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 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.
4. 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
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 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.
9. 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.
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 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
12. 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.
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 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.
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
• 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.
18. 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.
19. 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
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
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.
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.
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)
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.
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
Now we are at the who – Who is involved?
These are the large registrational studies