Chapter 17

For BA or BE studies conducted without an IND, the person conducting the studying including any CRO is required to notify the FDA of any serious adverse event within

15 days

Periodic Reporting

Sponsor is required to submit the following periodic reports to the FDA for the first three years following approval on a quartley basis. Unless otherwise requested by FDA, after three years, the sponsor shall submit the periodic ADE reports annual intervals

who and when are the adverse events (domestic and foreign submitted to the FDA/Medwatch

submit within 15 calendar days. use form 3500A

Guidance for Industry: Format and Content of Proposed Risk Evaluation and Mitigation Strategies- helps on

the format and content of the a proposed REMS, including REMS supporting documentation the content of assessments and proposed modifications of approved REMS what identifiers to use on REMS documents how to communicate with the FDA about REMS

What happens if anything in the 4 elements is missing

then don't submit, it will be sent back

goal of FAERS

to improve public health by providing the best available tools for storing and analyzing safety data and reports

How does the sponsor notify the FDA

via fax/phone and this is directed to CDEr or CBER

Adverse Drug Experience

1. an adverse event occurring in the course of the use of a drug product in a professional practice 2. an adverse event occurring from drug overdose whether accidental or intentional 3. an adverse event occurring from drug abuse 4. an adverse event occurring from drug withdrawal 5. any failure of expected pharmacological action

21 CFR 803 Medical device reporting

1. device user facilities must report deaths and serious injuries that a device has or may have caused or contributed to, establish and maintain adverse event files and submit summary annual reports 2. manufacturers or importers must report deaths and serious injuries their device has or may have caused or contributed to. In addition they must report certain device malfunctions. They also must establish and maintain adverse event filed. In addition manufacturers must submit specified follow up information 3. medical device distributor must maintain records of incident but are not required to file these incidents.

Due to the New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence studies in Humans the following information, not previously required by FDA, now must be reported to the agency within 15 days of the sponsors becoming aware?

1. findings from clinical or epidemiological studies that suggests a significant risk to study participants 2. serious suspected adverse reactions that occur at a rate higher than expected 3. serious adverse events from bioavailability studies and bioequivalence studies conducted without an IND

Which 4 elements should you have knowledge about

1. identifiable patients- NOT by name and address- assign unique code to each pt 2. identifiable reporter 3. an adverse experience or fatal outcome believed to be due to the suspect drug or biologic product

Under 21 CFR 314.80 the sponsor is required to review ADE information obtained from all potential sources, including

1. marketing experience 2. scientific literature 3. unpublished reports 4. post marketing and clinical investigations 5. post marketing epidemiological or surveillance studies

The post marketing period report should be divided into four sections in the order described

1. section I; narrative summary and analysis: a narrative summary and analysis of the information in the Post marketing period report and analysis of the 15 day reports ( serious unexpected adverse experience) submitted during the reporting period must be provided Section II; narrative discussion of action take- a narrative discussion of the action take must be provided, included any labeling changes and studies initiated. Section III: index line listing- an index line listing of form FDA 3500A or Vaccine Adverse Event Reporting Systen VAERs Section IV: form FDA 3500A or VAERS from must be provided for adverse events that have not already been submitted as 15 day alerts for experiences that occurred in the US

Quarterly reports are required to be filed within ____ days of the close of the quarter

30

Which form do you use?

3500A

A non sponsor should submit report to sponsor within how many days

5 days

annual reports are required to be submitted within _____ days of the close of year

60

And if the event is fatal or life threatening

7 days

when the sponsor finds out about the fatal or life threatening event- they have how many days

7 days from the day they found out

Adverse Event

An adverse event is any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug related

Unexpected Adverse Event or Unexpected Suspected Adverse Reaction

An adverse event or suspected adverse reaction is considered unexpected if it not listed in the Investigator Brochure 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.

What divisions does the Office of Surveillance and Epidemiology consists of?

Division of Drug Risk Evaluation (DDRE) Division of Medication Errors and Technical Supports (DMETS) Division of Surveillance Research and Communication Support SRCS

then the sponsor must contact who after they are informed?

FDA

FAERS

FDA adverse event reporting system

how are labeled

IND safety report

if an adverse event is serious, unexpected and associated with the use of the drug it must be submitted both as

IND safety report and 15 day alert Report

Who do they submit this information to for the BE and BA studies

OGD in CDER

DMET

The DMETS staff primarily provide pre marketing reviews for all proprietary names, labels and labeling in CDER to reduce the medication error potential of a proposed product. DMETS also provides post marketing review and analysis of all medication errors CDER recieves

DSNDCA

The Dietary Supplement and Non Prescription Drug Consumer Protection Act- signed in to law 2006- this amended the FD&C act to add safety reporting requirements for non prescription drug products that are marketed without an approved application.

