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Applied Clinical Trials November 2021

Proactive, pervasive, and strategic planning lead industry into future.

Biopharma-Academic Collaborations in 2021

The pharmaceutical research industry has seen a recent explosion of publications and conferences focused on decentralized and digital clinical trials. If you search the terms “decentralized versus digital clinical trials,” however, the results will overwhelmingly relate to decentralized clinical studies, as if “digital trial” were not a discreet category. Decentralized and digital clinical trials are are two different things. Digital trials can be decentralized. And decentralized trials can use digital tools. But the terms describe different concepts. Let’s look at the differences.

A decentralized trial is, by definition, one that is done away from a central research facility. Patients complete their clinical trial visit at a remote location, either through virtual tools, such as video calls and patient reported electronic assessments, or by face-to-face interactions. The relevant feature is the 

While digital tools are often used in decentralized trials, digital technology is not their defining feature. Decentralized trials can use paper forms exchanged by mail or through house calls, for instance.

A digital clinical trial uses no paper during the conduct of the study. There may be paper forms associated with the patient prior to study initiation, but they would be digitized and curated as part of the study, with the source document remaining as a paper record. Any study can be digital regardless of the location where the clinical visits are performed. The defining feature is the 

What makes a clinical trial “digital”?

To conduct a digital trial, several components are required:

A digital study begins with translating the written protocol into a set of digital objects and specifications that help feed other digital systems for feasibility studies, modeling, and optimization. They include:

In a digital study, electronic study documents for review and approval generated from the digitized protocol can facilitate a digital IRB submission package and IRB approval.

Linked to the Electronic Medical Record (EMR) system at each research clinic, the eScreening application identifies potential study participants at each site based on the criteria from the digital protocol. These patient records are reviewed by the site research staff, and eligible patients are invited to participate. Artificial intelligence tools can aid the curation process.

Qualified participants are referred to an eConsent system that digitally describes the study, presents the risks, benefits, and alternatives, and then captures patient consent using digitally documents approved by the IRB. This system facilitates required updates, reconsent procedures and post-study surveillance assessments.

Interoperability is major challenge for digital trials. Every clinical trial uses an array of systems to manage both study conduct and data collection during the trial. Each of these systems produces clinical study data and associated case report forms managed in an integrated system. They include virtual visit systems, electronic clinical outcomes assessments (eCOA), medical imaging results, clinical trial management system (CTMS), electronic data capture (EDC) system, adverse event reports, and safety and monitoring systems.

The data captured from the study electronically populates a set of digital case report forms aligned to study protocol and the target EDC system, where they can be reviewed and approval. Once complete, the digital case report forms create a seamless audit trail for data monitoring and verification.

Better identification of potential patients, efficient study site workflows, and simplified study monitoring enhanced by artificial intelligence are among the benefits of digital trials that will ultimately increase access to research studies. Building a digital trial requires an initial investment. Once the foundational systems and workflows are in place, however, the return will continue for many years.

, PhD, is Senior Vice President of Clinical Trial Solutions at ConcertAI

Articles

Decentralized vs Digital Clinical Trials: There is a Difference

ICON plc, a global provider of drug development and commercialization services to pharmaceutical, biotechnology, medical device, and government organizations, today announced that its Accellacare Site Network has expanded in reach and capabilities through new partnerships with six research sites across four countries.

Agreements with Asclepes Research and Olympian Clinical Research in the US, Curiositas ad Sanum and Intermed in Germany, Quironsalud in Spain, and KO-MED in Poland brings the Accellacare network to 112 active locations across eight countries and the entry to two new US states–Florida and California. Through these new partnerships, Accellacare is also enhancing its capability in the central nervous system (CNS) and immune-inflammation therapeutic areas.

ICON Announces the Expansion of its Accellacare Site Network

MediCapital Rent, a medical equipment solutions provider for clinical trials, today announced the company will begin operating under a new name, Emsere.

Emsere provides customers with proactive trial equipment solutions and manages those solutions with a single point of contact for all questions and support. Their global coverage with customs clearance and personalized study tracking of budget, inventory and delivery details provide exceptional, personalized service from study startup to study completion and all phases in between. Emsere’s equipment, supplies and software solutions extend to thousands of products, a rental fleet with over ten thousand devices and serving over 9,000 investigator sites to customers all over the world.

To read more about Emsere and their full range of capabilities, visit the company’s 

MediCapital Rent Is Now Emsere

Yes, you read that headline right. Intrigued? Good, but I have misled you just a little, as this paper 

 about Clinical Trial Diversity, but is not so much “politically incorrect” as “politically agnostic”. What I hope to accomplish in this paper is to briefly define the problem, answer the question “why should I care?” (Hint—it has nothing to do with political correctness), and some actions you may wish to consider for your next trial or submission.

