1. Update: 21 CFR PART 312 FDA Safety Reporting Requirements for INDs
Thank IACRN for the opportunity to……
I don't think that anyone would disagree that nursing can give critical input into what documentation should be included in the EMR. However, as nurses involved in clinical research we have additional data requirements to address in the development of a EMR. Today I’m not going to go into the benefits and challenges of EMRs but rather will highlight the benefits and challenges of the EMR in clinical research and the role the clinical research nurse plays.

2. Overview Final rule published 9/29/10
Amended IND safety reporting requirements under 21 CFR Part 312
Codifies FDA’s expectations for timely review, evaluation and submission of relevant and useful safety information
Implements internationally harmonized definitions and reporting standards, to the extent possible
Clarifies confusing terminology in existing regulations
Goals:
improve the overall quality of safety reporting
strengthen FDA’s ability to review critical safety information
improve the utility of premarket safety reports which enhances human subject protection
Effective date: March 28, 2011
IND Safety Reports ( )
Investigator Reports ( )

3. The Universe of Adverse Events
Suspected
Adverse Reactions
Adverse
Reactions

4. Change in Definitions Added: Adverse Events (AE)
Removed: Associated with the use of the drug
Added: Suspected Adverse Reaction (SAR)

5. New Definitions Adverse event Suspected adverse reaction
any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related
Suspected adverse reaction
Any adverse event for which there is a reasonable possibility that the drug caused the adverse event
“Reasonable possibility” means there is evidence to suggest a causal relationship between the drug and adverse event
Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug

6. Examples of Evidence
Single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome)
One or more occurrences of an event that is not commonly associated with drug exposure but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture)
An aggregate analysis of specific events observed in a clinical trial that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group

7. Changes: Serious Adverse Events
Clarified definition of disability when defining Serious Adverse Event (SAE)
persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
Added causality assessment can be made by Investigator or Sponsor

8. Causality Assessment for Serious Adverse Events
Investigator provides causality assessment to sponsor
Sponsor considers investigator’s assessment in making the sponsor’s causality assessment
Sponsor is responsible for determining causality (i.e., that there is a reasonable possibility that the drug caused the adverse event) for reporting purposes for both individual and aggregate cases
may not agree with investigator’s assessment

9. Serious AE or SAR…
AE or SAR is considered “serious” if, in the view of either the investigator or sponsor, it results in any of the following outcomes:
Death
life-threatening adverse event
inpatient hospitalization or prolongation of existing hospitalization
persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
congenital anomaly/birth defect

10. …Serious AE or SAR
Important medical events (IME) that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
allergic bronchospasm requiring intensive treatment in an emergency room or at home
blood dyscrasias or convulsions that do not result in inpatient hospitalization
development of drug dependency or drug abuse

11. Unexpected Definition
Added reference for AEs or SARs that are mentioned in Investigator’s Brochure (IB) as occurring with class of drug but not particular agent
First in human trials events are always unexpected even if seen in animals

12. Unexpected AE or SAR…
AE or SAR is considered “unexpected” if it is not listed in the IB or is not listed at the specificity or severity that has been observed; or, if an IB is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended.
Unexpected,” also refers to AEs or SARs mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation

13. IND Safety Reports Expedited reporting to the FDA
Sponsor’s responsibility to notify FDA and all participating investigators of potential serious risks, from clinical trials or any other source
All investigators to whom the sponsor is providing drug under its INDs or under any investigator's IND

14. What Constitutes an IND Safety Report?
Serious and unexpected suspected adverse reaction
Findings from animal or in vitro testing
Findings from other studies (new)
Increased rate of occurrence of serious suspected adverse reactions (new)

15. Serious and Unexpected Suspected Adverse Reaction
Any suspected adverse reaction that is both serious and unexpected
Report only if there is evidence to suggest a causal relationship between the drug and the adverse event

16. Findings From Animal or In Vitro Testing
Sponsor must report any findings from animal or in vitro testing, whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug, such as reports of mutagenicity, teratogenicity, or carcinogenicity, or reports of significant organ toxicity at or near the expected human exposure.
Ordinarily, any such findings would result in a safety-related change in the protocol, informed consent, investigator brochure (excluding routine updates of these documents), or other aspects of the overall conduct of the clinical investigation.

