4Drug Development Process/Overall Timeline Overall drug development process on average to bring one drug to market takes yearsPre-clinical testing takes 1-3 years, on average 18 monthsClinical research (phase I-III) takes 2-10 years, on average 5 yearsA single clinical trial in phase II-III will typically take anywhere from 1 year to 7 years from conceptual to publication) depending on therapeutic area and duration of individual subject participation. A phase III study in acute pain may be completed within 6 months whereas a study in PD looking for neuroprotection may take more like 5-7 years.NDA review takes 2 months to 7 years (on average 24 months)FDA approved 24 first of kind drugs in 2008 (vs. 18 in 2007, 22 in 2006 and 20 in 2005 (WSJ 1/2/2008). FDA missed the approval deadline for 32 out of 159 drug applications through 10/31/2008.Patents are good for 17 years..companys want to maximize their ability to have have an exclusive market for as long as possible, thus adhering to realistic yet stringent timelines is essential for drug developmentAs individual researchers you may be faced with different types of pressures that will require adherence to a realistic timeline including: limited funding, need to publish to advance career, creating better treatments for your patients etc.Today, its all about bringing products to market, and compressing drug development timelines is critical to focused product development and commercialization. Identifying, integrating and implementing cost effective development, regulatory, and quality strategies is a challenge for new firms especially those with biopharmaceutical and combination products. It takes broad experience, a solid understanding about how to deliver, knowledge of the latest strategies, and an ability to integrate a total system approach which delivers results. While there has been lots of emphasis over the past several years to reduce the length, cost and risk of drug development there has been limited success in this area.
5Drug Development Process It costs about $802 million* (in year 2000 dollars) over 12 years to bring one medicine from discovery in a laboratory to the patient.For everyone one medicine that reaches the marketable stage, between 10,000-30,000 compounds must be screened.*Ref: DiMasi JA, Hansen RW, Grabowski HG. The price of innovation; new estimates of drug development costs. J Health Econ2003;22:
6A Median Phase III study Includes ~800 subjects50 investigator sites~700 days (2 years) from First Subject First Visit (FSFV) to Last Subject Last Visit (LSLV)Costs ~$25 million (including per subject fees, drug supply, laboratory, Project and Data management fees) or ~$36,000/dayRef: Li, Gen: Site Activation, The Key to more Efficient ClinicalTrials; 2008 Advanstar Communications Inc.Gen Li: former head of R&D Operations for Pharmacia & Pfizer
8Life Cycle of a Clinical Trial Grant Award and/or Parent contract establishedProtocol finalizedModel ICF finalizedSites selectedOperations Manual/MOP completedCRFs finalizedIRB approvals obtainedSite subcontracts/ payment schedule in placeFinalize Contracts with third party vendors (labs, ECGs etc.)DSMB establishedBuild databaseFinalize Study drug packaging/labeling*Orientation or InitiationMeetingDatabase LockedAnalysisEnroll subjects*Distribution of study drugto sitesAnswer Protocol/CRFquestionsTake incident callsSAEsDosage AdjustmentsPremature WithdrawalsDrug DisclosureData query processClean/Close databaseTransfer database to BiostatisticsPerform primary/ secondary analysisSubmit abstractSubmit manuscriptSubmit CTRPost results onPost-hoc analysisProtocol Synopsis finalizedSchedule of Activities finalizedThis is a standard life cycle for any clinical trail regardless of therapeutic area or phase (1-1V). The life cycle is broken down into 4 phases: Conceptual, Planning, Implementation and Analysis/Publication. Planning for completion of the various tasks via a detailed timeline and scope of work documentAs you move into planning and implementation the amount of work and number of players involved increases significantly and management of multiple aspects of the study become critical in ensuring adherence to an established timelineFor most of the studies being conducted in Neurological disorders this lifecyle, not including the time to obtain funding is anywhere from 3-5 years and longer and for a phase III study.CONCEPTUALPHASEPLANNING PHASEIMPLEMENTATION PHASEANALYSIS/ PUBLICATION PHASE
