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FDA/DDC Meeting
Lynda Dee
July 28, 2008
PADUFA IV/FDAAA - NEW FDA LEGISLATION
 Congress reauthorized the Prescription Drug
User Fee Act (PADUFA) for another five years
under the Food and Drug Administration
Amendments Act of 2007 (FDAAA) .
 Before FDAAA, a number of areas addressed by
these amendments, including many pediatric
laws, were found in many different statutes and
were sometimes at odds.
FDAAA - NEW FDA LEGISLATION
 The FDAAA titles I will be addressing are Titles VII,
Conflicts of Interest, VIII, Clinical Trials Data Base and
IX Enhanced Authorities Regarding Postmarket Safety
of Drugs.
 The new focus of FDAAA with respect to drug safety is to
emphasize that it is equally important to ensure that
drugs are used as safely and efficiently as possible as
it is to ensure that drugs are getting drugs to market
quickly and efficiently. It should be noted that this safety
legislation was propelled by the Vioxx fiasco and by teen
suicides after using anti-depressant drugs. The goal of
some the new amendments is to maintain a systematic
and scientific approach to evaluating the risk/benefit
ratio throughout the life cycle of a drug, including postapproval, not just prior to approval.
Title VII - Conflicts of Interest
 No person can participate in FDA Advisory
Committees if they or their immediate family
members have a financial interest that
could be affected by their advice.
 The Secretary of HHS may make exceptions
and grant waivers if a person’s expertise is
essential to the Advisory Panel.
New Provisions:
 The agency should only consider term
appointments for Advisory Committees who will
not need waivers.
 Waivers are now limited and must be decreased
annually by 5% from 2007 through 2012.
 Not less than 15 days prior to the Advisory
Committee meeting, the name of any participant
who received a waiver must be posted on the
FDA website and the type, nature and magnitude
of the financial interest as well as the reason for
Title VIII - Clinical Trials Databases
 Clinialtrials.gov will be superceded by this new law. The NIH is charged
with ensuring that the proscribed information is made publically available on
the internet within 30 days of submission by the sponsor. $10,000,000 has
been appropriated annually.
New Provisions:
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The FDA is responsible for supplying and linking adverse
event (AE) information within 30 days of the information
becoming public beginning no later than 18 months after
enactment of FDAAA, including:
 A table of serious anticipated and unanticipated AEs, grouped
by organ system with the number and frequency of such
events, and
 A table of frequent anticipated and unanticipated AEs,
grouped by organ system if they exceed 5% within any arm of
the trial.
All clinical trials in Phase II and beyond will be included
in the new databases. The database shall include the
following:
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A brief title and summary of the trial,
The primary purpose and type of study,
The study design and study phase,
The primary disease or condition being studied,
The intervention name and type.
The study start and anticipated completion date,
The target number of patients,
Outcomes, including primary and secondary outcome measures,
Recruitment information, including eligibility criteria, gender and age
limits and recruitment status and individual site status,
Location and contact information,
The name of the sponsor and responsible party,
Faculty contact, including name, address, toll-free number and
facility name,
A protocol identification number as well as the FDA IND number.
Title VIII - Clinical Trials Databases
Searchable categories shall include one or
ore of the following:
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The disease or condition,
The name of the drug or intervention,
The site location of the clinical trial,
The age group being studied, including pediatric studies,
The study phase,
The study sponsor,
The recruitment status; i.e., open or closed studies,
The National Clinical Trial number or other study
number.
Timeline requirements for the above information:
 90 days after FDAAA enactment.
 21 days after the first patient is enrolled,
 1 year after FDAAA enactment if the clinical trial does
not involve a serious or life-threatening disease or
condition.
No later than 1 year after FDAAA enactment, the
database shall include the following:
 Demographic and baseline patient characteristics,
 Primary and secondary outcomes,
 Point of Contact
Title VIII - Clinical Trials Databases
Civil Monetary Penalties:
 Not more than $10,000 for all violations adjudicated in a
single proceeding,
 Not more than $10,000 per day for violation until
violation is corrected.
Notice of Violations must be posted online, including:
 The non-complying party or sponsor,
 Whether no information or misleading information
was provided,
 The penalties proscribed, and
 Whether the violation has been corrected
Title VIII - Clinical Trials Databases
Other Provisions:
 Informed Consent Documents shall be included.
Preemption:
 No state or other political subdivision may establish
or continue in effect any requirements for
registering clinical trials or for the inclusion of
information relating to clinical trials results.
Title IX - Enhanced Authorities Regarding
Postmarket Safety of Drugs
Prior to FDAAA, the FDA did not have the power to order sponsors to conduct
postmarket trials. The conduct of these trials had to be negotiated with
companies. Some companies were much better than others at complying with their
agreements in this regard.
New Provisions:
The FDA may require postmarket studies or clinical trials to:
 Assess known serious risks,
 Assess signals of serious risks,
 Identify unexpected serious risk when potential is identified.
Sponsors must submit a timetable for completion and periodic status reports.
Safety Labeling Changes:
 Submit changes to the labeling that reflect new safety information, including
boxed warnings, contraindications, warnings, precautions or adverse
reactions.
