April 30 1996
ICH GCP Development Date
Quality
ICH Q
01:13
01:41
Efficacy
ICH E
Safety
ICH
... [Show More] S
Multidisciplinary
ICH M
guidance for industry, consolidated guideance
ICH E 6
Clinical Safety Data Management Definitions and Standards
ICH E2A
Safety pharmacology studies for human pharmaceuticals
ICH S7A
Electronic records, electronic signatures
21 CFR Part 11
Informed Consent
21 CFR Part 50
Financial Disclosures
21 CFR Part 54
Institutional Review Board
21 CFR Part 56
IND Application
21 CFR 312
New Drug Application
21 CFR 314
Investigational Device Exemption
21 CFR 812
21 CFR Part 814
pre market approval of medical devices
45 CFR Part 46
Federal Research
Studies that investigate the potential undesirable PD effects of a substance on physiological functions in relation to exposure in the therapeutic range or above
Safety Pharmacology Studies (Pre-Clinical)
1) To Identify undesirable PD properties of a substance that may have relevance to its human safety.
2) To evaluate adverse PD and/or pathophysio effects of a substance observed in toxicology studies
3)to investigate the mechanism of the adverse PD effects observed and/or suspected
Drug Development Safety Pharmacology Study Objectives (3)
1) Cardiovascular
2)Respiratory
3)CNS
Three vital organ considered highest priority
1) PK and toxicokinetic
2) Single dose toxicity
3) Repeated dose toxicity
4) Local tolerance
5) Genotoxicity
6) Carcinogenicity
7) Reproduction toxicity
8) Supplemental studies if needed
Types of Non-Clinical Studies (Animal Trials)
Study that investigates the mode of action and/or effects of a drug substance in relation to its desired therapeutic target
Primary Pharmacodynamic Studies
Studies that investigate the mode of action and/or effects of a drug substance not related to its desire therapeutic target
Secondary Pharmacodynamic Studies
Blood Pressure
Heart Rate
ECG/EKG
Repolarization/conductance abnormalities
Core Battery for Cardiovascular System
Respiratory Rate
Functional Assessments (tidal volume, hgb Oxygen saturation)
Core Battery for Respiratory System
Motor activity
behavioral changes
coordination
sensory/motor reflex response
temperature
Core Battery for Central Nervous System
Investigational New Drug Application
FDA
Before clinical trials can be initiated, an application containing the appropriate information must be submitted to regulatory authorities, in the USA this is called XXXX and submitted to the XXX (21 CFR Part 312)
Unapproved drug to be shipped lawfully for the purpose of conducting investigations of the drug
An IND permits what? (21 CFR Part 312)
Assuring the safety and rights of subjects
FDA's primary objective in all phases of development is...
Phase II and III
These phase of trials, the FDA helps assure the quality of the scientific evaluation is adequate to permit evaluation of the drugs safety and efficacy (21 CFR Part 312)
The FDA
Who determines if Phase II/III studies are likely to yield data capable of meeting regulatory standards for marketing approval?
1) Novelty of drug
2)Extent the drug has been studied previously
3) Known of suspected risks
4) Phase of development
IND information depends on the amount of information available, these 4 things are: (21 CFR Part 312)
General Investigational Plan
Protocols for specific human studies
Initial IND should focus on (21 CFR Part 312)
Build logically on previous submissions
Be supported by additional information such as animal studies and other human studies
Amendments to IND with new or revised protocols (21 CFR Part 312)
Cover Sheet (FDA Form 1571)
Table of Contents
Introductory statement
investigator's brochure
protocol (s)
Chemistry and manufacturing information
pharm and tox information
previous human experience with investigational drug
A Sponsor Initiated IND must contain (21 CFR Part 312)
30 Days, unless FDA notifies sponsor of clinical hold
Upon earlier notification, investigations may begin
How long does it take for an IND to go into effect? (21 CFR Part 312)
1) To facilitate the availability of promising new drugs available to desperately ill patients as early in the drug development process as possible, before general marketing begins
2)To obtain additional data on the drug's safety and effectiveness
The purpose of Treatment Use of Investigational Drug (21 CFR Part 312)
1) The drug is intended to treat a serious or immediately life threatening disease
2) No comparable or satisfactory alternative drug/therapy is available to treat the stage of disease in the intended patient population
A treatment protocol or IND may be filed if: ((21 CFR Part 312)
Phase II/ III trials or
After all the clinical trials have been completed and the sponsor of the controlled clinical trial is actively pursuing marketing approval of the drug with due dilligence
A treatment protocol or IND are usually found in what phase of trials?
