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The FDA has taken a clear position with Project Optimus in shifting toward more progressive tailored approaches while rejecting antiquated study designs to evolve clinical trial strategies to better align with newer drug classes. 

Artificial Intelligence Drives Industry Response to Project Optimus

Video interview with Sepehr Shojaei, VP, Design Solutions, Lightship

Lightship's Approach to Accessible, Representative, and Impactful Clinical Trials

Lightship prioritizes patient accessibility and centricity in clinical trials, ensuring a seamless and positive experience for every participant. Learn more about:

Lightship's mission and core purpose as a company

How Lightship’s mobile nursing teams and home visits enhance study participation and retention

The role of mobile research units in the community and how they enhance participant education, accessibility, and convenience

Sepehr Shojaei, VP of Design Solutions at Lightship, talks about how the company works with pharma and contract research organization (CRO) partners to support clinical trials that are patient-first and accessible.

Latest Conference Coverage

Lightship’s Approach to Accessible, Representative, and Impactful Clinical Trials

Video interview with David MacMurchy, CEO of Lightship

Accelerate Inclusive Enrollment and Delivery with Lightship

Lightship focuses on patient accessibility and centricity in clinical trials, ensuring the patient experience is a positive one. Learn more about:

Lightship's impact on achieving diversity in clinical trials by engaging underrepresented patient populations

How Lightship utilizes hybrid and decentralized trial designs to reduce patient burden

The impact a patient centric model has on clinical trial participation and outcomes

David MacMurchy, Chief Executive Officer at Lightship, offers some insights into the company's mission toward improving equity and diversity in clinical trials. 

The FDA has announced it will now be publishing adverse event data from the FDA Adverse Event Reporting System (FAERS) on a daily basis. The agency stated that this action represents a “significant step forward” in modernizing safety monitoring as well as its continued commitment to improving transparency.

In an FDA news release, Commissioner Marty Makary, MD, MPH, said: “Adverse event reporting should be fast, seamless, and transparent. People who navigate the government’s clunky adverse event reporting websites should not have to wait months for that information to become public. We’re closing that waiting period and will continue to streamline the process from start to finish.”

The FDA's principal database for collecting and analyzing adverse event reports, FAERS, encompasses an array of information such as:

product quality complaints for prescription drugs and therapeutic biologics, 

and reports submitted by healthcare professionals, consumers, and manufacturers.

FDA increases transparency with CRL publications

Earlier in July, the FDA revealed another 

 geared towards increasing transparency, publishing over 200 complete response letters (CRLs) issued between 2020 and 2024 in response to drug and biologic applications.

In an FDA news release from the time, Makary said: “For far too long, drug developers have been playing a guessing game when navigating the FDA. Drug developers and capital markets alike want predictability. So today we’re one step closer to delivering it to them, with an ultimate goal of bringing cures and meaningful treatments to patients faster.”

Prior to this announcement, CRLs were only shared with product sponsors, limiting broader industry visibility into the specific deficiencies that prevented approval.

A 2015 analysis conducted by the FDA revealed that 85% of safety and efficacy concerns raised in CRLs were not publicly disclosed by sponsors. Further, in about 40% of cases in which the agency called for new clinical trials to address safety or efficacy issues, details regarding the issues were not released to the public.

While the FDA has made its approach to radical transparency known through these initiatives, there are still questions regarding the agency’s execution. Around the same time the 200 CRLs were made available through openFDA, Replimune and Capricor were handed CRLs which both companies considered to be surprising.

The CRL to Replimune concerned its BLA for RP1 (vusolimogene oderparepvec) in combination with nivolumab, noting that the Phase I/II IGNYTE clinical trial (NCT03767348) did not constitute an adequate and well-controlled study.

