On November 26, 2018, the U.S. Food and Drug Administration (“FDA”) announced the process for clearing most medical devices for marketing is being updated to incorporate changes the FDA laid out in an April draft guidance. For over forty years, most medical devices have entered the United States market through the 510(k) clearance process. The 510(k) process offers an expedited approval process available only for products that are substantially equivalent to products already on the market (known as predicate devices). The FDA is considering no longer allowing sponsors to rely on predicates older than ten years and making public information about cleared devices that relied on predicates more than ten years old. In addition, the FDA intends to finalize guidance establishing an alternative 510(k) pathway with different criteria that reflect current technological principles.

In a statement, FDA Commissioner Scott Gottlieb reasoned that newer products relying upon older predicates might not reflect new performance standards or latest scientific and medical understanding. Commissioner Gottlieb believes this change will promote the continual improvement of medical devices. However, the announced change received quick pushback. Many manufacturers argue that reliance upon older predicates can be necessary when no newer predicates are available, and older predicates can provide data that helps sponsors make new devices safer. In addition, many industry-observers believe the FDA’s plans may contradict and exceed its statutory authority, and therefore require additional support from Congress.

If the current proposal becomes law, the implications will include increased costs for manufacturers forced to innovate because of the inability to rely on older predicates. The agency’s statement indicates that new medical devices that utilize the 510(k) pathway should be better than predicates, rather than the applicable legal standard of substantial equivalence. Thus, manufacturers can anticipate increased agency scrutiny when submitting information in the 510(k) summaries. In addition, manufacturers may need to make alternative plans if developing a new device based on an older predicate.

On November 19, 2018, the FDA submitted a proposal to the White House Office of Management and Budget (OMB) to approve a review that will assess current communication practices between FDA review staff and Investigational New Drug (IND) sponsors.  The FDA has contracted with Eastern Research Group (ERG) to determine whether the current mode of communication between these parties needs to be adapted moving forward.  Depending on the results of this review, communication practices and requirements could be altered, which might have an effect on the IND application process. Possible modifications might occur that could assist in removing communication bottlenecks hindering approval timelines.

By filing an IND, a drug developer seeks approval to conduct human trials of investigational new drugs.  After an organization submits an IND application to the FDA for approval, the FDA review team must review the submission within a 30 day period and determine whether to approve or deny the application.  During this period, the FDA review staff and IND sponsors communicate regarding IND status, concerns, and questions, and the clock stops on the 30-day period any time the FDA requests additional information from the sponsor. Overall, this process is designed to minimize the risk of harm to clinical trial volunteers and confirm that the clinical trial protocols are appropriate. Further, the FDA reviews the proposed study protocol to confirm sponsors’ plans support compliance with good clinical practice requirements.  The FDA released guidance last December on best practices for communication between IND sponsors and FDA review staff in order to assist in improving the effectiveness, timeliness, and transparency in communications between the parties.  Additionally, the FDA believes that improved communication may assist in facilitating the availability of effective and safe drugs to consumers.

The FDA expects that the upcoming review, pending OMB approval, will shed more light on how commercial IND sponsors perceive their communications with FDA staff.  During this review, ERG will collect data from sponsors of “a sample of up to 150 active commercial INDs that have activity during a one-year period.”  The surveys (which can be found here) and interviews with IND sponsors are intended to assess sponsors’ experiences when communicating with the FDA review staff, and will examine “what is working well, ongoing challenges and pain points, lessons learned, and opportunities for improvement.” After this data is analyzed and reported by ERG, the FDA will “publish the report on the Agency’s public website and hold a public meeting about the assessment.”

The study findings may be useful in assisting the FDA in meeting its PDUFA commitment to promote transparency between sponsors and review personnel.  The PDUFA plan emphasizes its goal to promote effectiveness and efficiency of the first cycle review process while minimizing the number of review cycles necessary for approval. Sponsor recommendations through the surveys may very well shed light on current communication issues as well as other factors that might hinder the approval process.  An understanding of such hindrances may assist FDA in improving communication and transparency between parties and, thus, the IND approval process itself.

EBG will continue to monitor all developments in FDA’s regulation of the IND approval process as well as the forthcoming results from ERG’s review of IND sponsor communication with FDA review staff.

