Emory University School of Medicine Clinical Trials Office

Emory University School of Medicine Clinical Trials Office WELCOME! CTO Participation Form Tweaks… • Fax all signed ICF versions to CTO; CTO will scan into Emory Electronic Medical Record (EeMR) • Grady and Ponce Clinics only: Insurance plan payor code must be identified on form IMPACT: CTO ‘holds’ form until all data fields are met. If we cannot enter into EeMR immediately, this can prevent Emory Medical Lab postings (outpt. at Emory), EMCF notices for bill holds (at Grady) and post award audits on the 1st and 3rd subjects…Bad Bongos CTO Participation FormMetrics… To date, CTO has been notified of 1143 patient enrollments for 167 unique studies as of 6/11/07 156 of these are Grady subjects Clinical Trials Tab in EeMR Projected go-live date is 1/12/08 Implementation delay means that YOU have more time to get your active subject enrollment logs (as of 6/11/07) faxed to CTO who can then do the data entry When the system does go live, this data needs to be pre-populated into EeMR Clinical Trials tab… Request for CTO Coverage Analysis Cover Sheet - CHANGE Now includes a section to indicate if CTO has to notify other individuals besides the PI, CRC and DA about the finalized budget/MCA Please go to the CTO website and utilize the latest iteration of any form…things are a’changin’ to help meet your needs as well as others clinicaltrials.gov - A Central Registry of Clinical Trials    Clinical trials are registered with clinicaltrials.gov via a web based data entry system called the Protocol Registration System (PRS). Clinicaltrials.gov is a service of the US National Institutes of Health (NIH), provided through its National Library of Medicine (NLM). Clinicaltrials.gov facilitates registration of trials in accordance with the International Committee of Medical Journal Editors (ICMJE) initiative requiring prior entry of clinical trials in a public registry as a condition for publication. Multi-site trials and multi-sponsor trials are susceptible to duplicate registration, thus care must be taken in how the trials are registered. For multi-sponsor trials it is the lead sponsor who should take responsibility for registration. It is critical that investigators and sponsors work together to ensure that a trial is registered once and only once. EUSOM Clinical Trials Office is Emory University’s official Protocol Registration System Administrator. To get an account to register a trial, contact CTO@emory.edu clinicaltrials.gov Provides patients, family members, health care professionals, and members of the public easy access to information on clinical trials for a wide range of diseases and conditions. clinicaltrials.gov Recent legislation (Public Law 110-85, Title VIII) mandates the expansion of clinicaltrials.gov  Several data elements that are currently optional will be required  For certain device trials, sponsors will have the option to delay publication of full registration detials, pending clearance or approval of the associated device(s) Changes become effective 12/26/2007 (90 days after enactment of the law) clinicaltrials.gov  Newly required data elements, if left unspecified, are now identified in the PRS - You’ll get this message… WARNING: [Data Element Name] has not been entered   CTO recommends that registrants begin providing the revised set of data elements now for new registrations and active studies Studies completed prior to enactment (September 27, 2007) are not subject to the new registration rules but may be updated at the discretion of the registrant clinicaltrials.gov Clinical Trials that must be registered:  Trials of drugs: Phase II-IV controlled clinical trials  Trials of devices: Controlled trials with health outcomes, other than feasibility studies Who is responsible for trial registration 1. Sponsor of the clinical trial – OR – 2. PI of such clinical trial if so designted by a sponsor, grantee, contractor, or awardee New REQUIRED Fields on clinicaltrials.gov DESCRIPTIVE INFORMATION  Official Title  Intervention by Arms  Study Start Date  Completion Date  Enrollment (target # of participants)  Primary Outcome Measures  Secondary Outcome Measures RECRUITMENT INFORMATION  Accepts Healthy Volunteers?  Has Expanded Access? LOCATION and CONTACT INFORMATION  Collaborators  Responsible party (new data element – details pending) ADMINISTRATIVE DATA  Secondary Protocol IDs clinicaltrials.gov CTO does not manage content – YOU DO!  