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.
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William Jackson, Pharm.D., RPhBristol-Myers Squibb
Oncology Medical Affairs Fellow8/14/2014
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.
Cautionary tale of proper 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.
Jump from science to medicine
Objectives
• Define an Investigational 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
Investigational New Drug (IND) application
What it does1. 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.
• 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.
Necessary information for IND
• 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.
Forms 1571 and 1572
• 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.
Submission processClinical 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.
IND Maintenance
• All changes 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.
End of an Investigational 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.
Summary
• There are 3 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
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/approvalapplications/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/ElectronicSubmissions/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.