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72 Cards in this Set
- Front
- Back
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Adverse Events |
- Any untoward medical occurrence associated with the use of drugs in humans, whether or not considered drug related - Can be an unfavorable and unintended sign, symptom, or disease temporally associated with use of a drug, and does not imply any judgement about causality |
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Adverse Reaction |
Any adverse event caused by a drug |
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Suspected Adverse Reaction |
Any adverse event for which there is a reasonable possiblity that the drug caused the adverse event |
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Sources of safety information include: |
- Clinical or epidemiological investigations - Animal or in vitro studies - Reports in the scientific literature, unpublished scientific paper - Reports from foreign regulatory authorities and foreign commercial marketing experience |
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Safety Information: Increased Rate of Occurrence of AEs |
The sponsor must report any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure |
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Purposes of Trial Safety: Labeling |
Continued development of well informed: - IB - Informed consent form for subjects - core safety information Post marketing: - prescribing information - patient information leaflet |
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Collection:Clinical Trial, Day 0 |
Clinical trial site has an obligation to reportSAEs to the Sponsor’s representative (defined in study protocol) Day 0 = the day the clinical trial site notifiesthe Sponsor’s representative |
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Method of Adverse Event Management: Assessment |
Seriousness Severity Related vs. Unrelated MedDRA coding Expected vs. Unexpected Analysis of Similar Events
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Seriousness |
Investigator or Sponsor |
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Severity |
Investigator |
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Related vs. Unrelated |
Investigator or sponsor |
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MedDRA coding |
Sponsor |
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Expected vs. Unexpected |
Sponsor |
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Analysis of Similar Events |
Sponsor |
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Seriousness |
- death - a life‐threatening adverse event, - inpatient hospitalization or prolongation of existing hospitalization, – a persistent or significant incapacity or substantial disruption of theability to conduct normal life functions - congenital anomaly - important medical event that medical judgment , may jeopardize the patient or subjectand may require medical or surgical intervention to prevent one of theoutcomes listed in this definition. |
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Related vs. Unrelated |
‐ Sponsor is responsible for making thecausality judgment - Suspected Adverse reactions |
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Suspected adverse reactions |
- subset of alladverse events for which there is a reasonablepossibility that the drug caused the event. - need for thesponsor to evaluate the available evidence and make ajudgment about the application of the reasonablepossibility causality standard. |
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Expected vs. Unexpected |
adverse event or suspected adverse reaction is considered“unexpected” if it is not listed in the investigator brochure oris not listed at the specificity or severi |
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Analysis of Similar Events |
- Required for expedited IND safety reports - Sponsor must identify all IND safety reportspreviously submitted to FDA concerning a similarsuspected adverse reaction, and must analyze thesignificance of the suspected adverse reaction inlight of previous, similar reports or any otherrelevant information. - The analysis must include similar reports from allINDs held by the sponsor and any other relevantinformation known to the sponsor., |
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Assessment: Sponsor Medical comment |
- Discussion of caseinformation, such as time to onset, cosuspectmedications, dechallange, rechallenge, may beadded in a medical comment. - A sponsor need not admit, and may deny, thatthe report or information submitted by thesponsor constitutes an admission that the drugcaused or contributed to an adverse event |
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Reporting:7‐Day Alert |
• The sponsor must notify FDA in no case later than7 calendar days after the sponsor's initial receipt of anadverse reaction meeting these 3 criteria: – Suspected as related to study treatment by the Sponsor(i.e., including active comparators) – Fatal or life‐threatening – Unexpected • Then, on Day 15 full case information and Analysis ofSimilar Events – Submit to FDA – Submit to all study investigators – Submit to IRBs |
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Reporting:15‐Day Alert |
• 15‐Day Alerts are submitted to FDA for anyadverse reaction meeting these 3 criteria: – Suspected as related to study treatment by theSponsor (i.e., including active comparators) – Serious – Unexpected • Analysis of Similar Events • Submit to all study investigators • Submit to IRBs |
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Reporting:Unblinding/Unmasking |