Recently, I was asked to sit on a panel at the Octane MedTech Innovation Forum in sunny Irvine California October 2021. I was certainly happy to escape the 40-degree Minnesota Autumn, but perhaps not so overjoyed at the topic—Diversity in Clinical Trials. In my current role, I increasingly see a push for a diverse population in In Vitro Diagnostic (IVD) trials, but little, if any action in Medical Device trials. With respect to drugs and biologics, my company at least has major initiatives, training, and task forces on the topic. Perhaps the difference between IVDs and devices may be a function of the size of the IVD trials (the last one we were involved in was 10,000 patients), and Device trials tend to be a small fraction of that—in the low hundreds, and sometimes less than 100—but then again, perhaps the IVD people have cottoned on to something device has yet to fully realize, let alone embrace. What’s that? I contend, as I did on the panel, that it is not about being politically correct or “woke”, but rather it should be all about the science. If we are admonished to “follow the science” in other aspects of life, why not in our clinical trials, as after all, is that not what we’re supposed to be doing? Besides that, there are compelling longstanding ethical reasons to pursue 

This is not a new concept. In 2002, nearly 20 years ago, The New England Journal of Medicine published an editorial by T.E. King MD whose opening lines read

”The rational use of a new drug or treatment should be based on the results of controlled clinical trials that are well designed, avoid bias, and include subjects representing the full range of patients who are likely to receive the treatment once it is marketed. In addition to age, sex, diet, underlying disease, and the concomitant use of other medications, race and genetic factors may play pivotal parts in the variability of subjects' responses to a medication.”

As King observed two decades ago, despite the efforts of various government agencies “it is uncertain…whether the participation of minority groups in clinical trials has increased”. As we will see below, the situation remains unacceptable, but there are concrete measures that can be taken to effect meaningful change.

Fundamentally, our clinical trials to date have not been representative of the populations in which the therapy is used. This state of affairs is fundamentally bad science—you cannot expect to see the same results in a diverse heterogenous population that were seen in a relatively homogenous population. It is very simple: if you wish to extrapolate the results of a trial to the entire population who will use the drug or device (or IVD for that matter), then the sample (clinical trial participants) must be representative of that population. To fail to do this is a fundamental sampling error that may lead manufacturers to conclude their product is safe and efficacious when in fact it may not be for the intended population. Much has been made in the past about how good results seen in approval trials are not mirrored when the therapy is released “into the wild” or the general population—and whilst some of that may be related to difference in performance at research sites, off-label use, patient non-compliance, etc., perhaps some of the disparity might just result from initial sampling error.

 Why? Simply because the inclusion and exclusion criteria (I/E) are constructed in such a fashion as to control variables and ensure a degree of homogeneity in the trial population. From a purely scientific perspective, there’s nothing wrong with this—it’s actually good scientific methodology—but it does mean the population studied is not the same as the broader population who may meet one or more of the exclusion criteria: from the perspective of generalizability to the entire population, many approvals trial I/E criteria actually create a sampling error situation.

If we consider published data from Moderna on the COVE COVID-19 study in the US (and this is one of the more diverse studies where a conscious effort was made to represent population racial makeup appropriately)), we can see that 63% of patients were Caucasian, 20% Hispanic, 10% Black, 4% Asian and 3% other.

 US Census Bureau 2019 estimates for the same population breakout nationally are 60.3% Caucasian, 18.5% Hispanic, 13.4% Black and 5.9% Asian—other, including Alaskan Natives, Pacific Islanders etc. account for 4.3%

 We can see in this simple example that Caucasians were over-represented in the COVE study, whilst Blacks and Asians were quite under-represented (by 34% and 47.5% respectively). US FDA’s numbers for new drugs or biologics seeking approval in 2019 puts the Caucasian participation rate at 73%, with most other groups under-represented.

 For specific therapy types, the situation is even more unbalanced – Nazha 

 report on nine advanced-solid-tumor phase III trials comprising 1711 patients—Caucasian participation ranged from 77.2% to 97.5% whilst Black participation ranged from 0-4%.

 These disturbing figures are in the face of a known 28% higher cancer-related mortality rate in Blacks compared to Caucasians.

 In another type of cancer, Caucasian females have a 131.8/100,000 incidence of breast cancer and Blacks 124.7, yet Blacks are 39.7% more likely to die from the disease, despite the lower incidence rate.

 It would seem that appropriate representation in clinical trials should be a priority to ensure therapies developed are effective in the populations that need them the most.

Other examples abound in a variety of therapeutic areas. Just recently a meta-analysis published in May 2021 of over 33,400 open-angle glaucoma clinical trial participant data showed 70.7% of the study population was Caucasian, 16.8% was Black, 3.4% was Hispanic/Latino, and 9.1% consisted of other races/ethnicities, including Asian, Native Hawaiian or Pacific Islander, American Indian or Alaska Native, and unreported.

 For the sake of brevity, however, given the wide play this issue has been receiving in various news media in recent times, perhaps we can just take it as read that there are significant problems in the makeup of many clinical trials in terms of representation of the population in whom the therapy will be employed.

Think about it for a moment—if you release a therapy into a population in whom it has not been adequately tested, doesn’t that make it unproven? Is that ethical? The absolute bedrock of everything we do as researchers must be founded in ethical behavior. Must. Surely there is no debate on this topic? Scientifically, we know there are problems with sampling error—this is especially true in genomics: as part of the research for the panel discussion I was involved in recently I discovered that overall, according to 

 of 5729 samples sequenced to develop therapies for conditions such as prostate and squamous cell lung cancer, 77% (n = 4389) were white, 12% (n = 660) were black, 3% (n = 173) were Asian, 3% (n = 149) were Hispanic, and less than 0.5% combined were from patients of Native Hawaiian, Pacific Islander, Alaskan Native, or American Indian decent.

 How can a manufacturer possibly assure the unsuspecting public that their proposed treatment will work adequately in Asians, Hispanics, or Pacific Islanders for example? The simple answer is they can’t – and that borders on the unethical. How can this be? As I reported in 2014—seven years ago! —12.9% of households speak Spanish at home in the US.

