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Applied Clinical Trials June 2021

Early in the 1900s, the medical world began to suspect that different types of people were more prone to specific diseases than their peers. As the century progressed, others outside the medical world began to get suspicious, too.

And when the world lost its semblance of sanity last March, as minority groups were dying from COVID-19 at higher rates than Caucasians, the world reacted; it called for real-world diversity in clinical trials and medical parity in the clinic.

 Studies were published, opinion pieces, too, even ads were aired for clinical trial equality.

 Page after page in Google can provide the details.

No doubt, the historical dominance of the white man as a trial enrollee has thwarted gathering evidence-based knowledge regarding the health and welfare of non-Caucasians. Without the latter’s participation in interventional trials, little can be ascertained as to whether the drug helped, hindered, or even hurt them. This lack of knowledge is acutely felt in the field of oncology. “Certain compounds affect certain populations,” said Diana Foster, PhD, vice president, Strategy and Special Projects, Society for Clinical Research Sites (SCRS). Diverse populations are “critical in drug development.”

To say that pharma has not paid attention to the problem of inclusion prior to the pandemic is inaccurate, those interviewed for this article said. An important point: inclusion can be defined in numerous ways, beyond the color of someone’s skin.

Diversity, said Joan A. Chambers, Senior Director, Marketing & Outreach, Center for Information & Study on Clinical Research Participation, is difficult to define. “It can go down many different paths.”

One such path is pharmacogenomics. The human body has about 30,000 genes, and each one, on average, produces three proteins. That’s a lot of opportunity for therapies to encounter genetic hiccups and disrupted metabolic pathways.

 Add to that how bodies are influenced by prior generations, and the world they are living in now. A 2013 study of 167 new-molecule-based therapies showed that one in five of them acted differently in minority groups, in different races and ethnicities.

“Diversity certainly has a higher profile now, but pharma began funding [our Diversity Site Assessment Tool project] four years ago,” said Foster. “Diversity is a scientific and conceptual issue that continues to evolve and develop.”

COVID-19 was not the impetus for pharma’s current focus on diversity in its trials, said Marie-Pierre Hellio Le Graverand, MD, DSc, PhD, senior vice president and Pfizer’s Clinical Development & Operations, Global Product Development lead. “We have been working on [minority inclusion] for a number of years. It takes time to move the needle.” Hellio Le Graverand and colleagues recently published Pfizer’s own clinical trial diversity track record for the last 10 years.

 The Pfizer representatives recently called for industry to address equity access to clinical trials.

But the pandemic made it clear that the world wants that needle to move and move fast.

Scientists began noticing differences among various groups, early on, starting in the late 19th century. (Mendel was growing and analyzing his peas around 1865.) In 1932, J.M. Adams wrote about the differences in blood pressure levels between a “group of white and [African American] workmen” in the American Journal of Medical Sciences.

Researchers then started reporting that different types of people react differently to medical therapies. In 1952, Hockwald et al. showed that red blood cells of 10% of African Americans and some Caucasians were fated for destruction if these patients were regularly given the antimalarial primaquine.

 In 1962, Tarlov et al. deemed the problem to be “an intrinsic abnormality of the erythrocyte,” as this “hypersusceptibility to hemolysis by drugs is a genetically transmitted inborn error of metabolism.”

FDA began its decades-long quest for inclusion in 1993, telling trial sponsors that if they wanted financial support for their clinical trials, they had to enroll other people besides young and middle-aged white males. Five years later, FDA got specific: break out the efficacy data according to the participants’ age, race, gender and ethnicity. With the first installment of the Human Genome Project a few years away, maybe the agency was gearing up to review precision-based medicines.

In 2001, J.F. Wilson et al. set out to see how drug response worked in participants from China, New Guinea, Sub-Saharan Africa and Western Eurasia. They were tested for shared genetic regions and then grouped with their genetic kinsman. Ultimately, the participants were put into four groups. Expecting to find the four groups geographically aligned as well, what they found was that geographically, borders don’t exist: Ethiopians joined people of Jewish descent, Afro-Caribbeans were, genetically speaking, neighbors of the West Eurasians. Human demographics are complex, the authors said, with no apparent natural clustering arrangement. The work does provide, they continued, a framework “for assessing the appropriate level of resolution in relating genetic structure to drug response.”

While FDA has approved and continues approving assay tests to ensure that the right medication, primarily for cancer patients, reaches the right genetic target, pharma’s long-running, one-size-fits-all approach was still in use.

In 2015, the CDER approved 45 new drugs with more than 105,000 patients enrolled. White people comprised 79% of that number, African Americans, 5% and Asians,12%.11 By 2019, African American participation had reached 11%, according to FDA figures.

This past February, an overview of 230-U.S.-located vaccine trials with 219,550 patients conducted between 2011 and 2020 showed both ethnic and racial underrepresentation. About 100 of the trial sponsors, or 58%, reported race; 79, or 34%, ethnicity.

In mid-May, another enrollment overview, this time of 207 U.S trials from 2007 to 2020 involving 8,429 pancreatic ductal adenocarcinoma patients showed that rates of enrollment for minority groups weren’t reflective of real-world, higher diagnostic rates.

The rates of somatic and germline mutations in Black patients differ from other racial subgroups, so their response to therapy also differs, said co-author Kelly Herremans.

