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Applied Clinical Trials November 2023

Jim Kremidas, former executive director, Association of Clinical Research Professionals, shares his experiences as a patient in clinical trials.

Perspective and Hope From the ‘Other Side’

Senior leaders gather to share insights on the increased investment in real-world data to boost the quality and efficiency of drug development.

Executive Roundtable: The Rise of RWD in Clinical Research

The FDA has issued a warning regarding the risk of drug reaction with eosinophilia and systemic symptoms (DRESS) among patients taking antiseizure medications. Included in the FDA warning were levetiracetam, under the brand names Keppra and Keppra XR (GlaxoSmithKline); Elepsia XR (Sun Pharmaceutical Industries Ltd); Spritam (Prasco; Aprecia Pharmaceuticals); and clobazam, under the brand names Onfi (Lundbeck) and Sympazan (Otter Pharmaceuticals).

Image credit: Dr_Microbe | stock.adobe.com

DRESS, a rare but serious and potentially fatal reaction, may initially appear as a rash before rapidly progressing to impact internal organs, leading to hospitalization. Patients who develop DRESS may experience fever, rash, and swollen lymph nodes, as well as damage to the liver, kidneys, lungs, heart, or pancreas. Early signs of DRESS can include fever and swollen lymph nodes even without the presence of a rash. DRESS can manifest two to eight weeks following the start of treatment with variable symptoms and intensity on a case-by-case basis, according to the FDA.

The agency also stated that it will require warnings to be listed on prescribing information and on patient guides for the affected medications. FDA recommendations for healthcare professionals include awareness of the symptoms of DRESS, which is vital because initiating early treatment may improve outcomes and lower the risk of mortality. According to the FDA, DRESS may be confused with other adverse skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis. As such, the agency emphasized the importance of healthcare professionals recognizing and understanding the differences among these conditions to reduce the risk of adverse outcomes.

Additionally, healthcare providers are urged to educate patients regarding the signs and symptoms of DRESS, to cease use of their medications if symptoms develop, and to seek medical care if DRESS is suspected during treatment with levetiracetam or clobazam. The FDA emphasized that patients should not stop taking medications without first discussing it with their healthcare provider because this can lead to uncontrolled seizures. DRESS can be diagnosed with physical exams, laboratory blood tests, and additional clinical evaluations.

The FDA said that patients and healthcare professionals should report any adverse events (AEs) related to the use of levetiracetam or clobazam to its MedWatch Safety Information and Adverse Event Reporting Program, either via an online report or by downloading and mailing the form or submitting it via fax at 800-FDA-0178, according to the press release.

Levetiracetam has been approved by the FDA for use alone or combined with other drugs for seizure control in adults and children, including partial seizures, myoclonic seizures, or tonic-clonic seizures. Common AEs associated with these medications include irritability, aggression, confusion, loss of balance or coordination, and extreme drowsiness.

Clobazam is a benzodiazepine indicated in combination with other drugs that control seizures in individuals two years of age and older with Lennox-Gastaut syndrome. Commonly reported AEs among patients administered clobazam include difficulty speaking or swallowing, fatigue, changes in appetite, and challenges with muscle control or coordination, according to the FDA release. Although benzodiazepines affect the central nervous system, DRESS has not been associated with any other medications in this class, and has only been associated with use of clobazam, according to the FDA.

Antiseizure medicines Keppra, Keppra XR, Elepsia XR, Spritam (levetiracetam) and Onfi, Sympazan (clobazam): drug safety communication - FDA warns of rare but serious drug reaction. News release. FDA. November 28, 2023. Accessed November 30, 2023. https://www.fda.gov/safety/medical-product-safety-information/antiseizure-medicines-keppra-keppra-xr-elepsia-xr-spritam-levetiracetam-and-onfi-sympazan-clobazam

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Included in the FDA warning were levetiracetam, under the brand names Keppra and Keppra XR; Elepsia XR; Spritam; and clobazam, under the brand names Onfi and Sympazan.

FDA Warns of Rare But Serious Reaction to Antiseizure Medications

GSK announced positive results from an interim analysis of its DREAMM-7 head-to-head Phase 3 trial evaluating belantamab mafodotin (Blenrep) as a second-line treatment for relapsed or refractory multiple myeloma. 

Image credit: ibreakstock | stock.adobe.com

According to a company press release, the trial met its primary endpoint of progression-free survival (PFS) and showed that Blenrep when combined with bortezomib plus dexamethasone (BorDex) significantly extended the time to disease progression or death versus daratumumab plus BorDex, an existing standard of care for relapsed/refractory multiple myeloma.

“Patients with multiple myeloma need treatment options after first relapse that are efficacious, readily accessible and have novel mechanisms of action,” said Hesham Abdullah, SVP, global head, oncology, R&D, GSK, in a press release.

 “We are particularly encouraged by the potential for belantamab mafodotin when combined with BorDex to address high unmet need in relapsed/refractory multiple myeloma, given the head-to-head comparison with the daratumumab-based standard of care regimen.”