 You could argue that many Hispanics are actually racially Caucasian, and that has some degree of merit, but there are compelling other reasons to actively represent them in clinical trials, as will be discussed later.

The other reason you should care, if questionable ethics are insufficient to sway you (they can, and are, always debated to a degree) is that the US FDA cares, as do other Regulatory Agencies around the world. US FDA issued final guidance on the topic entitled 

Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs Guidance for Industry November 2020

 so you know they’re serious about it, especially as guidances rapidly turn into expectations with FDA. Unfortunately, FDA’s guidance refers explicitly to drugs and biologics, and makes no mention of my own particular specialty, Medical Devices. Despite this shortcoming, the guidance has broad application in the Device field.

On that topic, devices, I have often heard manufacturers observe “I get clinical trial diversity when it comes to drugs, but how does that apply to devices or combination drug/device products? Anatomy and Physiology (A&P) is changed that much by race or ethnicity, is it?” To this position I respond as follows – 1) in order to make that claim (lack of meaningful difference in A&P) you need to have studied it, and per the basic sampling error problem described above that hasn’t happened, 2) Racial and cultural differences can make a huge difference to how a patient interacts with Software as a Medical Device or even cares for an implanted device, 3) cultural activities and foods can vary how a device functions (think for example about long periods of fasting and an insulin pump (Ramadan), and 4) because of differential access to healthcare related to income, mistrust, lack of physical clinics etc. some minorities, especially Blacks and Hispanics present, if they present at all, with much more advanced disease than may be allowed in a clinical trial. On the panel which prompted this paper, one of my co-panelists observed that Blacks presented with far more advanced aortic stenosis than Caucasians, and this made use of their cardiac valves much more difficult – the problem is that in order to get the product approved in the first place, inclusion/exclusion criteria in pivotal studies often excludes really advanced disease, so you really don’t know how it will work in that population. That particular problem is worthy of its own brief discussion.

FDA’s guidance on enhancing the diversity of clinical trial populations has a lot to say about broadening inclusion criteria and easing up on exclusionary criteria to increase minority participation. There remains, however, a major problem in terms of establishing performance goals for a therapy – relevant priors. We’ve all had the experience of going to US FDA and proposing a study design with a particular performance goal in mind, and having FDA come back with “paper X shows this outcome – that should be your goal”. Paper X however, and most likely the research papers you used to develop your own performance goals in the first place, is almost certainly derived from a non-diverse population – that is, after all, the fundamental problem under discussion. Bayesian statistics rely on appropriate relevant priors to be worthwhile, so, if your (or FDA’s) relevant priors are fundamentally flawed by sampling error, how can you then rely on them to develop meaningful performance goals for our product? If you enroll minorities who present with much more advanced disease and/or considerably more co-morbidities due to lack of access to healthcare would you not expect to see poorer outcomes than in a much healthier population? Of course!

Manufacturers want to get their therapy approved—many will benefit from it. FDA wants to ensure it is safe and effective. Relying on flawed non-representative historical data to set performance goals is not going to achieve either outcome in a diverse population. Rather, it exacerbates the situation as manufacturers push to get their therapy into the population where it is most likely to be “successful”—if the relevant prior was in a predominantly Caucasian population, then a new study demonstrating comparative performance should be done in the same population: that is pretty basic science. FDA pushes for a very high-performance bar without considering performance may be lower in a diverse population. And so, it goes on—what to do?

Specific action items that can make a difference

Three simple principles can dramatically change the quality of your next study. There are more things you can do to be sure but trying to “boil the ocean” all at once is usually frustrating and unproductive. Consider these elements and you’ll be well on your way - Design, Sites, and Engagement

Look for truly relevant priors, if they exist

Have the conversation with FDA/other Regulatory Agencies and the validity of relevant priors and negotiate appropriate performance goals based on Real World Evidence in combination with prior research. There’s a whole series of guidances on RWE now available.13

Prospectively plan to do subgroup analysis on Races/ethnicities and have specific enrollment targets pre-specified for those sub-groups (this will help bolster your argument on appropriate performance goal setting)

Also ensure your biostatistician accounts for the likely higher rate of co-morbidities in minority populations – this may require literature searching outside of the specific therapy area/disease state you’re actually studying

Review the FDA Guidance on enhancing Diversity in Clinical Trials to think through inclusion/exclusion criteria to open up the trial to more patients

Reduce follow-up frequency and burden as much as possible—many minority populations have large numbers of low-income members who may not be able to take time off work—or be able to afford to—ensure patient compensation for their time is adequate and/or limited access to private transportation is considered.

Various companies now offer in-home visits specifically in support of clinical trials: consider if some follow-up visits may be suitable for this approach

Plan to go into the communities where the populations you seek to enroll live. Lots of sponsors focus on Academic centers—you may wish to have some of those, but to really reach communities, you need to go into…communities

Work with a CRO with a network of diverse clinics and hospitals with whom they have existing relationships and demographic profiles of the population served

Be wary of smaller and mid-tier CROs who claim to have this on tap—in my experience many don’t, or their “database” is a spreadsheet with a hundred or two sites they have worked with before—I personally work with CROs who have detailed databases with literally thousands of sites with detailed information: ask to see this

Ensure that Investigators are identified that are part of the targetted race/ethnicity are available at the sites in the communities of interest

Consider a decentralized trial—COVID19 gave considerable impetus to the development of supporting technologies and many are now available

Develop a presence online and in social media disease support groups to raise awareness of your particular therapy

Identify and develop KOL/champions of the race/ethnicity targeted; develop explanatory videos to be deployed on your website and other online services/patient groups

Ensure your CRO has diverse project team members who can interact with minority sites, ideally in their language of choice

Ensure informed consent materials are available in the patient’s native tongue—this is basic ethics and required by ISO 14155:2020 5.8.2 (d), 21 CFR 50.20 and other regulations require it—yet here in the US with at least 12.9% of the population speaking Spanish at home some Sponsors still don’t want to provide Spanish language information and consent materials: that’s just wrong. Additionally, different cultures perceive and receive information in different ways, and “health information literacy” is especially poor in minority groups—graphics, video, and other technologies should be explored.

