CCRP virtual course Flashcards
Assuring the safety, effectiveness, quality and security of human drugs, vaccines, biological products and medical devices fall under the direction of: LIST ALL LEVELS
United States Department of Health and Human Services
-FDA
–Center for Drug Evaluation and Research (CDER)
–Center for Biologics Evaluation and Research (CBER)
–Center for Devices and Radiological Health (CDRH)
Who develops SOPs? Who approves SOPs? What is the goal? Who is binded by the SOP
Developed by the organization
2. Sponsor, Investigational Site, Contracting Research Organization (CRO)
3. Compliance of regulations
4. Binding only on the organization.
CFR Title 21 Part 11?
Electronic Records; Electronic Signatures
CFR Title 21 Part 50?
Informed consent
CFR Title 21 Part 54
Financial Disclosure
CFR Title 21 Part 56
Institutional Review Boards
CFR Title 21 Part 312
Investigational New Drug Application
CFR Title 21 Part 314
New drug appication
CFR Title 21 Part 812
Investigational Device Exemption
CFR Title 21 Part 814
Premarket Approval of Medical Devices
CFR Title 45 Part 46
Federal research
45 CFR 46 part A is?
Common Rule
What is the largest grant making agency in the US
HHS
The Common rule provides what
set of protections for research subjects
The HHS regulations regarding human subject protection at
45 CFR 46 differ in limited but significant ways from the
FDA regulations regarding human subject protection at 21
CFR 50 and 56.
When a research activity is governed by both sets of
regulations, then there are certain regulatory provisions that
are allowable under 45 CFR 46 that are not allowable under
21 CFR 50 and 56, and thus cannot be applied to the
research.
What are those provisions
- The application of the exempt research categories
- provision of waiver of consent
- Waiver of documentation of consent
What is ICH
International conference of harmonizaiton
What does ICH do
brings together the regulatory authorities and
pharmaceutical industry to discuss scientific and
technical aspects of pharmaceuticals and develop ICH
guidelines
Mission of ICH
achieve greater harmonisation
worldwide to ensure that safe, effective and high quality
medicines are developed, and registered and maintained
in the most resource efficient manner whilst meeting high
standards.
2
What are the following ICH E series
E2A
E3
E6
E7
E8
E9
E11
Q
S
M
E2A – Clinical Safety Data Management
E3 – Clinical Study Reporting
E6 – Good Clinical Practice
E7 – Geriatric Populations
E8 – General Considerations for Clinical Trials
E9 – Statistical Principles
E11 – Pediatric Populations
Q -Quality Guidelines
S- Safety
M- Multidisciplinary
International Conference on Harmonization (ICH)
Good Clinical Practice (GCP) E6(R2) is
international ethical and scientific quality
standard for designing, conducting, recording
and reporting trials that involve the
participation of human subjects.
ICH GCP is a unified standard for who, and to do what?
What other jurisdictions did it cover
European Union, Japan and US.
facilitate the mutual
acceptance of clinical data by the regulatory
authorities in these jurisdictions
well as those of Australia, Canada,
the Nordic countries, and the World Health
Organization.
What is the focus of the ICH E6(R2) addendum to ICH E6 (R1)
Who does it affect the most?
focus of the revisions is on increasing
human subject protections and data integrity mainly
through better study design and conduct.
Therefore,
most of the changes affect the sponsor.
What is at the core of Nuremberg Code?
Informed consent
What are the 10 research principles for the research subject from the nuremberg code?
- The voluntary consent of the human subject is
absolutely essential. - The experiment should yield fruitful results for the
good of society, unprocurable by other methods or
means of study, and not random and unnecessary in
nature. - The experiment should be designed and based on the results of animal experimentation and a knowledge
of the natural history of the disease or other
problem under study, that the anticipated results
will justify the performance of the experiment. - The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and
injury. - No experiment should be conducted, where there is
reason to believe that death or disabling injury will
occur. - The degree of risk to be taken should never exceed
that determined by the humanitarian importance of
the problem to be solved by the experiment. - Proper preparations should be made and adequate
facilities provided to protect the experimental subject
against even remote possibilities of injury, disability, or
death. - The experiment should be conducted only by
scientifically qualified persons with the highest
degree of skill and care. - During the course of the experiment, the human
subject should be at liberty to bring the experiment
to an end, if he/she has reached the physical or mental
state, where continuation of the experiment seemed to
him to be impossible. - During the course of the experiment, the scientist in
charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the
exercise of the good faith, superior skill and careful
judgement required of him, that a continuation of the
experiment is likely to result in injury, disability, or death to the experimental subject.
What is the Declaration of Helsinki
A statement of ethical principles for medical research
involving human subjects, including research on
identifiable human material and data.
