1 Introduction to Post-marketing Drug Safety Surveillance: Pharmacovigilance in FDA/CDER Sara Camilli, PharmD, BCPS, Safety Evaluator Team Leader Selena Ready, PharmD, CGP, Safety Evaluator Division of Pharmacovigilance Office of Surveillance and Epidemiology Center of Drug Evaluation and Research May 30, 2015
Introduction to Post-marketing Drug Safety …wmshp.org/sg_current_event_content_new/Pharmacovigilance_2015_05.pdf1 Introduction to Post-marketing Drug Safety Surveillance: Pharmacovigilance
Introduction to Post-marketing Drug Safety Surveillance: Pharmacovigilance in FDA/CDER
Sara Camilli, PharmD, BCPS, Safety Evaluator Team Leader Selena Ready, PharmD, CGP, Safety Evaluator Division of Pharmacovigilance Office of Surveillance and Epidemiology Center of Drug Evaluation and Research May 30, 2015
Presenter
Presentation Notes
Thank you, Kara. Welcome and Good afternoon to everyone joining us for today’s webinar. My name is XYZ and I’m excited to present an Introduction to Postmarketing Drug Safety Surveillance. In particular, I will discuss Pharmacovigilance in FDA’s Center for Drug Evaluation & Research (CDER). I’ll start with our objectives… (slide change)
Acronyms
• CDER – Center for Drugs Evaluation & Research
• CFR – Code of Federal Regulations
• DEPI I & II – Division of Epidemiology I & II
• DILIN – Drug-Induced Liver Injury Network
• DMEPA – Division of Medication Error & Prevention Analysis
• DPV I & II – Division of Pharmacovigilance I & II
• DRISK – Division of Risk Management
• DSC – Drug Safety Communication
• EMA – European Medicines Agency
• FDA – Food & Drug Administration
2
Acronyms, cont’d
• FDAAA – Food & Drug Administration Amendment Act
• FAERS – FDA Adverse Events Reporting System
• HCP – Health Care Provider
• MO – Medical Officer • NDA – New Drug
Application • OND – Office of New Drugs
• PMC – Postmarketing Commitment
• PMR – Postmarketing Requirement
• REMS – Risk Evaluation & Mitigation Strategy
• SE – Safety Evaluator • WHO-UMC – World Health
Organization – Uppsala Monitoring Centre
3
4
Objectives
• Define Pharmacovigilance • Describe the Division of Pharmacovigilance’s (DPV’s) key
safety roles in FDA’s Center for Drug Evaluation and Research (CDER).
• Understand components of postmarketing drug safety surveillance.
• Understand regulatory requirements and the role of MedWatch for reporting postmarketing safety information.
• Describe how adverse event reports are collected and analyzed by FDA/CDER/DPV
Presenter
Presentation Notes
By the end of this presentation, participants will be able to……. READ objectives… And hopefully, at the end of this presentation, you’ll realize how important YOU (as healthcare providers) are in Pharmacovigilance.
5
Outline • Pharmacovigilance Background • Postmarketing Surveillance • Spontaneous Adverse Event Reports and the FDA Adverse
Event Reporting System (FAERS) • Signal Detection • Components of a Good Case Report • Case Series Development and Evaluation
Presenter
Presentation Notes
To fulfill these objectives I have organized the talk into the following sections… First I will discuss the FDA and where PV fits into the big picture of drug regulation Next, I will cover Postmarketing Surveillance and Spontaneous Adverse Event Reports and the FDA Adverse Event Reporting System (FAERS) I will then cover Signal Detection And finally I will detail Components of a Good Case Report and Case Series Development and Evaluation
6
Office of Regulatory Affairs (ORA)
Center for Food Safety & Applied Nutrition (CFSAN)
Center for Drug Evaluation & Research (CDER)
Center for Biologics Evaluation & Research (CBER)
Center for Devices & Radiological Health (CDRH)
Center for Veterinary Medicine (CVM)
Center for Tobacco Products (CTP)
Presenter
Presentation Notes
This slide briefly reviews FDA’s overall organizational structure and the 7 main centers that carry out the FDA’s public heath mission, which are divided by product type. This includes the centers for food, veterinary medicine, medical devices, biologic products, drugs, tobacco, and regulatory affairs. We love acronyms at FDA, and I included the acronyms for each center. The talk today will focus on drug safety activities within the Center of Drug Evaluation and Research or CDER (animation).
7
Office of Surveillance & Epidemiology
Office of Surveillance
& Epidemiology
Office of
Pharmacovigilance & Epidemiology
Office of Medication Error Prevention & Risk
Management
Division of
Medication Error Prevention &
Analysis (DMEPA)
Division of Risk
Management (DRISK)
Division of
Pharmacovigilance I and II
(DPV I and II)
Division of
Epidemiology I and II
(DEPI I and II)
Presenter
Presentation Notes
Looking closer at CDER, the drug safety activities and surveillance discussed today take place in CDER’s Office of Surveillance and Epidemiology or OSE. This slide displays the structure of OSE, and the main divisions and disciplines that work to fulfill our drug safety missions. In the bottom row, the Divisions of Pharmacovigilance is highlighted; Other divisions include epidemiology, medication error prevention and analysis, and risk management.
