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Informed Consent
• Communication between researcher and participant
• Nuremberg Code [4], the Declaration of Helsinki [5], the
Belmont Report [3], and the International Ethical
Guidelines for Biomedical Research Involving Human
Subjects.
• Surrogate consent i/c/o emotionally/ mentally impaired and
pediatric population.](https://image.slidesharecdn.com/clinicaltrialsphases0-3-200910085919/85/Clinical-trials-phases-0-3-54-320.jpg)
Uploaded byDR SHAKEEB SIRAJ DHORAJIWALA
Clinical trials phases 0 3
The document provides a comprehensive overview of clinical trial phases, highlighting historical developments, definitions, and methodologies relevant to drug development from phase 0 to phase III. It emphasizes the significance of micro-dosing in early trials, the importance of safety and tolerability studies, and the design elements crucial for effective evaluations of new therapies. Regulatory and ethical considerations, alongside the financial impacts of various phases, are also thoroughly discussed.
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Clinical trials phases 0 3
- 1. Clinical TrialPhase 0-3 Dr.Shakeeb Dhorajiwala, JR II, TNMC, Mumbai. 10-09- 2020 1
- 2. Historical Aspects 10-09-2020 2 850BC –The First Clinical Trial? The Book of Daniel in Bible Surgeon Ambroise Par´ e - boiled oil vs. mixture of egg yolks, oil of roses & turpentine - over soldiers’ wounds 1753- James Lind: citrus fruits cure scurvy
- 3. 10-09-2020 3 1863 –Gull & Sutton - used placebo treatment in rheumatic fever patients 1865 – Claude Bernard – used the word ‘control’ 1923 – 1st use of randomization – Fisher & Mac Kenzie (agricultural field experiments) 1924 – randomization 1st used in trial by Dr. Amberson - sanocrysin in treatment of pulmonary tuberculosis 1927- Fergusson- Blinding
- 4. General Aspects OfA 10-09-2020 4
- 5. Clinical Trial Def: Prospectivestudy comparing the effect and value of intervention(s) against a control in human beings. The ideal clinical trial is one that is randomized and double-blind 10-09-2020 5
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- 7. Where does itfit? 10-09-2020 7
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- 9. Phase 0 (Microdosing) • “A microdose is defined as < 1/100th of the dose of a test substance calculated (based on animal data) to yield a pharmacologic effect with a max. dose of < 100 micrograms (for imaging agents, the latter criterion applies).” (FDA) • First-in-human trial • Administration - single sub therapeutic dose. • Small no. of healthy human subjects (10 to 15) • Preliminary data of pharmacokinetics (PKs) in humans obviating the need for such study in animals and carried out before conducting toxicity studies in animal. 10-09-2020 12
- 10. • Based onthe principle of: ‘The best models for humans are humans’ • Fundamental concept of Micro-dosing :- Under conditions of PK dose proportionality, - PK data obtained at lower doses can be used to predict PK at higher doses. - Small dose, pharmacological effect - not intended , so adverse reaction - unlikely 10-09-2020 13
- 11. Bioanalytical Methods Methods Used: •Accelerator Mass Spectrometry (AMS) • Nuclear Magnetic Resonance (NMR) Spectroscopy • Positron Emission Tomography (PET) • Liquid Chromatography-Tandem-Mass • Spectrometry (LC/MS) 10-09-2020 14
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- 13. Advantages of Microdosing 10-09-2020 18 • Micro dose so low - risk of AE too small, Hence animal testing substantially reduced. . • Gives an estimation of therapeutic dose in human. • Preclinical animal data less predictive due to : species difference, unavailability of suitable animal models, metabolic differences • no prediction of racial or individual diff. in PK. • Conventional phase I - US $1.5- 5 million. • Microdosing - US $ 0.3-0.5million Impact on financial aspect:
- 14. COMPARISON OF MICRODOSING &PHASE I APPROACH Features Microdosing strategy Phase I -Conventional Approach Time from preclinical to first in man studies 6-8 months 12-18 months Cost of early phase of drug development US $ 0.3-0.5 million US $ 1.5-5.0 million Amount of drug required < 100 micrograms About 100 mg Special requirements 14C labelled Compound, if using AMS None required Regulatory requirements Very few and limited GLP to be followed for synthesis Established firmly GMP to be followed for synthesis 10-09-2020 19
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- 16. Phase I: Humanpharmacology Initial introduction of IND into man • Main objectives :- • Safety & tolerability • Dose finding • Design:- • Single ascending dose (SAD) • Multiple ascending dose (MAD) • Unblinded, Uncontrolled 10-09-2020 21
- 17. 10-09-2020 22 Duration :-12 – 18 months Population :- • Mostly healthy volunteers • Pts in Oncology & anti-HIV trials Special populations • children • pregnant & • breastfeeding females • not included unless drug specific for the population Informed consent form is mandatory Sample size :- 20 – 100 Location :- • Single well equipped center. • Emergency care available.