The Declaration is addressed primarily to physicians.
The WMA encourages others who are involved in
medical research involving human subjects to adopt
these principles
What are ethical foundations of the Declaration of Helsinki?
It is the duty of the physician to promote and safeguard
the health, well-being and rights of patients, including
those who are involved in medical research.
Medical progress is based on research that ultimately
must include studies involving human subjects.
The primary purpose of medical research involving
human subjects is to understand the causes,
development and effects of diseases and improve
preventive, diagnostic and therapeutic interventions
(methods, procedures and treatments).
Even the best proven interventions must be evaluated
continually through research for their safety,
effectiveness, efficiency, accessibility and quality.
Medical research is subject to ethical standards that
promote and ensure respect for all human subjects and
protect their health and rights.
While the primary purpose of medical research is to
generate new knowledge, this goal can never take
precedence over the rights and interests of individual
research subjects.
The responsibility for the protection of research
subjects must always rest with the physician or other
health care professionals and never with the
research subjects, even though they have given
consent.
Research on patients or healthy volunteers requires the
supervision of a competent and appropriately qualified
physician or other health care professional.
Groups that are underrepresented should be provided
appropriate access to participation in research. All
vulnerable groups and individuals should receive
specifically considered protection
How does the Belmont report give boundaries to practice?
Practice refers to interventions that are designed solely
to enhance the well-being of an individual patient or
client that has a reasonable expectation of success. The
purpose of medical or behavioral practice is to provide
diagnosis, preventive treatment or therapy to particular
individuals
How does the Belmont Report give boundaries to research?
Research designates an activity designed to test an
hypothesis, permit conclusions to be drawn, and
develop or contribute to generalizable knowledge.
Research is usually described in a formal protocol that sets
forth an objective and a set of procedures designed to reach
that objective.
What are the three basic principles for the belmont report?
Respect of persons
beneficence
justice
What are the specifics for respect of persons in Belmont report?
- Individuals should be treated as autonomous agents
capable of deliberation about personal goals. To respect
autonomy is to give weight to autonomous persons’ opinions
and choices while refraining from obstructing their actions
unless they are clearly detrimental to others.
Persons with diminished autonomy are entitled to extensive
protection. The extent of protection afforded should depend
upon the risk of harm and the likelihood of benefit.
Respect for persons demands that subjects enter into
research voluntarily and with adequate information
Specifically in Informed Consent
What are the specifics of Beneficence in Belmont report
Persons are treated in an ethical manner not only by
respecting their decisions and protecting them from
harm, but also by making efforts to secure their wellbeing.
Beneficence is an obligation:
Do not harm
Maximize possible benefits and minimize possible
harms
Assess risks and Benefits
Specifics of Justice in Belmont report
Fairness in distribution of burdens and benefits:
To each person an equal share
To each person according to individual need
To each person according to individual effort
To each person according to societal contribution
To each person according to merit
Selection of Subjects
What are the sponsor responsibilities for study
Select qualified investigators and monitors
Provide information needed to conduct the
investigation properly
Ensure Proper Monitoring, IRB Review and
Approval
Ensure investigation conducted in
accordance with the general investigational
plan and protocols contained in the IND/IDE;
maintain effective IND/IDE
Ensure FDA and all participating investigators are
promptly informed on significant new adverse
effects or risks with respect to the investigational
product
Obtain agreement from the investigator/
institution for adherence to the protocol, to obtain
IRB approval, and GCP compliance
Notify all involved parties, if warranted, of new
safety information adversely affecting subject
safety or IRB favorable opinion
Secure Compliance
When the sponsor obtains a signed 1572 (pharmaceutical
investigation) or Investigator Agreement (device
investigation) what does it include:
- CV
- Statement of Investigators relevant experience
- Explanation of termination circumstances
- Statement of investigator commitment
If the sponsor wants to transfer any or all of their responsibilities to a contract research organization what do they have to do
The transferred responsibilities must be described in
writing
Any responsibility that is not described is assumed to
remain with the Sponsor
The CRO assuming the responsibilities of a sponsor
must comply with the applicable regulations and is
subject to the same regulatory consequences as the
Sponsor for noncompliance
What are monitoring plans that the sponsor creates?
manage important
risks to human subjects and data quality and
address the challenges of oversight in part by
taking advantage of the innovations in modern
clinical trials.
What is a risk-based approach in monitoring?
does not
suggest any less vigilance in oversight of clinical
investigations. Rather, it focuses sponsor
oversight activities on preventing or mitigating
important and likely risks to data quality and to
processes critical to human subject protection
and trial integrity. is dynamic,
more readily facilitating continual improvement
in trial conduct and oversight.
