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WonnacottPhase1

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Published on January 16, 2008

Author: Regina1

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Phase I Trials and IND’s: From Conception through Application:  Phase I Trials and IND’s: From Conception through Application Division of Cellular and Gene Therapies Office of Cellular, Tissue, and Gene Therapies Center for Biologics Evaluation and Research Food and Drug Administration Keith Wonnacott, Ph.D. “Many things once thought to be science fiction now really are.”:  - Second grade essay on scientific progress “Many things once thought to be science fiction now really are.” A Brief History of the Drug Regulatory Agencies:  A Brief History of the Drug Regulatory Agencies 1860 PRESIDENT LINCOLN appoints a chemist, Charles M. Wetherill, to serve in the new Department of Agriculture. This was the beginning of the Bureau of Chemistry, the predecessor of the Food and Drug Administration. 1862 Chemical Division, Department of Agriculture 1889 Chemical Division, USDA 1890 Division of Chemistry, USDA 1901 Bureau of Chemistry, USDA 1927 Food, Drug, and Insecticide Division, USDA 1930 Food and Drug Administration, USDA 1940 FDA, Federal Security Agency 1953 FDA, Department of Health, Education, and Welfare 1972 FDA, Department of Health and Human Services 1909 Bureau of Chemistry Lab Brief History of the Biologics Regulatory Agencies:  Brief History of the Biologics Regulatory Agencies 1887 JOSEPH KINYOUN establishes Laboratory of Hygeine within the Marine Hospital Service at Staten Island, NY. This laboratory was moved to Washington D.C. in 1891 and became the predecessor of the NIH. 1930 Hygienic Laboratory is renamed the National Institute of Health 1937 Division of Biologics Control created within NIH 1944 Laboratory of Biologics Control 1955 Division of Biological Standards (DBS) 1972 DBS is transferred to FDA and becomes Bureau of Biologics 1982 Bureau of Biologics merges with Bureau of Drugs 1988 Center for Biologics Evaluation and Research created Regulatory Authority:  Regulatory Authority Federal regulatory authority is a 3-tiered system. Statutes: THE LAW --- passed by Congress and signed by the President Regulations: details of the law --- written by the Agency and approved by the Executive Branch Guidance: the Agency’s interpretation of the Regulations Slide6:  1901 13 children in St. Louis died of tetanus after receiving diphtheria antitoxin from a horse named Jim 9 children die of tetanus from contaminated smallpox vaccine 1902 Biologics Control Act authorizes Hygienic Laboratory to issue regulations to ensure purity and safety of serums, vaccines, and similar products 1901-1906 Dr. Harvey Wiley used ‘poison squad’ to test toxicity of food additives. Upton Sinclair published “The Jungle”. 1906 Food and Drug Act prohibits interstate commerce in misbranded and adulterated foods, drinks, and drugs. 1912 Sherley Amendment prohibits labeling medicines with false therapeutic claims intended to defraud the purchaser THE LAW Slide7:  1937 Sulfanilimide elixir containing diethylene glycol kills 107 people 1938 Food, Drug, and Cosmetic Act Extended control to cosmetics and therapeutic devices. Required new drugs to be shown safe before marketing-starting a new system of drug regulation. Eliminated the requirement to prove intent to defraud. Provided that safe tolerances be set for unavoidable poisonous substances. Authorized factory inspections. 1962 Thalidomide, a new sleeping pill, is found to have caused birth defects in thousands of babies born in western Europe. Kefauver-Harris Drug Amendments passed to ensure drug efficacy and greater drug safety. For the first time, drug manufacturers are required to prove to FDA the effectiveness of their products before marketing them. The new law also exempts from the Delaney proviso animal drugs and animal feed additives shown to induce cancer but which leave no detectable levels of residue in the human food supply. FDR signs Food, Drug, and Cosmetic Act Lessons from history:  Lessons from history Tragedy Public Response Political Intervention New Regulatory Authority Creating Regulatory Policy:  Creating Regulatory Policy Identify public need Engage community input Open process Paricipative decision making Evaluate risks and benefits Determine appropriate policy