In a clinical trial, there are few aspects of higher importance than protecting the privacy and trust of the patients who give their time and health data to further medical research. Unfortunately, regional and national governments each have their own set of laws for how to best safeguard this sensitive personal health data. But, as digital innovation grows and the amount of free-flowing data increases, regulations stopping at geographic borders may not be the best means to govern patient data use, and instead can result in a web of regulations that end up hindering research efficiency, patient trust, and ultimately, participation in clinical trials. The creation of nationally, or better yet, globally agreed-upon privacy standards is critical to give researchers a clearer framework around which to build studies, and patients a firmer foundation on what they can expect from privacy protections.

The maze of privacy regulations based on location

While well-intentioned, current national and international privacy laws can adversely stunt population-wide medical research. Regulations concerning collected patient health information (PHI) differ based on the location of the clinical trial. Researchers conducting clinical trials in the US must spend precious hours ensuring they are following the laws of the state, or multiple states, where the trial is taking place. Similarly, while the General Data Protection Regulation (GDPR) promulgated by the EU to govern the usage of personal data purports to provide researchers in the EU with a more consistent framework around which to design studies, country specific derogations and other regulations often result in a piecemeal approach to data privacy. Internationally-recognized and straightforward privacy regulations would give researchers more bandwidth to focus on advancing research instead of their jurisdictions’ regulations, and trial participants a clearer understanding of how their privacy will be protected and, in turn, greater trust in the system.

Citizens are justified in their hesitance to share their highly personal health information. Greater consistency in laws governing personal data use could increase trust in the medical field and participation in clinical studies. Unfortunately, populations that have historically exhibited higher rates of mistrust in the medical field are less likely to be represented in medical research, leading to an unfortunate chain of events—with lower participation in clinical trials, resulting treatments will not be as effective for all patients, and mistrust will persist.

De-identification technology offers an opportunity to strengthen trust and further the impact of the use of PHI for future research. It is critical for researchers to emphasize the severity of the guidelines in place to protect patients’ privacy and confidentiality, while also outlining how their PHI can be used in the future to advance science, especially for rare diseases. More consistent regulations around de-identification, security technology, and encryption will give patients better confidence in sharing their PHI for short and long-term use to support future research.

Collaboration is needed to create global data standards

Protecting patient privacy and advancing medical research shouldn’t be mutually exclusive. Medical and technology organizations are designed to help patients, so it is essential that patients not only have confidence in their ability to protect their information but also understand the critical role they could play in advancing treatments for generations to come. In order to bring about this sorely needed streamlining of data legislation, it is imperative for governments, technology, and healthcare institutions around the globe to unite to push for internationally-recognized privacy standards. This way, patients will have more confidence in giving their valuable health data to medical research, and researchers can then design treatments that more precisely meet patients’ needs.

When the appropriate regulations are in place, data sharing across institutions and borders will flow more freely, and researchers will be able to expand upon de-identified PHI from past studies, ushering in an unprecedented wave of breakthroughs in the medical field.

, general counsel, chief administrative officer, AiCure, LLC

Articles

A Closing Thought

Regulations that apply across geographic borders can provide researchers and patients a firmer foundation on data protection.

How a Global Privacy Standard Can Boost Patient Trust

Most drug developers seek new drug approvals in both the US and Europe, two of the largest markets with the most evolved regulatory landscapes and highest uptakes of new medicines. Approvals by FDA and the European Medicines Agency (EMA) provide a gateway to other countries that follow FDA or EMA guidelines, further extending the benefits of a combined approach.

Historically, submission teams have viewed and managed the two document submissions separately. After all, the US and Europe are an ocean apart, with different policies and their own regulatory bodies, respectively. But is there a better way?

Before plunging headlong into submission preparation, consider your whole global submission plan and the feasibility of simultaneous document submission to optimize the process. It takes more planning and deliberation up-front but streamlines each step thereafter. This article will discuss how drug developers can minimize rework, maximize efficiencies, compile optimal data packages, and create the most direct path to dossier development for the US and Europe with the goal of avoiding many of the common pitfalls experienced.

The traditional two-lane mindset served its purpose when the US and Europe truly represented two completely different regulatory environments with little to no crossover. That changed in 2000 with the finalization and adoption of International Conference on Harmonization (ICH) guidance. ICH guidance makes it feasible to construct a new drug submission dossier that can be used for applications to the regulatory bodies of the US, EU, and Japan and make new drug registration less resource intensive.

All drug developers are familiar with ICH guidance from a regulatory perspective, and most have been pursuing simultaneous submissions for the past 15 to 20 years. However, that harmonization has been drifting apart the past several years. Despite this, dossiers for the FDA and EMA can still be initially merged and managed as one for the bulk of the work, before later being adjusted as necessary to suit the final submissions.

The US and Europe have similar documentation requirements, but we must recognize important considerations that need special attention. For instance, terminology and seemingly small grammatical distinctions can loom large if overlooked. A submission team can greatly accelerate global document submission by first creating and reviewing a checklist of differences, agreeing on the best approach to address each one, planning the summary documents based on these decisions, and collaborating closely in pursuit of a successful outcome.

It can be helpful to understand how the FDA and EMA review submissions through different lenses. FDA is very data-driven, with robust requirements for data sets and programs used to generate statistical analyses. They first look at individual listings, case report forms for patients with adverse effects, and other deep documentation, working from the bottom up to arrive at a decision. EMA reviewers, on the other hand, tend to take a more top-down approach. They prioritize key messages and information in the clinical overview to develop their interpretation of what a drug is doing for patients and modern medicine. The EMA does not require data sets or case report forms like those required by FDA. In general, the EMA is more qualitative while FDA is more quantitative.