9The Process of Conducting Clinical Trials: Fully understand the full lifecycle of any clinical trial, regardless of the phase (I-IV) or indicationThe process stays the sameLove the process, not the compound under studyCompounds are a “dime a dozen” and come and go. (Quote from: Michael Poole, MD Vice President, Wyeth)The process is here to stay
10Keys to Staying on Schedule Are developed in the conceptual and planning phase.Develop a REALISTIC timeline and workscope in the planning phase of a studyKeep It Simple Stupid! whenever possible
12To Ensure Adherence to the Timeline HIRE a GOOD Project ManagerIs highly organizedIs remarkably flexibleHas planned and executed a large birthday party (Ira Shoulson, MD), Bar-mitzah/Bat-mitzah or a large weddingHas Anal Retentive tendencies (OCD)..a good thing in this industryCan still see the forest through the treesHas excellent oral and written communication skillsCan build strong relationships with all kinds of staff both internal and external to the institutionCan influence people without a direct reporting relationshipIs not afraid to raise issues early on and work on finding solutionsWilling to put in long hoursIs always planning at least 6 months ahead
13It Takes a Small Army to Run a Study: with Excellent Communication Steering CommitteeSponsorOperational TeamProject ManagerDatabase ManagerInformation AnalystAdministrative SupportBiostatisticanProgrammerMeeting PlannerMonitorsEnrolling Site TeamData Safety Monitoring BoardVendor Teams
15Formalize the idea/obtain funding Develop a Protocol Synopsis and Schedule of Activities (2-3 months)Develop full research plan following requirement for potential funding source (e.g. NIH, FDA, DOD, Pharmaceutical unrestricted educational grant, Foundation, or approval of internal pharmaceutical company budget etc.)Submit for funding and go through the review process (typically max of 2 submissions of the same idea)Can take anywhere from ~6-9 month to 4-5 years or longerIn some cases funding does not materialize….
17Key Planning Milestones Protocol Synopsis and Schedule of ActivitiesProcurement of Drug SupplySet-up and maintain Trial Master File (TMF)Final ProtocolModel Informed Consent Form (ICF)Develop patient recruitment materials: patient brochure; website; newspaper, TV and radio ads; call center scripts etc.Once the plan is created, the PM should manage the study according to this as well as the agreed to timeline. The sample timeline in your binder includes some standard industry variables for how long it typically takes for certain task to be completed. For each study you plan careful consideration needs to be given to the timeline with realistic milestones. Understanding how long it takes your site to obtain IRB approval as well as participating sites should be factored in as well as time to get signed contracts. Aileen Shinaman will spend more time on contracts later today. IRB approvals at academic institutions typically takes 60-90days while IRB approvals by for profit IRBS can take as littles as 15 to 30 days. You also need to take into account the 30 day time from submission of an IND before starting a study. Planning your orientation mtg such that within a week or so of the mtg sites are ready to start enrolling subjects, which means drug supply needs to be available. Having this meeting too early typically requires follow-up training meetings as people forget the materials.The items in red are the most critical if the study is pharmaceutically sponsored and often timelines are created based on set dates for FPI, which often have financial implications for the company with prior milestones planned backward from FPI.
18Regulatory Submissions IND submission(~2-4 wks after final protocol available)FDA approval/complete or partial hold status – (must wait 30 days before starting the study for FDA to respond)Most IRBs require proof of IND status via written documentation ( /formal letter) from the FDA that the trial may proceedPros/Cons of submitting Final protocol/model consent to sites prior to IND/protocol approval from FDASubmission to other Regulatory authorities as applicable (e.g. Health Canada, European Union etc.)
