Recently, MHRA posted, “Is your eSystem actually an eCRF?” (https://bit.ly/3CHzVMw), which identified an equivalency between IRT and eCRF as it relates to the investigative site’s ownership of the data. While reading this blog, an experience I previously had as a trial sponsor came to mind. During an MHRA inspection, a clarity in perspective about IRT data ownership was being communicated. The inspectors made sure we (the sponsor) weren’t as integrated into the data change process as is typical (i.e., site requests change, sponsor approves). The message was the investigative site was responsible for the validity of its IRT data and sponsors need to understand the implications.

Since entering the industry in the mid-90’s, my perspective has been that IRT data is seen more as transactional for the purpose of randomization and drug assignment. It’s not the same as eCRF data and shouldn’t be treated as such. But my perspective somewhat changed after this inspection and was reinforced upon reading MHRA’s blog.

In the blog, MHRA reminds us what a CRF is, defined as ICH GCP E6 R2 (2016), 1.11: A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject. So, basically any system that is designed to record the data of the protocol and report to a sponsor on each trial.

They drive home some key points, including:

“…regardless of what you call your system, if it is recording protocol-required information and providing this to the sponsor, then it is also a CRF and needs to have the required functionality of an eCRF.”

“The functionalities of such systems should permit data changes and authorizations by the investigator with a clear audit trail to verify the integrity of the trial data and to explain why the data was amended.”

“As per ICH GCP, this data belongs to the investigator and therefore should be available to, and under the control of the investigator (and not under the direct control of the sponsor).”

So, between my inspection experience and MHRA’s blog, it is clear to me that regulators are taking a closer look at how IRT data meets requirements to ensure data integrity, including data ownership. Equally clear is that the industry was not prepared to act on this and will benefit from best practices in light of the implications. 

I’ve since spoken with different trial stakeholders (sponsors, CROs, solution providers) and can suggest several questions that need to be addressed as best practices are established. The overarching question is, as IRT data belongs to the investigative site, do sponsors currently have too much input on data changes?

Additional questions centered around what happens at the end of a study include:

Data changes? Audit trails? Who made each change?

What process changes need to occur from a sponsor, provider, and site perspective?

Should data go directly to sites rather than via sponsors to ensure data integrity?

Will sites need to go through a culture shift to look at the data as more than just transactional?

How is the data to be transferred/what format?

Shouldn’t we be using modern data archive and delivery methodologies?

How will investigative sites respond to this clarity in IRT data stewardship?

What will investigative sites do with the data?

A change in the landscape regarding the clarity around who owns and is responsible for IRT data is ripe for industry discussion. As we come to a level set on what is expected and when, the challenge will be to look at this clarity in expectations and understand it not only as a change for trial sponsors, but one the whole industry is affected by, requiring input from different industry stakeholders to ensure effective implementation.

Vice President, Scientific eTech-Enabled Services, Calyx

Articles

A Closing Thought

Stakeholders from across the industry must discuss ownership to ensure effective implementation.

Clarifying Ownership of Clinical Trial IRT Data: Site vs. Sponsor

As citizens of the healthcare community, we’re all appropriately impatient for innovative medical products to achieve both regulatory approval and rapid market acceptance. To help meet those ends, the increased use of technology and new analytical capabilities has ushered in an influx of health-related real-world data (RWD) and real-world evidence (RWE) solutions.

Thus, draft guidance issued by FDA in late September provides welcome insights into how the regulatory agency views the underlying RWD that supports RWE. In brief, it reveals a greater acceptance of non-traditional study designs and data sources. However, the true significance of this guidance goes far beyond what can be read at face value. Indeed, the spirit of the guidance is as important—arguably even more important—than the letters written on its pages.

At its core, the guidance prompts all stakeholders to think much earlier and much deeper about two things: their data strategy, and their opportunities for collaboration.

The concept of “data strategy” is key. Throughout the guidance, FDA has raised the bar on the very mindset we must use to think about data. It cannot be an afterthought contemplated only at the later stages of development. Instead, it must be a strategic consideration at every mile along the product development roadway—from clinical research to commercialization. Furthermore, FDA has clearly indicated that it wishes to help provide useful roadside directions to those stakeholders who embrace early, collaborative conversations.

As with any guidance, there is much information to unpack and significant caution signs to observe. This article will delve into the speed bumps and the opportunities suggested by FDA’s guidance. It will also offer insights into factors FDA establishes for assessing RWD source and study design—including relevance, data capture, missing/absent data, validation, and study design elements.

FDA’s September 2021 draft guidance document titled, “Real-World Data: Assessing Electronic Health Records and Medical Claims Data to Support Regulatory Decision-Making for Drug and Biological Products” signals the regulatory agency’s willingness to consider the use of RWD and RWE at strategic points on the clinical development and commercialization continuum. Specifically, it opens the door to expanded labeling through the effective use of RWD as an alternative to traditional post-approval studies.

Although it is true that the guidance homes in on post-approval studies, we risk missing the forest for the trees if we fail to step back and observe it within the larger body of clinical research destined for regulatory review. This guidance is only the beginning.

Post-approval studies are the logical place to start RWD/RWE guidance because they represent the last leg of the research journey. The initial safety and efficacy mile markers have already been passed. So, the September document looks at the potential use of RWD and RWE, “…to help support the approval of a new indication for a drug already approved” or “…to help support or satisfy post-approval study requirements….”

While the guidance does not evaluate RWD and RWE in the context of pre-approval clinical trials, FDA unmistakably recognizes the constant need to pivot. The tone and tenor of the draft suggest openness to using RWD as a viable component of pre-approval drug development. By setting a precedent for the acceptance of RWD to expand a product label or for safety surveillance, the industry may reasonably anticipate a future for RWD in other aspects of clinical research as well.

That conclusion is bolstered if we take the September guidance in context. Consider other guidance on the use of RWD as an external control cohort, as well as moves such as FDA’s recently announced partnership with Health Canada and the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA). In late October, the three regulatory agencies unveiled their collective effort to provide “… guiding principles that we believe will support the development and maturation of good machine learning practice.”

Viewed holistically, FDA appears to be preparing for further change and industry disruptors on the RWD journey still to come. It also seems to recognize that continued engagement and collaboration will best position the agency to determine how to build a data-driven road forward that will help patients get to better outcomes faster. It will look favorably on stakeholders who are willing to smash historical siloes and engage in proactive collaboration both externally and internally.