17. Findings From Other Studies (NEW)
Sponsor must also report expeditiously any findings from clinical, epidemiological, or pooled analysis of multiple studies or any findings from animal or in vitro testing that suggest a significant risk in humans exposed to the drug
Reports are required for studies from any source, regardless of whether they are conducted under the IND or by the sponsor

18. Increased Occurrence of Serious SARs (NEW)
Sponsor must report any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.

19. Unexpected Fatal or Life-Threatening SAR Reports
Sponsor must notify FDA of any unexpected fatal or life-threatening SAR as soon as possible but in no case later than 7 calendar days after the sponsor's initial receipt of the information
Additional Safety reporting to FDA – own category not an IND Safety report, but safety reporting required of an IND

20. FDA Expedited Reporting Timeframes
IND safety reports (15-day)
Report within 15 calendar days after the sponsor determines that the suspected adverse reaction or other information qualifies for reporting
If FDA requests any additional data or information - submit to FDA as soon as possible, but no later than 15 calendar days after receiving the request
Unexpected fatal or life-threatening suspected adverse reactions (7-day)
Report within 7 calendar days after sponsor’s initial receipt of the information
Follow-up reports
Upon request from FDA, sponsor must submit any additional data or information that the agency deems necessary, as soon as possible, but in no case later than 15 calendar days after receiving the request

21. FDA Expedited Reporting
OLD
NEW
7-day report
unexpected & fatal or life-threatening experience associated with the use of the investigational agent
7-day report
unexpected fatal or life-threatening SAR
15-day report
adverse experience(s) associated with use of an IND agent that is both serious and unexpected
any findings from tests in lab animals that suggest a significant risk for human subjects (teratogenicity, mutagenicity, or carcinogenicity)
15-day report
serious and unexpected suspected adverse reaction
findings from animal or in vitro testing
findings from other studies
increased rate of occurrence of serious suspected adverse reactions

22. FDA Expedited Safety Reporting Formats
Narrative
overall findings or pooled analyses from published and unpublished in vitro, animal, epidemiological, or clinical studies
FDA Form 3500a
Council for International Organizations of Medical Sciences (CIOMS) I Form which is used with international studies
Electronic format that FDA can process, review, and archive
Safety Reporting Portal (SRP) – pending for drugs/biologics

23. Investigator Reports Part 312.64
Investigator to sponsor reporting
Types of reports
Progress reports: investigator to sponsor
Safety reports - updated
Final report
Financial disclosure

24. Investigator Reports: Safety Reports
An investigator must immediately report to the sponsor any serious adverse event, whether or not considered drug related, including those listed in the protocol or investigator brochure and must include an assessment of whether there is a reasonable possibility that the drug caused the event.
Study endpoints that are serious adverse events (e.g., all-cause mortality) must be reported in accordance with the protocol unless there is evidence suggesting a causal relationship between the drug and the event (e.g., death from anaphylaxis). In that case, the investigator must immediately report the event to the sponsor.
The investigator must record non-serious adverse events and report them to the sponsor according to the timetable for reporting specified in the protocol.

25. Investigator Reporting (§312.64(b))
Old
Must promptly report to the sponsor any adverse effect that may reasonably be regarded as caused by, or probably caused by the drug
If the adverse effect is alarming, the investigator shall report the adverse effect immediately
New
Must immediately report any serious adverse event to the sponsor, including those listed in the IB or protocol (except study endpoints)
Include an assessment of whether there is a reasonable possibility that the drug caused the serious adverse event
Nonserious adverse events are recorded and reported to sponsor according to protocol

26. Draft Guidance Topics
Provides examples and rationale for new definitions and requirements
Discusses a systematic approach for safety surveillance
Provides advice on other safety reporting issues that have generated questions from sponsors and investigators (e.g., Investigator brochure, unblinding)

27. Looking Forward Implementation: Expected outcome: To achieve this:
Effective March 28, 2011
Enforcement discretion through September 28, 2011
Expected outcome:
Investigators (and FDA) should receive fewer individual reports, but reports should be more complete and meaningful
To achieve this:
Protocols may need to be more specific
Sponsor will have more responsibility for aggregation and analysis of adverse events

28. Resources FDA Website:
Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans
Includes:
Guidance for Industry and Investigators: Enforcement of Safety Reporting Requirements for INDs and BA/BE Studies
DRAFT : Guidance for Industry and Investigators - Safety Reporting Requirements for INDs and BA/BE Studies (September 2010):
Provides examples and rationale for new definitions and requirements
Discusses a systematic approach for safety surveillance
Provides advice on other safety reporting issues that have generated questions from sponsors and investigators (e.g., Investigator brochure, unblinding)