FDA’s Califf: Clinical Research ‘Critical’ to Promoting Public Health

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Robert M. Califf, MD, MACC

Now more than ever, the work of clinical researchers is “absolutely critical” to identifying and vetting potential life-saving drugs and devices, U.S. Food and Drug Administration (FDA) Commissioner Robert Califf told attendees of the recent ACRP 2016 Meeting & Expo in Atlanta, Ga. “What you’re doing in clinical research is giving us the information and the knowledge we need to make the best decisions,” Califf said.

Lauding the conference as an opportunity for clinical research coordinators and others in the industry to share ideas and address “clouds on the horizon” in clinical research, Califf encouraged industry professionals to take their work seriously and recognize the sizable responsibilities they face. Simply put, clinical research “determines which products make it to the market,” he said.

He singled out a few of those “clouds” in his address. For example, the cost of clinical research is rising at an alarming rate. Califf cited data that suggest the cost of clinical trials is rising eight times as fast as the consumer price index.

He also asked attendees to take a good, hard look before falling into the trap of believing “one size fits all” in every aspect of clinical research. Stressing a “quality by design” approach, he noted as an example that early-phase clinical trials need to be heavily detailed, while trials further down the line sometimes have to address genomics and other biometric challenges.

Also, “there’s a deluge of data” coming from devices worn by trial subjects, Califf said. The trick is having best practices in place to sort through those data in the most effective way, he stressed.

For other coverage of the ACRP Meeting & Expo, visit acrpblog.org. Sessions will  be available May 20 for purchase through ACRP’s Online Conference Library.

R Txt Messages Right 4 U and Your Site?

When using mobile technology for outreach to potential and active study subjects, “The important thing to remember about text messaging is that, even though it’s a one-to-many [method for study staff], it’s really one-to-one communication” as far as the participant is concerned, says Noel Chandler, CEO of Mosio.
In a presentation today on “Mobile Technologies in Patient Engagement and Retention” at the ACRP 2016 Meeting & Expo in Atlanta, Ga., Chandler noted that 25% of Americans now access the Internet by phone exclusively, and that 90% of text messages are opened and read within three minutes, whereas only 22% of e-mail messages are ever read.
Clinical trial recruiters are turning to text messaging in particular for its utility in sharing alerts about new study opportunities to recruit and possibly pre-screen volunteer patients, send appointment/visit reminders, deliver motivational messages and incentives, provide patient newsletters, urge medication adherence/compliance, and more.

Among other details about how text messaging can be applied to clinical research, Chandler offered the following best practices and considerations:

• Stay professional (U don’t need 2 use txt speak rather than normal language, be clear with calls to action)

• Work with your vendor before you submit text messaging plans to your institutional review board

• Define the workflow processes and user experiences associated with your use of text messaging, for instance to see how it fits into your existing recruitment and retention strategies

• Decide what works best for your site’s particular communication challenges, and whether text messages are truly the right fix

• Start with just one, most-desired text messaging feature, pilot its use to learn the process and costs, and make sure your vendor has a suite of features so that you can add to your outreach capabilities as you grow

5 Action Items to Accelerate the Professionalization of Clinical Research

Clinical research “used to be a lot less complex than it is today…[but] it’s no longer an industry that you can dabble in,” says Jeff Kingsley, DO, CPI, MBA, MS, FAAFP, CEO of SERRG.

Presenting alongside Terri Hinkley, RN, BScN, MBA, CCRC, deputy executive director of ACRP, about “An Idea Whose Time Has Come: Next Steps in the Professionalization of Clinical Research” at the ACRP 2016 Meeting & Expo in Atlanta, Ga., Kingsley told session attendees that they are in the midst of an historic transition in terms of clinical research eventually becoming universally recognized as a profession.

Because of this ongoing transition, “We have to think differently about how we are preparing the future workforce” to conduct clinical trials, Hinkley adds.

Kingsley and Hinkley described five “action items” that clinical research coordinators (CRCs), clinical research associates, principal investigators, and regulatory administrators can pursue right now to accelerate professionalization in the field:

  • Demand credentials and/or certification in your existing workplaces
  • Change research-related job titles to reflect levels of professionalization (i.e., reserve the CRC title for coordinators who are certified)
  • Create apprenticeship programs so that new entrants into research are not given full research titles until they have graduated from the program
  • Pursue regulatory and/or compliance approval of research roles in your institutions through their credentialing bodies
  • Write continuing education mandates into your human resource policies specific to each job description to elevate the status and the demands of each job title

Thirty or 40 years from now, Kingsley says, it will be as clear that taking such steps led to professionalization in clinical research as it is today what the historic steps were that led to, for example, nursing being considered a true profession.

