Drug Development Study Resources

Drug Development What is a drug? • A therapeutically useful chemical must be able to: • • • • Be absorbed into the body Distribute to the target tissue Be stable enough to act on the target tissue for a desired amount of time Be Reversible in its action i.e. become biodegraded and excreted from the body • Be Safe i.e. not cause adverse effects, be nontoxic Lipinski rule of 4 (for small drug molecules): • Drug like molecules should: • • • • Have less than 5 hydrogen-bond donor atoms Have a molecular mass of less than 500 Have relatively high lipophilicity Have a sum of oxygen and nitrogen atoms less than 10 Starting point for search for a new drug • Natural products • Opium->Morphine • Cinchona officinalis->Quinine • Penecillium crysogenum->Penicillin • Rational design approach • ACE active site analysis ->Captopril • HIV protease ->Nelfinavir • Older drugs • Penicillin->Ampicillin • Cocaine->Procaine Drug development objective: •Finding a dose or dose range of a drug candidate which is both: • Efficacious (i.e. improves or cures the target disease condition) • Safe (has acceptable risk of adverse effects) Clarification of terminology: • Concentration-effect curve: • This is the relationship between concentration of the pharmacological agents (in biophase) and its effect • Usually logarithmic • Concentration of agent producing half maximum response is referred to as EC50 Clarification of terminology: 120 • Dose-response curve: 100 80 % responders • This is the relationship between the dose of a drug administered to a complete organism (e.g. a lab rat or a human) and the effects it produces. • Often it represents the frequency of responders • Usually logarithmic but fundamentally different from concentration-effect curve • The dose of the agent producing half maximum response is called: ED50 60 40 20 0 1 10 100 Dose 1000 Terms frequently encountered in drug development: • MinED: The lowest dose producing a clinically important response that can be declared statistically, significantly different from the placebo response • MaxED: The dose above which there is no clinically significant increase in pharmacological effect or efficacy • MTD: The maximal dose acceptably tolerated by a particular patient population • TI or Therapeutic index: the ratio of MTD over an effective dose (e.g., MaxED) • Sponsor: Pharmaceutical company, university or research institute that is developing a drug • Drug candidate: A chemical with possible pharmacological efficacy • Biologic: A protein, DNA, RNA or part of any of these molecules with specific pharmacological action • IND: Investigational new drug • NDA: New drug application Drug development process • Efficacy can defined as the ability of a drug to produce a clinically statistically significant response: • Drug A can achieve a clinical effect at a lower dose compared to drug B, therefore it is more efficacious • Drug C can achieve a greater clinical effect than drug A, so it is has more potency. Drug development process: • An ideal drug candidate has a large TI, i.e. there is spatial separation between dose-response and dose-toxicity curves. • This is referred to as Safety Drug development process • Nonclinical or preclinical phase • Pharmacological studies • Toxicological studies • Formulation • Clinical phase • • • • Phase I Phase II Phase III Phase IV Preclinical phase, pharmacological studies • Demonstration of selective biological activity of chemical substance in living cells/tissues • Screening procedures have to have sensitivity and specificity • Bioassays: Experiment for estimating the potency of a drug, material, preparation, or process by means of the reaction that follows its application to living matters: • Tissue/cell extracts • Tissue preparations • Cells in culture medium/ex-vivo models In vitro bioassays: Isolated guinea pig ileum: • Isolated guinea pig ileum: Used for the screening of drug candidates on: • Muscarinic receptors • 5-HT receptors • Histaminergic receptors In vitro bioassays: MTT Cell viability assay • Mitochondria in viable cells reduce 3-(4,5dimethylthiazo-2-yl)-2,5-diphenyltetrazolium to its insoluble purple formazan derivative • Formazan is dissolved by addition of DMSO • Colour is read by a platereader • More colour means more viable cells In vitro pharmacological studies aim to establish: • Biological activity and the level of selectivity • Efficacy of drug candidate compared to established drugs or drug candidates in terms of potency and selectivity • Possible side-effects of the drug • By obtaining EC50, the target concentration range in biophase needed during animal studies In vivo pharmacological studies • Pharmacokinetic studies • Single dose IV administration to determine half-life • Studies to establish absorption after IP, SC, IM and oral administration, early formulation work • Study of metabolic routes • Establishment of dose regimens In vivo pharmacological studies • With preliminary information about drug candidate pharmacokinetics, it can be tested in animals • Efficacy of drug candidate in disease models e.g.: • • • • • Spontaneously hypertensive rats Diabetic rats Tumor implants Kindling models of seizure etc Preclinical phase, toxicological studies • Acute studies: • Single dose administered, possible toxic effect investigated for 2 weeks • Subacute studies: • Repeated dose regimen for 30 to 90 day duration • May use an escalating dose protocol • Chronic studies: • Repeated dose regimen for greater than 90 days • Usually a rodent and at least one nonrodent species used • Reproductive cycle studies: • Used to determine drug effects on fertility • Includes investigation of possible teratogenic effects • Mutagensis (Ames test): • Salmonella typhimurium testing Preclinical phase, toxicological studies • Criteria for toxicological effect can be varied, examples: • Functional, e.g.: • • • • • Neurological effect (drowsiness, anxiety, memory deficit) Changes in enzyme levels Failure to thrive Weight loss … • Anatomical e.g.: • Cell damage • Anatomical abnormality during development • … Final outcome of toxicological studies • NOAEL(No Observed Adverse Event Level) for the drug candidate • Helps determine safe dosing regimens in clinical studies • Guidance as to what type of adverse events to be expected in human studies Drug formulation • Biologic: • Usually administered as a solution for injection • Problem with stability have to be dealt with • Small molecule: • • • • Variety of formulations may be possible Effect of formulation on drug disposition has to be determined Most suitable formulation for the required dose and dosing regimen has to be found Final form may be : • • • • • Injectable Tablet Capsule Oral Suspension or solution … Final outcome of preclinical studies: •Drug candidate or biologic is probably: • Safe • Efficacious Premarketing