There are valid reasons why silo mentalities exist to separate “clinical” and “commercial” life sciences endeavors. Yet, there is an increasing awareness that science and strategy must coexist and that both can be advanced through RWD and RWE. In fact, RWD and RWE represent the new and appropriate bridge between the two traditional land masses.

The September guidance gives a framework to sponsors that simultaneously advocates using RWD and RWE to springboard more cooperative discussions with regulators about data strategy. It acknowledges that sponsors and other industry stakeholders bring valuable perspectives and expertise to the table, and strongly encourages mutual dialog and informal data strategy partnerships. The agency wants to collaborate early and often:

“For all studies using EHRs or medical claims data that will be submitted to FDA to support a regulatory decision, sponsors should submit protocols and statistical analysis plans before conducting the study. Sponsors seeking FDA input before conducting the study should request comments or a meeting to discuss the study with the relevant FDA review division. All essential elements of study design, analysis, conduct, and reporting should be predefined, and, for each study element, the protocol and final study report should describe how that element was ascertained from the selected RWD source, including applicable validation studies.”

Sponsor companies and other industry stakeholders should embrace this new dynamic of collaboration. In fact, ignoring it could well be to their peril.

For sponsors, upfront regulatory input into a comprehensive data strategy could help prevent unnecessary risk and streamline costs and timelines. For regulators, more insights from stakeholders could help better refine FDA’s stance on RWD and RWE. As the entire field of data and analytics evolves, it is imperative to think about how working with various stakeholders—regulatory or otherwise—could help optimize data strategies to establish valuable RWE from multiple perspectives.

RWD and RWE can indeed be the critical bridge across traditional siloes, with plenty of positive implications for reaching the ultimate destination—better patient care.

Five factors to assess the veracity of RWD

It is important to note that FDA’s September guidance focuses narrowly on data sourced from electronic health records (EHRs) and medical claims, and on potential post-approval expansion of product indications. These data sets may describe the patient journey with considerable granularity, but neither was created to aid drug development or approval—and therein lies another crucial feature of the draft guidance. It acknowledges the limitations of data sources designed for other purposes, but at the same time, it proposes best practices for their selection and use.

The central “best practice” in any data strategy is determining whether the available RWD is of sufficient quality to be beneficial—or not—for its stated purpose. In every case, RWD needs such a purpose before it can be used effectively as RWE.

In selecting data sets, FDA guidance recommends starting with the hypothesis and working backward to understand the data elements and the sources. “Each data source should be evaluated to determine whether the available information is appropriate for addressing a specific study hypothesis.”

It is vital to be both transparent and humble when considering the data’s limitations. The potential to achieve economies and efficiencies through the use of RWD must never offset any data or analytical constraints. As promising as RWD may be, it is not an easy solution for replacing, augmenting, or complementing traditional studies. In truth, there may be many situations for which the value of traditional prospective RWE generation cannot be achieved through the use of RWD.

When contemplating the use of RWD and RWE, additional steps are necessary to assure FDA of the quality of the data and the analytical plan. Therefore, the guidance frames the following five factors for sponsors to evaluate when assessing RWD source and study design:

 Questions to ask include: What factors influence case inclusion, data integrity, and generalizability? We must clearly establish the reason for selecting any particular data source relative to the specific question being asked, and conscientiously explore all possible confounders. As the draft guidance notes, “For example, differences in the practice of medicine around the world and between healthcare systems may dramatically impact the usability of the data source considering the question being explored. Moreover, a particular RWD dataset may reflect disproportionate patient populations in terms of age, socioeconomic status, insurance coverage and access to care, risk factors and other potential confounders.”

 Sponsors must think about how a study protocol is addressed or accommodated by routine data collection in an EHR or claims system. In addition, how are linkages with other study components (e.g., PRO questionnaire processes) addressed? How are unstructured data (e.g., physician notes) acquired and used? The guidance explains, “For example, if the question pertains to real-world clinical effectiveness, would a patient’s use of non-prescription drugs—not typically captured in electronic medical records or claims datasets—‘cloud’ the assessment?” If such exposure is particularly relevant to the study question, the protocol should describe how the information gap will be addressed.

 How are missing (i.e., intended but not collected) or absent (not intended to be collected) data addressed? Furthermore, what are the reasons why the data are missing or absent? The guidance presents the issue this way:

“For example, lack of information about the result of a laboratory test could be caused by different circumstances: (1) the test might not have been ordered by the health care provider; (2) the test might have been ordered but not conducted; (3) the test might have been performed, but the result was not stored or captured in the data source; or (4) the test might have been performed and the result was stored in the data source, but data were not in an accessible format, or lost in the transformation and curation process when the final study-specific dataset was generated. Because providers might order a laboratory test based on a patient’s characteristics, the decision not to order the test or a patient’s decision to forgo the test may have implications on the data’s fitness for use in a proposed study.” It goes on to add, “Assumptions regarding the missing data (e.g., missing at random, missing not at random) underlying the statistical analysis for study end points and important covariates should be supported and the implications of missing data considered.”

The goal is to examine how data elements (study variables) are defined, obtained, classified, and verified. To that end, the guidance recommends these steps: “To understand how potential misclassification of a variable of interest (e.g., exposure, outcome, covariate) might impact the measure of association and the interpretation of results, sponsors should consider: 1) the degree of misclassification; 2) differential versus non-differential misclassification (e.g., differential misclassification of outcome by exposure); 3) dependent versus independent misclassification (e.g., correlated misclassifications of exposure and outcome when both are self-reported in the same survey); and 4) the direction toward which the association between exposure and outcome might be biased.”

 A data source should not define the study design, rather just the elements. The guidance states, “In other words, the question being explored must come first in order to provide the context necessary to ensure all the design elements—time periods, study population, exposure to and duration of treatment, outcome, covariates, etc.—have been addressed.”

Overall, the guidance suggests FDA wants sponsors to think carefully about the framework of these five points and form a data strategy—not merely react to data. The regulators invite sponsors to seek feedback while determining data relevance (factor #1), but they also want to see plans for the remaining four factors.