Advisory Committees: mechanism for input:  Advisory Committees: mechanism for input Advisory committees are panels of scientific experts formed to provide advice to the FDA Scientific information is presented and discussed Public comment is voiced and considered Recommendations are made to the FDA Slide12:  You have brains in your head. You have feet in your shoes. You can steer yourself any direction you choose. -Dr. Seuss Where to Next? “Oh, the Places You’ll Go” Do I Need an IND?:  Do I Need an IND? ? ? ? X ? Clinic Idea Do I Need an IND?:  Do I Need an IND? New biologic, drug, or device may not be entered into interstate commerce unless: Approved biological license, approved new drug application, approved premarket submission OR Investigational New Drug Application (IND) exemption Is an IND ever required for approved drugs?:  Is an IND ever required for approved drugs? YES, if an investigation is intended to support a significant change in labeling or advertising of the drug the investigation involves a the use of the drug in a patient population or a manner that significantly increases the risks associated with the use of the drug Do I need an IND for my cellular therapy?:  Do I need an IND for my cellular therapy? YES, if the cells are more than minimally manipulated are promoted or labeled for any use other than a homologous use are combined with or modified by the addition of any component that is a drug or a device have a systemic effect and are not for autologous, family-related allogeneic, or reproductive use What do I need to do before I submit an IND?:  What do I need to do before I submit an IND? ? ? ? X ? Clinic Idea Preparing for the Clinic:  Preparing for the Clinic Safety Safety Safety Remember the 6 P’s:  Remember the 6 P’s Proper Prior Planning Prevents Poor Performance “Proof of Concept” Studies:  “Proof of Concept” Studies Efficacy in animals or in vitro Isolation of the active component and determination of the mechanism of action Transitional Studies:  Transitional Studies Predict initial dose and dosing regimen Determine potential toxicities Acute, sub-acute, and chronic toxicity Reproductive, teratology, mutagenicity ADME (Absorption, Distribution, Metabolism, Excretion) Improve manufacturing process Determine appropriate tests and specifications for quality control Determine secondary efficacy endpoints PRE-CLINICAL DEVELOPMENT:  PRE-CLINICAL DEVELOPMENT Preparation, dose, route, and duration should be comparable to those proposed in clinical studies Should follow GLPs (21 CFR 58) Should be conducted in two animal models, including one non-rodent model Product Preparation:  Product Preparation Source controls Quality of the starting materials Process control Quality of the process, facilities, personnel, and the assays Final product testing Source controls:  Source controls Assurance that components will perform as desired in the manufacturing process Identity, purity, strength, and quality Assurance that components do not introduce an unreasonable risk to patients Free of toxic substances Free of contamination Free of transmissible diseases Source Control:  Source Control Sponsor can test the components A certificate of analysis (COA) can be obtained from the supplier An independent manufacturer or testing lab may be contracted Sponsor should ensure that: Tests are appropriate Specifications are appropriate Results are valid Special Considerations:  Special Considerations Drugs from human sources (e.g., appropriate donor screening procedures for tissues, blood, or other fluids; removal or inactivation of adventitious agents (e.g., viruses, bacteria, fungi, mycoplasma)) Drugs from animal sources (e.g., removal or inactivation of adventitious agents, transmissible spongiform encephalopathy (TSE)-free certification) Biotechnology drugs, particularly rDNA proteins from cell line sources (e.g., adequacy of characterization of cell banks, potential contamination of cell lines, removal or inactivation of adventitious agents, potential antigenicity of the product) Botanical drugs (e.g., raw material source, absence of adulteration) Reagents from animal or cell line sources (same considerations as for drugs derived from animal cell or cell line sources) Novel excipients Novel dosage forms (e.g., characteristics, potential for overly rapid release of dose, if applicable) Drug-device delivery systems (e.g., demonstration