- 18. 10-09-2020 24 Advantages oftolerability studies in healthy • Rapid enrollment & completion of study • Greater physiological reserve • If AE occurs, more likely to recover • Freq. measurements • Complete picture of drug obtained as observed. Not confounded by underlying disease or concomitant treatment. Advantages of including patients • PD effects measurable only in patients. • Tolerability differs in healthy subjects & patients
- 19. 10-09-2020 25 Inclusion criteria •healthy Volunteers (History + examn + lab) • age range (18-50) • body wt. (+ 15% of ideal) • not participated in any drug study in previous 3-4 months Exclusion criteria • h/o alcohol or drug abuse • regular medication • smokers • blood donation within 3 months Patients- depending on disease • age, gender • severity of disease • duration
- 20. Objective 10-09-2020 26 • Routeof administration • Drug in fed or fasted state • Extrapolation from animal to human dose • Dose ranging • Measurements • Pharmacokinetics • Pharmacodynamics • Safety parameters • Any predictable toxicity - AE
- 21. Routes Of Administration Intendedroute for patients IV route used even if systemic exposure in pts achieved by other route for PK studies Benefits of IV route • control of administration • If AE, drug can be halted • 100% exposure • overcomes problems related to bioavailability • less tissue & plasma conc. variability: less intersubject variability • easier assessment of PK/PD relationships 10-09-2020 27
- 22. Drug in Foodor Fasted State 10-09-2020 28 • Commonly – fasted state • Food – retardation & variable absorption • Fasted state – easier quantification of PKs. • Animal data - ↑ absorption in fasted state - initial dosing in fasted state • Fat soluble drugs – with food • Food-drug interaction study- not usually indicated in phase I
- 23. Initial Dose 10-09-2020 29 •Start with low dose - Fraction of “clean "or “no-effect” dose – observed in toxicology - Rule - dose1/25 to 1/100 of no effect dose in mg/kg. - 1/3 to 1/5 of which is lethal to 10% of animals(LD10) - expressed as mg/m2 for oncology drugs • Samples from a group of subjects. should be assayed first, - before enrollment of next group. - If non linearity of PKs, - then ↑ dose cautious
- 24. Dose Escalation 10-09-2020 30 •3 main schemes to obtain MTD (Max. tolerated dose) - ↑ dose in logarithmic manner - Doubling the dose - Fibonacci sequence • Other - Modified Fibonacci escalation scheme - Pharmacokinetically guided dose escalation - Accelerated titration designs - Modified continual reassessment methods - Intra-patient dose escalation
- 25. Fibonacci Sequence Step Ideal PercentDose Increment 1 D 2 2 × D 100 3 3× D 67 4 5× D 50 5 8× D 40 6 13× D 29 7 21× D 33 8 34× D 33 10-09-2020 31 Dose escalation to reach maximum tolerated dose (MTD) Dose escalation based on Fibonacci Series 1 2 3 5 8 13 . . . .
- 26. Measurements 10-09-2020 32 Predetermined inprotocol Plasma concentration of drug Deriving PK parameters like t1/2, bioavailability, clearance Helps in establishing dosing, frequency & duration of drug Also includes blood study, imaging, body fluid study etc
- 27. Absorption & Bioavailability 10-09-202033 • Absorption:- - solubility, lipophilicity, pKa - molecular size & animal data • Quantitative data of absorption & bioavailability - by comparison of areas under plasma conc-time curves - following IV & oral dosing • Other methods used - urinary estimation of drug & metabolites
- 28. Plasma Drug Concentration 10-09-202034 • Phase I & II • Guide to systemic drug exposure • Reason – lack of effect or exaggerated response • Early warning of nonlinearity • Provides plasma conc - time relationship • Enables development of sensitive assay method
- 29. Metabolism 10-09-2020 35 • Methodsused for universal detection of drug & metabolites 1) Incorporating 1 or more radioactive atoms in molecule - 14C commonly used - radiation hazard 2) Stable isotope labeled drug - requires mass spectroscopy - expensive 3) Using unmodified drug - by magnetic resonance spectroscopy - ↓ sensitivity
- 30. Safety Parameters 10-09-2020 36 •2 categories of safety issues:- 1) Result of extension of therapeutic effects - predictable & should be carefully monitored - should be related to exposure or plasma conc - so rational dosage schemes for further phases & eventual clinical use can be established. - effect seen in pts but not healthy subjects 2) Toxicological profile of drug Toxicity 2 types :- a) parallel with preclinical obs. b) unexpected
- 31. 10-09-2020 37 • Intrial design - Always consider human as most sensitive species compared to animal species - consider occurrence of unexpected & unpredictable effects Monitor - for early signs of severe toxicity - imp organ systems along with the critical & target organs identified in preclinical studies. - Broad effects initially and specific later.