Following up on its July 2017 guidance on the same topic (discussed in a previous blog post), FDA issued a proposed rule on November 15, 2018 to amend Agency regulations to allow Institutional Review Boards (“IRBs”) to waive or alter certain informed consent elements (or in some cases, waive the informed consent requirement altogether) for FDA-regulated, minimal risk clinical investigations (“Proposed Rule”).

What Clinical Investigations are Affected?

Importantly, the only clinical investigations affected by the Proposed Rule are those that are FDA-regulated and “minimal risk” – a term defined by FDA to mean that “the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.”

Such minimal risk investigations may be approved by IRBs through an expedited review procedure.  Although FDA has designated specific categories of research that may be reviewed through this procedure, the designated activities are not automatically considered minimal risk just because they are on FDA’s list.  Rather, inclusion on the list simply means that the research activity is eligible for expedited review where the specific circumstances of the research involve no more than minimal risk.  Still, the designated research categories shed light on the types of studies that may be deemed minimal risk, including: research on a drug or device where an investigational new drug application (“IND”) or investigational device exemption (“IDE”), respectively, is not required; prospective collection of biological specimens for research purposes by noninvasive means (e.g., hair and nail clippings); collection of data from voice, video, digital, or image recordings made for research purposes; and research on individual or group characteristics or behavior, or research employing survey, interview, oral history, focus group, program evaluation, human factors evaluation, or quality assurance methodologies.

What is the Intent of the Proposed Rule?

Sometimes it’s not practicable for sponsors to obtain informed consent when conducting clinical investigations.  As current FDA regulations offer only very narrow exceptions to the informed consent requirements – for life threatening situations or emergency research –  the inability of an investigator to obtain subject informed consent would have previously brought potentially valuable investigations to a halt.  However, the Proposed Rule seeks to provide increased flexibility with respect to FDA’s informed consent requirements for certain minimal risk studies.

In particular, the Proposed Rule implements changes made to the Federal Food, Drug, and Cosmetic Act (“FD&C Act”) by the 2016 21st Century Cures Act (“Cures Act”).  These changes authorize FDA to allow for exceptions to its standard informed consent requirements where the proposed clinical trial poses no more than minimal risk to the human subject and includes appropriate safeguards to protect the rights, safety, and welfare of the subject.  Specifically, under the Proposed Rule, FDA would allow IRBs to waive or alter informed consent requirements if the IRB finds and documents that:

  1. the clinical investigation involves no more than minimal risk to the subjects (see “minimal risk” definition above);
  2. the waiver or alteration will not adversely affect the rights and welfare of the subjects (in making this determination, the IRB may consider, for example, whether the waiver or alteration has the potential to negatively affect the subjects’ well-being or whether the subject population in general would likely object to a waiver or alteration being granted for the research in question);
  3. the clinical investigation could not practicably be carried out without the waiver or alteration (FDA defines “practicable” to mean (i) recruitment of consenting subjects does not bias the science and the science is no less rigorous as a result of restricting it to consenting subjects, or (ii) the research is not unduly delayed by restricting it to consenting subjects); and
  4. whenever appropriate, the subjects will be provided with additional pertinent information after participation.

As noted above, FDA already issued guidance for immediate implementation in July 2017 that states that FDA does not intend to object to IRBs waiving or altering informed consent requirements, as described in the guidance, for certain minimal risk clinical investigations (see our previous blog post).  However, FDA intends to withdraw this guidance after the Proposed Rule takes effect.

What are the Envisioned Benefits?

If finalized, the Proposed Rule would largely harmonize FDA regulations with the Common Rule, which governs human subject research conducted or supported by HHS and other federal agencies.  The Common Rule has included provisions allowing waiver of informed consent for minimal risk research since it was first issued in 1991.  We note, however, that January 2017 revisions to the Common Rule added a fifth criterion to the four listed above related to IRB waiver or alteration of informed consent (this fifth criterion requires that “if the research involves using identifiable private information or identifiable biospecimens, the research could not practicably be carried out without using such information or biospecimens in an identifiable format”).  FDA is not proposing to adopt this fifth criterion at this time.

Beyond harmonization, the Proposed Rule should pave the way for certain minimal risk clinical investigations to proceed that otherwise would have never gotten off the ground, offering greater opportunities for sponsors and investigators to further their product development efforts and make positive contributions to the public health.

