From multi cohort Phase I’s to integrated Phase III’s, FDA eyes efficiency

Two guidance documents, released a month apart this summer, suggest that the FDA is taking up a concern that sponsors and patients feel all too acutely: the need for speed.

That’s not a word anyone involved in clinical research takes lightly, with lives and knowledge on the line. But by issuing guidance on EHR integration in July, followed this month by guidance on simultaneous cohorts in Phase I oncology trials, the United States’ foremost regulatory body is placing a premium on efficiency. It’s not fair, or accurate, to claim that the policymakers at the FDA have never been interested getting safe, effective medicines to market quickly.  Like the population they serve, these policymakers are moms and dads, brothers and sisters, and patients. But they are also stalwarts of caution. That’s why their recent guidance communicates so much, even beyond its content.

First, what is the content? July’s guidance document, Use of Electronic Health Record Data in Clinical Investigations,  “clarifies [the] FDA’s expectations when EHRs are used as a source of data in [prospective] clinical investigations.” Unabashedly, the guidance “encourages sponsors and clinical investigators to work with entities that control EHR systems, such as health care organizations, to use EHR and EDC systems that are interoperable or fully integrated.” (The guidance defines interoperable systems as those capable of piping data from one to the other through a validated process. Think of a well-tested and well-documented API. Fully integrated systems, by contrast, “allow clinical investigators to enter research data directly into the EHR.”) Guidance sections with the most specific recommendations include those on:

  • structured and unstructured data (the first being preferred, but the second allowed if additional reliability and quality measures are in place)
  • validation (required for the EDC, but not for the EHR)
  • data from multiple EHR systems (“data from another institution’s EHR system may be used and transmitted to the sponsor’s EDC system provided that data sharing agreements are in place”)
  • ONC Health IT Certification for EHR system (“FDA encourages the use of such certified EHR systems”)
  • data custody and audit trails
  • maintaining the blind across all relevant systems
  • Informed Consent that makes the use of EHR data clear

The recommendations are sound, if not surprising. But the scope, which includes prospective studies but excludes postmarketing and registry ones, signals a focus on investigations designed to make new therapies available, or existing therapies available for new indications. A need, in other words, for speed.

What about the August guidance? Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics aims to bring order–and a seal of acceptability–to trials that are “intended to expedite development by seamlessly proceeding from initial determination of a potentially effective dose to individual cohorts that have trial objectives typical of phase 2 trials (i.e., to estimate anti-tumor activity).” These trials pose particular risks, most salient among them the possibility of exposing more participants than necessary to toxic or suboptimal doses. Because of these risks, sponsors should only consider an expansion cohort design for studies related to indications without curative therapies.  What’s more, to mitigate these risks, the guidance states that “it is imperative that sponsors establish an infrastructure to streamline trial logistics, facilitate data collection, and incorporate plans to rapidly assess emerging data in real time and to disseminate interim results to investigators, institutional review boards (IRBs), and regulators.”

Sections V, VI, and VII, dealing with considerations based on cohort objectives, statistical considerations, and safety considerations respectively, don’t lend themselves to summary, mandating study conduct requirements for physicians, pharmacologists, pharmacovigilance officers and biostatisticians. (To get a sense of the detail, note that both guidance on Food-Effect Bioavailability and Fed Bioequivalence Studies and Pharmacokinetics in Patients With Impaired Renal Function — Study Design, Data Analysis, and Impact on Dosing and Labeling are pre-requirements.) That such specific directives are issued here in a draft guidance hints at an urgency understood: getting quickly to Phase III safety and efficacy findings starts with a Phase I that can transition quickly transition to a Phase II.

Beyond the text of these documents, the FDA’s response to the industry’s need for speed is audible, and commendable. Why did the response (or so explicit a response) come now? We can only speculate. Certainly, the roads to knowledge are getting faster by the day. Just consider the early successes of machine learning. And despite some therapeutic victories, cancer is by no means in retreat. The will and the way are clear. The FDA has just supplied a good deal of the how.

Unsure whether your data capture system is build for speed? Versatile study build features, a robust API, and forms that drive “quality on entry” are all must haves.


Deadline to submit OC18 abstract is August 24

Submit an Abstract for OC18

Deadline: Friday, August 24

Would you like to share a case study with fellow power users? Eager to share your domain expertise with other data managers? Submit an abstract for a chance to take the stage at OC18. We love to showcase projects that demonstrate an innovative use of OpenClinica. But if you simply have an original take on the interestion of personalized medicine and data management, we want to hear from you.