CTO has many CT’s ‘in progress’ that need additional data or updates. CTO cannot release them to ct.gov until they are updated…  Keep data current - check on it frequently  Use spell check  Use care with ‘cut and paste’ from protocol…usually too technical for use on ct.gov website ‘lay language’ sections  clinicaltrials.gov #1 FAQ: Does my trial need Human Subjects Review Board approval before I enter it into ClinicalTrials.gov? You may register your trial in ClinicalTrials.gov prior to getting approval from your human subjects review board (i.e., institutional review board or ethics committee), provided the trial is not yet recruiting. Before the first patient is recruited, board approval must be obtained and the protocol record updated accordingly clinicaltrials.gov     Use lay language in certain sections; the public is reading this too so use 6th-8th grade level for wording and reduce technie talk Clinicaltrials.gov FACT SHEET available at http://prsinfo.clinicaltrials.gov Send questions to register@clinicaltrials.gov WIRB: Sponsor should have registered it but don’t make any assumptions Western IRB (effective November 1, 2007) Use WIRB for NEW Phase III studies that are industry-designed, industry-initiated and industrysponsored. Emory University will no longer be the IRB of record for these types of research projects. Excluded - Any research project that is:  Phase I, II or IV  Investigator initiated, cooperative group or federally funded  PI holds IND/IDE's  If any member of the research team has a financial interest in the research project  If the Atlanta VAMC is a participating site Request for CTO Coverage Analysis Cover Sheet - CHANGE Office of Business and Finance the “Blue Sheet”…Revised October 2007 OBF’s “Blue Sheet”… Earlier version does not have the Clinical Trials section where the Department is to include the account number for the CTO coverage analysis fee. If you used the old one, CTO will need to contact the Department to obtain this info and include it before routing to OBF…sooooo PLEASE USE THE NEW VERSION!! OBF’s “Blue Sheet”… The new Blue Sheet is available on the SOM Research website at: http://www.med.emory.edu/research/infor mation/announcements.cfm Questions on use of this form? Contact Pat Davis 727-3119 pdavi03@emory.edu or Lore Cole 712-2054 lcole@emory.edu Welcome CTO’s Newest Team Members… Clinical Research Finance Managers Amaka Wright Angela Hickman Janice Newman IT Technical Lead Bill Zhou Protocol Tracker Hilary Eiring, BA EUH Analyst Brenda Colquitt-Robbins Need: Three more CRFM’s (two to be RN’s) and a coding specialist for the Pre-Award Team Phase I Trials: Foundations in Anticancer Drug Development R. Donald Harvey, Pharm.D., BCPS, BCOP Assistant Professor and Director, Phase I Unit Winship Cancer Institute Emory University Why Are Phase I Trials Important?  They:   Begin the translation of new discoveries into clinical practice Identify ineffective treatments and/or redundant treatments  The more people take part, the faster we can:   Answer critical research questions Find better treatments Only 3% of US adults with cancer participate in clinical trials  But:  Definitions  Phase I trial - The first step in testing a new treatment in humans. These studies test the best way to give a new treatment (for example, by mouth, intravenous infusion, or injection) and the best dose. The dose is usually increased a little at a time in order to find the highest dose that does not cause harmful side effects. Because little is known about the possible risks and benefits of the treatments being tested, phase I trials usually include only a small number of patients who have not been helped by other treatments.  Phase I/II trial - A trial to study the safety, dosage levels, and response to a new treatment. www.cancer.gov Definitions “In a phase 1 trial, you may have lots of blood tests, as the researchers look at how the drug is affecting you. And at how your body copes with, and gets rid of the drug. People entering phase 1 trials often have advanced cancer and have usually had all the treatment available to them. This is because they may benefit from the new treatment in the trial, but many won't. The aim of the trial is to look at doses and side effects. This work has to be done first, before we can test the potential new treatment to see if it works. Phase 1 trials are important because they are the first step in finding new treatments for the future.” www.cancerhelp.org.uk Cancer Treatment Trials Cancer Treatment Trials  Phase 0  A very new concept  Phase I  First evaluation Testing effectiveness Testing against standard therapy Post-marketing experience  Phase II   Phase III   Phase IV  Phase I  What is the best way to give a treatment and what should the dose be?     