Brown Bag Series on Research Faculty FDA Approvals, IND, IDE and Clinical Trials March 16, 2011 Gerberding Hall 142, University of Washington

Brown Bag Series on Research Faculty Speakers Lynn Rose, Research Associate Professor, Pediatrics; Director, Regulatory and Clinical Affairs, Seattle Children’s Research Institute Ann Melvin MD, MPH, Associate Professor Pediatrics – Infectious Diseases Seattle Children’s Hospital Co-director Regulatory Support and Bioethics Core - ITHS

Brown Bag Series on Research Faculty Confidential Learning Goals of Presentation 1.Brief history behind FDA regulations and processes 2.Review IND and IDE Exemptions 3.Practical Considerations for Writing for INDs and IDEs 4.Review Investigator Commitments and Common Deficiencies 5.Overview of resources available through ITHS 3

Brown Bag Series on Research Faculty Confidential Safety is the Key to Initiating Clinical Trials Long, sad history of both abuses and ignorance leading to clinical disasters: – From past disasters come current laws – As the years have passed, more and more regulations (i.e. disasters) have been passed – People more risk averse 4

Brown Bag Series on Research Faculty Confidential

Brown Bag Series on Research Faculty Confidential 1937: Sulfanilamide Elixir S.E. Massengill developed Sulfanilamide Elixir for pediatric indications – Sulfa drug dissolved in diethylene glycol First death reported in October 1937 – Eventually 107 people died, mostly children – 108 th death was the chemist who invented it (suicide) – Dr. Geiling at the U. Chicago showed the solvent was toxic FDA seizures and prosecution – “Misbranded” – “elixir” implied it contained alcohol, which it didn’t – Massengill Co. paid a fine of $26,100

Brown Bag Series on Research Faculty Confidential Federal Food, Drug, and Cosmetic Act of 1938 Increased emphasis on safety: – Manufacturer had to test any new drug for safety and report results to the FDA No standards for safety testing were established No requirements for efficacy – Authorized FDA to conduct factory inspections No manufacturing standards were set – Labeling had to include All ingredients and quantity of each Directions for use, Warnings about dangers – Product was considered misbranded if it was dangerous to health when used in the dosage recommended in the label. No oversight of clinical trials was mandated

Brown Bag Series on Research Faculty Thalidomide “Wonder drug” for insomnia, coughs, colds, and headaches. Also an effective antiemetic for morning sickness. Thalidomide distributed to >1000 U.S. doctors on an “investigational” basis – > 20,000 patients received the drug; 624 were pregnant – Doctors were “invited” to report on their results, but were under no obligation to do so NDA for thalidomide was assigned to a new FDA examiner, Dr. Frances Kelsey, who had studied in the lab of Dr. Geiling as a graduate student

Brown Bag Series on Research Faculty Confidential Thalidomide Aftermath Dr. Kelsey won the President’s Medal for Distinguished Federal Civilian Service from President John F. Kennedy (highest recognition possible for civil service) Drug reform proposals that had been languishing were resurrected and enacted without a single dissenting vote in either the House or Senate

Brown Bag Series on Research Faculty Confidential Kefauver-Harris Amendments of 1962 FDA gained jurisdiction over testing of drugs before they would be approved for marketing – Drug firms (“sponsors”) had to apply to the FDA to perform human trials of a new drug: Investigational New Drug application, or IND – Sponsors had to inform FDA of what happened during clinical testing Patients in trials had to give informed consent (WWII aftermath) Animal testing had to be conducted prior to human testing Experiments had to be properly planned, and include controls Investigators conducting trials had to be qualified – Sponsors had to describe the scientific training and experience necessary to test the safety of the drug Drug had to show efficacy before it could be marketed Established Good Manufacturing Practices