8
The science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems.
* The Importance of Pharmacovigilance, World Health Organization 2002
Pharmacovigilance
Presenter
Presentation Notes
What is Pharmacovigilance? Pharmacovigilance is defined by the World Health Organization as the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems. Examples of other drug-related problems include: Wrong dose Drug interactions Risk assessment Name confusion, labeling
9
Divisions of Pharmacovigilance • Evaluate the safety of drug and therapeutic biologic
products • Advance public health by detecting and analyzing safety
signals from all available data sources, utilizing evidence-based methods
• Recommend appropriate regulatory actions, including labeling changes, Risk Evaluation and Mitigation Strategies (REMS), etc.
• Communicate relevant safety information
Presenter
Presentation Notes
Based on the Pharmacovigilance definition and our placement in the Office of Surveillance and Epidemiology this slide details the major responsibilities of the Division of Pharmacovigilance, which are, -Evaluating the safety of drug and therapeutic biologic products -Advancing public health by detecting and analyzing safety signals, utilizing evidence-based methods -Recommending appropriate regulatory actions, including labeling changes, Risk Evaluation and Mitigation Strategies (REMS), or other necessary means. AND finally Communicating relevant safety information we will go into detail on each of these aspects.
10
Safety Evaluators (SEs) • 10 teams of SEs
– Majority clinical pharmacists – Provide critical analysis of sources of postmarketing data to
identify and evaluate safety signals
• Team coverage aligned with the Office of New Drugs (OND) review divisions’ therapeutic areas
– ~ 4-7 SEs per team (including Team Leader) – Each SE covers assigned product group(s) aligned with therapeutic
area
Presenter
Presentation Notes
The Pharmacovigilance activities are carried out by safety evaluators (or SEs) divided into 10 teams. SEs are typically clinical pharmacists. They provide critical analyses of sources of postmarketing data to identify and evaluate safety signals. Team coverage is based on relevant clinical therapeutics area and is aligned with the Office of New Drugs in CDER, which is also divided by therapeutic area. There are approximately 4-7 SEs on each team, and each SE has particular product assignments in the respective clinical area. For example, my team covers metabolic and endocrine products and is aligned with the Division of Metabolic and Endocrine Products in the Office of New Drugs.
11
Medical Officers (MOs) • Provide clinical expertise in various therapeutic areas such
as dermatology, oncology, rheumatology, etc. • Collaborate with DPV teams on safety evaluation • Collaborate with Office of New Drugs (OND) on safety
evaluation
Presenter
Presentation Notes
In addition to the Safety Evaluators, the Divisions of Pharmacovigilance have Medical officers who provide clinical expertise in various therapeutic areas such as dermatology, hematology, oncology, rheumatology, and geriatrics. These Medical Officers collaborate with Pharmacovigilance teams and the Office of New Drugs (OND) on safety evaluation BACKUP Dermatology Epidemiology Gastroenterology Geriatrics Hematology/Oncology Infection Disease Internal Medicine Pathology Pediatrics Pulmonary Rheumatology
12
Postmarketing Surveillance
Presenter
Presentation Notes
Now, I will discuss the science and principles of post marketing surveillance/
13
Challenge Question #1
True or False Safety data is only collected during the later phases of
the clinical development program for a medical product.
Presenter
Presentation Notes
This brings us to our first challenge question. True or False, Safety data is only collected during the later phases of the clinical development program for a medical product. You can answer this question by selecting the appropriate radio button next to each answer choice. For those who answered False you are correct. Safety data collection is NOT limited to the later phases of the clinical development program. Answer: False
14
Phase 1
Safety &
Dosage
Phase 2
Safety &
Efficacy
Phase 3
Safety &
Efficacy
APP R OVA L
Post- Marketing
Safety
Surveillance
Pre-clinical
Safety
& Biological
Activity
Safety Concerns
Strategies and Actions to Minimize Risk
Safety in the Lifecycle of FDA-regulated Products
Presenter
Presentation Notes
Before we discuss postmarketing safety surveillance we need to discuss pre-marketing safety and safety in the overall life-cycle of FDA-regulated drug products. Many of you may have seen this graphic before. Not surprisingly, safety is addressed in all aspects of the product lifecycle. Prior to drug approval, safety is evaluated throughout the Phase 1 to Phase 3 clinical trials in conjunction with the dosage and efficacy evaluation. Following drug approval, safety surveillance continues in the postmarketing setting, with a variety of data sources that I will soon discuss. As the bottom region of this slide emphasizes, a critical part of the overall safety evaluation, whether prior to or following product approval, is the implementation of strategies and actions to minimize the risk of these identified safety concerns. In the next few slides, I will go over some of the differences between premarketing and postmarketing safety information.