The most notable difference is Module 1 of the ICH Common Technical Document. This consists of regional information that will need to be compiled separately. Module 1 is best set aside so it doesn’t hinder the rest of the information that can be compiled simultaneously. Additionally, there are some specific differences in requirements across other modules to which careful attention should be paid.

Aside from Module 1, submission teams should be happy to hear that Modules 2, 3, 4, and 5 are similar between FDA and EMA submissions. The US and Europe are two of the most similar regions in the world when it comes to their submission requirements, again thanks to ICH guidance on summary documents and submission format.

The main differences discussed in this article are really the exceptions, so we can reframe our approach to assume that 75% or more of the compilation can be conducted simultaneously. It is important to remember that small details can become big headaches in these large, technical documents. As such, careful planning is pivotal to gain an understanding of where the risks and opportunities lie.

It’s a lot less painful to learn from others’ mistakes than your own. Here are a few simplified examples of real-life teams running into submission roadblocks that could have been avoided:

The afterthought: A sponsor completed a full regulatory history review, accounting for all agreements and resolutions for a successful new drug Application (NDA) submission. However, they completed the NDA without considering the marketing authorization application (MAA) planned three to six months after NDA submission. This resulted in extensive rework of approved NDA versions to create MAA versions. They had also outsourced preparation of the NDA and MAA submissions to different vendors, making matter worse.

The comment carousel: With the goal of writing documents in a way that one version would work or at least require only minor revisions for all countries, the team took off running…and spinning…and sputtering. They were unable to stop commenting on standardized global introductory text, derailing a well-intended plan when version control between submissions finally caught up with them and caused delays.

The caveat: Starting with the assumption of no differences in Module 2.7 documents and identifying differences in Module 2.5, a submission team built a combined biologics license application (BLA) and MAA version up to point of first draft, including specific MAA sections highlighted. For BLA Draft 1, they removed the MAA sections. Once BLA Module 2.5 was approved, they used that approved version as the initial draft for MAA and replaced BLA-specific content with MAA-specific content. But by the time of MAA creation, data presentation agreements with EMA and team agreement to include label adverse reactions table in Module 2.7.4, required tedious EU-specific modifications to Modules 2.5 and 2.7.4 as well.

How can you avoid missteps like these? Quite simply, with planning.

The key takeaway with simultaneous submissions is that more planning and deliberation at the start of the documentation process can help alleviate issues and optimize submissions.

First, an understanding of deadlines and timing of submissions is necessary to inform planning. How soon after the first submission do you want (or need) to make the second submission? How long is the duration between submissions, and will that lead to additional study data being available or the need for a new cutoff date for safety data? What are the plans for supplements if filing for multiple indications? These are just a few of the many questions to ask early regarding timing of final submissions.

Second, there may be many possible strategies to employ when authoring dossiers, but there are four immediate considerations for authoring FDA and EMA dossiers simultaneously. These include deciding whether to use British or American English, use of “application” or “submission” as a generic identifier (rather than naming the submission, e.g., BLA vs. MAA), considerations for cross-referencing, and accounting for reviewer tendencies. Throughout the submissions, writers should be as universal as possible with language across applications and read the relevant guidelines in advance to minimize the work and uncertainty for editors later.

In the years since ICH introduction, regulatory requirements in the US and EU have slowly drifted apart. Still, the requirements are known, clearly stated, and can thus be planned for in the submission process. For example, in considering the inclusion of integrated summary of efficacy (ISE) and integrated summary of safety (ISS), it’s easier if the ISE and ISS are just the outputs. However, there are no issues with including ISS and ISE in an EMA submission after these pieces were developed for an FDA submission. Separately, for the benefit-risk sections, you can convert the content of an FDA benefit-risk framework table into subsections with the exact same text to fulfill the comparable EMA description. These are just a few glimpses of the efficiency attainable with simultaneous document submission, knowing and accounting for the regulatory requirements.

Given the similarities between FDA and EMA submissions, it’s quite feasible to pursue simultaneous drug application submissions. This is a significant undertaking by any measure but reviewing regulatory history early-on and highlighting any gaps that may present potential obstacles, should ensure timely and successful simultaneous submissions.

, vice president of Synchrogenix Regulatory Science, Certara

Feature Articles

A roadmap to avoiding the common pitfalls of concurrent FDA-EMA filings.

Simultaneous New Drug Submissions: Is it Possible?

Your first holiday gift of the season has arrived: updated FDA guidances from the past year—and one key update from the European Medicines Agency (EMA). These final guidances reflect the breadth of pharmaceutical and technology-related submissions that FDA now contends with. The agency even asks for help with its administrative tasks, such as asking stakeholders to put in submission cover letters whether there is real-world evidence or real-world data in the application.

Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) ­— Small Entity Compliance Guide

This guidance replaces the 2007 version. It is written for businesses that FDA refers to as “small entity establishments,” stakeholders who create human cells, tissues, or tissue-based products. The guidance details the agency’s regulatory framework on the manufacturing of these products.

Human Gene Therapy for Neurodegenerative Diseases

This guidance addresses creation of human gene therapy products for adults and children with neurodegenerative disease. Recommendations span the products’ development to clinical trial design.

Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing, and Controls Information in an NDA, ANDA, or BLA

This guidance was written to help stakeholders already in possession of an approved application, be it for a new drug application (NDA), an abbreviated new drug application (ANDA), or for a biologics license application (BLA), with making a chemistry, manufacturing, and controls (CMC) change, post-approval, by using a comparability protocol. The protocol is a plan to assess the identity, potency, purity, quality, and strength of the changed product.

Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drug and Biological Products

Sponsors who are submitting NDAs, investigational drug applications, and BLAs—and including real-world data and/or evidence in their supporting documents—are encouraged to identify uses of such evidence in their cover letters. The agency says such identifications will help with internal tracking.

Clinical Decision Support Software — Guidance for Industry and Food and Drug Administration Staff

This final guidance focuses on clarifying the types of functions included in clinical decision support (CDS) software that up until now were outside the definition of non-device CDS criteria. FDA’s existing policies on digital health products policies still apply to software functions that meet its definition of a device.

Medical Device Data Systems, Medical Image Storage Devices, and Medical Image Communications Devices

FDA is separating software and its purpose, determining which devices will be subject to oversight, and which will not. Software used to display data, images, and waveforms, are included in the latter.

Acute Myeloid Leukemia: Developing Drugs and Biological Products for Treatment

This guidance discusses the agency’s views on development programs and clinical trial designs for drugs and biologics intended to treat acute myeloid leukemia. It covers individual treatment phases.

ICH Guideline E19 on a Selective Approach to Safety Data Collection in Specific Late-stage Pre-approval or Post-approval Clinical Trials

This “internationally harmonized” guidance details those factors stakeholders can use to justify their reasons for collecting less types of data in specific interventional clinical trials.

 is a freelance writer for medical, clinical trials, and pharma information.

Summarizing important FDA and EMA revisions issued this year.

Key Guidance Updates in 2022

FDA has called upon the entire drug development industry to do more to improve racial and ethnic diversity in clinical trials. In its April 2022 draft guidance, it recommends that sponsors submit a “race and ethnicity diversity plan” to the investigational new drug (IND) application or the investigational device exemption (IDE) application.

 FDA further notes that it will consider this plan an “important part” of a product’s development program.

The draft guidance offers a glimpse into when —and how—the FDA expects sponsors to build a diversity plan into their drug development process. However, it also acknowledges that while these recommendations are a much-needed first step, they remain limited in scope. The text states:

“…this guidance focuses specifically on racial and ethnic demographic characteristics of study populations… However, FDA advises sponsors to seek diversity in clinical trial enrollment beyond populations defined by race and ethnicity, including other underrepresented populations defined by demographics such as sex, gender identity, age, socioeconomic status, disability, pregnancy status, lactation status, and comorbidity.”

Thus, even as the guidance is finalized, sponsor companies and other industry stakeholders seek added clarity on this critical issue. The idea that clinical trials must better represent their affected patient populations is not new, but it entails significant challenges. Some sponsors are starting to overcome these challenges by collaboratively creating practical tools and possible approaches for increasing participant diversity, equity, and inclusion (DE&I).

About a year before its draft guidance was released, FDA’s Center for Drug Evaluation and Research (CDER) published a Drug Trials Snapshots Summary Report that reviewed the clinical trial demographics for drugs approved in 2020.

 It found that 75% of participants were white, 8% were Black or African American, 6% were Asian, and 11% were Hispanic.

Since 2015, CDER’s reports have offered transparency into clinical trial diversity by race, ethnicity, gender, and age. Other organizations, too, have tried to drive awareness and change. For example, TransCelerate BioPharma’s Diversity of Participants in Clinical Trials Initiative was formed to work on developing tools to help sponsors and others better achieve DE&I objectives in clinical trials.

TransCelerate’s initiative recognizes that improving diversity in clinical trials is larger than an R&D issue or a sponsor-specific issue. To overcome common, industry-wide obstacles, we have begun proposing more sustainable DE&I practices. Among the proposals gathered to share with the industry are the following five solutions to common challenges:

Cultivating diversity in clinical trials is complex by its very nature. Just as there is no one root cause for the lack of diversity, there is no single solution for achieving diverse representation. It is not a “project” with a defined end date but rather an evolving and ongoing effort. Consequently, organizations should be prepared for shifts and changes over time.

One strategy: Commit to collaboration for the long term

DE&I efforts cannot be achieved in isolation. Instead, every stakeholder in the clinical trial continuum has a role to play.

Changing existing processes will take patience, time, and collaboration. Researchers, sites, regulators, sponsors, CROs, patient advocacy groups, and others should consider earlier and more frequent communication than they might have done in the past. To improve transparency about efforts to increase diversity in trials and identify opportunities for collaboration to enhance ongoing actions, stakeholders can leverage the 

 that summarizes publicly available tools and resources published by many organizations for improving diversity of participants in clinical studies.

Although the events of recent years have placed DE&I in the spotlight, regulators have been moving toward greater clinical trial inclusivity for years. A brief snapshot of US legislation, FDA guidance, and FDA publications since 2006 shows a flurry of activity.

One strategy: Understand the ongoing regulatory evolution

FDA’s most recent draft guidance indicates that the agency expects not only to see a race and ethnicity diversity plan but also for sponsors to have ongoing, open dialogue with FDA about it. The guidance notes, “This Plan should be discussed with the FDA as soon as practicable during medical product development.”

For sponsors, FDA’s desire to see and discuss a DE&I plan at the IND stage signals a greater need to bring both DE&I and regulatory considerations to the development table. Therefore, organizations may want to consider pulling together a cross-functional DE&I team that monitors the regulatory landscape and supports implementation. Organizations can consider the 

US Regulatory Landscape: Diversity in Clinical Trials 

resource to help identify key US legislation and FDA policy, regulation, and guidance as well as regulatory precedent to understand and improve diversity and inclusion of adult patients in clinical trials.