Brown Bag Series on Research Faculty Confidential Medical Device Amendments of 1976 Law passed to ensure safety and effectiveness of medical devices, including diagnostics Required manufacturers to register with FDA and follow standard quality control procedures Identified 3 classes of medical devices, each with unique requirements for marketing authorization – Class I – lowest risk devices and lowest set of requirements Clinical testing not required for marketing approval No regulatory application (i.e. 510 (k) or PMA required for marketing authorization) – Class II –medium risk devices, higher performance standards required Marketing authorization requires 510 (k) application Clinical testing may be required if product has no “predicate” as comparator – Class III – highest risk devices, highest level of performance standards Investigational Device Exemption (IDE) Premarket Authorization (PMA) for Marketing Approval Following the Dalkon Shield Deaths:

Brown Bag Series on Research Faculty Examples of Medical Device Classifications Medical Device Classes: Class I General Controls Most exempt from premarket submission Class II Special Controls Premarket Notification [510(k)] Class III Premarket Approval Require Premarket Application [PMA] Additional Classification: “De Novo” Device "types" that have never been marketed in the U.S., but whose safety profile and technology are now reasonably well understood Humanitarian Device Exemption (HDE) Devices for orphan diseases Intended to benefit patients in diagnosis and/or treatment of disease or condition affecting or manifested in fewer than 4,000 patients per year in the United States

Brown Bag Series on Research Faculty Confidential Since 1976…  The regulations embodied in the Food and Drug Administration Modernization Act (1997) have continued to evolve as new problems emerge  Requirements for post-market surveillance protocols  Safety data continues to be prioritized by FDA (over efficacy) when reviewing IND applications because history shows that safety risks lurk in unusual places  Cell lines (e.g., viral, mycoplasm contamination)  Expression Systems (e.g. antibiotic selection)  Formulation (e.g., sulfanilamide)  Contaminants from manufacturing  Guidance Documents have proliferated to aid investigators in understanding the requirements for INDs and IDEs  Product and Indication Specific 13

Brown Bag Series on Research Faculty Confidential Understanding the Regulations for INDs and IDEs Review 21 CFR Part 312- Investigational New Drug Application Review 21 CFR Part 812 – Investigational Device Exemptions – Table of Contents Clearly Delineated Review FDA Guidance Documents related to product type, disease, animal models, etc. Consider a Pre-IND/IDE meeting: Before you embark on animal safety studies Once preclinical data is sufficient to have a meaningful discussion. To clarify the product classification and FDA review division To determine if study is eligible for IND or IDE waiver

Brown Bag Series on Research Faculty Confidential Investigational New Drug (IND) Applications IND applications are required for clinical studies of investigational drugs that are not “exempt” from the IND regulations Investigational drugs means a “new” drug or biological drug that is used in a clinical investigation. The term “new” encompasses both unapproved drugs and approved drugs that are used in new ways (i.e., new indications)

Brown Bag Series on Research Faculty Confidential Conditions for IND Exemption Conditions for IND Waivers are provided in 21 CFR Part – Study results will not be reported to FDA for the purpose of changing the label or adding a new indication (Industry Sponsor) – Study results will not be used to change the advertising of the drug (Industry Sponsor) – The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of risks) associated with use of the drug product (Industry and Academic Sponsors) – The investigation is conducted in compliance with requirements for institutional review – The study will not be used for off-label promotion of the drug (Industry Sponsor)

Brown Bag Series on Research Faculty Confidential Practical Considerations for IND Waivers ―Would a change in the route of administration alter the safety profile?  Target Organ may change (i.e. inhaled vs parenteral)  Pharmacokinetics may be altered (i.e. increased renal exposure) ―Are the approved doses appropriate for the new indication?  Do animal model data suggest that higher doses should be tested? ―Is the intended patient population is within the same age range studied in approved indication Safety risks in young or older populations may be unknown ―Does the intended patient population have a disease condition that would put it at different (i.e., unknown) and/or greater risk than the population studied for the approval (i.e., pediatric versus adult, healthy versus sick) What were the safety findings for the original indication? Are those findings relevant for the condition under study? ―Don’t short-change the study to avoid an IND ―Read the label! 17

