Compliance In Focus

You may have heard the term Sponsor-Investigator before, but just who are they and what do they do?  Just as the title suggests, a Sponsor-Investigator is someone who both initiates (sponsors) and conducts (investigator) an investigation.  This may sound simple, but in actuality, the role can be quite complicated.  However, like anything else, with proper preparation and support it can be accomplished.  Sponsor-Investigators are a rare breed of extremely intelligent, hardworking people who are on the cutting edge of scientific advancement in their respective fields.  They are so committed that they are willing to do essentially twice the work to bring new technologies and advancements to the medical community.

You’ve received “the call” from the FDA auditor.  After an understandable quick moment of panic, what should your next steps be?

Monitoring remains our main focus at IMARC Research.  As discussed in a previous whitepaper, “Monitoring as a Mindset”, monitoring is defined by the FDA as the act of overseeing an investigation.  Specifically noted in 21 CFR 812.43, sponsors are required to select monitors qualified by training and experience.  In addition, 812.46 states that monitoring investigations should include securing compliance at investigative sites, whenever necessary.

ICH GCP E6 4.8.3 states that neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate in a trial, and special care must be taken to assure it is met when dealing with populations whose very nature places them in a situation where they might be more easily coerced or influenced.

As monitors we spend a significant amount of time reviewing the essential clinical investigation documents at the site during a monitoring visit.  These ‘essential documents’ are usually housed in a Regulatory Binder or sometimes they are referred to as an Investigator File.

This month, FDA officially released the new Guidance for Industry: Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring.  The draft guidance was originally released in August 2011, and has been a popular topic of conversation over the two year period before becoming final.  You may recall a recent blog we posted about the concept of Risk-Based Monitoring and how it seems to be met with some skepticism and confusion amongst the clinical research community.  Hopefully now, with FDA’s “current thinking” on the topic becoming official, we can all review what exactly FDA’s vision for the future of monitoring entails.

One of the fundamental principles of Clinical Research is: “if it is not documented, it is not done”. The attributes of source documentation, we, as research personnel, should be looking for are ALCOA: Attributable, Legible, Contemporaneous, Original and Accurate.  (The IMARC ALCOA Checklist is a helpful tool for understanding the importance of these qualities.)

When conducting clinical trials, it is of utmost importance that the data generated be free from threats to the validity and integrity of the research. As demonstrated in many FDA warning letters, a commonly cited source of bias in clinical research can be found in the financial ties between investigators and sponsors. It is not unusual for the innovations of individual physician investigators to receive research and development funding from larger organizations that possess the resources to bring these innovations to market, and under 21 CFR 54, it is the responsibility of sponsors to collect for each investigator who is not a full-or part-time employee either a certification of no financial conflict of interest (Form FDA 3454), or a disclosure of the financial arrangements between the sponsor and investigator (Form FDA 3455). These financial disclosures must be updated by the investigators if there are any changes in financial disclosure status throughout the study, until one year after the study is completed.

Often clinical research trials are conducted through large, academic medical centers. This is understandable as the cost of a research department infrastructure can be beyond the budget for a community hospital.  Yet for those community hospitals willing to become involved in clinical research trials, the dividends to the institution, its staff, and the community are phenomenal. A few of these benefits are reviewed.

Dr. Robert Findling, Director of Johns Hopkins Division of Child and Adolescent Psychiatry and leading researcher in pediatric psychopharmacology, views being a principal investigator as “a privilege, not a right.” Dr. Findling has been noted as saying “with privilege comes great responsibility”.  Principal investigators who subscribe to this philosophy can set themselves apart by leading the development of cutting edge technology and novel treatments. According to 21 CFR 812.100, General Responsibilities of investigators, P.I.s are responsible for conducting research according to the federal regulations, agreements with the sponsor, the investigational plan, and the requirements set forth by the IRB.

In 2010, author Rebecca Skloot published the #1 New York Times bestselling book titled The Immortal Life of Henrietta Lacks.  The book is a very thoughtful examination of the moral and ethical principles regarding the lack of consent on Henrietta’s behalf to donate her cells to science.  It is filled with first hand accounts from her family and friends about their experiences that resulted from Henrietta’s unbeknownst scientific contribution.

Informed consent checklists, just like the informed consent, are more than just a document, but rather can be a process. To begin, what is an informed consent checklist and how do you use one?

When a monitor has a tiny epiphany while working through a difficult compliance issue with a site, or an ‘Ah-ha!’ moment, we call that a ‘Regulation Revelation.’ After reviewing an informed consent that lacked the required statement regarding registration on clinicaltrials.gov (21 CFR 50.25(c)), I discussed it with the sponsor and had an ‘Ah-Ha!’ moment I’d love to share.

This week is FDA Warning Letter Week at IMARC! Have you had a chance to catch up on the first three blogs that aim to help you response to the FDA? This last blog in the series attempts to take the perspective of the agency when reading your response letters.

