The following information may be helpful to investigators when working with Penn State Cancer Institute’s Protocol Review Committee.
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Types of Reviews
The Protocol Review Committee chair or vice chair will determine the appropriate level of review for each study.
PRC-exempt studies do not require a PRC full committee or expedited review. Investigators must consult the PRC coordinator and vice chair regarding the exempt status determination and fill out a short submission form to request exemption.
The following studies are generally viewed as exempt:
- Retrospective studies. A retrospective study looks backward and examines exposures to suspected risk or protection factors in relation to an outcome that is established at the start of the study. Retrospective studies can include analysis of existing samples from the Institute of Personalized Medicine biorepository or retrospective chart review. Retrospective studies require a short PRC submission form.
- Non-oncology trials. These are studies in which the study aims are neither related to cancer nor cancer prevention and control.
- Registries or biospecimen banks of leftover biospecimens for the purposes of building capacity for future research. These projects do not seek to answer specific research questions.
- Single-patient or emergency use INDs. An investigational new drug (IND) application obtained for use of an unapproved drug for an individual patient does not require PRC review. However, note that any expanded access or phase IV protocols do require a PRC full-committee review.
The PRC vice chair may approve the oncology trial types listed below by expedited review. The PRC chairs have the discretion to require a full board PRC review of a trial. Examples of trials that generally receive expedited review are:
- NCI-approved cooperative group studies (National Clinical Trials Network (NCTN) and NCI Cancer Therapy Evaluation Program (CTEP)-approved studies.
- Other investigator-initiated studies that have or will receive external peer review by an approved NIH peer-review funding organization prior to activation. Extramurally funded studies that did not include a protocol as part of the peer-review process may, at the chair’s discretion, undergo a full committee review. See a list of NCI-approved peer-review agencies here.
- For multi-site institutional trials, the PRMS of the lead site is responsible for the full scientific review of the protocol (if that PRMS has been NCI-approved). The other participating sites are responsible only for an expedited review focused on prioritization, competing studies and feasibility at that site. Should the PRMS at the lead site be conditionally approved or disapproved, the full scientific review may occur at another participating NCI-designated cancer center with an approved PRMS.
- Prospective, hypothesis-driven, non-interventional studies involving cancer patients. Examples may include prospective tissue collection studies in which leftover specimens from standard-of-care procedures are being used for research, observational, ancillary and correlative studies.
For studies meeting the expedited review criteria defined above, the PRC chair and vice chair should review all submission material and give a rapid expedited review, assuring the following:
- conflicts with current studies do not exist;
- resources appear appropriate to implement and complete the study; and
- appropriate data and safety monitoring and recruitment plans are in place.
The following types of studies require PRC full-committee review:
- Investigator-initiated studies. These are studies developed within Penn State Cancer Institute PSCI faculty with funding from the institution, non-peer-reviewing agency or industry.
- Multi-institutional investigator-initiated studies where the study PI is at another non-NCI-designated institution and the study has not undergone formal peer review.
- New industry-sponsored clinical studies designed to collect prospective information by answering specific questions about the effects or impact of a particular cancer biomedical intervention such as drugs, treatment or devices. Participants in these studies may be patients with a cancer diagnosis or people at risk for cancer.
- Cancer-related hypothesis-driven interventional non-therapeutic trials that are sponsored by industry or institution. There may be exception for expedited review should the PI provide documentation of a prior external scientific peer-review of the trial from an acceptable peer-review mechanism, such as another NCI-designated center, or center with a deemed-competent PRMS review.
Full committee review focuses on the scientific merit of the study, prioritization of the study within the larger portfolio, competing studies and accrual feasibility. Committee members will address the scientific aspects of a proposed study according to defined review criteria, which are provided to all reviewers, which will include but not be limited to the following:
- Does the study address a relevant scientific question(s)?
- Are the primary and secondary objectives/endpoints clearly stated and appropriate?
- Is the study designed to meet the objectives?
- Are response criteria and endpoints clearly defined?
- Is the study designed and implemented with the appropriate statististical rigor?
- Is the data and safety monitoring plan appropriate?
- If there are early-stopping rules, are they adequately and clearly described?
- Has the investigator devised an appropriate plan to include women and minorities?
Risk Assessment Levels
Any Penn State Cancer Institute investigator-initiated study will undergo scientific review by the PRC, in part, to ensure that procedures are in place to protect the safety of all subjects depending on the degree of risk.
The PRC is mandated to assign a category of risk. The PRC chair and assigned reviewers will ensure that a study-specific DSMP is included in each protocol. The PRC has the right to request modifications to the study-specific DSMP. A PRC approval letter will be issued only if the DSMP is deemed adequate.