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- 33. Phase II: TherapeuticExploratory 10-09-2020 39 Objectives • Primary • evaluate efficacy • determine short term SE • Identify common risks • Secondary • evaluation of study endpoints • therapeutic regimen • target population for phase III
- 34. 10-09-2020 40 • Primaryfocus:- - Dose response & effects - Efficacy - Adverse effects • Design:- - Randomized, blinded - Placebo controlled • Duration :- 1-3 years • Population:- Individuals with target disease • Sample size :- 200-300 usually calculated from endpoints • Location :- Multiple centres, well equipped
- 35. Selection Of Subjects 10-09-202041 Patients with target disease • Inclusion criteria depending on the disease • age • gender • severity of disease • duration • not participated in trials - previous 3 months • Exclusion criteria (narrowly defined) • h/o alcohol or drug abuse • regular medication • smokers
- 36. Factors To BeStudied 10-09-2020 42 Therapeutic effectiveness Efficacy at various doses Pharmacodynamics Pharmacokinetics Patient safety Bioavailability Drug-food interactions Drug-drug interactions
- 37. Phase IIa 10-09-2020 43 Proofof Concept (POC) • Establish dose range for more definitive therapeutic trials • beneficial efficacy of drug • to be undertaken in late phase. • usually single blind • Small no. of patients (20-200) • Conducted on homogenous population • Use of surrogate biomarkers • POC realized if drug improves disease condition & alters surrogate biomarkers • Goal: To guide decisions on further development
- 38. Trial Types inPhase IIa 10-09-2020 44 Pilot trial to test drug in patients Dose response trial in patients Trials evaluating doses & dosing schedule Evaluation of duration of dosing
- 39. Phase IIb 10-09-2020 45 •Mainly to study efficacy in target population • Multicentric but few centers • In heterogeneous population • Mostly double blind • Estimation of clinical benefit versus placebo • Endpoint based detailed PD & safety evaluation • Observe safe dose range • Regular monitoring visits
- 40. Phase II b: Pivotal Trial Placebo / active drug controlled double blind trial At single or multiple sites Trials to focus on one or more aspects of II A Rigorous demonstration of efficacy Well controlled ‘Pivotal trials’ 10-09-2020 46
- 41. Intervention Vs Standard Treatment/PlaceboIn Phase II Usually std therapy as comparator & use of placebo only in self-limiting conditions if rescue available Declaration of Helsinki Statement on Placebo Use: • New intervention must be tested against best current proven intervention, except: • when no current proven intervention exists; • where use of placebo necessary to determine efficacy or safety • pts receiving placebo or no treatment 10-09-2020 47
- 42. Dose Ranging inPhase II Initial dose • no effect dose & max. effective dose Main aim → optimum dose for phase III • titrate dose upwards or downwards depending upon clinical/ surrogate endpoint Escalation • highest dose if large gap between desirable & SE - max. pts likely to benefit - ↑ cost & SE • Lowest dose – safe & tolerable Ideally –dose benefiting majority + min. SE 10-09-2020 48
- 43. Dose Response andTime course Of PD effects 10-09-2020 49 • Dose – plasma conc range is studied • C0 C50 & Cmax are found. • Conc- effect relationship studied • Time course considerations: - providing a clue to regulatory authorities - for dosing intervals selected - speed of onset &duration of action ↓ (whether consistent with desired clinical response)
- 44. Demonstration Of ClinicalBenefit 10-09-2020 50 Methods used: • Clinical benefit compared to std therapy • Clinical benefit compared to placebo • Statistical benefit compared to very low dose • Statistically significant dose response relationship • Regression of tumor size (oncology)
- 45. Efficacy Study 10-09-2020 51 1)Determination of primary efficacy parameter • Surrogate & • Clinical endpoint 2) Dose or plasma conc. a/w range • Lowest PD effects • Max. dose or conc. • Max. tolerated dose • Max dynamic effect over dosing interval 3) Dosing interval • Based on PKs • Based on PDs
- 46. Endpoints to determineclinical efficacy Endpoints - quantify the potential effect of treatment or therapy under study. Essential points • should predict outcome • measurement :- precise , accurate & reproducible • justification & rationale for selection • correlation with benefit • limitations should be known & substituted Clinical endpoint should be: • Relevant & easy to interpret; • Clinically apparent & easy to identify; & • Sensitive to treatment differences. 10-09-2020 52
- 47. Surrogate endpoint • physiologicalor biological markers that correlate with the clinical endpoints for which they are substituting. • used instead of clinical outcomes. • substitute for undesirable or rare primary endpoint. • track clinical course of disease • evident in short period Essential Criteria • should be validated for disease studied • should predict outcome of disease • correlation with outcome should be demonstrated • validated with a drug of known MOA • not appropriate for drug with other MOA 10-09-2020 53
- 48. Interaction Study 10-09-2020 54 Druginteraction • Does Exp. Drug affect PKs of std drug ? • Does concomitant drug affect PKs of Exp. drug ? • study only drugs with narrow TI • PKs of Exp. Drug + metabolic studies predicts interactions • e.g. in vitro enzyme study • renal clearance • protein binding Food interactions • imp to study as affects bioavailability • food → no effect, ↑ or ↓ absorption ? • determined by studying • small no. of pts ingesting drug • with a standard meal • postprandial changes in hepatic blood flow • Formal & adequately powered study required • for registration purpose
- 49. Comparison between PhaseI & Phase II Phase I Phase II First in man study First in patient- POC 20-80 subjects 100-300 subjects 12-18 mnths 1-3 yrs To establish basic safety & blood levels with diff. doses To establish drugs efficacy & dose range Study PK & duration of action Study safety & PK in special population & risk factors 10-09-2020 56
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- 51. Pre Requisites ForPhase III Trial 10-09-2020 58 Preclinical safety data • Toxicological • Teratological • Fertility studies Completed Phase 1 & 2 data; Decision to proceed taken by the sponsor Approval by the DCGI before commencing a trial at any site Review and Approval by the IEC/ IRB
- 52. 10-09-2020 59 Points InEthical Consideration* Seven criteria essential for the ethical conduct of clinical research: • Value, • Scientific validity, • Fair selection of participants, • Favorable benefit/risk balance, • Independent review, • Informed consent, • Respect for participants
- 53. 10-09-2020 60 Institutional ReviewBoard • Institutional Review Board/Research Ethics/Committees/ethics Committees/Ethics Review Committees. • Investigators and sponsors of clinical trials have ethical obligations to trial participants and to science and medicine
- 54. 10-09-2020 61 Informed Consent •Communication between researcher and participant • Nuremberg Code [4], the Declaration of Helsinki [5], the Belmont Report [3], and the International Ethical Guidelines for Biomedical Research Involving Human Subjects. • Surrogate consent i/c/o emotionally/ mentally impaired and pediatric population.
