1
May
Posted in Good Clinical Practice by admin |
FDA is amending the regulations to expand the scope of clinical investigator disqualification. Under this rulemaking, when the Commissioner of Food and Drugs determines that an investigator is ineligible to receive one kind of test article (drugs, devices or new animal drugs), the investigator also will be ineligible to conduct any clinical investigation that supports an application for a research or marketing permit for other kinds of products regulated by FDA. This final rule is based in part upon recommendations from the Government Accountability Office, and is intended to help ensure adequate protection of research subjects and the quality and integrity of data submitted to FDA. FDA also is amending the list of regulatory provisions under which an informal regulatory hearing is available by changing the scope of certain provisions and adding regulatory provisions that were inadvertently omitted. This rule is effective May 30, 2012.
The final rule is now available using the following web link:
http://www.gpo.gov/fdsys/pkg/FR-2012-04-30/pdf/2012-10292.pdf
By Phyllis B. Kent
FDA has recently released draft guidance on a risk-based approach to monitoring. Initial reactions have been that this is a new initiative. However, a thorough review indicates that FDA is not proposing a change to current monitoring approaches. This guidance is a reinforcement of the risk based monitoring plans currently used by Sponsors of clinical research.
The statement of the regulations, requiring only one monitoring visit per year, was viewed by some as a new FDA recommendation. However, the guidance focuses on the need for the Sponsors to evaluate the level of monitoring required to minimize the risk of compromised data being captured for a study. Some errors will probably always exist. But the objective is to produce a scientifically sound study without significant errors.
The guidance recognizes that some monitoring of data can be performed by ongoing electronic analysis. Although central (remote) monitoring can identify blanks on the CRF or flag inconsistent data, centralized monitoring can not determine if data has been omitted from the CRF (such as medical history, conmeds, changes in meds, adverse experiences) or if data has been captured incorrectly from the source (e.g., start and stop dates, AE severity, etc.,) These are the same items that are likely to impact a subject's qualification for a study, protocol compliance, and safety monitoring.
Additionally, electronic data can be trended to determine if any sites have data that is significantly different from the rest of the multi-center sites. Sponsors have been doing trend analysis of study data for this purpose for over twenty years. Sponsors conduct audits based on the results of trend analysis. What is new in this guidance is that FDA has finally acknowledged this practice as additional monitoring and verification of study data.
The guidance seems to focus on data and does not address the other functions of a monitoring visit. There is an additional risk assessment based upon the ability of a site to comply with GCPs. Sponsors have always had to perform enough monitoring to ensure appropriate study conduct. Sponsors will not want to risk undetected significant CRF errors, data that may be disqualified due to inappropriate delegation, or study drug incorrectly stored or dispensed, because of reliance on in-house monitoring. On-site monitors are essential to keeping the PIs on task and making sure that PIs, as well as, their study staff are trained and appropriately involved. Monitors are constantly assessing GCP compliance through observation of the staff, facilities and source documentation. These evaluations can only be made during site visits.
FDA will continue to cite data errors during site inspections, as well as inappropriate delegation, protocol non compliance, inadequate test article storage and lack of adequate staff training. FDA might not penalize the sponsors when errors are found on the unmonitored CRFs if the monitoring plans and SOPs were followed. There will be an assessment by the inspector to determine if the monitoring was robust enough for the nature of the study. However, FDA probably will continue to cite sponsors who have not adequately monitored sites to ensure proper study conduct regardless of what the monitoring plans require. The risk remains with the Sponsor.
The FDA minimum of one visit per year has not changed. But everyone recognizes that the minimum is too risky and therefore we develop Monitoring Plans to match the nature of each study. We are already doing risk-based monitoring. Possibly this guidance was intended to encourage more database review during the studies to identify sites that are outliers and address them earlier. My experience is that many companies are already doing this and, with site monitoring, are aware of their riskier sites. Monitoring is routinely increased when/if increased risk is identified. I think FDA’s intent was to acknowledge central data monitoring and to encourage sponsors to employ a variety of monitoring approaches to reduce risk of inadequate data or study conduct.
25
Aug
Posted in Good Clinical Practice by admin |
EMA finalizes guideline on missing data.
by Phyllis B. Kent
The European Medicines Agency (EMA) has published a final version of the “Guideline on missing data in confirmatory clinical trials” (EMA/CPMP/EWP/1776/99 Rev. 1), which came into force on 1 January 2011.
While this addresses totally missing data, it does provide some insight into what needs to be considered if thought is being given to excluding data for lack of validity (fraud) or missing source documents. It also includes expectations for handling the data in the Clinical Study Report.
“Missing data are a potential source of bias when analysing clinical trials. Interpretation of the results of a trial is always problematic when the proportion of missing values is substantial. This problem is only partially covered in ICH E9 (Statistical Principles of Clinical Trials).” It is unavoidable that some data are missing from all confirmatory clinical trials. “…it should be noted that just ignoring missing data is not an acceptable option when planning, conducting or interpreting the analysis of a confirmatory clinical trial. The reason for missing data and handling of missing data in the analysis represent critical factors in the regulatory assessment of all confirmatory clinical trials.”