Multiple myeloma, a malignant disorder of B cells, is the second most common hematological cancer and is associated with significant morbidity and mortality. Survival rates for the disease have improved over the past few decades because following the launch of promising new targeted treatments and combination therapies; however, most patients with multiple myeloma relapse, including patients who achieved remission.

Initially, Blenrep had been removed from the market in November of last year following a request from the FDA. According to the 

the request was based upon the previously announced outcome of the DREAMM-3 Phase 3 confirmatory trial, which did not meet the requirements of the FDA Accelerated Approval regulations. Despite the setback, GSK continued its clinical testing of the therapy, hoping to explore its potential further.

Currently, Darzalex, Johnson & Johnson’s (J&J) multiple myeloma treatment, is considered the standard of care treatment in the industry. Based on results of the DREAMM-7 trial, GSK believes Blenrep shows potential as a much stronger treatment, with the study reportedly showring superior results compared to its counterpart.

DREAMM-7 was a Phase 3, multicenter, open-label, randomized trial analyzing the efficacy and safety of Blenrep plus bortezomib and dexamethasone (BorDex) compared to a combination of daratumumab and BorDex in patients with relapsed/refractory multiple myeloma previously administered at least one prior line of treatment for multiple myeloma, with documented disease progression during or following the most recently administered therapy.

The investigators randomly assigned 494 patients 1:1 ratio to receive either Blenrep plus BorDex or a combination of daratumumab and BorDex. Blenrep was dosed at 2.5 mg/kg intravenously every three weeks.

GSK stated that its DREAMM clinical development program will evaluate the potential of Blenrep in early lines of treatment and in combination with novel therapies and standard of care treatments. This includes the ongoing head-to-head Phase 3 DREAMM-8 trial evaluating Blenrep in combination with pomalidomide and dexamethasone versus bortezomib in combination with pomalidomide and dexamethasone. More data are expected in the second half of 2024, according to GSK.

1. GSK announces positive results from DREAMM-7 head-to-head phase III trial for Blenrep in relapsed/refractory multiple myeloma. 

November 27, 2023. Accessed November 30, 2023. 

https://www.gsk.com/en-gb/media/press-releases/gsk-announces-positive-results-from-dreamm-7-head-to-head-phase-iii-trial-for-blenrep/

2. Ahmed A, Killeen RB. Relapsed and Refractory Multiple Myeloma. Updated June 8, 2023. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: 

https://www.ncbi.nlm.nih.gov/books/NBK592405/

3. Withdrawal of Blenrep from the US Market. 

November 23, 2022. Accessed November 30, 2023. https://www.myeloma.org/news-events/withdrawal-blenrep-us-market

4. GSK's Pulled Myeloma Drug Outperforms J&J's Darzalex in Key Trial. 

November 28, 2023l. Accessed November 30, 2023. https://www.econotimes.com/GSK-Drug-Pulled-from-Market-Beats-JJs-Multiple-Myeloma-Treatment-in-Phase-3-Test-1666931

DREAMM-7 was a Phase 3, multicenter, open-label, randomized trial analyzing the efficacy and safety of Blenrep plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma previously administered at least one prior line of treatment.

Blenrep Shows Promise in DREAMM-7 Phase 3 Trial for Relapsed, Refractory Multiple Myeloma 

Priothera Ltd. has announced that the FDA awarded Orphan Drug Designation to KRP203 (mocravimod) to improve outcomes after hematopoietic stem cell transplantation for the treatment of hematologic malignancies. The sphingosine-1-phosphate (S1P) receptor modulator is designed to improve leukemia-free survival by increasing graft-versus-leukemia (GvL) response.

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“We are very pleased that the US FDA granted mocravimod this Orphan Drug designation. This designation emphasizes the importance of developing novel therapeutic options to improve the outcome and success of maintenance therapy following allo-HSCT in blood cancer patients. This is an important milestone as this ODD complements the first ODD granted for prevention of graft-versus-host disease,” said Priothera co-founder and CEO Florent Gros, in a press release. “The two ODDs highlight mocravimod’s dual mode of action which for the first time is being leveraged to improve the allo-HSCT treatment outcomes in hematological malignancies to potentially increase the leukemia free survival—graft-versus-leukemia response—while reducing tissue damage resulting from the graft-versus-host disease.”

Mocravimod is currently being evaluated in the Phase 3 MO-TRANS (NCT05429632) trial, a pivotal global study of the efficacy and safety of the drug as an adjunctive and maintenance treatment to allo-HSCT in 250 adults with acute myeloid leukemia.

The intended dual mode of action for mocravimod seeks to maintain beneficial GvL activity while also decreasing damage to tissue associated with GvHD, which are consequences of allo-HSCT. This represents a high unmet need among patients, with mocravimod potentially improving their quality of life.

Prior testing in a Phase 1b/2a study of multiple autoimmune indications suggest mocravimod may improve the curative potential of allo-HSCT based on a clinically meaningful outcome in patients with hematologic malignancies undergoing allo-HSCT. Mocravimod was previously granted an ODD to prevent graft-versus-host disease.