- 55. 10-09-2020 62 Privacy AndConfidentiality • Electronic medical records have simplified the tasks of finding potentially eligible participants for trials, conducting international multicenter studies, following up on participants during and after the studies, and sharing data with other researchers. They have also led to laws restricting what kinds of medical records can be shared and with whom, in the absence of clear permission from the patients • It is probably not possible to share data and specimens that are useful to the recipient investigator while also maintaining perfect deidentifiability
- 56. Phase III 10-09-2020 63 •Primary objective : Demonstration or confirmation of therapeutic benefits • Designed to confirm that a drug is safe & effective for use in intended indication & recipient population • Provide an adequate basis for marketing approval • dose- response relationships, • use of drug in wider populations, • in different stages of disease , • in combination with other drugs
- 57. 10-09-2020 64 • Drugsintended to be administered for long periods – trials involving extended exposure to drug conducted in Phase III, although they may be initiated in Phase II • Complete information needed to support adequate instructions for use of the drug • New drugs approved outside India – phase III studies carried out to generate evidence of efficacy & safety of drug in Indian patients
- 58. 10-09-2020 65 Large scale,multi- centered Randomised, double blind controlled 1000 – 5000 patients Duration : 3 - 5 years Most rigorous & extensive type Most expensive, time consuming, difficult trials to design & run
- 59. Phase IIIA 10-09-2020 66 •Conducted after efficacy is demonstrated in Phase II and before submission of NDA (new drug application) • Provide confirmatory & additional safety and efficacy data in large no. of populations • Compare with previously established or placebo therapy • Information for package insert & labelling of drug • Determine the Risk – Benefit ratio of the treatment • Studies conducted after or during regulatory filing i.e. submission of NDA (New Drug Application) but before its approval • Supplement earlier trials , complete earlier trials • Effectiveness of drug in special patient subgroups- pregnant women, the elderly, children, or patients with other health- related problems • Long term studies Phase IIIB
- 60. Outline Of PhaseIII Trials 10-09-2020 67 Randomized controlled trial Type of control – standard or placebo Objectives - endpoints Patient selection Bias Randomisation Trial design Types of trials
- 61. RANDOMISED CONTROLLED TRIALS 10-09-2020 68 •Most reliable form of scientific evidence in hierarchy of evidence • Gold standard • Comparative studies with an intervention group and a control group; the assignment of the subject to a group is determined by randomization • Randomization: process by which all participants are equally likely to be assigned to either the intervention group or the control group.
- 62. 10-09-2020 69 • Removesthe potential of bias in the allocation of participants to the intervention group or to the control group. • Produce comparable groups (measured as well as unknown or unmeasured prognostic factors and other characteristics of the participants at the time of randomization will be evenly balanced between the intervention and control groups) • Validity of statistical tests of significance is guaranteed Advantages of RCTs
- 63. Pros and Consof an RCT Pros 10-09-2020 70 Limitations of external validity • Where RCT are performed • Characteristics of patients • Study procedures Cost Time Difficulty in studying rare events Cons •Controls selection bias •Balances confounding factors •Permit the use of probability theory to express the likelihood that any difference in outcome between treatment groups merely indicates chance
- 64. Study Objectives Study objectivesare often stated as primary and secondary endpoints (variables) Endpoints are measures believed to quantify the potential effect of a treatment or therapy under study Types of endpoints: • Primary or Secondary endpoints • Hard or Soft endpoints • Definitive or Surrogate endpoints • Composite endpoints • Health economic endpoints 10-09-2020 72
- 65. End Points: Primaryvs Secondary 10-09-2020 73 Primary vs Secondary Primary endpoint measure outcomes that will answer the primary (or most important) question being asked by a trial Secondary endpoints ask other relevant questions about the same study E.g. Objective : survival ( anti – cancer drugs) Primary endpoint: no of deaths Secondary endpoint : non fatal events, hospitalizations
- 66. Endpoints: Hard vsSoft 10-09-2020 74 Hard endpoints are definitive, quantifiable, no subjectivity required Soft endpoints either do not relate strongly to the disease or are subjective. E.g. Objective : efficacy of antihypertensive drug Hard endpoint : BP measurement Soft endpoint: patient’s self assessment of QOL
- 67. Endpoints: Definitive vs Surrogative 10-09-202075 Definitive endpoint relates to symptoms and/or course of disease Surrogate endpoint - measured in place of biologically definitive or clinically most meaningful endpoint; easy to measure, show an effect sooner E.g. Objective: efficacy of a lipid lowering agent Definitive endpoint : cardiovascular mortality Surrogate endpoint : serum cholesterol measurement
- 68. Composite Endpoints 10-09-2020 76 Compositeendpoints : An endpoint that combines several endpoints into one Mortality & morbidity due to cardiovascular diseases E. g : UK PDS
- 69. Health Economic Endpoint 10-09-202077 Quality of life: QALY : measurement of duration of individual’s life taking into account the well being that they experience during that time SF- 36, DASI ( Duke Activity Status Index), FACT – G ( Functional assessment of Cancer Therapy – Genaral) Cost : direct & indirect costs
- 70. Patient Selection 10-09-2020 80 Number •large population , 1000 - 5000 Inclusion/ Exclusion criteria • Medical or social standards determining whether a person may or may not be allowed to enter a clinical trial • Based on: • Age • Gender • Type & stage of disease • Other medical conditions • Previous treatment history