of device and its characteristics,potential for overly rapid release of dose, particle size distribution considerations, where applicable) Process Controls:  Process Controls Standard Operating Procedures Consistency and Accuracy Process stream segregation (don’t mix up products) Line clearance (clean up between manufacturing runs) In-process testing Safety, quality Final Product Testing:  Final Product Testing Is the product appropriate for human use? Safety General Safety Sterility Aerobic and anaerobic bacteria and fungi Mycoplasma Purity Endotoxin Potency (Efficacy) Identity Stability Specifications (acceptable limits):  Specifications (acceptable limits) Purpose: Ensure the safety and consistency of product lots Should be based on experience and may change with new data Should determine the criteria for acceptable product Should agree with current FDA standards Manufacturing Oversight:  Manufacturing Oversight QA/QC Quality assurance- Plans and systems designed to provide adequate confidence that an item, process or service will satisfy requirements for quality SOPs, audits, specifications, training, equipment evaluation, etc. Quality controls- the operational techniques and activities used to fulfill requirements for quality perform testing, analyze data, release product, etc. Clinical Protocols:  Clinical Protocols A protocol submitted for review under IND typically will contain at least the following elements: Background information on the product and the investigator and institution’s prior experience (clinical or in animals) in the field.  Goals of the proposed study and a scientific rationale for the selected approach to test the experimental therapy (e.g. using particular immunosuppressive combinations or other adjunct therapies, immunoisolation barriers, etc.). Clinical Protocols (cont.):  Trial design; single or multi-center study, open label, single- or double-blind, single arm or a controlled study, whether subjects are randomized or not to assigned treatments for comparison, etc. Well defined eligibility criteria, appropriate for the phase of development, with meticulous consideration related to the balance of risks and benefits, existence of alternative therapies and other considerations. Specific risk factors need to be taken into consideration that either significantly limit the potential benefit or endanger the subject. Clinical Protocols (cont.) Clinical Protocols (cont.):  Clinical Protocols (cont.) Specific and clear criteria defining the groups of subjects to be enrolled in the study. For each group clear criteria for each and the specific treatment regimen for each should be stated. Adequate safety monitoring and adequate monitoring of the parameters of bioactivity. Appropriate stopping rules should be established. For phase II and III trials additional complexity in trial design and implementation will be needed to ensure that the data produced are of sufficient reliability to be serve as the “substantial evidence” required for market approval, such as pre-specified endpoints and a statistical plan for endpoint analyses in their protocols. Slide34:  THE NUREMBERG CODE The person performing the task is qualified No experiment shall be undertaken where death or disabling injury will likely occur Proper preparation and adequate facilities to protect subjects must be present to prevent further injury Subjects should be allowed to discontinue participation at any time Upon observing the likely risk of injury, disability, or death the researcher should terminate the experiment 1947 Nuremberg Code 1964 Declaration of Helsinki (Revised 1975,1983,1989,1996, 2000) 1966 Dr. Henry Beecher in the NEJM criticized the lack of sincerity in implementing the basic concepts of informed consent and cited 50 episodes of potential “Code” violations which were published in peer-reviewed scientific journals in the U.S. 1966 NIH required establishment of IRBs for institutions receiving $ for medical research. It stipulated membership should include medical, nursing and lay-public and that research protocols should be reviewed & approved prior to conducting experiments 1974 National Research Act: requires IRB review and approval of all research involving human subjects 1981 HHS amended the policy to provide a framework within which IRBs would function Current Expectations are Codified (21 CFR Part 56) Biologics Control Act of 