On a cautionary note, sponsors cannot overlook the fundamental fact that sometimes deficiencies in these key factors will not be addressable. The very nature of data collected for specific purposes and only available retrospectively is that it cannot be altered, and overly creative interpretations rarely will be acceptable.

In many ways, FDA’s guidance indicates a very thoughtful and appropriately cautious mindset—as befits its mission to protect the public’s health. As the agency ponders the value of alternative data sources, it advises against racing forward too quickly. It points out that data limitations can be significant and that RWD is not an easy solution. A proactive data strategy is essential for ensuring that quality data inputs result in sound conclusions, and for achieving overall operational efficiency.

Yet, the guidance also acknowledges the potential value of RWD and RWE, and it shows a new openness to alternative data sources. Equally enticing are the invitations it offers to take a partnership approach to elevate data strategy. Many forward-thinking industry stakeholders have explored the use of RWD to help guide decisions for years. Now, FDA appears to be leading the way toward better and more collaborative RWD regulatory frameworks.

Like traditional studies, RWD has its imperfections. Still, with substantial and conscientious documentation and explanation, RWE derived from RWD has exciting potential for improving research efficiency. With the appropriate safeguards, RWD can help us better understand drug safety and effectiveness under real-world conditions—much like being able to kick the proverbial tires and test-drive a new car in actual traffic, not just on a simulated, exclusionary test track. All stakeholders benefit—including sponsors, providers, and most importantly, patients—when we enable this to happen by maintaining RWD and RWE quality standards.

US Food & Drug Administration. “Real-World Evidence.” 

https://www.fda.gov/science-research/science-and-research-special-topics/real-world-evidence

US Food & Drug Administration. “Real-World Data: Assessing Electronic Health Records and Medical Claims Data To Support Regulatory Decision-Making for Drug and Biological Products.” September 2021. 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/real-world-data-assessing-electronic-health-records-and-medical-claims-data-support-regulatory

Corrigan-Curay, J. “The FDA Real-World Evidence (RWE) Framework and Considerations for Use in Regulatory Decision-Making.” U.S. Food & Drug Administration. May 12, 2021. 

https://www.fda.gov/media/148543/download

US Food & Drug Administration. “FDA In Brief: FDA Collaborates with Health Canada and UK’s MHRA to Foster Good Machine Learning Practice.” Oct. 27, 2021. 

https://www.fda.gov/news-events/press-announcements/fda-brief-fda-collaborates-health-canada-and-uks-mhra-foster-good-machine-learning-practice

SVP of Worldwide Evidence, Worldwide Clinical Trials and 

VP, Global Head of Regulatory Strategy, Worldwide Clinical Trials

Feature Articles

Roadmap of twists and turns that lie ahead following most recent draft issued in September.

Reviewing FDA’s Latest Guidance on RWD 

At the October 2021 DIA conference on Digital Technologies in Clinical Trials, Pfizer reported the following timeline for the Pfizer-BioNTech COVID-19 vaccine
clinical program:

On May 4, 2020, the Phase I study was initiated, followed by initiation of the Phase II/III program on July 27, 2020. Positive interim results were reported on November 18, 2020 followed by the Emergency Use Authorization (EUA) submission request on November 20, 2020. The first Food and Drug Administration (FDA) EUA clearance occurred on December 2, 2020. The program, which evaluated over 46,000 subjects at approximately 150 clinical trials sites in United States, Germany, Turkey, South Africa, Brazil and Argentina, took just 8 months from first patient first visit (FPFV) to FDA clearance.

This major achievement by Pfizer, as well as the rapid development of products to prevent and treat the novel coronavirus disease 2019 (COVID-19) by others in the pharmaceutical industry and academic centers, are to be commended. Similarly, the FDA must also be commended on the speed that products have received EUA and full marketing approvals during the COVID-19 pandemic.

While clinical trials are costly and time consuming, they are necessary to assure that safe and effective products reach patients. As it is well known, the steps of drug development to approval involve multiple factors that could be improved in order to accelerate the process. The processes, resources and strategies to maximize efficiencies need to be revisited in order to continue exploring innovative study designs and methodologies that could result in reducing timelines and costs to product approval. On this topic, a recent article addresses the value of randomized clinical trials as well as the value of real world evidence together with novel approaches to statistical methodologies.

 Another recent article addresses the suitability of registries for embedding clinical trials.

Going forward, efforts need to be magnified to encourage biotech and pharmaceutical companies to continue promoting solutions to benefit of patients who are expecting solutions for their unmet medical needs. With this premise in mind, the current article first describes recent approaches to accelerate the marketing approval process, followed by a proposition of alternative strategies to accelerate the regulatory review approval process once it is concluded that an investigational product has passed the initial threshold of demonstrating safety and effectiveness in one or more clinical trials.

Current FDA programs to accelerate access

In order to accelerate the product approval process, four regulatory programs currently exist to reduce development and review times for products that address unmet medical needs for the treatment of serious or life-threatening conditions. In May 2014, FDA issued a Final Guidance for Industry entitled, “Expedited Programs for Serious Conditions–Drugs and Biologics” which addresses fast track designation, breakthrough therapy designation, priority review designation and accelerated approval.

In addition to this guidance document, under section 564 of the FD&C Act, 21 U.S.C. 360bbb-3, in a situation where the Secretary of Health and Human Services (HHS) issues a declaration of emergency or threat justifying authorization of emergency use for a product caused by chemical, biological, radiological or nuclear (CBRN) agents, as well as an infectious disease, the Commissioner of the FDA may authorize an EUA of an unapproved product or an unapproved use of an approved product. In 2004, the EUA authority was incorporated in the Project BioShield Act of 2004, which amended the FD&C Act. In January 2017, the “Emergency Use Authorization of Medical Products and Related Authorities” guidance was finalized.

Section 112 of the Food and Drug Administration Modernization Act of 1997 (FDAMA), entitled “Expediting Study and Approval of Fast Track Drugs,” mandates the facilitation of the development and processes to expedite review of therapeutics intended to treat serious or life-threatening conditions presenting with unmet medical needs. Fast Track designation, which also allows for the possibility of a “rolling review” of New Drug Applications (NDA) and Biologics License Applications (BLA), can be requested early in the development process at the time of Investigational New Drug (IND) filing or completion of Phase I studies. When a product receives a Fast Track designation, there is a strong emphasis on the importance of continuous communication with FDA so that questions and issues can be resolved quickly. Examples of diseases/therapeutic areas considered to be serious conditions include AIDS, Alzheimer’s disease, heart failure, cancer, epilepsy, depression, and diabetes, among others.

