OCR Newsletter: The Source Doc

OCR Newsletter: October 2018

NEW! Clinical Research Navigation Assistance Form

Asking for assistance with your clinical research just got easier!

Available now is the Clinical Research Navigation Assistance Form. You can request help with anything from budget development through study close out. Complete the form online and your request will be sent to the Office of Clinical Research.

Do I need to register my study on ClinicalTrials.gov Protocol Registration and Results System (PRS)?

The FDA
This is a good question since there are differing and overlapping requirements by several organizations and regulatory bodies that determine if your clinical trial should be registered and results reported in the ClinicalTrials.gov Protocol Registration and Results System (PRS).

Generally speaking, the FDA requires registration on ClinicalTrials.gov of any interventional study of any FDA-regulated product (other than Phase 1 or small feasibility device studies). The FDA requirement applies to studies that have a connection to the U.S., specifically, a site in the U.S., an exemption provided by the FDA, or involve a product that is manufactured in the U.S. or its territories. 

The NIH
The NIH however, has a broader requirement for registration; for any NIH-funded research, NIH requires registration of any research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. There is no exception from the NIH registration requirement for Phase 1 or small feasibility device studies. Also, NIH requires registration of behavioral interventions.

As part of its requirement, NIH also specifies that a dissemination plan be submitted as part of the grant application. The dissemination plan is to ensure that the grant applicant will see that the clinical trial is registered and the results are reported in required timeframes and that the informed consent documents include a statement regarding the posting of clinical trial results on ClinicalTrials.gov. The dissemination plan also requires that the institution have an internal policy in place to ensure that ClinicalTrials.gov registration and reporting are done in compliance with ClinicalTrials.gov requirements. SOP 204 documents PSOM’s policy regarding compliance with these NIH requirements.

Journals
Publishing your results: Also of note, the International Committee of Medical Journal Editors (ICMJE) requires registration of clinical trials in a public trials registry at or before the time of first patient enrollment as a condition of consideration for publication. Registration on ClinicalTrials.gov is one way to satisfy the ICMJE requirement. The ICMJE requirement applies to any research project that prospectively assigns people or a group of people to an intervention, with or without concurrent comparison or control groups, to study the cause-and-effect relationship between a health-related intervention and a health outcome. For those who are experienced with the PRS, you may want to check “What’s New” under the “Help” tab for the March 22 updates.

Reporting Results
A new problem type has been added to the home page Record List and Custom Filter: Incomplete Results - per FDA Administration Amendments Act (FDAAA). This problem notice is issued when the All Results Expected date has passed and results information has not been posted to ClinicalTrials.gov for all Primary and Secondary Outcome Measures.

To request to open a ClinicalTrials.gov account of a trial or any related questions, email OCR’s CT.Gov email.

An Update From the Penn Human Research Protection Program: Current Perspective on the Implementation of the Revised Common Rule

We are all aware that there is a lot of discussion and possible confusion as to where the Revised Common Rule lives right now. After many years of public commentary and development, it was anticipated that the revised version of the Common Rule governing human subjects research would take effect on January 19, 2018. Subsequently, the Department of Health and Human Services (DHHS) released a notification that the revised Common Rule would be delayed, and not go into effect until July 19, 2018. The notice indicated that none of the components of the revised Common Rule could be implemented if they were contradictory to the currently approved version. This was a disappointing approach because revisions would have reduced burden for both researchers and the Institutional Review Board (IRB).

The Penn IRB is still working to reduce administrative burden of the IRB submission and review/approval process, while remaining compliant with the current version of the Common Rule. We have implemented updated letter templates no longer requiring signatures and mechanisms for improved document sharing with the Principal Investigator (PI) and their research team. We have streamlined our approach for research proposals qualifying for IRB exemption (meaning no additional submissions are required) and limiting the revisions requested for research qualifying as minimal risk, especially social/behavioral research.

There are elements to the new rule that that are not contradictory to the currently approved version and can be implemented now if the PI/study team wishes to do so, but this is not required. For example, sites could include the use of a one-page summary introduction document, introducing lengthy and complex informed consent forms. Or they could include new elements of informed consent related to future use of biospecimens and data. These elements and corresponding tools/guidance are available on the IRB website.

However, nothing is mandatory at this point. We will await further notification from the government related to implementation dates (it is also a likely scenario that the July date will pass and they will push this to January 2019) or if any revisions to the final rule as it was proposed are incorporated prior to it becoming the revised rule. 

Who is Supposed to be Included on the FDA Form 1572?