What are the differences between on-site monitoring, remote monitoring and centralized monitoring
On-site Monitoring: periodic site visits by a
clinical research associate conducted in-person
Remote Monitoring: replace on-site with remote
activity
Centralized Monitoring: electronic data capture
involving analytical evaluation
What are the roles of a medical monitor?
provide medical expertise and
oversite to ensure clinical integrity and safety
accountability, and respond to subject safety and
trial management (e.g., inclusion and exclusion
criteria, unblinding procedure)
What are data safety monitoring boards
independent
group who conducts periodic review and
evaluates study data for patient safety, study
conduct and progress – will have initiated “event
triggers” prior to study start
What are the sponsor responsibilities around investigational product?
Manufacturing, packaging, labeling, and
coding of the investigational product
Providing the investigational product only to
investigators participating in an investigation
Maintain drug and device accountability
records from manufacturing through use,
return and destruction
Submit Safety Reports (Expedited
Reporting), if appropriate
Provide pre-clinical and clinical study
reports in information amendments to
the IND/IDE
Submit an annual report to the IND/IDE
What does the sponsor have to do if they determine the investigational product presents an unreasonable and significant risk to subjects?
Discontinue all studies that present the risk
Notify FDA, all investigators involved in the study(ies)
and their IRBs
Assure return and accounting for all investigational
product, its return to the Sponsor (or on-site
destruction)
A sponsor who discovers that an investigator is not
complying with the signed agreement, the investigational
plan, the IND/IDE requirements, any other applicable FDA
regulations, or any conditions of approval imposed by the
reviewing IRB or FDA must
Promptly either secure compliance, or discontinue
shipments of the investigational product to the
investigator and terminate the investigator’s participation
in the investigation.
A sponsor must also require that the investigator dispose
of or return the investigational product, unless this action
would jeopardize the rights, safety, or welfare of a
subject.
Under 21 CFR 54 requires financial disclosures; why does the sponsor require applicants to send these in?
Requires any clinical investigator conducting clinical studies covered by the regulation to certify the absence of certain financial interests and arrangements of clinical investigators that could affect the reliability of data submitted to FDA, or to disclose those financial interests and
arrangements to the agency and identify steps taken to
minimize the potential for bias (21 CFR § 54.4(a)).
Which financial disclosure form do clinical investigators have to submit if they do not have disclosable financial interests?
FDA 3454
Which financial disclosure form do clinical investigators need to file if the individual has participated in financial arrangements of holds financial interests?
FDA 3455
Who is responsible for registering trials and submitting results?
The responsible party for an applicable clinical trial (ACT)
must register the trial and submit results information. The
responsible party is defined as:
The sponsor of the clinical trial, as defined in 21 CFR 50.3; or
The principal investigator (PI) of such clinical trial if so
designated by a sponsor, grantee, contractor, or awardee, so
long as the PI is responsible for conducting the trial, has
access to and control over the data from the clinical trial, has
the right to publish the results of the trial, and has the ability to
meet all of the requirements for the submission of clinical trial
information.
ACTs generally include interventional studies (with one or
more arms) of FDA-regulated drug, biological, or device
products that meet one of the following conditions:
The trial has one or more sites in the United States
The trial is conducted under an FDA investigational new drug application or investigational device exemption
The trial involves a drug, biological, or device product
that is manufactured in the United States or its territories
and is exported for research
The overall purpose of monitoring by CRA is to verify what?
The rights and well-being of human subjects are
protected
Reported trial data are accurate, complete, and
verifiable from source documents
The study is conducted in compliance with the
study protocol, the GCP guidelines, and
applicable regulations
What should monitoring visits reports include?
the investigator’s name and site location
date of the visit
monitor’s name
site personnel contacted
summary of what information was reviewed
significant findings and corrective actions
What are other monitor responsibilities for visits?
Review and follow-up by the sponsor on corrective
actions should be documented
Identify missing data, inconsistent data, data outliers,
unexpected lack of variability and protocol deviations
Examine data trends such as the range, consistency,
and variability of data within and across sites
Evaluate for systematic or significant errors in data
collection and reporting at a site or across sites; or
potential data manipulation or data integrity problems
Analyze site characteristics and performance metrics
Select sites and/or processes for targeted on-site
monitoring.
What FDA form is for the statement of investigator or investigator agreement?
FDA 1572
What is required on the 1572
The name and address of the investigational
site(s)
The name and address of the responsible IRB
The name and address of clinical laboratories, if
any
For devices, the corresponding requirements are
contained in an investigator’s agreement (no form
comparable to Form FDA 1572)
After the investigator signs the 1572 what CRF TITLE WOULD THEY HAVE TO ENSURE RELATING TO OBTAINING INFORMED CONSENT AND WHICH ONE FOR IRB review and approval?