15
Limitations of Premarketing Clinical Trials
• Size of the patient population studied • Narrow population - often not providing sufficient data on
special groups • Narrow indications studied • Short duration
Presenter
Presentation Notes
Although premarketing clinical trials are the gold standard to determine safety and efficacy at the time of drug approval, many limitations exist. First, the Size of the patient population studied is small and only fairly common adverse events will be captured. For example drug-induced liver injury is a very serious reaction, but typically rare, thus if an event occurs in every 10,000 patients, trials (with even a few thousand patients) are too small to identify this risk. Also, a narrow patient population is usually included, thus if certain drug interactions or adverse events are more common in the elderly, they will not be captured in clinical trials since often times this population is excluded. Also children and pregnant women are rarely included in these trials. Next, narrow indications are typically studied and trials will often exclude patients with many comorbid conditions Finally trials typically have a short duration and thus are not reflective of a drug’s chronic use and cannot identify safety concerns that may only occur after long-term use of the drug.
16
Benefits of Postmarketing Monitoring
The ability to study the following: • Low frequency reactions (not identified in clinical trials) • High risk groups • Long-term effects • Drug-drug/food interactions • Increased severity and / or reporting frequency of known
reactions
Presenter
Presentation Notes
In contrast, post marketing safety monitoring can address many of the limitations of premarketing studies because it can better detect: - Low frequency reactions not identified in clinical trials, rare but serious adverse events. - Postmarketing monitoring can also address High risk groups (like the elderly and children) that aren’t typically included in clinical trials. - These data can also address long-term effects like lipodystrophy with protease inhibitors used for the treatment of HIV. - Drug-drug/food interactions may also be captured in postmarketing data - Finally increased severity or reporting frequency of known reactions can be monitored using postmarketing data, while clinical trials typically will only give a quick snapshot of the safety profile.
17
Types of Postmarketing Surveillance • Spontaneous/voluntary reporting of cases
– National (FDA MedWatch) – Local or Regional (Joint Commission Requirement) – Scientific literature publications
Knowing the advantages of postmarketing monitoring, here are various types of postmarketing surveillance data sources: First, Spontaneous/voluntary reporting of adverse events: cases can be found in National sources (like FDA MedWatch), at Local or Regional institution levels, or in Scientific literature publications like case reports or meta analyses. Second, Postmarketing studies: these studies can be voluntary or required by FDA. Types of studies include Observational studies (including those that use automated healthcare databases) or even Randomized clinical trials. Finally, active surveillance sources: such as the Drug-Induced Liver Injury Network (DILIN) which actively enrolls cases of DILI as well as the FDA’s Sentinel initiative which uses the information from health care claims databases to identify or strengthen drug-related safety concerns.
18
Postmarket Adverse Event Reporting and MedWatch
Presenter
Presentation Notes
The remainder of the talk will focus on postmarket adverse event reporting, a key aspect of postmarketing safety surveillance and how important YOU (as healthcare providers) are in Pharmacovigilance
19
Challenge Question #2
Which of the following countries does not require practitioners to report adverse events to a national registry? A. France B. Norway C. Sweden D. US
Presenter
Presentation Notes
This brings us to challenge question 2: Which of the following countries does not require practitioners to report adverse events to a national registry? A) France B) Norway C) Sweden or D) US Participants can answer this question by selecting the appropriate radio button next to each answer choice. The correct answer is D, the US. Here in the US there is no adverse event reporting requirement for practitioners.
