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Clinical Vice President, Internal Medicine, Signant Health

Recent FDA draft guidance on core patient-reported outcomes (PROs) in oncology clinical trials

 lays out a framework for effective patient-reported outcome measure (PROM) selection and implementation. This may be important in increasing the use of PRO data in oncology medication labeling in the US, where, historically, labeling claims based on PRO data have rarely been included. The reporting of PROM endpoints on drug labeling is valuable to both the patient and the prescribing physician in informing risk/benefit discussions beyond tumor response and survival endpoints. The lack of PRO-related labeling is clearly illustrated by the fact that only three out of 85 drug approvals in oncology submitted to FDA between 2010 and 2016 included PROM-related labeling claims.

While this may be related to trial design limitations (e.g., single-arm and open-label studies), it may also reflect weaknesses in clinical outcome assessment (COA) measurement strategies typically used in oncology research.

FDA’s draft guidance addresses two areas of potential weakness in current COA measurement strategies for oncology trials.

In oncology trials, PROMs are often implemented at clinic visits just ahead of starting each cycle of treatment. While administratively convenient, this is the time at which patients are feeling well enough to receive the next cycle of treatment, so this strategy may fail to measure the impact of treatment in the earlier stages of each cycle when treatment-related side effects are likely to be most pronounced. Just measuring at cycle start may provide a biased view of treatment toxicity.

The draft guidance stresses the importance of selecting measures that are highly specific so that treatment effects can be understood more granularly. FDA identifies five core measurement domains of interest: disease-related symptoms, symptomatic adverse events, an overall side-effect impact measure (single item), physical function (aspects such as walking, lifting, and reaching that are considered important for independent functioning), and role function (impact of a treatment on the ability to work and carry out daily activities). Not all commonly used instruments provide scores or subscores that provide the level of specificity required to separately assess these core areas.

In this article, we explore these two areas in more detail.

The draft guidance recommends more frequent measurement during initial cycles, with fewer later on (see Figure 1 below). In particular, FDA indicates that symptomatic adverse events, the overall impact of side effects, and physical function should be measured frequently at the start of treatment, before moving to less frequent cadences later in the treatment and subsequent follow-up periods. This schedule helps to mitigate chances of missing the incidence and severity of items associated with these domains, as may be the case if measuring only at the start of new treatment cycles.

This increased frequency of assessments raises several practical questions:

If these domains are measured by subscales of existing instruments, is it valid to use only the subscale items at these more frequent timepoints?

To enable this more frequent measurement schedule, patients would need to complete PROMs at home. Is this practical when patients are experiencing challenging treatment-related symptoms and side effects?

Should measurement timings be adjusted if a treatment cycle is delayed due to side effects?

It would be burdensome for the patient if we implemented the full 30-item EORTC QLQ-C30 questionnaire (a frequently used general oncology PROM) on a weekly basis when we only need to measure the physical function subscale (five items). However, discarding the other items within an instrument might impact the psychometric properties of the subscale, so it will always be important to verify that this approach is acceptable and valid with the instrument owner.

In the case of the QLQ-C30, the subscales are valid for independent use as discrete “item lists.” Therefore, referring to the schedule of assessments in Figure 1, the five physical function items from the QLQ-C30 could be applied independently on a weekly basis to enable more frequent assessment of this core domain. When doing so, it will be important to include the complete set of physical function subscale items, represent them in the same order as within the full instrument, and apply the same scoring and missing data rules as defined for the subscale within the full instrument.

methods to lessen patient burden should be explored, including use of electronic PRO capture that may allow for assessments outside of the clinic,”the more frequent assessment schedule may be perceived as burdensome when the effects of treatment are particularly compromising. Could this lead to increased missing assessments? In a qualitative interview study of oncology patients, it was identified that certain days within typical treatment cycles are the most difficult, with one patient saying: “Days three to six were my ‘dark’ days, and I did not leave my bed, speak to anyone, or even eat any food.”

Despite this, participants in this qualitative study did not feel that this would deter or inhibit them from completing PROM instruments on electronic devices. For example, one patient stated, “You can be bad, but not so bad that you can’t use nothing at all...I would make the effort.”