The newguideline provides general recommendations on acceptable frameworks for handling missing data in a regulatory setting.
Is there any regulation or requirement that only principal investigators are allowed to finally sign a CRF and subsequent queries?
Can sub-investigator sign as well?
What is your approach?
by Phyllis B. Kent
As per ICH GCP, “The investigator should ensure the accuracy, completeness, legibility and timeliness of the data reported to the sponsor in the CRFs" (section 4.9.1). In section 8.3.14, “Signed, dated and completed Case Report Forms (CRF)” are required, “to document that the investigator or authorized member of the investigator’s staff confirms the observations recorded.” FDA regulations do not address signing of CRFs but do address the need for Principal Investigators to personally conduct or supervise the study. In order to demonstrate this and provide documentation, medical record and CRF signatures have been requested.
We should not lose sight of the reason a PI is required to sign a document, namely to ensure review and awareness of the subject's care and to provide oversight to ensure that the data is accurate, and that SOPs, GCPs and the protocol are followed. Signing off on the CRF at the end of the study is not adequate documentation that this has been done. Figurehead investigators have always been discouraged. The PI should be someone involved in the subject's care. Therefore documentation of that involvement should be throughout the subject's medical records, lab reports, prescriptions, doctor's orders, etc.as well as on the CRF.
Having the PI sign each page of the CRF is generally a poor practice. It implies that each page was reviewed and verified against the source document by the PI. I don't think many PIs do this. I have watched a PI initial the bottom corner of each page by merely thumbing through the corners, never even opening up the full page for review. And he did this in front of an auditor! Of course it was an audit observation! Subsequently, the sponsor changed the forms to require a sign off after each visit which clearly stated that the signor was attesting to the fact that he/she had personally reviewed the source data against the CRF data and that the CRF accurately represented the subject's medical chart information.
The full treatment and care can be handled by a subinvestigator, if qualified, and thus it would make sense for that person to sign the CRF attesting to the accuracy of the document. This is frequently done in a shared medical practice where the subject's primary care giver will continue follow the subject on study. It also makes sense for the person signing off on the CRF to sign off on data queries and changes.
I like some site's method to have a second person verify the data for the PI. I have never seen this done. Usually, they rely on the monitor to be the verifier and the monitor does not sign the CRF indicating that it has been done. With less and less monitoring being done all the time, I think it would be a very good practice to have a data verifier at each site. Double signing is a standard in GMPs. In any case, the monitor's responsibility to ensure that the PI is actively involved will not be any less.
29
Jan
Posted in Good Clinical Practice by admin |
Informed Consent Elements
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
SUMMARY: The Food and Drug Administration (FDA) is amending the current
informed consent regulations to require that informed consent documents
and processes for applicable drug (including biological products) and
device clinical trials include a specific statement that clinical trial
information will be entered into a databank. The databank referred to
in this final rule is the clinical trial registry databank maintained
by the National Institutes of Health/National Library of Medicine (NIH/
NLM) which was created by statute. The submission of clinical trial
information to this data bank also is required by statute. This
amendment to the informed consent regulations is required by the Food
and Drug Administration Amendments Act of 2007 (FDAAA) and is designed
to promote transparency of clinical research to participants and
patients.
DATES: Effective date: This rule is effective March 7, 2011.
http://edocket.access.gpo.gov/2011/2010-33193.htm
Guidance for Industry1
Electronic Source Documentation in Clinical Investigations
This document provides guidance to sponsors, contract research organizations (CROs), data management centers, and clinical investigators on capturing, using, and archiving electronic data in FDA-regulated clinical investigations. This guidance is intended to ensure the reliability, quality, integrity, and traceability of electronic source data and source records maintained at the site for FDA inspection.
This guidance is intended to promote the capture of source data in electronic form, which will help to:
eliminate unnecessary duplication of data,
reduce the opportunity for transcription errors,
promote the real-time entry of electronic source data during subject visits, and
ensure the accuracy and completeness of data (e.g., through the use of electronic prompts for missing or inconsistent data).
This guidance is intended to be used together with the guidances for industry 2 entitled:
Computerized Systems Used in Clinical Investigations
Part 11, Electronic Records; Electronic Signatures – Scope and Application
General Principles of Software Validation; Final Guidance for Industry and FDA Staff
FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
1 This guidance has been prepared by the Office of Critical Path Programs, the Good Clinical Practice Program, and Bioresearch Monitoring Program Managers for the Center for Biologics Evaluation and Research, the Center for Drug Evaluation and Research, and the Center for Devices and Radiological Health at the Food and Drug Administration.
2 FDA guidances are available on FDA’s Web page at www.fda.gov/RegulatoryInformation/Guidances/default.htm. FDA guidances are issued and updated regularly. We recommend you check the Web site to ensure that you have the most up-to-date version of a guidance.