Auditing Your Site’s Vendors, and Other Pointers for PIs Who are New to Research

When taking on sponsored clinical research projects at their study sites, principal investigators (PIs) both new to, and experienced with, such activity may want to prepare for the eventuality of having a study audited by the U.S. Food and Drug Administration (FDA) by, among many other steps, performing their own audits of the quality of any vendors whose services will touch the studies.

This safeguard against possible study complications originating from the actions of persons not even based at the site, but capable of drawing criticism from an FDA auditor in terms of impact on the safety of study participants, could include PI-driven audits of data collection technology/service providers, of caterers providing meals for subjects, and even of the institutional review boards used to provide ethics approval of studies.

Such was the suggestion of an attendee at today’s session on “So, You Want to Be an Investigator: The Other Side of the Coin,” presented at the ACRP 2016 Meeting & Expo in Atlanta, Ga. by Charles Pierce, MD, PhD, FCP, CPI, medical director for Pierce One Consulting; Norbert Clemens, MD, PhD, CPI, director of clinical operations for MetaCure Germany GmbH; and Randall Stoltz, medical director of a Phase I unit for Covance.

According to the presenters, signing the FDA’s Form 1572 is the PI’s commitment in writing that she/he will be responsible for the study in question, including following the federal guidelines for the protection of the human subjects involved, interaction with the institutional review board(s) involved, and adhering to the details of the Investigational New Drug application to the FDA regarding adverse event reporting, record keeping, and being audit ready.

Through the 1572, the PI commits to the FDA to:

  • Personally conduct or supervise the investigation in accordance with the protocol (to the letter)
  • Ensure that all associates, colleagues, and employees assisting in the study conduct know their obligations
  • Comply with all requirements/obligations, including preparation and maintenance of study records
  • Inform the study participant of the investigational nature of the study
  • Ensure that the informed consent process is clear and valid and all IRB requirements are met
  • Accurately report all adverse events to the sponsor
  • Read and understand the investigator’s brochure

Aided by enthusiastic audience interaction in a roundtable format, the presenters addressed many other factors that play into the PI’s role in clinical studies and how it differs from everyday clinical practice.

FDA Inspectors Becoming More Specialized

Next time you have an encounter with an FDA inspector, don’t be surprised if they really know their stuff. In a policy shift, the agency is working to make its inspectors more specialized. It’s becoming less likely that your inspector “will come to your facility and then go to a factory the following week,” Chavon Steele, Senior Clinical Trial Monitor at Medtronic, told attendees at the ACRP 2016 Meeting & Expo in Atlanta today. She’s also a former FDA inspector.

While the FDA only inspects about 1% of all clinical trial sites each year, it’s still important to know how to prepare for the prospect, Steele said. Another point to consider, when FDA comes calling for an inspection with cause, your only notice will be if you happen to see them pulling into your parking lot. Even routine inspections can come with as little as one week notice, she pointed out. About 75% of inspections are of the routine variety.

When the FDA informs you they’re coming over to kick the tires, savvy CROs need to ask several questions, including:

  • How many inspectors will participate?
  • Which clinical trial(s) will be inspected?
  • Which location(s) will be inspected? For example, are they going to a satellite office or an outsourcing facility that does blood work for you?
  • Who on your team should be available and what documents should you be prepared to offer up at the outset?

Taking a closer look at document collation, Steele said to include all versions of the study protocol and informed consent, the investigator brochure, delegation log, evidence of training on the study, financial disclosure forms, signed informed consents, and the source documentation and medical records relevant to the clinical trial.

It’s also important to arrange for an adequate work space for the inspector, Steele said. For example, keep it away from a busy area. Reason? She’s seen situations where an inspector overheard staff talking in a nearby hallway. Sometimes, those comments, especially taken out of context, can change the whole focus of the inspection — and not necessarily to your benefit.

Getz: CROs Challenged by Increasingly Demanding Protocols, Miscommunication

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Ken Getz speaking at the ACRP 2016 Meeting & Expo in Atlanta

Total data points collected in a typical Phase III Protocol have nearly doubled since 2005, Ken Getz, founder and owner of CenterWatch, told attendees at ACRP’s 2016 Meeting and Expo today.