21 CRF 50
21 CFR 56
After the investigator signs the 1572 what CFR would they have to follow for reporting adverse events during the study
21 CFR 312.64
After the investigator signs the 1572 what CFR would they have to follow for maintaining adequate records and make study records available for inspection
21 CFR 312.62
21 CFR 312.68
How should study records be kept/ Which acronym helps remmeber?
Attributable, legible, contemporaneous original, accurate and complete (AKCoA-C)
What are GCP for investigators to verify via accountability records
Doses specified in the protocol were provided to
subjects.
Drug/device was provided only to study subjects.
Use by study subjects reconciles the amounts received
and returned to the sponsor.
Product was stored as specified by the sponsor and in
compliance with applicable regulations.
Device was used for its intended purpose.
What are financial disclosures by clinical investigators for 21 CFR 54
Any compensation made to the investigator by any sponsor
of the covered clinical study in which the value of
compensation could be affected by study outcome.
A proprietary interest in the tested product including, but not limited to, a patent, trademark, copyright or licensing agreement.
Any equity interest in any sponsor of the covered clinical study, i.e., any ownership interest, stock options, or other financial interest whose value cannot be readily determined through reference to public prices. The requirement applies to interests held during the time the clinical investigator is carrying out the study and for one year following completion of the study.
Any equity interest in any sponsor of the covered study if the sponsor is a publicly held company and the
interest exceeds $50,000 in value. The requirement
applies to interests held during the time the clinical
investigator is carrying out the study and for one year
following completion of the study.
Significant payments of other sorts are payments that
have a cumulative monetary value of $25,000 or more
and are made by any sponsor of a covered study to the
investigator or the investigator’s institution during the time the clinical investigator is carrying out the study and for one year following completion of the study.
what is involved in drug discovery steps for drug development in non-clinical/pre-clinical activities:
Identify potential new compounds
Test in appropriate laboratory and animal
models to assess potential activity in humans
Screening may involve thousands of
molecules
What steps are included during the develop the dosage form for drug development?
Manufacture pure, stable drug substance
(active ingredient)
Test various formulations to optimize the drug
product (active ingredient and excipients)
Stability testing in packaging planned to be
used for clinical trials and the marketed
product
Begin defining product labeling expectations
What is the goal of safety pharmacology studies?
Studies that investigate the potential
undesirable pharmacodynamic effects of a
substance on physiological functions in
relation to exposure in the therapeutic range
and above.
What are the goals of animal studies?
Establish general safety in multiple species
Summarize the toxicities observed
Determine the safety margins between the
planned human dose range and toxic effects
in animals
Optimize the dose range, formulation, and
frequency of administration
What are results used for in single-dose toxicity studies in multiple animal species?
results used to select doses for
repeated dose studies
What results are used for Repeated dose studies to assess toxicity after
multiple administrations
results used to
determine doses used for chronic
administration, e.g. – carcinogenicity studies in
animals
There are minimum requirements before clinical trials may begin.
What are included in applications to initiate clinical trials IND?
Summaries of all acute toxicity studies
28-day studies in one rodent and one non-rodent
species, usually rats and dogs
Regulatory authorities can require more information
Non-clinical studies have to support the
conclusion that the drug can be administered
safely to human subjects
What CFR correlates to general principles of IND submmission?
21 CFR 312.22
What are general principles of IND submissions (21 CFR 312.22) for Phases 2 and 3, FDA:
helps assure the quality of the scientific evaluation
is adequate to permit evaluation of the drug’s
safety and efficacy
determines if studies in Phases 2 and 3 are likely
to yield data capable of meeting regulatory
standards for marketing approval
During drug development IND general Considerations (21 CFR 312.22) the amount of information needed depends on:
Novelty of the drug, e.g. – a new mechanism of
action
Extent the drug has been studied previously
Known or suspected risks
Phase of development
What does the Initial IND focus on?