Risk Evaluation and Mitigation Strategies:
On a case by case basis, the Secretary shall determine what, if
any, risk evaluation and mitigation strategy is necessary to
ensure the benefits of the drug outweigh the risks
associated with the drug. This includes drugs approved prior
to enactment of FDAAA.
Risk Evaluation and Mitigation Strategies (REMs) shall include:
Timetable for submission,
 An 18 month assessment,
 A 3 month assessment,
 A 7 year assessment.
 Assessments may be increased or reduced as necessary or
eliminated after 3 years if the Secretary determines that the
serious risks have been adequately identified.
 Advisory Committees may be convened to review
the safety of a drug, class of drugs or before an
assessment of the risk evaluation and mitigation
strategy or strategies is decided.
 Medication Guide; Patient Package Insert:
 The sponsor may be required to develop and
distribute a medication guide or patient package
insert to each patient when the drug is dispensed.
 Communication Plan to Health Care Providers:
 The sponsor may be required to provide a
communication plan to health care providers by
letters or, through professional societies.
Access to Drugs with Known Serious Risks
That Would Otherwise Be Unavailable
Examples of Elements to Assure Safe Use:
 Required training or certification for health care providers,
 Specially certified pharmacies, practitioners or health
care settings,
 Dispensed only in certain settings or hospitals,
 Patient subjected to specific monitoring,
 Patient enrolled in a registry.
 Any system should not be unduly burdensome and to the
extent possible, minimized the burden on the health care
delivery system.
Dispute Resolution at Initial ApprovalDrug Oversight Board
 Not later than 5 days after a dispute letter is received by the Secretary, notice
shall be posted on the internet that the dispute will be reviewed by the Drug
Oversight Board.
• Review may be scheduled at next Drug Oversight Board Meeting or a special
meeting may be convened.
The proceedings are to be recorded and made public within 90 days of the
meeting. Trade secrets, etc. are to be redacted.
 Board makes a recommendation within 5 days.
 Secretary makes the recommendation available to the public within 5 days.
 Secretary shall issue an action letter resolving the dispute no later than 7
days after receiving the recommendation of the Drug Safety Oversight Board
which shall also be made public within 7 days.
 Agreement between the FDA and the sponsor terminates the proceedings.
Composition of the Drug Oversight
Safety Board:
 One Scientist and one health care practitioner who are
federal employees,
 FDA employees, including postmarketing office
employees,
 One NIH employee and one HHS employee, not including
FDA staff,
 Other appropriate agencies as determined by the
Secretary.
 The Drug Safety Oversight Board shall meet monthly to
provide oversight and advice on drug safety issues.
Prereview of TV Advertisements:
 The Secretary may require prereview of any drug TV
advertisements.
 The Secretary may require inclusion specific
disclosures if it is determined that the ad is false or
misleading.
 Statements relating to side effects and
contraindications shall be presented in a clear,
conspicuous and neutral manner.
 The Secretary may require disclosure of the
approval date of any drug within 2 years of the
approval date.
Civil Monetary Penalties:
 A party may be fined not greater than $250,000 for
disseminating false or misleading direct-toconsumer advertising for the first violation in any 3
year period, and not greater than $500,000 for each
subsequent violation in any 3 year period.
 The amount assessed may be deducted from any
amount owed by the US to the person charged.
 Misbranding penalties: $250,000 for the first 30day period, doubled for every 30 day period
thereafter, not to exceed $1,000,000 for any 30-day
period or $10,000,000 for all violations.
Benefit Risk Assessment:
 No later than 1 year after enactment of FDAAA,
the FDA Commissioner shall submit a report
to Congress on how best to communicate the
risks and benefits of new drugs and the role
of the risk evaluation and mitigation strategy in
assessing such risks and benefits.
 As part of the study, the FDA Commissioner
may consider the possibility of including a
unique symbol in the labeling of a new drug
and in any direct-to-consumer
advertisements promoting a new drug to
indicate that it is newly approved or has a
new indication.
A Statement to Be Included in Direct-toConsumer (DTC) Advertisements:
 In the case of published DTC ads, the following statement
must be printed in conspicuous text:
“You are encouraged to report negative side effects of
prescription drugs to the FDA. Visit www.fda.gov/medwatch,
or call 1-800-FDA-1088.”
 No later than 6 months after FDAAA enactment, the Secretary
shall conduct a study in collaboration with the Risk and
Communication Advisory Committee to determine whether
the above statement is appropriate for TV ads or if it detracts
from DTC risk information. If it is deemed appropriate, the
Secretary shall promulgate regulations requiring such a
statement.
Report on Direct-to-Consumer
Advertising (DTC):
 The Secretary of HHS shall make a report to Congress on DTC
and its ability to communicate to subsets of the general
population, including the elderly, children and racial and
ethnic minorities.
 The Risk Management Advisory Committee established
under this Act shall be used to advise the Secretary on this
report. The committee shall include patients, consumers
and health professionals
 No later than 1 year after enactment, the FDA shall submit to
Congress a report on how to best communicate to the public
the risks and benefits of new drugs and the role of risk and
mitigation strategies in assessing risks and benefits.