Meanwhile, in the CRL to Capricor for Deramiocel, the FDA cited the need for additional data, despite the cell therapy being granted Priority Review in March, which was supported by findings from the Phase II HOPE-2 study (NCT03406780).

 regarding these CRLs, Craig Lipset, co-chair, Decentralized Trials & Research Alliance (DTRA), said: “This is particularly challenging for those who have based development strategies and investments on the outcomes of meaningful communications strategies with FDA stakeholders prior to 2025. It raises questions for developers today as to whether past understandings still hold true, as well as the potential risks and benefits of re-engaging with FDA on active development programs based on those past agreements.”

Despite the FDA’s efforts to improve transparency, many in the industry are still unclear on the agency’s views regarding 

. Outside of the recently issued CRLs, the FDA has also made a clear stance on tightening up studies for vaccines.

 regarding the FDA’s recent actions, Meri Beckwith, Co-CEO, Lindus Health, emphasized that there could be even more scrutiny of trial design on the horizon as the agency transitions to new reviewers.

“…maybe over the next year or two, there's a pretty consistent pattern of the FDA rejecting more studies that aren't controlled or insisting on more robust results, more carefully scrutinizing sample sizes, those kinds of things, remains to be seen,” he said. “My view is that these decisions, it's just unpredictability, the result of one set of reviewers, maybe transitioning off or out of the FDA, and then a different set of reviewers with a different perspective coming in.”

1. FDA Begins Real-Time Reporting of Adverse Event Data. News release. FDA. August 22, 2025. Accessed August 25, 2025. 

https://www.fda.gov/news-events/press-announcements/fda-begins-real-time-reporting-adverse-event-data

2. FDA Embraces Radical Transparency by Publishing Complete Response Letters. News release. FDA. July 10, 2025. Accessed August 25, 2025. 

https://www.fda.gov/news-events/press-announcements/fda-embraces-radical-transparency-publishing-complete-response-letters

The FDA has initiated daily publication of adverse event data from the FAERS, enhancing safety monitoring and transparency. This move aims to streamline adverse event reporting, making information more accessible. Additionally, the FDA has published over 200 complete response letters (CRLs) to increase transparency in drug and biologic application processes. However, industry concerns persist regarding the execution of these initiatives, particularly in trial design and the unpredictability of FDA decisions. The agency's evolving stance on trial design, especially for vaccines, suggests increased scrutiny and potential challenges for developers.

The FDA will now publish adverse event data from FAERS on a daily basis, marking a major step toward greater transparency in drug development.

FDA Expands Transparency With Daily Adverse Event Reporting

Theravance Biopharma has announced the completion of enrollment in the open-label portion of its pivotal Phase III CYPRESS trial (NCT05696717), which is evaluating ampreloxetine for the treatment of symptomatic neurogenic orthostatic hypotension (nOH) in patients with multiple system atrophy (MSA).

The treatment has previously shown clinical evidence of improving symptoms without exacerbating hypertension. Theravance noted that the CYPRESS study represents the first randomized-withdrawal trial designed specifically for MSA patients with nOH.

How Could Ampreloxetine Change the Treatment Paradigm of MSA Patients with nOH?

"nOH is one of the most debilitating manifestations of MSA, which affects about 40,000 patients in the US alone,” said Horacio Kaufmann, FB Axelrod professor of neurology, professor of Medicine, NYU Grossman School of Medicine, in a press release. “Yet current therapies often fail to provide lasting symptoms relief, require frequent dosing and carry a boxed warning for supine hypertension. Ampreloxetine is designed to address the underlying cause of nOH.

“In Study 0170, it showed compelling improvement in OHSA composite score without worsening supine hypertension.1 If these benefits are confirmed, I would expect to use ampreloxetine in the majority of my patients living with nOH due to MSA. I am encouraged that enrollment in CYPRESS, the first randomized-withdrawal trial designed specifically for the MSA population, has been completed, and I look forward to seeing the data early next year."

The multi-center, randomized-withdrawal CYPRESS trial will evaluate the efficacy and durability of ampreloxetine in approximately 102 patients with symptomatic nOH due to clinically diagnosed MSA.