Hands up who wants to do questionable and flawed science! No takers? OK, then as researchers, let’s take representative population sampling seriously and employ 

 scientific methods instead. Is it easy? Well, it’s different, and change is often not easy. Is it necessary? Only if you actually take pride in your work and make people’s lives better with proven therapies.

is the Executive Director of Clinical Development for Syneos Health

King, TE, Racial Disparities in Clinical Trials | NEJM accessed 02 Nov 21

https://www.nytimes.com/2013/07/14/opinion/sunday/do-clinical-trials-work.html accessed 01 Nov 21

2020-COVE-Study-Enrollment-Completion-10.22.20.pdf (modernatx.com) accessed 01 Nov 2021

U.S. Census Bureau QuickFacts: United States accessed 01 Nov 2021. Note Caucasian % is expressed as not including Hispanics.

https://www.outsourcing-pharma.com/Article/2020/02/26/FDA-release-of-clinical-trials-participation-demographics accessed 01 Nov 21

Nazha B, Mishra n, Pentz R, and Owonikoko T, Enrollment of Racial Minorities in Clinical Trials: Old Problem Assumes New Urgency in the Age of Immunotherapy, American Society of Clinical Oncology Educational Book 2019 :39, 3-10

Aizer AA, Wilhite TJ, Chen MH, et al. Lack of reduction in racial disparities in cancer-specific mortality over a 20-year period. Cancer. 2014; 120:1532-1539.

https://seer.cancer.gov/statfacts/html/breast.html accessed 01 Nov 21

Allison K, Patel DG, Greene L. Racial and Ethnic Disparities in Primary Open-Angle Glaucoma Clinical Trials: A Systematic Review and Meta-analysis. JAMA Netw Open. 2021 May 3;4(5): e218348. doi: 10.1001/jamanetworkopen.2021.8348. PMID: 34003274; PMCID: PMC8132140.

Spratt DE, Chan T, Waldron L, Speers C, Feng FY, Ogunwobi OO, Osborne JR. Racial/Ethnic Disparities in Genomic Sequencing. JAMA Oncol. 2016 Aug 1;2(8):1070-4. doi: 10.1001/jamaoncol.2016.1854. PMID: 27366979; PMCID: PMC5123755.

https://www.appliedclinicaltrialsonline.com/view/informed-consent-observations-and-response-fdas-draft-guidance-july-2014 accessed 01 Nov 21

https://www.fda.gov/media/127712/download

Guidance for Industry (fda.gov) https://www.fda.gov/media/124795/download (RWE in Drugs & Biologics) https://www.fda.gov/media/99447/download (RWE in Medical Devices)

Some actions to consider for your next trial or submission.

Politically Incorrect Diversity in Clinical Trials

Emmes, a full service, global clinical research organization(CRO), is launching its new center, Orphan Reach as a ‘rare CRO’.

The new rare disease center will incorporate Emmes’ reputation in public health research across the public sector and biopharmaceutical industry, with the knowledge of Orphan Reach, a UK-based specialty CRO acquired by Emmes in May 2021. The addition of Emmes’ biostatistics, data management, and global clinical trial execution capabilities will enable the center to function as a full, end to end services organization.

The expanded Orphan Reach forms a global specialty center dedicated to the advancement of rare disease research by providing specialized clinical trial design and execution capabilities.

Emmes Launches Orphan Reach

KPS Life, a Functional Service Provider announced the opening of its European Headquarters in Warsaw, Poland.

The office provides a centralized pathway to medical research facilities and access to clinical research professionals in multiple therapeutic areas for clinical drug development.

KPS Life Opens European Headquarters in Poland

Project Manager, Clinical Trials, Raptim Research

Head, Clinical Operations, Raptim Research

The COVID-19 pandemic has forced the clinical trials industry to accept and accelerate the use of digital health technologies to alleviate disruptions and mitigate risks caused by the spread of the virus. As we are aware, more than 75 pharma and biotech companies faced significant disruption in their clinical trials during that time.

Further, approximately 67% of disrupted clinical trials were due to the suspension of enrollment, followed by the delayed start of planned trials at 18.4% and slow enrollment at 14.4%.

 Within the 14.4% of trials affected by slow enrollment, more than 20% of these were due to the lack of availability of sites and investigators.

There were numerous clinical trials in progress during pandemic and the first and foremost challenge was the safety of trial participants. Sponsors/CRO needed to make study decisions about continuing trial recruitment, continued use of the investigational product, collection and management and processing of biological samples, and reporting of serious adverse events (SAEs) in such dire circumstances.

Based on our experience, the following outlines what processes and solutions Raptim Research implemented to mitigate the risk of COVID and conduct our studies per study timelines.

A detailed manual was prepared, which contained full contingency plans with the following case scenarios: if the participant turns COVID-19 positive; if the site staff turns COVID-19 positive; and if the site turns into the COVID hospital. The manual was submitted to both the Independent Ethics Committees (IEC) and Drugs Controller General of India (DCGI) in parallel.