 Black participants were less likely, at 2.9%, to be included in a Phase III trial than in Phases I and II, with each about 10%.

Just two more studies of note: In 2010 Booske et al. found that social circumstances, environment and genetics affected health by half;

 by 2016, the United Health Foundation found those three drove a person’s health by 60%.

In 2019, a study underwritten by Merck & Co. along with many stakeholders, including the Association of Black Cardiologists, Inc. and SCRS, surveyed cancer centers, looking for those more successful in recruiting racially and ethnically diverse patients than others. In essence, these centers found it takes informed, back-and-forth communication among all involved, while giving enrollees, their family and their referring physician more of a voice in making decisions. These sites also trained their investigators in cultural mores.

 Work on the Diversity Site Assessment Tool, now scientifically validated, began in 2016. Merck wanted help in finding non-Caucasian trial participants. “We consciously decided to approach the work scientifically,” Foster said. “What are the sites lacking, what do they know and what are we going to teach them?” Over the next four years, the group devised self-assessment surveys to get answers to these questions. Its financial supporters include pharma members and CROs.

Some sites don’t know their own communities, she said. “The site could be in an urban location, and three blocks behind the hospital is a huge population of Spanish-speaking people, and they don’t even know it.”

For the last survey, questions were sent to 437 sites located in hospitals, private physician offices that conduct trials and academic institutions and other research companies. Foster said SCRS will make the tool available; no specific training programs have been developed yet.

The targeted improvements pinpointed in the study are similar to findings in the 2019 Merck-funded study: locate minority-based organizations that can help build a network to find minority participants, like community centers, churches, support groups; include different languages on the phone prompt; and help participants get over hurdles, like finding housing should the patient need to visit a site, for himself and family.

Joan Chambers knows all about the hurdles of finding minorities for trials, and the need to use local organizations to find them. CISCRP has been minority focused since its founding in 2003. The goal has always been “how do we share this information about clinical trials in easy-to-understand content that does not sound scientific,” she said. The group disperses the information in the community, but it’s up to the recruitment arm to tailor the message for a specific study.

Local organizations can support gatherings at community centers or churches, and educate about clinical trials. And when they do, the questions that people ask at these gatherings all punch the holes as the studies geared to find
minority patients:

Does a participant have to know English to participate in clinical studies?

Can your primary care doctor refer you to a clinical trial?

What are trials, why are they important, who is involved?

At ZS, helping with minority recruitment is more about getting to the roots of “I won’t participate,” and “I won’t invite this person in.” ZS, a professional problem-solving firm, began its cognitive and behavioral science project six years ago. It has pharma sponsors, as does
Foster’s work.

The point of this project, said Jacob Braude, principal, is to identify the so-called mental shortcuts people take to make decisions, and to dismantle those shortcuts that prevent someone from enrolling in a trial, as well as those shortcuts that site coordinators and referring physicians take to discourage a would-be participant. Braude said academics have identified 100 such shortcuts. An example: A person with osteoporosis in her knee can get site injections four times a year. But this person only comes once, because her physician has told her, “Come back when there is significant pain.” This shortcut is called moral regulation in which the patient is balancing good and bad behavior. “We asked the patients, ‘do you have to earn your injection? and 60% said yes.’”

Expanding inclusion criteria is a front-burner item, supported by FDA and not a few pharma houses.

At IQVIA, researchers are “pressure-testing” inclusion and exclusion criteria, said Mark Brown, head of Global Patient and Site Solutions at IQVIA in a statement. At Phase III, some eligibility criteria have become universally accepted, or used as a template across trials. The impact: certain patient populations have been excluded from participation “without strong clinical or scientific justification.” However, Brown continued, lifting those exclusions and using them to decide if these patients are eligible, and how including these patients would impact the trial—during trial design—could help trial sponsors better determine eligibility requirements.

During the COVID trials, pharma had little choice but to get creative in finding minority participants. Trial sponsors had constant contact with regulators; sponsors monitored trial sites to see who was enrolling, and then compared site numbers to make adjustments; they received FDA feedback and approvals while the trials were ongoing. The risk averse had morphed into the risk be damned.

They relied heavily on technology to find human beings: digital health suites, virtual study coordinators, and mobile phone information to look at traffic patterns that would indicate where people were in lockdown. If a trial site needed help in recruitment or its staff needed help with the technology, the sponsors would send in the Marines, as it were. They took the trial to the patients.

Janssen used mobile units to make sure its satellite services could help screen potentially eligible patients in their communities. Pfizer also monitored traffic. AstraZeneca “chased the virus with interactive speed maps to have a global picture of the affective areas,” said AZ’s Rachele Berria, vice president, U.S. Medical, BioPharmaceuticals in a Prix Galien webinar.

 AZ worked with IQVIA, governments and universities to find sites and used predictive modeling. It also ran systems in parallel (as did the others) and used wearables to monitor vital statistics. “We made ample use of telehealth,” she said.

In a typical trial, sponsors look post-trial to see how well recruitment went, and so on, said Terry Murphy, Janssen’s Global Head of Strategic Operations, Pharmaceutical Development and Manufacturing Sciences, in the webinar. With COVID, “we asked, how are we doing and how can we change things?”

The casual observer will note that these new approaches rely heavily on technology to achieve what ultimately is a person-to-person event. However, it is certainly the improved technologies and processes used during COVID—taking the trial to the patient—that can help change the overall inclusion demographic in clinical trials.