BioSpace. Priothera – US FDA grants Orphan Drug Designation to mocravimod to improve the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with hematologic malignancies. News release. November 27, 2023. Accessed November 28, 2023. 

https://www.biospace.com/article/releases/priothera-us-fda-grants-orphan-drug-designation-to-mocravimod-to-improve-the-outcome-of-allogeneic-hematopoietic-stem-cell-transplantation-allo-hsct-in-patients-with-hematologic-malignancies

KRP203 (mocravimod) is intended to improve outcomes after hematopoietic stem cell transplantation for the treatment of hematologic malignancies.

FDA Grants Orphan Drug Designation to Mocravimod to Improve Outcomes Following Stem Cell Transplantation 

The FDA has accepted a supplemental new drug application (sNDA) from Arcutis Biotherapeutics, Inc. for roflumilast cream 0.15% to treat atopic dermatitis in patients 6 years of age and older. The sNDA for the once-daily, steroid-free, next-generation phosphodiesterase-4 (PDE4) inhibitor was assigned a Prescription Drug User Fee Act (PDUFA) target action date of July 07, 2024.

“With this filing acceptance, we are one step closer to potentially providing a new topical option for the millions of Americans living with atopic dermatitis. Given the prevalence of this disease in both children and adults, as well as the need for better long-term management, we believe once-daily, steroid-free roflumilast cream has the potential to become the new standard of care in atopic dermatitis,” Frank Watanabe, Arcutis president and chief executive officer, said in a press release.

 “We look forward to working closely with the FDA during the review process as part of our ongoing efforts to develop topical roflumilast for the treatment of immune-mediated skin diseases.”

Atopic dermatitis is a chronic disease that leads to inflammation, redness, and irritated skin that can become extremely itchy. The disease typically begins in childhood but can develop at any age. In patients with atopic dermatitis, scratching the skin can exacerbate the condition, increasing redness, swelling, cracking, leaking of clear fluid, crusting, and scaling. Flare-ups of atopic dermatitis can be followed by periods in which the skin improves or clears up entirely.

“Atopic dermatitis is a chronic and recurring inflammatory skin condition that requires therapy that is effective, tolerable, and suitable for long-term use by both adults and children. Due to its waxing and waning nature, long-term disease control is ideal for the patient versus cyclical treatment, which consists of starting and stopping treatment when skin is controlled and when it is not,” study investigator Lawrence Eichenfield MD, chief of pediatric and adolescent dermatology at Rady Children’s Hospital-San Diego, professor of dermatology and pediatrics and vice-chair of the Department of Dermatology at UC San Diego School of Medicine, said in a press release.

Arcutis Biotherapeutics’ application was supported by significant findings from a trio of Phase 3 trials, a Phase 2 dose ranging trial, and a pair of Phase 1 pharmacokinetic studies. In the phase 3, parallel group, double blind, vehicle-controlled INTEGUMENT-1 and INTEGUMENT-2 (The INterventional Trial EvaluatinG roflUMilast cream for the treatmENt of aTopic dermatitis) trials, investigators assessed the safety and efficacy of roflumilast cream 0.15% in AD.

The cream achieved the primary endpoint of the trial with a validated Investigator Global Assessment—Atopic Dermatitis (vIGA-AD) Success rate of 32.0% vs. a vehicle rate of 15.2% (P<0.0001), and 28.9% vs. a vehicle rate of 12.0% (P<0.0001) at week 4, in INTEGUMENT-1 and -2, respectively.

More than 30% of patients administered roflumilast in each trial achieved Worst Itch-Numeric Rating Scale (WI-NRS) Success at week 4, showing quick and significant improvements in the symptoms of atopic dermatitis as early as 24 hours after the cream was initially applied.

Further, over 40% of patients administered roflumilast cream achieved a 75% decrease in Eczema Area and Severity Index (EASI-75) at week 4 vs. vehicle (INTEGUMENT-1: 43.2% vs. 22.0%, P<0.0001; INTEGUMENT-2: 42.0% vs. 19.7%, P<0.0001). Roflumilast showed significant efficacy as early as week 1 following administration in both studies.

In terms of safety, roflumilast 0.15% was well tolerated, with low incidence of treatment-emergent adverse events (TEAEs) across both the active treatment and vehicle cohorts. Most of the reported TEAEs were deemed mild to moderate in severity. The most common TEAEs were headache (2.9%), nausea (1.9%), application site pain (1.5%), diarrhea (1.5%), and vomiting (1.5%).

The FDA has previously approved roflumilast cream 0.3% (Zoryve) for the topical treatment of plaque psoriasis in individuals 6 years of age and older.

“In clinical trials, roflumilast cream demonstrated rapid and sustained improvement in the signs and symptoms of disease, as well as long-term proactive disease control with twice weekly maintenance dosing,” Eichenfield said in the release.

 “With this profile, patients will not need to make tradeoffs between long-term safety, efficacy, and tolerability. Roflumilast cream if approved, has the potential to simplify the approach to disease control for children and adults.”