Being sensitive to this is important, and we should consider guiding principles for ePRO implementation to limit burden and aid completion rates, including:

Ensure instruments are as short as possible to measure the domains of interest. Computerized adaptive tests may provide an approach to minimize the number of questions.

Implement multi-day completion windows, so that patients can elect to complete assessments on a subsequent day if they do not feel able to complete their PROM immediately.

If implementing more than one PROM, enable patients to come back later to complete the second instrument.

Consider a bring-your-own-device (BYOD) option. On days when the patient is feeling unwell, they may be interacting with their own mobile device but are less likely to have the trial device on hand.

Collect reasons for missing assessments so that intercurrent events, such as feeling too unwell to complete the PROMs at any given time, can be taken into account in the analysis plan, the interpretation of the results, and the optimization of future trials.

Implement PROM completion compliance strategies, such as patient alarms/reminders, site notifications, and reports, to monitor and proactively encourage completion behavior.

In oncology trials, it is common for physicians to implement delays in treatment when a patient has not recovered sufficiently from the previous cycle of treatment. When collecting PROMs at the site, this typically means postponing PROM completion to coincide with the new cycle start date. However, with the change in focus to more frequent measurement, we recommend that the trial objectives will most likely be met when the measurement schedule is not adjusted to allow for changes in the start times of subsequent treatment cycles, especially when the period of frequent measurement is long enough to comfortably cover several cycles. 

Separate and independent assessments of each of the five core domains requires careful appraisal and selection of the measures to be used. To measure each domain using a single scale, or a subscale of a broader instrument, questions should all be related to the domain and comprehensive enough to encompass all the meaningful elements of that domain.

While this sounds straightforward, nuances in the definitions of domains measured by different PROMs mean that researchers should carefully inspect instruments to ensure the FDA-defined domains are accounted for. Let’s consider two examples.

Example 1. NSCLC-SAQ (Critical Path Institute, Tucson, AZ)

The NSCLC-SAQ is a seven-item symptom assessment questionnaire for non-small cell lung cancer (NSCLC)

, developed specifically to assess disease-related symptoms across five concept areas (see Figure 2 below).

The qualitative work used to identify the set of disease-related symptoms that are meaningful to NSCLC patients

 provides strong evidence of the measure’s relevance and content validity. The measure only focuses on disease-related symptoms, so in addition to content validity, it also satisfies the requirement for specificity. For this reason, it is not surprising that this instrument was cited as an example of a suitable instrument to measure disease-related symptoms in the FDA draft guidance.

Example 2. FACT-B, Breast Cancer (FACIT Group, Ponte Vedra Beach, FL)

The Functional Assessment of Cancer Therapy - Breast (FACT-B) is a 37-item questionnaire that is used to measure five domains of health-related quality of life in breast cancer patients: physical well-being, social/family well-being, emotional well-being, functional well-being, and a breast cancer subscale.

 The naming of these domains differs from FDA core domains, and they represent slightly different concepts. For example, physical well-being is not the same as physical function.

If we examine the subdomain of functional well-being, we find that the first three items of the subscale measure one’s ability to work and whether that work is fulfilling, as well as one’s ability to enjoy life. Some of these map to FDA-defined domains—for example, ability to work may be a component of a measure of role function. However, the ways that the current subscales and their scoring are defined do not facilitate specific measures of one or more core domains as identified by FDA.

However, the FACT instruments are well validated and widely used. With that in mind, it may be possible and desirable to reorganize their subscale structure to measure FDA-defined core domains. This takes us to considerations around instrument adaptation.

As described, to meet FDA draft guidance around specificity to measure the five core domain areas, it is important to select PROMs carefully. In some cases, it may not be as simple as implementing an instrument in its off-the-shelf format. Instead, it may require some degree of adaptation. We discuss two examples ahead.