In contrast to Fast Track designation, a Breakthrough Therapy designation is assigned to an investigational product that is intended alone or in combination with one or more other products to treat a serious or life-threatening condition, and where there is preliminary clinical evidence that indicates that the investigation product may demonstrate substantial clinical benefit over existing therapies. Breakthrough Therapy designation requests usually occur at the end of Phase II. A drug that receives Breakthrough Therapy designation is eligible for all of the features of Fast Track designation.

The Accelerated Approval Program supports the concept that a treatment may be conditionally approved based on a validated surrogate biomarker or an intermediate clinical endpoint that strongly support the possibility of clinical benefit. Accelerated Approval agreements with FDA occurs close to the NDA or BLA submission. The regulation also requires that upon receiving Accelerated Approval, sponsors must perform a confirmatory study to demonstrate clinical benefit. If data from the confirmatory study does not demonstrate a clinical benefit, the product will be withdrawn from the market for use in that indication.

Under the 1992 Prescription Drug User Act (PDUFA), FDA committed to specific goals for improving drug review times. As a result, a two-tiered system of review times, Standard Review and Priority Review was created. A Priority Review designation means that the goal is for the FDA to act on a marketing application within 6 months of receipt, rather than a Standard Review of 10 months, as long as the investigational product can be shown to provide significant advantages such as:

Evidence of increased treatment effectiveness

Elimination or substantial reduction of a treatment-limiting adverse drug reactions

Documented enhancement of patient
compliance

Evidence of safety and effectiveness in a novel subpopulation of a disease

FDA informs the applicant the status of a Priority Review designation within 60 days of the receipt of the original BLA, NDA, or efficacy supplement.

Current FDA approaches to accelerate clearance of medical devices

In 1997, in order to improve the efficiency and timeliness of the 510(k) process of certain low-to-moderate risk new medical devices, the Accredited Persons Program was included in FDAMA. In 2018, a slide deck was published by FDA that describes how it is updating its 510(k) Third Party (3P) Review Program in order to avoid the routine re-review of 510(k) submissions already reviewed by a 3P Review Organization.

 As a follow-up, a March 12, 2020 final guidance document was issued entitled “510(k) Third Party Review Program Guidance for Industry, Food and Drug Administration Staff, and Third Party Review Organizations.”

 This guidance document provides medical device manufacturers with a voluntary process where FDA-authorized Third Party Review Organizations (3P510k Review Organizations) are permitted to evaluate and recommend approval or rejection of new devices. The guidance also delineates how decisions are made if certain medical devices are eligible for review under the Third Party Review Program. This new authority had been codified in the FDA Reauthorization Act of 2017 (FDARA) and allows discretion as to which devices are eligible for third party review. Approximately 50% of 510(k) applications now fall under this program.

The following section addresses proposed changes to existing FDA rules and regulations using a parallel format of the four phases of clinical trials during drug development. However, before moving forward, the are questions of special interest that should be addressed:

Under whose authority would it be to propose and implement these changes?

Would these proposed changes all fall within the jurisdiction of FDA rules and regulations, or would some require legislative action such as modifying the FD&C Act?

Based on lessons learned from the product approval process during COVID-19, and as previously published over 20 years ago, it is critical that sponsors continue to interact with FDA to discuss their development plans.

 In addition, FDA should expand the scope of exempt studies falling under IND and Investigational Device Exemption (IDE) regulations, and thus allow sponsors, with FDA concurrence, to proceed to clinical trials without FDA clearance of an IND or IDE. However, in order to control this process, each sponsor would be certified through an independent audit, that it complies with all relevant FDA rules and regulations, and training procedures are in place to guarantee that experienced staff manage all aspects of Good Laboratory Practices (GLP), and Good Manufacturing Practices (GMP) and Good Clinical Practices (GCP). The auditors will be certified by FDA based on their curriculum vitae and experience, and there will be an agreed upon fee across the industry, which will be paid by the company being audited. Each company will do yearly internal audits to assure continued compliance, and at the time of a marketing application, this process will be subject to regulatory review during preapproval inspections.

In addition, as is current practice, a clinical trial cannot be initiated without: 1) review and approval of the protocol and informed consent by an IRB or Ethics Committee; 2) review and signoff by an independent study Principal Investigator; and 3) review and signoff by each clinical site. Some academic organizations also have separate protocol review committees that must approve all new protocols.

From the data analysis perspective, the regulatory guidance ICH-E9 R1 is a key instrument to ensure more robustness and consistency during protocol development and statistical analysis planning. In order to minimize bias and increase the precision around the interpretation of the estimates associated with the clinical trial, the guidance forces trialists to provide more details about how the research questions, objectives, endpoints, and statistical analysis should be codified.

In terms of study designs, the discrepancies between the requirements and magnitude of the thresholds to demonstrate clinically significant safety differences, in most cases, is usually higher than the expectations for the efficacy profile. Thus, to have confidence that a study design is adequate to establish that an investigational product shows success both in terms of efficacy and safety in relationship with a comparator arm, the following issues must be addressed in all applicable phases of clinical development:

Clearly define the research question and hypothesis

Definition of the estimand and its attributes for the evaluation of all endpoints, including:

The endpoints and variables to be evaluated, and the validated instruments to be used for each case

Intercurrent events (ICE) that could impact the evaluation and interpretation of all endpoints, and the approaches to be used for each ICE

Population level summary for the evaluation of endpoints including the analysis dataset that will be used for each case

Sensitivity and supplemental analyses, for example:

Using the per protocol population or completers

Considering other missing data mechanisms different to the assumptions to the one used in the evaluation of the primary endpoint

Tipping point analysis under different scenarios

Supplemental analysis using different statistical models/methods

Testing strategies to control the familywise type I error

Assessments to capture the data associated with all endpoints using validated instruments

Description of the evaluation of the safety profile of drugs and devices including:

Treatment Emergent Adverse Events (TEAEs)

Treatment Emergent Serious Adverse Events (TESAEs)

Adverse Events of Special Interest (AESI)

Serious Unexpected Serious Adverse Reactions (SUSARs)

A general framework currently exists when FDA requests product approval recommendations from Scientific Advisory Boards for drugs and biologics and Third Party Review Organizations for devices. Thus, in order to expedite the review of marketing applications and reduce the time for a final marketing decision, in lieu of a detailed FDA review of all marketing applications, it is proposed that a framework be established for drugs, biologics and high risk new medical devices such that external expert committees, comprised of individuals certified by FDA, also be able to review the marketing applications and make product approval or rejection recommendations to the FDA review divisions responsible for final decision-making. However, in the event there are disagreements or basic questions that need to be resolved during the committee review, a process must be put in place for FDA, the expert review committee and sponsor to rapidly reconcile any and all issues.