Comments on the Proposed Rule must be submitted to the docket by January 14, 2019.

On November 1, 2018, the Office of the Inspector General (“OIG”) for the U.S. Department of Health and Human Services (“HHS”) published an audit report finding that the U.S. Food and Drug Administration’s (“FDA”) policies and procedures were “deficient for addressing medical device cybersecurity compromises.” (A copy of OIG’s complete report is available here and Report in Brief is available here.) Specifically, the OIG found that FDA’s policies and procedures were “insufficient for handling postmarket medical device cybersecurity events” and that FDA had not adequately tested its ability to respond to emergencies resulting from cybersecurity events in medical devices. Although the OIG report “did not identify evidence that FDA mismanaged or responded untimely to a reported medical device cybersecurity event,” it noted that “existing policies and procedures did not include effective practices for responding to these events.”

Citing cybersecurity of medical devices as a top management challenge for HHS, OIG conducted an audit to evaluate FDA’s plans and processes for timely communicating and addressing cybersecurity compromises in the medical device postmarket phase. Based on OIG’s audit of certain FDA internal policies, procedures, and website, as well as interviews with FDA staff, OIG recommended that FDA take the following actions: (i) continually assess the cybersecurity risks to medical devices and update its plans and strategies; (ii) establish written procedures and practices for securely sharing sensitive information about cybersecurity events with key stakeholders; (iii) enter into a formal agreement with federal agency partners; and (iv) establish and maintain procedures for handling recalls of medical devices vulnerable to cybersecurity threats. Although the OIG acknowledged that FDA has recently implemented some of its initial recommendations, it emphasized that its findings and recommendations with regard to FDA’s cybersecurity policies and procedures remain valid.

On the same date OIG published its report, FDA’s Suzanne B. Schwartz, M.D., M.B.A., published a post on FDA Voices asserting that the OIG report is an incomplete and inaccurate picture of FDA’s oversight of medical device cybersecurity. The post addresses FDA’s ongoing efforts to improve medical device cybersecurity over the past five years, including entering into a memorandum of agreement between FDA and the Department of Homeland Security (“DHS”) and publishing a new premarket cybersecurity guidance update in October 2018, which we wrote about in a previous blog here. FDA’s post also highlights FDA’s other partnerships with industry that aim to increase awareness of cybersecurity vulnerabilities and related concerns.

FDA reiterated that its regulatory approach to cybersecurity threats “is not static,” and reconfirmed its commitment to “work with the medical device industry and other stakeholders to proactively address emerging cybersecurity threats to medical devices in a way that puts patient safety first.” FDA has announced that it will hold a public Workshop on January 29-30, 2019 to discuss the newly released draft guidance on cybersecurity in premarket submissions. Instructions for registration are available on FDA’s website here.

In response to the OIG’s report, FDA will likely continue to develop new cybersecurity policies, initiatives, and guidance. Stakeholders in the medical device industry should monitor these developments and be prepared to address any such changes in policy or regulation. Meanwhile, regulated industry should consider reviewing FDA’s current cybersecurity guidance documents and assess whether its internal controls, quality systems, policies, or procedures adequately address potential cybersecurity risks or threats or could be improved.

EBG will continue to monitor all developments in FDA’s regulation of and policies related to medical device cybersecurity.

On October 24, 2018, President Trump signed sweeping bipartisan legislation to combat the opioid epidemic. The Substance Use–Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act, or the SUPPORT for Patients and Communities Act (“H.R. 6” or “the Law”), aims to “reduce access to the supply of opioids by expanding access to prevention, treatment, and recovery services.”[1] Congress has already appropriated $8.5 billion to implement this “landmark legislation” in 2018 and 2019.

In a series of Client Alerts, Epstein Becker Green will provide an overview of key components of H.R. 6, focusing on substantive requirements impacting an array of providers, manufacturers, health care professionals, community services organizations, and other health care entities. Forthcoming topics include the impact on treatment measures for opioid use disorders, addiction prevention measures, clarifications to U.S. Food and Drug Administration and U.S. Drug Enforcement Administration regulation and enforcement authority over opioid products, Medicare and Medicaid funding provisions, enhanced health care fraud protection, new data & reporting provisions, and telehealth requirements.

H.R. 6’s breadth requires impacted entities to take careful note of the Law’s requirements and varying effective dates.

