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Applied Clinical Trials December 2022

Ukraine invasion tests the resiliency and quick action of CROs and sponsors

Mobilizing and Maintaining Clinical Trials in Midst of War

ACT's biennial Salary Survey takes a look at the future of industry following increased adaptation of decentralized technology 

Salary Survey: The Age of COVID

 has been appointed as Head of Statistics for Quanticate.

Massive Bio announced the addition of two executives to its C-suite: 

 as their first Chief Product Officer, and 

 has been promoted to Chief Marketing Officer.

 has been named as Elligo’s Chief Operating Officer.

 as their new Vice President of Marketing.

 as Vice President and Head of Corporate Development.

NNIT has received its recertification as a Veeva Premiere Services Partner – Development Cloud.

 surpassed 1,000 clinical trials in 2022 as study deployments surged nearly 20%.

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The paper focuses on three major areas: patient safety, patient and investigator inclusion, and evaluating DCT risks and benefits. Trial participants' rights, safety, dignity, and well-being should come first, and decentralization in clinical trials should not increase participant safety, rights, and well-being risks. While this concept is not new, the paper emphasizes that early participant and investigator involvement in clinical trial design increases the scientific value and boosts trial trust, recruitment, and adherence. Moreover, patients' perspectives on living with a condition may influence the selection of decentralized elements, such as the feasibility of videoconference appointments, the use of digital tools, the measurement of meaningful endpoints, and the selection of the right population. A risk-benefit assessment should consider decentralized elements that may affect scientific validity, data integrity, benefit-risk ratio, or trial participant rights. Decentralized trials should follow general medical rules to protect patients, especially when away from traditional patient care centers. A responsible investigator with a trial population-specific medical background should assess each patient's risk profile, including anamnestic, physical, and laboratory or imaging data.

Study oversight includes delegating study tasks, vendor quality agreements, and establishing effective lines of communication. When parts of the clinical trial are conducted off-site, and additional service providers like home nurses or technology providers are involved, the sponsor, investigator, and any other parties must clearly define their roles and responsibilities before the trial begins. Additionally, when trial participants visit the clinical trial site less often, alternative methods of clinical monitoring of their health status and data collection may need to be deployed. Decentralization introduces unique risks to participant rights, safety, dignity, and results, necessitating oversight requirements for investigators and sponsors. Hence, the study's plans and procedures should show that the sponsor and investigator fully control their responsibilities, such as data processing, communication flow, and trial participants' rights, safety, dignity, well-being, and data reliability.

When sponsors outsource to vendors, all tasks must be documented in a quality agreement with the vendor. Suppose the sponsor selects a service provider, and the investigator is not involved in the contractual arrangement. In that case, the sponsor-investigator contract should document the contractual arrangements with the service provider for tasks under the investigator’s responsibility, and the investigator should be able to request additional information, require changes to the agreement or service, and have the option to reject a service provider’s trial-specific medical care tasks. The sponsor should also ensure that the contracted service provider is qualified and experienced in delegated trial tasks.

Effective lines of communication should be established, documented, and shared with all relevant parties, including trial participants, investigators, sponsors, and service providers. All parties should have access to the clinical trial information they need at any time, and an emergency communication plan allows all relevant parties to act quickly, and trial participants should receive contact information for acute cases, device failures, home visit questions, and more. Processes to recognize duplicate AE reports must be established since data tends to reside in multiple sources when deploying multiple DCT vendors. Digital tools, like wearables, increase data frequency, and hinders the investigators' time; hence, a clear process should be in place to handle constantly emerging data, and the investigator's review frequency should depend on the data's relevance to trial participant safety and efficacy. Risk-based safety data review should consider the IMP safety profile, indication, and known risks.

Investigational medicinal product home delivery

IMP home delivery was another topic reflected in the paper and included four main areas: authorization, responsibility, delivery, and dispensation and administration. Suppose the site investigator or delegated healthcare professional does not dispense the IMP to the trial participant. In that case, the vendors delivering it should be authorized and qualified to distribute or dispense medicinal products, and transportation steps should be minimized, per good distribution practices (GDP).