Active Postmarket Risk
Identification and Analysis:
 Not later than 2 years after enactment, the Secretary
shall develop postmarket risk and identification
and analysis methods to:
 Develop methods to obtain disparate data sources,
 Develop validated methods for the establishment of a
postmarket risk identification analysis system to link
and analyze safety data from 25,000,000 patients by
July 1, 2010, and 100,000,000 patients by July 1, 2012.
 Convene an expert committee to develop tools and
methods for ethical and scientific uses for
communicating postmarket data, including effective
research methods in this regard.
Postmarket Risk Identification
and Analysis System:
 Not later than 1 year after the development of risk identification
and anaylsis methods, the Secretary shall establish and
maintain procedures for a risk identification and analysis
system:
 For a risk and identification and analysis system based on
electronic health data,
 For the reporting of data in a standardized form all serious
adverse drug experiences, including events reported by patients,
providers and sponsors,
 To provide active electronic adverse event surveillance reports
from Medicare and the VA.
 To include approaches that would assess safety of drug use in
underrepresented populations, including the elderly, people
with comorbidities, pregnant women and children.
Postmarket Risk Identification
and Analysis System (cont):
 The Secretary must establish government collaborations and
contract with industry to establish this research, statistical,
epidemiologic and/or clinical capability and expertise.
 Congress has appropriated $25,000,000 for each fiscal year
from 2008 through 2012 in this regard and directed the GAO to
evaluate and ensure privacy, confidentiality and the
security of this data within 18 months of FDAAA enactment.
 Congress has also required the Secretary to report on the ways in
which the risk identification and analysis system can been used
to identify specific drug safety signals and better understand
the outcomes associated with drugs marketed in the US.
Postmarket Drug Safety Information
for Patients and Providers:
 Within 1 year the Secretary must improve transparency
of information about drugs and allow patients and
providers better access to drug safety information by
developing an Internet web site that:
 Provides links to drug safety information for
approved drugs,
 Improves communication of drug safety
information to patients and providers.
 The above shall be carried out by developing and
maintaining an accessible consolidated web site with
easily searchable drug safety information forms sources
such as US National Library of Medicine and Medline
Plus.
The web site shall include:
 Patient labeling and patient packaging inserts,
 Links to a list of each drug for which a Medication Guide is
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required,
Links to the registry and results data bank,
Most recent FDA safety information and alerts such as recalls,
warning letters, import alerts,
Publically available information about implemented RiskMAPs and
risk evaluation and mitigation strategies,
Guidance documents and drug safety regulations,
Surveillance summaries of known serious side effects,
Summary analyses of adverse events by either the later of 18
months after drug approval or use of the drug by 10,000 people,
Ability of patients and providers to report adverse events,
Educational materials on how to dispose of expired or unusable
medications,
Drug labeling no later than 21 days after approval.
Database for Generic Drugs:
 Not later than 9 months after enactment of
FDAAA, the FDA shall publish on the web
site a complete list of all authorized generic
drugs, including:
 The drug trade name,
 Brand name and manufacturer, and
 The date the generic drug entered the
market.
Action Package:
 The Secretary shall publish the action package for approval on
the web site no later than 30 days after the approval date of a
drug.
 The action package shall include:
 Related FDA generated documents.
 Application documents generated,
 Label submitted by the applicant,
 A summary review that documents conclusions from all
reviewing disciplines about the drug, noting any critical
issues, disagreements and resolutions, recommendations for
action and an explanation of any non-concurrence with the
review conclusions on the web site not later than 48 hours
after drug approval, and (see next slide)
Action Package (Cont.)
 Division Director and Office Director’s decision
document which include:
 Statement of concurrence with summary review,
 Separate review if not in concurrence with the
summary review,
 Names of each FDA employees who participated in
the decision if they consent to their names being
included.
 A scientific review of an application is considered
the work of the reviewer and shall not be altered
by management or the reviewer once final.
Response to the 2006 Institute of
Medicine (IOM) Report:
 No later than 1 year after enactment of FDAAA, the
Secretary shall respond to the 2006 IOM report
titled: The Future of Drug Safety—Promoting and
Protecting the Health of the Public. The report shall
include an FDA update and assessment of the
implemented recommendations as well as evidence
that the office responsible for reviewing the drug and
the office responsible for postapproval safety have
worked together to assess, implement and ensure
compliance with the requirements of FDAAA.
Adverse Drug Reaction Reports
and Postmarket Safety:
The Secretary shall:
 Conduct regular, biweekly screening of the Adverse Event
Reporting System database and post a quarterly report on the
Adverse Event Reporting System web site, including new safety
information or potential serious risk signals identified within
the last quarter.
 Report to Congress no later than 2 years after enactment of FDAAA
the FDA’s procedures and processes for addressing ongoing
postmarket safety issues and how recommendations are handled
within the agency.
 Annually review the entire backlog of postmarket safety
commitments to determine which commitments require revision
or should be eliminated, report to Congress on these
determinations, and assign start dates and estimated completion
dates for such commitments.