We encourage a broad interpretation of this year’s theme.

  • Have you led or participated in research that delved beyond an indication and eligibility criteria in its participants?
  • Have you personalized study workflows for your team?
  • How are you personally motivated by the research you do?

All are valid prompts for developing a session.

Still need some inspiration? Check out the OC17 program.

We received a record number of submissions in 2017, so we can’t guarantee extending the deadline past August 24. Tell us your idea today!

OC18 details announced. Register today!

We’re excited to open up registration for our 10th Annual User Conference. Prepare to get personal (in terms of data, anyways) for two learning-packed days at Le Meridien Cambridge-MIT. Together with our community of users, we are building a program bursting with the timely, real-world topics and case studies you’ve come to expect from our Annual Conference. Topics will include:

  • Data security
  • GDPR and Compliance
  • How to Conduct an Audit
  • Ultra-capable forms
  • Randomization
  • eConsent
  • Data visualization and reporting with OpenClinica Insight

On the second night, join your peers for an evening of elegance and education at the nearby Museum of Science. Super User training will be offered on October 17, 18, and 19 right in Cambridge.

Learn more and register here.

How Good Are We at What Matters?

For the last several months, we’ve asked professionals with data management responsibilities to evaluate their current processes for accomplishing critical tasks. We then asked them to rank three of these tasks as their first, second, and third priorities.

We asked respondents to evaluate their current processes

Respondents rank their EDC task priorities

Specifically, we each respondent to consider these EDC-related tasks…

  • Getting your eCRFs to look and act the way they should
  • Producing reports
  • Building and publishing studies on your eclinical platform
  • Keeping the number of queries at a reasonable level
  • Tracking source data verification
  • Getting timely data from study participants (diaries, questionaires, etc.)
  • Coding adverse events and conmeds
  • Integrating with other eClinical systems
  • Demonstrating compliance for regulatory and security purposes
  • Implementing protocol amendments
  • Getting data into SDTM
  • Creating and managing accounts for users and sites
  • Getting approval and sign-off from stakeholders on study design
  • Working with your system’s support team

… and to characterize their process for each one as either…

  • Ideal, or close to it
  • Very good
  • Tolerable for now
  • In desperate need of replacement
  • Not applicable (i.e. not part of my duties)

The data below reflects the responses of data managers (n=25), study and program leads ( n=13), IT/database professionals (n=6), and a CRA. To reduce bias, we did not include responses of known OpenClinica users.

What did we learn? Data managers and their colleagues are getting the job done (no surprise there) and are generally content with the way they’re doing it. But current processes usually fall short of ideal. How do your experiences compare?

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Getting eCRFs to look and act the way they should

Producing reports

Building and publishing studies

Keeping the number of queries at a reasonable level

Tracking source data verification

Getting timely data from study participants (diaries, questionaires, etc.)

Coding adverse events and conmeds

Integrating with other eClinical systems

Demonstrating compliance for regulatory and security purposes

Implementing protocol amendments

Getting data into SDTM

Creating and managing accounts for users and sites

Getting approval and sign-off from stakeholders on study design

Working with your system’s support team

Data Gets Personal at OC18, October 15 and 16 in Boston, MA

OC18 data gets personal logo boston skyline

“Can we get personal?”

More and more often, that’s the question motivating today’s most innovative research. Whether it’s an RCT with a biomarker cohort or an observational study based on real-world evidence, we’re seeing the “data funnel” widen to encompass much more about the participant than their diagnosis. Genomic medicine is just one example. Factors including phenotypical traits, diet, and lifestyle, among others, are all counting for more in studies that seek to match the right therapy with the right patient.

This year’s theme is a recognition of this important new paradigm. But it’s not meant to constrain. How are you adapting to the complexity of new and expanding data types? How do we make the tools of data management as personal and precise as the results we’re seeking?

We’ll explore these questions and more as data gets personal at OC18! 


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More than Checking Boxes: An eConsent Q&A [audio]

eConsent; tablet; mobile device; clinical research consentFor the second year in a row, we’re looking forward to hosting a panel session at the Society for Clinical Data Management Annual Conference.  Last year, we gathered four experts, including our own Ben Baumann, for a panel on ePRO. This year, we’ll turn our sights on eConsent. Our panelists represent a “who’s who” of seasoned professionals in this area. Learn who they are and read all about the issues they’ll discuss below. First, take a listen as one panelist, project manager and clinical trial educator Brittany Stark, walks us through the advantages of adopting eConsent and tells us why review boards are likely to embrace it as trial complexity grows.