For drugs and devices approved outside of the United States, the same processes should be followed by the expert committees, while taking under consideration any significant differences in regional differences in study designs and/or the population(s) studied.

Phase 3 - Post marketing safety monitoring

Currently, companies with FDA-regulated marketed products are required to track and report post marketing safety events either as expedited reports or as part of required annual reporting. Examples of the sources of these safety events include ongoing clinical trials, direct reports to companies of adverse events, data from electronic medical records, foreign data reports, the literature and data from patient registries and professional societies. Patient advocacy groups like the Cystic Fibrosis Foundation and professional societies like the Society for Thoracic Surgeons maintain patient registries.

 The Cystic Fibrosis Foundation registry tracks adverse events for all marketed and off label use of drugs for the treatment of patients with cystic fibrosis. In 1989, the Society for Thoracic Surgeons established the STS National Database to support the quality of patient care and to track safety events occurring during surgical procedures performed by their members. While some patient registries are being mandated by FDA to be used for safety monitoring, the use of patient registries should be expanded especially in rare diseases and in special patient population where there are active registries. However, if registries are mandated as a source of safety monitoring, the cost associated with this requirement should be reasonable and transparent so as remove any burdens, especially on smaller companies.

In the Food and Drug Administration Amendments Act (FDAAA; H.R. 3580) of 2007, Congress mandated that FDA track safety signals of marketed products. Subsequently, the Sentinel System was established in 2009 that uses electronic health data to assess post‐market medical product safety.

 The full Sentinel System was officially launched in February 2016. Through Sentinel, FDA assesses the safety of approved medical products including drugs, biologics, and medical devices. Sentinel’s data are based primarily on administrative claims and electronic health records (EHRs). The core Data Partner organizations include national and regional health plans partners, integrated delivery systems, and Medicare‐fee‐for service data. Sentinel partnerships also include EHR‐based organizations and networks, including CA Healthcare, the National Patient‐Centered Clinical Research Network (PCORnet), and several EHR data aggregators (TriNetX, Veradigm, IBM Explorys) who contribute data on a case‐by‐case basis.

There are currently over 70 million patients actively providing data to Sentinel. However, since there is a reported lag of 6-9 months from the date of health care and the data are only refreshed quarterly,

 we are pleased that FDA’s FY 2022 budget includes $82.9 million for an agency-wide data modernization and enhanced technologies initiative that supports medical product safety programs. These investments will modernize FDA’s data infrastructure by using current technology innovations that will allow FDA to more efficiently to gather data; identify, analyze, and respond to potential problems more quickly; and further improve review times for medical products.

Data from large national pharmacy chains can also be used to rapidly capture and report adverse events immediately upon product launch. For example, on May 20, 2021 CVS announced that their “CVS Health Clinical Trial Services is working with key stakeholders in the biopharmaceutical industry and across the clinical trial ecosystem to design and deliver innovative approaches to research and real-world evidence generation.”

While COVID-19 and previous pandemics have brought terrible devastation throughout the planet, government and societal reactions to COVID-19, for the most part, have demonstrated that it is possible to develop and release vaccines and other therapeutics in record times, and that humans have the ability and capability to collaborate for the common good. Regulators have also demonstrated that it is possible to accelerate the approval of much needed therapeutics in novel ways, and that if the proper resources are allocated both within and outside of governments, it becomes a win-win for citizens today and for all future generations.

Edwards, SJL, Bock, T., Palm, U., et al. The Case for Methodological Pluralism in Medical Science, The American Journal of Bioethics, 20:9,
39-41. 2020

Mikita, S., Mitchel, J., Gatto, NM, et al. Determining the Suitability of Registries for Embedding Clinical Trials in the United States: A Project of the Clinical Trials Transformation Initiative. Therapeutic Innovation & Regulatory Science. 2020

FDA: Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics. 2014

FDA: Emergency Use Authorization of Medical Products and Related Authorities. 2017

FDA: Eliminating Routine FDA Re-Review of Third Party 510(k) Reviews. 2018

FDA: 510(k) Third Party Review Program Final Guidance for Industry, Food and Drug Administration Staff, and Third Party Review Organizations. 2020

Mitchel, J. FDA Relations During Drug Development. Dialogues in Clinical Neuroscience. 2(3): 213–217. 2000

ICH: E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials. 2021

Cystic Fibrosis Registry Patient Registry | CF Foundation. 2019

Society for Thoracic Surgeons: STS National Database. 2021

How Sentinel Gets Its Data - Sentinel Initiative. 2019

Cocoros, NM, Fuller, CC, Adimadhyam, S., et al. A COVID‐19‐Ready Public Health Surveillance System: The Food and Drug Administration’s Sentinel System. Pharmacoepidemiology and Drug Safety. 30(7): 827–837. 2021

Martinez, AI. Monitoring Medication Use During the COVID-19 Pandemic in the Sentinel System: The Case of Anticoagulation for Thrombosis. 2021

FDA Press Release: FDA’s Budget: Data Modernization and Enhanced Technologies. 2021

CVS Health introduces Clinical Trial Services | CVS Health. 2021

President, CEO, THI Pharma Services Inc., 

Faculty, Program Coordinator, Senior Lecturer, MS in Regulatory Science & Food Safety Regulation Programs, Johns Hopkins University

Lessons learned from FDA’s current process and proposed alternative review strategies.

