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IND Application WJ 10Aug14 Final
The document discusses the investigational new drug (IND) application process. It provides an overview of the types of INDs, the roles of sponsors and investigators in clinical trials, and the necessary application materials for FDA review. It also describes the IND review process, including pre-IND meetings, submission requirements, maintenance responsibilities, and ways an IND can conclude. The key message is that safety is the primary focus of the IND process.
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IND Application WJ 10Aug14 Final
- 1. William Jackson, Pharm.D.,RPh Bristol-Myers Squibb Oncology Medical Affairs Fellow 8/14/2014 Investigational New Drug (IND) Application The following presentation represents my personal understanding and opinions. It does not represent or reflect the opinions of my partner company.
- 2. Cautionary tale ofproper pre-clinical testing and necessity for strong pre-IND reviews TGN1412 - Novel anti-CD28 monoclonal antibody that directly stimulates T-cells - On March 13, 2006, eight volunteers were put into a phase 1 study where six of the participants received investigational drug1 - All six patients had a systemic inflammatory response (SIRS) resulting in transfer to an intensive care unit1 - Two patients experienced cardiovascular shock and required intensive organ support for 8 to 16 days1 - Pre-clinical data was inappropriately assessed in mice models2 1. Ganesh S, Perry M, Ward S, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN142. NEJM. 2006; 355(10):1018-1028. 2. Fleming, N. Study claims to solve drug trial mystery. The Telegraph 2008.
- 3. Jump from scienceto medicine
- 4. Objectives • Define anInvestigational New Drug (IND) application • List the types of INDs • Understand the role of the investigator and the sponsor in various clinical trials settings • Describe the application materials necessary for a proper IND package for FDA review • Describe the IND review process and the various outcomes that may occur after IND review 4
- 5. Investigational New Drug(IND) application What it does 1. Request for FDA authorization to administer an investigational drug to humans 2. Necessary for interstate shipment and administration of any drug that is not an approved1 Regulations involved • Contained in 21CFR Part 312 and 314 • Industry Guidance Documents • There are 3 IND types 1. US Food and Drug Administration. Investigational New Drug (IND) Application. Accessed at: www.fda.gov. Retrieved on August 10, 2014.
- 6. Investigational New Drug(IND) application 1. US Food and Drug Administration. Investigational New Drug (IND) Application. Accessed at: www.fda.gov. Retrieved on August 10, 2014. 2. 21 Code of Federal Regulations 312.
- 7. IND application overview •Electronic common technical document (eCTD)1 – Electronically submit IND • Cover letter and forms 1571 and 15722 • Manufacturing information and supporting data3 • Proposed clinical protocols and investigator information1 • Pre-IND meetings – Opportunity for sponsor to get input on pre-clinical data necessary for approval1 1. Robinson-Kuiperi, C. FDA Considerations for eCTD INDs. November 6, 2008. 2. 21 Code of Federal Regulations 312. 3. The CDER Handbook, March 1998.
- 8. Necessary information forIND • Animal Pharmacology and Toxicology Studies – All preclinical data (pharmacokinetic and pharmacodynamic data) – May include any foreign clinical data – Focus is on safety • Manufacturing Information – Chemical data: composition and stability – Manufacturer and process (quality control process) • Clinical Protocols and Investigator Information – Detailed protocols: ensure minimal unnecessary risk of harm to subjects and information on credentials for investigators 1. 21 Code of Federal Regulations 312. 2. The CDER Handbook, March 1998.
- 9. Forms 1571 and1572 • Form 1571 provides all necessary pre-clinical data and protocol information • Form 1572 is required for primary investigator responsible for each clinical site Above images are screen shots of actual 1572 and 1572 forms. Form 1571 can be obtained at: http://www.fda.gov/downloads/aboutfda/reportsmanualsforms/forms/ucm083533.pdf. and form 1572 can be obtained at: http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM074728.pdf.
- 10. Submission of IND •After the IND is submitted, the sponsor must wait 30 calendar days before starting clinical trials for the FDA to provide a response • The FDA’s main goal is to review for unreasonable risk, and proper preclinical safety studies 1. The Center for Drug Evaluation and Research Handbook, March 1998.