The investigator is ultimately responsible for the participant and must document the treatment decision before delivering IMP to trial participants' homes. Delivery to the participant's home or another suitable address is allowed as long as regulatory requirements are met, risks of exposure to conditions that could affect product quality and integrity are minimized, and the GDP guidelines for medicinal products for human use are considered.

The investigator site pharmacy, a delegated pharmacy, or a depot can deliver the IMP. The sponsor should manage the process and contracts, and the clinical trial protocol or Investigational Brochure (IB) should describe IMP delivery to trial participants. Only the trial participant (or a representative) or a clinical trial healthcare professional should receive the IMP if applicable. Sponsors need to establish IMP delivery and receipt procedures, and if the pharmacies and labeling requirements are met, and national regulations allow, local pharmacies could dispense the IMP to trial participants instead of delivering it to their homes.

If an IMP needs medical supervision, shipping directly to the trial participant may not be appropriate. Suppose IMP must be shipped directly to the trial participant. In that case, clear instructions for storage and administration should be given to the participant; trial participants should be instructed in IMP preparation and administration if the protocol requires it, must be provided via a leaflet with easy-to-understand instructions. Visiting nurses can also be delegated to administer IMP, and either the investigator or delegees should regularly check in with participants to ensure they are taking the IMP correctly. Additionally, IMP accountability and trial participant treatment compliance procedures should be established, as safety regulations require the IMP to be returned and accounted for from trial participants' homes for destruction.

Sponsors should consider clinical trial suitability, patient risk, training, and patient monitoring when implementing DCTs. The investigator should determine if the trial participant's home is suitable for trial-related procedures and evaluate personal/social circumstances that may preclude home visits. Inclusion/exclusion criteria should include home adequacy for critical trial procedures, and the informed consent should explain home trial procedures. Only qualified and trained individuals should perform trial-related procedures at home. For instance, if a healthcare professional collects biological samples at home, the professional should be qualified, trained, and authorized to collect, document, and ship sample collections and ensure proper sample handling and storage throughout the process. Participants who perform trial-related tasks at home should be trained and considered for any additional burden, including digital data collection, and the sponsor and/or investigator should ensure that the delegated person(s) receives proper guidance and training for home tasks. The investigator (or delegee) should monitor trial participant compliance given the decrease in face-to-face visits/meetings with the investigator and/or delegated staff. Trial participants should be able to visit the investigator in person and have a direct line of communication if they need help with a trial-related task or data collection. During home visits, the trial participant or any delegated person should report and manage adverse events, and if a trial participant cannot or will not use their mobile device, the sponsor should offer alternatives.

The EMA paper elaborates on the importance of informed consent procedures if done remotely. Face-to-face communication between the potential trial participant, the investigator, or a qualified person is essential for informed consent, and if this discussion is done in a digital/virtual meeting, it is recommended that this takes place in real-time where the parties can both see and communicate with each other via audio and video. Remote face-to-face contact should allow for questions, and the investigator should make every effort to verify the participant's identity if they don't know them. The participant should also have the right to ask for proof of the investigator's identity if they haven't met before. If trial participants and investigators prefer on-site informed consent interviews, the sponsor should allow them to be conducted in person. The investigator should evaluate participant-related factors affecting decentralized elements of the clinical trial during the informed consent interview (such as the patient's ability to use technology), and the method should be reliable and confidential. Informed consent interviews should use encrypted communication channels to protect confidential information. While providing patient information via brochures and leaflets is helpful, the sponsor should also consider that electronic methods may unintentionally discriminate against participants who cannot or prefer not to use them and should have alternatives, such as paper or physical media, and trial participants should be able to store and retrieve the information provided to them easily and at any time.

, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials.

Latest recommendation places great emphasis on patients.

Summary of EMA’s Recommendation Paper on Decentralized Clinical Trial Elements

THREAD has announced its five-year collaboration with Sanofi. THREAD will serve as the sole provider of DCTs and eCOA technology for Sanofi's Integrated Patient Platform (IPP), part of its global Act4Patients program.

THREAD will serve as the sole provider of DCTs and eCOA technology under new five-year collaboration. 