30-Day Waiting Period
How long is the waiting period before the study can initiate after the treatment IND is submitted?
Need for investigational drug arises in an emergency situation
Insufficient time to allow for submission of an IND or a treatment IND
Request for specified use by telephone or other rapid means of communication
Emergency use of an investigational product (21 CFR Part 312)
5 Working Days
How quickly must a site notify the IRB of an emergency use of investigational drug? (21 CFR Part 312)
1) Notifying the FDA
2) Stopping all studies and notifying the investigators
3)All drug returned to the sponsor or destroyed as directed by sponsor
4)If withdrawn due to safety reasons, the sponsor must notify the investigators and the IRBs of those reasons
Sponsors have the right with withdraw an IND at anytime, without prejudice by completing the following: (21 CFR Part 312)
An order issued by the FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation
What is a "Clinical Hold"
Subjects may not be given the investigational drug
What does a FDA "Clinical Hold" mean for a proposed study?
no new subjects may be given the IP and subjects already taking the drug should be discontinued unless continuation is specifically permitted by the FDA
What does a FDA "Clinical Hold" mean for an ongoing study?
1) Subjects exposed to unreasonable risk, illness or injury
2)Clinical investigators are not qualified
3)Investigator's brochure is misleading, inaccurate or materially incomplete
4)The IND does not contain sufficient information to assess risk to subjects
Grounds for FDA Clinical Hold in Phase 1 Trials
1) All grounds related to holds in Phase 1 trials AND
2) The protocol is clearly deficient in design to meet the stated objects
Grounds for FDA Clinical Hold in Phase II/III Trials
1) Initial Safety, dose escalation studies to determine MTD
2) PK and PD property, might be cross over design
3) Absorption, distribution, metabolism and excretion studies
4) Efficacy assessment, if possible
Types of Phase I Trials
1) Initial demonstration of efficacy in subjects with the condition under investigation
2) obtain short term safety
Goals of Phase II Trials
1) Confirmation of short term efficacy and safety
2) Establish long term efficacy and safety
3) Assess overall therapeutic value
Goals of Phase III trials
Phase III
What phase of study usually has the largest number of subjects per study?
Phase I
What phase of study is usually single-center?
Phase II/III
What phases of stuides are usually multicenter?
1) Address FDA requirements for additional information not in NDA
2) Continue to assess overall therapeutic value
3)Surveillance for less common adverse events
Goals of Phase IV Trials
1976
What year was the Medical Device Amendment?
Medical Device Reporting
21 CFR Part 803
Investigational Device Exemption
21 CFR Part 812
Premarket Approval of Medical Devices
21 CFR Part 814
Quality System Regulations
21 CFR Part 820
Medical Device Classification Procedures
21 CFR Part 860
1) Achieve their primary intended purpose through chemical action within the body
2) Are dependent upon being metabolized for the primary achievement of the primary intended purpose
Device definitions excludes what 2 type of products
1976, With Medical Device Amendments
When was 510K Clearance Established?
Clearance
What is a 510k?
1) Required process of scientific review to ensure the reasonable safety and effectiveness of medical devices
2) FDA approval required before the device can be legally marketed
Pre-Market Approval Requirements
Lowest Risk, 510K often not required
How do you define Class I Devices?
Class I, II, III
How are devices distinguished by risk?
Moderate risk, usually requires 510k, might require PMA
How do you define a device with Class II risk?
Highest risk, PMA required
How do you define a device with Class III risk?
Elastic bandages, exam gloves, hand-held surgical instruments
Examples of Class I devices
1) Prohibition against adulterated or misbranded devices
2) Premarket notification 510k requirements
3) GMPs
4) Registration of manufacturing facilities
5) listing of device types
What are the general controls that provide reasonable assurance of safety for a device?
Class I
What type of device is sufficiently assured by general device controls?
1) Special labeling requirements
2) mandatory performance standards
3) post-market surveilance
In addition to general controls, Class II devices are also subject to these types of special controls
1) Are usually those that support or sustain human life
2) are of substantial importance in preventing the impairment of human health
3)Present a potential, unreasonable risk of illness or injury
Class III Devices Descriptions
Replacement heart valve
silicone-gel filled breast implants
implanted cerebella stimulators
implantable pacemakeres
Examples of Class III Drugs
Powered wheel chairs
infusion pumps
surgical drapes
Examples of Class II devices
Determined by the nature of the harm that may result to the subject in the study
How is risk determined in device studies?