Brown Bag Series on Research Faculty Investigational Device Exemption (IDE) Waivers Requirement for IDE based primarily on Device Class (i.e. I, II, or III) – Class III highest risk category – Existence of a “predicate” device IDE Waivers Based on Risk of Device and Experience with Device Type – Significant Risk (Requires an IDE to initiate a study) – Nonsignificant Risk (May require an IDE) – Exempt (Does not require an IDE)

Brown Bag Series on Research Faculty IDE Exempt Studies 510(k)-cleared and HDE- or PMA-approved devices, if used in accordance with approved label; Consumer preference testing of marketed device; Combinations of legally marketed devices; Custom devices (NARROWLY defined); Foreign Studies; Declaration of Helsinki Studies of diagnostic devices (with some caveats)

Brown Bag Series on Research Faculty Significant Risk Device Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject; Is purported or represented to be for use supporting or sustaining human life and presents a potential for ….; If for use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health and presents a ….; Otherwise presents a potential for ….. Is typically designated as a Class III device

Brown Bag Series on Research Faculty Nonsignificant Risk Devices An NSR Device is one that does not meet the definition of a Serious Risk Device Are typically Class I or Class II devices

Brown Bag Series on Research Faculty Who decides whether a device study is SR or NSR? Study Sponsors make initial determination and present case to IRB Unless FDA has already determined risk level, it is the responsibility of the IRB to make the determination FDA is available to consult with sponsor or IRB In cases of disagreement, FDA trumps IRB

Brown Bag Series on Research Faculty Confidential Some Practical Considerations  Plan ahead, evaluate the IND or IDE requirements well before you want to write one  Don’t avoid the FDA – you can save so much time if you ask the questions you need to ask  Read the drug labels, they guide you in determining the information you need to obtain about your own compound  Be thorough in your literature search, the FDA certainly will be  Plan sufficient time to complete the IND or IDE – it can take months to assemble and review all of the data, not days!  Understand import restrictions on clinical supplies and foreign devices  Proofread, proofread, proofread  Poor grammar, sloppy formatting, lack of consistency can impact your working relationship with the FDA  Ask for help – no sense wasting time on rework 23

Brown Bag Series on Research Faculty Confidential Common IND Misconceptions  The mechanism of action must be well understood prior to submitting an IND for a new drug or biologic drug  Important, but don’t shortchange safety  Use animal models to collect safety information  No safety findings is Good!  Yes, BUT you need to understand the margin of safety between the proposed human dose and the toxic dose  FDA will ask you to find the toxic dose  Regulatory requirements are not relevant to academic research  Early choices can make or break successful translation to industry  Cell line lineage, passage number, viral testing procedures  Antibiotic selection techniques – use of ampicillin not acceptable  Assay reproducibility and accuracy  Regulatory science is not “research”  FDA requirements are science-based  Your grant application is a clinical protocol 24

Brown Bag Series on Research Faculty Confidential IND/IDE Applications are not Forms They represent a major scientific effort Require commitment of time and effort! They carry a commitment to follow the regulations

Brown Bag Series on Research Faculty Confidential FDA Form 1572 or Investigator Agreement*  Legal Contract between Investigator and Sponsor and FDA  Provides the sponsor with information about the investigator’s qualifications and others at the clinical site  Informs the investigator of his/her obligations and provides the investigator’s written commitment to follow pertinent FDA regulations.  Making a willfully false statement is a criminal offense under 18 U.S.C  Submission of a deliberately false statement to the sponsor or to the agency can be taken into consideration in a disqualification proceeding. *for devices 26

