E8(R1) General Considerations for Clinical Studies 1 GUIDED BY Prof. Dr.P.M.GAIKWAD M.Pharm, Ph.D (Head, Dept of Pharmacology) COGUIDED BY Prof.V.V.Nimbalkar Dept. •1 Phase 3, 1 Phase 1/2 (n=20) . Smith TL, Lee JJ, Kantarjian HM, Legha SS, and Raber MN. Suggest design strategies to reduce bias, variability and 'placebo effects' in a proposed clinical study. Trial Design Further PD studies Design of Clinical Trials: Striking a Balance • Effective: - Avoid errors - Answer the right primary question definitively - Provide evidence about secondary questions • Satisfy the Needs of Multiple Stakeholders • Efficient: • Minimize Costs • Speed . 5 6. . Name at least 6 sources of potential bias in clinical studies. The Simon two-stage design is an exact design which allows flexibility regarding the null and alternative hypotheses while also allowing stopping for futility. At the conclusion of this module, the learner will be able to: • Describe five types of clinical trials. mRNA-1273 NIH-Sponsored, Phase 1, Safety and Dose-Ranging Study (N=120) Phase 1 trial overview (NCT04283461) Protocol Title Phase I, Open-Label, Dose-Ranging Study of the Safety and Immunogenicity of 2019-nCoV Vaccine (mRNA-1273) in Healthy Adults Study Groups Cohorts1 Age groups Dosage (D1, D29) Sample size Enrollment status 1-3 18 to 55 25, 100, 250 mcg 45 Fully enrolled (45/45) Standard design for phase I cancer clinical trials. Journal of Clinical Oncology, 14 (1), 287—295. 1997. The average number of patients who would be expected to have grade 0-1 toxicity as their worst toxicity over three cycles of treatment is 23.3 for design 1, but only After Cohort 1 enrollment is completed, Cohort 2 enrollment then occurs with up to an additional 40 subjects. and Yuan, Y. choose between doses) - Planning other studies (not recommended for confirmatory studies) • Blinded interim analysis: no grouping of treatments according to randomisation - Monitor total number of clinical events - Review ongoing safety data 4 The earliest phase trials may look at whether a drug is safe or the side effects it causes. Clinical and Translational Science Center 1 CLINICAL AND TRANSLATIONAL SCIENCE CENTER Design of Phase II Clinical Trials Susan Stewart, Ph.D. Division of Biostatistics. This design provides an opportunity to validate the promising OS, tolerability, immune cell changes, and mRNA expression signature observed in this phase 1 study and to quantify cytotoxic and immune-mediated effects in an effort to further confirm the mechanism of action of Toca 511 and Toca FC. When a first-course DLT or second first-course intermediate toxicity occurs, cohort expands and reverts to design 1 Design 3 has single patient cohorts with double-dose escalation steps (80% dose increments). Bayesian Optimal Interval Designs for Phase I Clinical Trials 3 it is highly desirable to minimize such decision errors so that the actual design behaves as closely as possible to the ideal (error-free) design. for phase I clinical trials. Study drug disposition (pharmacokinetics, PK) Proof of concept that drug inhibits its target (pharmacodynamics, PD) Determine dose and schedule for Phase 2. Based on investigator assessment of the clinically evaluable patients (measurable disease with ≥1 on-study scan); 14/18 patients (Phase 1/1b) and 51/79 patients (Phase 1/1b and 2 pooled) met these criteria. 1996. Compare and contrast the following study designs . These have ranged from small, single country marketing studies through to large global observational trials. Clinical Research All scientific approaches to evaluate medical disease in terms Prevention Diagnosis Treatment Humans 4. b At the time of the 30 August 2020 data cut off, 5 patients had unconfirmed PRs. CLINICAL TRIALS BANGKOK, 2-6 FEB 2009 APEC LSIF PROJECT "Capacity Building For Drug Regulatory Agencies on Clinical Trial and Good Clinical Practice (Phase 2)" 10 Single Ascending Dose Study: Interleaved Design Weeks Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week9 C Plac 200mg 1600 mg B 20 mg Plac 1600 mg A 20 mg 200 mg Plac . Zhou, Y., Li, R., Yan, F., Lee, JJ. Classical dose escalation scheme Durham SD, Flournoy N, and Rosenberger WF. Nonclinical Considerations for Dose Selection Course of Psychosis in Schizophrenia With Alcohol Use Disorder: A Post Hoc Analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness in Schizophrenia Phase 1 Study. Phase 1 clinical trial 1. UNDERSTANDING CLINICAL TRIAL DESIGN: A TUTORIAL FOR RESEARCH ADVOCATES 2 Figure 1. Outline the Phase 1 studies conducted to characterize the Clinical Pharmacology of a drug; describe important design elements of and the information gained from Phase 4 . Phase 2 studies 5. Requires Results Reporting (Sept 2008) Trials of FDA-approved or cleared drugs and devices 2.1 What is the question? Phase 1: Evaluate toxicity. Joshi Uttara L. M.Pharm (sem II) (Pharmacology) Roll no.08 Dr. V.V.P.F'S COLLEGE OF PHARMACY AHMEDNAGAR (2018-2019 ) 4. Phase 2 . Because of these changes in focus, the National Cancer Institute and Investigational Drug Steering Committee's Task Force on Clinical Trial Design met to evaluate the most efficient . This trial enrolled 15 patients, 12 with STS and 3 with invasive ductal carcinoma (IDC) of the breast. Phase I trials are generally dose- Although an extremely simple design, large-scale numerical studies show that BOIN has good performance that is superior to the mTPI and comparable with that of the more complicated CRM design ().As noted by a referee, because by default the BOIN uses a noninformative prior (i.e., a priori the . 