• The blind should ordinarily be broken for IND safety reportssubmitted to FDA and all participating investigators. • Report is due to FDA by Day 15. |
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IND Safety Assessment |
Report when rate of event is occurring more frequently in the drug group than ina control group, historical group, protocol or investigator brochure |
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Reporting:Adverse Events of Special Interest |
• Keep track of Adverse Events of SpecialInterest (AESIs) agreed upon with FDA • Follow through with commitments to FDA |
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Reporting:Reconciliation with Clinical Database |
• Safety Database and Clinical Database shouldbe congruent for at least this information – Patient Number – Reported term (conceptual match) – MeDRA Preferred Term – Reported Relatedness to study treatment – Seriousness |
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Reporting:Clinical Study Report |
• Safety Database narratives • Clinical Study Report narratives |
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• Safety Database narratives |
usually writtenper SAE |
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• Clinical Study Report narratives |
may bewritten per subject |
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Remedial Action |
any action other than routine maintenance orservicing of a device where such action is necessary to prevent recurrenceof a reportable even |
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Serious Injury |
– (1) Is life‐threatening, – (2) Results in permanent impairment of a body function or permanentdamage to a body structure, or – (3) Necessitates medical or surgical intervention to preclude permanentimpairment of a body function or permanent damage to a body structure. |
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Manuacturer |
any person who manufactures, prepares, propagates,compounds, assembles, or processes a device by chemical, physical, biological, orother procedure. The term includes any person who either: • (1) Repackages; • (2) Initiates specifications for devices that are manufactured by a second party; • (3) Manufactures components or accessories that are devices that are ready to be used; • (4) Is the U.S. agent of a foreign manufacturer |
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Importer |
ny person who imports a device into the United States and whofurthers the marketing of a device from the original place of manufacture to theperson who makes final delivery or sale to the ultimate user, but who does notrepackage or otherwise change the container, wrapper, or labeling of the device ordevice package. |
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Device user facility |
where device is used |
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Phase I Clinical Trials |
-early use of drug - evaluate safety and tolerability of study medication - identify the maximum tolerated dose - evaluate the pharmacokinetic profile - identify potential efficacy - use about 20-80 patients |
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Types of Phase I studies |
- conducted on the inpatient unit - usually 6-8 patients in each group - healthy volunteer studies |
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Screening - General Exclusions |
- history of seizures - known HIV+ - parole, probation - career subjects - violent or suicidal behavior - healthy volunteers |
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Doses in Phase I |
-initial doses based on: 1. preclinical testing in animals - dosing: 1. single 2. multiple - titrating the dose 1. equal amount 2. equal percentage |
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How high should you go in patients? |
- maximum tolerated dose - minimum intolerable dose |
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maximum tolerated dose |
this is the highest dose which can reasonably be tolerated |
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minimum intolerable dose |
the dose which produces mild-to-moderate sub-lethal toxic effects in a significant percent of patients |
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Goals of phase I |
- safety and toxicity - pharmacokinetics - bioavailability |
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Considerations When Conducting Inpatient Studies |
- setting - safety - comfort |
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Ensuring Patient Safety Compliance During the Study |
- clear written instructions - clear verbal instructions - follow-u phone calls if long-period of time between visits |
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Bridging Study |
a safety/tolerance study of a compound in the patient population |
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Bridging Study Objective |
to define the MTD in the patient population |
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Bridging Study Benefits |
- permits optimal determination of dose - accelerates drug development timeline |
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Multicenter Trials |
- Performed simultaneously, using the same protocol - data collected an analyzed as a whole - majority of these studies are randomized controlled trials - CRO/Sponsor Team Coordinates the activities |
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Rationale for Multicenter Trials |
- patient recruitment - large number of patients needed to show treatment effect - better basis for extrapolation - reduced bias - more investigators - assessment of therapeutic approaches |
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Selecting a Site |