Challenge #3: Partnering with key stakeholders

Building solid relationships with sites, support vendors, and others in the development lifecycle takes time and effort. Unfortunately, time is typically precious in clinical trials. Sponsors may wish or need to add to and further expand its network of partners that help support and run the sponsor’s trials. These efforts may take some thought and time, especially if these efforts entail bringing into the sponsor’s network sites or other stakeholders that have limited or no familiarity with the clinical trial process.

One strategy: Incorporate sites and other partners into the diversity plan

Who better understands underrepresented communities than those who live, work, and serve them? That may mean expanding the sponsor’s network to include sites, investigators, and advocacy groups within those communities and including partners such as CROs as sources for identifying and developing solutions to achieve DE&I clinical trials objectives.

Sponsors should also consider asking sites for suggestions on how best to connect with their diverse patient populations. Companies can leverage the 

Community-Based Site Engagement and Capacity Building

 resource to better understand strategies that sponsors, sites, and others have taken to enhance engagement and capacity building for community-based sites.

Site Engagement and Capacity Building Considerations for DEICT

 toolkit shares potential mitigation considerations designed to support efforts to sustainably partner with sites to enable the enrollment and retention of underrepresented patient populations.

FDA’s draft guidance notes, “Sponsors should define enrollment goals for underrepresented racial and ethnic participants as early as practicable in clinical development for a given indication.”1 The whole diversity plan relies on having a “gold standard” for epidemiology data. Yet, for some disease states, such data is not readily available. One of the most significant difficulties confronting the industry currently is a lack of comprehensive epidemiology data to inform enrollment goals for certain studies.

One strategy: Leverage collaborative data-sharing relationships

In such instances, companies may want to seek opportunities to work together with other stakeholders to critically think through how to find or generate baseline prevalence and enrollment data. For example, through TransCelerate’s Race & Ethnicity Enrollment Data Benchmarking effort, a subset of member companies participating in the diversity initiative are exploring how to share summary statistics of US participants enrolled in studies for seven disease states since 2011—specifically looking at race, ethnicity, age, and sex in cancer and inflammation and immunology trials. The goal is to develop proposed benchmarks that identify the disparity between disease prevalence and study representation among racial or ethnic groups.

Appropriate and relevant outreach is vital, especially in communities where a lack of trust and awareness about clinical trials may pose sizable obstacles.

One strategy: Understand & meet diverse patient populations wherever they are

As one sponsor-aimed tool suggests, engaging underrepresented patient populations to help create patient recruitment and retention strategies should be a key operational consideration.

 Sponsors may want to elicit the community’s guidance to understand the best methods for reaching, educating, and talking with prospective patients. Who are the leaders and decision-makers within the community? Knowing this can help inform the communication strategy.

Communication methods:e.g., social media, signage, marketing materials.

Messaging: Does it resonate with the community? Consider cultural sensitivity.

Reading comprehension level: Is it appropriate for the community?

Language: Consider the language used and whether the dialect matches that of the intended community.

Imagery: Is it culturally sensitive and relevant?

In its introduction, FDA states it “is publishing this guidance to provide detail on what sponsors should include in a race and ethnicity diversity plan,” outlining one of the lenses through which the agency will view new drug and device applications going forward. It puts the onus on us all to overcome challenges and include more diverse patient populations throughout the drug development lifecycle. By working in the true spirit of collaboration, stakeholders are already identifying ways to mobilize and make it happen.

, program director, TransCelerate BioPharma Inc.

FDA. “Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials — Guidance for Industry.” 

https://www.fda.gov/media/157635/download

Center for Drug Evaluation and Research, FDA. “2020 Drug Trials Snapshots Summary Report.” 

https://www.fda.gov/media/145718/download

TransCelerate BioPharma Inc. “Diversity Roundtable Reference Table and Visual Landscape of Available Resources.” 

https://www.transceleratebiopharmainc.com/wp-content/uploads/2022/02/Diversity-Roundtable-Reference-Table-and-Visual-Landscape-of-Available-Resources-1.pdf

TransCelerate BioPharma Inc. “U.S. Regulatory Landscape: Diversity In Clinical Trials.” Page 23. 

https://www.transceleratebiopharmainc.com/wp-content/uploads/2022/03/TransCelerate-Regulatory-Landscape_Diversity.pdf

TransCelerate BioPharma Inc. “Diversity Community-Based Site Engagement and Capacity Building.” 

https://www.transceleratebiopharmainc.com/wp-content/uploads/2022/10/Diversity-Community-Based-Site-Engagement-and-Capacity-Building.pdf

TransCelerate BioPharma Inc. “Site Engagement and Capacity Building Considerations for DEICT toolkit.” 

https://www.transceleratebiopharmainc.com/wp-content/uploads/2022/11/Sponsor-Toolkit-Site-Engagement-and-Capacity-Building-Considerations-for-Diversity-Equity-and-Inclusion-of-Participants-in-Clinical-Trials.pdf

TransCelerate BioPharma Inc. “Collaboration Hub Sponsor Toolkit: Portfolio and Program-Level Considerations for Diversity, Equity and Inclusion of Participants in Clinical Trials (DEICT).” 

https://www.transceleratebiopharmainc.com/wp-content/uploads/2022/06/Sponsor-Toolkit-Program-Portfolio-Considerations.pdf

Navigating FDA’s draft guidance and heightened diversity recommendations.