New! SOP 203: Statement of Investigator (Form 1572 and Investigator Agreement)

In general, if an individual is directly involved in the performance of procedures required by the protocol, and the collection of data, that person should be listed on the 1572. SOP 203 defines the responsibilities of Principal Investigators (PI) of clinical trials regarding completion of both:

  • FDA’s Statement of Investigator (Form FDA 1572) for all investigational new drug studies (IND)
  • Investigator Agreement for investigational devices (IDE) studies

SOP 203 will help your team decide who needs to be listed on the 1572. Both documents are also considered a Statement of Investigator. This SOP applies to all clinical investigations of drugs, biologics or devices requiring an IND or IDE within the Perelman School of Medicine (PSOM) for which a PSOM faculty member is the PI.  Read the full Form 1572 SOP 203 or watch the eLearning module for FDA Form 1572.

PennCTMS

In an effort to build a robust infrastructure for supporting clinical trials, PSOM has invested in a comprehensive trial management system for Penn researchers. The Penn Clinical Trial Management System (PennCTMS) is designed to manage trials, track patients, and offers robust reporting capabilities.

The PennCTMS provides a range of research related functions to help manage clinical research and creates a centralized repository of the institution’s clinical research data. Available functions include:

  • Tracking the status of studies allows departments to quickly identify the number of current trials recruiting or recently closed
  • Subject tracking within PennCTMS helps study teams get accurate and up-to-date information for accrual goals
  • Recording adverse events in this database makes the information accessible to Principal Investigators and compliance team members
  • Studies created within PennCTMS can be synced with their counterpart PennChart research records, allowing patient information and statuses to flow bi-directionally between the two systems
  • Patient schedule tracking
  • Milestone calendars
  • Electronic case report forms

Our goal is to work with research teams to implement PennCTMS in all departments and divisions within the Perelman School of Medicine in 2018. To date the PennCTMS team has onboarded 9 departments or divisions, including nearly 650 active research studies.

If you have questions about the system, or are interested in learning more about the onboarding process, please contact us about PennCTMS or refer to the website for more info on PennCTMS.

Monitoring Boards/Committees: All Your Questions Answered

DSMB- data safety monitoring board

DMC- data monitoring committee

DSMC- data safety monitoring committee

IDMC- Independent Data Monitoring Committee

The terms DMC, DSMC, and DSMB are used interchangeably.  These boards/committees carry out important aspects of clinical monitoring.  The term DSMB will be used in this document for consistency.

A Sponsor (IND, IDE, CTA holder) is not required by Health Authorities to have a DSMB for a protocol.  A Funder may require a DSMB.  When such a contractual agreement is in place, the Funder should pay for DSMB costs, as additional resources are required.

A Sponsor must assess the need for a DSMB, determining when a DSMB may be useful for study monitoring.  This is an ongoing assessment. 

When a DSMB is not chosen or is no longer useful, the assessment must be documented in the Sponsor TMF.

DSMBs are not required or recommended for most clinical studies.  DSMBs are recommended when:

  • A controlled trial of any size that compares rates of mortality or major morbidity
  • A study endpoint is such that a highly favorable or unfavorable result, or even a finding of futility, at an interim analysis might ethically require termination of the study before its planned completion
  • A priori reasons for a particular safety concern, as, for example, if the procedure for administering the treatment is particularly invasive
  • There is prior information suggesting the possibility of serious toxicity with the study treatment
  • The study is being performed in a potentially fragile population such as children, pregnant women or the very elderly, or other vulnerable populations, such as those who are terminally ill or of diminished mental capacity
  • The study is being performed in a population at elevated risk of death or other serious outcomes, even when the study objective addresses a lesser endpoint
  • The study is large, of long duration, and multi-center

All IND, IDE, and CTA protocol trials require safety monitoring.  Various individuals/groups play different roles in monitoring.  These groups all assist Sponsors in conducting trials that are ethical and that produce valid and credible results.  A DSMB is one such group.

DSMBs do not perform site clinical monitoring.  The Sponsor Monitor performs these tasks.

The DSMP must state who has a role in monitoring.

A DSMB is appointed by a Sponsor.  NIH, CDC, HHS, and similar government and funding organizations do not appoint DSMBs for Sponsors.  These DSMBs may not align with the Sponsor’s requirements.

A Sponsor must qualify each member of the board/committee.  There are three major aspects with respect to membership to be considered when establishing a DSMB:

  • composition of the board
  • qualifications needed by members  (experience, education)
  • independence of members (potential significant financial and intellectual COI)

There is no number requirement for a DSMB.  A Sponsor may have one or many members. 

Naming a DSMB Chair is not required, but is often helpful.