1. FDA Accepts Arcutis’ Supplemental New Drug Application for Roflumilast Cream 0.15% for the Treatment of Atopic Dermatitis in Adults and Children Down to Age 6. Arcutis Biotherapeutics, Inc. News release. November 29, 2023. Accessed November 30, 2023. 

https://www.arcutis.com/fda-accepts-arcutis-supplemental-new-drug-application-for-roflumilast-cream-0-15-for-the-treatment-of-atopic-dermatitis-in-adults-and-children-down-to-age-6/

2. Atopic Dermatitis. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Webpage. Updated November 2022. Accessed November 30, 2023. 

https://www.niams.nih.gov/health-topics/atopic-dermatitis

Arcutis Biotherapeutics’ supplemental new drug application was supported by significant findings from a trio of Phase 3 trials, a Phase 2 dose ranging trial, and a pair of Phase 1 pharmacokinetic studies for roflumilast cream 0.15% to treat atopic dermatitis in patients 6 years of age and older.

FDA Accepts sNDA for Roflumilast Following Promising Trial Results in Atopic Dermatitis 

The FDA has accepted a New Drug Application (NDA) for Karuna Therapeutics, Inc’s KarXT (xanomeline-trospium) treatment for schizophrenia in adult patients. The novel muscarinic antipsychotic is currently in development to treat schizophrenia and psychosis related to Alzheimer disease.

Image credit: Olivier Le Moal | stock.adobe.com

“There is a significant need for new treatment options for serious mental illness. If approved, KarXT could be one of the more important new product introductions in neuropsychiatry by providing a novel pharmacological approach for the treatment of schizophrenia,” said Bill Meury, Karuna Therapeutics president and chief executive officer, said in a press release.

Schizophrenia can be a disabling condition, potentially causing a combination of hallucinations, delusions, and extremely disordered thinking and behavior that has a negative impact on the ability to function in daily life. As such, patients with schizophrenia require lifelong treatment; however, treatment initiated early after diagnosis may help to get the symptoms under control prior to the development of serious complications, which may improve long-term outlook for patients.

Schizophrenia is estimated to affect approximately 0.3% of the global population and an estimated 2.8 million patients in the United States. The course of the condition is typically characterized by acute episodes of psychotic behaviors occurring at varying intervals between periods of relative symptomatic stability.

Its characteristics are classified as positive symptoms (hallucinations and delusions), negative symptoms (difficulties enjoying life and social withdrawal), and cognitive impairment (inhibited memory, concentration, and decision-making). Despite advancements in managing the symptoms of the condition, approximately 30% of patients do not improve with therapy, and 50% experience a partial improvement in symptoms.

KarXT has a novel mechanism of action that acts as a dual M1/M4 muscarinic acetylcholine receptor agonist in the central nervous system. Karuna stated the therapy is believed to produce improvements in the positive, negative, and cognitive symptoms of schizophrenia. The therapy may offer an alternative approach to treating schizophrenia because it does not directly block dopamine receptors.

The submission of the NDA was supported by data from the EMERGENT clinical program evaluating KarXT as a treatment for schizophrenia, which demonstrated the drug’s efficacy and long-term safety, according to Karuna. Across all three placebo-controlled trials in the EMERGENT program, the drug achieved the primary endpoint of statistically significant and clinically meaningful improvements in the symptoms of schizophrenia vs. placebo as measured by Positive and Negative Syndrome Scale (PANSS) total score.

In terms of safety, KarXT was generally well tolerated, with the most common adverse events (AEs) being cholinergic in nature and mild to moderate in severity. Significantly, the drug was not associated with the AEs that are common among currently available antipsychotics, such as weight gain, somnolence, and movement disorders.

“KarXT focuses on a novel pathway through muscarinic receptors to indirectly modulate dopamine signaling in key brain circuits, and in clinical trials completed to date KarXT has demonstrated the much-needed combination of strong tolerability and clinically meaningful symptom reduction,” EMERGENT program investigator Rishi Kakar, MD, chief scientific officer and medical director of Segal Trials, said in a press release.

 “This decision by the FDA marks an important step in working toward a new chapter in the standard of care for those facing the immense, daily struggle of this serious mental illness.”

The application has been granted a Prescription Drug User Fee Act date of September 26, 2024.

1. Karuna Therapeutics Announces U.S. Food and Drug Administration Accepts New Drug Application for KarXT for the Treatment of Schizophrenia. Karuna Therapeutics. November 29, 2023. 

https://investors.karunatx.com/news-releases/news-release-details/karuna-therapeutics-announces-us-food-and-drug-administration

2. Schizophrenia. Mayo Clinic. Webpage. Updated January 7, 2020. Accessed November 29, 2023. 

https://www.mayoclinic.org/diseases-conditions/schizophrenia/symptoms-causes/syc-20354443

Data from the EMERGENT clinical trial program show Karuna Therapeutics, Inc’s KarXT (xanomeline-trospium) produced statistically significant and clinically meaningful improvements in the symptoms of schizophrenia.

FDA Accepts New Drug Application for Novel Schizophrenia Treatment

The FDA has granted 510(k) clearance to Vivos Therapeutics, Inc. for its removable CARE (Complete Airway Repositioning and/or Expansion) oral appliances for adults with severe obstructive sleep apnea (OSA). The clearance includes the company’s flagship DNA oral appliance, the mRNA oral appliance, and the mmRNA oral appliance.