20
How Postmarketing Reports Get to FDA
Regulatory Requirements
FDA MedWatch
FAERS
Database
Manufacturer
Patients, consumer, and healthcare professionals
FDA
Voluntary Voluntary
5% of all reports 95% of all reports
Presenter
Presentation Notes
This slide explains how voluntary adverse events reports are submitted to FDA. Two pathways exist for patients, consumers, and health care professionals to report a suspected adverse event. 1st the reports can be submitted through FDA's MedWatch program, which encompass 5% of all reports, or they can be submitted to the product manufacturer who are then required to submit all such cases to FDA. It is through this route that the vast majority of the cases are received and entered in the FDA Adverse Event Reporting System (FAERS). Note that for serious and unexpected adverse events, the manufacturer is required by law to submit the reports to the FDA within 15 days of receipt of information. All other reports can be submitted periodically: quarterly for the first 3 years after approval then annually thereafter, as per regulations. We will discuss the components of MedWatch forms later. EXTRA Under the Code of Federal Regulations, Title 21, Part 314, Section 80, Paragraph (c), the manufacturer is required by law to submit all adverse event reports to the Agency. In addition, the manufacturer is required to report each adverse experience that is both SERIOUS AND UNEXPECTED within 15-days of receipt. For all other reports (except 15-day), the manufacturer is required to submit a quarterly periodic safety update report for the first 3 years after approval, then annually thereafter. 15-day verbatim from 21CFR314.80(c)(1)(we): The applicant shall report each adverse drug experience that is both serious and unexpected, whether foreign or domestic, as soon as possible but in no case later than 15 calendar days of initial receipt of the information by the applicant. Periodic verbatim from 21CFR314.80(c)(2): The applicant shall report each adverse drug experience not reported under paragraph (c)(1)(we) of this section at quarterly intervals, for 3 years from the date of approval of the application, and then at annual intervals. The applicant shall submit each quarterly report within 30 days of the close of the quarter (the first quarter beginning on the date of approval of the application) and each annual report within 60 days of the anniversary date of approval of the application. Upon written notice, FDA may extend or reestablish the requirement that an applicant submit quarterly reports, or require that the applicant submit reports under this section at different times than those stated. For example, the agency may reestablish a quarterly reporting requirement following the approval of a major supplement. Follow-up information to adverse drug experiences submitted in a periodic report may be submitted in the next periodic report. The regulatory definition of a serious adverse event is… (next slide)
• Under 21 CFR 314.80 postmarketing safety reports must be submitted to the agency for the following: o 15-day Alert reports: Serious and unexpected adverse experience
from all sources (domestic and foreign) o Periodic Adverse Events Reports: Domestic spontaneous adverse
events that are: - Serious and expected - Non-serious and unexpected - Non-serious and expected - Quarterly for the first 3 years then annually
21
Serious Adverse Event Results in any of these outcomes: Death Life-threatening adverse experience Inpatient hospitalization – new or prolonged Persistent/significant disability/incapacity Congenital birth defect Other serious: based upon appropriate medical
judgment, they may jeopardize the patient and require intervention to prevent a serious outcome
Federal Register - Code of Federal Regulations. 21 CFR 314.80 (a)
Presenter
Presentation Notes
Example of life-threatening: anaphylaxis Example of other: bronchospasm Verbatim from 21CFR314.80(a): Serious adverse drug experience. Any adverse drug experience occurring at any dose that results in any of the following outcomes: Death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience 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. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse.
23
Spontaneous Reports and FAERS
Presenter
Presentation Notes
But first, I will detail how the Center for Drug evaluation and research CDER and the Division of Pharmacovigilance use the adverse event reports in FAERS to contribute to our public health mission.
24
Challenge Question #3
True or False? The incidence of adverse drug events can be
determined through spontaneous reporting systems.
Presenter
Presentation Notes
This brings us to our third challenge question: The incidence of adverse drug events can be determined through spontaneous reporting systems. True or False The correct answer here is false. Because spontaneous adverse event reporting is voluntary, an incidence of that adverse event cannot be determined.
25
Spontaneous Reports • A communication from an individual (e.g., health care
professional, consumer) to a company or regulatory authority
• Describes a suspected adverse event(s) • Passive and voluntary reports
Presenter
Presentation Notes
As discussed earlier, spontaneous reports (like those submitted via MedWatch and stored in FAERS) are one type of postmarketing report used for safety surveillance. Spontaneous reports are communications from an individual to a manufacturer or regulatory authority that describe a suspected adverse event or events associated with a drug exposure. Spontaneous reports are passive and voluntary. They may be submitted by consumers or health care professionals. The voluntary nature allows many factors to affect the actual reporting. We’ll discuss some of those factors next.
26
Factors Affecting Reporting • Media attention • Litigation (class action lawsuits) • Nature of the adverse event • Type of drug product and indication • Length of time on market • Extent and quality of manufacturer’s surveillance system • Prescription or over-the counter (OTC) product status • Reporting regulations
Presenter
Presentation Notes
Here are some examples of factors that affect spontaneous reporting, both from consumers and health care professionals. These include… Media attention. In 2010 much publicity was devoted Avandia (rosiglitazone) and cardiovascular risk. Following discussions and media attention of an FDA advisory committee, FDA saw an increased reporting of these events. Litigation. Many commercials advertise law offices to help patients who may have suffered an adverse event, one example is the acne drug Accutane or the oral contraceptive Yaz. The seriousness of the adverse event, the drug product, and the indication also can affect whether and how often an event is reported. There are typically fewer reports for over the counter medications. The number of reported adverse events for a drug usually rises during the first few years of marketing, and then typically declines despite increases in prescribing rates. The quality of the manufacturer’s surveillance system may also impact reporting, as large companies have resources to follow-up and engage with reporters, but smaller or newer companies may lack these resources. Finally, regulations affect reporting, particularly in terms of what the manufacturers are required to submit to FDA.
