Take samples of organs and tissues for histologysamples fixed in formaldehdyeBoth normal and abnormal tissues/organs are taken |
|
|
Tests for Toxicology - Carcinogenesis |
Chemical carcinogenesis = induction or enhancement of neoplasia bychemicals Response of an organism to a carcinogen may be: 1. An increase in frequency of types of tumours that also occur in thecontrols 2.Development of tumours not seen in the controls 3.Occurrence of tumours earlier than in controls 4.An increase in the number of tumours in individual animals compared tocontrols |
|
|
Carcinogenicity studies |
Rapid screening tests 1.Short term tests for mutagenesis 2. Limited carcinogenic studies – short duration e.g. skin tumours, pulmonary or liver in mice Long term carcinogenicity studies Often a positive control group is includeda group of animals is dosed with a know carcinogen - shows sensitivityof the animals used in the study highest dose should be the maximal tolerated dose (MTD) RECORD: number of different types of tumours, number of animals with tumours, number of tumours per animaltime of onset of the tumours Considerations• Confidence is enhanced if the results are produced in another strain of animals• Negative results do not necessarily mean the chemical will not be carcinogenic inhumans due to possible differences in biotransformation• Inconclusive results may occur if too few animals survive until the end of thestudy• Expensive – large numbers of animals for a long time• False positives |
|
|
carcinogens |
1. Alkylating agents – e.g. Cyclophosphamide, chlorambucil, busulphanInhibit cell division by forming covalent bonds with DNA resulting intranscriptional problemsin normal cells as well as cancer cells – toxic effects in non-cancer cells 2. Radiationby direct effects on DNA or activation of cellular oncogenes e.g. UVradiation – skin cancer 3. Virusese.g. Hepatitis B is an important cause of hepatocellular carcinoma,Epstein-Barr virus is thought to cause Burkitt’s lymphoma. 4. Hormones |
|
|
Mutagenesis Studies |
Result from the interaction between mutagenic agents and the genetic material oforganismsVarious chromosomal abnormalities have been detected in human tumours |
|
|
Tests to detect gene mutations |
1. Microbial tests in vivo – e.g. bacterial reverse mutation - detection of point mutation 2. Microbial tests in vivo (host-mediated assay)• Toxicant and microorganism are injected into a mouse, then the mouse issacrificed after a few hours. Microorganisms are collected and examined forsigns of mutations3. Mammalian cells in culture• Cells from mouse lymphoma, human lymphoblasts, lung cells• Cells grow actively and have high cloning efficiency. Both forward andreverse mutations can occur.e.g. cells from mouse lymphoma which are heterozygous for thethymidine locus (TK +/-) can undergo forward mutation via the action ofmutagen and become TK -/-. Only the TK-/- form can grow in mediumcontaining 5-bromo-2’-deoxyuridine4. Mouse spot test – detect gene mutations in somatic cellsTreat pregnant mice whose embryos are heterozygous at a specific coatcolour loci and then examine the new born for mosaic patterns in the fur |
|
|
Tests to detect chromosome abnormalities |
1. In vitro tests – Chinese hamster ovaries and human lymphocytes - • Cells are exposed to different concentrations of chemical, after anincubation time cell division is stopped by the addition of colchcine.Cells are then mounted, stained and aberrations are scored. 2. In vivo Micronucleus test•Mice are treated twice with the chemical over 24h• 6 hours after 2nd treatment animals are killed and bone marrowcollected from both femurs• An increase in micronucleated cells over control is a positive result |
|
|
Tests to detect DNA repair |
1. Unscheduled DNA synthesis (UDS)• Synthesis is determined by the amount of radioactive thymidineincorporated per unit weight of DNA over the control value.• Detected in human cells in culture• Extent of DNA synthesis is determined using an autoradiographmethod |
|
|
Reproductive toxicity |
Fertility and early embryonic development toimplantation -Continue treatment throughoutmating to termination of malesand through implantation infemales Effects on pre- and postnatal development (Females (F0) exposed to the drug from implantation to the end of lactation) Effects on embryo-foetal development teratogen is a chemical that increases significantly the occurrence ofabnormalities in the offspring after being administered to either parent, ordirectly to the developing foetus Critical periods – an organism is more susceptible to a teratogen during theperiod of germ-cell formation and organogenesis (i.e. during the embryonicstage)• during this period the cells proliferate, differentiate and migration andorganisation occurs. The various organ systems are developed |
|
|
Animal studies |