- 71. 10-09-2020 81 General requirements: •Represent clinical practice scenario to the possible extent • Support a reasonable recruitment rate • Must have potential to provide scientifically valid data • Produce widely acceptable & extendable results • Special populations – children, pregnant & breastfeeding females- not included unless drug specific for the population • Informed consent form is mandatory
- 72. Bias Type of biasMethod of bias control Selection bias Randomized assignment Concealment of assignment Bias in study management Standardized study procedure Standard equipment Training and certification of research personnel Observer ascertainment bias Blinding or masking Biased introduced by inclusion after randomization Intention to treat analysis Worst case scenario analysis Publication bias Prospective registration of clinical trials Publication of negative trials 10-09-2020 82
- 73. Randomization 10-09-2020 83 • Randomizationis the unpredictable allocation of a patient to a particular treatment strategy in a clinical trial • To ensure that intervention & control groups are similar in all respects with exception of the therapeutic measure being tested • Maximizes the chance that a difference between 2 groups is due to true effect of the drug being evaluated
- 74. Method Of Randomization 10-09-202084 Common types of randomization: • Simple • Block • Stratified • Minimization or adaptive
- 75. Allocation Concealment 10-09-2020 85 •Procedure for protecting randomization process so that treatment to be allocated is not known before the patient is entered into study • Methods: • Sequentially numbered opaque sealed envelopes (SNOSE) • Sequentially numbered containers • Pharmacy controlled randomization • Central randomization
- 76. Blinding 10-09-2020 86 • Experimentalmethology in which groups of individuals involved in a trial are made unaware of which treatment the participants are assigned to • Open label: All parties are aware of treatment being received after randomisation • Single blind: Either the patient or clinician (usually the patient) remains unaware of the treatment assignment • Double blind: Both the patient & investigator are unaware of the allocated treatment
- 77. Trial Design 10-09-2020 87 •Parallel design • Crossover design • Factorial design • Withdrawal design • Cluster randomized design • Sequential design
- 78. Parallel vs Cross-over PARALLELCROSS OVER Groups assigned different treatments Each patient receives different treatment Shorter duration Longer duration Larger sample size Smaller sample size No carryover effect Carryover effect Between group comparison Within patient comparison Robust to problems like missing data, missed visits Less variability, greater sensitivity 10-09-2020 88
- 79. Latin2 Design 10-09-2020 89 Essentialfeature is that every treatment appears only once in every row (each subject) and once in every column (each time period)
- 80. Factorial Design 10-09-2020 90 •E.g. : Aim of the Canadian Trial in Threatened Stroke was to investigate the use of aspirin and sulfinpyrazone for preventing strokes and deaths
- 81. Withdrawal Design 10-09-2020 91 DARWINSTUDY: A Prospective, d/b, Placebo Controlled, Multicenter, Randomized/Withdrawal Efficacy and Safety Study of Dexloxiglumide for the Relief of Symptoms in Patients With Constipation-Predominant Irritable Bowel Syndrome
- 82. Cluster Randomized Design •Trials that randomize groups of subjects, not individuals E.g. : villages, schools 10-09-2020 92
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- 84. Interim Analysis 10-09-2020 94 •Performed at any time before the final data analysis, usually to evaluate treatment differences, efficacy, and significant safety issues • REASONS: • Ethical & scientific reasons • Financial • Practical • Purpose and timing of planned interim analyses must be stated in the protocol • One or more analyses may be specified at designated timepoints during the course of a study
- 85. Data Safety AndMonitoring Board 10-09-2020 95 • Independent committee of clinicians, statisticians, ethicists, and other specialists who are knowledgeable in the area of study • To assess the progress of a trial, its safety, and/or its efficacy at intervals specified in the protocol • Committee may recommend that a study may continued, modified or stopped based on the data provided at the time of interim analysis
- 86. New Drug Application 10-09-202096 • NDA – vehicle through which drug sponsors formally propose that US FDA approve a new drug for sale & marketing • NDA includes: • Full reports of animal & clinical studies carried out to determine whether drug is safe & effective • Statement of drug’s composition • Description of methods, facilities & controls used in drug’s manufacturing, processing & packaging. • Samples of drug & its components as required • Copy of proposed labelling
- 87. 10-09-2020 97 Goals ofNDA are to provide enough information to permit an FDA reviewer to reach the following key decisions: • Whether drug is safe & effective in its proposed use &whether benefits of drug outweigh its uses • Whether drug’s proposed labelling (package insert) is appropriate & what it should contain • Whether methods used in manufacturing the drug & controls used to maintain drug’s quality are adequate to preserve the drug’s identity, strength, quality & purity
- 88. 10-09-2020 98 • UnderFood & Drug Administration Modernization Act (FDAMA), reviews for NDA are designated either as Standard or Priority: • Standard designation sets target date for completing FDA review at 10 months after the date it was filed • Priority designation sets target date for FDA action at 6 months