27
FDA Adverse Event Reporting System • Computerized database • Spontaneous reports • Contains human drug and therapeutic biologic reports • > 9 million reports since 1969 • Over 1.2 million new reports in 2014
Presenter
Presentation Notes
The FDA Adverse Event Reporting System (FAERS) is a computerized database of spontaneous adverse events reports for human drug and therapeutic biologic products. Collecting data since 1969, over 7 million reports are currently stored in FAERS with nearly 1 million reports submitted in 2012 alone.
Number of Adverse Event Reports Entered into FAERS
28
Presenter
Presentation Notes
This graph shows the number of adverse event reports (the y-axis) entered into FAERS each year (x-axis). Each bar is stratified by report type. Yellow and red colors represent reports submitted from manufacturers, while blue represents the direct reports from MedWatch. As you can see, most reports come from the manufacturer and each year more and more reports are entered into FAERS.
29
FAERS Strengths • Includes all U.S. marketed
products • Includes all uses • Includes broad patient
populations: – elderly, children, pregnant
women, co-morbidities • Especially good for events
with a rare background rate
• Useful for events that occur shortly after exposure
• Detection of events not seen in clinical trials (“signal generation”)
• Identification of reporting trends, possible risk factors, at risk populations, and other clinically significant emerging safety concerns
Presenter
Presentation Notes
FAERS is a drug safety surveillance tool and has many strengths: It includes all U.S. marketed products and may include foreign products. FAERS includes all uses, both approved indications and off-label uses. For example, if a drug was approved for only schizophrenia, we may receive adverse event reports for patients with bipolar disorder or depression. FAERS includes broad patient populations: elderly, children, pregnant women, and patients with co-morbidities, who are often excluded from clinical trials. FAERS is Simple, and a relatively inexpensive reporting system So when is FAERS most useful? FAERS is ideal for events with small or rare background rates: like acute liver failure, serious skin reactions (such as Steven’s Johnson syndrome), or PML (progressive multifocal leukoencephalopathy) It is useful for events that occur shortly after exposure What is the impact? FAERS allows for detection of events not seen in clinical trials, identification of trends in reporting, possible risk factors (such as certain patient populations), and other clinically significant safety concerns.
30
FAERS is less useful for: • Events with high background rates • Worsening of pre-existing disease • Issue is beyond the name of the drug • Comparative incidence rates • Comparing drugs in the same class • Disease is reflected in the adverse event • Looking for drug interactions • Reporting Biases
Presenter
Presentation Notes
FAERS is less useful for events with high background rates, such as heart attacks in patients treated for diabetes. FAERS is not helpful if the event involves the worsening of pre-existing disease The MedWatch form does not require certain information, such as route of administration, product formulation, location of application, genetics or race. Thus if the issue is associated with one of these characteristics, such as issue with the oral solution but not the tablet form, the FAERS data may not be useful. Comparing drugs, including those in the same class, is difficult and often inappropriate. The time on the market and the actual drug use is usually different. This would be more appropriate for a clinical trial or a postmarketing observational study with a controlled setting. If the intended therapeutic disease is reflected in the adverse event FAERS is less useful. An example is the use of a psychiatric drug for a psychiatric condition and the adverse event of suicide. Finally, FAERS is less useful when looking for drug interactions and is subject to reporting biases and underreporting.
31
Did you see it??
signal
Safety Signal Detection
Presenter
Presentation Notes
As discussed, FAERS is a large database, with many reports, for all drugs and therapeutic biologics. It’s often difficult and complex to find what we are searching for.
32 33
Presenter
Presentation Notes
And this is a picture of how we often feel in the Division of Pharmacovigilance. The next few slides will discuss how we are able to best manage this data and identify safety signals.
33
Challenge Question #4 A safety signal could be:
A. New, previously unknown, adverse event B. New drug interaction C. An observed change in quantity, severity or the affected
populations of a known adverse event D. All of the above
Presenter
Presentation Notes
But before we do that, let’s define a safety signal. Here’s the next challenge question: A safety signal could be: A) A new, previously unknown, adverse event B) A new drug interaction C) An observed change in quantity, severity or the affected populations of a known adverse event D) All of the above The correct answer is D, all these features describe a safety signal.
34
What is a Safety Signal? • Reported information on a
possible causal relationship between an adverse event and a drug
• The relationship being previously unknown or incompletely documented
• Usually supported by multiple case reports
• New unlabeled adverse events
• An observed increase in a labeled event OR a greater severity or specificity
• New interactions
• Newly identified at-risk population
Presenter
Presentation Notes
There are many definitions listed on this slide, and the true definition is really a hybrid of these bullets. Safety signals are reported information that describe a possible causal relationship between an adverse event and a drug, the relationship being previously unknown or incompletely understood. Examples of signals include new adverse events or drug interactions, a new at-risk population, or greater severity or specificity about a known event. For example transient elevations in transaminases vs. fulminant hepatic failure. We usually require more than one case report to generate a signal. A great example of a safety signal involves Raptiva (efalizumab), a treatment for psoriasis, and PML (or progressive multifocal leukoencephalopathy) PML is an rare and fatal demyelinating disease that can cause brain lesions and lead to death. PML is an opportunistic infection seen in immunocompromised patients. In 2008 and 2009, 3 cases of PML in patients receiving efalizumab were identified in FAERS In February 2009, FDA issued a Public Health Advisory to notify healthcare professionals of 3confirmed, and 1 possible report of PML. Then in April 2009, Genentech withdrew Raptiva from the market, consistent with FDA’s recommendation.
