NIH Collaboratory leadership and Demonstration Project Principal Investigators have responded to the U.S. Food and Drug Administration’s (FDA’s) proposed rule to allow for a waiver or alteration of informed consent.
“We applaud the proposed rule to allow for a waiver or alteration of informed consent for clinical investigations posing no more than minimal risk to a human participant and including appropriate safeguards.
We agree about the broad benefits described in the proposed rule—healthcare advances, reduction in burden from harmonizing FDA’s regulations with the Common Rule, and reduced burden and costs for the IRB…”
The full letter is available for download and includes the list of signatories.
Real-world data: routinely collected information about a person’s health status in the electronic health record, claims, registries, and other sources, including patient-generated sources.
Real-world evidence: reliable, clinical information derived from real-world data about risks, benefits, and burdens of therapies.
This framework will apply to various pragmatic clinical trials embedded in health care systems and conducted as part of routine care (and will not apply to more traditional clinical trials conducted parallel to care).
Three main considerations are included in the framework:
Will the real-world data be fit for use (do they reliably and adequately represent the concept)?
Will the evidence generated by the trial provide adequate evidence to help answer regulatory questions?
Will the conduct of the study meet FDA regulatory requirements?
The Food and Drug Administration (FDA) is proposing a rule to allow for a waiver or alteration of informed consent for clinical investigations posing no more than minimal risk to human participants. This rule would align FDA regulations with the Common Rule, reduce burden and costs for Institutional Review Boards, and be expected to lead to advances in healthcare.
“We expect benefits in the form of healthcare advances from minimal risk clinical investigations and from harmonization of FDA’s informed consent regulations with the Common Rule’s provision for waiver of informed consent for certain minimal risk research.” — Federal Register /Vol. 83, No. 221
Currently, FDA allows a waiver or alteration of consent only in life-threatening situations. If aligned with the Common Rule, a waiver or alteration would be allowed if the IRB finds and documents that 1) the research involves no more than minimal risk, 2) the rights and welfare of subjects will not be adversely affected, 3) the research could not practicably be carried out without a waiver, and 4) the participants will be provided with additional pertinent information after completion of the trial.
Penny Randall, MD, MBA
VP and Global Therapeutic Head, CNS
A New Path Forward for Using Decentralized Clinical Trials
Decentralized clinical trials; Telemedicine; Mobile health; Clinical Trials Transformation Initiative; FDA
Decentralized clinical trials (DCTs) are defined as those executed through telemedicine, mobile, or local healthcare providers (HCPs), using procedures that vary from the traditional clinical trial model; for example, shipping investigational medical product directly to the trial participant.
DCTs are not “all or nothing.” They exist in a broad continuum and can expand the reach of traditional clinical trial sites.
Potential benefits of DCTs apply to all trials in all disease areas but may offer particular advantages in rare diseases, where patients are generally limited in number or are highly geographically dispersed.
Mobile HCP training is similar to that required for standard investigative sites: Good clinical practice, protocol-specific training, human subject protections, data protection, and clinical trial billing.
Will a decentralized trial lead to less diverse patient populations as participants will need to be technology literate and have access to technology?
Decentralized clinical trial safety monitoring plans should not be held to a higher standard than with traditional trials unless merited by a particular circumstance. It is important to develop protocol-specific safety monitoring and communication escalation plans.
John Hubbard, PhD
Healthcare Strategic Advisory Board
Barry Peterson, PhD
Cheryl Grandinetti, PharmD
Office of Compliance, Office of Scientific Investigations, Division of Clinical Compliance Evaluation
Center for Drug Evaluation and Research
Food and Drug Administration
Advancing the Use of Mobile Technologies for Data Capture & Improved Clinical Trials
Clinical trials; Mobile health technologies; Clinical Trials Transformation Initiative; CTTI; FDA; Data integrity
The goal of CTTI’s Mobile Clinical Trials program is to develop evidence-based recommendations that affect the widespread adoption and use of mobile technology in clinical trials for regulatory submission.
Potential benefits of using mobile technology include higher quality, patient-centric endpoints and fewer barriers to participation in clinical trials.
Data access issues to consider before selecting a mobile technology include:
How will the data generated by the mobile technology be accessed and used by the manufacturer?
What data will be provided by the manufacturer to the sponsor?
The mobile era creates new data security demands.