Tips and Tools to Overcome DE&I Challenges in Clinical Trials

The eCOA Consortium has served as co-sponsor of the Drug Information Association’s (DIA) Digital Technology in Clinical Trials Conference for the event’s first three years. All have been held virtually so far, delivering insightful and inspirational content that was deserving of a wider audience. This year, the central theme was how patients and sites are engaged in the context of the expanding use of digital health technologies in clinical development.

The committee tasked with developing the conference program aligned on the mindset of the content being progressive, yet honestly practical. Collectively, we aligned on two long-standing challenges—true patient engagement and the technology impact on clinical sites. Building on this, the conference explored the site perspective on digital technology, patient centricity in decentralized trials (DCTs), and regulatory implications for digital health technologies. Sessions also explored the use of AI and machine learning, and offered an intriguing exploration of how patient ownership of their own real-world data might impact clinical development.

Among the wealth of strong material, the final presentation, titled “We are All Patients”—and delivered by my eCOA Consortium colleague, Elena Izmailova, chief scientific officer at Koneksa—left a lasting impact. Izmailova, shared the story of her work utilizing digital technologies to track and support her recovery from cancer treatment.

Izmailova was diagnosed during the COVID-19 pandemic, which presented a series of challenges. Her knowledge drove her to construct an 

 technology kit that not only enabled an informed patient voice, but also delivered insights on her functional status to share with treating physicians in a remote setting. All post-surgery follow-up visits were virtual, and having digital technology-derived data allowed Izmailova to pressure-test sensor-based data collection as a DCT approach. She also used a non-structured patient diary to track symptoms of importance and relevance to her; a complaint among trial participants using electronic patient-reported outcome (ePRO) systems is repeated questioning on the same symptom across different copyrighted measures.

Noting a reduction in post-surgery step count, Izmailova was cognizant of how critical physical activity tracking is to patients, as described in the Ohri 

 that suggested step count may serve as a predictor of short-term hospitalization risk during chemoradiotherapy. Izmailova took ownership of tracking her activity and used the data to support consultations with the medical team. In discussing her elevated heart rate while walking, the need for an iron infusion was identified to address post-surgical anemia; having objective data to share with physicians was central to the decision to proceed with the infusion.

In essence, Izmailova created an individual trial, an N-of-1, defining her own assessment schedule based on known risks to patients with similar conditions. And there were broader learnings, such as the challenge of sharing data from multiple sources. Systems integration via portals has always focused on the site, but what about the patient? Izmailova’s N-of-1 study suggests the potential value of tracking vital signs and physical activity and provides an example of a methodology to assess data generalizability.1

Izmailova’s story highlights two key concepts; the value of technology and the critical need for meaningful patient engagement. The balance we must strike between delivering on working objectives and the realities of being a patient is a delicate one. We have talked often within the eCOA Consortium about how eCOA systems must adapt to the realities of managing serious disease. Talking the talk of true patient centricity doesn’t solve the realities of invasive methods and patient burden, but we have a duty to empower patients and trial participants with strategies and tools to help them manage their conditions and treatment.

Thankfully, Izmailova has fully recovered and continues to provide outstanding contributions to eCOA Consortium’s work. Beyond that,she reminds us that we are all patients and have a duty to think laterally and progressively to ensure patients are central to their care.

Izmailova, E; Ellis, D. “When Work Hits Home: The Cancer-Treatment Journey of a Clinical Scientist Driving Digital Medicine.” 

Ohri, N; Halmos, B; Bodner, WR; Cheng, A; Guha, C; Kalnicki, S; Garg, M. “Daily Step Counts: A New Prognostic Factor in Locally Advanced Non-Small Cell Lung Cancer?” 

International Journal of Radiation Oncology, Biology, Physics.

Data Collection

Final presentation at DIA reminds: "we are all patients."

First-hand Perspectives on Achieving True Digital Health Engagement

Key risk indicators (KRIs) are metrics designed to identify risks of specific interest to study teams and considered an essential component of centralized monitoring. The results presented here are compiled from studies for which one or more KRIs are implemented, and only those initiated on the risk-based quality management (RBQM) platform since 2020 to focus on the most current trends.* This comprises 294 studies contributed by 32 different organizations.

The average total number of KRIs implemented per study is 18. There is some variability around this average. For example, 25% of the studies have at least 23 KRIs, and another 25% have 14 or fewer KRIs.

Table 1 below summarizes the 10 most commonly used KRIs by the percentage of studies in which they have been observed. KRIs topping the list include screen failure rate, adverse event (AE) reporting rate (both serious and non-serious), and electronic case-report form (eCRF) visit-to-entry cycle time—and at least seven of the top 10 are confirmed to be used in a majority of studies. It should be noted that these KRIs were identified with the support of a machine learning algorithm that selected KRIs with names and descriptions that closely matched those presented in the table. It is, therefore, likely that some additional KRIs exist that are similar in purpose to these 10 but are not reflected in the percentages.

While there is a fair amount of variability in the average percentage of sites in each study that had risk alerts generated for each KRI, it is clear from our research that sites are most frequently alerted for risks related to delays in eCRF query response (15.8%) and eCRF data entry (12.5%). This is understandable given that most study teams choose to set discrete risk thresholds (e.g., average cycle time > 10 days) for these two KRIs, while other KRIs more often employ statistical or “relative” thresholds (e.g., p-value < 0.05). The use of relative thresholds, which are most often set based on a p-value < 0.05, will typically limit the number of sites flagged within a given study to 5% or less.

* This is the first installment in a planned series presenting industry insights and trends related to implementing risk-based quality management (RBQM). The insights presented are compiled from the CluePoints RBQM platform, which includes information from more than 1,000 studies contributed by 88 research organizations.

