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