1902 Still True:  Biologics Control Act of 1902 Still True “Although the preventive and curative powers of viruses, serums, toxins, antitoxins, and analogous products has long since been established, certain unfortunate accidents, notably those which recently occurred in St. Louis, Mo., have tended to discredit their use. The extreme value of the preparations in preventing and curing disease renders it of prime importance, therefore, that action be taken to preserve the confidence of the medical profession and of the community generally in them.” “Do not tell people how to do things. Tell them what to do and they will surprise you with their ingenuity.”:  “Do not tell people how to do things. Tell them what to do and they will surprise you with their ingenuity.” -General George S. Patton War As I Knew It [1947] pt. III, ch. 1 “If there is a way to delay an important descision the good bureaucracy, public or private, will find it”:  “If there is a way to delay an important descision the good bureaucracy, public or private, will find it” -Prof. Cyril Northcote Parkinson How Do I submit an IND?:  How Do I submit an IND? ? ? ? X ? Clinic Idea Getting Organized:  Getting Organized Learn about the IND process Gather relevant materials/data Request a Pre-IND meeting Submit the IND to the FDA FDA makes a decision to allow study Follow your protocol Learn about the IND process:  Learn about the IND process CDER has an excellent overview of the IND process on the web at: http://www.fda.gov/cder/regulatory/applications/ind_page_1.htm There is a guidance document describing the content and format for a new IND submission. It can be found at: http://www.fda.gov/cder/guidance/phase1.pdf Learn about regulations relevant to your IND:  Learn about regulations relevant to your IND 21 CFR part 25: Environmental impact considerations 21 CFR parts 210, 211, 225, & 226: Good manufacturing practices for drugs and biologics 21 CFR parts 312 & 314: IND, DMF, and NDA regulations 21 CFR parts 500, 510, 514, 515, & 558: Animal drug regulations 21 CFR parts 600, 601, & 610: Biological product regulations 21 CFR parts 812 & 814: Medical device regulations IND Checklist:  IND Checklist Form 1571:  Form 1571 Definition: A cover sheet providing information about the sponsor & submission contents Required for original submissions Recommended for amendments Instructions for completing the form: http://www.fda.gov/cder/forms/1571-1572-help.html Forms can be found at: http://forms.psc.gov/forms/FDA/fda.html Cross Reference Authorization Letters:  Cross Reference Authorization Letters INDs that are on clinical hold, inactivated, or withdrawn cannot be cross-referenced. IND may be converted to Master File to allow for cross-reference. IND Checklist:  IND Checklist Slide51:  Table of Contents Form FDA 1571 Table of Contents 1 Introductory statement and general investigational plan 3 Investigator’s brochure 10 Protocols 40 Chemistry, manufacturing, and control data 80 Pharmacology and toxicology data 120 Previous human experience 180 Additional information 185 IND Checklist:  IND Checklist Introductory Statement/General Investigational Plan :  Introductory Statement/General Investigational Plan Description of the drug Summary of previous human experience Overall plan for investigating the drug This section should be short (2-3 pages) and give an overview of the developmental plan IND Checklist:  IND Checklist Investigator’s Brochure:  Investigator’s Brochure Required if a commercial sponsor product is providing product to clinical investigators Not required for sponsor-investigators performing a trial at one clinical site IND Checklist:  IND Checklist Protocols:  Protocols Protocol for each planned study including: Statement of objectives and purpose of study Estimated enrollment Inclusion & exclusion criteria Dosing plan (dose, duration, route) Plan for patient monitoring Toxicity based stopping/dose adjustment rules Investigator data (Form FDA 1572) IND Checklist:  IND Checklist Product Information (CMC):  Product Information (CMC) Physical, chemical, and/or biological characteristics Manufacturers Source and method of preparation Removal of toxic reagents Quality controls (e.g., identity, assay, purity, impurities profile) Description of testing and acceptable limits Sterility (e.g., sterilization process, release sterility and endotoxin testing, if applicable) Linkage of