29
Jan
Posted in Good Clinical Practice by admin |
By Phyllis B. Kent
While most of the regulatory agencies do not specify exact requirements for GCP training, if your clinical team is not performing according to GCPs, FDA or the others can cite inadequate GCP training as an observation. Therefore,industry has the burden of determining what is sufficient to ensure that the clinical team knows GCPs in order to prevent these observations. Short of quizzing team members, it is a challenge to know how much GCP training is enough. How do we demonstrate due diligence in providing GCP training and assessing the training of contractors and site staff?
What about GCP Quizzes?
There are few GCP quizzes available. In addition, administering a GCP quiz can be problematic. There are many aspects to GCPs about which we must be knowledgeable necessitating either a very long GCP quiz or many short quizzes. Because of this issue and a multitude of logistical problems, most sponsors have decided not to assess GCP knowledge by testing, but rather focus on the frequency of GCP Training.
How often do we need GCP Training?
Currently, most sponsors require GCP training to be repeated frequently, usually annually. This reinforces the GCP principles and may drive home a point that was previously overlooked or forgotten. Since most companies now incorporate GCPs into their SOPs, GCP training usually coincides with SOP updates and makes it easier to sell to the clinical team. Institutions may set their own standards for the frequency of GCP training for Clinical Investigators and their staff. Independent CIs have only the sponsor prompting them to attend at least one formal GCP course.
What about Content?
A comprehensive GCP course should cover the ICH GCPs in detail. The course must cover the FDA IND requirements as well, if the studies will be submitted in the US. Topics should include Informed Consent, Ethics Committee/IRB requirements, Sponsor Responsibilities, Monitor Responsibilities, Investigator Responsibilities, Adverse Event Reporting, Investigational Product Accountability, and Required Record Keeping.
Once a full GCP course has been completed, annual updates should cover new GCP issues, regulatory updates and refresher topics on areas with frequent audit findings.
How long should a GCP Training Class be?
When evaluating GCP training, we need to look for the duration of the course. A one hour GCP course can't cover but one small aspect of GCPs. A minimum of 8 hours, preferably 16 hours of lecture and workshop activity to ensure a working knowledge of the GCP requirements is preferred. Once a full GCP course has been completed, annual updates should be at least 4 hours in duration.
How do we get Experienced CRAs and Investigators to attend?
Presenting GCP training to individuals who have been through GCP training annually for many years is a challenge. But do we know how well they understand GCPs? We need to make this a worthwhile investment for the sponsor and for the clinical team member. In order to engage the veterans, trainers must have depth of GCP experience beyond those in the class. GCP training must always be interactive and include workshops to allow the attendees to learn from the veteran participants. This recognition of the veteran breaks down resistance to repeat attendance and encourages them to open up to a refresher course. This also allows new team members to identify those with depth of knowledge for future contact. We find that even the veterans admit that they have learned something new after attending a QRTI GCP Training Course.
6
Aug
Posted in Good Clinical Practice by admin |
By Phyllis B. Kent
Excessive concerns over subject privacy may block clinical studies from being conducted at large institutions due to lack of monitor access to electronic source documents. Many large institutions bar non-hospital employees from accessing electronic medical records.
The recent incident of unauthorized access to George Clooney’s medical records (see Exposed: Clooney’s Medical Records http://abcnews.go.com/GMA/story?id=3711136&page=1) highlights the need for privacy of medical records. In the traditional paper medical record system, it was much easier to restrict access to a patient’s medical chart. A written Authorization for Release of Medical Records had to be signed by the patient before the chart, stored in Medical Records, could be accessed. In clinical research, the subjects authorized study team access via the Informed Consent document.
Read more… »
6
Aug
Posted in Good Clinical Practice by admin |
By Phyllis B. Kent
FDA has issued a Draft "Guidance for Clinical Investigators, Sponsors and IRBs Adverse Event Reporting- Improving Human Subject Protection." When this guideline is finalized, it will represent FDA’s current thinking regarding Adverse Event Reporting. FDA has issued this guidance in response to the IRB community reports of large volume of individual adverse experience reports inhibiting their ability to protect human subjects. It provides help interpreting the requirements for reporting unanticipated problems to the IRB and provides recommendations for improving the quality of the information provided to IRBs.
Read more… »
6
Aug
Posted in Good Clinical Practice by admin |
By Phyllis B. Kent
Do We Need to Audit Institutional Review Boards (IRBs) or Independent Ethics Committees (IECs)?
Historically, sponsors rarely audited IRBs. Sponsors relied on institutional oversight, accrediting agencies and federal regulations to assure that IRBs were in compliance. Even with the shift toward Independent Ethic Committees, most sponsors do not routinely audit Institutional Review Boards or Ethics Committees. So, why should we start auditing them now? After all, FDA does routine inspections, as well as, Office for Human Research Protection (OHRP) oversight.
Can we rely on government oversight?
Read more… »
6
Aug
Posted in Good Clinical Practice by admin |
By Phyllis B. Kent
What is the most effective way to assure GCP training of clinical sites? Sponsors rely on the site staff to conduct their studies in compliance with GCP requirements. Which of these typical methods do you use to assess the GCP competency of your sites?
Read more… »
