Regulatory Class - Dec 5 Flashcards
Different types of Clinical Trial Monitoring
Assessment of clinical investigator conduct, oversight,
and reporting of findings of a clinical trial
Ongoing evaluation of safety data and emerging risk- benefit profile of investigational product
Monitoring of internal sponsor/CRO processing and systems integral the clinical study
Risk-based Monitoring
Focus on most critical data elements
To identify the critical data and processes to be monitored, sponsors perform risk assessment of:
Types of data to be collected
Specific activities required to collect data
Range of potential safety and human subject protection concerns
Primary focus on processes:
Critical to protecting human subjects
Maintaining integrity of study data
Compliance with applicable regulations
On-site monitoring
In person evaluation by sponsor representatives at clinical trial site
Source document verification (data entry errors)
Identify missing data, confirm study documentation
Assess study personnel competence, training and compliance
Verify investigational product accountability
Confirm appropriate delegation of responsibilities and supervision of study personnel
Centralized monitoring
Remote evaluation by sponsor or representatives
Can use statistical assessment to identify sites needing
additional training and/or monitoring
Replace some on-site monitoring activities (Checks for completeness of data or unusual distribution of data)
Augment on-site monitoring (Statistical analyses to identify data trends)
useful to: Identify high-risk clinical sites Monitor data quality in real-time Verify source data remotely Identify sites that are outliers Complete administrative and regulatory tasks
Clinical Trial Monitoring: Risk Assessment
Some data errors are more important than others
Critical study endpoints (primary and secondary)
Protocol eligibility criteria
SAEs – evaluation, documentation and reporting
Processes to ensure subject safety (Protocol-required safety assessments)
Procedures related to blinding (site and/or sponsor)
Verification of informed consent
Investigational product accountability
Factors to consider for centralized monitoring
Complexity of study design (e.g. adaptive design, complex
dosing schedules)
Subjective rather than objective endpoints
Vulnerable patient population
Geographic differences between sites (e.g. standard of care, patient demographics)
Experience/inexperience of investigator
Use of electronic data capture (EDC)
Safety of investigational product
Stage of study
Quantity of data
Monitoring Plan
Description of each method
Criteria for determining timing, frequency and intensity of each activity
Activities required for each method and documentation
Triggers for changes in planned monitoring activities
Identification of deviations critical to study integrity
Communication of results
Addressing issues – root cause analysis and CAPA
Training required for monitors and quality monitoring
Pharmacogenomics
Study of variations of genetic characteristics as related to drug response
Drug response (PD) – all of the effects of a drug on physiologic and pathologic processes (including effectiveness and adverse effects)
Drug exposure – administered dose, drug levels, or pharmacokinetic (PK) profile following administration
FDA encourages general DNA sample collection (make part of clinical protocol - need consent)
Genetic differences most relevant to drug development
Genes relevant to the drug’s pharmacokinetics – absorption, distribution, metabolism, and excretion (ADME)
Genes that affect the drug’s intended and unintended targets (and its effect on these targets)
Genes that predict the occurrence of disease development (e.g. predict the likelihood of tumor development)
Genomic tests (diagnostics) identify individuals:
Most likely to have an efficacious response to investigational drug
More at risk for drug-induced AEs
Unlikely to benefit
Need modified dose or dosing schedule
May be used in Phase 1/Phase 2 studies, can help target Phase 3 studies
In vitro diagnostic (IVD) device [Purposes]
Therapeutic products (drugs and biologics) may depend on the use of an in vitro diagnostic (IVD) device for safe and effective use
Identify appropriate patients for treatment (Most likely to have an efficacious response)
Identify patients that should not receive particular treatment due to increased risk of a serious side effect
Identify patients that are unlikely to benefit from treatment
Identify patients that will need modified dosing
IVD companion diagnostic device
Provides information that is essential for the safe and
effective use of a corresponding therapeutic product
May be combination product with the therapeutic product – drug-device or biologic-device combination product
Use is stipulated in the instructions for use of both the IVD and the corresponding therapeutic product
IVD companion diagnostic device must be properly validated and meet criteria for approval or clearance
Adequate performance characteristics in the intended population
FDA Review of IVD companion diagnostic device
FDA reviews each IVD companion diagnostic device submission in conjunction with corresponding therapeutic product (510k or PMA)
FDA review conducted collaboratively
If the IVD companion device and therapeutic product meet definition of combination product, may file single application
FDA may approve a new therapeutic product without approval/clearance of the IVD companion diagnostic device if:
Therapeutic product is intended to treat serious or life- threatening condition for which no satisfactory alternative treatment exists
Benefits from use of therapeutic product outweighs the risks from lack of approved or cleared IVD companion diagnostic device
If drug is approved for use with IVD, IVD should be available for use when the therapeutic product is approved. If submitted as a combo product, they’d be approved at the same time.
Labeling with IVD companion diagnostic device
Therapeutic product label will be revised to include approved/cleared IVD companion diagnostic device (include a Pharmacogenomics subsection within the Clinical Pharmacology Section)
Therapeutic product labeling must include information regarding:
Specific tests necessary for selection or monitoring of patients who need the drug
Dosage modifications in special patient populations (defined by genetic characteristics)
Identity of any laboratory tests that are helpful in identifying possible adverse reactions or the patient’s response to treatment
Type of IVD companion diagnostic device – rather than the specific IVD product
IVD companion diagnostic device labeling must include information regarding:
Specify the therapeutic product or class of therapeutic product
Revise device labeling through approval or clearance of new submission or supplement for use in another disease or setting or for use with a different therapeutic product
Investigational IVD companion diagnostic devices
Significant risk device if used to make critical treatment decisions (IDE required)
May be one clinical study covering both IVD and therapeutic product
Must meet both IDE and IND requirements
If IVD is already marketed, must submit new 510k or PMA for the new indication.