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[1] Press Release, The White House, President Donald J. Trump Signed H.R. 6 into Law (Oct. 24, 2018), available at https://www.whitehouse.gov/briefings-statements/president-donald-j-trump-signed-h-r-6-law/.

[2] Press Release, U.S. Senate Committee on Health, Education, Labor & Pensions, President Trump Signs Alexander Bill to Fight Opioid Crisis (Oct. 24), available at https://www.help.senate.gov/chair/newsroom/press/president-trump-signs-alexander-bill-to-fight-opioid-crisis.

On October 2, 2018, FDA Commissioner Scott Gottlieb released a statement announcing new agency actions to further deter “gaming” of the generic drug approval process through the use of citizen petitions.  Among these actions, the most significant was the issuance of a revised draft guidance on citizen petitions subject to Section 505(q) of the Federal Food, Drug, and Cosmetic Act (“FDCA”), published on the same day.  The stated goal of this revision was to create a more efficient approach to 505(q) petitions and to allow the Agency to focus reviewer resources on scientific reviews.

For years, FDA has been addressing allegations that companies have been using the citizen petition process to delay competitor approval, thereby “gaming” the system, while also balancing the value of individuals exercising their First Amendment rights through the citizen petition process.  In 2007, Section 505(q) was added to the FDCA through the FDA Amendments Act (“FDAAA”).  This new statutory provision provided that FDA shall not delay the approval of a pending abbreviated new drug application (“ANDA”) or 505(b)(2) application as a result of a citizen petition (pursuant to 21 CFR 10.30) or a petition for stay of action (pursuant to 21 CFR 10.35), unless the Agency determines that a delay is necessary to protect public health.  Section 505(q) also requires FDA to take final agency action on a petition “not later than 150 days after the date on which the petition is submitted.”  In 2014, FDA issued a guidance document describing the Agency’s interpretation of Section 505(q) and the process by which it determines whether the section applies to a particular petition.

The revised draft guidance document that was released last week includes much of the same information contained in the 2014 guidance.  However, it also includes substantially more detail and clarification on how the Agency makes a determination that a petition would delay an ANDA or 505(b)(2) application.  For example, the revised guidance states that one criterion in finding a delay is that the ANDA or 505(b)(2) applicant has less than 150 days left on a pending review.  The draft guidance also explains that FDA will apply a “but for” test in evaluating whether a delay is caused, essentially asking, “Would the application be ready for approval but for the issues raised by the petition?”

The revised draft guidance also provides a number of factors that FDA will consider in making a determination that a petition was filed with the primary purpose of delaying approval.  These include factors such as whether the petition was submitted close in time to the expiration of a patent or exclusivity period, or whether the petition raises the same or substantially similar issues as a prior petition to which FDA has already responded.  FDA will also consider whether the petitioner took an unreasonable amount of time in filing the petition based on when the relevant information relied upon in the petition became known (or should have become known).  A full list of the factors can be found on page 16 of the guidance.

If FDA makes the determination that a petition has been submitted with the primary purpose of delaying an application, it will then decide whether the petition can be summarily denied pursuant to Section 505(q)(1)(E).  In addition, if the Agency makes such a determination, it intends to refer the matter to the Federal Trade Commission and notify Congress in its annual report. Such an FDA determination could potentially have serious consequences as it may support causes of action related to unfair competition under the Federal Trade Commission Act, Lanham Act, and various state laws, which can carry substantial penalties.

The FDA issued a new Draft Guidance today to ensure medical devices – an increasing potential target for hackers – are better protected from unauthorized digital access.

According to the FDA’s draft guidance issued today, “Cybersecurity incidents have rendered medical devices and hospital networks inoperable, disrupting the delivery of patient care across healthcare facilities in the US and globally. Such cyberattacks and exploits can delay diagnoses and/or treatment and may lead to patient harm.”

Under the proposed draft guidance manufacturers will be required to better protect their devices in a more uniform manner as prescribed by the FDA. The new pre-market submission proposals are designed to help guide the industry in designing these digital safety mechanisms from the beginning of product design and development.

The New Guidance covers Premarket Notification (510(k)) submissions (including Traditional, Special, and Abbreviated); De Novo requests; Premarket Approval Applications (PMAs); Product Development Protocols (PDPs) that contain software (including firmware) or programmable logic; as well as software that is a medical device.