pharmacological and/or toxicity batches to clinical trial batches Stability information IND Checklist:  IND Checklist Pharmacology and Toxicology Data:  Pharmacology and Toxicology Data Data for studies demonstrating Safety Efficacy Potential toxicities Optimal dosing Identification and qualifications of study evaluators Statement regarding where and how (GLP) studies were performed IND Checklist:  IND Checklist Previous Human Experience/ Additional Information:  Previous Human Experience/ Additional Information Previous human experience is only required when it is relevant It should be presented as a summary report Additional information may be submitted if the sponsor feels it is necessary Phases of Investigation (21 CFR 312.21):  Phases of Investigation (21 CFR 312.21) Phase I Investigational Studies Designed to evaluate safety and side effects Phase II Investigational Studies Designed to evaluate efficacy and dose ranging Phase III Investigational Studies Expanded study, additional information on efficacy and safety Getting Started:  Getting Started Ask for help from the FDA Request a Pre-IND meeting Pre-IND Meeting:  Pre-IND Meeting Meeting package should include: Pre-clinical data Product manufacturing scheme Data regarding the product characterization/ proposed specifications Proposed Phase I clinical protocol Specific questions/issues Pre-IND Telephone Conference - 1 hour Discussion of specific questions and issues Mechanisms for focusing on unresolved issues Pre-IND Process:  Pre-IND Process Sponsor may request a pre-IND teleconference in writing (FAX ok). Request should include: Description of the product Description of clinical indication and approach Identification of specific issues and questions to be addressed Meeting package due 4 weeks before meeting. Pre-IND Process:  Pre-IND Process Written requests submitted to: Ms. Andrea Wright, Branch Chief Regulatory Management Staff OCTGT/CBER HFM-705 1401 Rockville Pike Rockville, MD 20852 301-827-5101 Phone 301-827-5397 FAX Original Submission:  Original Submission Upon receipt, FDA Issues: Acknowledgement letter IND number IND Application reviewed within 30 days What happens when I submit my IND?:  What happens when I submit my IND? ? ? ? X ? Clinic Idea The Review :  The Review Emphasis of review is on data to support: Product safety and characterization Manufacturing and quality control issues Scientific rationale Sound scientific principles Pre-clinical studies Product development Clinical protocol Risk-based approach:  Risk-based approach Totally novel No data No experience Obvious theoretical risks Much precedent Excellent data Years of experience Risks well understood Stringent Relaxed 21 CFR 312.42(b):  21 CFR 312.42(b) FDA may place a proposed or ongoing Phase 1 investigation on clinical hold if it finds that: (i) Human subjects are or would be exposed to an unreasonable and significant risk of illness or injury The Review Format:  The Review Format We have a Team Approach to IND Review: Product reviewer Pharmacology/Toxicology reviewer Clinical reviewer The Decision:  The Decision We will give you our decision within 30 days (in effect or on clinical hold) We will tell you if there are any required changes (hold) or suggested changes (non-hold) by phone We will also issue a letter You must satisfactorily address hold issues before you can begin IND Status:  IND Status Pending-IND is in initial 30-day review period In Effect-Study may proceed Hold-FDA orders sponsor to delay or suspend a clinical investigation Partial Hold-A delay or suspension of part of the clinical investigation Inactivated-IND is subject to no activity, but may be reactivated Withdrawal-Sponsor requests to end IND, IND cannot be reactivated Terminated-FDA orders sponsor to end all clinical investigation, IND cannot be reactivated Exempt-Study does not have to be conducted under IND Resumption of Clinical Investigations 21 CFR 312.42(e):  Resumption of Clinical Investigations 21 CFR 312.42(e) Types of Responses: Complete & Adequate: Response adequately addresses all of the issues in the hold letter, and the hold may be removed. Complete & Inadequate: Response addresses all of the issues in the hold letter; however, the responses are inadequate, and the hold is continued. Incomplete: Response does not address all of the issues in the hold letter. 