The trial includes a 12-week open-label phase followed by an eight-week randomized withdrawal phase to rigorously assess durability of benefit.

The primary endpoint of the trial is change in orthostatic hypotension symptom assessment composite score from randomized-withdrawal baseline to week eight.

Key secondary endpoints included change from baseline in Orthostatic Hypotension Daily Activities Scale (OHDAS) item 1 at week eight post-randomization and change from baseline in OHDAS item 3 at week eight post-randomization.

Disease Background and Patient Population

patients with MSA have a median survival range of six to nine years.

The prevalence is estimated to be between one in every 20,000 people and one in every 50,000 people.

The most common age of onset is between the ages of 55 and 60 years.3 nOH affects approximately 80% of patients with MSA.

In the United States, there are an estimated 50,000 people living with MSA.

Theravance expects to release topline Phase III CYPRESS data in early 2026 and, if results are positive, plans to pursue an expedited New Drug Application submission to the FDA with a potential priority review designation.

"Completing enrollment in CYPRESS marks a major step toward bringing this potentially transformative therapy to patients with symptomatic nOH due to MSA – an underserved patient population in dire need for a new, effective and durable treatment with a favorable safety profile," said Áine Miller, PhD, head of Development, Theravance Biopharma, in the press release.

"Ampreloxetine is intended to target the root cause driving MSA-associated nOH by selectively inhibiting norepinephrine reuptake and demonstrated benefit in this patient population in Study 0170. The CYPRESS randomized withdrawal trial was designed with insights from Study 0170, and we are confident that, along with our careful study execution, this derisked program strongly positions us to evaluate ampreloxetine's full potential in this patient population."

Theravance Biopharma Completes Enrollment in Pivotal Phase 3 CYPRESS Study of Ampreloxetine in Patients with Symptomatic Neurogenic Orthostatic Hypotension due to Multiple System Atrophy. 

August 25, 2025. Accessed August 25, 2025. 

https://prnmedia.prnewswire.com/news-releases/theravance-biopharma-completes-enrollment-in-pivotal-phase-3-cypress-study-of-ampreloxetine-in-patients-with-symptomatic-neurogenic-orthostatic-hypotension-due-to-multiple-system-atrophy-302537380.html

Phase 3 Efficacy and Durability of Ampreloxetine for the Treatment of Symptomatic NOH in Participants with Multiple System Atrophy (CYPRESS). 

https://clinicaltrials.gov/study/NCT05696717?term=CYPRESS&intr=multiple%20system%20atrophy&rank=1

https://www.orpha.net/en/disease/detail/102

Theravance Biopharma has completed enrollment for the Phase III CYPRESS trial, evaluating ampreloxetine for treating symptomatic neurogenic orthostatic hypotension (nOH) in multiple system atrophy (MSA) patients. Ampreloxetine has shown promise in improving symptoms without worsening hypertension. The trial, the first of its kind for MSA patients, includes a 12-week open-label phase and an eight-week randomized withdrawal phase. If successful, Theravance plans to expedite an FDA New Drug Application. MSA affects approximately 50,000 people in the U.S., with nOH impacting 80% of these patients.

Ampreloxetine is being developed to address the root cause of blood pressure instability in multiple system atrophy, aiming to improve patient outcomes and independence.

Theravance Biopharma Completes Phase III CYPRESS Trial Enrollment for Novel Norepinephrine Reuptake Inhibitor in Multiple System Atrophy

Results from part 1 of a Phase I/II trial (NCT06569823) showed that Z-1018, Dynavax Technologies’ investigational shingles vaccine, produced immune responses comparable to Shingrix in healthy adults aged 50 to 69 years. Based on these findings, the company plans to advance Z-1018 into part 2 of the trial, which will focus on adults over 70 years of age.

Could Dynavax’s Z-1018 Offer a Safer Alternative to Shingrix?