Daniel B. Chastain, Sharmon P. Osae, Andrés F. Henao-Martínez, et al. Racial Disproportionality in Covid Clinical Trials. NEJM. Aug.
11, 2020.

Nature Hunt, S. (2008) Pharmacogenetics, personalized medicine, and race. 

A. Ramamoorthy, M.A. Pacanowski, J. Bull, et al. Racial/ethnic differences in drug disposition and response: review of recently approved drugs. 

M. Rottas, P. Thadeio, R. Simons, R. Houck, D. Gruben, D. Keller, D. Scholfield, K. Soma, B. Corrigan, A. Schettino, P. J. McCann III, M-P. Hellio, K. Natarajan, R. Goodwin, J. Sewards, P. Honig, R. MacKenzie, Demographic diversity of participants in Pfizer sponsored clinical trials in the United States.

Rod MacKenzie, Peter Honig, Judy Sewards, Robert Goodwin, Marie-Pierre Hellio. COVID-19 must catalyse changes to clinical development. 

Adams, J. M. Some racial differences in blood pressures and morbidity in a group of white and colored workmen. 

RS Hockwald, MJ Arnold, CB Clayman, et al. Toxicity of primaquine in Negroes.1952; 

Alvin R. Tarlov, George J. Brewer, Paul E. Carson, et al. Glucose-6-Phosphate Dehydrogenase Deficiency: An Inborn Error of Metabolism of Medical and Biological Significance. 1962; 

Wilson, J. F., et al. Population genetic structure of variable drug response. 

FDA. List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools). Current as of April 27, 2021.

FDA, 2015-2016 Drug Trials Snapshots Summary Report.

FDA, 2015-2019 Drug Trials Snapshots Summary Report.

Herremans K, et al. “Trials and tribulations: Diversity and inclusion in pancreatic ductal adenocarcinoma clinical trials” 

Diana Swift. Diversity in Pancreatic Cancer Trials Lacking. 

Laura E. Flores, Walter R. Frontera, Michele P. Andrasik, et al. Assessment of the Inclusion of Racial/Ethnic Minority, Female, and Older Individuals in Vaccine Clinical Trials. 

Bridget C. Booske, Angela M. K. Rohan, David A. Kindig, et al. Grading and Reporting Health and Health Disparities. 2010; 

Margarita Alegría, Kiara Alvarez, Rachel Zack Ishikawa, et al. Removing Obstacles To Eliminate Racial And Ethnic Disparities In Behavioral Health Care. 2016; 

Jeanne M. Regnante, Nicole A. Richie, Lola Fashoyin-Aje, et al. US Cancer Centers of Excellence Strategies for Increased Inclusion of Racial and Ethnic Minorities in Clinical Trials. 

https://ascopubs.org/doi/full/10.1200/JOP.18.00638

Galien DH 2021 / The Impact of Digital Technologies – Lessons from COVID-19

Articles

How COVID-19 blazed a new trail for greater patient inclusion.

The Many Paths of Diversity in Clinical Trials

Throughout the pandemic, clinical research stakeholders have been both amazed and immensely proud at the collective effort to adapt and address a monumental global health crisis in record time.

A great deal has been written and said about the factors that have contributed to the delivery of COVID-19 vaccines more than five years faster than typical development timelines and to the more than 1,000 COVID-19 treatments and vaccines now in the pipeline. The top contributing factors include:

The proactive and accommodating way that regulatory agencies and ethical review committees have supported development planning and activity.

The rapid mobilization of internal and external scientific and operating teams with a singular and common focus.

The fast deployment of remote and virtual technology solutions supported by more open data, information sharing, and advanced analytics.

The execution of parallel clinical trials and the compressed time between clinical trial phases.

The de-risking of development activity through the availability of global funding and resources.

The unusual frequency and extent of global media coverage contributing to unusually high public visibility.

The clinical research enterprise has much to celebrate, especially in light of the fact that most adaptations and changes represent a major departure from normal operating conditions. Many of the approaches and solutions deployed—such as remote monitoring, e-consent, home nursing visits, and integrated data management platforms—faced significant difficulty replacing legacy approaches before the pandemic. Many were stuck in planning or piloting stages for decades.

There is now substantial speculation about how the clinical research enterprise will function when the pandemic is fully behind us. How will the enterprise apply and embrace the experiences and lessons learned during this unprecedented period? Beginning in late 2020, articles, podcasts, webinars, and conference presentations began surfacing, most with both wishful thinking and pledges not to return to pre-pandemic operating conditions.

In recent months, we have learned more about underlying conditions that have supported pandemic response and a clearer picture is emerging of issues and challenges that will contribute to some retrenchment and more conservative application of adaptive and innovative practices as we move into a post-pandemic world. Two recent Tufts Center for the Study of Drug Development (Tufts CSDD) studies help paint that picture: the first study is an in-depth collection of interviews with principal investigators and senior study coordinators from the global community of investigative sites and site networks. The second study is a global survey—conducted in collaboration with the Bill & Melinda Gates Medical Research Institute (Gates MRI).