“Make no mistake: this is a huge development on the landscape of treatments for OSA. As the medical profession has gained a better understanding of the complex factors contributing to OSA, we now recognize that a critical component to this condition is the form and functionality of the oral vault,” said medical sleep specialist David McCarty, MD, in a press release.

 “This is where medical collaboration with an airway-centered dentistry approach like Vivos offers is a game-changer. This decision by the FDA could be life changing for patients who suffer from severe OSA and for whom other treatments have failed.”

The clearance makes Vivos the first company to receive FDA approval for, and to bring to market, an alternative to continuous positive airway pressure (CPAP) or surgical neurostimulation implants for patients with severe OSA. Eleven months earlier, the FDA granted Vivos 510(k) clearance for its DNA oral appliance that treats mild-to-moderate OSA. According to Vivos, this is the first time the FDA has granted clearance to an oral appliance indicated for moderate and severe OSA in adults, 18 years of age and older, along with positive airway pressure (PAP) and/or myofunctional therapy.

“This achievement is a pivotal milestone for Vivos and elevates our proven treatment options right into the mainstream of sleep medicine. It is even more important for the millions of severe OSA patients who are desperate for an effective alternative treatment,” said Kirk Huntsman, chairman and CEO of Vivos, in a press release. “Before this, severe OSA patients’ only realistic treatment options were CPAP, neurostimulation implants or other invasive surgeries. Today, they have what we believe is a far more desirable option that is very affordable and doesn’t require surgery or a lifetime of nightly use and intervention.”

In patients with OSA, breathing is interrupted during sleep for at least 10 seconds for an average of at least five times per hour during sleep. Risk factors for OSA include excess weight, older age, narrowed airway, hypertension, smoking, chronic nasal congestion, diabetes, and asthma.

Vivos reported that data submitted to the FDA from 73 patients with severe OSA showed 80% achieved an improvement of at least one classification or at least a 50% improvement in the Apnea Hypopnea Index (AHI), whereas 97% of patients improved or stayed the same over an average treatment time of 9.7 months. The company reported that treatment results were superior among patients with severe OSA compared with patients with mild and moderate OSA.

“Vivos trained providers can now treat patients with OSA and conditions associated with OSA comprehensively using our suite of FDA cleared devices, without regard to the severity of their OSA condition and across a range of price point options,” Huntsman said in the release. “We believe this unprecedented decision by the FDA will generate broader acceptance throughout the medical community for Vivos treatment options, leading to the potential for higher patient referrals and case starts as well as collaboration with medical professionals. We also believe it will enhance our value proposition to third-party distribution partners such as durable medical equipment (DME) companies. This approval could also clear the way for greater reimbursement levels from medical insurance payors and Medicare. We believe that all these factors should favorably impact our ability to grow our revenues in 2024 and beyond.”

1. Vivos Therapeutics Receives First Ever FDA 510(k) Clearance for Oral Device Treatment of Severe Obstructive Sleep Apnea. Vivos Therapeutics. News release. November 29, 2023. 

https://www.biospace.com/article/vivos-therapeutics-receives-first-ever-fda-510-k-clearance-for-oral-device-treatment-of-severe-obstructive-sleep-apnea-/

2. Obstructive sleep apnea. Mayo Clinic. Webpage. Updated July 14, 2023, Accessed November 29, 2023. 

https://www.mayoclinic.org/diseases-conditions/obstructive-sleep-apnea/symptoms-causes/syc-20352090

The clearance includes the Vivos Therapeutics, Inc's DNA oral appliance, the mRNA oral appliance, and the mmRNA oral appliance for adults with severe obstructive sleep apnea.

FDA Grants 510(k) Clearance to Obstructive Sleep Apnea Oral Appliance

Non-Hispanic white populations comprise 78% of participants enrolled in US clinical trials, despite only accounting for 61% of the country’s population.

 Increasing clinical trial diversity is imperative for health equity and ensuring the clinical research sector develops treatments suitable for all Americans, no matter their background.

Sam Whitaker and Jason Dong are co-founders and co-CEOs of Mural Health.

Patient-first trial design, based around the tenets of adaptability and personalization, has emerged as a key solution to increase diversity and improve trial outcomes for all. There is an increasing focus on the need to flex trial designs to meet the needs of participants, whether they are logistical, financial, or educational. 

However, uptake of new technologies that offer patient optionality is far from universal, in part due to the industry’s desire to stay in its comfort zone. This hesitation is particularly apparent in clinical trial payments.

Financial and logistical barriers persist for clinical trial participants

In recent years, there has been greater recognition from FDA regulators of the nuances and different ethical considerations of reimbursement for expenses, compensation for time and burden, and incentives. Despite this, the industry has been slow to adopt a similarly nuanced approach to the use of patient-focused payment technologies, and it shows:

The routine costs associated with participation in a clinical trial—such as travel, accommodation, and childcare—continue to create barriers to enrollment for economically disadvantaged populations.

Patients with a household income below $50,000 are less likely to participate in clinical trials and trial participation decreases as income decreases.

 This includes American Indian, Alaskan Native, and Black ethnic groups in the United States, who all had a median household income below $50,000 as of 2021.