Examples of the above?

allergic bronchospams requiring intensive treatment in an emergency room or at the home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of a drug dependency or drug abuse.

disability

an adverse event that results in a substantial disruption of a persons ability to conduct normal life functions

serious adverse drug experience

any adverse drug experience occurring at any dose that results in any of the following outcomes 1. death 2. life threatening adverse experience 3. in hospitalization 4. persistent or significant disability/incapacity 5. cogenital/anomaly

life threatening adverse experience

any adverse drug experience that places the patients, in the view of the initial reporter, at immediate risk of death from the adverse drug experience as it occurred, i.e it does not include an adverse drug experience that had it occurred in a more severe form, might have caused death

The sponsor is responsible for notifying the FDA and all participating investigators in a written IND safety report of

any adverse experience associated with the use of the drug that is both serious and unexpected OR any findings from tests in laboratory animals that suggests a significant risk for human subjects, including reports of mutagenicty, teratogenicity or carcinogenicity.

who is held to these ADE reporting requirements

any company listed on the approved product labeling

risk management is identified as

assessing products benefit-risk balance developing and implementing tools to minimize a products risk while preserving its benefits evaluating tool effectiveness and reassessing the benefit risk balance making adjustments as appropriate to the risk minimization tools to further improve the benefit: risk balance

US medical device Post marketing surveillance system depends on

medical device reporting medical product safety network post approval studies post marketing surveillance studies FDA discretionary studies other tools

When an adverse event is encountered by the investigator during clinical trials, what should the investigator do?

contact the sponsor with the information ASAP

Suspected Adverse Reaction

is any adverse event for which there is a reasonable possibility that the drug caused the adverse ever. For the purpose of the iND application safety reporting, reasonable possibility means there is evidence to suggest a causal relationship between the drug and the adverse event.

21 CFR 806

medical devices, reports of corrections and removals

when does the first quarter begin

date of approval of the application

What else is the sponsor required to do?

develop written procedures for the surveillance, receipt, evaluation and reporting of post approval ADE reports to FDA and maintain records of all ADEs known to the applicant for a period of ten years, including raw data and any correspondence relating to ADEs

Section 921 of the FDAAA

directs FDA to conduct regular biweekly screening of the Adverse Event Reporting system AERS database and post a quartlery report of new safety information or potential signal of a serious risk identified in the last quarter.

when a potential serious risk signal is identified from FAERS data what happens

it is entered as a safety issue into the CDERS document archiving reporting and regulatory tracking system DARRTS or into CBERS SST

DDRE

evaluator staff- primary role is to detect and assess safety signals for all marketed drug products, they work closely with medical reviewers in the Office of New drugs so potential safety signals are placed in the context of existing preclinical, clinical or pharmacologic knowledge of the drug in question. The DDRE staff review study protocols that are required of manufacturers as Phase 4 commitments. They evaluate various post marketing surveillance tools that may be incorporated into risk management strategies such as patient registries and restricted distribution system.

SRCS staff

handle data resources risk communication and outcomes and effectiveness research components of drug safety risk management programs. This division oversees Med WATCH risk communication research and activities such as medication guise, patient package inserts and pharmacy information surveys and international regulatory liaison activities for all drug and biologic post marketing safety issues. SRCS also manages the expansion in the use and number of safety and epidemiological data resources.

Guidance: drug safety information

help FDA rapidly collect and analyze information

when is a adverse event or suspected adverse reaction considered serious

if in the view of either the investigator or sponsor ir results in any of the following outcomes 1. death 2. a life threatening adverse event 3. in patient hospitalization 4. prolongation of existing hospitalization 5. persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 6. congenital anomaly/birth defect.

when is an adverse event 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 adverse event or suspected adverse reaction that had it occurred in a more severe form, might have caused death

when are the medical events considered serious?

important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based on the 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 definitions

Mini Senitinel

is a pilot project sponsored by FDA to create an active surveillance system, The Sentinel System to monitor the safety of the FDA regulated medical products.

How should the reports from animal or epidemiological studies be submitted

narrative format

The regulation require a post marketing periodic report roc ontain

narrative summary and analysis of the information in the report and an analysis of the 15 day alert reports submitted during the reporting interval a form FDA 3500A for each spontaneously reported adverse experience occurring in the US that was not reported in a 15 day alert report a history of actions taken since the last report because of adverse experiences

If the applicant wants to submit a different format than the one described above what do they do?

obtain waiver, and then submit either PSUR or PBRER, need waiver for each

how can the ADE reports be submitted?

paper or electronically

21 CFR 822

post market surveillance