Tufts CSDD conducted a total of 26 in-depth interviews during March and April 2021, approximately one full year after the international community began locking down and clinical trial activity abruptly shifted to remote monitoring and decentralized support. Investigators and study coordinators noted several positive outcomes. The majority pointed to sponsor company and regulatory agency responsiveness and encouragement of adaptive practices as critical success factors. Site professionals felt that the most positive outcome in the transition to virtual and remote clinical trials has been the increased choice and accessibility offered to patients considering participation and the substantial improvement in study volunteer convenience.

But with few exceptions, the global community of investigators and study coordinators indicated that operating remotely and virtually has greatly increased workload for site personnel. Many noted the inordinate amount of time they have dedicated to learning new technology solutions; providing support to remote monitors and health professionals; training vendors unfamiliar with the clinical research process; and coordinating and integrating disparate and fragmented activities. Most interviewees pointed to significant delays that they have encountered starting up studies, receiving clinical trial supplies and lab kits.

Many conveyed concerns about the delays they experienced in receiving payments to help defray the substantial upfront risk sites assumed in supporting modified and adapted execution models.

In nearly every in-depth interview, investigative site personnel discussed the wide variability in approaches and solutions deployed by sponsors and contract research organizations (CROs) that contributed to high levels of uncertainty and the increased potential for errors and mistakes.

Between mid-January and April 2021, Tufts CSDD and Gates MRI gathered 344 global responses primarily from pharmaceutical, biotechnology companies, and CROs. The purpose of this online survey was to assess the experiences and effectiveness of development teams operating remotely. Two-thirds of respondents are employed by major and mid-sized companies and a similar percentage reports having team management responsibility within clinical, data management, and clinical operations functions.

Overall, respondents reported very high levels of productivity while operating remotely. Nearly all (97%) indicated that they can perform their role as a remote employee “very effectively” or “somewhat effectively.” But more than half of respondents (55%) report feeling burned out and 42% report that connections with their colleagues have deteriorated.

Factors contributing to burnout are intuitive and generally familiar to us all. The top three included the frequency of virtual meetings (by 67%); increased workload and additional responsibilities negatively effecting life balance (65%); and the emotional impact of dealing with uncertainty and isolation (54%). Unaddressed, it is likely that the feelings of burnout and loss of connection will continue to rise.

In open-ended responses, several indicated that the inability to travel and meet face-to-face with colleagues detracted from their collaborative effectiveness. Several also noted the challenges of not having a clear sense of the return on investment (ROI) for various solutions deployed and of the higher relative start-up cost and time investment required to support decentralized clinical trial activity.

Despite these experiences and concerns, the vast majority of respondents want to preserve their ability to operate remotely: 86% want their employer to continue offering “mostly remote” work when the pandemic is over; 6% indicate that they are uncertain about what operating model they want in place; and 8% said that they do not want their organizations remote operating model to continue.

We plan to publish the full results of the Tufts CSDD–Gates MRI study in 

Pandemic experience and response has exposed drug development organizations to numerous possibilities that would not have otherwise been widely adopted. Many observers would argue that this unusual adoption experience is not a reflection of a new standard operating environment but rather a one-time occurrence—a grand pilot program—providing a unique opportunity to consider, integrate, and apply “suitable” new options and choices.

Once the pandemic is behind us, these options and choices will likely be offered simultaneously with other more traditional approaches to balance and best satisfy study volunteer preferences, convenience, and scientific and operating requirements. Ultimately, these more expansive hybrid approaches will increase clinical trial complexity and customization, resulting in well-known outcomes: inefficiency, poorer quality, slower timelines, and higher costs.

Given cultures that have historically been risk-averse and resistant to change, many sponsor companies and their CRO partners will step-up efforts to scrutinize capital, personnel, and resource investment in, and double down on challenging, newer innovative practices. For the majority of organizations, it is likely that the pendulum will swing back toward slower, more measured response and more
limited acceptance.

A minority of organizations—those willing to take more risk—are already applying the implications of pandemic experience. Many are evaluating ways to better support teams operating remotely with more variable, agile, and flexible staffing models, infrastructure, and standard operating procedures. Several have shared the intent to consolidate their fixed, physical operating footprint, to continue to reduce study participant burden, and to entertain more open collaboration models.

Clinical research data volume has been rising dramatically for decades as protocol design objectives and scope have increased. The diversity of sources for clinical research data—including specialty labs, mobile and wearable devices, and patient health records—has also intensified. Post-pandemic, the juggling of highly customized clinical trial executional models will drive the collection of more data informing operating performance, efficiency, and quality. This rapid expected growth in rich data volume cannot be managed by traditional means alone and will rely more heavily on sophisticated and augmented analytics, including machine learning, risk-based quality management, and risk-mitigation techniques.

As the pandemic recedes and we gather more robust data on its full impact, we can anticipate wider variation in sponsor, CRO, and investigative site operating strategies and practices.

We will look back at our collective response with not only amazement and pride but also the knowledge that the pandemic did not solve our perennial drug development operating conditions. Rather, it necessitated experiences that affirmed, informed, and elevated enterprise-wide commitment to patient engagement and digital transformation.

Affirming and advancing patient engagement and digital transformation.

Contemplating the Full Measure of Pandemic Response

Clinical research sites are modernizing trial operations with site-centric applications to provide a digital patient experience. Crofoot Research Center, a Houston-based practice that has run over 200 clinical studies in rare disease, is one site realizing the benefits of using patient-centric, site-first solutions.