19Initiate Site Selection Process Send Confidential Disclosure Agreement (CDA) to possible sites (must be returned before site selection materials can be sent) (~2 weeks to send and receive)Site selection questionnaire sent to sites with fully executed CDAs (completed ~1 week after final protocol synopsis is available)
20Select Sites Based on: Notify selected and back-up sites of status Access to patient population/geographic distributionPast performance of investigator/coordinator teamProjected number of subjects/anticipated enrollment rateReceipt of FDA 483sLack of competing studiesAbility to attend orientation mtgAvailability of required equipment or specialized staffNotify selected and back-up sites of statusNotify sites not selected
21Site Activation Drives Enrollment Budget/Contract negotiationGain Institutional Review Board (IRB) approval in the US or ethics Board approvals in Europe/CanadaCollect other regulatory documents (e.g. FDA form 1572, CVs, financial disclosure etc.)Provide sites with clinical supplies (e.g. lab kits, drug supply)Patient RecruitmentBegins once above elements are completed
22Site ActivationEnrollment cycle time varies by disease state and sponsor, but across disease states site activation accounts for 70% of enrollment cycle timeActivation of a single center on average takes 100 days (3.3 months)20-50% of studies have rescue missions where new sites are brought in late in the game to enhance enrollmentRef: Li, Gen. Site Activation the Key to More Efficient Clinical Trials. Pharmaceutical Executive, 12/12/2008.
23Site Subcontract Responsiveness-NIH contract July 1997 Ref: Data from A. Shinaman, Clinical Trials Coordination Center. Unpublished data
24Subcontract Response Rate-Industry Sponsored contract 2000 Ref: Data from A. Shinaman, Clinical Trials Coordination Center. Unpublished data
25Data Management Creation of Case Report Forms (CRFs)/eCRFs First draft of full set of forms within ~4 weeks of final protocol, final version available ~4 weeks after first draftObtain appropriate permissions to use forms, often including purchase of such forms (e.g., Beck Depression Scale, SF-36)Include appropriate references on published forms (e.g. UPDRS, UHDRS, MMSE, PDQ39 etc.)Database creation/validationCannot begin until final CRFs/eCRFs are availableTakes ~6-8 weeks to completeTimeframe varies base on whether a CRF library is already available for most of the CRFs or if all is being created from scratchCreate/Finalize Data Management Plan (DMP)First draft ~4 weeks after final CRFs available, with final DMP ~2-3 weeks after first draft
26Operations Manual/Manual of Procedures (MOP) Includes detailed operational instructions for the site on:SAE reportingDrug packaging, distribution and storage requirementsFull complement of CRFs and instructions for completionMonitoring expectationsProject Team contact listLaboratory proceduresContents of Regulatory binderProper procedures for conducting various assessmentsFirst draft available within 4-6 weeks after final protocolFinal MOP available for the Orientation mtg/Site initiation mtgTypically updated throughout the study via Study Newsletters or complete replacement of certain sections
27Select and Contract with External Vendors Central laboratory for safety labsPK analysisCentral ECGsElectronic diariesHolter monitoringManufacturer of study drugPrimary and secondary drug packager and distributorMonitoringObtain bids from ~2-3 vendors to compare prices/services early in planningAll vendor contracts should be completed prior to Orientation mtg
28The number one rate limiting step in any clinical trial is: Study Drug!!!Study Drug!!ACTIVELY MANAGE ALL ASPECTS OF THE STUDY DRUG AS EARLY AS THE CONCEPTUAL PHASE (INITIAL GRANT SUBMISSION)
29Drug Supply Items for consideration: Purchase active and matching placebo or have donated?How will drug be delivered (e.g. Bulk shipment in drums, unit packaged, all at once, quarterly shipments)Secondary packaging/labeling and distribution requirements?Blindedness testing: Are active and placebo identical in: color, taste, smell, appearance, shape, size?Stability testing: ambient and accelerated: how many lots of each or is it even required?Expiry/retest issues?Storage requirements: ambient, refrigerated, light sensitive, moisture sensitive?Drug Accountability centrally and at site levelSite SOPs to address all aspects of study drug receipt, dispensing, return etc. (overall accountability)