The general investigational plan
Summary of preclinical studies
Protocols for specific human studies
Reasons for IND amendments include:
New protocols or amendments to studies in
progress
Submission of reports for completed preclinical
and clinical studies, as well as relevant preclinical
and clinical information in the public domain
Expedited reporting of serious adverse events
Changes in ingredients or manufacturing process
for the active ingredient or final drug product
Submission of the annual report
What CFR is associated with IND format and Content
(21 CFR 312.23)
A sponsor initiated IND must contain:
Cover sheet (Form FDA 1571)
Table of contents
Introductory statement and general investigational
plan
Investigator’s brochure
Protocol(s) for clinical trials
Chemistry and manufacturing information
Pharmacology and toxicology information
Previous human experience with
investigational drug
Additional information, e.g. – drug
dependence and abuse potential, exposure
to radiation, plans for pediatric studies
What CFR is associated with administrative actions
(21 CFR 312.40)
Under administrative action 21 CFR 312.40 an IND can go into effect when…
30 days after the FDA acknowledges receipt
unless FDA notifies sponsor of clinical hold
Upon earlier notification clinical investigations
may begin
What CFR is associated with clinical holds and requests for modifications
(21 CFR 312.42)
what is a clinical hold, what is put on, and who issues it
is an order issued by the FDA to the
Sponsor to delay a proposed clinical investigation or
to suspend an ongoing investigation
If a clinical hold happens to a proposed study, what happens
/
subjects may not be given the
investigational drug
If a clinical hold happens to an ongoing study, what happens?
no new subjects may be given the
investigational drug and subjects already taking
the drug should be discontinued unless
continuation is specifically permitted by FDA
What are grounds for clinical holds on Phase 1
Human subjects are or would be exposed to an
unreasonable and significant risk of illness or
injury
The clinical investigators named in the IND are not
qualified by reason of their scientific training and
experience to conduct the investigation described
in the IND;
Investigator’s brochure is misleading, inaccurate,
or materially incomplete
The IND does not contain sufficient information
required under 312.23 to assess risk to subjects of
the proposed studies
What are additional grounds for clinical hold phases 2 and 3
The protocol is clearly deficient in design to meet
its stated objectives
what CFR is associated with withdrawal of an IND
(21 CFR 312.38)
A sponsor may withdraw an IND at any time
without prejudice by:
Notifying the FDA
Stopping all studies and notifying the
investigators
All drug is returned to the sponsor or destroyed
as directed by the sponsor
If withdrawn for safety reasons, the sponsor must
notify the investigators and the IRBs of those
reasons
What are protocol amendments allowed under an IND
New protocols
When a sponsor wants to conduct a study not
already covered by the IND
Changes in current protocols
Any change in Phase I that significantly affects
safety of subjects
Any change in Phase II or III that affects safety of
subjects, scope of investigation, or scientific quality
of study
New investigator added to a current study
What CFR is associated with information amendments with IND amendments and what are they?
312.31
Information Amendments (312.31):
Chemistry/Microbiology
Pharmacology/Toxicology
Clinical
What are other amendments
IND Safety Reports
Response to FDA Request for Information
Response to Clinical Hold
General Correspondence
Annual Report
Request for Re-instatement of IND
A new Drug Application for a drug or biologic is filed when the sponsor considers that there is sufficient info to meet the regulatory requirements for approval
Chemistry, manufacturing and controls (CMC), full
reports appended
Summaries of all non-clinical studies, full reports
appended
Summaries of all clinical studies , full reports
appended
Integrated summary of safety (ISS)
Integrated summary of efficacy (ISE)
Risk evaluation and mitigation strategy (REMS)
When is a decision on the NDA supposed to be made?
Within 12 months after submission
What is expanded access
is a potential pathway for a patient with an immediately
life-threatening condition or serious disease or
condition to gain access to an investigational medical
product (drug, biologic, or medical device) for treatment
outside of clinical trials when no comparable or satisfactory
alternative therapy options are available
What are the different types of expanded access
Emergency use
Compassionate USe
Treatment Use
Continued Access
When are expanded releases appropriate?
Patient has a serious disease or condition, or whose life is
immediately threatened by their disease or condition.
There is no comparable or satisfactory alternative therapy
to diagnose, monitor, or treat the disease or condition.
Patient enrollment in a clinical trial is not possible.
Potential patient benefit justifies the potential risks of
treatment.
Providing the investigational medical product will not
interfere with investigational trials that could support a
medical product’s development or marketing approval for
the treatment indication.
What are characteristics of phase 1 studies
Normal volunteers or subjects with condition
under study
Usually conducted at Phase 1 units, tightly
controlled, in-patient setting
Usually single-center studies
Small numbers of subjects/study and overall:
“…generally in the range of 20 to 80.”
What are characteristics of phase 2 clinical trials
Initial demonstration of efficacy in subjects
with the condition under investigation
Obtain short-term safety data
Multicenter, well-controlled studies
Relatively small number of subjects per
study
Combined population: “…usually involving
no more than several hundred subjects.”
What are characteristics of phase 3 clinical trials
Confirmation of short-term efficacy and
safety
Establish long-term efficacy and safety,
as appropriate
Assess overall therapeutic value
Expanded controlled and uncontrolled
studies
Additional evidence of efficacy and safety
Establish overall benefit-risk relationship
Supports the final labeling content
Combined population from several hundred
to several thousand subjects.”
