This week, the Journal of Clinical Neurophysiology published a special issue about recent innovations and their regulatory implications for clinical trials in multiple sclerosis. Dr. Mark Skeen, Senior Medical Scientist at VeraSci and Professor of Neurology at Duke University Medical Center served as a guest editor and contributor for the issue.

The issue includes the article “Biomarkers and Surrogate Endpoints in Multiple Sclerosis Clinical Trials: Regulatory Issues” co-authored by Dr. Skeen and Dr. Luca Pani, VP Regulatory Strategy and Market Access Innovation at VeraSci and former Director-General of the Italian Medicines Agency (AIFA).

Evoked potentials have long played a role in the diagnosis of Multiple Sclerosis (MS), but have recently gained attention as a possible outcome measure for use in clinical trials. Like any surrogate endpoint, evoked potentials must demonstrate their precision and reproducibility, the settings in which they are meaningful, and the degree to which they predict clinically significant outcomes to gain acceptance with regulatory agencies and payers in the further evaluation of a product’s potential for reimbursement. This article explores regulatory issues associated with using evoked potentials as biomarkers and surrogate endpoints for use in clinical trials.

View the article here.

The issue also includes the article “Changing Paradigms and Unmet Needs in Multiple Sclerosis: The Role of Clinical Neurophysiology” authored by Dr. Skeen which reviews the change in the understanding of MS over past years with the focus on axonal loss, remyelination, and progressive MS (read more here). Dr. Skeen also contributed an editorial entitled “The Use of Evoked Potentials in Multiple Sclerosis Clinical Trials” (read more here).

Members of the Parkinson’s Foundation and the Parkinson’s Study Group (PSG), including VeraSci Senior Clinical Director of Movement Disorders Dr. Travis Turner, recently published a consensus statement titled “Expediting telehealth use in clinical research studies: recommendations for overcoming barriers in North America” in Nature Partner Journal (NPJ) Parkinson’s Disease. The paper outlines supporting evidence as well as barriers and solutions to implementation. A brief synopsis is provided below.

Although telehealth started gaining traction during the COVID-19 pandemic, good reasons exist to continue using telehealth in future studies. Increasingly, patients with Parkinson’s disease accept, and even prefer, telehealth for both clinical care and research visits. In a recent phase 3 clinical trial in Parkinson’s disease, 95% of participants completed remote video visits, and 75% said they were more likely to participate in future research if some visits could be conducted remotely. Additionally, telehealth can expand access to clinical trials to patients living in rural areas that would not be able to participate if it meant traveling to a distant study site for visits.

Despite the advantages of incorporating telehealth into clinical research, several barriers exist. The article focused on three key barriers:

  • Differences in state licensure requirements for telehealth
  • Limited access to telehealth among disadvantaged populations
  • Lack of consistency between IRBs

When it comes to clinical care, the Center for Medicare and Medical Services in the US allows clinicians to provide care across state lines when the patient resides in a state where the clinician is not licensed. The guidelines are less clear for clinical research, and site IRBs have differing interpretations of whether a clinician can conduct a remote study visit with a participant that is not in a state where they are licensed. Canadian provinces have similar issues with consistency.

Telehealth also presents challenges for reaching underrepresented groups. Up to 20% of Americans do not have broadband access at home or do not have smartphones. While Telehealth circumvents some of the transportation issues that impact underserved populations, those same groups are more likely to lack access to the technology that enables telehealth.

The FDA has published a Guidance on the Conduct of Clinical Trials of Medical Products During COVID-19 Public Health Emergency, but not all IRBs have adopted the recommendations in the guidance. This means that sponsors must navigate varying requirements for telehealth use on a site-by-site basis when a central IRB is not used.

The comment concludes with a set of recommendations to standardize IRB requirements in a way that allows for remote and hybrid visits, encourages parity in payment for on-site and remote visits, and encourages the development of a field-wide guidance document for the use of telehealth for study visits.

Read the full article here.

The Movement Disorder Society (MDS) recently developed and validated a new scale for assessing non-motor fluctuations in Parkinson’s disease patients. The Non-Motor Fluctuations Assessment Questionnaire (NoMoFA) is a patient-reported outcome measure that seeks to characterize the non-motor symptoms that may fluctuate in parallel with motor symptoms.