35
Sources of Possible Safety Signals • Routine pharmacovigilance
– FAERS – Data mining – Periodic Safety Update Reports from drug manufacturers
• Study results • Medical literature • Media • New Drug Application (NDA)
Routine pharmacovigilance may include review of FAERS, datamining databases (which will discuss more on the next slide), and periodic safety reports from drug manufacturers Other sources of safety signals may also be included in routine pharmacovigilance and include… - Study results from clinical trials, epidemiologic studies, or registries - Case reports or studies in the published medical literature - Media - The New Drug Applications safety database - And - Outside inquiries, such as Citizen’s Petitions or interactions with foreign regulatory agencies. This list is endless as there are always new resources, tools, and data streams
36
Use of Data Mining
• Mathematical tool identifies higher-than-expected frequency of product-event combinations
• Tool for hypothesis generation
• Supplements FAERS data review
• Does not replace expert clinical case review
Presenter
Presentation Notes
One tool that helps us identify safety signals in the FAERS database is datamining. Datamining is a mathematical tool that identifies higher-than-expected reporting frequency of product-event combinations. Datamining aids in finding reports, and events, that are out of the ordinary. Datamining is intended to be hypothesis generating and may supplement the comprehensive review of the reports in FAERS. It does not confirm causality or replace the clinical review of the case reports. Now, I’ll discuss how to report to MedWatch.
37
How to report to MedWatch
Presenter
Presentation Notes
I discussed where safety information comes from and what constitutes a safety signal. Now I will discuss how you can report an adverse event to the FDA via the MedWatch Program. Then I will provide an example of a good case report.
38
Patient Identifier
Product
Event or Problem
Reporter
Reporting to MedWatch
Presenter
Presentation Notes
The MedWatch program allows for easy and convenient reporting of suspected adverse events to FDA. Here you can see the MedWatch 3500 Form that is targeted for health care professionals. Many of you have probably seen or filled one of these out. There are 4 requirements of an adverse event report: there has to be a patient, a product, an event, and a reporter. Additionally there is a section for serious outcomes, which are defined (per regulations) as death, life-threatening, hospitalization, disability or permanent damage, congenital anomaly or birth defect, and other serious. For devices, there is also a category of ‘required intervention to prevent permanent impairment or damage’. It’s not only voluntary to report in general, but also voluntary on what to report. Reports range from one-sentence descriptions of an event to carefully detailed narratives and accompanying laboratory details and medical records. It all depends on how much information the reporter is willing to share. Later on, we will discuss components of a “good” report.
39
Consumer MedWatch Form
• MedWatch Form 3500B • Includes 4 primary components
• Patient • Product • Event • Reporter
• User-friendly format for non-health care professionals
Presenter
Presentation Notes
In 2012, FDA released a MedWatch Form designed specifically for consumers. The form, called the MedWatch 3500B, is shown on this slide. The form contains the same primary components of the MedWatch 3500 form (a patient, a product, an event, and a reporter), but is written at a reading-level intended for the general public. Input from consumer advocacy groups and the general public was considered when developing the form.
40
• How to Report: – Online
(www.fda.gov/medwatch) – Download the form
• Mail • Fax 1–800–332–0178
• For questions about the form: 1–800–332–1088
Presenter
Presentation Notes
There are 2 ways to report to MedWatch: online at the website listed, www.fda.gov/MedWatch, or the forms can be downloaded from the site, completed and then mailed or faxed to FDA.
41
Components of a Good Case Report
Presenter
Presentation Notes
Pharmacovigilance work at CDER depends a great deal on FAERS. We receive about 1 million reports annually, and as we have stated these data are quite heterogeneous. The quality of the reports and their data in FAERS are highly variable, yet the public health impact of signal detection and pharmacovigilance is dependent on these data. Therefore, we want to present the components of a good case report.
42
Case #1
A health care worker reported a male patient started Drug X at 5 mg daily for type 2 diabetes on February 11, 2011. On an unknown date, the patient developed liver failure; additional information was not provided.
Presenter
Presentation Notes
I will begin with case #1. It reads: a health care worker reported a male patient started Drug X at 5 mg daily for type 2 diabetes on February 11, 2011. On an unknown date, the patient developed liver failure; additional information was not provided. Although this case contains the 4 required elements of having a patient, a drug, an adverse event and a reporter, additional important details are missing. Therefore, this would not be considered a good case report. We can not assess for temporal relationship or other confounders like concomitant medications or co-morbidities.
