Compliance In Focus

A well-controlled clinical trial is much like a well-controlled experiment: They are both rooted in the cornerstone of the scientific method.

Fortunately for sponsors and their research teams, the FDA gives explicit guidance on what it means to run an adequate and well-controlled clinical trial in 21 CFR 314.126. 

Let's take a closer look. 

Making sense of the many clinical research trial acronyms sometimes feels like swimming in alphabet soup.

After you've been in the field for some time, using these abbreviations often becomes second nature. But for those who are new to this industry, understanding these clinical research acronyms can seem daunting. 

If you need help decoding them, we're here to help. Here are 30 acronyms commonly used in clinical research and what they mean. 

During a training module this week, a group of monitors were discussing the importance of back-up coverage. Monitors that are conducting visits in the field know that juggling schedules can be very challenging. To provide thorough and consistent monitoring, experienced monitors are assigned to a clinical trial or a study team. Next, training is extended into the therapeutic area of research and sponsor specific trainings including SOPs and monitoring plans.  But what about back-up coordinators- are they trained and ready?

As monitors, we spend a decent amount of time preparing for the visit – before we even head out the door. On the road, we’ve noticed that the most effective coordinators tend to be those who also prepare for the visit. Spending an extra hour or two before the visit can decrease the amount of queries, follow-up items and even the length of the visit itself. Before your next monitoring visit, consider asking yourself these five questions:

We’re often asked- What makes a good monitor? What’s involved in the day-to-day of being a CRA? Well, it’s no secret that a good monitor often wears and juggles many hats; from reporter, to auditor, to traveler. And like many with this New Year quickly unfolding there are some resolutions from those that live out the day-to-day of clinical research monitoring:

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:

Regardless if you are reading this from a sponsor, site, monitor or IRB perspective, we have all worked on a protocol with a medical test that really seems unnecessary or obsolete, not to mention, difficult to obtain with in the time window specified by the protocol.

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:

Most of us have been there before.  In an attempt to get that last item completed before the end of another long day on the job in the field of clinical research we inadvertently scribe the wrong date on the research record we are completing.  We are all human after all, and mistakes do happen from time to time.  Sometimes we know instantly and can correct ourselves, and others someone else points out the discrepancy that we may have over looked.  It’s how we respond after we are made aware that we have made the mistake that I want to focus on for this blog post because there are multiple different options one can take.

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.

It just depends!

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.

According to the regulations for clinical trials, the PI is personally responsible for conducting and supervising the conduct of human subjects research by “protecting the rights, safety, and welfare of subject’s under the investigator’s care”.  The PI also has to ensure that all the research he is responsible for is conducted in an ethical manner and in accordance with all federal, state, and local laws and regulations, institutional policies, and the requirements of the IRB. So what exactly is “oversight”?  Oversight is defined in the Merriam-Webster’s online dictionary as “management by overseeing the performance or operation of a person or group; watchful care, superintendence, general supervision”. As you can imagine, this can be quite an undertaking.

IMARC Monitors sometimes have a challenging job; they are often on the road, trying to balance work and home life.  They juggle multiple studies from different Sponsors, have many relationships to maintain, sites to visit, and reports to write.  At IMARC we want to always provide the very best monitoring services we can.  In order to do that we must have great monitors on staff, so, what makes a great Monitor?

IMARC monitors are all over North America on a weekly basis traveling to a wide range of sites from the small community hospital to the large medical center that also serves as a teaching institution. What makes a periodic monitoring visit a Good Visit? To those in the medical field, they may determine a good visit by the notability or prestigiousness of the facility itself. To the general population in the outside world, they may say - destination. After all, who wouldn’t want to be monitoring at the site next to the sunny, beautiful beach in southern Florida versus next to the corn field out in no man’s land? If you ask an insider, a monitor, the response would sound something like- “That visit was great. The research coordinator – she (he) was a ROCK STAR!” 

Several months ago, we wrote the above blog about consent by phone. Recently, I discovered the following guidance from a FAQ document:

In a perfect world, all the data needed to complete a clinical trial case report form would be found in the medical record. Unfortunately, we do not live in a perfect world!