The FDA Bioresearch Monitoring Program (BIMO) was created to: “Protect the rights, safety, and welfare of human research subjects involved in FDA-regulated clinical trials; Verify the accuracy and reliability of clinical trial data submitted to FDA in support of research or marketing applications; and To assess compliance with statutory requirements and FDA's regulations governing the conduct of clinical trials.” But, how exactly does FDA safeguard human subjects, ensure data integrity, and verify compliance with applicable standards?

On December 31, 2012 the guidance, “eCopy Program for Medical Device Submissions: Guidance for Industry and Food and Drug Administration Staff" was issued as an official guidance document.  The guidance provides step-by-step instructions on how to make submissions for medical devices to FDA using the new eCopy format.  Yet to anyone attempting to issue a submission to FDA after January 1st utilizing a strictly paper format, it was quickly learned that this wasn’t a typical FDA guidance document.  FDA responded to those “paper only” submissions with an eCopy hold notification; in essence, not received.

Informed consent is arguably the most important aspect of patient protection in clinical research. The informed consent process is intended to protect the rights and welfare of subjects by educating them about their potential participation in a clinical trial. Unfortunately, informed consent remains an issue today. In fact, the FDA has sent out many warning letters regarding informed consent over the last few years.

In the realm of clinical research, two functions often work together to complement each other to create an additive impact on the overall quality and integrity of a clinical trial. The two functions are clinical monitoring and auditing. But how do these work hand-in-hand, and how are they different?

In the clinical research industry many rely on a regulatory strategy, or a regulatory plan. Having a strong foundation to build upon for a research team is vital for success. When regulations are the building blocks the goal of compliance can be more readily achieved- and in the end, keep patients safe. This is the main objective of our industry; how can it be realized?

A project that has long been in the mind of Sandra Maddock’s has come to life.  The challenge was how to translate key events in clinical history into a series of images that depicted both the amazing and tragic events that have impacted medical research.

The FDA issued a draft guidance on the study and evaluation of gender differences in medical device clinical studies. The guidance is issued with hopes to increase the number of female subjects enrolled in clinical trials.

Jim Dickinson recently published an article on the Medical Device and Diagnostic Industry website about the most recent Health and Human Services Office of the Inspector General (OIG) report.  The report raises the issue of whether or not FDA should be forced to tighten their review process for Sponsor’s to submit complete financial disclosure information on investigators with IND/IDE applications.  The article also mentions that OIG is critical of FDA’s current adverse event reporting review process.  With that being said, OIG will be re-focusing a previous recommendation that FDA obtain complete financial disclosure information, as well as develop more strict device adverse event reporting review requirements.

While procedures, checklists, guidance documents, report templates and all sorts of other things combine to form the infrastructure for monitoring, what is possibly even more important is the shared mindset of those on a clinical research team.  The acceptance by all that regardless of the title, there is a shared responsibility in calling out issues, in looking purposefully at this document, in questioning that blank to facilitate running a well controlled, compliant clinical trial.

Many believe good monitoring should heavily focus on Source Data Verification (SDV), which stripped down to its simplest meaning equates to “X=X” and “Y=Y”.  And maybe some of you reading this are thinking “Isn’t that exactly what monitoring is?”  While data integrity is absolutely essential, it is only the beginning of what comprehensive monitoring encompasses.

FDA regulations can seem all encompassing at times, especially when trying to run a clinical trial in compliance with the various rules and standards. While many in clinical research would not argue that there are not enough regulations governing clinical research practices, the question remains: Are there too many gray areas?

This question was recently raised by an article published in the Wall Street Journal and a blog published on ieee spectrum. Currently patients cannot have access to the information without going through their healthcare provider. Should industry support patient access to all information pertaining to their medical device?

In clinical research many rules and regulations exist to govern the way research is conducted and to protect those patients who are participating in research. One of the standard principles directing clinical research is Good Clinical Practice. Good clinical practice is more than any one document; rather, it is a collective compilation of many thoughts, ideas and learning moments spanning the globe over.

With this year coming to an end it’s time to look back and review the past year and start making the “to-do” list for the upcoming year. FDA has already taken this initiative and recently posted their Strategic Priorities for 2013. We’ve summarized the priorities and the planned steps to complete these proposals.

As part of the Patient Protection and Affordable Act, the Sunshine Act requires medical device, pharmaceutical and similar companies to report any payment or other transfer of value to the Health and Human Services (HHS). This will effect many companies that conduct clinical research and clinical trials, but the question remains- will this negatively impact physician’s willingness to participate in research?

As technology evolves, it is only natural that there will new ways to consider doing the same task. FDA is catching this wave of the future with the new FDA Draft guidance titled, “Electronic Source Data in Clinical Investigations.” As this draft guidance promotes the electronic age we’re evolving into, FDA hopes this will assist source data overall in clinical research.