Analysis: FDA’s COVID-19 Accelerated Pathways 

During the COVID-19 pandemic, some have observed that principal investigators with minimal experience, limited infrastructure, and low study grant income have divested from clinical trial activity. Delays, and in some cases cancelled clinical trials, during the early stages of the pandemic made it difficult for these investigators to cover their operating costs and remain viable. Anecdotal evidence supports this observation but there is no hard evidence to confirm it and characterize the magnitude of these departures.

A recent analysis by the Tufts Center for the Study of Drug Development (Tufts CSDD) provides updates on the global landscape of FDA-regulated investigative sites that will serve as a useful baseline for comparisons. The results of this analysis show that this global landscape remains very fragmented with a disproportionately high concentration of low-volume principal investigators. But the data also suggests that—even without the effects of the pandemic—the landscape is scaling and maturing with a growing proportion of higher-volume principal investigators now operating in North America compared to 10 years ago.

Consistent with past studies, Tufts CSDD analyzed data from the Bioresearch Monitoring Information System (BMIS) maintained by FDA’s Center for Drug Evaluation and Research (CDER). The Tufts CSDD team extracted data on investigators filing form 1572 between 2010 and 2020. A unique identifier based on last name, first name, and country was used–instead of the Reviewer ID—to avoid counting duplicate records inadvertently created by slight variations in variables due to typos and alternate spellings.

For this analysis, investigator productivity is defined as the volume of clinical trials associated with each unique identifier. Turnover rates are defined as the percentage of unique identifiers who filed at least one 1572 form in a given year but had not filed another 1572 form within the subsequent four years. Past research conducted by Tufts CSDD has demonstrated that if an investigator does not file a new 1572 form within four years, it is highly likely that they will never file again.

To assess investigative site landscape changes, Tufts CSDD considered using ClinicalTrials.gov, as it is becoming a more valuable and reliable source for data. However, for our purposes, use of ClinicalTrials.gov is problematic. It lacks data on individual clinical investigators, instead providing a less granular view at the facility level that cannot determine investigator-level changes. It cannot detect, for example, if a site network loses a clinical investigator but remains listed as active due to involvement by other investigators at that facility. Dedicated sites and site networks may engage individual investigators located in distinct geographic locations, yet the ClinicalTrials.gov filing may only list the facility’s central address.

Slowing growth, especially among low-volume investigators

There were 32,077 active principal investigators operating worldwide in 2020. This number continues to grow but at a slower overall rate of 1.5% annually during the most recent 10-year period compared to 4.6% annually in the prior decade.

The least productive principal investigators—those filing only one 1572 in 2020—make up the highest proportion (66%) of the global site landscape. Approximately one in four (23%) investigators filed two to three form 1572s in 2020 and 11% filed more than four form 1572s last year. But growth in the least productive principal investigator segment has remained flat during the past decade and the segment share of the total has been declining steadily. This compares to 3.2% annual growth for this segment during the previous 10-year period.

The most active principal investigator segments have been growing at a much faster rate: the segment comprised of those who filed between four and six form 1572s each year has grown 5.2% annually since 2010; those who filed seven or more form 1572s have grown 8.6% annually during that same period.

The distribution of FDA-regulated principal investigators remains highly global but the movement away from North America observed 10 years ago has now reversed direction. In 2020, 63% of all principal investigators were based in the US and Canada; 19% in Europe; and 18% in the rest of the world. This compares to 57% in North America; 20% in Europe; and 23% in the rest of the world a decade ago.

The rest-of-world segment—which includes the highly populous areas of China and India—has lost the largest share of total FDA-regulated principal investigators. The shift is due in part to drug development sponsors having difficulties dealing with legal, regulatory, and health authorities and limited oversight and investigative site infrastructure there. The growing proportion of investigators based in North America, and the sustained proportion in Europe, confirms sponsor and CRO preference for placing clinical trials in more mature and established regions during the past decade.

The principal investigator segment in North America is scaling as site selection practices dictate engaging study conduct providers with more experience, infrastructure, and patient diversity. In 2010, the proportion of low-volume, single-form 1572 filers was 63%. In 2020, the proportion had declined to 55%. During this period, the higher-volume, more experienced principal investigator segment grew from 11% to 17%. In Europe, the reverse has occurred: whereas in 2010, 84% of principal investigators were low volume filers, in 2020 that proportion grew to 91%. In the rest of the world, the proportion of low-volume, single-form 1572 filers declined modestly from 82% in 2010 to 78% in 2020.

Turnover rates among FDA-regulated principal investigators remain high but they have been improving during the last 10 years. In 2010, 40% of all individual investigators who had filed form 1572s four years earlier failed to file again. In 2020, that proportion had declined to 35%. Turnover rates have improved during the past decade in North America, but they have worsened in Europe and the rest of the world. Whereas in 2010, 48% and 46%, respectively, of all individual investigators in Europe and the rest of the world who had filed form 1572s four years earlier failed to file again, in 2020, the proportions increased to 56% and 50%, respectively.

And similar to that observed 10 years ago, turnover rates among the least-active principal investigators—those filing a single 1572 form each year—are the highest, with approximately half choosing not to file again.

As we continue to move into a post-pandemic operating environment, new benchmarks and measures will inform trends in the global investigative site landscape. Once data from 2021 and later years is published by the FDA, the fate of novice principal investigators can be quantitatively assessed. In addition, we look forward to documenting the ongoing impact of virtual and remote support on traditional clinical trial execution models. 

Clinical Trial Insights

New benchmarks uncover a maturing and globally-shifting market.

Tracking Change in the Global Investigative Site Landscape

Applied Clinical Trials: You are Chief Research Officer at GRYT Health, can you explain what your position entails?

My team and I are responsible for ensuring that the patient experience research projects we take on align with and are conducted in a way that supports GRYT Health’s mission and values. Our patient and caregiver community is at the center of everything that GRYT Health does and, therefore, it is critical to build trust with our community at every step of the research process. We collaborate with research teams that prioritize the patient’s interests—from study design to transparency during participant interactions to engaging with participants beyond data collection.

ACT: Can you tell us more about your move from academia into a more patient-friendly industry?

Early in my career, I struggled with the disconnect between the basic pharmacological research that I was conducting and the end goal of positively impacting the lives of patients through improved health outcomes. I felt that I was too far removed from the end goal and, therefore, made a conscious decision to transition initially to clinical research and then more recently to leading our patient experience research at GRYT Health. This transition was also impacted by my own personal health journey, and the desire to empower others with the information they need to make health-related decisions.