1/3 = 0.33, which is between λ e = 0.236 and λ e = 0.358, then the design retains the current dose. Simon's Two-Stage Design is a type of phase II clinical trial. Numerous statistical and design approaches exist to increase trial efficiency Many have been tried in cardiology, oncology and other areas We review a selection here including - Event driven trials - Composite outcome - Adaptive designs - Enrichment designs - Borrowing of controls - Opportunities in era of big data of 0.1 in 10,000 to 30,000) - based on randomized clinical trial in pediatric and adult patients (N = 117, 2:1 randomization) Note: Incidences reported are approximate and what are available on . J Clin Psychiatry. Trials have historically been conducted in the logical sequence of single ascending dose, multiple ascending dose . The first one is a phase I . 31. clinical trials types and design. Many of the trials that we have supported have been phase IV studies or late phase clinical trial programs. Tables 1 and 2 show optimal designs for a variety of design parameters. IND Content and Format • 21 CFR 312 . Use of the 3+3 results in fewer agents with successful phase III trials compared with the CRM or BOIN. Trials have historically been conducted in the logical sequence of single ascending dose, multiple ascending dose . Nature Reviews. clinical trials - Few treating physicians, few treatment centers . There are two Cohorts in this study design. Phase 0 trials are also known as human micro dosing studies. Submission of New Drug Application (NDA) is the formal step asking the FDA to consider a drug for marketing approval. The arms have independent decision rules including rules for . The main focus of this book is on Phase III randomized-controlled field trials of health interventions. a very small fraction of phase I trials. Rely on phase 1,2 safety/activity data to support prospect of direct benefit (PDB) Single arm design acceptable; PK pivotal data • Critical value is usually 5% or 0.05 (2.5% 1- sided, or 0.025 1- sided, but p-values usually reported 2- sided - watch out for this if 1- sided p-values are reported but 0.05 still used as critical value) • "A had a change from baseline of 3 points, while B achieved only 1 A Random Walk Rule for Phase I Clinical Trials. doi: 10.4088/JCP.19m12731. The optimal designs are shown on the left half of the tables. Cohort 1 (Phase 1) enrolls up to 30 subjects total. Safety concerns also make the DCT model less suitable for early phase trials or any study using an IMP that does not have an established safety profile, since in-person supervision and quick access to medical Clinical trials for drug development are classically divided into four phases: I to IV (Fig. Founder and Chief Scientific Officer, Oncomind, LLC . Phase I clinical trials The objective of phase I clinical trials is to find the maximum tolerated dose (MTD) that has a target toxicity rate ˚. Dose Escalation Study Design Example . Adolescent trial can be initiated along the Phase 3 adult clinical trial. Requires Trial Registration (Dec 2007) Phase II-IV drug and device trials for all diseases. 1.0 Phase I Clinical Trials The major objective of phase I trials of cytotoxics is determining a dose of the drug or regimen that is safe for use in subsequent clinical studies. The second portion of the study is a dose expansion phase where four cohorts of patients will receive AG-120 to further evaluate the safety, tolerability, and clinical activity of the recommended Phase II dose. The early development plan is driven by someone with expertise in clinical pharmacology who provides outline for Phase I and Phase IIA (proof of concept) studies including the countries where these studies would be conducted, the study design, and the biomarkers used. Phase 1/2 Study of MRTX849 in Patients With Cancer Having a KRAS G12C Mutation KRYSTAL-1 The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Purpose: Randomized phase II (RPh2) designs are popular in cancer clinical trials because of the smaller sample size requirements when multiple treatments are being evaluated. illustrating key concepts for results data entry in the