The Department of Health and Human Services (HHS) is the United States government’s principal agency for protecting the health of all Americans and providing essential human services, especially for those who are least able to help themselves, according to the government website.

The informed consent process is arguably one of the most important parts of a clinical research study. From the Principles of ICH GCP: the rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society. Proper informed consent ensures that the patient is aware of the risks and requirements of being in a research study and has voluntarily agreed to participate in research.  The regulations, CFR part 50 also cover the importance, rules and process of informed consent.

Recently, my inbox has been inundated with training opportunities for Risk-Based Monitoring.  Since the FDA’s release of its latest guidance on monitoring in August 2011, the pharmaceutical and device industries have made this a hot topic of discussion.  It seems the term, Risk-Based Monitoring, in spite of the guidance, has become an obstacle.  What is Risk-Based Monitoring?  And what is causing the confusion?  Perhaps the clearest definition for Risk-Based Monitoring was given by a presenter at the Global ACRP Conference this year in Tampa.  She referred to it as “Intelligent Monitoring”.  That says it all, doesn’t it?  Visually, I see the AT&T Commercial (It’s Not Complicated “Infinity”) with all the kids sitting around a table discussing big numbers with a grown-up.  When a little girl responds “Infinity times infinity” the grown man responds by motioning that his head just burst.

According to the National Institute of Health (NIH), nearly 3,500 people participate in the Clinical Research Healthy Volunteer Program (CHVP). The program, started in 1954, provides an opportunity for healthy volunteers, locally, nationally, even internationally, to participate in medical research studies to provide researchers with important information for comparison with people who have specific illnesses.

We have had this discussion numerous times over the years.  Many believe that the informed consent form is documentation enough.  On the other hand, others would like to see all consent processes documented with a progress note, in addition to the consent document.

It just depends!

On a recent monitoring visit, the coordinator asked an IMARC monitor if the study sponsor could have their consent translated into Spanish. However, the site had one caveat – their IRB also required a “back translation” of the translated consent. Why would the IRB require this back translation?

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?

Dr. Harvey Arbit of Arbit Consulting has penned a whitepaper for IMARC Research titled, “Significant Risk/Non-Significant Risk Determination and IDE Applicability.”  Although the Medical Device Amendments were enacted on May 28, 1976, it still seems that after all these years there is confusion and misunderstanding regarding the process for determining if an investigational device is Significant Risk (SR) or Non-Significant Risk (NSR).

Running a clinical trial is a tremendous effort, requiring extensive resources.  No company wants to spend any more effort than required to get their product to market.  A recent whitepaper published by ImageIQ talks discusses the application of preclinical study in clinical trials to help save time and money.

What is the difference between Significant Risk studies (SR) and Non-significant Risk studies (NSR)? Who makes the decision, why do they make the decision and how can it effect a clinical trial? Based on the FDA’s guidance for medical device studies and the Regulations, a SR device:

Outcomes research can be defined as “the study of the end results of health services that takes patients' experiences, preferences, and values into account—is intended to provide scientific evidence relating to decisions made by all who participate in health care.” Recently, the push has been for greater emphasis on outcomes and a new joint effort is a giant boost in this direction.

It is critical that the group of patients enrolled in a study represent the population that may receive the device once it is on the market. Certain medical devices could elicit different responses depending on gender, according to the federal watchdog agency. Basic differences such as genetics, hormones, body size, diet and socio-cultural issues may play a role in the efficacy of medical devices in patients, according to FDA.

According to the CDC- 31.9% of adults over 20 years old are hypertensive. The American Heart Association equates that to 77.9 million, or 1 out of 3 adults. High blood pressure is known as the “silent killer” often has no warning signs or symptoms. The CDC also links high blood pressure to $131 billion annually in costs to direct medical expenses a year.

In response to The Medical Device User Fee Amendments of 2012 (MDUFA III),which authorizes FDA to collect user fees for the review of certain premarket submissions, FDA proposed process improvements to provide further transparency to the review process and to update the Agency’s approach to the Interactive Review to reflect FDA’s commitments in the MDUFA III Commitment Letter.  The updates are described in the draft guidance released on March 5, 2013 titled Types of Communication During the Medical Device Submissions.