"These positive data mark an important inflection point for our novel shingles vaccine program as we strive to develop a product with a potential best-in-class profile with the aim to disrupt the multi-billion-dollar shingles vaccine market, which is currently dominated by one product," said Ryan Spencer, CEO, Dynavax, in a press release. "We met our goal for this study, as the results show immune responses comparable to Shingrix, along with a favorable tolerability profile, and provide the basis for selecting the dose and regimen to advance into further development. Based on these findings, plans are underway to initiate part 2 of the Phase I/II trial in the 70 and older population, an opportunity to further de-risk this program ahead of Phase III development."

Part 1 of the randomized, active-controlled, observer-blinded, dose-escalation multi-center trial evaluated the safety, tolerability, and immunogenicity of Z-1018 compared to Shingrix in approximately 440 healthy adults between the ages of 50 and 69 years.

The primary endpoints of the trial were the percentage of patients with solicited local and systemic post-injection reactions, percentage of patients with adverse events (AEs), and percentage of patients with serious AEs, medically attended AEs, and immune-mediated AEs of special interest.

Key secondary endpoints included geometric mean concentration of IgG antibodies to varicella-zoster virus (VZV) antigen glycoprotein E (gE) four weeks after the second injection and geometric mean ratio of IgG antibodies to VZV antigen gE.

Results showed that Z-1018 demonstrated a 100% antibody response rate compared to 96.9% for Shingrix.

CD4⁺ T-cell responses were 89.7% for Z-1018 and 3.5% for Shingrix.

Notably, Z-1018 demonstrated a stronger safety profile, with only 12.5% local and 27.5% systemic grade 2/3 AEs, compared to 52.6% and 63.2%, respectively, for Shingrix.

According to the Centers for Disease Control and Prevention, shingles affects one in three people in the United States during their lifetime.

The risk increases with age and in people with weakened immune systems.

Anywhere from 1% to 4% of people who get shingles will go to the hospital due to complications, and nearly 30% of hospitalized shingles patients are immunocompromised.

Shingles results in fewer than 100 deaths each year in the United States, with nearly all of these cases occurring among older adults or individuals with weakened immune systems.

Postherpetic neuralgia, which is the most common complication of shingles, occurs in anywhere from 10% to 18% of people with shingles.

Clinical Significance and Potential Impact on Patients

"We are very encouraged by the magnitude and consistency of the immune responses observed, particularly the robust CD4⁺ T cell activity for Z-1018 compared to Shingrix," said Robert Janssen, MD, CEO, Dynavax, in the press release. "Shingles is a painful disease driven by cellular immune decline with age. A vaccine that provides a strong immune response alongside favorable tolerability, compared to the current standard of care, could provide an important new option for protection against this debilitating disease."

Dynavax Announces Positive Topline Phase 1/2 Results Supporting Potential Best-in-Class Shingles Vaccine Profile. 

August 21, 2025. Accessed August 22, 2025. 

https://investors.dynavax.com/news-releases/news-release-details/dynavax-announces-positive-topline-phase-12-results-supporting

Safety and Immunogenicity of an Investigational Herpes Zoster Vaccine (Z-1018) Compared to Shingrix® in Healthy Adults. 

https://clinicaltrials.gov/study/NCT06569823#study-overview

https://www.cdc.gov/shingles/data-research/index.html

Dynavax Technologies' investigational shingles vaccine, Z-1018, demonstrated immune responses comparable to Shingrix in a Phase I/II trial involving adults aged 50-69. The trial showed a 100% antibody response rate and stronger CD4⁺ T-cell responses for Z-1018, alongside a more favorable safety profile compared to Shingrix. These promising results have prompted plans to advance Z-1018 into further trials focusing on adults over 70. The potential for Z-1018 to offer a safer alternative to Shingrix could significantly impact the shingles vaccine market.

Results from the first part of a Phase I/II trial (NCT06569823) showed that Z-1018 generated immune responses comparable to Shingrix, with a 100% antibody response rate and nearly 90% CD4⁺ T-cell response in patients with shingles. 

