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Clinical Investigation and Outcomes Research Clinical Research in Drug Development Marcia A. Testa, MPH, PhD Department of Biostatistics Harvard School of Public Health 1 Drug Development • Process of bringing a new drug or device to the market. It includes drug discovery and product development, pre-clinical research (microorganisms/animals) and clinical trials (on humans). New Chemical Entities (NCEs), also called New Molecular Entities (NMEs), are compounds which emerge from the process of drug discovery. 2 Drug Development • NCEs/NMEs have promising activity against a particular biological target thought to be important in disease; however, at the time of discovery little will be known about their safety, toxicity, pharmacokinetics and metabolism in humans. It is the function of drug development to assess all of these parameters prior to human clinical trials during the pre clinical research phase. 3 Drug Development • Many aspects of drug development are focused on satisfying the regulatory requirements of drug licensing authorities. • www.sfda.gov.sa/ – US: Food and Drug Administration (FDA) • www.fda.gov – Europe: European Medicines Agency (EMEA) – Japan: Pharmaceuticals and Medical Devices Agency (PMDA) 4 Drug Development • Regulatory Requirements generally constitute a number of tests designed to determine the major toxicities of a novel compound prior to first use in man. •It is a requirement that an assessment of major organ toxicity be performed (effects on the heart and lungs, brain, kidney, liver and digestive system), as well as effects on other parts of the body that might be affected by the drug (e.g. the skin if the new drug is to be delivered through the skin). 5 Drug Development 6 Global Drug Market by Region 7 Leading Drug Therapies 8 Clinical Studies • Once the preclinical research has been completed, an Investigational New Drug (IND) application (US), or equivalent, is made to receive approval for testing in humans. • After human testing confirms that the drug is efficacious and does not have serious adverse effects in at least 1,000 – 3,000 patients, a New Drug Application (NDA – in US) is filed, reviewed, and a decision for approval/disapproval for marketing to the public is made. • There are many opportunities for clinical investigators to participate at all stages of drug development research, especially during Phase I – Phase IV Clinical trials. 9 Development Time • Average time to develop a new drug is 10 – 12 years • Out of 10,000 – 30,000 potential substances only 1 is likely to make it to market Drug Development Research can be broadly divided into Pre-Clinical Clinical 10 The IND and NDA 11 Life Cycle of Drug Development 12 Drug Discovery Typically over 10,000 – 30,000 compounds are screened before finding one worthy of further preclinical testing 13 Pre-Clinical 14 15 Pre-Clinical Drug Development • Pre-clinical drug development is a complex, regulatory-driven process designed primarily to assess the safety and viability of new molecular entities. • Preclinical encompasses toxicology, pharmacology, metabolism, bioanalysis, pharmaceutical analysis and biosafety testing 16 Pre-clinical Drug Development • During preclinical drug development, a sponsor evaluates the drug’s toxic and pharmacologic effects through in vitro and in vivo laboratory animal testing. • Genotoxicity screening is performed, as well as investigations on drug absorption and metabolism, the toxicity of the drug’s metabolites and the speed with which the drug and its metabolites are excreted from the body. 17 Investigational New Drug (IND) • IND Submission – Request to the regulatory agency (e.g., FDA in US) for permission to begin testing the product in humans – Compilation of the following: • Data obtained during nonclinical investigation stage and from previous human experience • Chemistry, manufacturing, and control data • Protocol • Detailed description of proposed studies – Review Period (e.g.,30-day review period by FDA)18 19 Phase I – III Clinical Studies • Clinical Studies – Conducted in healthy volunteers or in patients – Three Phases (I-III) during this stage of development and one phase (4) following marketing approval – Takes an average of 6 years to complete the first three stages 20 Phase I Clinical Studies • The first testing of a new compound in human subjects • For the purpose of establishing the tolerance of healthy human subjects at different doses • Defining its pharmacological effects at anticipated therapeutic levels, • And studying its absorption, distribution, metabolism, and excretion patterns in humans 21 Phase I Clinical Studies • Phase I studies also evaluate drug metabolism, structure-activity relationships, and the mechanism of action in humans. • The total number of subjects included in Phase I studies varies with the drug, but generally requires a minimum total in the range 20 to 100. • Final objective of Phase I studies is to have determined the maximum-tolerated dose with potential toxicities well-defined 22 Phase I - Multiple Sclerosis • In human trials, CTLA4Ig was shown to be effective in improving the signs and symptoms of rheumatoid arthritis (RA) and has been approved by the US Food