2 species – rodent and non-rodent (usually rabbit)Use animals that haven’t been pregnant before Administration of the chemical• At least 4 groups – 2 controls, low and high dose groups• High dose should cause some maternal toxicity e.g. a reduction in body weight• Low dose should not produce any toxic effects Controls - 1 group receives vehicle- other group receives a positive control (to show theanimals are sensitive), e.g. aspirin is used in rodents (verypotent teratogen in rodents)• Route of administration should be same that intended for humans• Chemical is administered during entire organogenesis stage Assess pregant and foetus. But difficult to Extrapolation to humans? |
|
|
Safety Pharmacology studies |
Objective is to 1. To identify undesirable pharmacodynamic properties to its human safety (i.e. adverse effects) 2. To evaluate adverse pharmacodynamic and/ or pathophysiological effects of asubstance observed in toxicology and/or clinical studies 3. To investigate the mechanism of the adverse pharmacodynamic effects observedand /or suspected Consider Adverse effects associated with members of the therapeutic class . Check for CNS, Respiratory and Cardiovascular effects (also GI, Renal, Autonomic) |
|
|
Summary |
Studies: Define the dose-response relationship of the adverse effect observed Determine onset and duration of adverse effectCompare the dose range producing therapeutic effect with the dose level inducing theadverse effect Animal models – use sufficient numberspositive and negative controlsuse expected clinical route of administrationdose levels should include and exceed the therapeutic rangegenerally a single dose administration Safety pharmacology studies not necessary:1. For locally applied substances where systemic exposure or distribution is very low2. Prior to first administration in humans anticancer drugs intended for treatment ofterminally ill cancer patients |
|
|
Which preclinical studies are required prior to first dosing in humans (phase 1 clinicaltrials)? |
1. Safety pharmacology2. Toxicokinetics and pharmacokinetics3. Local tolerability4. Acute (single-dose) toxicity5. Repeated-dose toxicity6. Genetic toxicology7. Effects on embryofetal development (teratogenesis studies) |
|
|
Which studies are recommended prior to marketing approval? |
1. Acute / single dose study2. Repeat dose (subacute, subchronic)3.* Reproductive toxicity studies4. Local tolerance studies5. Genetic toxicity6.* Carcinogenic studies7. Safety Pharmacology8. Pharmacokinetic (ADME) studies |
|
|
Toxicokinetics |
Describe systemic exposure in animals Relationship to dose and duration of dosing Relationship between exposure and toxicity Assess clinical relevance of toxicity findings Support choice of species Usually integrated within toxicity studies |
|
|
Clinical trials |
Purpose• To ensure that the medicines supplied to the public are safeand efficacious, ie they are fit for their intended use Types • Phase I - "non-therapeutic", "safety and tolerability" • Phase II - "therapeutic", "preliminary efficacy","safety and tolerability" • Phase III - "pivotal", "therapeutic" • Phase IV - "postmarketing", "surveillance" Note• The new drug is known as an "Investigational MedicinalProduct" (IMP) once it enters clinical studies |
|
|
Phase I Clinical trials |
Purpose • To assess the safety and tolerability of the IMP in humans(possibly using micro-dosing) • To assess the pharmacokinetics and pharmacodynamics of theIMP in humans Timing• After the 1 month Safety Assessment studies(one rodent / one non-rodent)• After initial formulation studies Regulatory status • Needs Investigational New Drug Application (IND) in the USA • Needs Clinical Trials Application (CTA) in Europe Subjects • Healthy volunteers if the IMP is "conventional"• Patients if the IMP is "higher-risk" • These subjects are not expected to gain therapeutic benefitfrom the study . honest• Payment is minimal - expenses plus a bit Numbers• 50 to 200 people Location• Conducted under full medical supervision in a hospital / clinicalcentre - subjects stay in |
|
|
Phase 1: Clinical Trials continued |
Single rising-dose study• Small single dose given initially • Slightly larger dose given to the next group if first dose is safe• Repeated as appropriate Multiple rising-dose study• Small dose given repeatedly to the first group of subjects• Slightly larger dose given to the next group if first dose is safe• Repeated as appropriate Food effect study• Oral dosing • Assess the effect of food on drug absorption• Each subject receives the same dose of the IMP with andwithout food • Usually just a single, high dose of the IMP • Defined "high fat" meals for single dose studies • Nutritionally-balanced diet for multiple dose studies |
|
|
How are the doses selected? in Phase I Clinical trials |
• Safety-first approach• Starting dose is calculated based on MABEL (minimalanticipated biological effect level) from the pre-clinical data • MABEL is based on exposure (AUC) rather than dose• Always start with a minute dose in one individual only |
|
|
Phase II Clinical trials (purpose. Timing, regulatory status) |
Purpose• To establish preliminary efficacy of the IMP in patients• To establish the effective range of doses in patients• To provide an initial comparison to the "market leader" andto placebo Timing• After Phase I studies• After the 6 month (rodent) and 9 month (non-rodent) SafetyAssessment studies Regulatory status• Needs new or updated IND in the USA• Needs new or updated CTA in Europe |