To minimize or eliminate immediate hazards or to protect the life and well-being of research participants and limit exposure to COVID-19 infection, amendments to the protocols were developed following evolving FDA guidelines. It was implemented at the site prior to approval from IEC to eliminate immediate risk of COVID exposure. IEC and regulatory were then submitted with the amended protocol for approvals.

Participant visit was limited to the hospital. Visits where investigational product (IP) was supposed to be dispensed to the participant, then a possibility of delivering the IP to the participant’s residence was explored to minimize exposure. Participants were encouraged to contact the investigator over a video call in case it was required. In the event of rescheduling of visits, it was undertaken as a precautionary measure for COVID-19, these protocol deviations were not considered as violation unless they were found to be impacting participant's safety.

Raptim was involved in oncology study where pharmacokinetic samples of patients were being collected as part of the primary objective of the study. Participants were provided pick up and drop-off transportation at a sanitized and safe conveyance facility.

A secure system was implemented to upload source data, and remote verification was implemented to avoid on-site monitoring visits and thus would not impediment the review process. Backup CRCs (clinical research coordinators) and CRC for entry of data into the CRF were kept as a separate team to avoid delay. The monitoring plan was amended to accommodate remote monitoring visits. IEC were notified of this change and source was verified remotely via "21 CFR" compliant secured platform created by Raptim.

Based on the FDA guidelines, we have implemented following options to facilitate remote monitoring access to clinical site records:

If the site can provide appropriate resources and technical capabilities, consider establishing a secure remote viewing portal that would permit site staff to provide access to the site’s study documentation and/or trial participants’ source documents for the study monitor’s review.

Sites could upload certified copies of source records on an electronic system that contains appropriate security controls. The monitor could access the documents remotely for the purpose of source data verification.

The IEC played a major role during the pandemic to approve changes in the process and protocol amendments, as well as conducted online meetings to accelerate the procedures and provide expedited approvals.

New sites in tier two cities were initiated, which were not in red zone as per the existing guidelines at that time. Non-recruiting sites, which were under the red zones, were closed and new sites were initiated after conducting a remote qualification visit, which was properly documented.

In a single day, up to five participants maximum were scheduled for randomization, keeping the COVID protocol in background to minimize site staff visits and exposure. Follow up visits were synchronized as well. Site staff visits to hospitals, however, were eliminated to maintain safety.

If any questionnaires were to be completed by the principal investigators after physical examinations, that was done via video calling. Here the participant was observed through video calling, and the time of call and questions asked were documented in the source.

Medical monitors assessed the impact of COVID-19 on patient safety and IP dosing compliance and formulated mitigation strategies with project managers and with sponsors medical and operational teams, with the following outlines.

Precautionary measure for COVID-19 for all participants

Precautionary steps education, including social distancing, use of mask, hand washing, avoid gathering, and no touching nose, eyes, face

Use of medical facility if any COVID-related symptoms developed

History taking for COVID19 and general physical examination to rule out signs and symptoms of COVID-19

Separate record maintained of screening procedure for COVID-19 and safety measures taken for COVID-19. COVID screening checklist was created for assessment at each visit

If participant does not have any history related to contact with COVID participant and/or no signs/symptoms, it was considered as normal and no further testing was required. Re-emphasis of precautionary measures

If the test for COVID-19 was mandatory per protocol, the test was conducted for each participant at the time of screening or enrollment

Unless and until symptoms develop, testing for COVID-19 was not allowed for any participant as per the government regulation, and testing was only done as per government modalities

If suspicious of positive COVID-19, the participant was discontinued or dropped from the trial. However, during this time we did not find any suspicious patients.

Screening for signs and symptoms at the time of virtual visit by asking question related to COVID-19 disease. If apprehensive regarding COVID-19, immediate testing was performed and the respective authority was informed 

Suspended or minimized the scheduled in-person visit to avoid contamination from COVID-19. Virtual interim visits were implemented and only in-person screening, study-end visit and emergency visit for AE/SAE if possible and feasible

If participant was infected with COVID-19, but was asymptomatic, they were told to self isolate. If symptomatic, they were admitted in hospital.

Raptim Research was conducting a study for FDA submission in a dermatology indication during the pandemic with sample size of more than 900 patients. The plan was to screen around 1,000 patients to find eligible be and be enrolled. Out of the total randomized participants, 98.04% have completed the study and only 1.96% were withdrawn. Due to continuous patient retention strategy, only three participants were lost to follow up, while 15 participants withdrew consent.

The pandemic impacted the initial plan of recruitment. To cope with challenges, the following steps were implemented:

Initially, the study was planned with 10 sites; later 20-23 sites were approached to conduct the study

Ethics committee submission was done at 20 sites to get maximum sites ready to conduct the study.

Green zones (zero confirmed cases of COVID-19 in the last 21 days) as per the prevailing guidelines were initiated to conduct the study.

Initially, only half the IP was shipped to all sites to keep check on recruitment. Only the higher recruiting sites were re-supplied IP.

To replace the low recruiting sites, the backup sites with good patient population were initiated.

Efforts, such as arranging transportation for visits and regular follow up, were made to retain the enrolled patients and continue until the end of study.