Brittany on eConsent

Download the mp3



Hello and welcome from OpenClinica. My name is Bryan Farrow and I’m joined today by my colleague, project manager Brittany Stark. Brittany, may I ask you a few questions about e-consent, the topic of our panel at this year’s SCDM conference?


Let’s start by having you tell us about your clinical research career, especially as it pertains to consent.

Working in the professional services department here in OpenClinica, we get a variety of projects invlving eConsent. Prior to joining OpenClinica, I worked at Beth Israel Deaconess Medical Center in their Cancer Clinical Trials Office, where I worked as a clinical research coordinator, later in the regulatory affairs department, and then as a clinical trial staff educator, all involving different aspects of either the education of informed consent documentation of collection.

Great, thank you. For the sake of brevity, I’ll assume our audience is familiar with the basics of econsent and steer our conversation toward the advantages and obstacles associated with it. Let’s start with the obstacles. A common one is the anticipated resistance of review boards. Brittany, why might an IRB resist econsent?

Well they’re used to paper-based methods with an established precedent.

Fair enough, but why should they consider embracing eConsent?

eConsent has the potential to enhance patient understanding by means of an eLearning experience that is engaging and informative. This can be achieved through the use of graphics, interactive tutorials, videos, or even quizzes tapping into their understanding of the study.

An eConsent form can guide a patient through this experience, step by step, only presenting a signature box at the end of these exercises. Paper-based methods, on the other hand, can allow for corners to be cut.

All that sounds terrific. So why are sponsors sometimes reluctant to adopt econsent?

Here again, there’s the weight of tradition. They may also anticipant resistance from local IRBs, which in their eyes could cause delays.

Those are legitimate concerns. What might you say to a sponsor to persuade them to take another look at eConsent?

Sponsor’s shouldn’t assume that an IRB will reject this method. Simply put, an IRB’s priority is patient safety. Patient safety starts with their understanding of the trial and all of the inherent risks involved. As I mentioned before, this is where eConsent can offer more protection through a step-by-step online experience.

Sponsors can achieve tremendous time and cost savings. eConsent eliminates the costs involved in chasing that paper trail, reducing the research team’s time involved in the consent process.

eConsent can also provide real time recruitment rates to study sponsors. This is very important when studies cannot risk going over set enrollment goals.  Sponsors can also more accurately project future recruitment with this kind of real time reporting.

Based on everything you said, do you think the future of eConsent looks bright?

Absolutely, and I look forward to talking about this more during our panel.

About the Panel

“More Than Checking Boxes: Integrating Electronic Informed Consent in a Compliant and Ethical Way”
a panel session as part of the 2018 SCDM Annual Conference
Tuesday, September 25, 2017 from 11:15am to 12:15pm
Hyatt Regency Bellevue, Seattle


Cal Collins CEO, OpenClinica


John Wilbanks, Sage Bionetworks
Kristen Warren, DxTerity
Kevin Johnson, Intermountain Heart Institute
Brittany Stark, OpenClinica
Vincent Miller, Duke Clinical Research Institute
Sandra Sather, CRF Health

Session overview:

Regulatory authorities have been clear that Informed Consent is a multifaceted process that goes far beyond obtaining a signature. Genuine consent involves providing potential participants with adequate information about the research to allow for an informed decision to participate, facilitating and verifying comprehension of the information, and allowing adequate opportunity for questions and consideration. The process often continues after enrollment. Investigators are frequently obligated to provide additional information to participants as the research progresses, and even obtained informed re-consent.

Electronic informed consent (e-Consent) must accommodate all these requirements. Done well, e-Consent can maximize patient understanding, engage non-English speakers with multilingual tools, improve documentation and reporting, and standardize the consent process across sites, all while reducing cost and administrative burden. Attendees of this session will learn how to determine the suitability of e-Consent in light of a study’s setting, participant profile, and indication (among other attributes), as well as the best way to adapt the principles of fully informed consent in its usual, paper-based context to one where the process is electronic.

Learning objectives:

  1. Translate the requirements of informed consent in its usual, paper-based context to one where documentation is electronic
  2. Understand which contexts are suitable for electronic informed consent, which are not, and which allow for a hybrid method
    3. Leverage interactive forms and media to improve patient understanding and better document their comprehension and consent
    4. Accurately project the time and cost-efficiency gained for a study that relies on e-consent

Optimized AE management, “any file” uploads, and more in this week’s OC4 release

The first major update to OC4 went live early today, with new features that extend your study’s flexibility so much that we wanted to call them out in this post.