With an eRegulatory system and eConsent from Veeva Systems, Crofoot is shifting from manual and paper-based processes to more streamlined, digital execution. Charles Sydnor, CCRA, ACRP-CP, project manager at Crofoot, discussed how offering a digital patient experience in trials enables the site to provide better patient care.

: What challenges did Crofoot experience with traditional, paper-based informed consent?

 Patient reach and accessibility have always been our biggest barriers in studies. COVID-19 made reaching new patients even harder, as most could not physically come into our practice. Using paper-based consenting wasn’t a feasible option because of the travel, distance, and safety concerns, impacting our reach and preventing many patients from considering research as a treatment option.

Over the years, we have seen how paper complicates execution, reduces efficiency, and provides limited accountability. Using paper, paying for storage, and hiring additional staff to manually check all the consent forms for completion, errors, and appropriate signatures dramatically increased our economic burden.

Lastly, we want to ensure that the potential participant understands the study, especially the risks and benefits. The traditional paper-based model of consenting does not lend to better participant comprehension but rather the exact opposite. Handing a 20-plus page consent document is an intimidating and overwhelming event, and many participants complain that the font can be too small for review.

ACT: How has paper-based consent impacted the patient experience?

 Ideally, we’d want to give patients as much time as possible to consider participation, ask questions, and talk to their support system at home before choosing a trial. But once a patient travels into our practice, they usually feel pressure to make a quick decision to avoid another visit. That pressure takes a toll on patients who want to consult family members before deciding to participate in a study, leading to early opt-outs.

Patients also have to come in for a screening, often not scheduled on the same day as consenting. An appointment to provide consent could be in several days or several weeks, but it almost always ends up in another visit for the patient. Thus, paper consent increases the patient burden of participating in trials, requiring more time and travel.

ACT: How has Crofoot’s shift to digital improved the patient experience?

Since we already had an eRegulatory system in place, it made sense to bring in an eConsent solution that enables seamless exchange of information. Implementing eConsent has given patients the flexibility to review documents on their own time and wherever they feel most comfortable.

As clinical research protocols become more complex, the patient’s complete understanding of a study is paramount. Using eConsent allows us to format study information in a more digestible form. This ensures that each participant fully understands what they are signing up for. It is important to remember that each person has different needs, and removing paper will optimize the patients’ experience.

We’ve noticed a significant improvement in patient understanding of studies with eConsent. Numerous patients have expressed gratitude for the ease at which they can access documents, allowing review with those closest to them.

ACT: What improvements has your research center achieved by using eConsent?

 Our mission is to reflect the diversity of Houston. But patient reach has been the most significant barrier for us to overcome. This makes our efforts to digitize consent even more critical. eConsent has helped us gain access to individuals in rural areas and underserved communities that may not have access to healthcare.

eConsent allows us to provide patients with more flexibility and minimizes travel. Patients appreciate this, as we’ve seen an increase in recruitment numbers and participant diversity.

Using a digital consenting solution that can exchange information with our investigator site file (ISF) has removed many of the hurdles we experienced for years with paper filing and maintaining ICF logs. As a result, our team is now better prepared to review documents, ensure accuracy, and seamlessly file a patient’s information.

In addition, audits are now handled more efficiently. Our digital solutions allow sponsors and CROs to quickly validate information and ensure all our activity is compliant. Having the ability to share documents across our systems and with our partners has allowed us to work more systematically and cost effectively.

For research sites thinking that the cost of technology is a barrier to adoption, this isn’t always the case. For us, as a small private practice without a large budget, eConsent presented a very achievable point of entry. We have significantly reduced our administrative workload and expenses on storage, printing, and tangible goods. Using a digital consenting solution has improved productivity, enhanced the patient experience, and increased our site’s ability to handle larger workloads.

ACT: You’ve now implemented an eRegulatory system and eConsent, two solutions transforming how research sites work. What advice would you give a site considering new technology?

 The thought of implementing new technology was scary for me at first. But digging in and investing the time has paid off. My advice to sites exploring new solutions would be to commit and follow-through, from evaluation to deployment. Bringing in technology takes a lot of work upfront and is a cross-team effort, but in the end, the benefits for your research site can be transformational. That level of change and improvement to site operations allows you to spend more time where it makes an impact: with patients.

Charles Sydnor, CCRA, ACRP-CP, project manager at Crofoot, discusses how offering a digital patient experience in trials enables the site to provide better patient care.

Shifting from Paper to Digital Patient Consent

CROs, as an industry, appear to be in a period of change. The overall market for mergers and acquisitions since the year of COVID have needles moving in various directions. Let’s dial those in.

First up is largest financial transaction, Thermo Fisher’s acquisition of PPD, worth $17.4 billion, which should close in the third quarter. Thermo Fisher has long eyed its importance to the clinical trials space because of its manufacturing capabilities around APIs and clinical trial supplies. It, like others, jumped on the decentralized trials bandwagon in late October through its Direct-to-Patient service offering bringing those medications directly to the patient. The acquisition of PPD grows its clinical trials scope, as well as nests its existing manufacturing customers with an extended value proposition in the services chain.

Two additional M&As worth mentioning are the Syneos acquisition of CRO Synteract for $400 million in late October. This acquisition calls for the former to leverage the latter’s small-to-midsize biopharma client base. The second is ICON’s $12 billion purchase of PRA Health Sciences in February. That acquisition elevates the number fifth and sixth largest CROs to the second spot, behind IQVIA. The ICON/PRA merger also plans to capitalize on the decentralized trials movement through its mobile technologies and site platform network.