During this time, the discontinuation of one participant was the only choice when they tested positive for COVID-19, as the dermatology trial could not continue because of a 15-day abstinence from treatment, creating a non-compliance of treatment situation

Successful studies conducted during a pandemic require collaboration, transparency and agility, along with a deep understanding of clinical research. With the right knowledge and experience, leveraging strategic partnerships can help to manage and execute clinical operations, even amid the most uncertain times.

The use of electronic tools and technology needs to be elaborated on by the Indian regulatory authority for conducting of clinical trials in pandemic. Solutions to conduct oncology/unmet medical need studies in the country need to be more technology driven. IECs needs to be empowered by the regulatory authority to make appropriate decisions considering the extent of pandemic in their area/city. Raptim Research has implemented tools and technology in order to finish the study with optimum quality and as per the timelines. The blend of human resources and the appropriate use of technology is essential to ride the wave of challenges in conducting clinical trials in the current, and potentially future, pandemic era.

 is a Project Manager, Clinical Trials; and 

 is a Head, Clinical Operations both forRaptim Research,Mumbai,India

https://www.biocentury.com/article/304745/a-biocentury-bio-joint-survey-finds-covid-19-has-forced-many-companies-to-modify-their-clinical-trials

https://endpts.com/covid-19-has-roiled-clinical-trial-plans-around-the-world-raising-concerns-over-the-industrys-future-on-new-drug-approvals/

How one CRO in India quickly implemented processes and technology to mitigate risk

Managing Clinical Trials During the COVID Pandemic

Clinical Ink, a global clinical trial data and technology company, has announced its acquisition of Digital Artefacts, a digital endpoint-based technology company with a modular platform for complex cognitive, behavioral, and physiological data capture.

The combination of Clinical Ink and Digital Artefacts will provide benefits including:

Scientifically validated neurocognitive assessment and research tools (50+ modular, self-administered assessments)

Combination of standardized eCOA scales/assessments with digital endpoints to produce quantitative patient outcomes

Trial specific remote active and passive behavioral assessment, including wearable and sensor data

Precision Real-World Data and insights across complex therapeutic areas for which cognition is an endpoint

Scaled delivery capabilities in logistics, helpdesk, project management, and device acquisition/support for DCTs

Clinical Ink Acquires Digital Artefacts

Analysis Group announced the publication of research examining the US Food and Drug Administration's (FDA's) commentary on the use of real-world evidence (RWE) in successful oncology product approvals between 2015 and 2020.

A team of researchers from Analysis Group, Pfizer, and the Dana-Farber Cancer Institute analyzed 133 original and 573 supplemental oncology new drug application and biologics license application approvals to identify the attributes of a successful RWE study that contributes to an accelerated or full drug approval.

Drug developers may prepare stronger submission dossiers for RWE studies by drawing on the research's key insights:

to confirm appropriate data sources and whether the RWE study should be designed as a natural history study for contextualization, or as an external control study for comparison with the pivotal trial. A hybrid study design to combine trial with external control data through Bayesian or frequentist methods, and ambi-directional RWE data collection (both prospective and retrospective) are study designs worth considering.

 to ensure that real-world data (RWD) are high quality and fit for purpose. Although chart review was the most common source for RWE, the FDA also commented that data from such studies could have limited generalizability and are subject to selection bias.

Align the RWE and pivotal trial populations

 by matching on trial inclusion and exclusion criteria to the extent possible and adjusting for the remaining imbalance in baseline characteristics with propensity score weighting methodology, such as inverse probability treatment weighting. Critically, the study protocol needs to be developed 

Describe methods to minimize residual confounding and unmeasured confounding

, including appropriate index date and reduction in missing values. If imputation methods are used to address missing values, validation of the imputation algorithms is recommended. The impact of unmeasured confounding should be evaluated through quantitative bias analysis.

The analysis, "Real-world Evidence in Support of Oncology Product Registration: A Systematic Review of New Drug Application and Biologics License Application Approvals from 2015-2020," was published in 

, an American Association of Cancer Research journal

 Coauthors include Bhakti Arondekar, Bryon Wornson, and Alexander Niyazov of Pfizer; and George D. Demetri of the Dana-Farber Cancer Institute and the Ludwig Center at Harvard Medical School. Funding for the work was provided by Pfizer.

Clinical Cancer Research Publishes Review of Regulatory Real-World Evidence in Successful Oncology Product Approvals

With the evolving regulatory landscape in Oncology there is an increasing emphasis on using patient-reported outcome (PRO) data to provide additional information on clinical benefit of an investigational treatment, beyond the traditional survival and tumor response endpoints. With this new regulatory landscape comes the responsibility of those designing and conducting clinical trials to not only collect what is meaningful to patients, but to do so in a way that does not add burden to patients’ already demanding lives. Using example PRO strategies based on current recommendations for cancer clinical trials and our own operational data, we analyzed how long it takes patients to complete PROs and explored strategies for implementing PROs in a way that is not only easy but motivating for patients. In reviewing patient data on preferences on reporting symptoms, we shed light on the importance of symptom reporting in Oncology trials and how we can make clinical trials worthwhile for oncology patients. In considering new regulatory guidances that recommend a variety of PRO measures and more frequent administration of these measures, it is imperative to implement strategies for reducing patient burden. 

Considering patient burden when incorporating patient reported outcomes in oncology

It is no secret; We as an industry need to do better for our oncology patients as they embark on clinical trial journeys. How do we do better? We need to measure what is important to patients and make it as easy as possible for patients to participate in clinical trials.