Non-motor symptoms have a significant impact on the quality of life for patients with Parkinson’s disease. These symptoms are wide-ranging and can include cognitive symptoms, fatigue, pain, restlessness, urinary symptoms, vision changes, shortness of breath, and more. Recognition of these symptoms’ impact has been a key driver behind efforts to create valid assessments of non-motor symptoms. However, existing scales measuring non-motor symptoms either do not address fluctuations in those symptoms or only look at fluctuations as a subset. The NoMoFA is the first scale that directly and specifically assesses non-motor symptoms in the OFF state. Many patients are at least as bothered by these non-motor OFF symptoms as by motor OFF symptoms and are a likely target in developing future treatments.

MDS has published the results of a study validating the use of the NoMoFA to assess fluctuating non-motor symptoms in patients with Parkinson’s disease. The study included 180 English speaking subjects from the US and Canada with a clinical diagnosis of Parkinson’s disease and ranged from mild to severe cases. The NoMOFA makes it possible to conduct the studies needed to determine whether non-motor symptom fluctuations improve with intervention. This opens the door to trials that would support expanding some of the recently approved medications for motor fluctuations to include a new indication of non-motor fluctuations.

Learn more about VeraSci’s expertise in Parkinson’s disease.

References

Kleiner, G., Fernandez, H. H., Chou, K. L., Fasano, A., Duque, K. R., Hengartner, D., Law, A., Margolius, A., Poon, Y., Farret, M.S., Saleh, P. Vizcarra, J.A., Stebbins, G.T., Espay, A. J. (2021). Non‐Motor fluctuations in Parkinson’s Disease: Validation of the non‐motor Fluctuation Assessment Questionnaire. Movement Disorders. doi:10.1002/mds.28507

 

Psychedelics are a group of drugs that facilitate the experience of non-ordinary states of consciousness through the activation of serotonin 5-HT2A receptors. This group includes psilocybin (a molecule present in 200+ mushroom species), lysergic acid diethylamide (LSD), and mescaline. An expanding body of research suggesting that psychedelics could treat CNS disorders like substance abuse, depression, chronic pain, and schizophrenia has sparked a renewed interest in recent years by drug developers and investors. A recent search of ClinicalTrials.gov shows nearly 300 trials of psychedelics currently registered.

As the field of psychedelic drug development advances, several challenges are surfacing. These challenges include selecting an appropriate control condition, implementing guided therapy, navigating a regulatory landscape with limited guidance, and the sub-field of microdosing.

Selecting an Appropriate Control Condition

A placebo-controlled study design is the gold standard for clinical trials conducted to support a marketing application. Psychedelics (with the probable exception of microdosing) present a unique challenge because of their hallucinogenic effects. These effects would make it apparent to both investigators and participants whether an active substance or the placebo was received. Additionally, since some of the proposed treatments, such as those being tested for treatment-resistant depression, are designed as a single treatment rather than an on-going treatment regimen, cross-over designs may not be feasible. Many early phase studies that have been conducted are open-label. Some studies use a comparison to a behavioral intervention or an active comparator. Still, others are moving forward with a placebo-controlled randomized design despite the likelihood that participants may become aware of their treatment assignment.

Guided Therapy

In many instances, regulators are mandating psychotherapy in conjunction with the administration of psychedelics in a research setting to ensure participants’ physical and psychological safety. This therapy often includes a preparation session between a trained therapist and the participant the day before drug administration to help the participant understand what to expect. The therapist helps the participant practice skills which will help the participant have the best possible experience. During the administration, a therapist trained as a guide is present during the entire experience. At a follow-up integration session after the psychedelic experience, the guide supports the participant through the experience and helps them make sense of it. In some instances, studies offer additional follow-up sessions using talk-based psychotherapy.

Designing the guided therapy is an important part of the study design. Regulators will expect it to be highly structured to ensure each participant has a similar experience and to decrease variability. In the US, two trained therapists are required during the session where the drug is administered. It is crucial that all guides are adequately trained. In addition to appropriate professional credentials and experience related to psychotherapy, training for guides may include a combination of online training, in-person training, clinical training, and on-going professional development.

Limited Regulatory Guidance

For many years, research into psychedelics was extremely restricted and, in some cases, banned. Because of the recency of renewed interest in psychedelic research and the particular challenges research in this area faces, there is limited guidance and precedence available from regulatory agencies about how to proceed. Although new guidance from regulators has been expected for some time, no formal guidance has been published yet. Drug developers will need to seek direct guidance from regulators beginning early in their program.