While manufacturers are required under Quality System Regulations to establish and maintain procedures for validating the devices design including software validation and risk analysis, FDA is recommending validation include design controls to ensure medical device cybersecurity and maintain medical device safety and effectiveness. Including these design controls may make it easier for FDA to “find your device meets its applicable statutory standard for premarket review.”

The recommendations in the newly released Draft Guidance describe using a more risk-based approach to the design and development of appropriate cybersecurity protections. The FDA wants manufacturers to design programs to follow their devices throughout the device lifecycle, monitor new and potential threats, and issue cybersecurity updates to thwart new attempts at unauthorized digital access of the devices.

Because devices that connect to the internet or wirelessly to other devices pose a new and larger threat to cybersecurity, the FDA is requiring a Cybersecurity Bill of Materials be included in the manufacturers filing to identify key components and accessories that could render the device vulnerable to “hacking”. The FDA is creating a new Tier 1 level of standards for these devices to ensure greater security than Tier 2 devices (those that are not wirelessly or internet connected).

Design controls should include appropriate authorization such as ID’s, passwords, time limited sessions with auto logout, layered authorization (i.e. patient, healthcare professional, technician) should now be used in the design of these devices. Authentication and authorization of critical safety commands will be considered in new submissions. In addition, proper labeling to warn patients and providers of the cyber security risks involved in these devices is essential.

For an updated list of FDA recognized consensus standards the Agency recommends that you refer to the FDA Recognized Consensus Standards Database.

 

 

 

On September 28, 2018, the U.S. Food and Drug Administration (FDA) released two draft guidances for industry. The purpose, according to FDA Commissioner Scott Gottlieb, M.D., is to modernize the approach to clinical trial design in efforts to (1) make clinical trials more efficient while maintaining patient safety and (2) increase the amount of information concerning product safety and benefits. The two draft guidances are entitled: “Master Protocols – Efficient Clinical Trial Design Strategies to Expedite Development of Cancer Drugs and Biologics” and “Adaptive Designs for Clinical Trials of Drug and Biologics.” This is the second of the two-part blog series describing the updates to the agency’s recommended approach to incorporating master protocols in clinical trials of new drugs and biological products for the treatment of cancer. The first of the two-part blog series described FDA’s recommended considerations to “adaptive designs” used in clinical trials.

In brief, the “Master Protocols Guidance” provides FDA recommendations to sponsors that desire the opportunity to run several related oncology studies concurrently under a master protocol, defined as “a protocol designed with multiple substudies, which may have different objectives and involves coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes within the overall trial structure.” This would give sponsors the ability to expand the reach of their oncology clinical studies to observe safety and efficacy in multiple subtype populations, disease subtypes, drug combinations and/or dosages.  Master protocols may be utilized to provide data for exploratory purposes or to support a marketing application.

Running an oncology clinical trial with a master protocol potentially benefits the sponsor by allowing the sponsor to concurrently evaluate multiple studies that may have different objectives, thus potentially saving time and costs as compared to running separate clinical trials. However, FDA also acknowledges that a master protocol may introduce challenges that, if not properly addressed, can increase risk to study subjects or delay the development of the product. Therefore, FDA released this guidance to provide recommendations to sponsors that are considering incorporating a master protocol into their clinical trial design to help them avoid unnecessary delay in the IND review process.

In the Master Protocol Guidance, FDA describes two types of master protocol designs: (1) the “basket trial” design and (2) the “umbrella trial” design. The basket trial is designed to test a single investigational oncology drug or drug combination in different populations (e.g., disease subtypes, biomarkers, demographic characteristics, etc.). FDA states that each substudy within a basket trial should include specific objectives, the scientific rationale for inclusion of each population, and a detailed statistical analysis plan that includes sample size justification and stopping rules for futility. In contrast, the umbrella trial is usually designed to evaluate multiple investigational oncology drugs administered as single drugs or as drug combinations in a single disease population. FDA reminds sponsors that appropriate dosages should be established for each investigational drug in Phase 2 studies prior to evaluation of the drug in a master protocol. Because umbrella trials can be used to compare the activity of investigational drug(s) in randomized controlled studies with a common control arm, FDA strongly recommends that the control arm be the standard of care (SOC) for the target population, noting that the SOC may change over time as newer treatments are adopted.

