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Part 11 Q&A Guidance August 10, 2017

Posted by Michael Hamrell in Uncategorized.
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In August 2017, the FDA released a draft guidance that provides recommendations to sponsors, clinical investigators, IRBs, CROs, and other interested parties on the use of electronic records and electronic signatures under Part 11 in clinical investigations of medical products. Part 11 is the FDA regulation, published in 1997, on the use of electronic records/electronic signatures. The guidance is the first update to guidance and information regarding Part 11 compliance in clinical trials in a number of years. It clarifies, updates, and expands upon the recommendations in the 2007 Part 11 guidance that pertains to FDA-regulated clinical investigations conducted under parts 312 and 812. The guidance attempts to clarify and update recommendations for applying and implementing part 11 requirements in the current environment of electronic systems used in clinical investigations. It also encourages the use of electronic records and systems to improve the quality and efficiency of clinical investigations. The guidance also discusses the use of a risk-based approach when deciding to validate electronic systems, implement audit trails for electronic records, and archive records that are pertinent to clinical investigations conducted under parts 312 and 812. Since the use of computers in clinical trials is the norm these days the recommendations in this guidance should be helpful to everyone engaged in clinical trials.

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New User Fee Laws Coming August 8, 2017

Posted by Michael Hamrell in Uncategorized.
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The Congress has just voted and authorized the Prescription Drug User Fee Act (PDUFA) for another five years. The final bills to reauthorize all the user fee programs are waiting for the President to sign them. This law, originally passed in 1992, allows FDA to collect fees associated with submission and review of a New Drug (and Biologic) Applications along with product and establishment fees. The Act requires that Congress reauthorize the law every five years. Each cycle, the reauthorization has included a review and reexamination of FDA progress in meeting review goals and protecting the public. Over the years, new aspects of FDA oversight have been included as part of the reauthorization, including the addition of REMS, requirements for post-approval studies, the development of pediatric information for labels and other initiative to encourage development of new drugs and expedite their review. The success of the PDUFA program for drugs (and biologics) led to the implementation of User Fees for medical devices in 2002 (MDUFMA) and starting in 2013, user fees for generic drugs, as well as a novel structure for user fees for biosimilar products. The law is expected to be finalized this summer to be ready for implementation in the next Fiscal Year, starting October 1, 2017. Stay tuned for more details.

What’s New in GCP August 8, 2017

Posted by Michael Hamrell in Uncategorized.
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I haven’t updated this Blog in some time, but i thought it would be a good idea to write about what is new, and not so new in GCP.

In September 2013, FDA published a Guidance on Electronic Source Data in Clinical Investigations.  This guidance provides recommendations to sponsors, Contract Research Organizations (CROs), clinical investigators, and others involved in the capture, review, and retention of electronic source data in FDA-regulated clinical investigations.  The guidance promotes capturing source data in electronic form.  It is intended to assist in ensuring the reliability, quality, integrity, and traceability of the data from electronic source to electronic regulatory submission.

In December 2016, the FDA also published a Question and Answer Guidance on the use of electronic informed consent.  This guidance has been prepared jointly by the Department of Health and Human Services (HHS) Office for Human Research Protections (OHRP) and the Food and Drug Administration (FDA). This guidance provides recommendations on the use of electronic systems and processes that may employ multiple electronic media to obtain informed consent for both HHS-regulated human subject research and FDA-regulated clinical investigations of medical products, including human drug and biological products, medical devices, and combinations thereof.

Final new version of Declaration of Helsinki is Approved February 4, 2014

Posted by Michael Hamrell in Regulatory Thoughts.
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In October 2013, the World Medical Association (WMA) approved the latest version of the Declaration of Helsinki (DoH). Since its adoption in 1964, this document has served as the foundation basis for the ethical conduct of medical research in humans. The document has been revised eight (8) times so far since 1964.