, data and knowledge manager; both with CluePoints

RBQM

Study indentifies trends in most commonly used KRIs.

Identifying Important Risk Indicators in Clinical Development

Moe Alsumidaie: What do the results from the AEGEAN study mean for healthcare professionals and patients?

 The long-term prognosis of patients with NSCLC, even among those with early-stage disease, is poor. With the Phase III AEGEAN trial, we are evaluating an immunotherapy—durvalumab—in combination with chemotherapy before surgery to prime the immune system, followed by adjuvant durvalumab to maintain immunosurveillance in patients with early NSCLC, to see if this approach induces a more robust immune response and improved outcomes.

Earlier this year, we shared an interim trial analysis that showed administering durvalumab in combination with chemotherapy before surgery demonstrated a statistically significant and meaningful improvement in pathologic complete response (pCR) compared to neoadjuvant (pre-surgical) chemotherapy alone. We also observed a statistically significant improvement in pathologic response (MPR). The safety and tolerability of adding durvalumab to neoadjuvant chemotherapy were consistent with the known profile for this combination. These high-level results from the ongoing trial are encouraging for patients and the multi-disciplinary teams who treat them because the surrogate endpoints of pCR and MPR have been associated with improved event-free survival in this setting.

MA: The results you reported relate to pathologic complete response. What is the significance of this endpoint for these patients and clinical trials?

 Surrogate endpoints such as pCR allow us to make an earlier assessment of efficacy after a patient completes neoadjuvant treatment and has shown promising potential as a surrogate endpoint for OS (overall survival). The increased rate of pCR seen in the AEGEAN trial suggests that adding durvalumab to neoadjuvant chemotherapy significantly increases the chance of eradicating lung cancer in Stage II/III patients with resectable NSCLC without decreasing the number of patients able to undergo successful surgery, compared to neoadjuvant chemotherapy alone.

As more data from AEGEAN and other randomized trials evaluating pCR as a surrogate endpoint are announced, it will inform a greater clinical understanding of the role of pCR and potentially lead to validation as a formal endpoint.

MA: Why is immunotherapy essential for this patient population?

 Treating resectable lung cancer early provides the best chance for a cure. Engaging the immune response with durvalumab before and after surgery in patients with early (Stage II/III) NSCLC is a new strategy. These early findings from AEGEAN could improve lung cancer patients’ survival in this potentially curative setting. This neoadjuvant and adjuvant strategy explored in AEGEAN builds on the expanded use of immunotherapy in earlier settings when lung cancer was more treatable. This is an exciting time to see if the benefits of immunotherapy can extend to the perioperative setting.

MA: How are you using the AEGEAN trial to show the value of precision medicine to cancer patients?

 The interim AEGEAN trial results demonstrate the potential of prioritizing precision medicine to deliver the treatment for the right patient at the right time. Biomarker testing is crucial in identifying those patients who might benefit the most. It also helps us ensure we’re not giving additional treatments to patients who will not benefit from them. Enrollment in the AEGEAN trial required that patients with Stage II/III NSCLC have confirmed PD-L1 status based on the Ventana PD-L1 immunochemistry assay before randomization and the absence of other known targetable biomarkers.

We have already seen the success of this approach in the ADAURA trial, which required confirmed positive epidermal growth factor receptor (EGFR) mutation for enrollment. We are committed to pushing the boundaries of science in immuno-oncology to change the practice of medicine.

Nabil Chehab, medical affairs head of lung cancer franchise at AstraZeneca, discuss strategies used in the Phase III AEGEAN trial for treating non-small lung cancer (NSCLC).

Using Solid Endpoint Strategies for Successful Cancer Trials

As Europe’s healthcare community holds its breath for the European Commission’s wide-ranging proposals on reform of the EU’s pharmaceutical rules, lobbying efforts on all sides are mounting preemptive campaigns on the most controversial issues likely to be covered by the legislation, with incentives for antibiotic research the latest topic in the spotlight.

There is no controversy over the need for urgent action as antimicrobial resistance (AMR) continues to erode the dwindling arsenal of effective therapies for infectious disease, but the emphasis varies on whether to focus on protecting existing antibiotics or whether—and how—to promote the development of new agents.

The debates have been given added urgency by disconcerting reports from European Union institutions on the growing risks of AMR. “We see concerning increases in the number of deaths attributable to infections with antimicrobial-resistant bacteria, especially those that are resistant to last-line antimicrobial treatment,” said Andrea Ammon, director of Europe’s disease control center, ECDC, in November. “Each day, nearly 100 people die from these infections” in the 30 countries covered by her agency’s estimates—“more than 35,000 people each year,” she stressed. The burden on healthcare systems and society has an economic cost, too, with healthcare expenditures and productivity losses totalling nearly $2 billion in the EU.

For ECDC, the focus is on reducing unnecessary antimicrobial use, improving infection prevention and control practices, and ensuring “adequate microbiological capacity at national level.” A decrease of 23% in total antimicrobial consumption in humans over the last 10 years masks a worrying increase in the proportion of broad-spectrum antibiotics used in hospitals.

The World Health Organization identifies AMR as one of the top current global public health threats—it’s up there alongside climate change, air pollution, famine, poverty, and war. European Commission President Ursula von der Leyen listed it as a priority when she took office in 2019, and her health commissioner, Stella Kyriakides, sees the threat as “potentially catastrophic.” The head of the Commission’s AMR unit, Sabine Pelsser, warns that “we must act as one to avert the worse consequences of AMR,” insisting that “no single action will, in isolation, provide an adequate solution.” In light of the experience of COVID-19, her emphasis is on a comprehensive response to help prevent the next health crisis. She foresees progress being made with the upcoming revision of the pharmaceutical legislation, with its dual plan for stimulating development and marketing of new antimicrobials while also addressing appropriate use. She sees “the failure to develop effective new antibiotics” as one of the drivers of the predicament, despite the EU’s injection of close to a billion dollars in antibacterial research and innovation since 2014.