What are characteristics of phase 4 clinical trials
(Post-marketing):
Address FDA requirements for additional
information not in NDA
Delineate additional information about
the drug’s risk, benefits and optimal use;
continue assessing overall therapeutic
value
Surveillance for less common adverse
events (spontaneous reports, registries)
Design and number of subjects
depends on study objective
May be similar to Phase 2 or Phase 3
studies in design
What are the regulatory submission paths for pharmaceutical companies
Preclinical > IND> PHase I, II, III > NDA
wHAT IS THE REGULATORY SUBMISSION PATH FOR MEDICAL DEVICE PLAC
If needed, Pre-IDE > If clinical trials needed: IDE via IRB approval or FDA approval > Pilot, Pivotal > LEtter to file, 510(k), OMA
What is the development timeline for drugs/biologics
Has to have Phase I, II, III and has thousands of subjects over 10-12 years long
What is the development timeline for devices
Pilot study, Pivotal Stdy, hundreds of subjects 1+ years
What is the definition of a device
An instrument, apparatus, implement, machine, contrivance,
implant, in vitro reagent, or other similar article, including any
component, part, or accessory which is:
Recognized in the official National Formulary, or the United States
pharmacopeia, or any supplement to them
Intended for use in the diagnosis of disease or conditions, or in
the cure, mitigation, treatment, or prevention of disease in man
or other animals
Intended to affect t
What is the definition of intended use
The general purpose of the device or
its function. The intended use of a device
encompasses the indications for use.
What is the definition of indications for use
The disease or condition the
device will diagnose, treat, prevent, cure or mitigate,
including a description of the patient population for
which the device is intended.
What established FDA’s jurisdiction over costmetics and medical devies
Federal Food, Drug and Cosmetic ACt 1938
What amendment was the first major amendment specifically for devices and established three regulatory classes for medical devices based on degree of control necessary to assure that the various types of devices are safe and effective?
Medical Device Amendments 1976
What is the CFR for Medical Device Reporting
21 CFR 803
What is the CFR for INvestigational Device Exemption (counterpart to IND requirements 21 CFR 312)
21 CFR 812
Premarket Approval of Medical
Devices (counterpart to NDA requirements 21 CFR 314)
21 CFR 814
Medical Device Classification PRocedures
21 CFR 860
During device development there are distinguished classes according to risk factors, what are those classes and describe them
Class I: Lowest risk, clinical trials generally not
required
Class II: Moderate risk, usually requires 510(k),
Might require PMA
Generally requires some clinical data
Class III: Highest risk; PMA usually required,
clinical trials absolutely necessary
What general controls are regulatory class I device developments required to follow
Prohibition against adulterated or misbranded devices
Pre-market notification 510(k) requirements
GMPs
Registration of manufacturing facilities
Listing of device types
Generally do not require clinical trials
Examples include: elastic bandages, examination gloves, hand-held surgical instruments
For Class I regulatory for device developments describe the general controls
General controls alone are sufficient to
provide reasonable assurance of the safety
and effectiveness of the device
Regulatory Class II for device development
Are devices for which general controls alone are
insufficient to assure safety and effectiveness,
and existing methods are available to provide
such assurances.
In addition to complying with general controls, Class II devices are also subject to special controls, what are they?
Special controls may include:
Special labeling requirements
Mandatory performance standards
Post-market surveillance
Examples: powered wheelchairs, infusion pumps,
and surgical drapes
Regulatory class II device deleopment
devices are those for which insufficient information exists to assure safety and effectiveness solely through general or special controls
examples include: replacement heart valves, silicone gel-filled breast implants,
implanted cerebella stimulators, and implantable pacemaker pulse
generators
What is an IDE and what does it do
investigational device exemption
is the mechanism the sponsor uses to submit documents to the FDA; protocols reports correspondence. IT applies to all clinical investigations of devices to determine safety and effectiveness
An approved IDE permits a device to be shipped lawfully for the purpose of conducting investigations of the device
Significant Risk (SR) and Non Significant Risk (NSR)
determination is based on risk of the device to the subject ______________________________
as it will be used in the study
- A SR device study is defined as a study of a
device that presents a potential for serious risk to
the health, safety, or welfare of a subject:
- is an implant,
- is used in supporting or sustaining human life,
- is of substantial importance in diagnosing, curing,
mitigating or treating disease, or otherwise prevents
impairment of human health, or - otherwise presents a potential for serious risk to the
health, safety, or welfare of a subject. - Misdiagnosis and/or error in treatment caused by
inaccurate test results would be considered a significant
risk.