30Sources for Drug Supply Delays Lack of sufficient animal toxicology dataHeld up in manufacturing: impurities found, long queue, API not available, stability issuesProblems matching active with placebo suppliesFailure to place order with enough lead timeCustom delays (e.g. shipment exported/imported from other countries)
31Cosmetic Bottling (paneling) Problem Paneling caused a 4 month delay in study start due to inspection time, Corrective Action Plan, and requirement for resupply
32Establish Data Safety Monitoring Board (DSMB) and Charter Select DSMB membersTypically 3-5 independent scientists with no conflicts-of-interest and no other role in the study (should include: a biostatistican, disease expert, expert on drug under study, expert in body system with AE profile of greatest concern , ideally most have prior clinical trials experience)Create/Finalize DSMB charterSpecifies exactly what the DSMB is charged to monitor, stopping rules for efficacy/safety, major areas of concern (e.g. renal, hepatic etc.)DMSB members and final charter should be in-place prior to FPFV
33Register Trial with www.clinicaltrials.gov Before FPFV Food and Drug Administration Amendments Act of 2007 or FDAAA), Title VIII, Section 801 mandates that a "responsible party" (i.e., the sponsor or designated principal investigator) register and report results of certain "applicable clinical trials":Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I investigations, of a product subject to FDA regulation;Trials of Devices: Controlled trials with health outcomes of a product subject to FDA regulation (other than small feasibility studies) and pediatric postmarket surveillance studies."Applicable clinical trials" generally include interventional studies (with one or more arms) of drugs, biological products, or devices that are subject to FDA regulation, meaning that the trial has one or more sites in the U.S, involves a drug, biologic, or device that is manufactured in the US (or its territories), or is conducted under an investigational new drug application (IND).
34Orientation Meeting or Site Initiation Meeting Depending on size of the study “training” of investigators, coordinators and other site staff can be accomplished via either mechanismMaterials to be created include:AgendaPresentations to include: Study overview, review of inclusion/exclusion criteria, drug/device under study, GCPs, adverse event reporting, eCRF/CRF completion, use of eDC system, laboratory requirements, unique safety assessments, primary outcome measure, diaries etc.
35Orientation MtgSecure meeting space and lodging ~3-6 months prior to the planned mtgTiming of the mtg should be such that at least half of the sites have IRB approval and subcontracts in placeMeetings held too soon are wasteful given staff turn-over, people forget etc. Typically requires additional training mtgs when sites are actually ready to go
36Initiation MeetingDirectly at the participating site; conducted by the lead monitor, project manager, and the PI or their designeeNot conducted until individual site has IRB approval, subcontract in place and has received drug supplyAllows for complete training of ALL staff at the site that have been delegated responsibilities per the “Delegation of Authority Log”Sites should be ready to start screening/enrolling subjects immediately following this trainingFormat usually used for smaller studies (1-7 sites); phase I-IIMost phase III studies use the Orientation mtg format where all investigators/coordinators attend the mtg and hear the same informationSome pharmaceutical sponsor may have both a Orientation Mtg and a Site Initiation Meeting
39Key Implementation Milestones Drug Supply available at the site – (within days of the orientation mtg or at the initiation visit)FPFV = First Patient First Visit (typically a screening visit; within days of the orientation mtg)FPI = First Patient In (randomized) - (within days of the orientation mtg)Submit Press Release announcing study startFPLV = First Patient Last Visit - (determined by duration of treatment)LPI = Last Patient In (randomized) – [based on planned enrollment period. (# Subjects Enrolled/Site/Month)]LPLV = Last Patient, Last VisitDatabase Lock – (eDC: ~1-2 weeks following LPLV; paper: ~6- 8 weeks following LPLV)
40Implementation Timeline Killer ENROLLMENT DELAYS86%: Percentage of studies in which enrollment is delayed 1 to 8 months14%: Percentage of studies in which enrollment is completed on timeSignificant effort should be spent on identifying appropriate sites and setting up realistic enrollment expectations.Always have a back-up planBe sure to train any back-up sites brought on board after study start and any new site staff at existing sitesRef:http://www.ciscrp.org/information/documents/101FactsaboutClinicalResearch.pdf