Patients have exhausted available therapies, but still feel well enough to get more treatment Determines side effects Measures where the drug goes and if it hits the target Tells what dose to take into phase II trials   Small numbers of patients (15-30) Crucial step for further drug evaluation Phase I Trials   Required for development PubMed review – 365 published evaluations from 2005-present  25% increase over 2003-2004     Clinicaltrials.gov – 2266 active studies ASCO abstract publication rate = 44% Single agent, first-in-human studies declining Success stories – cisplatin, imatinib Roberts TG Jr, Goulart BH, Squitieri L, et al. JAMA 2004;292:2130-2140. Classic Methodology  Objectives     Modified Fibonacci   Dose derivation for phase II Toxicity  Maximum tolerated dose (MTD) Pharmacokinetics   Starting dose = 1/10 no adverse effect dose in animal models Cohorts of 3-6 patients per dose level Dose escalation  e.g.: x, 2x, 3.3x, 5x, 7x, 9x, 12x, 16x….. No dose escalation in a specific patient  Rationale – better assessment of cumulative and delayed toxicities Classic Methodology  Assumptions     Greater toxicity = greater efficacy Dose tolerance in phase I = dose tolerance in subsequent phases Dose tolerance as a single agent = dose tolerance in combinations Phase I patient characteristics = later phase patient characteristics Classic Methodology – Drawbacks  Patients exposed to doses unlikely to provide benefit      Poor model for new classes of agents MTD derived from 1st cycle DLT only May not predict true toxicities  Beneficial dose = 80-120% MTD Animal model PK may not predict human disposition  MTD becoming obsolete Metabolites   Plasma concentrations may not predict intracellular tumor sensitivity Inefficient use of resources Novel Methods  New agents/combinations Sequence alteration/evaluation Continuous phase I studies Model-based drug development Improved trial designs     Novel Trial Designs  Increased starting dose levels  1/5-2/5 of no adverse effect animal model  Pharmacologically guided dose escalation (PDGE)  Requires real-time PK Escalation with overdose control (EWOC)   Statistically-based methods  Incorporates in-trial information Pre-trial dose-response curve required Reduce cohort size from 3 → 1  Modified continual reassessment method   Novel Endpoints  Optimal biologic dose vs. MTD  Improved correlative studies     Early incorporation of molecular measures Target saturation/inhibition Surrogates Functional imaging  Expanded use of pharmacodynamics Pharmacodynamics – Current Applications   Carboplatin Dose-adjusted EPOCH (n=50)    Rationale: significant interpatient variability in etoposide, doxorubicin PK Increases in myelosuppressive agents (20%) based on prior cycle ANC nadir Age significantly predicted etoposide/doxorubicin dose intensity  Driven by reductions in clearance    Doses escalated in 58% of cycles CR = 92%, PFS = 70% at 5 years bcl-2 expression only factor that correlated with PFS Wilson WH, Grossbard ML, Pittaluga S, et al. Blood 2002;99:2685-2693. Phase I Trials – Societal Concerns   Safety Validity of informed consent  Concern that benefits may be misconstrued Motivation  Volunteerism   Change in quality of life  Poorly measured to date Best supportive care Older regimens, agents Disease dependent   Alternative treatment options?    Pancreatic vs. breast cancer Phase I Trials – Societal Concerns   Expectation of benefit Risk-benefit ratios  Risk  On trial mortality = 0.5% Historically, response rates = 5-7%   Benefit  CR = 0.7%   Based on cytotoxic chemotherapy agents Do not reflect improved supportive care Estey E, Hoth D, Simon R, et al. Cancer Treat Rep 1986;70:1105-1115. Decoster G, Stein G, Holdener EE. Ann Oncol 1990;1:175-181. Phase I Trials – Societal Concerns  Have risks and benefits changed over time?  Have trials of newer agents changed expectations? Risks and Benefits: 1991-2002  CTEP sponsored trials  460 trials, 10,402 patients  Agents classified into six categories with four subgroupings   Cytotoxics, immunomodulators, receptor/signal transduction inhibitors, antiangiogenesis, gene transfer, vaccine One agent, multiple agents, combinations with FDAapproved agents, FDA-approved only Receptor/signal transduction inhibitors = 26%  Cytotoxics = 48% of trials  Horstmann E, McCabe MS, Grochow L, et al. N Engl J Med 2005;352:895-904. Risks and Benefits: 1991-2002  Results - Benefits  Overall response (CR/PR) = 10.6%  CR = 3.1%   Varied by agent (immunomodulators = 13.6%) Combinations superior to single agents Horstmann E, McCabe MS, Grochow L, et al. N Engl J Med 2005;352:895-904. Risks and Benefits: 1991-2002  Results – Risks  Deaths possibly related to treatment = 0.5%   Immunomodulators = 0.07% Combination FDA-approved + investigational = 0.77%  Grade 4 toxicity = 