Sanofi Selects THREAD as Global Decentralized Clinical Trials Provider

Signant Health has introduced a novel electronic diary data capture solution designed to simplify the experience for patients and research sites participating in epilepsy trials. Developed in collaboration with The Epilepsy Study Consortium, the new patient-reported outcome measure offers clinical research sponsors and organizations a standardized solution to capture common seizure-data elements with high-quality data.

New patient-reported outcome measure developed in collaboration with The Epilepsy Study Consortium.

Signant Health Debuts Standardized Electronic Seizure Diary

Vice President, Neuroscience, Scientific Solutions at Worldwide Clinical Trials

The recent revitalization of neuroscience drug development is welcomed by those seeking innovative mental health solutions. Most existing treatments for neuropsychiatric diseases such as anxiety, depression, substance use disorders (SUDs), and post-traumatic stress disorder (PTSD) are only modestly effective, and many have significant side effects.

Thus, sponsors, investors, and the public are enthusiastic about once again researching psychedelic compounds. More than 80 organizations are now publicly engaged in psychedelic drug development.

 By 2027, the market for psychedelic substances is predicted to grow to $10.75 billion from $2 billion in 2020.

 However, while longstanding stigmas around mental health and psychedelic drugs may be dissipating, misunderstandings remain about why it is imperative to design methodologically rigorous clinical trials designed to fully characterize safety and efficacy.

The reason for rigor is simple: If approved, psychedelics could be widely used in a vulnerable patient population. Rigorous trials provide data to develop a roadmap for how to best use these compounds in different types of patients. So, this article will:

examine two misconceptions about psychedelic pharmacotherapies that undermine rigor,

discuss the current research landscape, and

delve into ways sponsors can infuse rigor into psychedelic studies.

Some argue that formal, rigorous trials of psychedelics are unnecessary, given that Indigenous cultures have used them for millennia. This view perhaps comes with the misconceptions that: 1) psychedelic compounds are natural and therefore safe, and 2) the population that may ultimately use these compounds is homogeneous.

Misconception 1: Psychedelics are safe and natural.

Classic psychedelic drugs are defined by their mechanism of action. They act as agonists at serotonin 2A receptors (5-HT2A), which can alter consciousness and perception. Among the drugs considered classic psychedelics are psilocybin (found in “magic mushrooms”), lysergic acid diethylamide (LSD), mescaline (found in peyote), and dimethyltryptamine (found in various plants).

It is true that some psychedelic compounds are derived from nature and have been safely used for millennia by Indigenous cultures, and we should not discount the experience gained from generations of traditional use. However, scientifically sound clinical trials are critical for several reasons:

The pharmacology of psychedelic compounds is complex and variable. Their precise mechanisms of action remain poorly understood.

 natural; many modern psychedelics have been newly developed, chemically manipulated, or manufactured synthetically.

Adverse effects are not uncommon. While some may be relatively mild (e.g., nausea, vomiting), others may be severe (e.g., cardiac events, seizures, hyperthermia, suicidal ideation, and death).

Misconception 2: The population with mental health issues is largely homogeneous; if psychedelics safely work for some patients, they will safely work for all patients.

Patients’ clinical presentations and medical histories are highly variable—both within and across mental health conditions. Careful attention to obtaining a proper diagnosis and detailed medical history is critical, but additional considerations should include the following:

It is unclear if psychedelics should be reserved for severely ill patients or if they should also be considered for a mildly ill population. This is a testable hypothesis in a carefully designed study; patients should meet predefined severity requirements using cutoffs on standard assessments (e.g., the Hamilton Depression Rating Scale [HAM-D] or Montgomery-Asberg Depression Rating Scale [MADRS] for depression, or the Clinician-Administered PTSD Scale for DSM-5 [CAPS-5] for PTSD). Further, highly variable symptoms make it difficult to identify if treatment effects are due to the drug or other nonspecific factors, so symptoms should also be relatively stable.

family history or personal history of psychosis

. Patients with a personal or family history of psychosis, such as schizophrenia or bipolar disorder, may be at higher risk of a psychotic episode after taking a psychedelic substance. These patients should be excluded from early psychedelic trials until safety is further characterized.