43
Case #2: Best Case Representative
• 59-year-old male with type 2 diabetes, hyperlipidemia, and hypertension. No history of liver disease.
• Started Drug X on February 11, 2011.
• Other medications: simvastatin and lisinopril.
• Labs drawn on Feb 11 revealed Liver enzymes, INR, creatinine, and bilirubin all within normal limits.
• No alcohol use.
• 8 weeks after starting Drug X patient presented to ER with 5 day history of jaundice, dark urine, and nausea/vomiting.
• He was admitted to ICU and subsequently diagnosed with acute liver failure.
• Drug X stopped upon admission. • Viral hepatitis was ruled out. • 7 days after stopping the
medication, all lab values returned to normal.
Presenter
Presentation Notes
Now here is case #2. READ. Note, this case is not very long, but it has all the essential elements, and many other details, including pertinent baseline lab values and pre-existing medical conditions to rule out other causes and help establish a temporal relationship and an association between the adverse event and the use of Drug X.
44
Components of a Good Postmarketing Report • Description of adverse event • Suspected and concomitant product therapy details (e.g., dose, dates of
morbid condition, family history, other risk factors • Documentation of the diagnosis • Clinical course and outcomes • Relevant therapeutic measures and laboratory data • Dechallenge and rechallenge information • Reporter contact information • Any other relevant information Guidance for Industry - Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, March 2005
Presenter
Presentation Notes
Here is a list of components of a good postmarketing report. Most, if not all, were included in the previous example and allow for adequate assessment of the case. This list includes: READ list When you are filling out MedWatch reports in your practice this can serve as an excellent guide.
45
Case Series Development and Evaluation
Presenter
Presentation Notes
We will now discuss the development and evaluation of a case series for an adverse event.
46
Developing a Case Series
• Identify a well-documented case in FAERS, published literature, data mining, or other sources to identify a safety signal.
• Using our knowledge of the clinical course of the disease, formulate a case definition which may include both clinical features and laboratory findings, sometimes even demographic information if we believe the safety signal is for a specific population.
• Complete a thorough database search for additional cases.
Presenter
Presentation Notes
For example, a safety evaluator comes upon a MedWatch report describing a patient taking a newly approved product for diabetes. The report describes a patient who developed liver failure 6 weeks after starting this product. Using this example, we will walk through the case series development and signal evaluation process. Now that we have identified a safety signal of interest. We use our knowledge of the clinical course of the disease to formulate a case definition which may include both clinical features and laboratory findings. We conduct a search in the FAERS database using MedDRA terms. MedDRA stands for Medical Dictionary for Regulatory Activities. All FAERS cases are coded using MedDRA terms. Thus, for our possible liver failure signal FAERS will be queried for additional cases with events related to liver failure for the drug in question. This not only includes diagnoses or clinical presentations, but also laboratory information. A thorough search for our example would include terms like ‘acute hepatic failure’, ‘alanine aminotransferase increased’, ‘transaminases increased’, ‘transaminases abnormal’, ‘encephalopathy’, etc., and sometimes even demographic information, just to name a few.
47
Principles of Case Evaluation • Temporal relationship • Causality assessment- World Health Organization, the Uppsala
Monitoring Centre (WHO-UMC): – Certain – Probable/Likely – Possible – Unlikely – Conditional/Unclassified
• Key factors in causality assessment including, but not limited to – Dechallenge/rechallenge – Comorbidities – Concomitant medications – Consistent with pharmacological effects ( biologic plausibility)
Presenter
Presentation Notes
After a thorough search of the database the next step is to evaluate the cases to determine how many cases will be included in our case series. The main principles are temporal relationship and causal association. Temporal relationship is important. If we cannot be sure that the adverse event occurred after the drug was taken, perhaps we don’t have a good case. Causality assessments (like the one developed by the World Health Organization) classify cases in a range from unlikely to certain. Several factors determine the strength of the association. These factors may include Dechallenge/rechallenge: did the event improve after stopping the drug and/or recur if the drug was restarted. Comorbidities or concomitant medications, could they have contributed to the development of or even caused the event (with our example pre-existing liver disease, heart failure, other drugs that can damage the liver would be seen as confounders). And are there data to support that such an adverse event is biologically plausible based on the pharmacologic effects of the product? Of notes, sometimes after reading through the cases, new information or revelation may come up. So a new case definition and a new search may be needed.