1) In an Implant
2)is used in supporting or sustaining life
3)is of substantial importance in diagnosing, curing, mitigating or treating disease or other prevents impairment of human health
4)otherwise presents a potential for serious risk to the health, safety, or welfare of a subject
A Significant Risk (SR) Device Study is defined as:
Does not meet the criteria for significant risk
How do you define a non-significant risk device study?
The sponsor, the IRB evaluates the determination
Who makes the initial determination of SR or NSR?
The probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological exams and tests
IRB definition of Minimal Risk
Significant Risk Trials
What type of device studies are subject to all IDE regulations (21 CFR Part 812)
Non-significant risk trials
What type of device studies are subject to abbreviated IDE regulations? (21 CFR Part 812.2b)
Pilot Study
Pivotal Study
Types of Device Trials
the shipment of a device for the purpose of conducting investigations of the device without complying without FDA requirements that would apply to devices in commercial distribution
What does an Investigational Device Exemption (IDE) permit?
1)Legally marketable device in accordance with its labeling
2)diagnostic device complying with labeling requirements, testing is non-invasive
3)Does not require invasive sampling procedure
4)Does not introduce energy into subject
5) It is not used as a diagnostic procedure without confirmation by a medically established diagnostic product
Devices can be granted IDE if:
1) Any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with a device
2)if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application
2) any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects
Definition of Unanticipated adverse device effect
Unanticipated adverse device effect (UADE)
What is the SAE counterpart in device trials?
Investigational agreement
What is used in device studies instead of a 1572?
5 Working Days, IRB and sponsor
What time frame and to whom do sites have to report deviations from investigational plan in order to protect life or well being of patients on device trials?
10 Working Days, Sponsor and reviewing IRB
What timeframe and to whom do investigators have to report UADEs?
5 Working Days (Sponsor and IRB)
Notification time requirement for emergency use of investigational device
Sponsor
Who is responsible fore maintaining an effective IND or IDE?
Sponsor
Who is responsible for ensuring all investigators are conducting studies according to the general investigational plan and protocols in the IND?
Sponsor
Who is responsible for promptly reporting information about significant new adverse events or unanticipated adverse device effect with respect to the investigational product?
Sponsor
Who is responsible to terminate all studies if the product presents an unreasonable and significant risk to study subjects?
Sponsor
Who is responsible for selecting qualified investigators?
Sponosr
Who is responsible for providing information needed to conduct the study?
Sponsor
Who is responsible for selecting qualified monitors?
1) Medical Monitor
2) Data Safety Monitoring Boards
3) On-site monitoring
What are three types of monitoring the sponsor is responsible for?
Sponsor Medical Monitor
Who is responsible for clinical oversight, evaluating safety information-trial wide?
Data Safety Monitoring Board
Who is responsible for periodic review of study data while study is in progress?
On-Site Monitors
Who is responsible for periodic site visits?
1) Manufacturing, packaging, labeling and coding of the investigational drug
2) Providing the investigational product only to investigators participating in an investigation
3)Maintain drug and device accountability records from manufacturing through use, return and destruction
What are SPONSOR responsibilities with regard to IP?
1) Signed 1572 or investigational agreement
2)CV
3)Protocol
4) Financial disclosure
What documents must be obtained from an investigator prior to study start?
Sponsor
Who is responsible for submitting safety reports to sites?
Sponsor
Who is responsible with providing pre-clinical and clinical study reports in the information amendments to the IND?
Sponsor
Who has the responsibility in submitting an annual report to the IND/IDE?
Sponsor
Who has the responsibility in maintaining quality assurance and quality control systems, with SOPs, for all activities?
Sponsor
Who has the responsibility to ensure the study is designed by qualified individuals?
Sponsor
Who has the responsibility to obtain an agreement from the investigator to adhere to the protocol, obtain IRB approval and GCP compliance?
Sponsor
Who is required to notify all parties involved, if warranted, of new safety information adversely affecting subject safety?
During Marketing Applications
When do sponsors have to submit summary forms of financial disclosures to the FDA?
1) Compensation affected by study outcome or in the form of equity interest in sponsor or compensation tied to sales
2)Significant equity interest in sponsor
3) Proprietary interest in tested product
4) Significant payments of other sorts to investigator or institution supporting activities of investigator
What are 4 types of financial disclosures?
