Pocket Oncology (Pocket Notebook Series), 1st Ed.

REGULATORY ASPECTS OF CLINICAL TRIALS

Aki Morikawa and Gregory J. Riely

General Principles

Good clinical practice (GCP) guideline developed by the ICH (http://www.ich.org/)

Health Insurance Portability and Accountability Act (HIPAA) defines research as a systematic investigation including research development, testing & evaluation, designed to develop or contribute to generalizable knowledge, covers both living & deceased individuals

Protected health information (PHI): Unique pt identifiers such as name, medical record number, address, social security number, health/insurance plan, employers/family members, all elements of date except y, etc.)

Key Individuals/Components

Principal investigator (PI): Detailed in GCP; oversees conduct of trial

Sponsor: Individual or organization pharmaceutical or non-pharmaceutical → assumes legal responsibility, ensures investigator appropriateness, ethics review, data quality assurance, AE reporting

Sponsor-investigator: Individual initiates & conducts a clinical investigation & under whose immediate direction the investigational drug is being administered or dispensed. For administrative reasons, only one individual/organization. If a pharmaceutical company will be supplying the drug, but will not itself be submitting the IND, the company is not the sponsor.

IND application: For therapeutic trials, filed w/the FDA; required to conduct clinical studies w/an investigational drug involving interstate commerce for drugs as well as biologics (eg, vaccines); describes formulation, toxicology, & other drug-related info such as nonclinical efficacy; submitted by the study sponsor; FDA has 30 d to review initial submission. Certain protocols may be IND-exempt.(www.fda.gov/drugs/developmentapprovalprocess)

Trial registration. Section 801 of the Food and Drug Administration Amendments Act (FDAAA 801) requires Responsible Parties to register & submit summary results of clinical trials w/ClinicalTrials.gov

Types of trials/funding: IITs, ISTs, cooperative group trials, trials conducted w/the NCI/CTEP

Important Documents

Protocol: Includes aims/objectives, background, protocol description/schema, statistical consideration, tox/AEs, plan for dose modification for DLT, criteria for subject inclusion/exclusion, end points/outcome assessment, randomization procedure, data management plan, protection of human subjects, informed consent procedures, references

Informed consent: Document detailing purpose of research, description of research procedures, drugs, possible risks/AEs, benefits, alternatives, financial costs, right to withdraw or refuse, termination, & confidentiality & privacy

Research authorization: Obtains approval from the pt that PHI can be disclosed for research purposes, describes in detail how info is shared

Investigator’s brochure: Summary document of study drug info on physical, chemical, pharmaceutical properties, PK data & previous studies (nonclinical & clinical)

Contract: Details responsibilities, intellectual property, payment schedule, publication rights, etc.

Budget: Details study-specific expenditures, includes items which are not billable to the pt or insurance

Protocol Review Process

Institutional review board (IRB): Organization required by federal law to review research that is federally funded or subject to FDA oversight; can be local, central, or commercial, minimum of 5 members (including 1 scientist, 1 non-scientist, & 1 person not affiliated w/institution) → ensures that risks are reasonable given potential benefits, risks are minimized, participant selection is equitable, informed consent is obtained properly, rights & welfare of participants are maintained as appropriate; may approve, disapprove, modification requirement, terminate/suspend

Institution-specific committees: Conduct review in addition to IRB, often w/a different focus (eg, to determine if protocols align w/departmental or institutional interests

Certain research may be exempt from requirement for informed consent (eg, retrospective studies), but requests require review by IRB or privacy board—require a waiver of HIPAA authorization & informed consent; requires that the following criteria be fulfilled: (1) Research could not be practically conducted w/o a waiver, (2) research could not be conducted w/o PHI, (3) use & disclosure is no more than min. risk to participants’ privacy

During and After the Conduct of Clinical Trials

Ongoing review: Modification, AEs, study reports, annual reports, audits; conducted by the institution (IRB), sponsor, & FDA

Data safety monitoring board (DSMB): A group of experts that independently review trial data on a regular basis & gives advice to sponsor regarding safety & scientific validity & merit of the trial for continuation or discontinuation; not required for all the trials but recommended for trials w/associated risk for significant morbidity or mortality, large trials, multicenter trials

May be preset & precalculated interim evaluation boundaries -> helps determine threshold to stop or continue trial

FDA guidance on DSMB. (www.fda.gov/Regulatoryinformation/guidances)

Safety monitoring required for all, but not all require formal committee; may be external to the trial organizers, sponsors, & investigators

Meeting w/FDA: May be requested to ensure adequacy of trials for NDA & registration; often after phase I or phase II

New drug application (NDA): Submitted by sponsor → includes preclinical data, clinical studies, info on safety & efficacy, proposed labeling & manufacturing detail. FDA approval for specific use evaluated in clinical trials; effectiveness of drug → OS or surrogate outcome; approved can be fast track for accelerated approval.

Postmarket studies/surveillance: Required as a condition for approval if fast track or pediatric indication

Figure 2-3 Drug Development Overview