Regulatory Actions
48
Market Withdrawal
REMS
PMR/PMC Enhanced
Pharmacovigilance
Dear HCP Letter or DSC
Boxed Warning
Warnings And
Precautions
Adverse Reactions
REGULATORY ACTION
49
Regulatory Actions • Product information changes – Warnings, Precautions,
• Drug Safety Communication (DSC) • Market withdrawal
Presenter
Presentation Notes
Our evaluation is complete, but what should the agency do with this new information? Several action items are possible and the appropriate next steps are based on the strength of the data and association, the severity and significance of the event, the predicted frequency, and the overall public health impact. This slide lists the most common regulatory actions which include - Product information changes: adverse events added to the Warnings & Precautions or Adverse Reactions sections, for example. - New Pharmacovigilance activities such as enhanced surveillance (e.g., expedited reporting), creation of a registry, or perform epidemiological studies - a Risk Evaluation and Mitigation Strategy (REMS) can be created or a pre-existing one can be modified. - Drug Safety Communications (DSC) are also common and are an effective way of sharing and explaining this new safety information to HCPs and patients. - Market withdrawal is possible in extreme scenarios.
50
Communicating Safety Issues
51
Communicating Safety Issues to the Public and Internationally
• MedWatch Safety Alerts • Postmarket Drug and Biologic Safety Evaluations (FDAAA
915) • Potential Signals of Serious Risks/New Safety Information
Identified from FAERS (FDAAA 921) • Published literature and scientific meetings • Video and teleconferences with foreign regulatory
agencies: – EMA: European Medicines Agency – 4-Way: Canada, Australia, New Zealand, (Singapore in writing)
Presenter
Presentation Notes
This slide contains examples of how new safety information is shared with the public. This is for Both emerging and established safety concerns MedWatch safety alerts: these often provide links to drug safety communications. An example of a Recent MedWatch alert and DSC from August 2013 detailed the risk of potential permanent nerve damage with the use of fluoroquinolones. FDA Drug Safety Newsletter for health professionals provides drug safety-related news. - In accordance with Section 915 of the Food and Drug Administration Amendments Act of 2007 (FDAAA), FDA website contains links to postmarket drug safety information to improve transparency and communication to patients and healthcare providers. As part of Section 915, postmarketing evaluations are performed when at least 18 months has passed after drug approval or its use has reached at least 10,000 individuals. The findings of these reviews are posted to the public. Also, section 921 mandates the posting of a quarterly report on the FAERS website of any new safety information or potential signals or serious risks identified by FAERS within the last quarter. Additionally, the PV work is sometimes published in the medical literature or presented at scientific meetings. Finally, important safety information is also shared with our foreign regulatory counterparts with a clear public health objective.
52
MedWatch: The FDA Safety Information and Adverse Event Reporting Program
http://www.fda.gov/safety/medwatch/default.htm
Presenter
Presentation Notes
This screen shot of the MedWatch FDA internet page is a one stop shop for most of these examples on the previous slide. New MedWatch alerts are seen at the top; Past alerts, MedWatch sign up, and the Safety Newsletter are in the columns on the left and FDAAA 915 and 921 posting are seen in the bottom panel.
53
http://www.fda.gov/Safety/MedWatch
Presenter
Presentation Notes
The web address for this ‘one stop shop’ is www.fda.gov/safety/medwatch You can sign up to receive emails or Tweets regarding safety alerts for drugs, devices, vaccines, other biologics, dietary supplements, and cosmetics from MedWatch.
54
Questions
Presenter
Presentation Notes
This concludes my presentation and I am now open to addressing any question.
55
References • Arthur N et al. The Importance of Pharmacovigilance – Safety Monitoring of Medicinal Products. WHO
2002. • Drug Safety Communications: http://www.fda.gov/Drugs/DrugSafety/ucm199082.htm • FDA Patient Safety News: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/psn/index.cfm • Guidance for Industry- Postmarketing Safety Reporting for Human Drug and Biological Products including
Vaccines, March 2001: http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm074850.htm
• Guidance for Industry- Good Pharmacovigilance Practices and Pharmacoepiemiologic Assessment, March 2005: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126834.pdf
• MedWatch: The FDA Safety Information and Adverse Event Reporting Program: http://www.fda.gov/Safety/MedWatch/default.htm
• MedWatch Medical Product Safety Information: http://www.fda.gov/Safety/MedWatch/SafetyInformation/default.htm
http://www.fda.gov/AboutFDA/ContactFDA/StayInformed/RSSFeeds/MedWatch/rss.xml • Postmarket Drug Safety Information for Patients and Providers (FDAAA 915):
• Postmarketing Drug and Biologic Safety Evaluations: (FDAAA 915): http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/ucm204091.htm
• Potential Signals of Serious Risks/New Safety Information Identified from AERS (FDAAA 921): http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm082196.htm#QuarterlyReports
![Zlott Updates on the Treatment of Metastatic Melanoma[1]wmshp.org/sg_current_event_content_new/Zlott_Updates_on... · 2015-04-21 · 4/20/15 2 MelanomaEpidemiology’! Melanomaincidencehasbeenincreasingabout1.8%’](https://img.dokumen.tips/doc/110x75/5f20532a62ce4c5129005500/zlott-updates-on-the-treatment-of-metastatic-melanoma1wmshporgsgcurrenteventcontentnewzlottupdateson.jpg)