CTTI’s recommendations aim to help sponsors determine the right device to use, how to write the protocol for remote data capture, and how to protect and analyze the data.
Know what you want to measure before selecting the mobile technology. The appropriateness of the selection should be justified through verification and validation processes.
Ensure the authenticity, integrity, and confidentiality of data over its entire lifecycle.
To reduce risk in large trials, conduct feasibility studies before full implementation.
The FDA is conducting a public workshop on Monday, March 19, to obtain input from stakeholders—including patients, patient advocates, academic and medical researchers, expert practitioners, drug developers, and other interested persons—to inform the drafting of a patient-focused drug development guidance as required by the 21st Century Cures Act. Workshop attendees will discuss considerations for development and submission of a proposed draft guidance regarding patient experience data submitted by an external stakeholder. The guidance is intended to help stakeholders continue progress in developing new medicines to respond to patient’s needs.
Registration for the event, either in person or via a live webcast, ends March 12. More meeting details, including background materials, will be posted by FDA as available.
As part of their ongoing effort to improve the speed and efficiency of conducting clinical trials, the NIH-FDA Joint Leadership Council has created a draft clinical trial protocol template. The template contains instructional and sample text intended to assist NIH-funded investigators in writing protocols for phase 2 or 3 clinical trials that require Investigational New Drug (IND) or Investigational Device Exemption (IDE) applications. Feedback is sought from investigators, investigator-sponsors, institutional review board members, and other stakeholders involved in protocol development and review.
Our goal is to provide an organized way for creative investigators to describe their plans so that others can understand them. – Dr. Pamela McInnes, NIH
Details on the rationale and development of the protocol template are on these blog posts:
A new report (PDF) containing recommendations for the creation of a national registry system for evaluating and monitoring medical devices has been released for public comment today. The report, a joint project of the Medical Device Registry Task Force and the Medical Device Epidemiology Network (MDEpiNet), is available on boh the US Food and Drug Administration (FDA) website and on the MDEpiNet website.
The report reflects the results of a year-long effort, prompted by the FDA’s Center for Devices and Radiological Health (CDER), that is focused on fostering a national system for monitoring the use of medical devices in the “real-world” setting of patient care, once the devices have been approved for the market (known as “postmarket surveillance”).
The term “medical devices” encompasses a wide range of technologies, including implantable pacemakers, cardiovascular stents, robotic surgical devices, and artificial joint replacements, among many others. At present, information about the use of these devices in routine care settings, including safety issues reported by doctors and patients, is collected in a variety of registries and health record systems. A networked national system, such as the one described in the task force report, would be able to unite and build upon both existing and novel data resources, thereby improving safety monitoring and accelerating the development of new devices:
“Task Force recommendations for [Coordinated Registry Network] CRN architecture, and thus for the National System, center on leveraging existing, self sustaining electronic resources, such as device registries, electronic health records, administrative data and even social media and personal mobile device sources.”
The Task Force Report offers recommendation in several key areas, including:
Establishing a national dialog about medical device evaluation that includes all stakeholders;
Leveraging existing efforts in the arena of device registries and electronic data systems;
Describing the desired characteristics of a national Coordinated Registry Network (CRN) for medical devices;
Outlining priorities for developing and refining medical devices in multiple therapeutic areas;
Identifying and improving methods for analyzing data on medical devices; and
Addressing network governance and issues related to patient privacy and informed consent.
Each of these key areas also features suggested pilot projects designed to inform ongoing efforts.
A related perspective article summarizing the National Registry System project has also been published online in the Journal of the American Medical Association.
A new analysis of data from the ClinicalTrials.gov website shows that despite federal laws requiring the public reporting of results from clinical trials, most research sponsors fail to do so in a timely fashion—or, in many cases, at all. The study, published in the March 12, 2015 issue of the New England Journal of Medicine, was conducted by researchers at Duke University and supported by the NIH Collaboratory and the Clinical Trials Transformation Initiative (CTTI). The study’s authors examined trial results as reported to ClinicalTrials.gov and evaluated the degree to which research sponsors were complying with a federal law that requires public reporting of findings from clinical trials of medical products regulated by the U.S. Food and Drug Administration (FDA).
“We thought it would be a great idea to see how compliant investigators are with results reporting, as mandated by law,” said lead author Dr. Monique Anderson, a cardiologist and assistant professor of medicine at Duke University.