Protocol Registration and Results System (PRS). This chapter gives a brief overview of Phase IV studies that are carried out after an intervention has been shown to be efficacious in Phase III trials. - Adapt the study design (e.g. based on a prespecified rule, similar to "3+3" design 3 Sound statistical properties ! An investigational new drug application (IND) : outlines what the sponsor of a new drug proposes for human testing in clinical trials. comparable or better than commonly used designs Late Phase Clinical Trials. Required toxicology studies completed. Enacted on September 27, 2007. pii: 19m12731. (2020) BOIN Suite: a software platform to design and implement novel early phase clinical trials, JCO Clinical Cancer Informatics, to appear. The Indacaterol to Help Achieve New COPD Treatment Excellence (INHANCE) trial was an adaptive two-stage (i.e., phase 2-3), confirmatory . Treatment trials test experimental . The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is funding the trial. Further define toxicity. The 1 st workshop in December 20071 had provided an opportunity to introduce and discuss the EMA's "Reflection Paper on Methodological Issues in Confirmatory Trials Planned with an Adaptive Design"2. Phase 1 clinical trial Dr Banhisikha Adhikari 2. for both finite and large samples 4 Superior operating characteristics ! Key outcomes and open questions were summarized by Prof. Bruno Flamion while Dr Common rationales for Phase IV studies are to evaluate the real-world effectiveness of an intervention, and/or as part of pharmaco . After demonstrating that LUM015 selectively labeled sarcoma and breast cancer in mice, we performed a first-in-human phase 1 clinical trial of LUM015. After preclinical study in the laboratory, a drug is generally first tested in humans in Phase I trials that generate key safety and pharmacokinetic and pharmacodynamic data for small numbers of participants. There are 3 main phases of clinical trials - phases 1 to 3. We consider two motivating cancer clinical trials. Phase 1 trials are the earliest phase trials and phase 3 are later phase trials. Goal may be superiority, non-inferiority, or equivalence. post- pre-IND . Seymour L, Ivy SP, Sargent D, Spriggs D, Baker L, Rubinstein L, Ratain MJ, Le Blanc M, Stewart D, Crowley J, Groshen S, Humphrey JS, West P, Berry D (2010) The design of phase II clinical trials . Clarity and understanding of the research question can require much deliberation often entailing a transition from a vague concept (e.g., "to see if the drug works" or "to look at the neuro-biology of the drug") to a particular hypothesis that can be tested or a quantity that . Use this PowerPoint template to communicate the details of a clinical trial and its results. e t ra y t ci xi o t t e rg a T Ying Yuan BOIN: A Novel Platform for Designing Early Phase Clinical Trials • Discuss the objectives, endpoints and standard design for Phase I, II, and III clinical trials. The optimal design of phase II studies continues to be the subject of vigorous debate, especially studies of newer molecularly targeted agents. 23 General principles of clinical study design are described in Section 2 of this document, 24 followed by a discussion of design quality into clinical stuing dies in Section 3A broad . by Statistical Consultancy Team on Wed, Oct 17, 2018. Design 1 is as for 3 + 3 design but with 40% dose increments Design 2 has single patient cohorts during accelerated phase. • Phase 1: Safety - Initial introduction of a new drug into humans . Of pharmacology PRESENTED BY Miss. Phase 1, 2 trials completed in adults. The UC Davis CTSC receives support from the NIH National Center for Advancing Translational Sciences (award TR001860). 1 1 PHASE I/II CLINICAL TRIAL DESIGN AND DOSE FINDING (PART I) (CHAPTER 1, 7) NAITEE TING, BOEHRINGER-INGELHEIM 2 DRUG DEVELOPMENT PROCESS Drug Discovery Non-clinical Development Clinical Development • Phase I Clinical pharmacology (PK/PD, MTD) • Phase II Drug efficacy/safety, dose ranging • Phase III Long-term, large scale, confirmatory • A clinical trial design that allows for prospectively planned modifications to one or more aspects of the design based on accumulating data from subjects in the study It is one of the most common multi-stage designs used in Phase IIa clinical trials. The observations that many new therapeutics "fail" in definitive phase III studies, coupled with the numbers of new agents to be tested as well as the increasing costs and complexity of clinical trials, further emphasize the critical importance of . The 3 þ 3 design (1-3), Phase 3 studies 6. Masking: None (Open Label) Primary Purpose: Other: Official Title: A Guide to Phase 1 Clinical Trial Designs. clinical trials and • Information about - trial design - overall drug efficacy and safety Phase 1/2 study in ~20 pts with MWS • Total