- 11. FDA role inIND process • Focus is ensuring that subjects are exposed to minimal risk in first-in-human studies • Receiving all proper paperwork submitted from the sponsor • Providing approval (no comment) or clinical hold on an IND application • Provide guidance throughout the IND application process
- 12. Pre-IND Meeting andconsultation program • Prior to submission, sponsor can request for guidance from the FDA review divisions on the data necessary to warrant IND submission1,2 • The main goal is to determine what nonclinical pharmacology, toxicology, drug activity, or animal models should be required for an IND application2 • Prior to the Pre-IND meeting, a pre-IND meeting package should be submitted2 1. US Food and Drug Administration. Investigational New Drug (IND) Application. Accessed at: www.fda.gov. Retrieved on August 10, 2014. 2. Skarlatos, SI. Preparing for FDA Pre-IND Meetings and IND Submissions.
- 13. Industry Sponsored Trials •Company is responsible for holding the IND and submitting proper forms to FDA • Company is required to ensure all safety signals are reported by participating sites • Lead investigators at each site will sign form 1572 – They will be responsible for proper protocol adherence at their site – Investigator provides proper educational support and updates on any suspected unexpected serious adverse (SUSAR) events 1. US Food and Drug Administration. Investigational New Drug (IND) Application. Accessed at: www.fda.gov. Retrieved on August 10, 2014. 2. 21 Code of Federal Regulations 312.
- 14. Investigator Sponsored Research •Investigator is responsible for submitting forms 1571 and 1572 • They can cross-reference the company’s IND if the company allows this • Investigator is responsible for submitting all safety events to FDA • Industry may support investigators through this process – Provide guidance when FDA has specific questions about study drug – Provide necessary documents for cross reference letter 1. US Food and Drug Administration. Investigational New Drug (IND) Application. Accessed at: www.fda.gov. Retrieved on August 10, 2014. 2. 21 Code of Federal Regulations 312.
- 15. Life cycle ofan IND application • After the IND is submitted, the sponsor will hear back from the FDA with approval or comments • The IND must be appropriately maintained by sponsor • The IND will eventually end via 3 distinct mechanisms 1. US Food and Drug Administration. Investigational New Drug (IND) Application. Accessed at: www.fda.gov. Retrieved on August 10, 2014. 2. 21 Code of Federal Regulations 312.
- 16. Submission process Clinical Hold •An order by the FDA to the sponsor to delay clinical investigations or halt any ongoing clinical trials1 • Types1,2 – Complete: delay or suspension of all clinical studies – Partial: delay or suspension of only part of the clinical studies The above image was taken from the CDER Handbook.21. 21 Code of Federal Regulations 312. 2. The Center for Drug Evaluation and Research (CDER) Handbook, March 1998.
- 17. IND Maintenance • Allchanges in initial clinical design/package MUST be reported to FDA – Protocol amendments – New investigators • Safety reporting throughout life of IND and all clinical trials • Annual reports of clinical trials under the IND 1. 21 Code of Federal Regulations 312.
- 18. End of anInvestigational New Drug application • Inactive – No subjects are entered into clinical studies for greater than 2 years – IND on clinical hold for greater than 1 year – Can be reactivated after contacting FDA – Will be terminated after 5 years of inactivity • Terminate – Phase 1 data demonstrates unreasonable and significant risk to subjects – IND does not contain enough data to assess safety to subjects – Significant deviations from protocol or manufacturing process – Failure to report safety data • Withdrawal 1. 21 Code of Federal Regulations 312. 2. Frey, Joyce L. Overview of the IND Process.