Additionally, FDA provides specific design considerations that sponsors are strongly recommended to address in their master protocols:

  • If sponsors are investigating a novel combination of two or more investigational drugs, the master protocol should summarize available safety, pharmacology, and preliminary efficacy data for each investigational drug; the biological rationale for use of the drugs in combination instead of individually; and evidence, if any, the interaction of the drugs when used together.
  • If sponsors are investigating drugs that target multiple biomarkers, the master protocol should include a prespecified plan for allocating patients who are potentially eligible for more than one substudy.
  • If sponsors seek to potentially add, expand, or discontinue treatment arms, sponsors should ensure that the master protocol and its associated statistical analysis plan (SAP) describe the conditions that would result in making such adaptations.
  • If sponsors anticipate utilizing the results from one or more of the substudies in support of a marketing application, the master protocol should describe and provide the charter for an independent radiologic review committee to perform blinded tumor-based assessments, a charter for an independent data monitoring committee (IDMC) to monitor efficacy results and safety results or alternatively an independent safety assessment committee (ISAC). The charter should authorize these committees to conduct prespecified and ad hoc assessments of efficacy, safety, and futility and recommend protocol modifications or other appropriate actions (i.e., adjusting sample size; discontinuing the substudy based on futility or substantial evidence of efficacy).
  • If sponsors are utilizing master protocols to evaluate biomarker-defined populations, the master protocol should explain why the use of the biomarker is appropriate and also include a validated in vitro diagnostic (IVD) test.

According to the Master Protocol Guidance, each sponsor will need to submit each master protocol as a new IND. When submitting an IND with a master protocol, the sponsor should consider the following:

  • The master protocol should be the only trial conducted under the IND;
  • The master protocol should be submitted to either CDER or CBER for review of the primary indication(s). If more than one indication is being investigated, the IND should be submitted to the most appropriate clinical review division within the Office of Hematology and Oncology Products in CDER or CBER, taking into account the population to be studied.
  • In addition to the elements required to be included in an IND submission under 21 CFR Part 312, the master protocol should include:
    • A detailed description of the trial design as text and as a visual illustration;
    • Procedures for sample acquisition, handling, and testing of biomarkers, if appropriate;
    • Identification of all substudies;
    • A description of all committee groups responsible for patient safety monitoring;
    • A description of the plan for submitting interim safety and efficacy results; and
    • The proposed informed consent document.

* * *

As mentioned above, incorporating master protocols into a clinical development program may have advantages, as these studies may reduce burdens associated with conducting separate studies and increase product speed to market.  If these benefits are realized, the end result may be improved patient access to therapeutic oncology interventions and lower costs of drugs through reduced development costs and greater competition.  However, concurrent evaluation of multiple oncology drugs and/or disease populations within a single trial is complex. Therefore, it is important that the trials are well-designed and well-conducted to ensure research subject safety and obtain quality clinical study data in support of drug or biological product approval. This guidance provides a glimpse of FDA’s approach to modernizing product development. Sponsors and stakeholders with an interest in developing their products under a master protocol are strongly encouraged to review this guidance and submit comments to FDA by November 30, 2018.

Two draft guidances issued together late last month seek to increase both clinical trial efficiency and the amount of information that is available about a drug’s safety and benefits.  The two draft guidances address, respectively, adaptive designs and master protocols.  This blog post discusses FDA’s recommendations for adaptive designs; master protocols will be addressed in a subsequent blog post.

An adaptive design is a “clinical trial design that allows for prospectively planned modifications to one or more aspects of the design based on the accumulating data from subjects in the trial.”  The ability to make changes to a study in progress allows investigators to take into account new information that was not known when the study began.  According to FDA, adaptive designs can both provide a greater chance to detect a true drug effect and reduce the number of patients exposed to ineffective investigational treatments (since effectiveness will be more easily detected earlier in the trial).  Because adaptive designs allow for greater flexibility, they also may be more acceptable to those conducting and those participating in clinical trials. For sponsors in particular, adaptive designs can potentially both save time and reduce costs.  Adaptive design can also have ethical advantages by facilitating early termination of trials once it becomes clear that a trial is unlikely to demonstrate effectiveness, thereby minimizing risk to participants.