IL-1β(complex) increases after dosing and can be measured • Reduction in free IL -1βcorrelates with change in clinical signs and symptoms. What is a clinical trial? Overview •Introduction • Clinical Trial Designs •Challenges •Application in different phases of trial •Summary 3. Seamless Phase 2-3 Design — the INHANCE Trial. Phase 3 . Generally, this phase has been conducted in order to analyze the safety, tolerance, pharmacodynamic and THE PURPOSE OF THE TRIAL. Clinical trial design is an important aspect of interventional trials that serves to optimize, ergonomise and economize the clinical trial conduct. FDAAASec.801 Expanded Clinical Trial Registry. and Yuan, Y. Design and Results of Phase I Cancer Clinical Trials: Three-Year Experience at M. D. Anderson Cancer Center. Background: Phase I and Phase II clinical trials aim at identifying a dose that is safe and active. Later phase trials aim to test whether a new treatment is better than existing treatments. Clinical Trials. Ref: Orloff et al. Table 1 applies to trials with Pl - P0 = 0.20 and Table 2 is for trials with pl - p0 = 0.15. Both phases are increasingly combined. IND . Each clinical trial phase brings up lots of data that can contribute to major medical discoveries. Phase 0 • Phase 0 is a recent designation for exploratory, first-in-human trials conducted in accordance with the United States Food and Drug Administration's (FDA) 2006 Guidance on Exploratory Investigational New Drug (IND) Studies. 2009. 8 d n a 1 23 e 45 7 6 n i l e s a B Control Diet Fruits-and-vegetables Diet DASH Intervention Week * ** Conlin et al., Am J Hypertens, 2002 Cross-Over Study Design (OmniHeart) Period 1 6 weeks Period 2 6 weeks Period 3 6 weeks Randomization to 1 of 6 sequences Washout Period 2-4 wk Washout Period 2-4 wk Data: Run-In 6 days Participants Ate . Biometrics, 53, 745—760. The difference is more pronounced among highly effective agents. 2. Study design: • Phase 1, open-label dose ranging clinical trial in healthy adults • Subjects received an intramuscular (IM) injection (0.5 milliliter [mL]) of mRNA-1273 on Days 1 and 29 in the deltoid muscle and will be followed through 12 months post second vaccination (Day 394) Primary endpoint: would likely be prohibitive for phase 1 trials or other studies with small numbers of patients and very short follow-up times. In certain circumstances, we have also been able to support clinical monitoring in addition to the data and safety-related aspects of the trials. The goals and objectives of phase 1 clinical trials are changing to include further evaluation of endpoints such as molecular targeted effects, in addition to dose-toxicity profile of the investigational agent. concepts for results data entry in the Protocol Registration and Results System (PRS). The primary aims of Phase 1 Clinical Trials are to determine the safety, tolerability and pharmacokinetics (PK) of a compound. LUM015 is safe in humans. Design: The trial design, statistical properties, conduct, data analysis, results, and reporting were examined in RPh2 trials reported from 1986 . Phase 1 studies 4. BOIN is a novel phase I design that is as simple to implement as the 3 þ 3 design, but yields significantly better performance comparable to more complicated model-based designs. A Phase 1 clinical trial evaluating an investigational vaccine designed to protect against coronavirus disease 2019 (COVID-19) has begun at Kaiser Permanente Washington Health Research Institute (KPWHRI) in Seattle. The purpose of the clinical trial is assessment of efficacy, safety, or risk benefit ratio. Design of Clinical Trials: Striking a Balance • Effective: - Avoid errors - Answer the right primary question definitively - Provide evidence about secondary questions • Satisfy the Needs of Multiple Stakeholders • Efficient: • Minimize Costs • Speed . Phase 2: Estimate anti-tumour efficacy. Phases of Clinical Trials Preclinical Trial (Usually done on animals to determine the drug is safe enough for human testing) Phase I (Determine Pharmacological actions and Tolerability*) Phase II (Evaluate Safety and Efficacy) Phase III (Evaluate Effectiveness** and risk-benefit ratio) Phase IV (Monitor long term effects and effectiveness) Dose Escalation Study Design Example 1 of 4 September 2019 . General definition: A clinical trial is any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes. The objective is to try and establish . Upon completion of this lesson, you should be able to: State 6 general objectives that will be met with proper trial design. Clinical Trials Design Dr Ritu Budania MBBS , MD 2. Each individual treatment arm within the randomized phase II design is structured as an independent phase II study with determination of "promising activity" based on a comparison against historical control with appropriate thresholds for α (typically 0.1) and β (typically 0.1).