30 day clock does not start. Slide79:  What should I do after I send in my IND? ? ? ? X ? Clinic Idea IND Amendments:  IND Amendments Definition: Any document, from the sponsor, in support of their IND Must be submitted in hard copy Triplicate for INDs and IDEs Duplicate for Master Files If electronic submission no hard copies are needed We recommend that a form 1571 be submitted with each amendment Types of Amendments:  Types of Amendments Protocol Amendments New protocol, Protocol changes, New investigator Information Amendments Safety reports Annual reports Annual Reports – 21 CFR 312.33:  Annual Reports – 21 CFR 312.33 Within 60 days of the anniversary date that an IND went into effect, the sponsor must submit a brief report of the progress of the investigation including: Individual study information Summary information Description of the general investigational plan for the coming year Any revisions to the investigators brochure Any significant protocol modifications Foreign marketing developments Any outstanding business Product Development:  Pre-IND I II III IND Phase Product License Phase IV Product Development Phase I: Designed to evaluate safety and side effects Phase II: Designed to evaluate efficacy and dose ranging Phase III: Expanded study, additional information on efficacy and safety Phase IV: Post marketing commitments to monitor safety and efficacy 21 CFR 312.42(b)(2):  21 CFR 312.42(b)(2) FDA may place a proposed or ongoing Phase 2 or 3 investigation on clinical hold if it finds that: (ii) The plan or protocol for the investigation is clearly deficient in design Step Wise Approach:  Step Wise Approach Spirit of cGMP vs total compliance Degree of SOP preparation Degree of Validation Assay Process Cleaning Equipment Degree of Product Characterization Degree of QC/QA Slide86:  Regulations for manufacturers of Foods, Drugs, Cosmetics to assure the purity, quality and consistency of their product. 21 CFR 211 Regulations to help assure the scientific quality, integrity and ethics of clinical studies conducted on humans. ICH Document E6 Regulations to help assure the scientific quality and integrity of data from nonclinical (animal) laboratory studies. 21 CFR 58 Good Laboratory Practices (GLPs) Good Manufacturing Practices (GMPs) Good Clinical Practices (GCPs) Elements of cGMP:  Elements of cGMP Facility designed to control operations Adequate documentation/records Production and process controls Quality control/assurance Validation Equipment calibrated/qualified Personnel training & certification Environmental monitoring IND: Principles:  IND: Principles Assure safety and rights of subjects Encourage innovation by allowing maximum flexibility in early research Assure quality of study design (Phases 2 and 3) to permit evaluation of effectiveness and safety Maximize efficiency of BLA review by promoting early consultation An Example:  An Example Dendritic cell vaccine for the treatment of cancer Slide90:  ? Contact Information:  Contact Information CBER Office of Communication, Training & Manufacturers Assistance Manufacturers Assistance and Technical Training Branch Telephone: 800-835-4709 or 301-827-1800 E-mail: matt@cber.fda.gov Internet: http://www.fda.gov/cber/manufacturer.htm CDER Office of Training and Communications Division of Communications Management Drug Information Branch 5600 Fishers Lane Rockville, MD 20858 Telephone: 301-827-4573 Fax: 301-827-4577 Fax-on-Demand (FOD): 800-342-2722 or 301-827-0577 E-mail: druginfo@cder.fda.gov Internet: http://www.fda.gov/cder/guidance.htm Where do I send my IND?:  Where do I send my IND? CBER For a Biologic: Food and Drug Administration Center for Biologics Evaluation and Research, HFM-99, Rm 200N 1401 Rockville Pike Rockville, MD 20852-1448 CDER For a Drug: Food and Drug Administration Center for Drug Evaluation and Research Central Document Room 12229 Wilkins Ave. Rockville, MD 20852-1833 Where can I find more specific information?:  Where can I find more specific information? Guidance for Industry: Guidance for Human Somatic Cell Therapy and Gene Therapy, March 1998. PTC in the Characterization of Cell Lines to Produce Biologicals, CBER, FDA, 1993. Proposed Approach to Regulation of Cellular and Tissue-Based Products, February 1997. ICH Harmonized Tripartite Guideline: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin http://www.fda.gov/cber/publications.htm

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