Using a publicly available database developed and maintained at Duke by CTTI, the authors were able to home in on trials registered with ClinicalTrials.gov that were highly likely to have been conducted within a 5-year study window and to be subject to the Food and Drug Administration Amendments Act (FDAAA). This federal law, which was enacted in 2007, includes provisions that obligate sponsors of non-phase 1 clinical trials testing medical products to report study results to ClinicalTrials.gov within 12 months of the trial’s end. It also describes allowable exceptions for failing to meet that timeline.
However, when the authors analyzed the data, they found that relatively few studies overall—just 13 percent—had reported results within the 12-month period prescribed by FDAAA, and less than 40 percent had reported results at any time between the enactment of FDAAA and the 5-year benchmark.
“We were really surprised at how untimely the reporting was—and that more than 66 percent hadn’t reported at all over the 5 years [of the study interval],” said Dr. Anderson, noting that although prior studies have explored the issue of results reporting, they have until now been confined to examinations of reporting rates at 1 year.
Another unexpected result was the finding that industry-sponsored studies were significantly more likely to have reported timely results than were trials sponsored by the National Institutes of Health (NIH) or by other academic or government funding sources. The authors noted that despite a seemingly widespread lack of compliance with both legal and ethical imperatives for reporting trial results, there has so far been no penalty for failing to meet reporting obligations, even though FDAAA spells out punishments that include fines of up to $10,000 per day and, in the case of NIH-sponsored trials, loss of future funding.
“Academia needs to be educated on FDAAA, because enforcement will happen at some point. There’s maybe a sense that ‘this law is for industry,’ but it applies to everyone,” said Anderson, who points out that this study is being published just as the U.S. Department of Health and Human Services and the NIH are in the process of crafting new rules that deal specifically with ensuring compliance with federal reporting laws.
According to Anderson, increased awareness of the law, coupled with stepped-up enforcement and infrastructure designed to inform researchers about their reporting obligations, have the potential to improve compliance with both the letter and the spirit of the regulations. “I think reporting rates will skyrocket after the rulemaking,” she says.
In the end, Anderson notes, reporting clinical trials results in order to contribute to scientific and medical knowledge is as much an ethical obligation for researchers as a legal one: “It’s something we really promise to every patient when they enroll on a trial.”
On March 9, 2015, the U.S. Food and Drug Administration (FDA) issued draft guidance on the Use of Electronic Informed Consent in Clinical Investigations (document opens as a PDF). In a question-and-answer format, the guidance provides recommendations for investigators, sponsors, and institutional review boards (IRBs) on the use of electronic media and processes to obtain informed consent for FDA-regulated clinical investigations of medical products, including human drug and biological products, and medical devices, and combinations thereof.
Electronic informed consent, or eIC, refers to the use of electronic systems and processes to convey information related to the study and to obtain and document informed consent. Electronic media formats may include text, graphics, audio, video, podcasts, and interactive websites, biological recognition devices, and card readers. Use of electronic systems may allow for rapid notification to study participants of any amendments pertaining to the informed consent, promote timely entry of eIC data into the study database, and allow for timely collection of the informed consent data from remote locations.
The guidance provides answers to these questions:
How should the information in the eIC be presented to the subject?
How and where may the eIC process be conducted?
How and when should questions from subjects be answered?
What steps may be taken to facilitate the subject’s understanding of the information being presented?
What steps may be taken to ensure that new or additional information is conveyed to the subject during the course of the clinical investigation?
Does FDA allow the use of electronic signatures to document eIC?
What special considerations should be given to the use of eIC for pediatric studies?
Should subjects receive a copy of their eIC and have easy access to the material and information presented to them in their eIC?
What steps can be taken to help ensure confidentiality of the information once eIC is obtained?
Can HIPAA authorizations for research, which are frequently combined with informed consent documents, be obtained electronically?
What are the IRB’s responsibilities in the eIC process?
What eIC documentation does FDA require for submission with applications?
What steps can be taken to ensure the system archives the documents appropriately?
What materials or documents will FDA require during an inspection?
The comment period ends May 7, 2015. Users can submit electronic comments using the docket number HHS-OPHS-2015-0002 at the Federal eRulemaking Portal: http://www.regulations.gov.