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Financial Disclosure August 19, 2011

Posted by Michael Hamrell in Regulatory Thoughts.
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In May 2011 the FDA issued an updated draft “Guidance for Clinical Investigators, Industry, and FDA Staff: Financial Disclosure by Clinical Investigators”.  This document is a revision of the original  Guidance for Industry: Financial Disclosure by Clinical Investigators dated March 2001. This revised guidance addresses issues raised by the Office of the Inspector General (OIG), Department of Health and Human Services in its 2009 report, as well as questions FDA has received from industry and the public.

The regulation has been in place since February 1999 and applies to clinical studies submitted in a marketing application that the applicant or FDA relies on to establish that the product is effective, and any study in which a single investigator makes a significant contribution to the demonstration of safety.  This includes drugs, device, biologic products subject to premarket approval or authorization including ANDAs and 510(K) submissions.  The Financial Disclosure by Clinical Investigators regulation (21 CFR Part 54) requires applicants who submit a marketing application for a drug, biological product or device to submit certain information concerning the compensation to, and financial interests and arrangements of, any clinical investigator conducting clinical studies covered by the regulation.

The new Draft Guidance provides background information on the requirements of the regulation and what is a disclosable interest.  There is also additional information provided in the form of questions and answers that addresses many of the common aspects of the regulation.  In particular, the guidance document describes FDA’s renewed focus in reviewing the disclosures provided by the clinical investigator and documentation of this during a BiMo site inspection.  The FDA indicates that failure to provide the required disclosures or adequate evidence of efforts to obtain the information could lead to FDA to refuse to file and consider a marketing application.

Clinical Investigator Disqualification May 13, 2011

Posted by Michael Hamrell in Regulatory Thoughts.

The FDA recently proposed to revise the regulations regarding the disqualification of a clinical investigator to cover all investigational products regulated by FDA.   Under the current regulations, if FDA has information that an investigator has repeatedly or deliberately failed to comply with applicable requirements for the conduct of clinical investigations, or has repeatedly or deliberately submitted to FDA or to the sponsor false information in any required report the FDA can initiate a disqualification proceeding against the clinical investigator.  The regulations describe a process that can include a response to the allegations, a hearing (under Part 16) and a review of the documentation by a hearing officer at FDA.  If the FDA determines that the clinical investigator should be disqualified, the Commissioner’s decision currently only provides for disqualification of the clinical investigator for the type of investigational product involved in the investigation.  What this means is, for example, if a clinical investigator is disqualified from receiving investigational devices for study, this person would still be eligible to receive investigational drugs (or biologics) for investigation.

The April 2011 proposed regulation when finalized, would change the language in the corresponding regulation (21 CFR 312 for drugs and biologics and 21 CFR 812 for medical devices) to provide that if an investigator is to be disqualified, the individual would be disqualified from receiving any investigational product in the future, regardless of the study conducted.  Due to the public availability of the list of disqualified and restricted investigators, it is unlikely that any company would use any investigator that has been disqualified by FDA, regardless of the type of investigational product.  However, this change will give FDA the ability to assure that the disqualification bars the clinical investigator from receiving any investigational product.  The investigator will be ineligible to conduct any clinical investigation that supports an application for a research or marketing permit for products regulated by FDA.  Those products include drugs, biologics, devices, new animal drugs, foods, including dietary supplements that bear a nutrient content claim or a health claim, infant formulas, food and color additives, and tobacco products.

FDA Revised Inspection Guide April 18, 2011

Posted by Michael Hamrell in Regulatory Thoughts.
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The FDA has published an update to the Compliance Program Guidance Manual on the conduct of inspections of Sponsors/Monitors and CROs (CPGM 7348-810).  This is the first revision to this inspection manual since it was last updated in February 2001.  The basic inspection program has not changed, but there are several new considerations for the inspection.  The Manual instructs the Inspector to pay closer attention to the collection of investigator’s financial disclosure information, the company’s reporting of the study to clinicaltrials.gov, and the use of international data and the review of the study records.  There are also some revisions and updates to the oversight of the use of electronic records and electronic signatures.  As computerized systems become a bigger and bigger part of clinical trials, it is not surprising that this has received more attention.  Finally, the revised Guidance Manual gives the inspectors more detailed instructions on documenting violations, especially those that may involve fraud.