The purpose of assigning a level of risk (low, moderate or high) to a Cancer Institute investigator-initiated trial is to ensure that data and safety monitoring activities are appropriate for the level of subject risk. In order to make a decision, the PRC reviews the following criteria:
- Expected duration of the study based on the study design and estimated rate of enrollment
- Nature of the study population (e.g., children, pregnant women, etc.)
- Procedures to ensure the safety of subjects in accordance with the degree of risk
- Methods to ensure the validity and integrity of the data, including adequate biostatistical design and appropriate data analysis
- Adequate data management systems including case report form records and a plan for data collection
- Procedures for reporting serious adverse event to the appropriate departments/committees (IRB, FDA, etc.)
The level of risk determines the frequency of monitoring for a protocol, which may be altered (increased or decreased) if issues arise.
Low-risk interventional trials are studies in which there is a minor increase over minimal risk. The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, physiological, social or educational situations. These studies do not involve a Penn State Health Milton S. Hershey Medical Center/Penn State Cancer Institute-held investigational new drug (IND).
The recommended guidelines for DSMPs of low-risk studies are:
- annual audits during study conduct;
- DSMC review of annual progress reports; and
- limited to no monitoring during study conduct.
Medium-risk trials include studies that involve increased risk due to the nature of the research or the population being evaluated. These studies typically include therapeutic interventional trials using a Phase II or III design. These studies typically do not include a Penn State Health Milton S. Hershey Medical Center/Penn State Cancer Institute-held investigational new drug (IND).
The recommended guidelines for DSMPs of medium-risk studies are:
- real-time monitoring by principal investigator and study team;
- annual DSMP audits during study conduct; and
- DSMC progress reports semi-annually.
Considerations regarding monitoring frequency should be identified in the DSMP, and may vary by protocol. For example, considerations regarding monitoring frequency may be based on the projected rate of enrollment. If the rate of enrollment is expected to be fast and/or the study will be conducted as a multi-center trial, more frequent interval of progress reporting may be warranted.
High-risk studies involve greater than a medium risk. These studies may involve first-in-human agents, or test articles having a high expectation of toxicity, or gene/cell transfer.
These therapeutic interventional trials are typically a Phase I or Phase I/II design and require close monitoring of toxicities and/or determination of a maximum tolerated dose. These studies typically include a Penn State Health Milton S. Hershey Medical Center/Penn State Cancer Institute-held investigational new drug (IND).
The recommended guidelines for DSMPs of high-risk studies are:
- real-time monitoring by principal investigator and study team;
- annual DSMC audits during study conduct; and
- DSMC review of PI-submitted progress reports no less than quarterly.
Considerations regarding monitoring frequency should be identified in the DSMP, and may vary by protocol. The DSMC chair or committee member independent of the PRC may recommend more frequent auditing or reporting if appropriate based on study population and/or design.
PRC Decision Definitions
The study can proceed to IRB review. At times, comments may be forwarded to the principal investigator and/or sponsor that convey the committee’s suggestions, but subsequent action is not required and would not affect the vote of “approved.”
PRC members request minor clarifications or additional information. A committee’s vote of “approved with contingencies” allows a study to be approved after the principal investigator responds and the reviewers are satisfied with the response. The study does not have to be brought back to either the chair or full committee, depending on the nature of the condition, and can be approved in the interim between meetings.
This outcome indicates that the committee has significant concerns with the study design, statistical considerations, prioritization or other major issues. The committee may make suggestions to improve protocol design, and the principal investigator is invited to resubmit a revised study that will be reviewed again by the full committee.
This review outcome demonstrates that the committee has significant concerns that the study is not scientifically sound. The rationale for denial will be provided to the principal investigator. If the study is revised, it must be entered as a new submission; it will receive a new number and will go back to the DST and Feasibility Review Committee.
Principal Investigator Expectations
This list details what is expected of principal investigators (PIs) of studies to which PRC review applies.
The PRC review outcome will be emailed to the principal investigator as well as the submitter no later than three business days following a meeting, with an electronic copy of a signed letter containing a summary of the committee’s comments or contingencies, if applicable.
After receiving the PRC decision letter, the PI should provide a response within 15 business days for “approved with contingencies” protocols and within 30 business days for “deferred” protocols. A two-week extension may be granted for significant rewriting, but a PI must make a formal request to the PRC chair. If no response is received within the defined timelines, the study will be withdrawn from PRMS.
Written requests for any extension of this process will be considered on a case-by-case basis.
No other entity can override the decision of the PRC. However, PIs may appeal the initial determination of the PRC to the PRC.