A NSR device study is defined as a study _____________
that
does not meet SR criteria
The sponsor makes an itial determination for SR or NSR studies… what are the next steps for NSR
If NSR, the sponsor submits device description, rationale for determining NSR status, and protocol to the investigator who provides to the IRB
If IRB concurs, the sponsor sends device description,
rationale for determining NSR status, IRB concurrence and protocol to the FDA
The sponsor makes an intial determination for SR or NSR studies… what are the next steps for
If either the sponsor or IRB consider the device to be SR,
the sponsor consults CDRH about submitting an IDE
FDA can override the determination by either sponsor or
IRB; FDA determination of SR or NSR is final
- NSR Abbreviated Requirements (Sponsors):
- Label device
- Maintain records
- Ensure investigators maintain records and make
reports - Obtain IRB approval; SR vs. NSR designation
- Ensures informed consent is obtained (IRB can waive
if minimal risk) - Submit reports
- Monitor the study
- Refrain from promotion and other practices
Yes. Under § 812.5 an investigational device or its
immediate package must bear a label with the following
information:
the name and place of business of the manufacturer,
packer, or distributor;
the quantity of contents, if appropriate; and
the statement, “CAUTION Investigational device.
Limited by Federal (or United States) law to
investigational use.”
The label must also describe all relevant contraindications,
hazards, adverse effects, interfering substances or devices,
warnings, and precautions.
Sponsor must report the results of an evaluation of
an unanticipated adverse device effect to FDA
and all reviewing IRBs and investigators within _____
working days after the Sponsor first received
notice of the adverse effect.
10
Sponsor must report the following when?
Withdrawal of IRB approval
5WD
Sponsor must report the following when?
Withdrawal of FDA Approval
5WD
Sponsor must report the following when?
Current List of Investigators
(every 6 months)
Sponsor must report the following when?
Progress Reports
at least yearly to IRB
at least yearly to FDA for SR
The legally marketed device(s) to which equivalence
is drawn is known as the
predicate device
________________________ is the FDA process of
scientific and regulatory review to evaluate the
safety and effectiveness of Class III medical
devices.
- Premarket approval (PMA)
Medical device manufacturers as well as other firms
involved in the distribution of devices must follow certain
requirements and regulations once devices are on the
market to include:
Implementing tracking systems
Reporting device malfunctions
Reporting serious injuries or deaths
Registering establishments where devices are produced
or distributed
What are the required elements of informed consent
The study involves research
Explain purposes of the research
Expected duration of the subject’s participation
Description of procedures to be followed
Identification of experimental procedures
2. Description of any reasonably foreseeable risks or
discomforts to the subject
3. Description of any benefits to the subject or to others
which may reasonably be expected from the research
Disclosure of appropriate alternative
procedures or courses of treatment, if any,
that might be advantageous to the subject
5. Statement describing extent, if any, to
which confidentiality of records identifying
the subject will be maintained:
FDA regulations require notice that the Food and Drug
Administration may inspect the records
ICH extends this notice to “regulatory authority(ies)”, the
Sponsor and/or its representatives, and IRB
representatives
Explanation as to whether any compensation
and whether medical treatments are
available if injury occurs
7. Explanation of who to contact for pertinent
questions regarding:
The research project
Research subjects’ rights
Research-related injury
8. Participation is voluntary
Refusal will involve no penalty or loss of benefits to
which the subject is otherwise entitled
The subject may discontinue participation at any time
without penalty or loss of benefits to which the subject
is otherwise entitled
What is 21 CFR 50.27
Short form consent
Who signs what when using a short form consent
Oral consent followed by subject and
witness signing and dating short form
Person obtaining consent and witness sign
written summary
Copy of written summary and short form
given to subject or representative
What is 21 CFR 50.23
Informed Consent Exception from General
Requirements
If, in the investigator’s opinion, immediate use of the test
article is required to save the subject’s life and time is
not sufficient to obtain independent confirmation before
using the test article:
The investigator makes the determination
Within 5 working days after use, a physician not
otherwise involved in the clinical trial will review the
use and make a written evaluation.
In both scenarios, the required documentation must be
submitted to the IRB within 5 working days after the use
of the test article.
What is 21 CFR 50.24
Informed Consent - Exception from
Informed Consent Requirements for
Emergency Research
21 CFR 50 Subpart D -
45 CFR 46 Subpart B -
45 CFR 46 Subpart D -
Children
Pregnant minors, Neonates
Children
The IRB can waive assent requirements if:
clinical trial involves no more than minimal risk
waiver will not adversely affect the rights and welfare
of the subjects
clinical trial could not practically be carried out without
the waiver
When appropriate, pertinent information is given to
the subjects after participation
Rules of characteristics of those on an IRB
-minimum 5 members
- varied backgrounds
-diversity and expertise
-no gender discrimination
-at least one non scientific member
-at least one not affiliated with institution
No IRB member may participate in initial or
continuing review in any project that might
involve conflict of interest
Experts may assist the board, but may not vote
What are the vulnerable populations
prisoners,
pregnant women, children,
handicapped,
mentally disabled,
economically or educationally disadvantaged
The following should be submitted to the
IRB for review:
Protocol and Amendments
Written informed consent
Subject recruitment procedures
(advertisements)
Investigators brochure
Available safety data
Information about payments and
compensation to subjects
Current curriculum vitae and/or other
documentation of qualifications for
investigator and sub investigators (critical
staff)
Additional material as individual IRBs may
find necessary
What are the key topics for IRB continuing review?