- needs to be competent to conduct the research - needs to be able to recruit the patients - adheres to ICH GCP |
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What is a Well-Designed Clinical Trial? |
- should have a control - should be blinded - should be randomized |
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Advantages of Clinical Trials |
- strong claims for causality - control of most bias - tight control on exposure/treatment - high internal validity - possible to examine multiple outcomes |
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Disadvantages of Clinical Trials |
- time consuming - expensive, resource intensive - compliance, patient drop-out - sometimes severe ethical constraints - may not mirror practice - may be difficult to generalize |
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Adaptive Clinical Trials |
- flexible or innovative designs - adaptive design study |
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Adaptive Study Design |
includes a prospectively planned opportunity for modification of one or more specified asepcts of the study design and hypothesis based on analysis o data |
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Adaptive Trial - Pros |
- reduction in number of patients required - eliminate treatments with little promise sooner - effective treatments get to market more quickly |
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Adaptive Trial - Cons |
- logistics - Bias - Errors - Regulatory - Disease Targets |
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Documentation |
• Keeps track of events and data • Keeps track of steps inprocedures • Keeps track of who administerstests • Keeps track of unplannedevents |
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Essential Documents |
- documents whichindividually and collectively permit evaluation ofthe conduct of a trial and the quality of the dataproduced. - serve to demonstrate thecompliance of the investigator, sponsor and monitorwith the standards of Good Clinical Practice andwith all applicable regulatory requirements |
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Minimum list of essential documents which will be normaly generated |
1) before the clinical phase of the trial commences 2) during the clinicalconduct of the trial, and 3) after completion ortermination of the tria |
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Case Report Forms |
- A printed, optical, or electronic document designedto record all of the protocol required information tobe reported to the sponsor on each trial subject |
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Changes to Case Report Forms |
- dated - initialed - explained |
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Monitoring Case Report Forms |
(i) The data required by the protocol are reported accurately on the CRFsand are consistent with the source documents. (ii) Any dose and/or therapy modifications are well documented for eachof the trial subjects.(iii) Adverse events, concomitant medications and intercurrent illnessesare reported in accordance with the protocol on the CRFs. (iv) Visits that the subjects fail to make, tests that are not conducted, andexaminations that are not performed are clearly reported as such on theCRFs.(v) All withdrawals and dropouts of enrolled subjects from the trial arereported and explained on the CRFs. |
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Source documents |
- any original documents,data, and records. - is a document in which data is collected for clinical trial is first recorded - These data are usually later entered in the casereport forms. |
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Case Report Forms |
- made for sponsor use - contain info sponsor needs - are in format sponsor wants: often one test per page (multiple dates) - easiest for person using data |
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Source Documents |
- are made for hospital use - are in format useful to hospital personal - are in format sponsor wants: often one test per page (multiple tests) - easiest for hospital staff |
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How to design your CRFs |
• Pre‐planning: start with protocol and make a list • Pre‐planning: make a template for:o Study ID - Patient ID: number and initials - PI signature and date - CRF review procedures: CRA, data entry, etc - Form ID • Make draft of the CRF and include: - Date of each test / data collection - Event at each test / data collection (3 weeks, 6 weeks) - Name of test and each procedureo Body side if relevant - Units |
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All studies need CRFs for... |
• Subject information: - Age, date of birth, sex, height, weight, ethnic group - Diet, smoking, illegal drug use, pregnancy, previous treatments • Inclusion / exclusion criteria • Concomitant use of other drugs / treatment • Outcome measure results • Adverse events: type, duration, intensity,consequences, measures taken • Reasons for withdrawal and breaking code |
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Data Presentation-What type of Questions to ask |
• Open – text or standardized • Closed – binary and multiple choice |
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Answer Format |
• Dates per ISO Standard format • Closed questions |
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Make it easy for the clinical coordinator - avoid mistakes |
• Gray out areas that shouldNOT be filled • Have consistent format:date, time, order, font. • Walk the coordinator through the questions |
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Data Obtained from Subjects |
use non-medical terms |