As described, while the subscale construction of the FACT-B does not appear to map directly to the FDA’s core domains, the instrument and its items are well-validated. To satisfy the draft FDA guidance, researchers may consider working with the scale author to validate an alternative subscale based on existing items within the instrument. As a hypothetical example, we might consider developing a specific measure of disease-related symptoms by grouping items from the physical function subdomain (e.g., lack of energy, pain, and nausea) along with items from other subdomains (e.g., shortness of breath, swelling/tenderness of the arms). This would require working with the scale author and evaluating the psychometrics of the new subscale.

Adding to existing instruments using item banks

Item banks are databases of individual validated PROM items. It is possible to use items banks to assemble tailored PROMs more rapidly for specific populations and measurement domains. Most applicable to oncology research are the PROMIS (Northwestern University, IL) and EORTC item banks. The latter, for example, contains around 1,000 items, with many translated in up to 100 languages.

A good illustration of this approach is the use of the EORTC item bank to supplement items in the EORTC’s core instrument (QLQ-C30), to ensure full coverage of all important items in order to measure drug benefit in a set of rare hematological stem cell disorders.

 Instrument developers identified the symptoms and impacts important to patients with these diseases, and used the EORTC item bank to map these to concepts that were not contained within the QLQ-C30. They conducted further testing in patients to confirm the suitability and content validity of these additional selected items. We may see this type of approach more often as we carefully and strategically consider PROM selection for future oncology trials in light of the FDA draft guidance.

Core Patient-Reported Outcomes in Cancer Clinical Trials 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/core-patient-reported-outcomes-cancer-clinical-trials

Gnanasakthy, A.; DeMuro, C.; Clark, M.; et al. Patient-reported Outcomes Labeling for Products Approved by the Office of Hematology and Oncology Products of the US Food and Drug Administration (2010-2014). 

https://pubmed.ncbi.nlm.nih.gov/27069082/

Gnanasakthy, A.; Barrett, A.; Evans, E; et al. A Review of Patient-reported Outcomes Labeling for Oncology Drugs Approved by the FDA and the EMA (2012-2016). 

https://pubmed.ncbi.nlm.nih.gov/30711065/

Mowlem, F.D.; Sanderson, B.; Platko J.V.; et al. Optimizing Electronic Capture of Patient-reported Outcome Measures in Oncology Clinical Trials: Lessons Learned from a Qualitative Study. 

https://pubmed.ncbi.nlm.nih.gov/33274651/

McCarrier, K.P.; Atkinson, T.M.; DeBusk, K.P.; et al. Qualitative Development and Content Validity of the Non-small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ), a Patient-reported Outcome Instrument.

https://pubmed.ncbi.nlm.nih.gov/27041408/

Bushnell, D.M.; Atkinson, T.M.; McCarrier, K.P.; et al. Non-Small Cell Lung Cancer Symptom Assessment Questionnaire: Psychometric Performance and Regulatory Qualification of a Novel Patient-Reported Symptom Measure. 

https://pubmed.ncbi.nlm.nih.gov/34567289/

Functional Assessment of Cancer Therapy - Breast. FACIT. 

EORTC Quality of Life Group Item Library User Guidelines, First Edition. 2022, 

Bell, J.A.; Galaznik, A.; Pompilus, F.; et al. A Pragmatic Patient-reported Outcome Strategy for Rare Disease Clinical Trials: Application of the EORTC Item Library to Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia. 

https://pubmed.ncbi.nlm.nih.gov/31218454/

Articles

Examining the two areas of weakness cited in FDA draft guidance.

Optimal COA Measurement Strategy in Modern Oncology Trials

announced the addition of Dr. Scott Smith as SVP, global therapeutic area head of hematology. Prior to joining Parexel, he held several positions at Loyola Medicine's Cardinal Bernardin Cancer Center.

announced the appointment of Ramees Raja as global energy manager. Previously, he spent the previous two years as energy manager for Muntons Pic.

announced that Seema Verma has been named senior vice president and general manager, life sciences. Most recently, she served as a senior advisor to private equity firms Cressy & Co. and TPG.

revealed that they have hired Erica Prowisor as SVP, patient and provider networks. Before this, she spent time as the global head of recruitment and retention for IQUVIA.