. It is also unclear if frequent use of psychedelics is safe at varying dose levels, or if efficacy response changes with frequent use. Formal clinical trials can assess whether previous use (for clinical treatment or recreation) is associated with poorer safety outcomes or different response rates. Early clinical trials often exclude patients with a history of psychedelic use, particularly if they experienced a negative or no response in a medical treatment setting.

. Concomitant use of selective serotonin reuptake inhibitors (SSRIs) may blunt the effectiveness of psychedelics. Further, patients taking both SSRIs and psychedelics may be at increased risk for developing serotonin syndrome. These are also testable hypotheses, but the safety and efficacy of concomitant use have not yet been well established.

Psychiatry studies are uniquely intricate, even when they don’t involve psychedelics. Psychedelics add extra layers of regulatory and operational difficulty, partly because the drug class differs significantly from other pharmacotherapies for mental health conditions. Ethical considerations are magnified, too, as vulnerable patient populations become even more vulnerable when administered consciousness-altering compounds.

Despite the inherent complexity of psychedelic trials, psychedelics could change the treatment landscape for challenging neuropsychiatric diseases. Rigorous trials offer tremendous opportunities to shed light on:

the short- and long-term safety profiles of psychedelics.

the durability of psychedelic treatment effects and how often redosing should occur.

which patients might be helped vs. harmed by psychedelic treatments.

whether treatment effects are due solely to psychedelic compounds or the combined effect of the drug plus psychotherapy.

Better understanding these current unknowns requires conclusive results from large, well-controlled studies. The good news: Regulators seem willing to ease the path to such studies.

For example, FDA and the UK Medicines & Healthcare products Regulatory Agency (MHRA) have granted breakthrough designation and fast-track status for several psychedelic-assisted mental health therapies. The US Drug Enforcement Agency (DEA) has also accelerated its Schedule I research licensing process.

Designing and running a methodologically rigorous psychedelic clinical trial is difficult, but it can be accomplished when sponsors, contract research organizations (CROs), and sites work together. Sponsors, for example, may not be prepared for the extended timelines required to successfully conduct a psychedelic trial because of the need to:

obtain a Schedule I license. Psychedelic compounds almost always fall into the Schedule I category, so a license is needed to transport and use them in a research setting.

 Researchers that have never had a Schedule I license must be inspected, and the process can take many months.

submit a new license application for each protocol. In the United States, licenses are granted on a protocol-specific basis for research only.

build in extra time for site selection. While more and more sites are capable of conducting psychedelic trials and have the appropriate licenses, staff, training, facilities, equipment, and processes in place, thorough feasibility studies are crucial to assess each site’s capacity to manage a study within the study's projected time frame due to demand.

Sponsors should also be aware that many psychedelic trials entail three preparatory sessions, one to two dosing sessions, and two to three integration sessions to help patients assimilate the experience and to ensure psychological stability. Although patient retention is usually not a significant issue, one vital aspect of psychedelic trials is seeing how long the drug dose is effective. That makes it critical to keep patients in the trial through the follow-up visit(s), which may be after six months or longer. Sponsors are encouraged to offer an open-label extension to help with patient recruitment and to assess the durability of effect.

Along with these and the patient enrollment considerations discussed above, here are a few additional considerations for strengthening site selection, staffing, safety monitoring, and post-study care continuity for patients:

Studies generally benefit from leveraging a good mix of academic institutions and non-academic psychiatric sites. Some academic institutions have years of research knowledge about psychedelic substances, as well as appropriate research facilities and infrastructure. However, they may need support for working in a regulatory-controlled environment.

Conversely, sites that conduct industry-sponsored psychiatric trials may be experienced with regulatory-controlled research. They also may have established referral networks for patient recruitment, but may not commonly employ psychotherapists or have experience specifically with psychedelic compounds.

Ideally, sponsors should look for sites with the proper Schedule I licensing and staff training, standardized facilities, session recording technology, trained raters, and specialized therapists who are distinct from the safety monitors. The good news is that an increasing number of sites now have these capabilities.