clinical development • If after preclinical animal testing a drug candidate is deemed to be safe and efficacious, it can enter the clinical phase • From this point on, the drug candidate becomes Investigational New Drug (IND). • IND application is submitted (containing all the relevant preclinical data) to the regulatory authority (e.g. the FDA in the USA) • After the review process, the sponsor will be given permission for submitting clinical trial application IND document contains: • Name and description of the drug (such as chemical structure, other ingredients) • How the drug is processed during the chemical manufacturing and also formulation • Any information regarding the safety of the drug from preclinical studies • Forecast about marketing of IND • Past experiences for the certification of the drug in other countries • The Clinical Development Plan (CDP) including signed statements from the investigators and initial protocols for planned investigation Results of Regulatory Examination of the IND application: • Approval to begin clinical trials • Clinical hold to delay or stop the investigation • • • • Participants are exposed to unreasonable or significant risk Investigators are not qualified Materials for the volunteer participants are misleading The IND application does not include enough information about the trial’s risks Clinical development aims, mainly to: • Phase I: • Establish short-term pharmacokinetics • Pharmacodynamic effects • Dose ranges • Phase II: • Determine IND efficacy in well-defined subject populations • Establish dose-response relationship • Phase III: • Long-term and large-scale studies • Confirm prior findings • Detect adverse effects from repeated use • Phase IV: • When the first 3 phases are completed successfully, phase IV trials (or postmarketing studies) are carried out • Usually designed by the regulatory authority Main aims of Phase I trials • Understanding drug pharmacokinetic properties: • • • • AUC Cmax Tmax Half-life • Different formulations are compared in bioequivalence studies Phase I clinical studies • Between 20-80 healthy volunteers • Drugs intended for cancer treatment, are tested in cancer patients • Subjects are monitored closely for changes in normal physiological function • • • • Cardiovascular function Hematological changes Liver and kidney function etc • Duration is usually several weeks • Once safety and dosage have been established, can move on to Phase II • Usually 70% of drugs pass this stage Phase II clinical trials • Aim to show efficacy and safety in target patient group • Usually conducted in Parallel Treatment Groups (i.e. one group receiving IND, the other group receiving placebo) • No cross over of subjects between groups • Response variable is directly related to the condition the IND is developed for e.g. antihypertensive is efficacious if it lowers blood pressure • The study lasts a few months to a couple of years • Subjects are usually a few hundred Phase II clinical trials • Subjects are selected such that: • They have the disease/condition the IND was developed for • The severity of the condition is mild to moderate • No other compounding conditions exist in the subject • The main aim of study is to determine answer to these questions: • • • • Is there any evidence the drug is effective under clinical conditions? What doses cause a response which is statistically different from placebo? What is the nature of the dose-response relationship? What is the optimal dose? Phase II clinical trials: • At the end of phase II trials, the review committee decides whether: • No important adverse effects caused by IND • Evidence of efficacy is presented for the IND • The IND is allowed to proceed to phase III studies • Usually about 30% of INDs are permitted to proceed Phase III clinical studies • Aim to determine efficacy in target group • Aim to monitor adverse effects • Are therefore, long term (can last a few years) • Participants are around a few hundred to a few thousand • Subject population has the disease or condition for which the IND was developed • Subject selection is less restrictive, i.e. patients with more severe disease or other compounding conditions may be included • The IND group(s) is compared with normal treatment (and sometimes placebo) New Drug Application • At the end of Phase III investigation (or during its final stages) a NDA is filed, containing all information from preclinical and clinical studies: • • • • • • • • • • • • Proposed drug label Pharmacological class Foreign marketing history Chemistry Manufacturing and controls Nonclinical pharmacology and toxicology summary Human pharmacokinetics and Bioavailability summary Microbiology summary Clinical data summary Results of statistical analyses Benefit–risk relationship Postmarketing or phase IV clinical studies: • Several thousand subjects are recruited • This postmarketing study is long term • The aim is • To confirm safety: monitoring for adverse effects missed in previous studies • To develop drug’s market potential: Assessment of quality of life (QoL) and pharmaco-economic study • Dose adjustments based on large population data • Maybe a lower dose works just as well • May be that certain patients need higher doses • etc • Indications other than the disease/condition drug was tested for in the original application The review team (from the FDA website) • Project Manager: Coordinates the team’s activities throughout the review process, and is the primary contact for the sponsor. • Medical Officer: Reviews all clinical study information and data before, during, and after the trial is complete. • Statistician: Interprets clinical trial designs and data, and works closely with the medical officer to evaluate protocols and safety and efficacy data. • Pharmacologist: Reviews preclinical studies. • Pharmakineticist: Focuses on the drug’s absorption, distribution, metabolism, and excretion processes.Interprets blood-level data at different time intervals from clinical trials, as a way to assess drug dosages and administration schedules. • Chemist: Evaluates a drug’s chemical compounds. Analyzes how a drug was made and its stability, quality control, continuity, the presence of impurities, etc. • Microbiologist: Reviews the data submitted, if the product is an antimicrobial product, to assess response across different classes of microbes. Clinical development plan • At early stages of drug development (preclinical phase) a CDP should be drafted which guides Phases I to III studies • CDP draws on a draft drug label document • A drug label is a document that contains detailed information about how a drug is used including: • • • • Target patients Dose Dose regimen etc • E.g. If the drug labels foresees the use of the drug as once a day, the clinical design should be for single dose treatment Drug development overview