Between 2001 and 2005, sponsors sought 494,236 data points in a typical Phase III Protocol.  Between 2011 and 2015, CROs had to contend with 929,203, according to statistics collected by Tufts CSDD, DRI, and Medidata Solutions. Getz is also Director and Associate Professor, CSDD, at the Tufts University Medical School. “The increasing complexity of clinical trials is challenging,” he noted.

Making matters more challenging, there’s an increasing trend among Sponsors to spread their business around. The result? “More sites are being employed but they are being asked to recruit fewer patients.” Obviously, that’s not the business model of choice for the site.

There’s also a frustrating communication disconnect between CROs and Sponsors, Getz reported. Only 14% of CROs say they have the opportunity to regularly participate in upfront planning and study design, according to a 2014 Tufts CSDD report. More than half, or 64%, also believe amendments and scope changes could be decreased if they had more input.

That’s not how Sponsors see it. According to the same study, 38% say that their collaborations with CROs consistently fail to meet cost and cycle time expectations.

The most troubling statistic of all? Half of Sponsors and 60% of CROs flat out concede they cannot effectively collaborate. That’s a tough environment in which to evolve together and work most efficiently within new market realities, Getz said.

FDA Shares Nine Secrets to Effective 483 Response

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FDA’s David Burrow at the ACRP 2016 Meeting & Expo

FDA’s Office of Scientific Investigations (OSI) conducted 430 clinical investigator-related inspections in 2015, and while just six resulted in 483s (compared to 16 in 2014), it’s not something industry should take lightly. In fact, while responses are optional, the wise strategy is to respond as soon as possible, advised David Burrow, Acting Deputy Director at the agency.

First, it’s helpful to know what FDA looks for during an inspection, he told attendees of ACRP’s 2016 Meeting & Expo today. Agency focus can essentially be distilled down to ten areas:

  • Verify primary efficacy and safety data.
  • Source of subjects; did subjects exist?
  • Did they meet inclusion/exclusion criteria?
  • Was IRB Review obtained? Consent?
  • Adherence to protocol?
  • Verify primary efficacy measurement.
  • Adverse events?
  • Adequate safety data, e.g. Labs, EKG, etc.
  • Drug accountability? Blinding of data?
  • Was informed consent properly documented, including substance and process?

Burrow emphasized that, while there is no regulatory requirement to respond to a 483, a well-reasoned, complete and timely response is “in your best interest.” Still, there’s a pretty strong motive. “A complete and timely response could mitigate an FDA compliance decision,” he said. He cited three other important motivations. It:

  • Demonstrates acknowledgement and understanding of the FDA observations.
  • Demonstrates commitment to correcting the observations.
  • Establishes credibility with the agency.

Burrow offered nine 483 response suggestions:

  • Include a commitment from senior leadership.
  • Address each observation separately.
  • Note whether you agree or disagree. Bonus tip: Prove it.
  • Provide both corrective and preventative actions.
  • Provide both completed and planned actions.
  • Provide a method of verification or monitoring the effectiveness of the actions.
  • Submit documentation of training, SOPs, and other records.
  • Submit the response within 15 working days.

Keynote Speaker Kai Kight Inspires ACRP Members to Dream Big

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Kai Kight performing and speaking at the ACRP 2016 Meeting & Expo

Kai Kight knew something was wrong the moment he saw his mother’s face. She’d been crying. She wouldn’t look him in the eye. Finally, she told him the terrible news: She had breast cancer.

“We talked into the night,” the virtuoso violinist told a rapt audience at the ACRP 2016 Meeting & Expo in Atlanta today. As the hours passed that evening, Kai was surprised by the direction the conversation took. “She didn’t talk about her fear of the chemo, or the radiation, or even the surgery.” What was on her mind as she stared cancer in the face? “Regrets.”

Growing up poor, intelligent, and talented, his mother had played it safe to ensure a level of financial success without significant risk. That terrible evening, as mother and son talked well into night, he heard for the first time that she’d always wanted to open a jewelry store or design her own line of clothing. Both high-risk endeavors, her mind was now mulling regrets for the road not taken. Kai learned a lesson that night he wanted to share with ACRP members.