appointed Dustin Owen as the new CEO. Previously, Mr. Owen Thermo Fisher Scientific/PPD, where he was SVP and general manager of accelerated enrollment solutions.

announced the hiring of three executives. Nick Campbell joins as chief commercial officer, Nick Spittal as chief operating officer, and Steph Anderson has been promoted to chief of staff.

announced the appointment of Julie Springer as the company’s first chief marketing officer. Julie joins ArisGlobal following tenures as CMO at Fast Radius as well as at TransUnion, where she helped lead the company on a significant transformation journey and highly successful IPO.

named SAFIRA Clinical Research Co-founder and clinical trial technology innovator Willie Muehlhausen Scientific Advisor, offering 20 years of experience.

opened a new clinical research center in Austin, TX. According to the company, this new center is three times larger than the original location at their headquarters.

The latest people and business news from the past month, all in one place.

People and Business News – 5/23

Senior Director, Therapeutic Strategy Lead, Rare Disease, Worldwide Clinical Trials

This year marks the first time multiple gene therapies for the same non-oncology rare disease may be market authorized in the United States. They include treatments for beta-thalassemia, hemophilia B, and potential treatments for sickle cell disease.

With the FDA predicting the approval of 10 to 20 cell and gene therapies (CGT) every year starting in 2025, the industry is at a significant turning point.

 Some of these therapies can potentially create durable change in the lives of vulnerable patient populations. Therefore, clinical trials to develop these advanced therapeutics carry a different risk tolerance—and a different value assessment—than many other product types. For example, clinical holds in cell and gene therapy programs can rightly be viewed as valuable “risk mitigation” measures, rather than harbingers of failure.

There are many ways in which cell and gene therapies require industry stakeholders to alter their traditional mindsets regarding risk, such as their opinions about the possible value of innovative trial designs and clinical holds. Thus, this article will explore the following:

Why clinical holds in CGT trials must be viewed differently than in other types of development programs.

How innovative designs benefit early-phase CGT development by uncovering the most promising versions of a treatment.

Key takeaways from FDA’s recent guidance on early-phase CGT umbrella trials exploring multiple versions of a product.

Clinical holds: Responsible risk moderation

The number of FDA-imposed clinical holds is rising swiftly, driven partly by an increasing number of innovative technologies and treatment modalities.

 While clinical trials to develop a CGT represent a relatively small minority of the development space, about 40% of clinical holds are for these programs.

Traditionally, of course, clinical holds are considered undesirable. Not only do these holds delay programs, but they also often negatively influence investors, sites, and patient perception and participation. Yet, despite the logistical and financial complications they may cause, clinical holds on CGT trials should be viewed as responsible, risk-moderating measures that help ensure the ultimate development of safe and efficacious new treatments. These holds are not necessarily an obvious sign that a program is less than promising. Rather, they indicate that we are all paying close attention to each participant from the relatively small and often vulnerable patient populations involved in these trials.

This perspective may not be intuitive for all observers. However, given that some CGTs offer what are intended to be durable treatments for diseases with few other options, an abundance of caution is appropriate. In any study, the risk formula could be described as Risk = Impact x Probability. In the case of CGTs, the “impact” portion of the equation is often high and durable. So, even if the “probability” is low, responsible parties rightly hit the brakes at the first sign of a potential problem.

One industry editorial notes, “A clinical hold can be nothing more than a right-angle check—a ‘time-out’ taken to check your work. It can even be self-instigated by the sponsor company.”

Indeed, out of the above-mentioned abundance of caution, some sponsors voluntarily pause a trial when an unexpected outcome is detected. For instance, sponsors voluntarily delayed a study examining a gene therapy for hemophilia A after a participant developed deep vein thrombosis. FDA subsequently added, then lifted, its own clinical hold.

 Another sponsor voluntarily paused its Phase I/II trial of a gene editing therapy for sickle cell disease after the first patient dosed experienced a serious adverse event.

Being put on clinical hold by FDA is not necessarily a prognosticator for whether a product will be found unsafe. Research indicates that the majority of FDA-imposed clinical holds are eventually lifted.