Update to Informed Consent January 26, 2011

Posted by Michael Hamrell in Regulatory Thoughts.
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The FDA has published a final regulation to amend the informed consent regulations effective in March 2011. This rule will require that a statement be added to all informed consent forms to inform subjects that information regarding the study is available in a public registry database at clinicaltrials.gov .  Although the rule goes into effect in March 2011, it has an implementation date of March 2012 for all trials that are initiated on or after that date.  In addition, for any trial that has been initiated prior to that date, it will not be necessary to revise the informed consent form or reconsent subjects to comply with this new regulation.  In other words, it will not be applied retroactively.  Instead it only applies prospectively to new trials initiated on or after the implementation date.  Once the regulation is effective, even if a consent form is modified for other reasons and subjects are reconsented, compliance with this regulation will not be required.

The regulation goes into some detail to describe what FDA means by an study that has already been initiated. Basically, if the study has been approved by any IRB or other such committee it is considered initiated.  This also applies to multicenter trials.  If the trial has been initiated at any site, the whole study is considered initiated.  FDA acknowledges that as a result there will be a gap for some time period before all studies have this language, but they do not consider this to be a problem since the requirement for clinical trial registration has actually been in place since 2007 and many investigators verbally inform subjects of such access already or subjects have themselves figured it out.

PostMarketing Commitments November 26, 2010

Posted by Michael Hamrell in Regulatory Thoughts.
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More and more drug manufacturers are now required or agreeing to complete additional studies after approval of their drug product by the FDA. These postmarketing studies may be required as a condition of approval or agreed to by a sponsor to address additional issues, but not required by statute or regulation.

The FDA recently issued their 2nd Annual report on the status of the postmarketing studies for drug and biologic products. The FDA is required to report annually on the status of the postmarketing studies, as outlined in FDAAA from 2007. The report was completed by Booz Allen Hamilton for FDA. According to the report that covered over 1500 studies, 40 percent of the postmarketing studies/clinical trials had been closed (either fulfilled or released) by FDA. Of the remaining 60 percent, most were in progress and on schedule or the final report has been submitted for FDA review.

The information about postmarket requirements and commitments comes from Agency letters and from annual status reports submitted by applicants. According to the FDA, the information will be verified for accuracy before it is posted on the Web site, that is supposed to be completed ever quarter. Only 17% of the backlog of PMRs/PMCs were now considered delayed.

New SAE Reporting Regulation November 5, 2010

Posted by Michael Hamrell in Regulatory Thoughts.
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On September 29, 2010, the FDA announced the long awaited Final Rule on changes and updates to the adverse event reporting regulations. This Final Rule is based on part on the proposed rule published back in 2003. In that proposal, FDA had proposed to amend, change and modify some of the requirements and details regarding adverse event reporting for investigational products and approved products in the marketplace. The Final Rule only deals with investigational products and safety reporting. The FDA indicated that accompanying rule will be published later to cover post-approval safety reporting. The Rule will go into effect in 180 days, on March 28, 2011.

This final rule codifies the agency’s expectations for the review, evaluation, and submission of safety information. It also implements internationally harmonized definitions and reporting standards based on the ICH Guidances (ICH E2A). The FDA hopes that the changes will improve the usefulness of IND safety reports and in particular, reduce the number of reports that do not contribute in a meaningful way to the developing safety profile of the drug. One important change is the inclusion now of ‘suspected’ serious adverse events as part of the definition of what requires expedited reporting. There are also new requirements regarding review and evaluation of safety information, monitoring of the safety database and only reporting to FDA events for which there is evidence to suggest a causal relationship between the drug and event. The new rule also will require sponsor to report any clinical important increase in the rate of a serious event over that already listed as an expedited report.

Obviously, the goal of these changes is to improve the FDA oversight of critical safety information and provide better protection for subjects enrolled in clinical trials. In addition, for the first time FDA now will require that companies conducting Bioequivalence studies also must report serious adverse events to the FDA according to the same time frames. In the past these studies that are largely conducted without an IND, were not subject to safety reporting requirements. A Sponsor or CRO will now be required to report all serious adverse events, from either treatment group, as a 15 day expedited report.

For anyone involved in or overseeing the conduct of clinical trials, this will require some changes to the way we collect, process, evaluate and report safety information during clinical trials.