Why traditional payment solutions aren’t working

There are several existing methods for reimbursing clinical trial participants, but most pose problems for both sites and trial participants.

In these cases, reimbursements are issued for submitted expenses, or an average amount of estimated expenses is provided. But these methods are often admin intensive, creating more burden for sites and slowing down the overall process. An online qualitative study of rare disease patients and their caregivers found most felt payments were too slow, with respondents reporting waiting weeks or months to be reimbursed.

 These delays are likely to have a greater impact on individuals of lower socio-economic status.

 Many sponsors have opted to use prepaid debit cards, which removes the need for participants to wait for reimbursement claims to be processed. However, cardholders face a series of fees, including having to pay for activation, transactions, ATM withdrawals, and periods of inactivity—a high burden for socio-economic groups already struggling to participate in clinical trials.

The value of modern, patient-first reimbursement options

Patients are used to speed, convenience, and accessibility in their daily financial life. Payment app PayPal has more than 420 million users worldwide

 and 60% of consumers say they are interested in using a digital bank in the next year.

 Participants, and by extension sponsors, would benefit from similarly flexible solutions in clinical trial payments.

To ensure a truly patient-first approach, next-generation payment systems should:

Give every participant the same high level of security, control, and oversight, as well as the option to choose how they get paid, whether that is via PayPal, bank transfer, or checks that can be cashed at minimal cost.

Be easy to use. Participants should be given appropriate training to ensure there is no added burden.

Be available without the fees, extraneous charges, and delays of the old systems.

Include tools such as in-app ride hailing functions, which invoice the sponsor directly and eliminate the participant’s worry of not being able to afford to get to appointments or paying out of pocket and waiting months for reimbursement.

Financial burden is one of the core barriers to participating in a clinical trial. This hinders diversity, which in turn, impacts the efficacy of treatments for the entire American population. New patient-first approaches can give participants of all backgrounds the financial control and flexibility they need to sign up and stay on track.

To truly embrace patient optionality, sponsors should focus on proven barriers to participation, eradicate erroneous fees and give every participant the option to take control of their trial experience.

Sam Whitaker and Jason Dong, co-founders and co-CEOs, Mural Health.

1. National Academies of Sciences, Engineering, and Medicine. (2022). Improving representation in clinical trials and research: building research equity for women and underrepresented groups. Available at: https://www.ncbi.nlm.nih.gov/books/NBK584396/#:~:text=An%20FDA%20summary%20report%20of,Ortman%20and%20Guarneri%2C%202009). Last accessed: 14 February 2023.

2. National Library of Medicine (2016) UngePatient Income Level and Cancer Clinical Trial Participation: A Prospective Survey Study. Available at: 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824189/

3. Clincierge. (2022) Clinical Trial Payments: Patient Insights in Rare Disease Trials. Available at: 

https://www.clincierge.com/clinical-trial-payments-patient-insights-in-rare-disease-trials/

4. Journal of Clinical and Translational Science (2021). Fair payment and just benefits to enhance diversity in clinical research. Available at: 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427546

5. Global Data (2022). Number of Active PayPal Accounts: Global (Q3 2015 – Q1 2022). Available at: 

https://www.globaldata.com/data-insights/financial-services/number-of-active-paypal-accounts-global/

6. Bankrate (2023). Digital banking trends in 2023. Available at: 

https://www.bankrate.com/banking/digital-banking-trends-and-statistics/

Patient-first trial design, based around the tenets of adaptability and personalization, has emerged as a key solution to increase diversity and improve trial outcomes for all.

Increasing Clinical Trial Diversity Through Patient-First Payment Options

 examined the proportion of pivotal randomized controlled trials (RCTs) that used optimal control groups supporting newly approved drugs for systemic rheumatic diseases (SRDs) in the United States. The study authors analyzed RCTs specific to this therapeutic area between January 2012 and October 2022 for design, study duration, control group, and primary end point. The quality of control groups was determined by comparison with published guidelines before and during the trials.

SRDs are heterogenous groups of diseases characterized by systemic inflammation and dysregulation of the autoimmune system. Interactions between genetic and environmental factors may lead to the triggering of immune pathways, producing multiple autoantibodies and inflammatory factors, and finally, causing damage to multiple organs.

 While there have been advances in RCT execution, they are still lacking considering the global disease burden that SRDs carry, according to the investigators.

“Given the potential of severe and widespread organ damage, SRDs are associated with a considerable disease burden globally despite advances in the treatment landscape of SRDs,” the study authors wrote. “There is an urgent need for changes in current therapies and the development of new approaches.”

The investigators observed that a comprehensive evaluation of the quality of control groups in pivotal RCTs supporting SRD drug approvals by the FDA is lacking. As such, they noted that RCTs must strive to use optimal control groups to reflect the best available treatments.

According to the Himmelfarb Life Sciences Library at George Washington University, an RCT is: “A study design that randomly assigns participants into an experimental group or a control group. As the study is conducted, the only expected difference between the control and experimental groups in a randomized controlled trial is the outcome variable being studied.”