43Other Implementation Milestones Continuous management of drug supply from FPFV to LPLVDevelop Statistical Analysis Plan (SAP):Created within ~4 weeks of a complete Data Management Plan (DMP) being finalizedMust be finalized BEFORE database lock and unblinding of study resultsConvene the Data Safety Monitoring Board (DSMB)Regularly during the conduct of the trial per the DSMB charter developed/finalized in planningSubmit DSMB letters indicating findings following each meeting to the sites for submission to their IRBs
44Other Implementation Milestones Submit unexpected SAEs to the IND as they occurSubmit Annual IND reports (per 21 CFR part )Must be submitted annually within 60 days of the IND submissionSubmit required regulatory reports to other Regulatory authorities as requiredSubmit Annual Progress Reports to Funding AgencyDepends on the funding institute what information the report requires and timeline for submission (e.g., NIH requires annual reports that coincide with each contract year)
48Full AbstractDevelop and submit press release with findingsComplete ManuscriptPost Results onShare Results with SubjectsSubmit Final Clinical Technical Report (CTR) to the INDSubmit Reports to other Regulatory Authorities as applicable
49The Finish Line: Anywhere from 1-7 years later. Driven mostly by:Enrollment DurationDuration of subject participationAdequate Drug Supply
51Key Points to Remember Create a REALISTIC TIMELINE from day 1 There are many road blocks along the way that impact timelinesDon’t be discouraged, just figure out how to go around, over, under or through the road block and you will eventually get there!!!Re-evaluate timelines along the way based on nature/timing of “roadblocks”
52Failure to adhere to realistic timelines Increases study budgetPlanned resources downstream may not be available (e.g. enrollment goes longer than planned, DM staff may not be able to lock the DB based on competing priorities)Reduces time for market exclusivity: every day of delay in getting to market = $ 2-3 million/day in lost revenuebased on annual sales of a good drug $500M/year – blockbuster sales of $1B/yearDelay in getting needed drugs to patients
53Metrics Champion Consortium www.metricschampion.org The MCC is an open, multidisciplinary, non-profit organization comprised of biotechnology, pharmaceutical, research institutions and service provider organizationsThe mission of the MCC is to develop, Performance Metrics within biotechnology and Pharmaceutical industry with the intent to jointly encourage performance improvement, effectiveness, efficiency and appropriate levels of controls for both Sponsors and Service Providers in support of the drug development processMetrics for: central laboratories, ECG , CRO and imaging; including standard timeline metrics
55PDUFA The Prescription Drug User Fee Act of 1992 PDUFA The Prescription Drug User Fee Act of Legislation passed by Congress authorizing the FDA to collect "user fees" for regulatory review of human drug applications. The FDA agreed to use the income from the fees to hire more reviewers to speed up drug review without compromising review quality.
57Post results on www.clinicaltrials.gov Report results on (Sept 2008)Basic Results: Baseline characteristics, Primary and secondary analysis, statistical analysisGenerally submission within 12 months of the earlier of estimated or actual trial completion date (of primary outcome)Adverse Event Reporting (Sept 2009)Expansion of results by rulemaking (Sept 2010)
58Sharing Results with Subjects In conjunction with Press Release, coordinate webnairs/teleconferences with subjects/families to discuss results and particularly impact on treatments*Notify subjects of study results via copy of the abstract and/or full manuscriptNotify subjects of their individual treatment assignmentThis typically takes place months following subject completion in the study. Ensuring sites maintain accurate contact information for this follow-up is important.*Reference: Dorsey E. R., Beck C., Adams M., Chadwick G., de Blieck E.A., Mcallum C., Briner L., Deuel L., Clarke A., Stewart R., Shoulson I., and the Huntington Study Group TREND-HD Investigators. Communicating Clinical Trial Results to Research Participants. Arch Neurol. 2008; 65(12):