Combatting the threat “is a high priority” too for the European Medicines Agency (EMA), which underlines how the lack of new antibiotics entering the market exacerbates this “global public health problem.” EMA is supporting the development of new medicines and treatment approaches in concert with the Japanese and US regulatory authorities, to provide a single development program that satisfies the requirements of each of the three agencies and to agree on an aligned approach to clinical trial design. There is even a Transatlantic Task Force on Antimicrobial Resistance.

In a Europe where one in two citizens still think that antibiotics are effective against viruses, the European Parliament is helping to spread the message of appropriate use, supporting a campaign under the slogan “Let’s keep antibiotics working.”

But policy statements and slogans are not going to solve the problem, industry executives mutter increasingly loudly in the corridors of the European institutions. “Action is needed to address the market failure for antimicrobials, so as to drive sustained private research and development investments,” says the European Federation of Pharmaceutical Industries and Associations (EFPIA), the main industry body in Europe. And what it wants the EU to introduce in its legislative rewrite is a new incentive in the form of a transferable exclusivity extension (TEE), “to revitalize antimicrobial R&D.”

Skeptical of the ability of current EU schemes to incentivize at the scale required, industry insists that successful innovation depends on reward at a level that is sufficient to attract the investment required, and to take on the substantial risks. In EFPIA’s view, a TEE, entitling a company successfully bringing a priority antimicrobial to the market to a transferable right to extend the exclusivity period of another product, could provide the incentive required.

View from Brussels

Debates caught between focusing on existing antibiotics and developing new agents.

Europe’s Debate on AMR Becomes Another Proxy War Over Money

This past year has been marked by continued efforts to develop, regulate, and distribute important therapies and vaccines to treat deadly and rare diseases, including the still dangerous COVID-19 virus. Despite generally high praise for biopharmaceutical companies in advancing these efforts, industry was unable to block the adoption of price controls for prescription drugs, a policy that risks limiting research in some areas. At the same time, the tense political environment leading up to the November mid-term Congressional elections blocked agreement on many important legislative and regulatory initiatives for FDA, delaying until the very last moment reauthorization of critical user fee programs to support the agency. Despite the anxiety generated by that cliff hanger, FDA succeeded in maintaining an efficient oversight and approval program for new and important therapies and issued multiple new guidances, renewed field inspections, and launched a range of initiatives to support public health.

On the R&D front specifically were pursuits from regulators and industry to advance novel approaches. A preferable strategy for pharma in curtailing drug prices, for example, is to achieve more efficient and less costly clinical trials, a goal that has prompted a range of initiatives to modernize biopharma research operations. The pandemic supported wider use of remote and online systems to enroll study participants and oversee treatment and patient status, with digital technologies becoming more widely used for patient monitoring. These approaches also appeared effective in advancing diversity among study participants, where remote site visits may facilitate enrollment of individuals facing difficulties traveling to clinical sites.

The ongoing surge in R&D for cell and gene therapies prompted a reorganization and expansion of FDA offices overseeing these products and efforts to clarify and update regulatory policies in this area. The importance of FDA providing individualized advice for these cutting-edge therapies highlights the critical need for the agency to attract experts to its staff able to oversee and encourage new methods and innovations.

The expansion in innovative biotech therapies and vaccines also highlighted the importance of modern production methods able to quickly ramp up production of new treatments. In 2022, FDA continued to advance several initiatives to improve product quality, including proposals for a quality management maturity program for drugs and biologics; appropriate oversight of products with limited chemistry, manufacturing, and controls (CMC) information due to expedited development treatment; and wider use of smaller, mobile drug production methods, such as distributed and point-of-care manufacturing.

FDA recognized the challenges in overseeing these developments as it moved to revive field inspection operations for manufacturing facilities and bioresearch operations. The agency indicated its intent to continue utilizing alternative remote inspection methods adopted during the pandemic based on the experience of inspection personnel in gaining needed information remotely on the status and compliance of sites, especially those with strong histories of meeting regulatory requirements. This shift to a dual inspection mode that incorporates document reviews and online “site visits” with real-time inspections is likely to become a permanent part of the agency’s oversight operations for manufacturers and clinical research operations in the US and overseas.

This past year was a difficult one for FDA Commissioner Robert Califf, who faced critical questioning and a long delay in gaining Senate confirmation to head the agency again after a brief time as commissioner in 2016. Califf came back to FDA with long experience in advancing the development and oversight of important new therapies to further combat global pandemics and deadly diseases. However, the commissioner had to spend much time and energy on a host of health crises, including a serious shortage in infant formula, rising death rates from opioid overdoses, and pressure to curb marketing of vaping products and e-cigarettes.

A serious challenge for Califf and health authorities is the continued rise in misinformation about coronavirus medical treatments and vaccines. FDA and other public health agencies struggled to boost COVID vaccination rates and counter anti-vaccine voices, while also combatting the promotion of untested and dangerous “treatments” for COVID and other serious health conditions.

Meanwhile, the delay in Congress renewing user fees for drugs, biologics, generic drugs, medical devices, and biosimilars hampered FDA planning and put multiple new programs on hold.