and Drug Administration (FDA) for the treatment of RA. • CTLA4Ig was also tested in patients with psoriasis, a T cell–mediated skin disorder, in a Phase I, open label, dose-escalation trial showing clinical improvement that correlated with decreased T-cell infiltrates and diminished epidermal proliferation. • It was the tested in individuals with multiple sclerosis (MS) 23 Phase I - Multiple Sclerosis • Disease: multiple sclerosis (MS). • Drug Mechanism: infusions of CTLA4Ig to block the CD28/B7 T-cell costimulatory pathway. • Design: Phase I dose-escalation study – 16 patients with relapsing–remitting MS received a single CTLA4Ig infusion and were monitored for up to 3 months after treatment. – assigned to one of four dose cohorts (2, 10.0, 20.0, or 35.0 mg/kg), each one consisting of 4 subjects. – Patients were enrolled starting with the lowest dose (2.0 mg/kg) and proceeding to the next dose group after a 1month safety evaluation was completed. 24 Phase I - Multiple Sclerosis • Results: CTLA4Ig was well tolerated in patients with MS, and most adverse events were rated as mild. • Immunologic assessment of the patients showed a reduction in myelin basic protein (MBP) proliferation within 2 months of infusion and decreased interferon- production by MBP-specific lines. • Viglietta V et al. CTLA4Ig treatment in patients with multiple sclerosis: an open-label, phase 1 clinical trial. Neurology. 2008 Sep 16;71(12):917-24 25 Phase I Clinical Studies There are several separate Phase 1 Studies conducted to yield 100 total patients Adverse events at different doses 26 Phase II Clinical Studies • Phase II includes the early controlled clinical studies conducted to obtain some preliminary data on the effectiveness of the drug for a particular indication or indications in patients with the disease or condition. • This phase of testing also helps determine the common short-term side effects and risks associated with the drug. • Phase II studies are typically well-controlled, closely monitored, and conducted in a relatively small number of patients per study with the total number in the Phase II studies usually involving several hundred people. 27 Phase II Clinical Studies • Initial assessment of efficacy (proof-of-concept) and further assessment of safety • Involve patients who have the indicated disease or condition • Small patient population (100 - 300 in total for all Phase II studies) • Usually last 2 years (37% of drugs fail Phase II testing) • Final objective of Phase II Studies is to have rigorously defined the dose regimen of the drug that elicits the desired therapeutic benefit and that outweighs the observed clinical risks 28 Phase II Study – Dry Eye keratoconjunctivitis sicca • Objective: To explore the safety and efficacy of CF101, an A3 adenosine receptor agonist, in patients with moderate to severe dry eye syndrome. • Design: Phase II, multicenter, randomized, doublemasked, placebo-controlled, parallel-group study. • Participants: Sixty-eight patients completed the study, 35 patients in the placebo group and 33 patients in the CF101 group. • Intervention: Patients were treated orally with either 1 mg CF101 pills or matching vehicle-filled placebo pills, given twice daily for 12 weeks, followed by a 2week post treatment observation. 29 Phase II Study – Dry Eye • Primary Outcome Measures: • Improvement of more than 25% over baseline at week 12 in one of the following parameters: – (1) tear break-up time; – (2) superficial punctate keratitis assessed by fluorescein staining results; and – (3) Schirmer tear test 1 results • Laboratory tests, ophthalmic examinations, intraocular pressure measurements, electrocardiographic evaluations, vital sign measurements, and adverse events. 30 Phase II Study – Dry Eye 31 Phase II Study – Dry Eye 32 Phase II Study – Dry Eye • Results: A statistically significant increase in the proportion of patients who achieved more than 25% improvement in the corneal staining and in the clearance of corneal staining was noted between the CF101- treated group and the placebo group. • Conclusions: CF101, given orally, induced a statistically significant improvement in the corneal staining and an improvement in the BUT and TM in patients with moderate to severe dry eye syndrome. The drug was very well tolerated. These data and the anti-inflammatory characteristic of CF101 support further study of the drug as a potential treatment for the signs and symptoms of dry eye syndrome. 33 Phase II Clinical Studies 34 Phase III Clinical Studies • Phase III studies are expanded controlled and uncontrolled trials. • They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained in Phase II and are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug. • These are often referred to as “pivotal” – you usually have to have at least two large “successful” Phase II studies before receiving drug approval 35 Phase III Clinical Studies • Large-scale studies aimed at verifying efficacy establishing safety, and establishing the optimum dosage • Involve a larger number of patients (minimum total studied for all Phase III trials -1,000-3,000). Often, as many as 6,000 (or more) patients will be studied. • Usually lasts 3 years (6% fail Phase III testing) • Objective of Phase III Clinical Studies – To provide the data sufficient to convince the agency of the favorable benefit/risk ratio of the drug under investigation 36 Phase III – Renal Carcinoma • Purpose: Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor,platelet-derived growth factor receptor, and c-Kit. • Design: Randomized, double-blind, placebocontrolled Phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive andcytokine-pretreated patients with advanced renal cell carcinoma (RCC). 