Brown Bag Series on Research Faculty Confidential Statement of Investigator (paraphrased)  Agrees to follow the investigational plan (i.e., the protocol)  Agrees to personally conduct or supervise the conduct of the investigational study and to ensure that all associates, colleagues, understand their obligations to the study  Agrees to inform any study subjects that the drugs /devices are being used for investigational purposes and obtain their consent for participation in the study  Agrees to report adverse experiences that occur in the course of the investigation  Agrees to maintain adequate and accurate records and to make those records available for inspection  Agree to obtain and document IRB approval for the study  Adequately monitor supplies of investigational products used in the study 27

Brown Bag Series on Research Faculty Confidential Clinical Investigator Inspections  You can expect to be inspected by the FDA if:  You are participating in a Phase 3 industry- sponsored study that will support registration (i.e., approval) of a new drug or biological drug  You are participating in an industry study that will support registration of a new medical device or diagnostic  You are conducting a study funded by the FDA  You are conducting high risk research  A complaint has been lodged against you  You have never been inspected before 28

Brown Bag Series on Research Faculty Clinical Investigator Inspection Search NameLocationTypeClassification Deficiency Codes Aboulafia, David M MD Virginia Mason Med Ctr DAVAI05 Ahmad, Suhail MD Scribner Kidney Ctr/Univ Washington DAVAI03,06 Altman, Leonard C MD NW Asthma & Allergy Ctr DAVAI201 Bensinger, William I MD Fred Hutchinson Ca Res Ctr FCVAI05,18 Bierman, Charles W MD a.s.t.h.m.a. incDAVAI203,04,05,06,07 Blackmon, John R MD Univ Washington Hosp DAVAI203,04,05,06 Bockow, Barry I MDArthritis NWDAVAI05,18 Bowden, Raleigh A MD Fred Hutchinson Ca Res Ctr DAVAI03,04,05 Caplan, Robert A MD Virginia Mason Med Ctr DANAI00 FC = for cause; DA = data audit

Brown Bag Series on Research Faculty FDA Inspection Codes Classification Codes NAI – No Action Indicated VAI – Voluntary Action Indicated OAI – Official Action Indicated CANC – Cancelled WASH – Washout Frequency of Classification in Washington State Inspections NAI – 27% VAI – 69.5% OAI – 1% CANC – 1.5% WASH – 0.5%

Brown Bag Series on Research Faculty Errors Frequently Committed by Clinical Investigators in Washington State Deficiency Code (%)Deficiency Code(%) 00 - No deficiencies noted – Inappropriate delegation of authority – Records availability – Inappropriate use of IND – Failure to obtain/document informed consent – Failure to list additional investigators – Inadequate informed consent form – Subjects receiving simultaneous investigational products – Inadequate drug accountability – Failure to obtain/document IRB approval – Failure to follow investigational plan – Failure to notify IRB of changes – Inadequate and inaccurate records – Failure to report adverse drug reaction – Unapproved concomitant therapy – Submission of false information 0 08 – Inappropriate payment to subjects Other – Unapproved use of drug (no IND) 0 * Compiled from CDER Clinical Investigator Inspection Database n=197 Inspections ( )

Brown Bag Series on Research Faculty ITHS Preclinical Research and Development Core  Consulting on IND/IDE Content  Preparation of IND/IDE  Review Development Programs  Assist in identification of industry and academic partners  Funding Program for Translational Research (Ignition Awards for Nonhuman Primate studies, Pharmaceutics, and Manufacturing)  32

Brown Bag Series on Research Faculty Thank you For additional information contact: Lynn Rose

Brown Bag Series on Research Faculty CLINICAL TRIALS: HOW DO I GET STARTED?

Brown Bag Series on Research Faculty Objectives Provide an overview of: – How to assess study feasibility – Clinical research approval process- UW – Where you can go for help 35

Brown Bag Series on Research Faculty 36 Study feasibility Population Procedures Collaborations Staff Budget Space etc.