According to the WMA, the current changes “provide for more protection for vulnerable groups and all participants by including the issue of compensation, more precise and specific requirements for post-study arrangements and a more systematic approach to the use of placebos.” 2014 will be the 50th anniversary of the first edition of the Declaration from 1964. There is a nice editorial in the Journal of the American Medical Association from November 2013 that discusses the newest version along with the history of the document at: JAMA article .

For more details on the final document and to obtain a copy visit: WMA page

FDA Publishes Final Guidance on Risk-Based Monitoring August 18, 2013

Posted by Michael Hamrell in Regulatory Thoughts.
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The FDA published the final Guidance for Industry: Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring in August 2013. This is the final version of the draft released in August 2011.

This guidance document reiterates the FDA current thinking on a risk-based approach to monitoring. There is a growing consensus that risk-based approaches to monitoring, focused on risks to the most critical data elements and processes necessary to achieve study objectives, are more likely than routine visits to all clinical sites and 100% data verification to ensure subject protection and overall study quality. This final guidance goes into some detail on different methods that can be used to put in place an effective monitoring plan for a clinical study. This guidance makes clear that sponsors can use a variety of approaches to fulfill their responsibilities for monitoring investigator conduct and performance in investigational new drug (IND) studies conducted under 21 CFR §312 or investigational device exemption (IDE) studies conducted under 21 CFR §812. The guidance describes strategies for monitoring activities that reflect a modern, risk-based approach that focuses on critical study parameters and relies on a combination of monitoring activities to oversee a study effectively.

FDA recognizes that this guidance places greater emphasis on centralized monitoring than appeared feasible at the time ICH E6 was finalized. However, FDA considers the approach to monitoring described in this guidance to be consistent with ICH E6 and ISO 14155:2011 (devices).

Again the guidance does not suggest eliminating on-site visits. Rather, what it operationalizes and supports is the role of centralized review of data along with on-site visits to enhance quality. The guidance specifically encourages greater use of centralized monitoring methods where appropriate. CRAs will still make on-site visits, but they will spend less time focusing on some issues, like data consistency that can easily be checked by a computer, and focus on items that need a close live eye view to verify, like ICF forms, visit dates, or AEs not reported, etc. The guidance suggests that sponsors should prospectively identify critical data and processes that if inaccurate, not performed, or performed incorrectly would threaten the protection of human subjects or the integrity of the study results.

This guidance reflects FDA’s general approach in recent years to risk based approach to quality in a number of areas. This includes manufacturing quality, safety reporting and even FDA’s own inspection planning in CDER is moving to a risk based approach. The guidance discusses risk assessment as applied in the context of clinical monitoring. Risk assessment generally involves identifying risks, analyzing risks, and then determining whether risks need to be modified by implementing controls. The key tool in risk assessment and planning is to develop and implement a formal monitoring plan for each study that addresses the risk plan in writing.

The guidance also emphasizes that one of the key risk tools in obtaining quality data is a well designed and articulated protocol and related tools such as the informed consent document and case report forms.

FDA to revise regulations for acceptance of data from medical device trials conducted outside of US April 28, 2013

Posted by Michael Hamrell in Regulatory Thoughts.
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In February 2013 the FDA proposed to amend the regulations in §814 regarding the acceptance of data from medical device trials. The current regulation in §814.15 states that FDA will accept the data if the data are valid and the investigator has conducted the studies in conformance with the Declaration of Helsinki or the laws and regulations of the country in which the research is conducted, whichever accords greater protection to the human subjects. In addition, the regulations regarding 510K submissions and investigational device exemptions (IDE) do not address the acceptance by FDA of data generated outside of the US.

FDA will accept information on clinical studies conducted outside the United States to support an IDE or a device marketing application (510K or PMA) or other submission if the data are valid and the information specified in other sections is submitted. The first item is a statement should be provided that all such studies have been conducted in accordance with good clinical practice (GCP). For the purposes of this section, GCP is defined as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials in a way that provides assurance that the data and reported results are credible and accurate and that the rights, safety, and well-being of trial subjects are protected. The sponsor or applicant who submits data from a clinical study conducted outside the United States in support of an IDE or a device marketing application or submission, in addition to information required, shall provide a description of the actions the sponsor or applicant took to ensure that the research conformed to GCP.