 A recent meta-analysis of 255 trials involving the development of adeno-associated virus (AAV)-vectored gene therapies saw 30 clinical holds, 18 of which were related to toxicity findings.

 In fact, each of the past two years saw the approval of a gene therapy that had previously experienced an FDA-imposed clinical hold, including Skysona and Hemgenix.

As the number of clinical trials for CGTs proliferates, sponsors may want to reconsider how they approach the possibility that a study could—or should—be placed on clinical hold. A proactive and collaborative mindset may prove beneficial. For example, sponsors could proactively plan for a clinical hold in the trial timeline. Likewise, they could include the concept of a clinical hold—along with some context—in their patient-facing and family-facing study information. Sponsors could note that a clinical hold is a common measure taken in these drug development programs, and that it reflects careful and continuous oversight of the well-being of every participant.

Clinical holds don’t necessarily indicate gene therapies are unsafe but that the industry is developing them thoughtfully and carefully. There is value in truly examining every meaningful event with every patient. By encouraging an abundance of caution, clinical holds can help promote confidence in the groundbreaking therapies that come out the other end of the pipeline.

Improving efficiency with innovative designs

Today nearly 80% of gene therapy products in clinical development are for the treatment of rare diseases or cancers.

 These are complex programs, many with inherent recruitment challenges, which unfortunately can extend timelines. While every corner of clinical development could benefit from increased efficiency, CGT programs serving rare disease and oncology patient communities have some of the most pressing needs.

Fortunately, recent years have seen notable progress in master protocols, specifically in the areas of rare diseases, pediatrics, and precision oncology.

 These master protocols, which include basket trials, umbrella trials, and platform trials, are novel designs that investigate multiple hypotheses through concurrent sub-studies. Basket trials, for example, test a single treatment in several different patient populations simultaneously, and have become rather commonplace in the development of precision anticancer treatments. Conversely, umbrella trials enable simultaneous testing of multiple versions of a given product in a single patient population.

In other words, several potential treatments for one disease are tested directly against each other in umbrella trials. By uncovering which versions of a treatment in development are the most promising, the use of umbrella trials in early-phase clinical trials has the potential to decrease development time and increase the odds of an ultimately successful product.

However, umbrella trials remain somewhat underutilized despite the value they can bring to product development.

 In part, that is because they are tricky to design in a way that enables confident submission and interpretation. They require carefully crafted master protocols—as well as a different mindset regarding protocol creation.

In nearly any other setting, specificity is the aim of protocol writing. The more specific the protocol, the better for quality assurance and data interpretability. But that deeply ingrained wisdom must be selectively set aside to construct an effective master protocol.

Master protocols may seem more daunting to write because they must strike a delicate balance between specificity and flexibility. It’s important to know where the protocol needs to provide space instead of tight confines, so those elements can be written in a way that offers the freedom to operate each arm of the trial as necessary.

Think of a master protocol like a Mad Libs® game in which you don’t know exactly 

 adverbs to use, but you know that adverbs are needed. Likewise, when sponsors begin to develop the protocol and IND submission package, they may not know precisely which variants they’ll pursue within the various arms of a study. Still, they’ll want to know what 

of elements may mark one variant from another. That is where to build in flexibility, so each variant can be included per the exact language of the master protocol. Rather than describe each variant precisely, the master protocol should employ intentionally flexible language for aspects related to how product variants differ from one another. It is the lack of flexibility on these topics that leads to the inefficiency of amendments.

With that thought in mind, consider these two best practices for thoughtfully writing master protocols for early-phase CGT umbrella trials:

Come to a firm conclusion about how many variants will be studied, prior to the first IND submission.

Decide what will differentiate the variants from one another.

The answers to those two questions will guide where to create flexibility in the master protocol. In addition, FDA recently released its own timely guidance to help sponsors conduct early-stage umbrella trials for cell and gene therapies.

With the increasing number of cell and gene therapies on the horizon, FDA’s recent guidance on studying multiple versions of a cell or gene therapy product comes at an opportune moment.