“Common Events”: the new, intuitive way to accommodate AEs and conmed changes

Common events are not associated with a visit date, and do not occur at a scheduled time-point. Instead, they are incidental events that often recur, such as adverse events and concomitant medications. This update makes it easy to include common events in your study. You can include multiple forms in a common event, which allows each form to repeat independently within the event. 

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Study designers can even select key fields in the forms to display those field values on the (new, UX-optimized) Subject Details page, allowing users to view form data without having to open the form.

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“Upload a file, any file”

You now have several distinct widgets for collecting files.

Image, audio, and video widgets allow users to upload these file types, which may then be viewed or played within the browser window.

We have also added a generic file widget for uploads of any type. (However,  these files do not support a preview in the browser window.)

Any uploaded file may be downloaded from within the form.

Draw, annotate, or sign

Used judiciously, free text fields can enrich the data collected in a study. So just image what free drawing can do. This latest update supports:

  • Drawing on a blank canvas, from a palette of 12 colors plus black, with a mouse, finger, or stylus
  • Annotating an uploaded image with freehand notes or diagrams (from the same color palette, using a mouse, finger, or stylus)
  • Signing one’s name, in black only, with a mouse, finger, or stylus

The annotate and draw widgets allow the user to undo individually added lines.

Central User Management

A new feature allows administrators to view a directory of all users created for at least one test or production environment in their instance. Each user record indicates:

  • First name
  • Last name
  • Username
  • Email address
  • Organization (e.g. Site 1234)
  • all roles for all study environments (e.g. EUPHONY Study (Test): Clinical Research Coordinator, PRAXIS Study (Production): Data Entry Person, etc.)
  • Role type (Admin or User)
  • Status (Created > Invited > Available/Signed In)
  • Date and time created
  • Date and time last updated
  • Date and time of last login

An edit button allows an administrator to update a user’s first name, last name, phone number, e-mail address, organization, or user type (i.e., attributes that are independent of any one study or environment). A deactivate button removes access for that user to any study environment to which they had been assigned. For deactivated users, a Reactivate button restores all access.

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Have will you leverage these capabilities? Let us know with a comment.

“You’ve Got Findings!”: To the 90’s and Back with GCP E6(R2)

dowload GCP; download GDPR; download 21 CRF 11; regulatory documentsImagine a time when phones boasted no smarts. When technophiles worshipped noisy gadgets called modems. When The Human Genome Project sounded (to most ears) like the name of a progressive rock band.

Not to your ears, though. Suppose further that you’re an accomplished research professional of the era, medically trained, with degrees and vision to spare. Someday, you’re certain, paper records will give way to more efficient storage and retrieval. Zip disks, maybe? And this digital highway that’s all the rage, the “Web”, well, who knows? When adequate security measures are in place, maybe sites could email a digital CRF to the data manager.


A relic from pre-history (i.e. before Facebook timelines). Scholars are still uncertain of the fate of this “virtual settlement.”

It’s that foresight which, in the mid-1990s, has earned you membership to an international committee of your peers; a committee tasked with devising guidelines to “facilitate the mutual acceptance of clinical data” by regulatory authorities in Europe, Japan, and the United States. At least, that’s the operational goal, and a worthy one, too. You started in this business to push the best research out of silos and ivory towers and into the real world. But that mission is fraught with potential dangers. Not forty years prior, inadequate testing of an immunomodulatory drug led to the births of more than 10,000 children with limb malformations in Germany. Just three years ago, in a trial conducted by the NIH, five participants died of liver toxicity following experimental treatment for hepatitis B. Whatever standard you propose for maximizing the benefits of clinical research, it had better provide “public assurance that the rights, safety and well-being of trial subjects are protected.” After all, your committee is bound by the ethical good in its pursuit of the clinial good. You suggest calling the standard Good Clinical Practice.

Welcome to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. And welcome to 1996.

But don’t get comfortable. This is the story of GCP–more precisely, the Guideline for Good Clinical Practice–and it is headed right back to the present, with its first amendment already in force in Europe. Why did the ICH amend its original guideline? Why twenty years later? There’s no single answer, but all the best answers revolve around one theme. Just as our phones have gone on to earn a postdoc in the last 22 years, the possibilities for research have matured, too. What’s more, their modern histories are linked, with technological breakthroughs inspiring the search for clinical ones, and clinical triumphs spurring ever more capable technology. Behind that push and pull, the need to ensure safety and quality remains constant. The story of the GCP’s amendment is a story of time-honored values upheld in new ways.