For psychedelic-assisted psychotherapy models, the therapist’s role is to prepare patients for the trial experience, support them during dosing sessions (as the psychedelic experience can often be difficult), and then help patients integrate their experience after dosing. In a research setting, therapists also walk a fine line in setting treatment expectations for patients and their families. Therapists must develop trust and rapport with patients, yet also convey that patients may not get better after participation in the trial. Therefore, assessing therapist qualifications and providing quality study-specific training are critical. 

It’s also tough to blind these trials given the pronounced and well-known effects of psychedelic compounds. To minimize non-specific therapeutic treatment effects on efficacy outcomes, therapists and clinical efficacy raters should never be the same individuals. Raters have a different responsibility from therapists; they must collect unbiased outcome data and thus should remain independent from and blinded to dosing sessions, safety monitoring, and other study processes. To improve the collection of unbiased data and minimize potential rater inflation, sponsors can:

Train raters on their role and the proper administration of the outcome measurement instrument (e.g., the HAM-D, MADRS, or CAPS-5).

Employ centralized, third-party raters blinded to patients’ study visits and experiences.

Use one scale to qualify patients for study enrollment (e.g., the Hospital Anxiety and Depression Scale for Depression [HADS-D]) but another scale (e.g., the HAM-D) for baseline and subsequent measurements.

Blind the study’s entry criteria in the protocol. We sometimes suggest that sponsors avoid including entry criteria in public disclosures (e.g., their clinicaltrials.gov postings). Only the Institutional Review Board (IRB) sees the unblinded protocol. Sites, staff, and patients would then not know required threshold scores in entry criteria, reducing the possibility of rater inflation, patient or staff manipulation, etc.

Safety monitoring carries its own unique challenges. Altered states of consciousness caused by psychedelics can last anywhere from a few minutes to many hours, depending on the compound, with lingering effects after the initial response has worn off. Proper safety monitoring is needed during dosing sessions and afterward to protect not only vulnerable patients—whose vulnerability may be heightened by the psychedelic—but also site staff and therapists.

To strengthen safety monitoring, ideally:

The informed consent process should be detailed and include active facilitation by site staff.

“What if” boundaries should be established with therapists. For example, the patient could stipulate whether physical touch should be used if the session becomes challenging or difficult.

Two trained staff members should be in the room during dosing sessions. Ideally, one male and one female; at least one should be a licensed therapist.

Sessions should be videotaped and monitored—either observed in real-time or reviewed as needed by a third party (with proper patient consent).

Sites should have safeguards for psychological or physical adverse effects—including real-time availability of medical personnel.

Patients should have regular post-dose check-ins and be closely monitored between clinic visits for adverse effects, including worsening symptoms and suicidality. The protocol should establish suicidality measures that are actively monitored, and each site should have a written action plan to follow if patients develop suicidal ideation.

We recommend incorporating a discharge readiness evaluation before patients leave the dosing session. It should work in tandem with preparatory sessions given to family members and caregivers that explain what they should expect once the patient gets home and what to do should concerns arise.

Sponsors, CROs, and sites should work together proactively to define how care will persist once a psychedelic study is over, whether the patient continues with the study therapist or is referred to another therapist to ensure continuity of care. We recommend that sites have a documented plan for individual patient care when the patient completes or discontinues from the study—and sponsors should confirm that plan is in place. Best practices encourage coordination between the site, study therapists, and referral providers to ensure that much-needed psychotherapy doesn’t simply cease once the trial concludes.

The renewed interest in psychedelic research and promising data have opened encouraging new paths for treating neuropsychiatric diseases. Yet less experienced sponsors must be alert to common misconceptions undermining the urgent need for methodological rigor in psychedelic study designs.

These trials often involve fragile patients in desperate need of relief. Sponsors, CROs, and sites that create scientifically rigorous clinical trials stand the best chance of developing psychedelic pharmacotherapies that can materially enhance these patients’ lives.