 It sheds light on the agency’s recommendations to help sponsors achieve value by creating rigorous early-phase umbrella trials that could result in faster, more efficient cell and gene therapy development.

While the guidance itself isn’t lengthy—eight pages plus a two-page appendix—it offers sponsors several key takeaways, including recommendations about:

. As FDA outlines, the primary IND using an umbrella approach is no different from a regular IND. Primary INDs include clinical information about the umbrella trial, while secondary INDs do not. However, FDA suggests that sponsors request 

 IND numbers for the primary and all secondary INDs. The agency takes its recommendation further by advising sponsors to clearly state in each cover letter whether an IND is primary or secondary, then cross-reference all the numbers for the other INDs that support the study. In other words, they’d like sponsors to group everything together from the very beginning.

That means sponsors would have to know upfront how many secondary IND numbers they want. It’s a “measure twice, cut once” scenario. While it’s not impossible for sponsors to change their minds about the number of product versions they ultimately want to test, it would unnecessarily complicate matters. Sponsors would either be left with numbers that don't correspond to an actual secondary IND or unaligned numbers. So, the sooner sponsors nail down how many versions of the product they wish to include in an umbrella trial, the better for all stakeholders involved.

. It’s worth knowing that a clinical hold in an early-phase CGT umbrella trial may not affect the whole program. Clinical holds may be placed either on the entire program—meaning all arms of the study—or just a single arm. Conceivably, even a clinical hold caused by a potential safety concern could primarily affect just one arm (if the problem doesn’t apply to all product versions).

. It’s also worth noting that the guidance offers a mechanism to ensure adverse events in an umbrella trial aren’t overcounted. While sponsors must submit safety reports for all relevant primary and secondary INDs, FDA recommends that they clearly identify reports submitted to secondary INDs as “duplicates” so that the same adverse event is not counted more than once.

Innovative mindsets, innovative therapies

It is an exciting time in the evolution of cell and gene therapies. We have only begun to tap their ability to create substantial clinical benefits. Inevitably, however, innovations of this magnitude require us to step back and take a fresh, more holistic look at the clinical trial landscape.

Given the small and typically vulnerable patient populations often involved in cell and gene therapy studies, it’s clear we must redefine the concepts of risk and value. Such therapies are “high-reward” because of their potential to treat—or even cure—disease, but thus are also high-risk. So, clinical holds must be valued more for the responsible safeguards that they are. At the same time, umbrella trials should be embraced for their capacity to uncover the most auspicious treatments faster and more efficiently. It’s energizing to think about what altering our mindsets could mean for clinical trial speed, efficiency, and the ability to pursue treatments that truly hold the most promise for patients.

, PhD, PMP, senior director, therapeutic strategy lead, rare disease, Worldwide Clinical Trials

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https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-treat-adult-and-pediatric-patients-beta-thalassemia-who

U.S. Food and Drug Administration. “FDA Approves First Gene Therapy to Treat Adults with Hemophilia B.” 22 Nov 2022. 

https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treat-adults-hemophilia-b

Mullin, E. “A Gene Therapy Cure for Sickle Cell Is on the Horizon.” 

https://www.wired.com/story/a-gene-therapy-cure-for-sickle-cell-is-on-the-horizon/

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https://www.worldwide.com/wp-content/uploads/2023/01/Bioanalytical-Assays-of-AAV-Therapeutics-Recent-Advances-and-Considerations-VF.pdf

Essley Whyte, L. “FDA Increasingly Halting Human Trials as Companies Pursue Risky, Cutting-Edge Drugs.” 

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CenterWatch. “Cell & Gene Therapy Fueled Large Surge in Clinical Holds Last Year.” 07 March 2022. 

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Pillar, M. “Navigating A Clinical Hold.” 

https://www.bioprocessonline.com/doc/navigating-a-clinical-hold-0001

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https://www.fiercebiotech.com/biotech/fda-frees-pfizers-hemophilia-gene-therapy-clinical-hold

Business Wire. “Graphite Bio Announces Voluntary Pause of Phase 1/2 CEDAR Study of nulabeglogene autogedtemcel (nula-cel) for Sickle Cell Disease.” 05 Jan 2023. 