- 19. Summary • There are3 types of IND submissions (investigator, emergency, treatment) that fall into 2 categories (commercial or research) • The submission process for an IND includes meetings with the FDA and proper completion of necessary forms (1571 and 1572) • Industry, investigators, and the FDA have specific responsibilities during the IND review process prior to phase 1 trials being implemented Key message: Safety is the key element in the investigational new drug application process
- 20. References 1. Ganesh S,Perry M, Ward S, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN142. NEJM 2006. 355;10:1018-1028. 2. Fleming N. Study claims to solve drug trial mystery. The Telegraph. 2008. Accessed at: http://www.telegraph.co.uk/news/uknews/1540591/Study-claims-to-solve-drug-trial-mystery.html. Retrieved on August 10, 2014. 3. US Food and Drug Administration. Investigational New Drug (IND) Application. Accessed at: http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalap plications/investigationalnewdrugindapplication/default.htm. Retrieved on August 10, 2014. 4. 21 Code of Federal Regulations 312. Accessed at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRsearch.cfm?CFRPart=312. Retrieved on August 10, 2014. 5. The CDER Handbook, March 1998 Accessed at: http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM198415.pdf. Retrieved on August 10, 2014. 6. Robinson-Kuiperi C. FDA Considerations for eCTD INDs. November 6, 2008. Accessed at: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/Elec tronicSubmissions/UCM229717.pdf 7. Skarlatos SI. Preparing for FDA Pre-IND Meetings and IND Submissions. March 5, 2013. Accessed at: https://www.nhlbismartt.org/content/webinars/SMARTT_webinar_March_5_2013_final.pdf. Retrieved on August 10, 2014. 8. Frey JL. Overview of the IND Process. March 22-24. Accessed at https://secure.emmes.com/pactweb/system/files/cber101032204jf.pdf. Retrieved on August 10, 2014. 20
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Editor's Notes
- #3 Within 90 min, all 6 pts had SIRS characterized by a rapid induction of proinflammatory cytokines and accompanied by headache, myalgias, nausea, diarrhea, erythema, vasodilatation, and hypotension. Within 12 to 16 hours after infusion, they became critically ill, with pulmonary infiltrates and lung injury, renal failure, and disseminated intravascular coagulation. Severe and unexpected depletion of lymphocytes and monocytes occurred within 24 hours after infusion. All six patients were transferred to the care of the authors at an intensive care unit at a public hospital, where they received intensive cardiopulmonary support (including dialysis), high-dose methylprednisolone, and an anti– interleukin-2 receptor antagonist antibody. Prolonged cardiovascular shock and acute respiratory distress syndrome developed in two patients, who required intensive organ support for 8 and 16 days.
- #4 The IND application represents an important interface is the development of a drug. It is the area where science meets clinical application. Up to this point, only successful use and characterization of a chemical compound in vitro and in animal models has been seen. In a way, it is still science fiction for if it can treat a disease, let alone be used in humans.
- #5 Current Federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines. Because a sponsor will probably want to ship the investigational drug to clinical investigators in many states, it must seek an exemption from that legal requirement. The IND is the means through which the sponsor technically obtains this exemption from the FDA. Today my goal is for you to understand the what (What are we talking about? IND), the who (Who are the important stakeholders? industry, investigators, FDA), and the how (How does the process for IND approval/exemption)
- #6 This is going over the what! During a new drug's early preclinical development, the sponsor's primary goal is to determine if the product is reasonably safe for initial use in humans, and if the compound exhibits pharmacological activity that justifies commercial development. When a product is identified as a viable candidate for further development, the sponsor then focuses on collecting the data and information necessary to establish that the product will not expose humans to unreasonable risks when used in limited, early-stage clinical studies. FDA's role in the development of a new drug begins when the drug's sponsor (usually the manufacturer or potential marketer), having screened the new molecule for pharmacological activity and acute toxicity potential in animals, wants to test its diagnostic or therapeutic potential in humans. At that point, the molecule changes in legal status under the Federal Food, Drug, and Cosmetic Act and becomes a new drug subject to specific requirements of the drug regulatory system.
- #10 http://www.fda.gov/downloads/aboutfda/reportsmanualsforms/forms/ucm083533.pdf
- #13 Elements of Pre-IND Meeting Package 1. Product name and application number (if applicable) 2. Chemical name and structure 3. Proposed indication 4. Dosage form, route of administration and dosing regimen (frequency and duration) 5. Updated list of attendees, affiliations, roles, and titles 6. Background section that includes: Brief history of development program Supporting preclinical safety data Preclinical and clinical strategy 7. Brief statement summarizing purpose of the meeting 8. Proposed agenda 9. List of FINAL questions, grouped by discipline 10. Data to support each question organized by discipline and question CMC Pharmacology/Toxicology Clinical Development Plan
- #14 Now we are at the who – Who is involved? These are the large registrational studies
- #15 These may be non-registrational studies that
- #17 Frey, Joyce L. Overview of the IND Process.
- #18 Center for Drug Evaluation and Research