It’s an unfortunate reality in clinical research; Oftentimes sites struggle to recruit subjects.  Frustration trickles down from the principle investigator and on down to the coordinators as sponsors put pressure on sites to enroll, enroll, enroll.  What are the barriers to recruitment and how can they be overcome?

Recently, when discussing Institutional Review Board (IRB) adverse event reporting, a Project Manager for a leading medical device Contract Research Organization (CRO) brought up a valuable question regarding reporting compliance- whose job is it to ensure an investigator is compliant with IRB reporting policies?

There continues to be much discussion over the FDA’s 510(k) program, which has led to controversy and confusion over the direction of the program.  In fact, we have posted many blogs devoted to this topic, so we thought it was time to create a whitepaper focusing on the topic.

Conflict of interest can be defined as occurring when an individual or organization is involved in multiple interests, one of which could possibly corrupt the motivation for an act in the other.  While many may see disclosure of conflict of interest as just another form to check off the list, it’s an important aspect in a study to ensure the trial is conducted with the utmost integrity and responsibility.

Being a CRO that specializes in helping companies gain FDA and world-wide approval through monitoring, auditing, training and consulting services- it’s fair to say we’ve come across a wide range of fellow CROs, investigative sites, research teams, and hospital systems. It’s amazing how much innovation exists- not just with the investigative products- but with technological advances to platforms used the healthcare industry.

You may have heard the term Sponsor-Investigator before, but just who are they and what do they do?  Just as the title suggests, a Sponsor-Investigator is someone who both initiates (sponsors) and conducts (investigator) an investigation.  This may sound simple, but in actuality, the role can be quite complicated.  However, like anything else, with proper preparation and support it can be accomplished.  Sponsor-Investigators are a rare breed of extremely intelligent, hardworking people who are on the cutting edge of scientific advancement in their respective fields.  They are so committed that they are willing to do essentially twice the work to bring new technologies and advancements to the medical community.

Recently the headline: “Why do Cell Therapy Clinical Trials Fail?” caught our attention. The blog stems from a presentation by Greg Bonfiglio on the topic at a recent conference. We found this quite exciting as the cell therapy field is growing here in the US and so is our interest in this niche of research.

A medical device company files a marketing application with FDA and awaits a determination on whether or not its clinical trial data is sufficient to support product approval and/or clearance.

A new report was published by the Institute of Medicine (IOM), which outlines ten recommendations to achieve a better health care system. The report, “Best Care at Lower Cost- The Path to Continuously Learning Health Care in America,” touched on elements that directly influence our industry. The ten recommendations fell into three main categories:

ICH GCP E6 4.8.3 states that neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate in a trial, and special care must be taken to assure it is met when dealing with populations whose very nature places them in a situation where they might be more easily coerced or influenced.

At the recent OMTEC 2012 Conference in Chicago, there was a panel discussion on the current status and future challenges facing the orthopaedic industry.  Interestingly enough, it seems similar adversities stretch across most of the clinical research industry touching various segments.

As monitors, we often encounter sites that utilize Standard Operating Procedures (SOPs) to help ensure clinical research trials are consistently conducted according to FDA regulations.  According to the International Conference on Harmonisation (ICH), SOPs are “detailed, written instructions to achieve uniformity of the performance of a specific function.”  While most would not argue the value of SOPs when it comes to the successful completion of a clinical trial, it’s important to take a closer look and think about them critically prior to implementation.

Often, when one thinks of the team that actually brings a new medical device or drug to market, the first people that come to mind are those at the sponsor company and the investigators at the individual sites – the leaders of the study.  What may be less known, though, is that often the study hinges on the shoulders of the Clinical Research Coordinator (CRC).  Briefly, CRCs are responsible for the accurate maintenance of the records for the trial, as well as many parts of the trial that otherwise may be overlooked.  Some of the major responsibilities of the CRC are:

According to 21 CFR 812.110 an Investigator is responsible for conducting an investigation in accordance with the signed agreement with the sponsor, the investigational plan, this part and other applicable FDA regulations, and any conditions of approval imposed by an IRB or FDA.

In a clinical research, patients are the most important key to a study. Subject retention is vital for data integrity, and lack of subject participation can have costly delays for the Sponsor.  Since research sites spend a great deal of time and effort finding qualified subjects, they should also be equipped with reasons subjects withdraw to help prevent this from happening.

The FDA has recently released a draft guidance titled “Medical Devices: The Pre-Submission Program and Meetings with FDA Staff” that will update and expand the pre-IDE program established in 1995 and the associated Blue Book Memo from 1999. The program will be renamed the Pre-Submission, or Pre-Sub, program, and will be broadened to include other device submissions, including PMA applications, HDE applications, and 510(k) Submissions.