When measuring what is important to patients, we need to look beyond traditional endpoints in order to get a more complete and accurate picture of treatment benefit for patients. In recent years, there has been growing expectation that indicators of clinical benefit beyond survival and tumor responses, such as a patient’s quality of life and disease symptoms, be measured and incorporated into the risk-benefit evaluation for cancer trials. These can be most effectively evaluated through the use of patient-reported outcome (PRO) measures, where information on the impact of disease and treatment is obtained directly from the patient. With mounting regulatory-driven patient-centered initiatives, such as the numerous programs of the FDA’s Oncology Center of Excellence (OCE), the new focus on PROs in oncology is not only to better evaluate drug efficacy, but to make sure that the patient's voice is heard. Understanding what matters to patients during the course of their disease and treatment and creating thoughtful strategies on how to measure these concepts is imperative if we are to create drug development programs that are truly patient-focused.

The recent emphasis on patient-focused drug development continues in the oncology landscape with the FDA’s new draft guidance for industry on “Core Patient-Reported Outcomes in Cancer Clinical Trials”, issued by the OCE, Center for Biologics Evaluation and Research (CBER), and Center for Drug Evaluation and Research (CDER).

 Although still in draft form, this guidance helps solidify years of FDA COA public workshops and literature best practices in PRO data collection in oncology. It provides industry guidance on how to best incorporate core PRO measurements into oncology clinical trials in efforts to correct the historical “heterogeneity in PRO assessment strategies [that] has lessened the regulatory utility of PRO data from cancer trials”. In addition to trial design and labelling considerations, the guidance recommends five core PRO concepts that should be collected in oncology clinical trials: 1) disease-related symptoms, 2) symptomatic adverse events, 3) overall side effect impact summary measure, 4) physical function, and 5) role function. While these core PROs include essential measures of symptoms and quality of life, it is important to note that measuring additional concepts that are important to patients outside of these core PROs may be warranted in order to truly measure what is important to patients (i.e., impact of cancer and treatment on their personal relationships, family, financial stability, etc.).

With this new draft guidance on core PROs in oncology, and with detailed guidance on how to incorporate the patient voice in drug development with CDER’s Patient-Focused Drug Development program

, we are encouraged to determine what is important to oncology patients. In doing so, it is imperative that we keep the patient in mind not only when choosing which PRO measures to include, but also when deciding 

 they are implemented into the clinical trial strategy. One key area for consideration is patient burden. The life of a cancer clinical trial participant is not easy. Debilitating cancer symptoms, treatment side effects, long travel times to clinical trial sites, all in addition to their everyday responsibilities such as work, childcare, and household tasks, make life extra difficult for these patients. Therefore, while we may have a better picture of what PROs to collect in clinical trials, how do we make completing these PROs motivating instead of burdensome? What is the right balance between collecting a thorough picture of the patient’s symptoms, experiences, and quality of life, and not over-burdening patients with PROs?

First, let’s consider how long it takes patients to complete PROs. The FDA’s new draft Oncology PRO guidance specifically states that sponsors can collect additional PROs beyond the five core PROs identified, but that additional PROs should be “carefully considered to minimize patient burden and improve the quality of data collected by focusing on the most meaningful and measurable outcomes.” This is not to discourage the collection of additional measures that are important to the specific patient population being studied, but to emphasize that PRO selection should be thoughtfully considered.

Following the FDA’s new draft Oncology PRO guidance, we created an example PRO strategy for a study in Multiple Myeloma and a study in Breast Cancer and evaluated the time it would take to complete assessments in each example (Table 1). The table does not represent the frequency of each PRO administration but represents the amount of time it would take a patient to complete all study PROs. The new draft guidance encourages thoughtful consideration of assessment frequency, recommending more frequent assessments in the first weeks of treatment. Although each assessment frequency is unique and can be different depending on research objectives, our example is modeling the scenario of the highest patient burden where patients would complete all PROs at a single study visit (or at the same time). The second column in Table 1 shows the time it takes to complete each assessment according to the license holder and/or author’s website for that assessment (i.e., eProvide), which is usually based on paper administrations. The examples show an estimated time of completion around 16 minutes to complete all PROs in the Multiple Myeloma example and around 18 minutes to complete all PROs in the Breast Cancer example. We then explored the amount of time to complete these assessments when implemented electronically (ePRO). The third column shows the average time it takes to complete each assessment via ERT’s eCOA devices, with the number of administrations noted in Column four. For both examples, the average time to complete is about ten minutes.

BPI-SF = Brief Pain Inventory - Short Form; EORTC QLQ-C30 = EORTC Quality of Life Questionnaire - Core Questionnaire; EORTC QLQ-MY20 = EORTC Quality of Life Questionnaire - Multiple Myeloma Module; FACT-B = Functional Assessment of Cancer Therapy - Breast; Functional; FACT- Item GP5 = Assessment of Cancer Therapy - Item GP5; PRO-CTCAE = Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events; N/A = Not Available

ƚ The number of forms does not represent all forms ever deployed, but the forms on active ERT studies collected as of the date of analysis (Aug 3, 2021).

* Electronic completion time data not available. Estimated completion time from copyright holder is used: 

https://www.facit.org/measures/FACT-Item-GP5

# Number of items in PRO-CTCAE varies among studies. License holder/author-reported estimated time is based on 20 items. Number of items in electronic completion time data is unknown.

While the advantages of ePRO in Oncology clinical trials has been shown across numerous contexts (i.e., preferred and recommended by patients, reduces missing data, increases quality of life and survival

), our data extends these advantages by showing ePRO may also decrease patient burden by reducing time to complete assessments. In a recent PinkSheet publication, a medical officer in the FDA’s Division of Oncology II was cited as recommending capping assessment items and time spent completing assessments to 50 items and less than 10 total minutes per visit.

