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

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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.

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.

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.

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 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.

FDA role in IND 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

Pre-IND Meeting and consultation 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.

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.

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.

Life cycle of an 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.

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.

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