Microdosing

Microdosing has been practiced for hundreds of years. By the 1960s, there was a growing body of evidence suggesting that microdosing of psilocybin and LSD could potentially increase cognition and creativity. Government agencies halted the majority of scientific investigations of microdosing by the late 1960s over concerns about recreational use. As the investigation of psychedelics for medical use has seen a significant revival in recent years, interest in exploring microdosing has grown as well.

Microdosing is characterized by three features—a low dose that does not impair normal functioning, multiple dosing sessions, and an intention to improve well-being or enhance cognitive processes. The study of microdosing avoids some of the pitfalls of other studies of psychedelics, yet it carries some unique challenges. Because it involves doses so low that any perceptual effects are absent, microdosing avoids the deleterious consequences of hallucinations. Additionally, microdosing does not have the same problems with control conditions. Participants can be properly blinded to a placebo condition because the active component does not result in psychedelics’ pharmacological effects. Some have argued there are fewer safety concerns given historical indications that this is a relatively safe practice.

There are also challenges associated with microdosing. One is that there are no current standards for what dose is considered a microdose. Current studies are using a fairly wide range of doses—anywhere from .045 mg/kg to 0.315 mg/kg. Additional work is needed to determine optimal dosing. The risk-benefit profile is also different. Many other psychedelic studies are targeting diseases and disorders where there is a significant unmet medical need. Existing treatments for conditions like substance abuse, treatment-resistant depression, schizophrenia, and chronic pain leave patients with significant unaddressed or under-addressed symptoms. Most microdosing studies are targeting cognitive improvements in otherwise healthy patients. The bar for safety is much higher for use in a healthy population. Although there is a historical basis for believing that microdosing is safe, there is limited nonclinical and clinical data supporting this belief, and additional animal and human safety studies are needed.

Conclusion

The emerging field of psychedelic drug development presents exciting opportunities to address important unmet medical needs for CNS disorders. While there are some significant challenges, the potential to make significant strides in improving patients’ lives provides a sense of optimism for the future of the field. As a leader in CNS clinical research, VeraSci is well positioned to assist with developing your psychedelic product. Contact us to learn more about how we can support your development program.

References

VeraSci—a global clinical research company offering eClinical software, translation services, and expertise in endpoints and assessments—is pleased to announce a new partnership with Aural Analytics, Inc., a global leader in speech analytics for clinical research.

VeraSci has embedded the Aural Analytics’ A2ETM speech analytics mobile application SDK and web API into the Pathway eCOA platform in preparation for multiple upcoming pivotal trials, including a psychiatric trial, as well as a diagnostic program in a neurological indication. Speech analytics will be utilized alongside more conventional clinical outcome measures to provide a richer picture of patients’ neurological health. VeraSci is also exploring the potential use of speech analytics for upcoming studies in additional psychiatric conditions and neurological disorders.

Scientists have known for some time that patients’ speech patterns change with different clinical conditions. Automated analysis of speech can be used to identify and track neurological diseases and psychiatric disorders by measuring objective features of speech and language production, including articulation, prosody, verbal volition among others.  These measures have been investigated for use in diseases such as ALS, Parkinson’s disease, Alzheimer’s disease, migraine, and schizophrenia.

“Using speech analytics to provide a more comprehensive picture of cognitive and clinical symptoms in CNS disorders opens new avenues for assessing patients,” says VeraSci CEO Dr. Rich Keefe, “Our partnership with Aural Analytics advances our commitment to pairing scientific knowledge with cutting-edge technology to improve the tools and measurements available in clinical trials.”

VeraSci’s Pathway eCOA platform brings together scientifically driven processes with cutting edge technology to deliver higher quality data while reducing site and patient burden. The addition of Aural Analytics’ speech analysis capabilities to Pathway provides sponsors with a completely unique and state-of-the-art method for evaluating patients. Only VeraSci’s Pathway offers a single integrated device across a broad range of assessments, including clinical, cognitive, functional, and speech endpoints. In addition, speech analytics will play an important role as more clinical trials move to remote assessments virtual trials.