“Don’t just play the notes that other people have written,” he told ACRP members. Instead, ask yourself if “you are writing new music or playing notes of the past?”  Listen to that internal voice telling you that you can do more. You know what? According to Kai Kight, it’s probably right.

Have You Incorporated the Core Competency Domains into Your ePortfolio?

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Carolynn Jones, DNP, MSPH, RN

In a wide-ranging ACRP 2016 Meeting & Expo presentation on the value of developing and sharing electronic portfolios (ePortfolios) devoted to demonstrating your clinical research skills and accomplishments to current and potential employers, several experts today raised the utility of using the ePortfolio format for documenting and explicitly tying your experiences to the eight core competency domains for clinical research professionals.

As developed by the Joint Task Force for Clinical Trial Competency and described by Sonstein, et al. in the June 2014 issue of the ACRP Clinical Researcher journal, the Core Competency Framework covers the realms of Scientific Concepts and Research Design; Ethical and Participant Safety Considerations; Medicines Development and Regulation; Clinical Trials Operations (Good Clinical Practices); Study and Site Management; Data Management and Informatics; Leadership and Professionalism; and Communication and Teamwork.

ACRP Meeting & Expo speaker Carolynn Jones, DNP, MSPH, RN, assistant professor of clinical nursing for the Master of Clinical and Preclinical Research program at the Ohio State University, suggested ePortfolio users should sort their professional experiences according to the core competency domains and provide personal reflections on how they have applied their strengths in each domain to their day-to-day responsibilities. Structuring an ePortfolio in this way is not only useful to employees, but also to their managers, who can provide more targeted feedback to their staff based on each competency domain.

“Eighty-five years of research indicate that work samples are the best indicator of on-the-job performance…[and that] people want to see what you know,” Jones added. “Ninety-three percent of employers say demonstrated skills are more important than a degree. Eighty percent of employers will remember your portfolio versus only 30 percent who will remember your CV.”

Other session speakers who explained various aspects of “Using Personalized ePortfolios to Demonstrate Professional Competency in Clinical Research” were Barbara Pennington, MS, RN, a clinical research program coordinator and instructor at the University of North Carolina Wilmington campus; Barbara Gladson, PhD, director of the Rutgers Biopharma Initiative and the MS Degree in Clinical Trial Sciences; and Al Pacino, president of HealthCarePoint.

Consent Concerns Slow Clinical Trial mHealth Adoption

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Jennifer Lentz, Eli Lilly and Company, speaking at the ACRP 2016 Meeting & Expo

MHealth technology is moving too quickly for regulatory bodies to keep up, according to panelists at the ACRP 2016 Meeting & Expo in Atlanta today.

Adoption has been slow in part because consent issues remain fuzzy, said Phillip Coran, Senior Director Quality and Regulatory Affairs at Medidata Solutions.

“We’re still at a pretty early stage of usage in clinical trials,” Coran told attendees. Across the board, the clinical trial industry remains hesitant to fully embrace mHealth usage despite its many benefits in terms of subject acquisition and utility.

There are 194 interventional trials in progress relying in some way on mHealth tools, according to data retrieved from clinicaltrials.gov in February, Coran noted.

Consent is always a big issue, as demonstrated by the fact that FDA issued findings to 42% of investigators audited. Inadequate informed consent was a top finding — including use of an incorrect version of the consent form. The vast majority of these trials do not include mHealth components. However, there is no reason to expect different findings for trials that do use them down the line, experts generally agree.

From the sponsor perspective, Eli Lilly Global Informed Consent Form Process Owner Jennifer Lentz is looking for “continued development” in four key areas:

  • Validation/qualification for use in trials,
  • Legal/regulatory guidance on the use of mHealth solutions,
  • Scientific and technical challenges related to use of mHealth solutions, and
  • Feedback from sites and patients regarding the usability of mHealth solutions.

From a regulatory perspective, FDA is focusing on the functionality of an mHealth device when determining whether or not it has oversight authority, Coran pointed out. Broadly speaking, the agency will focus its regulatory flashlight on three categories:

  • Apps that transform a mobile platform by using a mobile platform’s built-in features, such as light, vibrations or camera, to perform a medical device function,
  • Apps that connect an existing device type for purposes of controlling its operation, function, or energy source to control the operation or function of an implantable or body worn medical device, or
  • Apps that are used in active patient monitoring or analyzing patient-specific medical device data from a connected device.