When implemented, this regulation will be similar in language and scope to the updated language added to the IND/NDA regulations in 2008 in §312.120. It will thus provide greater consistency in expectations for the conduct of studies outside of the US for drugs, devices and biologics by defining a single standard of conduct as good clinical practice (GCP). As with the drug regulations, it will eliminate a direct reference to the Declaration of Helsinki (DoH) and a particular version of the declaration in the regulations. This is not to imply that the FDA and the US government do not support the Declaration of Helsinki. On the contrary, the DoH is still the foundation document for the ethical conduct of clinical trials. It is in fact referenced in the ICH GCP Guideline (E6), the ISO 141255 Guideline for Medical Device clinical trials, the Pan American Health Organization (PAHO), World Health Organization (WHO) and CIOMS Guidances on good clinical practice and ethical considerations in clinical trials as the ethical basis for these Guidelines. Collectively, these documents all define a standard of conduct known as GCP and documents that the FDA references as GCP.

No timetable is provided for the finalization and implementation of these proposed changes to the regulations.  It is still pending final approval and publication.

HIPAA Update January 24, 2013

Posted by Michael Hamrell in Regulatory Thoughts.
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The Department of Health and Human Services (DHHS) has released a long-anticipated final rule modifying its regulations regarding the Health Insurance Portability and Accountability Act, (HIPAA) more commonly known by its acronym, HIPAA.

HIPAA contains a number of data privacy protections, most notably the “privacy rule,” which closely regulates how protected health information (PHI)—any health-related information about a person that can personally identify them—may be used by an entity covered by the law. Most disclosures outside of ones intended to facilitate payments or treatment directly require authorization from the patient in order to proceed. The rule, released on 18 January 2013, is substantial both in length and effect. The final rule with four distinct rules combined into one affects a huge number of industries, including companies conducting clinical trials.

Companies will be further restricted from using some of the information they obtain from patients, for example, and can no longer sell PHI or use it for marketing or fundraising purposes.

Impact on Clinical Trials
Clinical trial sites will also be exempted from certain requirements, such as those limiting the use of single authorizations (“compound authorizations”) for the release of PHI.

“Permitting the use of protected health information is part of the decision to receive care through a clinical trial, and health care providers conducting such trials are able to condition research-related treatment on the individual’s willingness to authorize the use or disclosure of protected health information for research associated with the trial,” DHHS explained in its rule.

However, trial sites will still be prohibited from using compound authorizations for tissue banking purposes, though they can ask for such samples in a separate authorization form or in the same package so long as it is unconditional. DHHS suggested the use of separate check boxes and authorization signature lines for entities that wish to simplify the enrollment process.

These exemptions could prove crucial to companies hoping to use collected data for “corollary research activity,” such as for research databases or repositories used to find common genetic markers or other information used to generate new information on therapies.

Many of the remaining provisions of the final rule, if not already in effect, will come into effect on 26 March 2013, and require full compliance 180 days after that date.

Other Provisions
Patients would also have the right to receive electronic copies of their health information and be permitted to restrict insurance companies from finding out about healthcare received but paid for out of pocket in full. The latter could be construed as a potential incentive for some clinical trials, as some patients now are wary of participating if it has the potential to increase their premiums.

It would also become easier to release information to the family of deceased patients—a potential benefit (or liability) to those testing products on patients who die in the midst of treatment.

Other parts of the rule focus more on compliance. Those found to have violated HIPAA provisions, for instance, will be subject to tiered and increased civil monetary penalties. Entities will also be bound by an objective definition of what constitutes a leak of information that could negatively impact a patient.

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.
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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 2010.  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.