“We are proud to partner with VeraSci to embed A2E, our global speech collection and analytics suite, into VeraSci’s Pathway eCOA platform, enabling the seamless collection and analysis of speech alongside other digital assessments of neurological conditions,” said Daniel Jones, CEO and co-founder of Aural Analytics. “Speech analytics, coupled with VeraSci’s deeply scientific approach to data collection and analysis, will enable clinical researchers with a robust, unique, and compelling solution in today’s dynamic clinical research landscape.”

About VeraSci

VeraSci is a clinical research company offering eClinical software, translation services, and expertise in endpoints and assessments. VeraSci brings scientific expertise, strategic innovation, and unwavering commitment to each project, helping clients worldwide develop novel therapies. Learn more at www.verasci.com.

About Aural Analytics

Aural Analytics is the industry’s leading speech neuroscience company building the world’s most advanced clinical-grade speech analytics platform for health applications across the lifespan. Its suite of applications and embeddable SDKs and APIs are available in up to 30 languages across Android, iOS, and the web are easy to use, secure, and provide robust, clinically relevant, interpretable, and validated metrics reflecting the neurological and respiratory health of its users. For more information, please visit auralanalytics.com or follow Aural Analytics on Twitter, LinkedIn, Medium, and Facebook.

Most products being developed today for CNS diseases and disorders are under development for a specific indication like depression, Parkinson’s disease, or schizophrenia. This approach focuses on obtaining approval to treat patients with a specific diagnosis and impacts drug development from selecting assessments and outcome measures to the recruitment of patients to the label claims presented to regulators and payers.

A new approach, however, is emerging. A transdiagnostic approach focuses on the notion that a single biological mechanism of action may be present across multiple disorders. With this approach, clinical trial protocols, including inclusion/exclusion criteria and endpoints, are designed to target a biological dimension and associated symptoms and signs rather than targeting a diagnostic category. For example, an investigational product could target apathy via the dopaminergic pathway. This would broaden the potential for an approval covering any disorder with apathy as a symptom to be treated using this product and more so if the mechanism of action (MoA) could be linked to increase dopaminergic transmission.

Transdiagnostic approaches are already being used in therapeutic areas outside of CNS. For example, they have been used with immune checkpoint inhibitors in the field of oncology. Programmed Death-1 (PD-1) inhibitors such as nivolumab have been approved to treat various cancers where blocking the PD-1/PD-L1 pathway promotes immune control over cancerous cells. The underlying mechanism of action is the same regardless of the original type of tissue for the cancer.

The transdiagnostic approach in CNS disorders has some challenges that need to be addressed. Generally speaking, less is known about the underlying biological cause of many CNS disorders compared to non-CNS medical disorders. If the mechanism of action of a disease or treatment is not established, even if a product is shown to work on a particular symptom across multiple diagnoses, it may be more prudent to follow a more traditional development pathway. As scientific discovery about the underlying biological cause and mechanism of action of a treatment become established, given the transdiagnostic approach’s relative newness, early and frequent interaction with regulatory authorities is strongly recommended.

When implementing a transdiagnostic approach, questions may emerge regarding outcome measures and endpoints. In the example of immune checkpoint inhibitors given previously, there were already some generally accepted, well-defined endpoints such as disease-free survival and time to progression that were used across numerous indications in oncology. Many validated and accepted endpoints in CNS are disease-specific, such as the Montgomery-Åsberg Depression Rating Scale (MADRS) in depression or the Expanded Disability Status Scale (EDSS) in multiple sclerosis. Consideration must be given to selecting endpoints and assessments that can be used appropriately across the spectrum of conditions that could be addressed by a transdiagnostic label claim.

Recruitment and selection of trial participants will also change. In order to take a transdiagnostic approach, it will be important to select trial participants who accurately reflect the intended patient population. If the proposed drug could treat a wide range of psychiatric disorders in adults of all ages, it would not be appropriate to select only patients in the 20–40-year-old range diagnosed with depression. For sponsors used to relying on sites to identify their own patients, it may mean reassessing their recruitment plans to ensure a representative population.

Transdiagnostic approaches represent a promising path for new therapeutics targeting CNS disorders. Yet there are many challenges that need to be addressed when implementing this new scientifically-grounded approach. Several of the VeraSci scientific and regulatory experts have been central members of the development of these approaches for the National Institue of Health, National and European regulatory agencies. We are available to help you take full advantage of the emerging science in this area and tailor your program for success.

Contact us today to learn more.