ACT: Your CEO says that everyone at GRYT Health has been personally affected by a cancer diagnosis. Can you share your story?

My closest familial cancer connections are through my paternal bloodline. Around the time I was following the cancer journey of a personal friend, I lost my paternal grandmother to ovarian cancer and my father was diagnosed with prostate cancer. Years later that same personal friend, Shelley Nolden, became one of the founders and the chairwoman of GRYT Health and connected me to the organization.

ACT: What does the pharma industry need to know more about the patients that GRYT Health helps?

GRYT Health helps pharma better understand their end client—the patient. However, it doesn’t end there. We help to build relationships and trust with the patient and advocacy community, and beyond. Our platform provides patients and caregivers connection and education, and empowers them to advocate for themselves and others. GRYT Health also provides opportunities to learn more about research and become involved in it. Because of the services we offer to the patient community and our relationships with advocacy organizations, this allows us to better support our research participants. For example, if a particular need is identified during research participation, we are able to connect that participant to the appropriate resources. We pride ourselves on the humanity and transparency that we bring to research participation. Patient experience research should be neither transactional nor a unidirectional flow of information. Additionally, we provide pharma innovative solutions to patient education through custom virtual platforms that deepen engagement and collaboration.

ACT: How do you view the overall academic/industry/pharma relationship in regard

Drug development is a lengthy, complex process that involves balancing a wide variety of factors and pressures. Collaboration of knowledge, resources, and experience across organizations has the opportunity to accelerate the drug development process. At the core of drug development is identifying and interacting with a drug target to elicit the desired downstream effect; however, this alone will not yield a safe, successful product that is widely adapted by its target population. GRYT Health aids drug development by helping to incorporate patient experience data into the development process. Patient experience data can give insight into patient awareness, experience, goals, perception, and preference, and ultimately provide insight into how a drug might perform within its targeted population pre- and post-approval. Additionally, we help support active clinical trials and the populations they target through our clinical trial awareness services, which utilize our custom virtual platform, relationships within our patient, survivor and caregiver community, and medical, research and marketing expertise. Through this service we are able to directly engage with patients and caregivers through education and resources to increase awareness of clinical trial options and empower them to make informed decisions.

Darcy Flora, PhD, chief research officer of GRYT Health, a digital oncology company, discusses her career, the company, and drug development.

Building Relationships

The legislation-based boost to the powers of the European Medicines Agency has been well-documented and closely watched. But there are straws in the wind suggesting a further change is creeping over the agency, more a matter of character than of law–and this could spell far-reaching shifts in the role of EU regulators.

First, the formal changes–endorsed in principle by EU legislators at the end of October, and now awaiting full ratification by the European Parliament and the European Council, perhaps as early as December. These changes arise directly from the COVID pandemic, and aim to equip EMA better to manage future health crises, giving it closer control of the management of supplies of medicines and medical devices. The agency will also acquire new authority to release early data of clinical trials conducted in the EU, and fuller data on authorized medicines.

Over recent months, however, EMA has unilaterally adopted an increasingly high profile of its own. Part of this is the result of the inevitable public attention given to its decisions on the assessment of COVID vaccines and treatments, which has elevated not only its operations but also some of its staff to an unprecedented visibility. But part of its new profile is also the consequence of some deliberate seeking of attention, in an equally unprecedented campaign of direct communication to the broadest public. For the best part of a year, the agency has been holding regular briefings about COVID treatments–designed for the media, but also open to the public, and available on YouTube.

As a logical complement to its public briefings, it has become increasingly communicative on other social media. Its interaction with the public has developed from simple reports about the number of COVID vaccines authorized to more timely alerts as to when decisions are scheduled. And as the pace of product development has risen, so too the announcements have become more frequent, with recent days including tweets of the start of its reviews of COVID-related products such as Pfizer's or GSK's sotrovimab.

A further COVID-linked development, inspired by the urgent search for medical responses, is also driving this process: a new degree of regulatory flexibility. Introduced in the wake of the outbreak, this has given rise most obviously to rolling reviews as a way of speeding assessments. But it is accompanied by a new EMA readiness to publicly countenance–if not actually to endorse–member states taking their own decisions on emergency use of innovations that have not yet obtained EU authorization. The announcement of the start of the review of Paxlovid added that the review is "to support EU countries who may decide on its early use for COVID-19 before authorization." Similarly, EMA has tweeted its "advice to support EU countries who may decide on early use of the oral antiviral molnupiravir," outlining that the medicine can be used to treat adults with COVID who don’t require supplemental oxygen and who are at increased risk of severe disease.

The public engagement goes further. Abandoning its traditionally remote and neutral stance as a discreet center of regulatory excellence serving an esoteric scientific purpose, it is moving into overt position-taking and public advocacy. "There are excessive cases of COVID, particularly in unvaccinated people," it tweeted the other day, remarking that "many EU countries have large unvaccinated populations" who "are the most likely to go to hospitals and suffer from severe disease." It went one step further, adding: "We should close the gap between vaccinated and unvaccinated." In similar vein, it is now tweeting recommendations of shifts in personal behavior: "We encourage everybody who is offered a flu vaccine to get the shot and protect themselves and their family, friends, and colleagues." And in connection with the current campaign against antimicrobial resistance, it is itself now campaigning with tweets urging "Let’s educate our children about the risks of antimicrobial resistance and include this topic in family conversations!" and warning that "We cannot get to the point where antibiotics no longer work to treat or prevent infections."

But the latest development crosses a new frontier from the descriptive to the normative. "Pharma companies need to focus more on R&D for innovative medicines against infections," it tweeted in mid-November. "Pharmaceutical companies need to boost research and development." Irrespective of the truth or relevance of this message, the nature of this public communication marks a radically different approach by the agency to the way it presents itself to the world–interventive, persuasive, even combative… and even undaunted in entering into one of the hottest current debates in European medicines policy, about the extent to which the private sector should enjoy autonomy over its operations.

The full implications of this personality mutation have yet to be teased out. But it carries intriguing resonances at a time when the entire EU policy framework for medicines is under review. The amendment to current law governing EMA is just one of a handful of legislative proposals that the European Commission has branded as part of the "European Health Union"–an ambitious but still embryonic concept springing from Commission officials to give the EU more of a say in how member states make their own decisions on medicines.