Immediate and long-term studies may benefit from a DSMB.  DSMBs are helpful during study follow-up periods, after the intervention delivery has been completed.  The need for monitoring in studies often extends beyond the time when individuals are treated; trends in survival or other serious outcomes may not become evident until sometime during the follow-up period.  The DSMB’s responsibility to monitor may continue until the planned completion of follow-up.

The Sponsors works w/the DSMB to author the DSMB charter.  The Sponsor assesses the responsibilities of a DSMB.   Sponsors and Investigators bear the final responsibility for the conduct of a trial. This responsibility cannot be transferred to a DMC.  The Sponsor drafts this charter and presents it to the DSMB for agreement or the Sponsor tasks the DSMB with drafting the charter.  The Sponsor should establish procedures:

  • Assess potential conflicts (financial and intellectual) of interest of proposed DSMB members (Ensure that those w/serious conflicts are addressed, limited, or not included on the DSMB)
  • Provide disclosure to all members of any potential conflicts that are not thought to impede objectivity and thus would not preclude service on the DSMB
  • Identify and disclose concurrent member service on other DSMBs of the same, related or competing products
  • Description of the DSMB responsibilities
  • Frequency and format of meetings
  • Description of communication procedures, including data flow
  • Documentation of meetings

The frequency of board meetings depends on the expected rate of accrual and event occurrence at the time of trial design, as well as the perceived risk of the protocol processes, procedures, and products.

DSMB minutes and notes are shared with the Sponsor.  Complete minutes (exs, data and administrative details), in many situations, are not shared with PIs and IRBs.  Reports do not need to be extremely detailed, but should include sufficient information to explain the rationale for recommended changes. An IRB may request DSMB recommendations.* 

Examples of DSMB recommendations may include:

  • Terminate the trial
  • Proceed with no modifications
  • Proceed with modifications
    • Changing the eligibility criteria when the risks of the intervention seem to be concentrated in a particular subgroup.
    • Altering the product dosage and/or schedule when the AEs observed appear likely to be reduced by such changes
    • Instituting screening procedures that could identify those at increased risk of a particular adverse event
    • Informing current and/or future study participants of newly identified risks via changes in the ICF and, in some cases, obtaining re-consent of current participants
    • Pause and conduct further analyses

Address requirements and confidentiality issues in written agreements between the Sponsor and DSMB members.

DSMB members may receive payments to cover expenses and service time.

*An IRB is responsible for considering information arising from the trial that may bear on the continued acceptability of the trial at the study site(s) it oversees. A DSMB, on the other hand, generally has access to much more data than the IRB during the trial, including interim efficacy and safety outcomes by treatment arm, and makes recommendations with regard to the entire trial.  An IRB may request DSMB recommendations.

Please join us in welcoming Alia Kirkland and Donya Short, Esq. to the Clinical Trial Contracting Unit!

Alia Kirkland joins the CTCU as a Senior Contract Administrator from Penn’s Office of Research where she previously worked as a Senior Contract Administrator. Alia has been a Penn employee since 2013 and also has substantial public sector contract administration experience, having served for three years in the California Department of Health. She will assist the CTCU with coordinating assignments, negotiating amendments, confidentiality agreements and task orders, and will collaborate across OCR and PSOM to keep our clinical trial and all related agreements moving forward to rapid conclusion.

Donya Short, Esq. comes to the CTCU after many years in private practice, conducting litigation and engaging in negotiations in association with several large law firms where she honed her skills over multiple disciplines. At the CTCU she will be responsible for the negotiation of complex corporate-funded clinical trial and other related agreements. Donya will also engage in problem-solving with research stakeholders in assigned departments and provide guidance to Principal Investigators and other staff. 

Announcing New Research Ethics and Policy Series (REPS) - Save the dates

Starting in January 2019, please hold FIRST MONDAYS 12-1PM for the new RESEARCH ETHICS AND POLICY SERIES (REPS). The goal of the series is to focus on emerging issues in research ethics and policy, in order to draw attention to these topics, provide a forum to discuss them with experts and trainees, and facilitate connections between those working in research ethics to promote collaboration across Penn and CHOP.

Potential topics may include:

  • Right to Try and Expanded Access
  • Research in emergency settings
  • Return of research results
  • Data sharing
  • Bystander risks in research
  • Paying research participants
  • Broad consent to future research
  • Ethical issues in biobanking
  • Engaging patient research partners for diseases like Alzheimer’s
  • Informed consent under the revised Common Rule
  • Research with terminally ill patients
  • Nudging research participation
  • Research with prisoners

We will circulate a list of speakers and their topics in the coming months, as well as the central meeting location. The format will include both lectures and panels, with at least half the time reserved for discussion.