37 Phase III – Renal Carcinoma • Subjects: Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. • Endpoints: – primary end point was progression-free survival (PFS). – secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. 38 Consort (Study Flow) Diagram 39 Survival Results 40 Phase III Clinical Studies 41 New Drug Application (NDA) • Formal proposal to the regulatory agency (e.g., Food and Drug Administration in the US – FDA) to approve a new drug • Research evidence provided to agency – Drug is safe and effective – Benefits outweigh risk – Proposed labeling is appropriate 42 Market Launch-Phase IV Phase IV Clinical Studies Begin 43 Phase IV Clinical Studies • Also known as Post Marketing Surveillance Trial • These are structured clinical trials – often open labeled, can be randomized or observational • Phase IV studies may be required by regulatory authorities 44 Post Marketing Surveillance • Also known as Post Marketing Surveillance Trial • These are structured clinical trials – often open labeled, can be randomized or observational • Phase IV studies may be required by regulatory authorities 45 Post Marketing Surveillance Pharmacovigilance Studies • Clinical trials are designed to approve new drug entities and indications. • Pharmacovigilance is the term used to describe drug safety surveillance after a drug is approved. 46 Pharmacovigilance • “the pharmacological science relating to the detection, assessment, understanding and prevention of adverse effects, particularly long term and short term side effects of medicines.” • Source: The Importance of Pharmacovigilance, WHO 2002 47 SFDA National Pharmacovigilence Center http://www.sfda.gov.sa/En/Drug/Topics/Administrations/PostmarksurvAdmin.htm • Gathers and evaluates adverse drug reactions • Manages tje spontaneous reporting system. • Performs surveillance of high incidence side effects. • Conducts Pharmacoepidemiology studies. • Provides up to date information to health professionals regarding safety of pharmaceutical products. 48 Safety Data Mining Analysis • Use of computer algorithms to systematically and objectively analyze records contained in huge drug safety databases. • Goal: to discover hidden interesting patterns of unexpected adverse drug occurrences. 49 Safety Data Mining at FDA • Algorithm: Multi-Item Gamma Poisson Shrinker (MGPS) • Database: FDA’s Adverse Event Reporting System (AERS) 50 Ev e nt Code and Total Re port Count Clozapine _21939 Se rtraline _16467 Drug and Total Report Count Insulin_14492 Le v onorge stre l_14236 Ce faclor_13757 Isotre tinoin_13566 Valproate _12842 Intraute rine De v ice _12672 Warfarin_12455 Diatrizoate _12275 Lov astatin_10748 44 28 322 62 42 24 38 19 20 7 31 44 19 10 9 15 9 3 1 1 156 101 71 35 37 27 28 10 31 29 27 9 18 17 8 14 3 1 62 18 12 4 11 11 21 7 9 21 17 4 13 9 13 3 3 3 41 30 20 22 2 5 7 23 4 5 2 1 17 1 50 29 41 13 13 6 14 12 3 4 3 3 4 3 1 222 65 33 56 4 46 13 4 19 15 11 5 8 7 11 6 389 100 80 74 160 28 75 8 31 45 34 55 14 17 11 14 20 19 1 2 91 21 32 28 13 15 15 12 12 4 3 6 6 3 11 5 1 2 1 69 191 1 890 191 Hepatorenal syndrome_846 Cholestasis_1295 Cholecystitis NOS_1371 Hepatic disorder NOS_1824 Hepatic necrosis_1939 Hepatomegaly_2118 Cholelithiasis_2502 Jaundice cholestatic_3401 Hepatocellular damage_3651 Hepatic failure_5052 Hepatic encephalopathy_903 88 Hepatic cirrhosis NOS_1547 116 Hepatic steatosis_2147 161 Blood bilirubin increased_4067 467 Hyperbilirubinaemia_6245 Jaundice NOS_8173 Fluoxe tine _37443 Showing the actual (“observed”) count AND the RR05 for each drug-event combination (EB05 >2 are in red boxes) Hepatitis NOS_9579 64 32 16 8 4 Hepatic function abnormal_19982 RR05: Value > 64 > 32 and <= > 16 and <= > 8 and <= > 4 and <= > 2 and <= <= 2 RR05: The estimated lower 95% “confidence limit” for the unadjusted N/E value Note: you cannot automatically look at the numbers or 43 unadjusted scores to determine 53 37 30 32 15 7 23 28 10 6 4 signals! 2 14 3 30 37 49 44 20 18 2 17 39 2 6 51 [email protected] data JUL-2003, page 1 - Run_96_N1_conc label_____.bin Spatial Needle In A Haystack RR05-----.dsn Drug Development Summary (minimum number subjects) Phase III FDA Approval 3.5 1-2 2-4 4-6 1.5 Total = 12 - 17 Lab and Animal Studies 20 to 100 Healthy Volunteers 100 – 300 Patient Volunteers 1,000 to 3,000 Patient Volunteers Assess Safety and Biologi cal Activity Determine Evaluate Safety and Effectiveness. Dosage Look for Side Effects. 70% of INDs 30% of INDs Verify Effectiveness, Monitor Adverse Reactions from Long-Term Use 27% of INDs FILE NDA Phase II FILE IND Phase I % of all new drugs that pass Purpose Test Population Years Pre Clinical Testing Phase IV/Post Marketing Safety Monitoring Review Process Large Scale Manufacturing -------------Distribution -------------Education 20% of INDs 52 53