Meanwhile, in mid-May, mid-size CRO Premier Research acquired Camargo Pharmaceutical Services. Camargo will allow Premier to leverage its focus on emerging biopharma’s needs for rare disease and complex development programs, as well as the accelerated approval pathways more common among smaller biopharma.

What trends can we untangle from these transactions? The CMO/CDMO space is looking to capitalize on the needed manufacturing capabilities for vaccines and biologics that are more prevalent in the drug development landscape by offering those services as part of their portfolios. Not since the transformation of the INC Research and inVentiv Health to Syneos Health and the IMS/Quintiles to IQVIA for an extended clinical research-to-commercialization chain has a market extended its horizontal reach to existing customers.

We can infer that that the attraction to emerging, small and midsize biopharma clients will continue to be a focus for the expertise in clinical operations, regulatory, decentralized trials, and manufacturing they require. What does that mean for clinops professionals? Not so much day-to-day, but an understanding of the bigger picture regarding the needs of smaller sponsors is vital.

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

A brief look at the market for mergers and acquisitions since the year of COVID.

The Tangled Web of Large Outsourced Providers 

Chairman and Founder of MJH Life Sciences

As we know, the pandemic brought the topic of clinical trials to the forefront of the general population. Never before have people been exposed to daily news from the mainstream media on clinical trials, the therapies in trials for COVID-19 and the need to have data that supports efficacy and safety of these therapies, which are generated from clinical trials. Further, when Moderna briefly halted its vaccine trial to ensure that data from broad, diverse populations was included, did people understand the importance of trials including all population groups. The clinical trials industry itself has struggled with the inclusion of underrepresented groups for some time and is not blind to this multi-faceted problem.

 explores what the term "diversity" can mean when studying different populations. It also points to technologies used in decentralized trials as a way to reach underrepresented populations and allow them to participate in a clinical trial. If we struggle to include an underrepresented population in clinical trials, then those who suffer from rare diseases could certainly be a part of such a discussion. In another article, we learn that rare disease patients were disproportionally affected with healthcare access during COVID and that technologies could improve both their access to healthcare, as well as clinical trials. We have also included an article that informs on the five ways that decentralized trials can positively impact clinical trial diversity.

We applaud industry stakeholders—sponsors, CROs, investigative sites, and technology providers—on focusing their attention on the diversity and inclusion issue. Many have come forth with important programs and resources to improve the situation. However, as Pfizer executives penned in a 

, "Racial and ethnic disparities in clinical trial populations remain unacceptably abundant, and trust in the health-care system among those who suffer racial injustice is low. It is difficult to find a trial and the requirements for participants are often burdensome, contributing to unacceptably high dropout rates." They call on the stakeholders "to find common solutions that build trust and address the socioeconomic barriers to clinical trial participation." They elaborate on the specific commitments to improve clinical trial access and build trust, and to improve awareness. Hopefully, the articles in this issue will help industry in these endeavors.

, Chairman and Founder, MJH Life Sciences

Chairman and Founder of MJH Life Sciences, Mike Hennessy Sr. explores the main discussion points covered in the June issue of ACT. 

Clinical Trials Diversity and Inclusion

In laying out its formal budget proposal for fiscal year 2022, the Biden administration supports a notable increase in funding for public health and research as a lead priority for the coming year. While Congress will reject or modify many of the specifics, the federal government’s remarkable success in combatting the COVID-19 pandemic continues to generate bipartisan support for advancing biomedical research and public health and safety.

FDA’s oversight and guidance in speeding the development of critical COVID-19 vaccines, diagnostics, and therapies is rewarded with additional funding to continue and strengthen those capabilities. The 

 requests $6.5 billion for the agency, up 8%, with $3.6 billion in public appropriations and $2.9 billion in user fees paid by industry. The added $344 million, according to the 

, is allocated primarily to three main areas: critical public health infrastructure, including data modernization and expanded laboratories, facilities, and staff; core safety programs for food and medical products and global supply chains; and ensuring public health by increasing secure inspections, promoting health equity, and addressing the opioid crisis.

Among the specifics, FDA seeks $19 million to enable its field inspection program to carry out site visits delayed by the pandemic and to avoid a reduced frequency in both domestic and foreign inspections going forward. To help end the opioid crisis, FDA would gain $38 million to support research for developing overdose reversal treatments and new non-opioid pain medications and to devise systems to better track and manage opioid use.

For several years now, FDA has emphasized the need to modernize its data and communications systems for medical products and food, and the new budget may finally advance its Enterprise Technology and Data modernization efforts. An additional $45 million would support wider use of artificial intelligence and advanced IT systems to enable data sharing across product centers and ease communications among agency offices, streamline core business processes, and better track medical product manufacturing to better anticipate shortages.

The budget plan also cites the need for legislation to make permanent certain temporary policies that will expire with the end of the current public health emergency. This includes authority to require medical device manufacturers to notify FDA of product shortages, to request records and other information from medical device makers and clinical research sites in advance or “in lieu of” a physical facility inspection, and to require data and studies from drug manufacturers to extend product expiration dates as a way to prevent product shortages.

