MORIAH Consultant's Blog

New draft of Declaration of Helsinki is released for comment April 28, 2013

In April 2013, the World Medical Association (WMA) released a draft of the revised language for a new 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, most recently in 2008. The draft is proposed for finalization and release later in 2013.

According to the WMA, the current round of proposed changes is intended “to 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.” The working group will then produce a final revised draft to be considered by the WMA’s ethics committee and Council at their meetings in Fortaleza, Brazil in October 2013, when a decision will be taken whether to forward the document to the WMA Assembly at the same meeting for adoption.

For more details on the proposed changes and to see a draft of the language visit: WMA page

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

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 typically take 1-2 years for all the comments and feedback to be reviewed and evaluated before a final regulation is issued. Once issued it typically takes effect within 6 months of publication.

2013 Edition of the GCP Q&A Guide April 26, 2013

The 2013 Good Clinical Practice Question & Answer (Q&A) Guide – For CRAs, investigators/sites, auditors, compliance, legal, and other clinical professionals will be published and available in May 2013. I serve as the Editor-in-Chief of this publication. Published by Barnett International (GCP Q&A Book), this book is considered by most persons in the field as the most authoritative source of GCP information available. It is now also available both as a print version, spiral bound book or as an electronic book resource. It has been updated and revised for 2013 to reflect the most current information regarding GCP issues.

HIPAA Update January 24, 2013

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.

Good Clinical Practice Q&A Book Published August 4, 2012

The 2012 Good Clinical Practice Question & Answer (Q&A) Guide – For CRAs, investigators/sites, auditors, compliance, legal, and other clinical professionals has been published. I serve as the Editor-in-Chief of this publication. Published by Barnett International (GCP Q&A Book), this book is considered by most persons in the field as the most authoritative source of GCP information available. It is now also available both as a print version, spiral bound book or as an electronic book resource. It has been updated and revised for 2012 to reflect the most current information regarding GCP issues.

FDA User Fees Reauthorized July 10, 2012

The FDA Safety and Innovation Act was signed into law by the President on July 9, 2012. This law reauthorizes user fees for device and drugs and establishes user fees for biosimilar products and generic drugs. There are also a number of other initiatives and incentives added to FDA Law. One of the key points is that in the next few years all submissions to FDA for drugs and biologics will have to be electronic, no more paper submissions.

More details to follow as the final details are published.

Updated PDUFA Law is Coming May 27, 2012

The Congress is in the process of voting and reauthorizing the Prescription Drug User Fee Act (PDUFA) for another five years. This law, originally passed in 1992, allows FDA to collect fees associated with submission and review of a New Drug Application 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 and the development of pediatric information for labels. The success of the PDUFA program for drugs (and biologics) led to the institution of User Fees for medical devices in 2002 (MDUFMA). New for 2013 going forward will be user fees for generic drugs for the first time, 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, 2012. Stay tuned for more details.

FDA’s Updated Monitoring Guidance has Arrived October 3, 2011

The FDA recently published the new Draft Guidance for Industry: Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring , was released in August 2011 for industry comment. The comment period ends in November 2011.

This guidance document is designed to help industry develop a proper monitoring plan to assure quality and reliable data during the conduct of clinical studies. Monitoring of a clinical study is required by regulation in 312.50 and 812.40, but the regulations do not describe what this means, how often and what steps are involved. This has always been part of industry practice and will vary from company to company. FDA also expects ‘adequate oversight’ of a clinical trial but also never defined what is adequate. Adequate monitoring has always been the issue for the proper conduct and oversight of clinical trials. What has happened over the years is that companies chose to interpret this to mean, lots of visits and 100% SDV is the only way to be adequate. However, if this were truly working, there would be no warning letters to PIs for study conduct issues, Right??

There are companies who have chosen to take a risk based approach for years and focus on the important stuff and have had acceptable studies for FDA, based on lack of audit findings. So clearly this approach can work. What I think we are seeing is FDA acknowledging that the old way is not the only way, and the use of existing (and future) technology can enhance monitoring to improve oversight and quality. Remember in 1988 when the original guidance was issued, there was no email, no internet, no eCRF, cell phones were almost nonexistent and smart phones were those wired devices on your desk where you had buttons to answer more than one line and place a call on hold. The greatest ‘e-technology’ we had at that time was the Fax machine.

So, I do not see it eliminating on-site visits, as many others have also pointed out and concurred. What I think this operationalizes and supports, is the role of centralized review of data along with on-site visits to enhance quality. CRAs will still need to make on-site visits, but they can 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. No eCRF system and this risk based approach, can detect something if it is not captured and reported.

The other important aspect of this new draft guidance is that it again 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.

Financial Disclosure August 19, 2011

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

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.