All amounts
What is the $ reportable amount for a financial disclosure if the amount is based on study outcome?
All amounts
What is the $ reported amount for a financial disclosure for proprietary interest in the test product?
All amounts
What is the $ reported amount for a financial disclosure for equity interest in the sponsor?
>$50,000
What is the $ reported amount for a financial disclosure for equity interest in a publicly traded company?
>$25,000
What is the $ reported amount for a financial disclosure for significant payments?
Contract Research Organization
Who may the sponsor transfer responsibility of duties or functions?
Monitor Responsibilties
ICH E6, Section 5.18
1) Verify the rights and well-being of human subjects are protected
2)Reported trial data are accurate, complete, and verifiable from source documents
3)The study is conducted in compliance with the study protocol, the GCP guidelines and applicable regulations
What are the primary purposes for study monitoring?
1) The investigator's name and site location
2) date of the visit
3) monitor's name
4) site personell contacted
5)summary of what information was reviewed
6)significant findings and corrective action
Written monitoring reports should include what elements?
Investigator Responsibilities
21 CFR 312.60-70
Investigator Responsibilities
ICH E6 Section 4
1572
What form documents investigator agreement to investigator responsibilities in drug trials?
Maintain adequate and accurate records
Investigator responsibilitiy
21 CFR Part 312.62
Make study records available for inspection
21 CFR Part 312.68
1) Inventory of product received by site, and date
2) Dispensing and return information for each subject
3)Specific protocol information like batch numbers, expiration dates, serial numbers, unique codes assigned to trial subjects
Drug accountability records should contain:
Single line through the error
Enter correct information
Initial and date the change
Provide explanation if needed
Do not obliterate error
No erasures
No white-Out
How should source document corrections be made according to GCP guidelines?
1947
When was the Nuremberg code developed?
1) Voluntary consent
2) Fruitful results
3) Based on animal studies
4)avoid unnecessary physical or mental suffering
5)should not be conducted if death or disability will occur with a priori knowledge
6)humanitarian Benefits outweigh risk
7) proper facilities and preparation
8)conducted by qualified individuals
9)freedom to withdraw consent
What did the Nuremberg code establish?
1964
When was the Declaration of Helsinki?
Reiterated Nuremberg Code, "Informed Consent" obtained, design and performance of experiment procedure is clearly formulated in a protocol
What did the Declaration of Helsinki accomplish?
1979
When was the Belmont Report?
1974
When was the National Research Act passed by congress?
Boundaries between practice and research?
What did the Belmont report establish?
Interventions designed solely to enhance well-being of the patient with reasonable expectation of success
How does the Belmont Report Define "Practice"?
Activity designed to rest a hypothesis, draw a conclusion to develop or contribute to generalized knowledge
How does the Belmont Report define "Research"?
1) Respect for persons
2) Beneficience
3)Justice
What are the three principles of the Belmont Report?
1) treated as independent agents, those with diminished autonomy are entitled to protection
2) subjects enter into research voluntarily and with adequate information
What does "Respect for Persons" entail?
1) Respecting decisions
2) Protecting from harm
3)securing well being: do no harm and maximize benefits while minimizing possible harm
What does "Beneficence" entail?
1) Fairness, potential participants should be treated equally
2)Benefit of research not restricted to those who can afford it
3)Research should not involve persons from groups not likely to benefit from application of the research
What does "Justice" entail?
Informed Consent
ICH E6 Section 4.8
Informed consent
What must be obtained from the subject or LAR prior to initiating any research related exams?
When there is no additional relevant information to provide to the subject?
When is the informed consent process over?
1) Statement that includes the nature of the research, the purpose, duration, procedures and experimental procedures
2) Description of risks/discomforts
3) Benefits to the subjects or others
4)Alternative procedures or courses
5) Statement of record confidentiality
6) Compensation
7)Who to contact
8) statement that participation is voluntary
What 8 ICF elements are required by 21 CFR 50
1) Risks to embryo or fetus
2) circumstances that might end trial
3)additional costs
4)approximate number of subjects
5)consequences of subject's decision to withdraw
6)significant new finding statement
What additional elements can be included in an ICF, but not required?
The Informed Consent Form
What cannot contain language that waives or appears to waive the rights of the subject?
The Informed Consent Form
What cannot include language that releases or appears to release investigator, institution, sponsor or their agents from liability for negligence? [Show Less]