, PhD, VP, neuroscience, scientific solutions at Worldwide Clinical Trials

Halford, B. Drug companies are investing big in psychedelics, but can they engineer out the trip? Chemical & Engineering News. March 6, 2022. 

https://cen.acs.org/pharmaceuticals/drug-development/Drug-companies-investing-big-psychedelics/100/i9#:~:text=They%20need%20something%20that%20is,the%20business%20information%20platform%20Crunchbase

Phelps J., Shah RN, Lieberman JA. The Rapid Rise in Investment in Psychedelics—Cart Before the Horse. JAMA Psychiatry. 2022; 79(3):189-190. DOI:10.1001/jamapsychiatry.2021.3972

Goodwin GM, Aaronson ST, Alvarez O, et al. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.N Engl J Med. 2022; 387:1637-1648.
DOI: 10.1056/NEJMoa2206443

Armenian P, Mamantov TM, Tsutaoka BT, et al. Multiple MDMA (Ecstasy) overdoses at a rave event: a case series. J Intensive Care Med.2013; 28(4), 252-8

Leonard JB, Anderson B, Klein-Schwartz W. Does getting high hurt? Characterization of cases of LSD and psilocybin-containing mushroom exposures to national poison centers between 2000 and 2016. J Psychopharmacol.2018; 32(12), 1286-1294

U.S. Drug Enforcement Administration. DEA speeds up application process for research on Schedule I drugs. January 18, 2018. 

https://www.dea.gov/press-releases/2018/01/18/dea-speeds-application-process-research-schedule-i-drugs

U.S. Drug Enforcement Administration. Drug Scheduling. 

https://www.dea.gov/drug-information/drug-scheduling#:~:text=Schedule%20I%20drugs%2C%20substances%2C%20or,)%2C%20methaqualone%2C%20and%20peyote

Renewed interest in psychedelic research shows great promise for patients in need of more effective therapies.

Why and How to Infuse Methodological Rigor into Psychedelic Clinical Trials

Crescendo Health has announced its official launch. Founded by the co-founder of Datavant (merged with Ciox in a $7 billion deal), and a  product-management leader from Grand Rounds (merged with Doctor On Demand to form Included Health), Crescendo Health is a public benefit corporation that is seeking to improve access to traditionally siloed health data for both patients and clinical research sponsors. The company works with researchers from many types of healthcare organizations, including biopharma, medical device manufacturers, and contract research organizations, to provide the tools and support required to collect and integrate information from patients' routine clinical care.

New public benefit corporation seeks to unlock access to traditionally siloed data through RWD platform.

Crescendo Health Announces Official Launch

Bioethics International announced the publication of its fair inclusion score, a method to measure and rank pharmaceutical companies on their fair inclusion of women, older adults, and racial and ethnic minoritized patients in clinical research, in 

New index will score pharma companies on clinical trial diversity and appear in BMJ Medicine.

Bioethics International Publishes Fair Inclusion Score

Huma Therapeutics announced results of a new study in collaboration with the Medical Research Council Epidemiology Unit at the University of Cambridge showing that participants using Huma's clinical trial platform had high, sustained levels of engagement in an observational, fully remote COVID-19 study.

, involved 62.61% (2524/4031) participants from the longitudinal 

Study in collaboration with the Medical Research Council Epidemiology Unit at the University of Cambridge showed participants had high levels of engagement in remote COVID-19 study.

Huma Therapeutics Releases Results from COVID-19 Study

The "AI-based Clinical Trial Solutions For Patient Matching Market Share, Size, Trends, Industry Analysis Report, By Therapeutic Application; By End-Use; By Region; Segment Forecast, 2022 - 2030" report has been added to Research and Markets' offering.

The global AI-based clinical trial solutions for patient matching market size is expected to reach $1.969 million by 2030, according to a new study. The report gives a detailed insight into current market dynamics and provides analysis on future market growth.

Market size expected to reach $1.96 million by 2030.

Research and Markets Releases 2023 AI-based Clinical Trial Solutions For Patient Matching Market Report

Southern Star Research has announced its expansion into South Korea to offer clients access to medical and clinical services and patients in the region.

The Seoul, South Korea office is expected to open next month and the Singapore office to follow. The Singapore office will serve as the hub to support the Asia region.

New South Korea office location part of APAC expansion plan for 2023.

Featured Content

Applied Clinical Trials December 2022

Mobilizing and Maintaining Clinical Trials in Midst of War

Salary Survey: The Age of COVID