View from Washington

Pandemic Spurred New R&D Approaches from Pharma, FDA in 2022

Currently, we are straddling two worlds, or more—post-pandemic, always endemic, another full-fledged pandemic? People are looking to these coming winter months with trepidation. Flu? RSV? Or COVID? It’s a toss-up.

But this confusing 2022 world impacts trends for 2023. Let’s take a look at a tiny fraction.

Telemedicine as a basis for decentralized clinical trials (DCTs)

. Telemedicine and receiving healthcare remotely was the basis of clinical trials and healthcare delivery during COVID. According to data from IQVIA, after its “dramatic entrance,” telemedicine is holding steady at 8% of all claims data through 2022. Not a decline, 

, but not a demonstration of ongoing growth. Other models of DCT visits—pharmacies, or home nurses, for example, are also not without challenges. For home nurses, it’s the consideration that some patients may not be amenable to others in their home. And large pharmacy retailers have shuttered over 700 stores in the past two years (IQVIA, September 2022).

 As DE&I initiatives and patient engagement outreach outside of urban areas continues, the “community” approach is a primary target for growth, in theory. Historically, however, that last mile from community outreach to participant enrollment is still a tricky one. Numerous ways to reach those community sites (hospitals/health systems/sites) include networks or partnerships; EMR search for potential participants; physician referral programs; and boots on the ground efforts in underrepresented population areas to amplify trust and further local engagement. Each of these is not an insignificant lift for clinical operations.

Not one presentation this fall has failed to note the decline of available professionals to staff clinical trials operations, on numerous levels and roles. At the site. At the CROs. Hospitals. Pharma. Turnover is high, and overall, the healthcare field is suffering a dearth of trained staff. This is not a 2023 problem, this is a long-term projected problem that is impacting all levels of healthcare delivery.

I didn’t intend for this column to only highlight challenging trends. But the truth is, as industry weaves its way through hybrid clinical trials and delivering on underrepresented populations for participation, there is no one way to success; it’s a complex 2023 world. 

 is Editor-in-Chief of Applied Clinical Trials. She can be reached at 

From the Editor

Industry straddling two worlds as new year approaches.

From Present to ‘Post’: Holdover Trends to Watch 

Issue PDF

Click the title above for a link to open the Applied Clinical Trials December 2022 issue in an interactive PDF format.

Applied Clinical Trials December 2022 Issue (PDF)

Optimizing drug dosing in oncology has long been a challenge. The current drug development paradigm is oriented toward identifying a maximum tolerated dose (MTD) in early-stage trials, and evaluating the MTD for drug activity and efficacy in Phase II and III trials. In recent years, the limitations of this approach have become clearer.

First, the existing oncology drug development methodology does not adequately evaluate inter-patient variability in treatment response and toxicity. As a result, the dose-exposure-response relationship is rarely well defined for oncology drugs, despite their narrow therapeutic indices. Secondly, the current approach also leaves room for clinically meaningful pharmacodynamic endpoints—such as target inhibition—to be overlooked, despite their potential importance for new classes of medicine. Neglecting the impact of biological modulation may result in poor outcomes for patients.

Most importantly, the classical drug development paradigm does not adequately characterize long-term toxicity. This oversight is problematic, as patients on new biological therapies are expected to undergo treatment for much longer periods of time. Patients may use targeted drugs for months or years, which increases the importance of evaluating long-term tolerability.

 that many approved oncology drugs are inadequately characterized with approved doses that may be too high, the FDA’s Oncology Center of Excellence has launched an initiative to reform the dose optimization and dose selection paradigm in oncology drug development. Known as 

, this initiative recommends a core change in how doses are selected during oncology clinical trials and post-approval studies.

As the design of drug trials is guided by the results of prior research phases, the FDA is recommending a concerted effort to rethink dosing beginning with first-in-human studies. At present, Phase I oncology studies are almost entirely designed to identify and achieve the maximum tolerated dose (MTD), which is unique to oncology drug development. Non-oncology trial designs have a long history of employing dose-ranging approaches that balance efficacy outcomes with toxicity profiles.

In Phase I oncology trials, the objective is to determine the highest tolerable dose, based on the assumption that higher doses will provide greater efficacy (i.e., disease-free survival). In these trials, increasing doses of a drug are sequentially evaluated in small cohorts of patients until a pre-specified rate of dose-limiting toxicity (DLT) is reached. The dose immediately below that which elicited DLT is considered the maximum-tolerated dose (MTD); in most cases, the MTD is then used for Phase II and subsequent Phase III trials, which are used to evaluate drug activity and efficacy. Currently, it is rare for Phase II or III studies of oncology drugs to evaluate more than one dose, although this approach is common in other therapeutic areas.

Trial design flexibility has lagged behind innovation in oncology research. The flourishing of gene therapy, biologics, and anti-body drug conjugates (ADCs) has reinvented how we approach oncology treatment. The promise of more targeted treatment approaches with lower toxicity is a near reality, and will in turn require a much more thoughtful and patient-specific dosing strategy. A true targeted approach requires a molecularly targeted therapy with a tailored dosing regimen that maximizes the benefit/risk ratio for patients receiving the drug.

Likely impacts of Project Optimus on drug development

Clearly, a migration away from MTD-focused study design is long overdue, and the FDA’s guidance has already begun to influence oncology drug development processes. The first impact of Project Optimus concerns imminent drug candidates for regulatory approval. The volume of post-marketing requirements and commitments will increase, placing a greater burden on pharmaceutical companies that have not conducted earlier phase dose optimization. Anecdotally, the pursuit of 

Applied Clinical Trials-12-01-2022