 With total time to complete assessments over 10 minutes according to copyright holder estimates, the reduced completion time using ePRO suggests electronic implementation may be an important method for reducing patient burden. Indeed, according to the FDA’s new draft Oncology PRO guidance, ePRO is stated as a method to decrease patient burden, with emphasis on how ePRO allows for assessments outside of the clinic. The ability of ePRO to support remote assessment can minimize time spent in transportation and during a visit to a clinic and is increasingly being utilized to allow for decentralized or hybrid trials. Our data show that not only does ePRO have the potential to reduce patient burden by offering completion in a more convenient remote setting but may also reduce the time it takes patients to complete assessments. The reasons for faster completion time using ePRO versus paper need to be further explored but could include ePRO’s engaging interface or single-click page turning.

Although the time it takes to complete PROs may be minimal, due to busy lives or debilitating symptoms, 10 minutes of PRO completion may still be a lot to ask. Therefore, an additional step we can take to minimize patient burden related to PRO completion is providing training for patients on the importance of PROs. Content can include education on their role and responsibilities in the study, which PRO assessments they will complete, the importance of compliance, their valuable role in the trial, and what to expect in a clinical trial. Training not only ensures that patients understand the importance of reporting honestly and accurately but helps them understand the valuable contribution they are making by participating. In appreciating their contribution during training, we align with many patients who have an intrinsic motivation to contribute meaningfully to science. Although not the only reason for participating, an altruistic desire to advance therapeutic options has been found to be a major motivator for patients in cancer clinical trials.

 It is important to let patients know we are listening and responding to their needs. By adding such elements to training, instead of seeing PRO assessments as burdensome, patients may see them as an important way to communicate their symptoms and experiences. Clinicians and other site staff can also benefit from training on the importance of PROs and how they will be utilized within the endpoint strategy of the clinical trial. Clinicians may traditionally put more emphasis on objective clinical trial endpoints, like imaging, which could undervalue the importance of PROs. Patients might notice such an attitude. Therefore, training is important for both patients and clinicians, and this importance was noted frequently by patient advocates and experts alike in this year’s 2021 FDA COAs in Cancer Clinical Trials Public Workshop.

Finally, let’s consider further the fact that patients 

 to report on their symptoms. A long instrument is not necessarily burdensome if it helps the patient tell the story that matters to them. For example, oncology patients reported minimal response burden upon completing a large battery of PRO measures (176-180 items), with almost a third of patients indicating that more questions could have been asked.

 However, a portion of patients (22%) noticed questions that were repetitive or ones that were not relevant to their concerns, highlighting the importance of carefully selecting relevant and meaningful PROs. In a recent published data set, we found that almost all surveyed participants (95%) with a self-reported history of cancer would want to report their symptoms during a clinical trial, and most indicated that there would be significant benefit to them (“very much” or “quite a bit”) in doing so.

 With the term “symptoms” being used generally, this preference for symptom reporting likely includes symptoms of their disease and treatment (i.e., treatment side effects). Additionally, most respondents preferred a higher frequency of reporting (as symptoms occur or daily) versus a lower frequency (weekly), and there was a significant preference to report symptoms in an electronic diary versus either a paper diary or verbally to their doctor during study visits (Figure 1). Although patient burden is often raised as a concern when including PRO measures in oncology trials, this data shows that patients feel there is benefit of reporting symptoms and want to do so frequently. Further, the willingness of patients to frequently report their symptoms was shown in a recent publication reporting high compliance (91%) of weekly electronic PRO completion over a year-long period.

Adapted by Peechatka et al., 2020, N=166, 57% female, age range 18-87 years (mean=61 years)

So, how do we incorporate PRO assessments without increasing patient burden? Be thoughtful and targeted when developing a PRO strategy. Consider FDA’s five core PRO categories released in their new draft Oncology PRO Guidance and align frequency of reporting with research objectives. Avoid repetitive questions, focus on the most meaningful and measurable outcomes, and consider whether the item content justifies extending the reporting time. In training both patients and site staff, genuinely recognize the value of learning from the patient experience. Use electronic implementation of PROs as a strategy for minimizing the time spent on completing assessments and to align with patient preference for electronic reporting. Finally, take the opportunity to explore content directed at measuring what matters most to patients.

FDA Draft Guidance for Industry: Core Patient-Reported Outcomes in Cancer Clinical Trials. June 2021. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/core-patient-reported-outcomes-cancer-clinical-trials

FDA CDER Patient-Focused Drug Development. Aug 2021. 

https://www.fda.gov/drugs/development-approval-process-drugs/cder-patient-focused-drug-development

Ring et al., 2008. A randomized study of electronic diary versus paper and pencil collection of patient-reported outcomes in patients with non-small cell lung cancer. Patient 1(2):105-113.

Velikova et al., 1999. Automated collection of quality-of-life data: a comparison of paper and computer touch-screen questionnaires. J Clin Oncol, 17(3):998-1007.

Mody et al., 2021. Electronic patient-reported outcomes monitoring during lung cancer chemotherapy: A nested cohort within the PRO-TECT pragmatic trial (AFT-39). Lung Cancer 162:1-8.

A new regulatory landscape comes with the responsibility of designing and conducting trials that not only collect what is meaningful to patients, but also don't add burden to patients. 

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