17.4% Response = 4.4% Deaths possibly related to treatment = 0.57%  Single agent cytotoxics   Horstmann E, McCabe MS, Grochow L, et al. N Engl J Med 2005;352:895-904. An Optimal Phase I Program   Clinical trial culture Multiple party involvement     Patient recruitment efforts  Design  Clinicians  Basic science  PK/PD  Biostatistics  Ethics Conduct  Patients  Nursing  Data management  Pharmacy  Trial offerings Investigator incentives, minimize inefficiencies Timing Future Applications  Improved utilization of newer designs, molecular genomics  Maximize likelihood of benefit  Optimal inclusion of phase I techniques in later stages  Phase I/III, phase I/IV   Dose derivation using anti-tumor endpoints Normal, healthy volunteers Why Do So Few Cancer Patients Participate in Clinical Trials? Doctors might:  Lack awareness of appropriate clinical trials  Be unwilling to “lose control” of a person’s care  Believe that standard therapy is best  Be concerned that clinical trials add administrative burdens Public Perception of Clinical Research 99% US should provide health and medical research training Medical and health research is important to the economy Spend more time on research “even if no immediate medical benefit” JAMA Sept 21 2005 issue 94% 55% Public Perception of Clinical Research - Barriers 73% 61% Competition slows progress Regulatory barriers impede discovery 49% Not enough money dedicated to research at the federal government Not enough researchers JAMA Sept 21 2005 issue 40% Investigational Drug Services (IDS) and Clinical Research at Emory Shawn Akkerman, PharmD Director, Office of Sponsored Programs Emory University IDS and Clinical Research    Overview of IDS at Emory Describe current issues/concerns with management of drugs used in clinical research at Emory Provide information about upcoming policy and operational changes regarding use of pharmacy/IDS for clinical research at Emory Overview of IDS at Emory  IDS at Emory:  Operated at EUH voluntarily serving EHC facilities, trials and investigators for over 20 years  Single satellite with 2 pharmacists, 1 technician managing about 150 trials  IDS is supported by EHC and by incoming service revenue only Current Issues/Concerns with Drug Management in Trials at Emory  Regulatory/Legal Requirements for Drug Management in Clinical Research:  FDA, ICH and GCP: 21 CFR 312.59-62, ICH/GCP section 4.6 - describe specific responsibilities for investigators and sites regarding management of drugs  JCAHO standards – require oversight of investigational drugs by pharmacy Current Issues/Concerns with Drug Management in Trials at Emory  Regulatory/Legal Requirements for Drug Management in Clinical Research:   State of Georgia – laws allow MD to dispense/administer drugs but require MD be physically present; tasks cannot be delegated solely to research nurse AAHRPP standards – accreditation of IRB; encompass many policies related to human subjects including management of investigational drugs Current Issues/Concerns with Drug Management in Trials at Emory  Regulatory/Legal Requirements for Drug Management in Clinical Research:   Indemnification – conditioned upon compliance with laws/regs and appropriate management of drug; protection against suits from subject injury at risk FDA audits – inspections at Emory over the last few years have noted violations/deficiencies in specific area of drug management New IDS Policy at Emory  New policy regarding investigational drug management for trials involving Emory investigators:   Will require use of pharmacy/IDS for management of drugs in clinical research New studies not yet received by CTO – expected start date January 1, 2008 New IDS Policy at Emory (cont.)  New policy:    Approved by executive leadership, Council of Chairs, SOM Dean, etc. Will be communicated via L/L, policy letters from Deans Lawley and Stephens, CTO website Will involve increase in IDS fees that will apply to all studies New IDS Policy at Emory (cont.)  New policy:    Allows for exception requests where justifiably exceptional circumstances exist whereby drugs cannot be managed by IDS/pharmacy Exceptions to be reviewed on a case-bycase basis Exceptions granted will still involve education and periodic audits New IDS Policy at Emory (cont.)  New policy:   Applies to studies at affiliates (VA, CHOA, GMH); affiliate pharmacies will provide IDS services Emory IDS expanding to 2nd location in Clinic A bldg and using courier service to provide deliveries, upon request, to Emory locations Questions? It’s been a BIG year! Thank you for supporting the CTO Lunch and Learn Series From our office to yours, best of health and happiness in the New Year…see you in 2008!