Brown Bag Series on Research Faculty Population Do you have access to the right patient population? Are the enrollment goals realistic? Will you need to recruit outside of your system? Will enrollment compete with other studies? Are there special consent issues? Have you reviewed the inclusion/exclusion criteria and are they too restrictive? 37

Brown Bag Series on Research Faculty Procedures Are procedures approvable? Are procedures frequent/painful/inconvenient? Do procedures require special equipment/expertise? 38

Brown Bag Series on Research Faculty Collaborations Do you need additional specialists? Do you need access to outside clinics/schools/etc? 39

Brown Bag Series on Research Faculty Personnel Do you have qualified staff? Any special training required? Do you need an RN? Do you have time to devote to the protocol? Does your staff have time to devote to the protocol? 40

Brown Bag Series on Research Faculty Budget Considerations Your time Staff time Sub-investigator time Consultant time Cost of procedures Cost of labs Cost of space (CRC) Cost of shipping Records Storage Cost of storing specimens Pharmacy costs Cost of data collection system Cost of monitoring (study and site) Cost of statistician Manuscript preparation and presentation 41

Brown Bag Series on Research Faculty Budgets If budget is determined by sponsor do they allow time for – Study start-up activities (non-refundable) – Training – Unanticipated activities – protocol amendments, unanticipated monitoring visits, audits, etc – Keep in mind industry budgets are negotiable If you are writing the budget, is the RFA amount sufficient for all the study activities? – If not – what will need to be cut from the protocol. 42

Brown Bag Series on Research Faculty Budgeting help CRBB Detailed Budget Tool udget.shtml udget.shtml For help contact CRBB – –

Brown Bag Series on Research Faculty Space Do you have room for: – Research personnel – Study binders – Any equipment needed – Lab supplies OR Will you have to look for more space? 44

Brown Bag Series on Research Faculty Start up activities - contracts Read the protocol – Make sure everyone on the research team reads the protocol Decide if the study is feasible Let your Division/Departmental administrator know you are thinking of pursuing/accepting the contract 45

Brown Bag Series on Research Faculty Considerations if you didn’t write the protocol Is it well designed? Any ethical issues? Is there potential benefit to participants? Will the sponsor allow modifications if you don’t think it is feasible as written? Are the visits/procedures onerous for participants? Drug available at the end of the study? 46

Brown Bag Series on Research Faculty 47 Study start-up activities - Develop all study materials Regulatory Binder Study visit records Case report forms Eligibility checklist Adverse event report forms Protocol deviation report forms Screening logs Training logs PI Delegation log ITHS forms

Brown Bag Series on Research Faculty Study start up activities – training Human Subjects Protection Good Clinical Practice HIPAA Clinical Research Budget and Billing Office of Sponsored Research seminars Clinical Research Education Series – ITHS Fundamentals of Clinical Research - ITHS 48

Brown Bag Series on Research Faculty Who to go to for help General questions about clinical research at the UW – Ella Mae Kurashige, Director Clinical Research Services - Office of Sponsored Programs - sp sp ITHS Research Navigator - UW Clinical trials handbook research-handbook//: submission checklists, repository for how to do clinical research at the UW Medicine research-handbook// 49

Brown Bag Series on Research Faculty Who to go to for help How to get assistance from a research coordinator – Michelle Doyle – ITHS Research Coordinator Core Study design and biostatistical help – ITHS Center for Biomedical Statistics Investigational Drug Service – Sheree Miller – Research Bioethics – Ben Wilfond - ITHS RSB core 50

Brown Bag Series on Research Faculty Who to go to for help Research labs - Research Testing Service – Regulatory questions – Ann Melvin, Jason Malone ITHS RSB core Working with the UW CRC – Paul Hughes – ITHS Bionutrition Core – Holly Callahan - ITHS Body Composition and Exercise Laboratory– Holly Callahan - 51

Brown Bag Series on Research Faculty 52 Additional Resources Institute for Translational Health Sciences (ITHS) Additional education Translational Research Toolkit – UW Healthlinks: search for Translational Research Toolkit PRIMER toolkit -