|
|
Phase II Clinical trials (Subjects, Location and study design) |
Subjects• Patients with a defined disease• Specific stage of disease progression• No ongoing therapy or controlled ongoing therapy Location• Conducted under full medical supervision in hospital orclinical centres• Generally out-patients• May be multi-centre and multi-national• Generally run by medical "opinion leaders" Study Design: PLACEBO May compare against market leader. OD dosing. Usually 3 or 4 subject groups with different doses• Washout (baseline) period for ongoing therapy, generally2 weeks where everyone is given placebo 100 patients approx |
|
|
Washout period |
When a subject is asked to stop taking some or all medications prior to beginning a drug treatment study, this is called a drug washout. Or may take placebo -To get rid of existing drug in system - gives an idea of natural symptom history -trains patient compliance |
|
|
Phase III Clinical trials (Purpose, Timing, Regulatory status) |
Purpose• "Pivotal" studies• To confirm efficacy of the IMP in patients• confirm final selection of dose(s) for marketing• To confirm relative efficacy to the market leader Timing• After Phase II studies• DART and carcinogenicity Safety Assessment studies ongoing Regulatory status• Needs new or updated IND in the USA• Needs new or updated CTA in Europe |
|
|
Phase III Clinical trials (Subjects, Location) |
Subjects• Patients with a defined disease• Specific stage of disease progression• No ongoing therapy or controlled ongoing therapy Location• Conducted under full medical supervision in hospital orclinical centres• Generally out-patients• Multi-centre and multi-national• Generally run by medical "opinion leaders" |
|
|
Phase IV Clinical trials |
Purpose• Post market surveillance• To gain more experience in more patientsNote:• A completely new indication would mean starting at Phase IITiming• After approval and marketing |
|
|
Bioavailability Studies |
Bioavailability (BA) studies • To define the oral bioavailability in patients of the IMP fromthe final clinical formulation(s) at the clinical dose(s) • A successful 14 day safety assessment study (on animal) is required on the intravenous formulation Before the start of the BA study (on human) • Usually conducted in Phase III • Compare pharmacokinetic parameters of oral dosing andintravenous dosing • An intravenous formulation is required - may be tricky Aim for high bioavailability • Single dose cross-over study • Number of patients - 24 (12 with drug, 12 with IV) |
|
|
Bioequivalence studies |
• Bioequivalent products have the same pharmacokinetic profile The same clinical effect is obtained from different formulations via the same route • Two or more oral dosage forms of the same drug must bebioequivalent eg solution, suspension, tablet, capsule, lozenge • Usually conducted in Phase III (if required) • Compare oral pharmacokinetic parameters of the formulations• AUC, Tmax, Cmax • Statistical Definition: Products are bioequivalent if the 90 % confidence interval ofthe test formulation is 80 to 125 % that of the referenceformulation • Single dose cross-over study• Number of patients - up to 24 |
|
|
Proportional BE and BA studies |
• Two or more strengths of the same formulation must showproportional equivalence, eg a tablet containing 20 mg drugmust show 2 x AUC of a tablet containing 10 mg drug • Usually conducted in Phase III (if required) • Compare oral pharmacokinetic parameters of the formulations• AUC, Tmax, Cmax • Products are proportionally equivalent if the 90 % confidenceinterval of the test formulation is 80 to 125 % that of thereference formulation, corrected for dose • Single dose cross-over study• Number of patients - up to 24 |
|
|
Safety Assessment studies |
Purpose • To understand the likely safety profile of the drug, before thehuman clinical studies start • To be used to define doses for the initial clinical studies or tomake the decision as to start or stop a clinical study Types • 1 month study - usually OD per animal. • 6 rodent / 9 non-rodent month study - multiple dose groups • Development and reproductive toxicity (DART) studies - multiple dose and placebo, needed before women can be enrolled on clinical studies. • Carcinogenicity studies - usually mice, OD, Multiple dose and placebo. Usually started around Phase II / III• Needed to predict very long term effects of the drug in humans |
|
|
Pre-clinical stage and Safety Assessment formulations |
• Formulation scientists involved with selection of lead drug • Assess likely oral bioavailability • Assess possible stability issues • Assess likely formulation type necessary -
|
|
|
Safety Assessment formulations |
• Oral liquids• Easy to adjust to an exact dose• Weight of mouse, rat, dog, monkey ? mouse - 30g, rat 300g dog and rhesus monkey 10kg • Considerations:• pH, ease of preparation, stability• Needed before safety assessment studies begin• Bulk drug and analytical method required beforeformulation work can start |