In response to The Medical Device User Fee Amendments of 2012 (MDUFA III), which authorizes the FDA to collect user fees for the review of certain premarket submissions, the FDA proposed process improvements  to provide further transparency to the review process, including new communication commitments. These new communications are in the context of acceptance review, substantive interactions, and missed MDUFA goals. The communications are outlined in the MDUFA III Commitment Letter and are further described in the draft guidance released on March 5, 2013 titled Types of Communication During the Medical Device Submissions.

Just released on FDA’s website concerning The Center for Devices and Radiological Health (CDRH) is a posting that reads “Data Standards and Terminology Standards for Information Submitted to CDRH” which is intended to benefit device manufacturers, hospitals, and clinical investigators. But what exactly are the benefits to data and terminology standards?

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. Perhaps more clarity is needed in order for those in the clinical research industry to be brought into compliance with 21 CFR 54?

Third Party Recognition Boards (TPRs) provide manufacturers of eligible devices a voluntary alternative review process that may yield more rapid 510(k) decisions.  Recently FDA issued draft guidance, “Accreditation and Reaccreditation Process for Firms under the Third Party Review Program.” TPRs are intended to enable FDA to use its resources for reviewing higher-risk and complex devices and also hopefully increase the review times for the medical device industry.

What is the ultimate goal for every clinical trial?  High-Quality Data that proves safety and/or efficacy endpoints while safeguarding clinical trial participants. How can data integrity be ensured? This requires a combination of a few key players during the course of a study.

You did it!

We’re often asked- What makes a good monitor? What’s involved in the day-to-day of being a CRA? Well, it’s no secret that a good monitor often wears and juggles many hats; from reporter, to auditor, to traveler. And like many with this New Year quickly unfolding there are some resolutions from those that live out the day-to-day of clinical research monitoring:

As we enter 2013, how often do you find yourself in a city different from your relatives? In an emergency, many hospitals have policies and procedures to obtain consent for treatment from your legally authorized representative by phone, email or fax.  When a research subject is unable to participate in the informed consent process, and their Legally Authorized Representative cannot physically sign for them, should this automatically exclude them from participating in clinical research? Can a discussion via video chat or phone, well documented, satisfy the requirements?

There are many factors that go into a successful clinical study start-up.  Having the proper team assembled can be a critical factor in the success of any study. Choosing the right site is another factor that can make or break a successful study start-up.  Having a research coordinator and principal investigator that are engaged is important too.

We call it providing a "Third Set of Eyes."  Interestingly enough, most IMARC monitors have a background in nursing, or as research coordinators. It may very well be that this experience has assisted us in monitoring to empathize with each subject. After all, so many years were spent one-on-one with patients; we see them as individuals- not just subject numbers.

A recent article published by the Cochrane Group examined industry sponsorship and research outcome. In order to gather the necessary data, researchers conducted a systematic review of 48 reports of studies involving drugs and medical devices. The results may have researchers rethinking the way medical review and guidelines are handled.

For quite some time we’ve watched the blame for slow review times pass between industry and FDA. One side claims the pathway to approval lacks transparency and predictability, the other claims the submissions are of poor quality. But could this coming year be the start of a new relationship between FDA and industry? According to a new report on FDA’s website, the plan implemented in January 2011 aimed to modernize and improve the premarket review of medical devices is working. This development seems promising as the speed and predictability of medical device review has improved for the first time in almost a decade- according to FDA’s report.

Currently, the FDA is in the process of developing an implementation strategy and policy for the proposed Unique Device Identification (UDI) Rule. While this has been in the works for quite some time, still more changes are being made and more questions are being raised concerning this rule.

While the goal was for FDA to develop the proposed Unique Identification Rule in close collaboration with the clinical community, patient and consumer groups, and with the data from four pilot studies- is it possible FDA missed the mark? According to the industry group The Advanced Medical Technology Association (AdvaMed) changes need to be made to the agency’s rule to make it useful, cost-effective and practical.

Seeing those greatly effected by the recent storms is devastating. While in various places the assessment of damage is still being assessed, physically, FDA also is assessing the set-backs from the recent natural disaster. This was expressed in a recent FDA Voice Blog by Margaret Hamburg, M.D., FDA Commissioner.