Among 65 pivotal RCTs supporting 44 FDA-approved SRD drugs, only 16 (24.6%) utilized optimal control groups, while 55 trials (84.6%) lacked active treatment groups, 47 of which (85.5%) were considered suboptimal. Notably, trials for systemic arthritis, including rheumatoid arthritis (RA) and psoriatic arthritis (PSA), predominantly employed suboptimal control groups. Investigating drug groups generally exhibited significant improvement in response rates compared to placebo groups, emphasizing the potential biases introduced by suboptimal controls.

“From an ethical standpoint, it is not acceptable to subject patients to placebos or therapies that are ineffective for a prolonged period, especially for diseases that warrant early control. It is important to avoid such practices at all costs,” the authors wrote. “From an ethical standpoint, it is not acceptable to subject patients to placebos or therapies that are ineffective for a prolonged period, especially for diseases that warrant early control. It is important to avoid such practices at all costs.”

The findings suggest a need for improvement in the quality of control groups in pivotal clinical trials supporting SRD drug approvals, with potential implications for regulatory decision-making and patient outcomes, according to the authors. Based on the results, they recommend consistently prioritizing efforts toward promoting appropriate control groups for pivotal clinical trials.

“When planning a pivotal RCT, it is important to use the best treatments available as the control group while carefully selecting inclusion and exclusion criteria,” the authors wrote. “At least from the operational perspective, informed consent should reflect all the available choices for participants to review.”

Liu, Y., Xu, Y., & Cheng, X. (2023). Quality of Control Groups in Randomized Clinical Trials Supporting Systemic Rheumatic Disease Drug Approvals by the US Food and Drug Administration. 

https://doi.org/10.1001/jamanetworkopen.2022.31743

Gourley M﻿, Miller FW﻿. Mechanisms of disease: environmental factors in the pathogenesis of rheumatic disease.

Wang L﻿, Wang FS﻿, Gershwin ME﻿. Human autoimmune diseases: a comprehensive update.

Bossuyt X﻿, De Langhe E﻿, Borghi MO﻿, Meroni PL﻿. Understanding and interpreting antinuclear antibody tests in systemic rheumatic diseases.﻿

Study Design 101: Randomized Controlled Trial. (n.d.). Himmelfarb Health Sciences Library. Retrieved from 

https://guides.himmelfarb.gwu.edu/studydesign101/randomized-controlled-trial

Results from decade-long analysis suggest great improvement is needed in the quality of control groups.

Study Examines Use of Optimal Control Groups in Randomized Clinical Trials for Systemic Rheumatic Diseases

Roche has launched the Elecsys HBeAg quant, an immunoassay capable of detecting the presence and quantity of the hepatitis B e antigen (HBeAg) in human serum and plasma.

According to the manufacturer, the Elecsys quant combined with other laboratory data and clinical information will allow patients to find out whether they have hepatitis B virus (HBV) infection, the extent of the infection, and will enable treatment monitoring through a single assay.

 The Elecsys HBeAg quant is designed to use on the cobas e analyzers in countries that accept the CE Mark, Roche stated in the release.

“Hepatitis B affects millions of people each year and is a major global health burden. An accurate diagnosis is critical to ensuring timely treatment options. If hepatitis B is left untreated, it can cause chronic infections, putting people at high risk of death from cirrhosis and liver cancer," said Matt Sause, CEO of Roche Diagnostics, in a press release. "The addition of the Elecsys HBeAg quant immunoassay to our viral hepatitis testing portfolio underlines Roche’s commitment to tackle healthcare’s biggest challenges to support clinicians and their patients.”

The World Health Organization estimated that in 2019, 296 million individuals had chronic HBV, with 1.5 million new infections reported each year. Data from 2019 also show an estimated 820,000 deaths associated with HBV, primarily from cirrhosis and hepatocellular carcinoma.

HBV is typically diagnosed via detection of active infection using the HBV surface antigen (HBsAg) test. Different types of antigens within the HBsAg suggest the degree of infectiousness. Patients infected with hepatitis Be antigen (HBeAg) carry a greater viral load. Acute or ongoing chronic infection is associated with antihepatitis Bc IgM.

HBV surface antibodies have viral DNA in blood and liver tissue that can be further analyzed with polymerase chain techniques. Patients with HBV may develop a wide range of symptoms, such as fever, fatigue, loss of appetite, and nausea and vomiting.

Studies note the importance of maintaining antibody levels against the virus. One of the only treatments available for active HBV infection is interferon alfa (IFN-a), which directly inactivates viral DNA by inhibiting protein synthesis.

 HBV is the most common type of viral hepatitis, and can impact all ages groups, creating a significant burden on global healthcare systems.

According to Roche, the Elecsys HBeAg quant test complements current HBV testing markers. The test will allow care providers to determine the disease phase of patients with suspected infection, assess viral activity in the liver, as well as the risk of progressive liver disease and hepatocellular carcinoma.

Roche notes that Elecsys HBeAg lowers complexity and improves operational efficiency because of a leaner workflow for lab personnel. The qualitative result provided by Elecsys HBeAg helps to diagnose patients with HBeAg as an early marker of acute HBV and can indicate chronic or active HBV, according to Roche. They added that this will improve patient management and help facilitate the most appropriate treatment plan.