At the same time, the draft guidance recognizes that adaptive designs increase the risk of “Type I” (false positive) errors, i.e., concluding that a drug has a beneficial effect when it does not.  To mitigate this risk, the draft guidance recommends sponsors employ methods to determine appropriate statistical thresholds for interim and final analysis to ensure that the overall Type I error is controlled at 2.5 percent.  Similarly, the draft guidance acknowledges the risk of bias that can result from early unblinding of a study, and recommends limitations on who may access such data to mitigate this risk.

A key element of adaptive design is pre-specification (i.e., planning in advance), including pre-specification of the number and timing of interim analyses, what statistical methods will be used to interpret the interim data, and how the study design will be changed depending on the results of such analyses.  Failure to pre-specify can result in the introduction of bias and thereby put the quality and integrity of study data at risk. Therefore, FDA strongly recommends that prespecified protocols are included in the clinical study design to ensure that access to comparative interim results are limited to individuals with relevant expertise who are independent from personnel involved in conducting or managing the trial.

Because adaptive designs introduce certain added complexities, FDA recommends that sponsors provide additional information when submitting a protocol for FDA review, including a detailed description of the monitoring and adaptation plan, information on who will be responsible for implementing the adaptive design, pre-specification of the statistical methods to be used, and a comprehensive written data access plan to maintain data integrity and quality.

The new adaptive designs draft guidance supersedes an earlier draft guidance issued in 2010.  At that time, adaptive designs were in their infancy, and proponents of adaptive designs viewed FDA’s initial guidance as a first step in considering how best to integrate them into clinical trials to support FDA regulated products and recommended that FDA guidance evolve in response to greater experience with the use of different adaptive study designs.  The new draft guidance reflects such evolution in FDA’s thinking; for example, in acknowledging the potential adverse impact arising from Type I error and in eliminating confusing categorization of “well understood” and “not well understood” adaptive design methods in favor of a more focused assessment of factors, such as unblinding, that can increase risk of bias.

FDA encourages sponsors to consider and discuss prospective design options with FDA.  Clinical trial sponsors and other stakeholders may want to consider the potential impact of the new guidance on their approach to clinical trials, and to submit comments to the FDA.  The deadline for submitting comments is November 30, 2018.

On September 20, 2018, the U.S. Food and Drug Administration (“FDA”) released draft guidance “Civil Money Penalties Relating to the ClinicalTrials.gov Data Bank” (“Guidance”). The purpose of this Guidance is to explain FDA’s protocol in (1) determining how the centers will identify whether responsible parties failed to comply with submission and certification requirements to the ClinicalTrials.gov or submitted false or misleading documents to the data banks and (2) deciding when, why, and what civil monetary penalties will be assessed against the responsible parties or submitters. The new guidance seeks to address requirements of responsible parties involved in the performance of clinical research and submission of applications for marketing authorizations to register their trial, submit clinical results information and make certain certifications regarding their compliance with these requirements.  In order to mitigate their risk of civil money penalties in accordance with this guidance,  sponsors and researchers should (1) have policies and procedures that ensure correct clinical trial information is submitted to the ClinicalTrials.gov data bank, (2) have policies and procedures that ensure routine monitoring for missing or inaccurate clinical trial information in the data bank, (3) make timely submissions of the required information, and (4) remain responsive to any inquiries by FDA concerning clinical trial data and/or certifications to FDA.

Background

Under section 801 of the Food and Drug Administration Amendments Act of 2008 (the “FDAAA”), which amended section 402(j) of the Public Health Service Act (42 U.S.C. 282(j)(5)(B)), responsible parties engaged in certain clinical research activities are required to submit registration and results information to the ClinicalTrials.gov data bank. Additionally, submitters of certain applications and other items to FDA regarding drug, biological, and medical device products are required to certify to FDA that all requirements of section 402(j) have been met. Similarly, the FDAAA amended section 301(jj) of the Food Drug and Cosmetics Act (the “FD&C Act”) to prohibit: (1) the failure of submitting or knowingly submitting a false certification to FDA, (2) the failure to submit required clinical trial information, and (3) submitting false or misleading clinical trial information to the ClinicalTrials.gov data bank. Further, the FDAAA amended section 303(f)(3) of the FD&C Act, authorizing FDA to assess civil monetary penalties against the person committing the prohibited acts.