|
|
Excipient compatibility studies |
• Assess suitability of excipients• Binary compacts and model tablet formulations• Expose to elevated temperatures and humidity• Assess stability and generation of degradates (and toxicity) • Needed before "real" formulation work can begin• Bulk drug and analytical method required beforethis formulation work can start |
|
|
first human formulation |
• Usually oral dosing • Traditionally hand-filled capsules: Easy to blind, Easy to vary the dose,Can be done on almost any scale • Bulk drug and analytical method required beforeformulation work can start • Stability data needed before going into clinical studies |
|
|
"Real" formulations and biobatch |
• Aim is to get a "real" formulation as soon as possible - so can do as much testing as possible in clinical tests • Absolutely required for Phase III• Challenges:• Dose selection• Market image• Market pack (blister pack, bottle) • Process scalability• Production capability (factories) Biobatch -Ultimate reference batch• Applies to bulk drug and formulated product• Must be used in Phase III pivotal studies• Must be used in market container stability studies |
|
|
Why have a regulatory system? |
• To ensure that all medicinal products used by the public are• Safe• Efficacious• Of a suitable quality • Avoid bad quality or ineffective medicinalproducts being sold or supplied to the public• "Snake oil"• "Patent remedies"• Contaminated or impure products• Products with variable strength |
|
|
What is subject to the regulatory system? |
• All drug molecules• All formulated medicinal products• Oral medicines eg tablets, suspensions• Topical medicines eg creams, patches• Inhaled medicines eg aerosols• Injectable products• All medical devices• Replacement partseg hip joints, heart valves, pacemakers• Life support equipment• All medical gases |
|
|
Important regulatory bodies |
Medicines and Healthcare Regulatory Agency (MHRA) - responsible for inspection and licensing of allmanufacturing and distribution sites in the UK•licensing of all clinical trials and approval of all drugs products for use in the UK for both human medicine andveterinary medicine
European Medicines Agency (EMA)• EU regulatory body • Supersedes national bodies• Contracts out work to national bodies Food and Drug Administration (FDA) Similar role to MHRA• But also responsible for food and cosmetics• Will inspect foreign sites International Committee on Harmonisation (ICH) -advises the regulatory bodies - made up of FDA, EU, Japan; industry representatives fromthe three regions |
|
|
Regulatory documents for clinical studies |
Investigational New Drug (IND) Application• USA document OR Clinical Trials Authorisation (CTA)• European document Contents• Everything you know about your drug at this point• Pre-clinical pharmacology and toxicology studies• Manufacturing information - bulk drug and formulatedproduct• Intended clinical protocols and investigator information |
|
|
Regulatory documents for product approval |
New Drug Application (NDA)• USA document Marketing Authorisation Application (MAA)• European document Contents• Absolutely everything you know about your drug• All animal data• All manufacturing data including scale up, biobatchinformation and production plans• All human data including "failed" studies• All proposed marketing information Common Technical Document -common format data - contains • Module 1• Region-specific information - pricing • Module 2• Overall summary of data• Module 3• Quality data - produciton • Module 4• Non-clinical data• Module 5• Clinical data |
|
|
Approval Processes in the EU |
EU Centralised procedure• Mandatory for specific drug types (high risk or 1st of type) • MAA submitted to EMA• Review conducted by the EMA Committee for Medicinalproducts for Human Use (CHMP) within 210 days• Approval valid for all member states EU National procedure• MAA submitted to and reviewed by one member state only• In the UK, the MHRA reviews applications within 210 days EU Decentralised procedure• Applicable only when an MAA has not already been submittedin any EU member state• Applicable only when the centralised procedure is notmandatory• MAA submitted to many individual ("concerned") EU memberstates (CMS) simultaneously• Review conducted by one designated reference member state(RMS) within 70 days, and sent to CMS• CMS have 30 days to reply to the RMS• RMS issues final report within 30 days• CMS grant national licences within 30 days "Fast-track" Approval Processes - no other option for disease treatment - no effective medicine exists It is for chronic, debilitating diseases for which availabletreatments are ineffective or otherwise inadequate• It is for severe or life-threatening diseases for whichavailable treatments are ineffective or otherwise inadequate• There has been emergence of a disease with wide-spreadresistance to treatment with currently available treatments• There has been emergence of a new disease entity whichhas severe or life-threatening effects and for which currentlyavailable treatments are ineffective or inadequate |