- 89. 10-09-2020 101 Selection biasesled historical control studies to favor inappropriately the new interventions Not all clinical studies can use randomized controls for e.g. in case when the disease prevalence is too low that a large enough population cannot be readily obtained. In such an instance, only case–control studies might be possible. Another major criticism of this controversial design centers around the ethical concern of not informing participants that they are enrolled in a trial. efficiency of the design has also been evaluated. It depends on the proportion of participants consenting to comply with the assigned intervention. To compensate for this possible inefficiency, one needs to increase the sample size Limitations of Clinical Trials
- 90. Conclusion 10-09-2020 102 • PhaseI & II yield important results that affect further Phases. • Only 30 % drugs clear phase I & II. • Must ensure well-being of participant • Microdosing can reduce the time & cost required for drug development • After the successful completion of Phase III the road is further paved for Phase IV after marketing approval to assess its clinical usefulness in actual population. • Clinical trials are only ethical if there are adequate resources to conduct them and see them to completion • To fail to complete the study is a serious breach of ethics
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Editor's Notes
- #3 The First Clinical Trial? The Book of Daniel in the Bible describes a comparative trial – in which Daniel experiments with feeding youthful palace servants legumes and porridge rather than the rich meats eaten by the king and his court. The Result? “And at the end of ten days their countenances appeared fairer and fatter in flesh than all the children which did eat the portion of the king’s meat.” (Daniel 1:15 KJV
- #6 clinical trial is prospective, rather than retrospective A clinical trial must employ one or more intervention techniques. These may be single or combinations of diagnostic, preventive, or therapeutic drugs, biologics, devices, regimens, or procedures
- #9 Treatment Trials- test experimental treatments, new combinations of drugs, or new approaches to surgery or radiology/radiation therapy. Prevention Trials- look for better ways to prevent disease in people who have never had them or prevent them from returning. Diagnostic Trials- conducted to find better tests or procedures for diagnosing a particular disease or condition. Screening Trials- test the best way to detect certain diseases or health conditions. Quality of Life- explore ways to improve comfort and the quality of life for individuals with chronic illness Alternate way: Efficacy or explanatory trials refer to what the intervention accomplishes in an ideal setting- such trials justifies the exemption of use of Intention-to-treat analysis.
- #13 EMEA & FDA Definition of Microdose: less than 1/100th of the dose calculated to yield a pharmacological effect of the test substance based on primary pharmacokinetic data obtained in vitro and in vivo (Typically doses in, or below, the low microgram range) and at a maximum dose of less than or equal to 100 microgram.
- #14 EMEA & FDA Definition of Microdose: less than 1/100th of the dose calculated to yield a pharmacological effect of the test substance based on primary pharmacokinetic data obtained in vitro and in vivo (Typically doses in, or below, the low microgram range) and at a maximum dose of less than or equal to 100 microgram.
- #17 It included several drugs for which it was difficult to predict human PK because of, for example, high first-pass effects. Each of the compounds was administered to subjects at a microdose level and at a therapeutic dose level in an appropriate randomized crossover design.
- #18 Preclinical species used to project human PK parameters - can be used as preclinical model for microdosing. More than one preclinical species could also be used to strengthen the projection of linearity in humans. Thereby increasing confidence in the utility of microdosing studies in humans
- #19 Also, microdosing in humans has the potential to replace animal use in determining suitable pharmacokinetic profiles of compounds. If microdosing in humans turns out to be more predictive than the current animal methods, there would be less drug candidates proceeding through extensive safety and toxicology testing involving animals, because more compounds will be terminated after early microdose studies. With a Maximum Tolerated Dose (MTD) approach, it is impossible to predict the amount of compound which will be required until the MTD is actually established. This situation creates problems for synthetic chemists producing candidate compounds and often leads to over estimating drug requirements, as well as long delays in initiating the clinical study
- #24 Definition of Study Population: The study population is the subset of the population with the condition or characteristics of interest defined by the eligibility criteria. The group of participants actually studied in the trial is selected from the study population. Inclusion criteria ICF must healthy volunteers exception- patients only for toxic agents Exclusion criteria children , women of child bearing age , elderly Sample size 20 -100
- #25 Measured by rate of drop outs
- #30 PAD – pharmacologically active dose no observed adverse effect levels (NOAELs) Several definitions of NOAEL exist, but for selecting a starting dose, the following is used: the highest dose level that does not produce a significant increase in adverse effects in comparison to the control group In the absence of data on species relevance, a default position is that the most appropriate species for deriving the MRSD for a trial in adult healthy volunteers is the most sensitive species (i.e., the species in which the lowest HED can be identified). F The process of calculating the MRSD should begin after the toxicity data have been analyzed. Although only the NOAEL should be used directly in the algorithm for calculating an MRSD, other data (exposure/toxicity relationships, pharmacologic data, or prior clinical experience with related drugs) can affect the choice of most appropriate species, scaling, and safety factors. The NOAEL for each species tested should be identified, and then converted to the HED using appropriate scaling factors. For most systemically