The principal investigator and study team will be expected to maintain the study record in OnCore, including:
- any change in accrual goals as reported to the IRB of record;
- change in anticipated primary completion date; and
- updates of the status to “suspended” during any periods when the study temporarily cannot enroll new participants (study placed on hold by sponsor due to drug shortages, statistical analysis, etc.)
This must be done in order to accurately assess accrual and scientific progress.
Investigators of PRC-approved research are responsible for providing study updates to the PRC as follows:
- Changes in study status: The PRC must be informed of any study status changes such as active to enrollment, closed to enrollment, temporary suspensions or terminations. Any applicable IRB letter regarding this change in status should be provided the PRC.
- All significant protocol amendments: All protocol amendments that significantly impact the scientific design of the protocol and have not undergone a previous external scientific review shall be reviewed by the PRC. The determination of whether the modification requires a full committee review shall be made by the PRC coordinator, in conjunction with the PRC chair or vice chair. Trials that are considered externally peer-reviewed will be excluded from this amendment review requirement because amendments have already undergone scientific review by an approved entity. Any significant change to an institutional or industry-sponsored trial requires PRC approval prior to implementation. Significant protocol changes are defined as changes in any of the following:
- study objectives
- research plan or study design
- statistical considerations
- patient population and/or accrual figures
- (for Penn State Cancer Institute-sponsored institutional trials) changes to the approved Data Safety Monitoring Plan
- Accrual updates: The PRC requires updated accrual information be provided to allow accurate evaluation of study progress. The principal investigator is expected to keep the PRC abreast of patient accrual information by submitting a PRC accrual form at regular intervals. This is in addition to PRMS’ routine monitoring of accrual data in OnCore. If a study is an institutional trial managed by the Cancer Institue, PIs are required to submit detailed accrual information for the Cancer Institute to ensure it can properly report the accrual information to the NCI Clinical Trials Reporting Program (CTRP) when appropriate. If the Cancer Institute-managed institutional trial is multicenter, accrual information must be submitted to reflect global accrual from all participating sub-sites, in which case the patient accrual information must also indicate the enrolling center for each patient record. See accrual monitoring details here.
- Ongoing scientific validity: The PI must report new data or publications that may have emerged after a protocol’s approval that may alter a protocol’s scientific rationale.
When a principal investigator fails to submit study updates to the PRC, the omission impacts the integrity and validity of data submitted by the Cancer Institute, ultimately to the NCI. When such deficiencies are identified and not corrected within a timely manner, the PRC reserves the right to initiate a focused administrative audit of the study.
The intent of the review is to ensure that PRC records of the study are brought up-to-date and that current protocol amendments are on file and undergoing PRC review as required.
Additionally, patient accrual may also be verified and reconciled.
This review may be conducted by the Clinical Trials Office coordinator or by Penn State Cancer Institute DSMC.
Accrual monitoring will be conducted on all interventional cancer clinical studies that are open to enrollment except for studies of rare disease or rare molecular subtypes.
Studies are expected to accrue at least 50% of target, as described below. Studies that are open more than 12 months but not meeting accrual goals will be evaluated for possible closure every six months, with warning notices issued three months prior.
Accrual goals can be modified, and the PI is given the opportunity to explain poor accrual and any corrective action plan. Trials that are first-in-human/Phase I with a dose-escalation/dose-expansion phase will be evaluated according to criteria listed below for rare subtypes.
Accrual monitoring will occur semiannually.
As stated above, there will be a review of accrual targets and screening efforts for trials of rare/orphan disease and molecular selected studies during scientific progress reviews as well as accrual reviews. Screening activity will be reviewed for the prior 12 months for consideration on length of time a study will remain open.
The principal investigator and research team will be responsible for identifying trials of rare disease including rare molecular subtypes and uncommon clinical subsets of more common cancers on the PRC submission form. The rare determination will be discussed and verified during the PRC review. After verification at the PRC review, the rare categorization will be captured in OnCore.
The following justifications are deemed acceptable for extensions:
- study on clinical hold
- drug delivery difficulties
- changes in exclusion/inclusion criteria
An exception may also be granted if the PI demonstrates that at least 25% of the accrual is based on a minority population as defined by the NIH.
Special consideration for low enrollment may be taken for studies that meet the following criteria:
- Unique correlative science will be undertaken by a Penn State Cancer Institute investigator that will be informative even with a small number of accruals
- Cooperative group studies (e.g., where a Penn State Cancer Institute researcher is a lead investigator, author or significant contributor, or where the ongoing activation of the study is critical to maintaining LAPs)
- Pediatric studies