The Biden spending plan further outlines initiatives to enhance public health more broadly, including programs to address gun violence and the opioid epidemic and to continue investment in biomedical research to prepare for future pandemics. Reforms that allow Medicare to negotiate prices with drug manufacturers and impose rebates on companies that raise prices faster than inflation would save more than $500 billion over 10 years, the analysts calculate, but without offering many specifics for implementing such contentious changes.

While the National Institutes of Health (NIH) would see a hefty 22% rise in funding for a $50.5 billion 2022 budget, $6.5 billion of that increase would fund the new Advanced Research Projects Agency for Health (ARPA-H) within NIH, a hot-button proposal that has raised many questions. Designed as a parallel to the Defense Department’s Defense Advanced Research Projects Agency (DARPA), stakeholders already are debating if ARPA-H should reside within NIH or be independent, how it could advance “transformational” research issues for multiple diseases, and how its projects would involve private sector R&D and technology transfer. A 

review of the ARPA-H initiative from the Congressional Research Service

 summarizes these issues and options for going forward.

The administration also seeks an $8.5 billion budget for the Centers for Disease Control and Prevention (CDC), a notable $1.5 billion increase (up 21%) in funding for this usually neglected agency. And the Biomedical Advanced Research and Development Authority would gain $227 million for a $823 million spending plan to build the national stockpile and help prepare for future pandemics.

Congressional debate on FDA’s budget will begin June 10 at a hearing before the Senate Appropriations subcommittee that deals with the agency. Acting Commissioner Janet Woodcock will make the case for the administration’s spending plan and FDA program priorities, and again before the relevant House appropriations subcommittee. But the main decisions on budget support for the agency will turn on broader revenue and spending issues for federal programs as the nation continues to promote economic growth and public health recovery.

The Biden administration supports a notable increase in funding for public health and research as a lead priority for the coming year.

Biden Budget “Wish List” Maps FDA and Health Care Priorities

Syneos Health has launched its Patient Voice Consortium. The Consortium is a cross-functional hub designed to share knowledge, resources, and relationships. These efforts seek to define best practices for gaining patient insights to pressure-test, problem-solve and co-create clinical trial design, communications, stakeholder education, access initiatives and launch strategies.

The Consortium builds on Syneos Health knowledge including patient journey mapping, behavioral science referenced in the Syneos Health subject matter authored book 

 and ongoing DE&I efforts designed to expand access and diversity in clinical trials. The Consortium seeks to learn from the widest range of patient communities possible. Inclusive, transparent methodologies, rooted in shared purpose and bidirectional communications, will guide Consortium efforts.

Syneos Health Launches Patient Voice Consortium

On the heels of its acquisition by AIXIAL, the CRO of ALTEN Group, Cmed Technology announced enhancements to encapsia, its advanced enterprise, cloud-based clinical data system. The updates address decentralized trials capabilities, including the ability to add images and files into encapsiaEDC to facilitate remote monitoring; ability of a user to ‘pin’ their favorite reports/visualizations for immediate access; options for clients collecting eSource data, and a new home visit option.

Cmed Technology Updates EDC System

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.

The shift towards a more comprehensive and efficient form of European collaboration between regulators, health technology assessment bodies and drug developers is evident in a 

 from the European Medicines Agency and EUnetHTA, the soon-to-be-terminated organization of European health technology assessment bodies. 

The trend is apparent in figures on the use of early scientific advice for drug developers in Europe. There have now been 31 'consolidated parallel consultations' completed under the single process for parallel consultation which was revised to ensure that scientific consultation involves both EMA and HTA bodies. This has gradually replaced the former parallel scientific advice procedure with EMA (known as individual parallel consultations) in which medicine developers had to contact member state HTA bodies individually. In fact, so popular has the new process become that the demand from developers exceeded the capacity by HTA organizations to keep up, demonstrating the need—say EMA and EUnetHTA—for "a sustainable framework with adequate financial resourcing." The same joint approach has served in parallel consultations on registry qualification and on the qualification of a project under the EU's Innovative Medicines Initiative, where HTA bodies were fully engaged alongside EMA.

This parallel consultation platform is also being used now to provide guidance on requirements for post-authorization data generation and data collection plans, including registries. This experience with early discussion of post -launch evidence has so far focused on plans with specific products such as advanced therapies or on specific regulatory processes or tools such as conditional marketing authorization, adaptive pathways, or the priority PRIME scheme. The process is proving its value in improving later decision making, but, says the report, "more proactive proposals from developers for discussion in parallel consultation are needed." Better utilization of patient-reported outcomes is also highlighted as a valuable element in evidence generation plans. "This is an area of great importance for future collaboration in view of the developing methodologies and stronger reliance on such data in the context of decision making," it observes.

The report also records recent joint work on methodologies to identify the treatment eligible population, in which experience has been shared on how regulators define therapeutic indications and the impact of their wordings in HTA boards’ definition of who should qualify for treatment. It has been agreed to continue sharing information on how labelling and European public assessment reports are taken account of in decision making, especially regarding subpopulations where limited data is available. This discussion has been closely linked to a search for mutual understanding of the extrapolation concept, particularly in the pediatric population. The report concludes that while the concept of extrapolation or evidence transfer will be relevant in certain developments, such as those affecting small populations, it will require further joint methodological work, and "It is important to understand each other’s reasoning for accepting extrapolation acknowledging the different remits" of EMA and of HTA boards.