For more details, view the Draft Guidance on the new reporting requirements at: Draft Guidance on Safety Reporting

GCP Update from FDA September 25, 2010

Posted by Michael Hamrell in Regulatory Thoughts.
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In September 2010 the FDA issued an update on the accomplishments and status of various initiatives related to good clinical practice and human subject protection. This is an update to the first progress report issued in January 2009. The report highlights accomplishments and progress since the first report.

Listed below is a summary of some of the items that FDA featured about their accomplishments.

  • New Regulations – Five new final or proposed regulations
  • New Guidance – Five new guidance documents
  • Improvements to FDA’s Internal Procedures – four proposal and plans to improve the clinical trial oversight
  • Clinical Trial Transformation Initiative (CTTI) – Five programs as part of the initiative that is a cooperation between FDA and Duke University
  • International Harmonization, Capacity-Building, and Outreach Activities – this section highlights a number of meetings and programs to extend FDA’s cooperation with regulatory authorities in other countries. In particular, the joint EMA-FDA inspection program for GCP studies is mentioned
  • Guidance in Development – Five new or revisions to existing guidance documents in development. This includes an updated guidance on informed consent and financial disclosure. No date is given for release of the various documents
  • Modernizing FDA Regulations – Four proposed updates to existing regulations, including IND safety reporting and international clinical trials for medical devices and an update to the GLP regulations, which were finalized in 1978 and have not been substantially updated in over 30 years.
  • For a complete copy of the report go to this link:

    FDA GCP Inspections July 21, 2010

    Posted by Michael Hamrell in Regulatory Thoughts.
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    The Food and Drug Administration has recently updated its Information Sheet Guidance on inspections of clinical investigators. This guidance updates their existing policy on GCP inspections and reiterates the expectations during an inspection. It also discusses the differences and similarities between inspections for drug and biologic products and medical device studies. The goal of the inspections are basically the same; to confirm the validity of the submitted data and confirm that the study was conducted according to the regulations. The Guidance also discusses intenrational inspections and confirms what has been long known, that FDA will inspect a study when the studies are part of a marketing application submitted to FDA and provide data critical to decision-making on product approval. One difference you will note is that the regulations for drugs and biologics require that the study be conducted according to Good Clinical Practice, as defined in the regulations, while the device regulations require the study be conducted in accordance with the Declaration of Helsinki or the laws and regulations of the country, whichever provides more protection for human subjects.

    The reference to the Declaration of Helsinki (DoH) has become an issue and controversy in recent years. The FDA device regulation refers to the 1983 version of the DoH. The FDA acknowledges that there have been subsequent revisions to the DoH (most recent in 2008), but they have not adopted the more recent versions. This does create some issue for multinational device companies, where their international colleagues reference the most recent version of the DoH, while the FDA only recognizes a 17 year old, outdated version. Some ask; does the FDA no longer subscribe to international ethical standards? The answer is a bit more complex than that, but in the end the FDA does endorse the principles of the DoH. They just prefer to express it in their own regulations, under their own control, and in their own way.

    So fear not. The DoH is still a guiding document and standard.

    Upcoming Meeting May 18, 2010

    Posted by Michael Hamrell in Regulatory Thoughts.
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    if you plan to attend the 2010 DIA Annual Meeting in Washington, DC in June, check out all the great sessions and topics being presented. In particular, I will be presenting my annual tutorial on 14 Steps to Research and Development, as well as a session on Clinical Trial documentation and Part 11 issues. See more details under Upcoming Presentations.

    Another Example of Lack of Oversight May 18, 2010

    Posted by Michael Hamrell in Regulatory Thoughts.
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    In another example of problems with clinical study oversight, Pfizer Inc. recently received a Warning Letter citing the firm for failing to properly monitor the clinical investigation. According to the April 2010 letter, Pfizer’s monitoring failed to detect numerous cases of “…widespread overdosing of study subjects at multiple study sites was neither detected nor corrected in a timely manner…”. Study monitors were reportedly on site numerous times while the alleged overdosing occurred but failed to review and detect the problem. The overdosing was finally detected some months later by data management during a review of data submitted. Pfizer did acknowledge to the FDA the problem and reportedly took steps to correct this along with several other problems cited in the Warning Letter.

    This is another example where the failure to adequately monitor a study led to signficant compliance and protocol problems that likely could have been prevented or captured earlier with a more vigilant monitoring program. I think this points out the current compliance focus of the FDA; when problems are detected at a study site in protocol execution, it can often be traced back to inadequate monitoring and oversight.