The tool can also be used for perinatal screening by monitoring antiviral treatment response among patients with HBV. This may help to support developing a treatment plan that targets each individual patient’s needs, according to Roche.

1. Roche expands hepatitis diagnostics portfolio to help clinicians diagnose and monitor patients with acute or chronic hepatitis B infection. Roche. News release. November 27, 2023. Accessed November 28, 2023.

2. WHO 2023. Hepatitis B Fact sheet. Available at 

https://www.who.int/en/news-room/fact-sheets/detail/hepatitis-b

3. Gregorio, Germana V, et al. Viral Hepatitis. National Center for Biotechnology Information, U.S. National Library of Medicine, 1995, 

4. Houglum J. E. (1983). Interferon: mechanisms of action and clinical value. 

, 2(1), 20–28. Accessed November 28, 2023.

The Elecsys HBeAg quant can detect the presence and quantity of the hepatitis B e antigen (HBeAg) in human serum and plasma.

Roche Launches Immunoassay to Detect Acute Hepatitis B Infection

The FDA has approved nirogacestat (Ogsiveo) for adults with progressing desmoid tumors requiring systemic treatment.

The action makes Ogsiveo the first FDA-approved treatment for desmoid tumors. The approval was supported by results from the Phase 3 DeFi trial (NCT03785964), which showed that Ogsiveo reduced the risk of disease progression or mortality by 71% compared with placebo.

“Desmoid tumors can have a significant impact on people’s lives and are difficult to manage due to their invasive nature and high rates of recurrence. Ogsiveo is a highly innovative therapy with efficacy data demonstrating both meaningful antitumor activity and a significant improvement in desmoid tumor symptoms,” said DeFi investigator Mrinal M. Gounder, MD, sarcoma medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, New York, in a press release.

 “As a treating physician, it was encouraging to see in the DeFi trial that Ogsiveo achieved statistically significant and clinically meaningful improvements across the primary and all key secondary endpoints, while also having a manageable safety profile. This approval represents an important therapeutic advance for patients.”

Desmoid tumors, or aggressive fibromatosis, are most commonly diagnosed in patients between 20 and 44 years of age, with a prevalence up to three times higher in women. Historically, desmoid tumors were treated with surgical resection, although a high recurrence rate after surgery elevates the need for effective treatments.

Desmoid tumors are noncancerous growths that develop in connective tissue, most commonly found in the abdomen, arms, and legs. Some desmoid tumors grow slowly without a need for immediate treatment, whereas other types of the tumor rapidly develop and require surgery, radiation therapy, chemotherapy, or other treatments. Although these tumors are not considered cancers because they don't metastasize to other areas of the body, desmoid tumors can grow aggressively into nearby structures and organs.

The global, randomized, double-blind, placebo-controlled DeFi trial analyzed the efficacy, safety, and tolerability of Ogsiveo in patients with progressing desmoid tumors. The trial randomly assigned 142 patients to receive 150 mg of Ogsiveo or placebo twice daily with the primary endpoint of progression-free survival (PFS). Secondary and exploratory endpoints included safety and tolerability measures, objective response rate (ORR), duration of response, changes in tumor volume, and changes in patient-reported outcomes.

In the trial, median PFS in the Ogsiveo cohort was not yet reached compared with 15.1 months in the placebo cohort. The trial achieved all key secondary endpoints, with statistically significant improvements in ORR and patient-reported outcomes vs. placebo.

Ogsiveo was generally well tolerated with a manageable safety profile. Most women with childbearing potential had adverse events that were found to be consistent with ovarian dysfunction and were generally consistent with previously reported data.

Ogsiveo was previously granted Orphan Drug Designation for desmoid tumors and from the European Commission for soft tissue sarcoma. The FDA also granted the drug Fast Track and Breakthrough Therapy Designations for adults with progressive, unresectable, recurrent, or refractory desmoid tumors or deep fibromatosis.

1. FDA approves nirogacestat for desmoid tumors. FDA. November 27, 2023. Accessed November 28, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nirogacestat-desmoid-tumors

2. Ogsiveo (nirogacestat). Prescribing information. SpringWorks Therapeutics, Inc. Updated November 2023. Accessed November 28, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217677s000lbl.pdf

3. SpringWorks Therapeutics announces FDA approval of Ogsiveo (nirogacestat) as the first and only treatment for adults with desmoid tumors. News release. SpringWorks Therapeutics, Inc. November 27, 2023. Accessed November 28, 2023. https://ir.springworkstx.com/news-releases/news-release-details/springworks-therapeutics-announces-fda-approval-ogsiveotm

4. Desmoid tumors. Mayo Clinic. Webpage. Updated January 22, 2022. Accessed November 28, 2023. 

https://www.mayoclinic.org/diseases-conditions/desmoid-tumors/symptoms-causes/syc-20355083#:~:text=Desmoid%20tumors%20are%20noncancerous%20growths,don't%20require%20immediate%20treatment

Results from the Phase 3 DeFi trial (NCT03785964) showed that nirogacestat (Ogsiveo) reduced the risk of disease progression or mortality by 71% compared with placebo.

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