Identifying Noncompliant Responsible Parties and Submitters

In this Guidance, FDA states its intention to utilize evidence collected during FDA’s Bioresearch Monitoring Program (“BIMO”) inspections to assess compliance with registration and results reporting requirements as described in Form FDA 2438 – Chapter 48 – Bioresearch Monitoring (Apr. 19, 2017). FDA also intends to identify violations as a result of complaints received by the Agency, which may entail reviewing public and non-public information, including, but not limited to information submitted to the ClinicalTrials.gov data bank and to FDA.

It is in the best interest of sponsors, researchers, and other parties subject to an obligation to submit clinical trial registration, information, results, and/or certifications to FDA to have policies and procedures in place to ensure correct information is submitted to ClinicalTrials.gov data bank. Policies and procedures should also include periodic review of the data bank to monitor for any missing or inaccurate clinical trial information. Developing and implementing these policies and procedures will mitigate the risk of enforcement for noncompliance with registration and clinical trial results reporting requirements, as outlined in the Guidance.

Determining When to Seek Civil Monetary Penalties

Under Guidance, FDA intends to provide the responsible parties with an opportunity to remedy any prohibited acts under section 301(jj) of the FD&C Act and corresponding regulations (42 CFR Part 11) before initiating an action to recover penalties. Pursuant to the procedures detailed in the Guidance, when FDA determines that when submissions are not timely filed or inaccurate, FDA will generally send the responsible party or submitter a Preliminary Notice of Noncompliance Letter describing the potential violation. The responsible party or submitter will have thirty (30) calendar days to remedy the violation. Should FDA conduct further review and find further or continued noncompliance with the applicable clinical trial requirements, the agency will then issue a Notice of Noncompliance, giving the responsible party or submitter another thirty (30) days to remedy noncompliance after receipt of the notice.

It is in the best interest of sponsors and researchers to promptly respond to any FDA inquiries and notices concerning registration, clinical trial information or certification issues related to the ClinicalTrials.org data bank. Failure to comply within the thirty (30) days of receipt of Notice of Noncompliance will result in FDA escalating regulatory action, including civil monetary penalties, of up to $10,000 for all violations adjudicated in a single proceeding.  Additional penalties of up to $10,000 each day may be included if the violation continues and if said violation is not corrected within thirty (30) days following notification. FDA may also pursue injunction and/or criminal prosecution.

In determining monetary penalties, the FDA will evaluate the circumstances, nature, extent, and gravity of the violation(s) with respect to the individual.  Other factors will include the violator’s ability to continue conducting business, any prior history of such violations, and the degree of culpability in the matter.

Responding To Civil Monetary Penalties by FDA

If FDA seeks civil monetary penalties, according to 21 CFR Part 17, the responsible party or submitter has the opportunity to either: (1) pay the penalty prescribed in the complaint or (2) file an Answer, contesting the allegations either in part or in whole, within thirty (30) days of date of service.

Should the responsible party or submitter contest the allegations by submitting an Answer, generally settlement discussions with FDA are entered into, providing the responsible party or submitter to present mitigating evidence to FDA for purposes of reducing the penalty amount. If a settlement is not reached before a decision on appeal, a presiding officer will make an initial decision, followed by the usual administrative appeal process (e.g., Department of Health and Human Services Departmental Appeal Board and then the U.S. Court of Appeals for the District of Columbia or any other circuit in which the responsible party or submitter resides or conducts business), should either party appeal the initial decision.

 

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A recent BMJ article, “Compliance with requirement to report results on the EU Clinical Trials Register: cohort study and web resource,” reported that for approximately half of the clinical trials, the responsible person did not report results on the EU register while a 2015 New England Journal of Medicine article, “Compliance with Results Reporting at ClinicalTrials.gov,” reported that approximately 20% of industry trials did not report results when required to do so, and 50% of NIH-sponsored research went unreported. While the registration, reporting, certification requirements, and the penalties for noncompliance are not new, FDA’s release of this Guidance should be taken as a signal to sponsors and researchers of its plan to enforce those requirements more rigorously. Therefore, sponsors and researchers should take this opportunity to evaluate the sufficiency of their policies and procedures for compliance with registration and reporting requirements and audit their submissions to ensure they are up-to-date.  Comments are due by November 20, 2018.