1) Risk Assessment;
2) Adequacy of Informed Consent;
3)Local Issues, and
4) Trial Progress
Progress report should include:
Risk/benefit assessment (e.g. Data Monitoring Cttee Report)
The number of subjects entered (locally and study wide)
Summary of:
amendments since initial or last continuing review
experiences ( including benefits and adverse events)
unanticipated problems
complaints
subject withdrawals and reason for withdrawals
Research results thus far
what is 21 CFR 56.110
Expedited Review
What are the four types of control groups
Placebo concurrent control
Active-treatment concurrent control
Dose-comparison concurrent control
No-treatment concurrent control
What is the trial design for placebo concurrent control
Placebo is expected to provide no or only minimal
efficacy.
This type of study is intended to show the investigational
product is better than a presumed inactive treatment
regarding efficacy.
Placebo also provides a valuable reference for
determining which safety endpoints (AEs, abnormal
laboratory, vital signs, ECGs, physical examinations,
etc.) might be associated with the investigational product.
Generally used when the treatment period is short, and
lack of treatment of the medical condition is not expected
to have clinically relevant impact on the subject’s overall
health (example: hypertension treated for 6-8 weeks)
Trial design for active-treatment concurrent control
Active controls generally are used when it is
unethical to use placebo, e.g. – anti-infective
drugs, chemotherapy, other conditions where
non-treatment could result in significant
health consequences, even in the short term
Generally are intended to demonstrate
equivalence (neither better nor worse than
the comparator) or non-inferiority (at least as
good as the comparator)
Trial Design:
Dose-comparison Concurrent Control
Multiple dose levels of the investigational
product might be evaluated in the same
study, with prospective randomization to
treatment groups
These studies might be conducted using the
dose-escalation design
Primary objectives are to compare the
efficacy and safety at multiple doses of the
investigational product
Trial Design:
No-treatment Concurrent Control
Subjects are randomly assigned to test
treatment or no (i.e., absence of) study
treatment.
The principle difference between this design and
a placebo-controlled trial is that subjects and
investigators are not blind to treatment
assignment.
Usually used only when it is difficult or
impossible to double-blind (e.g., treatments with
easily recognized toxicity).
______________________________is an adverse reaction that is
both serious and unexpected
suspected and unexpected adverse reaction
IND Safety Reports
Sponsor must notify the FDA and all participating
investigators of any adverse events______ that are both __________
This should be done as soon as possible but no
more than ______ after the sponsor’s
initial receipt of information
associated
with the use of a drug
both serious and
unexpected
15 calendar days
- An unexpected fatal or life threatening
experience associated with the use of the drug
must be reported to FDA in writing no later than
________ after the receipt of information - Followed by a written report no more than ________ after the initial receipt of
information
7 calendar days
15 calendar days
what is FDA 21 CFR 312.62
Investigator recordkeeping and record retention
The IRB should retain all relevant records
for a period of ______years after completion of
the trial and make them available upon
request from the regulatory authorities
3
What are the types of FDA investigator inspections
PDUFA-related inspections
Directed inspections
When would PDFUA-related inspections occur
“Routine” inspections
Triggered by submission of an NDA (NME, pivotal
studies not conducted in US, only foreign data)
When would directed inspections occur
“For cause”
Triggered by allegations that raise concerns regarding
data integrity or the rights, welfare and safety of study
subjects have been compromised
what are some triggers for directed inspections
Participation in a pivotal study
High enrollment
Irregularities in drug management
High percentage of subjects excluded from the perprotocol population
If an IRB’s contact or chair person information changes, the IRB must
revise its registration information by submitting any changes in that information within ______ days of the change.
90
An IRB’s decision to
review new types of FDA-regulated products (such as a decision to review studies pertaining to food additives whereas the IRB
previously reviewed studies pertaining to drug products), or to discontinue reviewing clinical investigations regulated by FDA is a
change that must be reported within ________ days of the change.
30
An IRB’s decision to disband is a change that must be reported within
_____ days of permanent cessation of the IRB’s review of research.
30
