Update: 21 CFR PART 312 FDA Safety Reporting Requirements for INDs

Elizabeth Ness, RN, MS Director, Staff Development Office of the Clinical Director

Center for Cancer Research, NCI

Overview

• Final rule published 9/29/10– Amended IND safety reporting requirements under 21 CFR Part

312• Goals:

– improve the overall quality of safety reporting– strengthen FDA’s ability to review critical safety information– improve safety monitoring of human drug and biological products,

and harmonize safety reporting internationally• Effective date: March 28, 2011• IND Safety Reports (312.32 )• Investigator Reports (312.64 )

IND Safety Reports Part 312.32

• Definitions (a)• Review of Safety Information (b)• IND Safety Reports (c)• Follow-up (d)• Disclaimer (e)

Definitions (a)

OLD• Associated with the use of

the drug• Disability• Life-threatening adverse

drug experience • Serious adverse drug

experience • Unexpected adverse drug

experience

NEW• Adverse Event• Suspected adverse

reaction • Serious adverse event or

serious suspected adverse reaction

• Life-threatening adverse event or life-threatening suspected adverse reaction

• Unexpected adverse event or unexpected suspected adverse reaction

New: Adverse Event (AE)

• Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related

ICH GCP• An AE is any untoward medical occurrence in a patient or

clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal investigational) product, whether or not related to the medicinal (investigational) product

New: Suspected Adverse Reaction (SAR)

• Any AE for which there is a reasonable possibility that the drug caused the AE

• Reasonable possibility means there is evidence to suggest a causal relationship between the drug and AE

Serious: Changes

• Renamed “Serious adverse drug experience “ to “Serious adverse event or serious suspected adverse reaction “

• Switched “adverse drug experience” for “adverse event or suspected adverse reaction”

• Added assessment of seriousness can be made by Investigator or Sponsor

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

…Serious AE or SAR

– Important medical events 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

Life threatening: Changes

• Renamed “Life-threatening adverse drug experience ” to “Life-threatening adverse event or life- threatening suspected adverse reaction ”

• Switched “adverse drug experience” for “adverse event or suspected adverse reaction”

• Assessment can be made by Sponsor, not just Investigator

Life-threatening AE or Life-threatening SAR

• AE or SAR is considered “life-threatening” if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death.

• It does not include an AE or SAR that, had it occurred in a more severe form, might have caused death.

Unexpected: Changes

• Renamed “Unexpected adverse drug experience ” to “Unexpected adverse event or unexpected suspected adverse reaction ”

• Switched “adverse drug experience” for “adverse event or suspected adverse reaction”

• Added reference for AEs or SARs that are mentioned in IB as occurring with class of drug but not particular agent

Unexpected Adverse Event or Unexpected Suspected Adverse Reaction…

• 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 investigator brochure 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. – hepatic necrosis would be unexpected (by virtue of

greater severity) if the IB referred only to elevated hepatic enzymes or hepatitis

– cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the IB listed only cerebral vascular accidents.

…Unexpected Adverse Event or Unexpected Suspected Adverse Reaction

• 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

Review of Safety Information (b)

The sponsor shall promptly review all information relevant to the safety of the drug obtained or otherwise received by the sponsor from any source, foreign or domestic, including information derived from any clinical or epidemiological investigations, animal investigations, commercial marketing experience, reports in the scientific literature, and unpublished scientific papers, as well as reports from foreign regulatory authorities that have not already been previously reported to the agency by the sponsor.

IND Safety Reports (c)…

• Sponsor’s responsibility to notify FDA and all participating investigators of potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later than 15 calendar days – all investigators to whom the sponsor is providing drug

under its INDs or under any investigator's IND

…IND Safety Reports (c)

• Sponsor must:– Identify all IND safety reports previously submitted to

FDA concerning a similar SAR– Analyze the significance of the SAR in light of

previous, similar reports or any other relevant information

What Constitutes an IND Safety Report?

• Serious and unexpected suspected adverse reaction • Findings from other studies (new)• Findings from animal or in vitro testing • Increased rate of occurrence of serious suspected

adverse reactions (new)

Serious and unexpected suspected adverse reaction

• Sponsor must report any SAR that is both serious + unexpected

• Also report an AE as a SAR only if there is evidence to suggest a causal relationship between the drug and the AE, such as:– Single occurrence of an event that is uncommon and known to be

strongly associated with drug exposure – 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

– 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

• known consequences of the underlying disease or condition under investigation

• other events that commonly occur in the study population independent of drug therapy

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

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.

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.

Formats of Submission of IND Safety Report

• 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• Electronic format that FDA can process, review, and

archive– Safety Reporting Portal (SRP) – pending for drugs/biologics

Submission of IND Safety Report

• Identify the report’s content (i.e., “IND Safety Report”)

• Transmit to review division in CDER or CBER has responsibility for review of the IND

• 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

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

FDA Expedited Reporting

• 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)

OLD

• 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

NEW

Follow-up (d)

• Renamed from ‘adverse drug experience’ to ‘AE’ or ‘SAR’

• The sponsor must promptly investigate all safety information it receives. Relevant follow-up information to an IND safety report must be submitted as soon as the information is available and must be identified (i.e., “Follow-up IND Safety Report”). If the results of a sponsor's investigation show that an adverse event not initially determined to be reportable under paragraph (c) of this section is so reportable, the sponsor must report such suspected adverse reaction in an IND safety report as soon as possible, but in no case later than 15 calendar days after the determination is made.

Disclaimer (e)

• Changed from ‘Adverse experience’ to by ‘AE’

• A safety report or other information submitted by a sponsor under this part (and any release by FDA of that report or information) does not necessarily reflect a conclusion by the sponsor or FDA that the report or information constitutes an admission that the drug caused or contributed to an adverse event. A sponsor need not admit, and may deny, that the report or information submitted by the sponsor constitutes an admission that the drug caused or contributed to an adverse event.

Investigator Reports 312.64

• Investigator to sponsor• Types of reports

– Progress reports: investigator to sponsor– Safety reports - updated– Final report– Financial disclosure

Investigator Reports: Safety Reports (b) OLD

An investigator shall 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.

Investigator Reports: Safety Reports (b) NEW

• 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 nonserious adverse events and report them to the sponsor according to the timetable for reporting specified in the protocol.

Summary

• Changes in safety reporting to the FDA– IND Safety Reports (312.32 )– Investigator Reports (312.64 )

• Effective March 28, 2011• New definitions

– Adverse Event (AE)– Suspected Adverse Reaction (SAR)

• New criteria added to report IND Safety Reporting– Finding from other studies– Increased rate of occurrence of serious SARs