The EHU brand has yet to achieve enthusiastic endorsement from member states, who are suspicious of a stealthy power grab. But at the same time, member states have not–yet–directly opposed the brand, perhaps sensing that a COVID-weary public might at present be happy to see greater collaboration on health at EU level, and resentful of conspicuous resistance to it from member states. Against this background, EMA's flexing of unsuspected muscles in the public domain takes on another possible interpretation, and raises the inevitable questions as to whether the higher profile is simply the unremarkable consequence of its status at the center of an unprecedented public health emergency, or a conscious bid to boost its own influence over the longer term and on a wider scope.

View from Brussels

Increased public engagement leads recent change in EMA profile.

EMA: A Change in Character as Well as Powers?

Drug development and regulation will never be the same following the momentous changes in health care delivery and biomedical research over the past year. The desperate need for new vaccines and therapies to tame the deadly COVID-19 virus required new policies and procedures for how biopharma companies select, test, and manufacture medical products—and revised regulatory practices for evaluating clinical data, manufacturing operations, and procedures for submitting and analyzing information.

Most visible have been the many changes in the conduct of preclinical and clinical studies for new vaccines, drugs, and medical products. The shutdown of many clinical sites and difficulties in visiting medical facilities required researchers to utilize virtual and remote methods for identifying potential trial participants, obtaining informed consent, and tracking clinical data. Sponsors looked to deliver experimental treatments directly to patients and to record symptoms and treatment effects at home. Interest rose in innovative clinical research methods, such as master protocols, adaptive trial designs, and Bayesian analytical methods to reduce study size and duration. Digital technology was adopted to track novel endpoints, and the value of utilizing real-world data and real-world evidence from health care systems and disease registries gained acceptance for supporting pre- and post-approval research requirements.

Sponsors gained important advice from FDA on conducting clinical trials during the pandemic from a steady stream of new guidances addressing the need for flexibility while maintaining study integrity. Multiple advisories discussed new analytic approaches, protocol management, and dealing with missing data, among other critical issues. At the same time, important guidances advised manufacturers on strategies for testing and producing new vaccines and therapies to treat COVID patients.

An important innovation was FDA’s expanded use of the emergency use authorization (EUA) process to speed successful products to patients during the health emergency. At the same time, the regulators required vaccine trials to test thousands of patients to assure the public of the safety and viability of these new preventives. Vaccine experts at the Center for Biologics Evaluation and Research (CBER) worked overtime to clarify the size and diversity of efficacy trials and key analytical assessments needed to gain EUA status and later full approval, establishing standards and procedures that will shape research for health emergencies to come.

The need to quickly produce millions of doses of new vaccines and therapies spurred industry adoption of innovative testing and production methods. Biopharma companies invested resources to update facilities and establish new modular, flexible line operations. Competitors formed partnerships and licensing arrangements to meet production goals at home and for other regions. FDA continued to promote industry adoption of modern manufacturing methods and advanced quality assurance programs to expand biopharma operations in the US and overseas.

Broader investment in efficient manufacturing systems for generics as well as brand-name medicines was critical also to head off drug shortages and ensure reliable production of widely used medicines needed to treat patients in emergency rooms as well as those relying on established therapies for serious diseases. FDA utilized its expanded authority to respond quickly to shortage situations to prevent gaps in the medical product supply chain for multiple vital medicines.

At the same time, curbs on FDA inspections to evaluate manufacturing sites during the pandemic prompted regulators to expand their use of alternative oversight methods. FDA officials relied more on past inspection reports, current documents from manufacturing sites, and inspection reports prepared by trusted foreign regulatory authorities and shared under mutual recognition agreements. In some cases, FDA “visited” a site through remote online systems. Officials at FDA’s Office of Regulatory Affairs (ORA) indicate that the agency will continue to utilize many of these strategies for streamlining oversight of manufacturing operations, even as on-site visits increase overseas and at home, leading to a more “hybrid” inspection process going forward.

In addition to remote field inspections, FDA review staff organized virtual meetings with medical product sponsors to assess and devise appropriate, yet more flexible R&D programs. Even with most agency staffers working off site, reviewers for drugs, biologics and generics formed multi-disciplinary teams to assess research proposals remotely to clarify what data and analysis were needed for a product to gain market approval. Such team efforts have been particularly effective for analyzing new anti-COVID vaccines and therapies, as well as for timely review of the steady stream of NDAs, BLAs and supplements to treat multiple conditions.

One result is that drug approval processes for fiscal year 2021 remained strong, with 53 novel drugs approved by the Center for Drug Evaluation and Research (CDER) as of Sept. 30, 2021. That includes multiple treatments for cancer and rare diseases, many utilizing expedited and accelerated approval pathways. CDER also maintained steady review rates for generic drugs as seen in the approval of more than 800 ANDAs, including more than 90 first generics and complex generic therapies. There were important advances in biosimilars, moreover, with the approval of the first two interchangeable products.

Despite these changes, FDA officials had to contend with public criticism that the review process was taking too long to save dying patients, or that the agency was speeding experimental products through the review process, threatening public health and safety. The highly pressured atmosphere exhausted many FDAers, as seen in recent announced departures of several agency officials and experienced staffers, and such departures are likely to pick up in the coming months.Changes in agency leadership, in regulatory strategies, and in decisions by researchers and manufacturers on where and how to plan future investments are slated to alter drug development and oversight for years to come.

View from Washington

Lessons learned from COVID-19 vaccine development.

Applied Clinical Trials-12-01-2021

Clarifying Ownership of Clinical Trial IRT Data: Site vs. Sponsor

Reviewing FDA’s Latest Guidance on RWD

Analysis: FDA’s COVID-19 Accelerated Pathways

Tracking Change in the Global Investigative Site Landscape

Building Relationships

EMA: A Change in Character as Well as Powers?

Pandemic Alters Policies for Drug Development

2022 Trends, More of the Same but More

Applied Clinical Trials December 2021 Issue (PDF)

Assessing Sponsor and CRO Awareness

Decentralized vs Digital Clinical Trials: There is a Difference

Considering Patient Burden in Oncology

Consequences of Brexit for Clinical Trials in Europe