administered therapeutics, this conversion should be based on the normalization of doses to body surface area. Although body surface area conversion is the standard way to approximate equivalent exposure if no further information is available, in some cases extrapolating doses based on other parameters may be more appropriate. This decision should be based on the data available for the individual case. The body surface area normalization and the extrapolation of the animal dose to human dose should be done in one step by dividing the NOAEL in each of the animal species studied by the appropriate body surface area conversion factor (BSA-CF). This conversion factor is a unitless number that converts mg/kg dose for each animal species to the mg/kg dose in humans, which is equivalent to the animal’s NOAEL on a mg/m2 basis. The resulting figure is called a human equivalent dose (HED). The species that generates the lowest HED is called the most sensitive species. When information indicates that a particular species is more relevant for assessing human risk (and deemed the most appropriate species), the HED for that species may be used in subsequent calculations, regardless of whether this species is the most sensitive. The NOAEL is not the same as the no observed effect level (NOEL), which refers to any effect, not just an adverse one, although in some cases the two might be identical. The definition of th NOAEL, in contrast to that of the NOEL, reflects the view that some effects observed in the animal may be acceptable pharmacodynamic actions of the therapeutic and may not raise a safe concern. The NOAEL should also not be confused with lowest observed adverse effect level (LOAEL) or maximum tolerated dose (MTD). Both of the latter concepts are based on findings of adverse effects and are not generally used as benchmarks for establishing safe starting doses in adult healthy volunteers. (The term level refers to dose or dosage, generally expressed as mg/kg or mg/kg/day.) VII. STEP 4: APPLICATION OF SAFETY FACTOR Once the HED of the NOAEL in the most appropriate species has been determined, a safety factor should then be applied to provide a margin of safety for protection of human subjects receiving the initial clinical dose. This safety factor allows for variability in extrapolating from animal toxicity studies to studies in humans resulting from: (1) uncertainties due to enhanced sensitivity to pharmacologic activity in humans versus animals; (2) difficulties in detecting certain toxicities in animals (e.g., headache, myalgias, mental disturbances); (3) differences in receptor densities or affinities; (4) unexpected toxicities; and (5) interspecies differences in ADME of the therapeutic. These differences can be accommodated by lowering the human starting dose from the HED of the selected species NOAEL. In practice, the MRSD for the clinical trial should be determined by dividing the HED derived from the animal NOAEL by the safety factor. The default safety factor that should normally be used is 10. This is a historically accepted value, but, as described below, should be evaluated based on available information.
- #40 First in Patient study: After satisfactory preliminary evidence of safety .First opportunity to observe efficacy of long term administration Participants ideally without concomitant disease .Obtain data of efficacy & common short time side effects (7) Therapeutic exploratory trials (Phase II).- (i) The primary objective of Phase II trials is to evaluate the effectiveness of a drug for a particular indication or indications in patients with the condition under study and to determine the common short-term side-effects and risks associated with the drug. Studies in Phase II should be conducted in a group of patients who are selected by relatively narrow criteria leading to a relatively homogeneous population. These studies should be closely monitored. An important goal for this Phase is to determine the dose(s) and regimen for Phase III trials. Doses used in Phase II are usually (but not always) less than the highest doses used in Phase I. (ii) Additional objectives of Phase II studies can include evaluation of potential study endpoints, therapeutic regimens (including concomitant medications) and target populations (e.g. mild versus severe disease) for further studies in Phase II or III. These objectives may be served by exploratory analyses, examining subsets of data and by including multiple endpoints in trials. If the application is for conduct of clinical trials as a part of multi-national clinical development of the drug, the number of sites and the patients as well as the justification for undertaking such trials in India shall be provided to the Licensing Authority.
- #41 100- 300 patients Few months to 2 years One third of drugs successfully complete Designs used: case series or randomized placebo controlled double blind .determines optimal dose response range Verify drugs efficacy More chances of detection of adverse effects Development commonly fails here due to poor activity & toxic effect Special populations - children - pregnant & - breastfeeding females - not included unless drug specific for the population
- #44 The proof of concept is usually considered a milestone on the way to a fully functioning prototype. They offer the advantage of investigating the efficacy of a product using a very simplified study design and a lower number of subjects, thus reducing the amount of control and references substance required and time.Proof of concept? Proof of Concept or PoC refers to the next stage of clinical drug development, most commonly called Phase II and conducted in typically up to 100 patients with the disease of interest. Studies in this Phase aim to show that the new drug has a useful amount of the desired clinical activity (eg, that an experimental antihypertensive drug reduces blood pressure by a useful amount), that it can be tolerated when given to humans in the longer term, and to investigate which dose levels might be most suitable for eventual marketing.