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BLA Clinical Review Memorandum. Skysona. 14 Oct 2022. 

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Stakeholders must alter their mindsets when it comes to early-phase design and interpreting regulatory guidance for CGT trials.

Evolving Tools and Perspectives for the Development of Cell and Gene Therapies

Doug Warner, MD and CMO for eFFECTOR Therapeutics, a clinical stage biopharma targeting oncology, discusses the complexities of oncology clinical trials, bringing his career-long learnings with Amgen to his current role, and the important relationship medical directors should have with their clinical study teams.

Podcasts

Doug Warner, MD and CMO for eFFECTOR Therapeutics, discusses the complexities of oncology clinical trials, the important relationship medical directors should have with their clinical study teams, and more.

Clinical Studies Take Teamwork

Rhoda Au remembers well when her interest in using digital biomarkers for disease research was not shared among her peers. The Boston University anatomy and neurology professor recalled when she delivered a keynote speech at a conference, about seven years ago.

“I had [finished] my digital spiel,” says Au, who is also director of neuropsychology, Framingham Heart Study, at Boston University. “Someone stood up and said that everything I said was all nonsense.”

It is unlikely that anyone today would express such a sentiment, at least not as publicly and rudely as that. In the years since, some smart people have hypothesized, and shown, that digital biomarkers can fill in some blanks about disease progression, symptoms, and therapeutic effects of investigational molecules. The interest is strong in using these biomarkers with the latter.

“In general, digital biomarkers will teach early signs and symptoms we don’t know yet about diseases,” Antonella Santuccione Chadha, MD, chief medical officer, Altoida, tells 

. “In early diagnosis, in disease monitoring, in treatment response, and in active populations, they will allow us to learn” and characterize even new disease phases. Altoida has designed an augmented reality platform that measures functional and cognitive brain health.

From a business vantage point, says Chris Benko, CEO, Koneksa, the ability to know steps in disease progression, both physiological and behavioral, and to predict treatment response and dose selection can reduce the number of patients needed for a trial. “Unquestionably, when you get to a point where you can get a signal in half as many patients, the economic value is just staggering.” Koneksa develops digital biomarkers for monitoring, diagnostics, treatment responses, and clinical event prediction.

Traditional blood or cerebrospinal fluid (CSF)-extracted biomarkers show point in time but digital biomarkers can show a patient’s response to a cognition test multiple times a day, every day. It is sussing out the pathway to the response that is important, says Au, who added that digital data will forever be available, whereas blood must be used judiciously.

The data from a digital biomarker can be gathered with various devices, including smartphones and smart watches. There are also platforms for various diseases; Altoida has a platform for Alzheimer’s disease, and Koneksa is developing digital biomarkers for Alzheimer’s and Parkinson’s disease.

Many people in the digital biomarker world are primarily interested in identifying those signs and symptoms of disease before actual onset and the inevitable deterioration they cause. About 80% of all diseases in the US are chronic, notes Au. Such an illness has been “coming for a long time before anyone said there is a problem.”

Today, adds Jason Hassenstab, PhD, associate professor of neurology and of psychological and brain sciences, and director, Cognitive Technology Research Laboratory, Washington University in St. Louis, people understand that decline from neurological disease is not simple or linear. In early disease stages, the brain can reorganize itself a bit, allowing for the patient to cope for some time.

“We have a cognitive reserve, rerouting our skills and wiring in network, to compensate for the cellular level changes,” says Hassenstab, who also leads the Cognition Cores for the Dominantly-Inherited Alzheimer Network-Trials Unit (DIAN-TU) and the DIAN observational study. He and his team designed a smartphone app for use by these patients a few years ago. “We know so much more about cellular level changes,” notes Hassenstab. “It was just a matter of time to find behavioral measures to detect.”

What researchers have long hoped, he adds, is to find changes in the brain as early as possible. “I think digital biomarkers have their place as outcome measures,” he says. “It will be difficult to approve a drug for [Alzheimer’s] without testing behavior.”