The work has also encompassed improving understanding of the similarities and differences between the concepts of significant benefit and added therapeutic value in the context of orphan drugs. No major differences between significant benefit assessment and relative efficacy assessments have been identified, and the conclusion is that early interactions between stakeholders might further diminish differences in the future. "HTA organizations might benefit from reviewing the orphan maintenance assessment reports, as provided on the EMA website," the report recommends. But on unmet medical need, where work has also been undertaken, the conclusion is that it is necessary "to explore further collaborative work on the concept to inform prioritization by different decision makers."

There is a long list of items requiring further discussion. "Priority topics for the work stream" include increased personalization leading to smaller patient populations, smaller trials, less evidence, and increased need to manage uncertainty. The list also features companion diagnostics and other diagnostics for targeting therapeutics but where not directly related to use of specific therapeutics, such as genetic signatures and next generation sequencing. New treatment paradigms such as highly individualized combinations of immune-oncology products targeted through NGS also feature on the "to do" list, as do operational issues around patient access to companion diagnostic tests.

The clear identification of achievements and of outstanding tasks comes at a crucial moment in the evolution of European cooperation on HTA, with EU member states on the brink of agreeing on only a very limited legislative framework to take forward the work conducted by EUnetHTA over the last fifteen years. Within weeks it is expected to become clear whether the road to closer collaboration remains open, or whether national reticences over handing over too much power to the EU will inhibit progress.

A new report from the EMA and EUnetHTA shows a shift towards a more efficient form of collaboration.

Closer European Collaboration on the Ground on HTA and Marketing Authorization—But Under a Political Cloud

In the face of a growing clamor for greater worldwide access to COVID-19 vaccines, biopharma companies are promising to expand distribution of free and low-cost preventives to curb the pandemic globally. Efforts to promote “vaccine equity” and “dose sharing” also aim to limit challenges to international patent protections, as manufacturers maintain that calls to waive intellectual property (IP) rights for pandemic vaccines will stymie innovation and the development of new preventives against COVID variants and future disease outbreaks.

The issue has heated up as the Biden administration announced support for a waiver to IP protection for COVID-19 vaccines under the World Trade Organization (WTO), a move that surprised manufacturers as well as other industrial nations. European leaders at the recent G20 meeting in Rome instead backed voluntary and compulsory IP licensing agreements, technology transfers, and patent pooling arrangements to help low- and middle-income countries access and produce vaccines. The European Commission said it would seek to open global supply chains, expand vaccine production capacity and end export bans on vital supplies, explained EC president Ursula von der Leyen, as part of a program to promote voluntary licensing and knowledge transfer in the context of the TRIPS trade agreement.

 Along with setting these goals, manufacturers pledged to provide more than 1 billion vaccine doses from BioNTech/Pfizer, Johnson & Johnson and Moderna at no- and low-profit rates to lower income countries.

Similarly, the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) announced programs to advance global vaccine equity based on projections that manufacturers willproduce some 11 billion doses this year. The program supports greater dose sharing with other countries, more collaboration to increase vaccine output, eliminating trade barriers that block access to needed materials, and partnering with governments to assist low-income countries distribute available vaccine doses.

In addition to promoting expanded access to vaccines made in the U.S. and Europe, policy makers look to advance biopharma production on a global basis. IFPMA eyes collaborations to increase access to needed supplies of raw materials and to maximize COVID-19 vaccine output without compromising safety and quality.

An initial step is to link vaccine output to available fill and finish operations, an initiative advanced by the COVAX Supply Chain and Manufacturing Task Force, recently formed by leading international health organizations to address current gaps in manufacturing inputs and to ultimately expand production of vaccines and therapies to combat future disease outbreaks. The task force includes IFPMA, the Biotechnology Innovation Organization (BIO), the Coalition for Epidemic Preparedness Innovations (CEPI), the World Health Organization (WHO), the GAVI vaccine alliance, the Bill & Melinda Gates Foundation, and other public health entities. Immediate goals involve coordinating supply chains to identify shortages in raw materials needed for vaccine production and facilitating voluntary technology transfers between manufacturing partners.

Looking to the future, the task force will work to expand vaccine manufacturing capacity in multiple regions by upgrading existing facilities, stimulating public-private investments in vaccine manufacturing innovations, and developing sustainable regional supply chains. The U.S. recently provided $2 billion to support COVAX and additional funding in the near future. At the same time, the Biden administration’s promise of some 80 million vaccine doses for developing nations appeared highly inadequate.

By the time the World Trade Organization (WTO) addresses biopharma IP issues more formally at its year-end ministerial meeting, manufacturers expect that expanded production and distribution of COVID-19 vaccines will be filling global vaccine needs more visibly. Industry has gained strong support forpatent protections from Republicans on Capitol Hill, and the notable success of firms in developing and producing effective COVID vaccines in less than a year has heightened support for IP protections and their potential for further stimulating biopharma innovation. And the fact that the Chinese government expressed enthusiasm for patent waivers only heightens concerns about the impact of such a critical change.

https://ec.europa.eu/commission/presscorner/detail/en/IP_21_2605

https://www.ifpma.org/resource-centre/five-steps-to-urgently-advance-covid-19-vaccine-equity/

Biopharma companies’ efforts to promote “vaccine equity” and “dose sharing” also aim to limit challenges to international patent protections.

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Applied Clinical Trials June 2021