- #48 Defnition of placebo? Sham procedure pg 205 vgood Fundamentals of clin trials – pg 116 Randomization tends to produce study groups comparable with respect to known as well as unknown risk factors, removes investigator bias in the allocation of participants, and guarantees that statistical tests will have valid false positive error rates. Randomized control trials are comparative studies with an intervention group and a control group; the assignment of the subject to a group is determined by the formal procedure of randomization. Randomization, in the simplest case, is a process by which all participants are equally likely to be assigned to either the intervention group or the control group. The features of this technique are discussed in Chap. 6. There are three advantages of the randomized design over other methods for selecting controls [35]. Pg 88 First, randomization removes the potential of bias in the allocation of participants to the intervention group or to the control group. Such allocation bias could easily occur, and cannot be necessarily prevented, in the nonrandomized concurrent or historical control study because the investigator or the participant may influence the choice of intervention. This influence can be conscious or subconscious and can be due to numerous factors, including the prognosis of the participant. The direction of the allocation bias may go either way and can easily invalidate the comparison. The second advantage, somewhat related to the first, is that randomization tends to produce comparable groups; that is, measured as well as unknown or unmeasured prognostic factors and other characteristics of the participants at the time of random- ization will be, on the average, evenly balanced between the intervention and control groups. This does not mean that in any single experiment all such characteristics, sometimes called baseline variables or covariates, will be perfectly balanced between the two groups. However, it does mean that for independent covariates, whatever the detected or undetected differences that exist between the groups, the overall magnitude and direction of the differences will tend to be equally divided between the two groups. Of course, many covariates are strongly associated; thus, any imbalance in one would tend to produce imbalances in the others. As discussed in Chaps. 6 and 17, stratified randomization and stratified analysis are methods commonly used to guard against and adjust for imbalanced randomizations. The third advantage of randomization is that the validity of statistical tests of significance is guaranteed. As has been stated [35], “although groups compared are never perfectly balanced for important covariates in any single experiment, the process of randomization makes it possible to ascribe a probability distribution to the difference in outcome between treatment groups receiving equally effective treatments and thus to assign significance levels to observed differences.” The validity of the statistical tests of significance is not dependent on the balance of the prognostic factors between the two groups. The chi-square test for two-by-two tables and Student’s t-test for comparing two means can be justified on the basis of randomization alone without making further assumptions concerning the distri- bution of baseline variables. If randomization is not used, further assumptions concerning the comparability of the groups and the appropriateness of the statistical models must be made before the comparisons will be valid. Establishing the validity
- #53 E.g. In cardiology trial LDL-C (low density lipoprotein cholesterol), CRP (C-reactive protein, a marker for inflammation), carotid intimal thickness, serum cholesterol levels, and myocardial infarct (heart attack) size
- #60 Emanuel et. Al Part of GG pg. 6
- #77 two main advantages of using a composite endpoint. An endpoint with multiple outcomes means that more outcome events will be observed in total. Since the number of patients needed in the trial decreases as the number of events occurring in the control group increases, a composite endpoint allows us to evaluate a new treatment by using a smaller number of patients in the trial. In a composite endpoint of multiple outcomes we make the assumption that avoiding any one outcome has an equal importance as avoiding any other outcome. The second assumption made when using composite endpoints is that all individual outcome measures are related to the disease process and are equally meaningful. An additional limitation of composite endpoints is that they can also give inconsistent results, with certain outcomes improving and others worsening, making overall interpretation of the study difficult.
- #78 SF-36, one of the most widely used instruments to measure health-related QOL, includes 36 questions covering 8 domains: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality, 6) social functioning, 7) role limitations due to emotional problems, and 8) mental health. It is available for multiple acute and chronic disorders, and is translated into 110 languages worldwide. Very importantly, it has reference data on normal populations to aid in understanding and interpreting scores both for clinical and research uses. DASI (Duke Activity Status Index) is a measure of physical functioning,developed and validated in cardiac patients, that measures general health related ability to perform 12 physical activities.4 The WOMAC (Western Ontario and McMaster University Osteoarthritis Index) instrument is a disease-specific measure of health status designed for use in osteoarthritis studies. It allows researchers to measure the intensity of pain and frustration of functional limitations related to arthritis. The FACT-G (Functional Assessment of Cancer Therapy–General) instrument is a 27-item general questionnaire intended for use in patients with any type of cancer as well as a variety of other long-term illnesses such as HIV/AIDS and multiple sclerosis. The questions focus on physical well-being, social/family well-being, emotional well-being, and functional well-being. This tool is available in 30 languages and has several disease-, treatment-, and condition-specific subscales. economic impact of a treatment can be measured in terms of direct and indirect costs. Direct costs include the actual charges for hospitalization, treatment, drugs, medical supplies, and professional services; these are listed on a medical bill. Indirect costs, which are more difficult to measure, include such things as time away from work, loss of wages, and pain and suffering.
- #83 bias is defined as systematic distortion of the estimated intervention effect away from the truth, caused by inadequacies in the design, conduct, or analysis of a trial [2], or in the publication of its results
- #91 Advantages: Two drugs studied simultaneously b) Discover interactions c) Fewer number of patients than in parallel arm study Disadvantages: a) Test assumes no interaction in hypothesis b) Compliance
- #92 All participants start the study treatment and only improved patients (the "responders") are randomized to active treatment or placebo Any difference between the group receiving continued treatment and the group randomized to placebo would demonstrate the effect of the active treatment
- #93 Adv: Optimal design for evaluating quality improvement strategies in healthcare intervention & education program studies B)Easier to administrate the randomisation & centres Disadv: a A)Larger sample size b)Patients & clinicians may recognize whether they are in active or placebo arm c)Clinicians might transfer information between clusters e.g: community trials on flouridisation of water