, “While diagnosis, disease monitoring, and intervention are traditionally addressed using distinctly separate tools, these different use cases may be overlapping or integrated in single solutions in the digital brain health space.” Sleep trackers, they wrote, can monitor quality of sleep; proffer advice for improving it; and possibly detect changes that are early neurological-disease signs.

The tools of the trade are being used on measures such as voice, temperature, activity, gait, blood oxygen, heart rate, and touch. These are but a handful of examples of what researchers look for in biomarkers.

 But there are literally hundreds more, depending on the disease.

For instance, Alzheimer’s. Published data show that the Altoida platform, which incorporates augmented reality and artificial intelligence, captures 800-plus multimodal features of the patient, through many different sensors.

 These features are then tested against fluid-based biomarkers. Eisai is testing the Altoida platform in a five-year trial with 3,500 patients to diagnose neurological diseases in their earliest stages.

Au’s research is looking at voice as one potential biomarker in particular. As a Framingham researcher, Au started recording participants’ responses to neurological testing beginning in 2005; hand-written notes didn’t provide the objective consistency she wanted, nor would they provide the informational pathways that the participants used to arrive at those answers.

By 2017, the Au team had 5,200 recorded sessions. A subset of 146 participants’ recordings were used from those that showed normal cognition, mild cognitive impairment, or dementia. A panel of neurology experts verified each case via diagnostic process.

 The researchers looked for pauses, hesitations, word-finding difficulties, circumlocution, pitch, timbre, and more. “When you are trying to think about what to say, you will” pause, stutter, or repeat words, says Au. These are all indicators of the person’s cognitive state, she adds.

According to Benko, at Koneksa, the company spent five years developing its Parkinson’s platform with partner Sanofi. In November 2021, the pharma giant extended the collaboration with Koneksa into central nervous system trials, which includes the evaluation of tolebrutinib a novel Bruton’s tyrosine kinase inhibitor for multiple sclerosis.

 He declined to discuss current findings, but demonstrated, via Zoom, how one of the measurements worked. He clicked on “ready.”

“‘With the phone in your right hand,” a voice said, “‘turn your palm up and down as many times as you can for 20 seconds.’” The platform, says Benko, “can measure tremor better than my eyeball.” He adds that Koneksa tested the algorithm in healthy people and then in those with Parkinson’s.

Koneksa is also looking at voice as a biomarker in Parkinson’s, and is recruiting for an asthma trial, comparing at-home mobile spirometry to in-clinic spirometry in participants with moderate asthma who take a long-acting beta agonist.

Not all attempts to find biomarkers are rooted in a smartphone. In order to find early detection of Alzheimer’s and related dementias, the National Institute of Aging and Indiana University are using a machine learning algorithm, embedded in electronic health record (EHR) systems at two sites, to monitor 4,000 Medicare patients using either the patients’ annual wellness visit by itself; the wellness visit with the digital marker; or the digital marker with the Quick Dementia Rating scale.

Not all studies are focused on myriad physiologic and/or cognitive issues. A biomarker of major interest is gait. Mobilise-D is a large 34-partner, 10-country, 2,400-person trial in the planning stages that will look at Parkinson’s; chronic obstructive pulmonary disease; multiple sclerosis; and fall-related issues, diseases, and frailty in the real world.

Other researchers are investigating how digital biomarkers can help with other serious conditions, such as death by suicide and alcoholism. In the latter work, which is testing whether problem drinkers can disassociate with Pavlovian cues, participants will use a smartphone, equipped with a GPS, every day to report on their drinking, activities, and moods.

Evidation is a consumer platform, five-million app-downloads strong, that allows people to get a new view of their health situation. “People can tell us what conditions they have, and whether they are using a smartphone, Fitbit, or CGM (continuous glucose monitor),” says Ernesto Ramirez, Evidation’s chief data scientist. “We use that data to help contextualize their health in everyday life.”

‘No longer just a cool technology,’ efforts to validate these signals are evolving.

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