Preserving the Past

In a literal sense, E6(R1) hasn’t been replaced at all. The authors of E6(R2) choose an integrated addendum format when drafting the updated guidance. The original language, with all that it mandates, remains:

The addendum text clarifies the scope and meaning of preceding terms. Twenty years ago, the word “storage” brought to mind file cabinets. Early in this millenium, we might of have pictured hard drive volumes. Today, our heads are in the cloud. But in all of these contexts, storage that is secure and accessible is a must. It’s how we achieve it that differs.

Embracing the New

But just how do we achieve it–meaning everything from security to safety to data quality–in 2018, when so many tasks once considered part of an “honest day’s work” are now specialties of automation, algorithms, and analytics?

Not even the full sixty pages of the document provide a specific, once-and-forever answer. (As a guideline, it shouldn’t.) What E6(R2) does propose is a 21st-century mantra for maximizing safety and quality. The mantra sounds like this:

“Oversee it all. Take action on what matters.”

There are some loaded terms in this phrase. “Oversee” might translate to “maintain real-time digital access,” particularly in the case of processes occurring daily all over the world, such as eConsent. And “take action” needs to cover both proactive and corrective measures. But with those common sense glosses in mind, we could do worse than take the directive above as the crux of E6(R2). What evidence do we have for this reading? Before we look at specific clauses in R2, we can gain a strong sense of how the amendment differs from the original by looking at the frequency of key terms.

Frequency of key terms and contexts; ICH GCP E6(R2); ICH GCP E6(R1)
Clues that the GCP has grasped an important truth. The sheer volume of data now available to us raises probabilistic, “big data”-inspired thinking to a virtue.

Terms like “risk-based” simply weren’t part of the vernacular in 1996, so it’s no surprise that they should make their first appearance only now. But the concept of risk is as old as modern, statistically-informed research itself. So why does the word itself occur twice as frequently in R2 as opposed to R1?

The answer is that risk is omnipresent now, not primarily in the sense of an unintended consequence, but as a factor in decision-making. How did this come to be the case? Along almost any dimension we consider–target enrollment, sources of data, self-reports–research is doing, and producing, more than it ever has. In some cases, like the breadth of genomic factors analyzed, research is doing more than we thought possible back in 1996. On the other hand, the number of hours in a day has remained disconcertingly flat (anyone working on this?). Human cognitive capacities and attentional reserves likewise remain more or less the same. Our technological capacities have grown in orders of magnitude, and that’s all good. But until self-organizing, self-monitoring trials (powered by AI) are the norm, we humans will continue to serve as the chief executives of research.

While the amendment stops shy of saying it explicitly, R2 recognizes that distributing our time and attention equally among all processes works against safety and quality. That’s because some studies are now so complex, or collect so much data, that line-by-line “box checking” not only becomes impractical, it distracts us from those risks that only become apparent on a “big data”-like view of key metrics. In other words, it’s crucial that we see the risk forest for the data element trees. That’s the message behind much of the amendment text:

From the Introduction:

From section 2, “The Principles of GCP”:

From section 5, “Sponsor”:

Does this mean less rigor in oversight? Just the opposite. The GCP amendment will require more vigilance from all parties, from sponsors and sites to CROs and vendors. It means bringing alertness and analysis to bear in order to find the boxes, not just check them. This isn’t the ICH throwing up its hands now that the “scale, complexity, and cost of clinical trials have increased.” It’s the ICH demanding that we learn, and practice, new survival skills in a new world.

So drop the Nintendo controller. Time to pick up some neural implants.

Intelligent, visual reporting is here!

See the video now, join the webinar on March 26 or 28.
You know it better than anyone: clear, on-demand reporting is more than a “nice to have” in our field. It’s essential to conducting research that’s efficient and safe. That’s why we’re launching OpenClinica Insight. Insight makes it easy to ask questions of ALL of your clinical and operational data and visualize answers via interactive reports and dashboards.

Learn more at either of these upcoming webinars:
Monday, March 26, 8pm GMT, or
Wednesday, March 28, 8am GMT


The idea is simple, but the results are powerful: ask your questions, choose your visualizations, then return often for updated, interactive results that link you to all of the underlying data.

Learn more about Insight now, or schedule a time to speak with our team. We hope you can join us in March.