Dynavax Technologies’ Investigational Shingles Vaccine Achieves Complete Antibody Response in Phase I/II Shingles Trial

In a 5-4 decision, the Supreme Court has allowed the Trump administration to continue with funding cuts to medical research that aim to advance diversity, equity, and inclusion (DEI).

The 5-4 ruling by the justices lifted an order from June made by US District Judge William Young of Massachusetts, who ruled an earlier policy implementing National Institutes of Health (NIH) funding cuts to be unlawful. Young’s ruling forced the NIH to restore funding for over 1,700 grants in the areas of heart disease, HIV/AIDS, Alzheimer’s disease, alcohol and substance abuse, and mental health issues.

The deciding vote in the Supreme Court’s latest ruling on August 20 was made by Justice Amy Coney Barrett.

In a statement, Barrett said: "As today’s order states, the District Court likely lacked jurisdiction to hear challenges to the grant terminations, which belong in the Court of Federal Claims.”

She added: “The Government is not entitled to a stay of the judgments insofar as they vacate the guidance documents.”

Meanwhile, Massachusetts Attorney General Andrea Joy Campbell, representing one of 16 states against the NIH cuts, said she was disappointed by the Supreme Court’s decision.

In a statement, she added: "Even though the Court did not dispute that the Trump Administration’s decision to cut critical medical and public health research is illegal, they ordered the recipients of that funding—hospitals, researchers, and the state—to jump through more hoops to get it back. All the while, our research institutions, economy, and residents who depend on this lifesaving medical research will suffer.”

Impact on diversity and clinical research

The clinical research industry has been deeply impacted by 

—such as the turmoil around NIH grants and DEI initiatives—in 2025. These challenges date back to when the administration began taking steps to address DEI policies in clinical research earlier in the year.

Just days after taking office in January, President Donald J. Trump issued an executive order effectively banning federal recognition of gender identity apart from biological sex. In response, the FDA quietly removed a previously issued draft guidance on diversity in clinical trials from its official website.

Only weeks later, the NIH announced that it would cut “indirect expenses” in the funding it provides to research grants by nearly half. Immediately after the cut took effect on February 9, 22 states sued the NIH and the US Department of Health and Human Services, citing the cut as unlawful.

Industry perspectives on long-term effects

Kyle McAllister, co-founder, CEO, Trially, discussed the impact of funding cuts on underrepresented populations in medical research, emphasizing the importance of diversity-focused research.

“I don't see a way that walking back diversity requirements, walking back funding for research focused on diversity doesn't have a long-term impact,” he said. “Without direct investment in research into diverse populations, […] I think we really risk putting those populations further behind and increasing the care gap between the folks that aren't in those underrepresented populations and those that are.”

In terms of how the industry can continue to move forward and ensure that a steady pipeline of medical research is maintained, Ron Lanton, partner, Lanton Law, noted that researchers will have to view their trials through a more conservative lens.

, he said: “This entire situation is disheartening. It could halt many clinical trials focusing on minority groups and stifle progress on certain vaccines. This could lead to entire sectors of science receiving neither funding nor attention. I don’t think we fully understand the magnitude of this yet—it won’t be clear until it actually happens.”

1. Gerstein, J. (August 21, 2025). Supreme Court lets Trump admin cut off health grants it says advance DEI or ‘gender ideology extremism’. 

https://www.politico.com/news/2025/08/21/supreme-court-nih-funding-grants-00518782

2. Hurley, L. Grumbach G. (August 21, 2025). Supreme Court allows Trump's cuts to health research grants over DEI policies. 

https://www.nbcnews.com/politics/supreme-court/supreme-court-allows-trump-cuts-nih-grants-dei-policies-rcna222470

The Supreme Court's 5-4 decision permits the continuation of funding cuts to medical research aimed at promoting diversity, equity, and inclusion (DEI), reversing a previous ruling by US District Judge William Young. This decision affects over 1,700 grants related to critical health issues. Massachusetts Attorney General Andrea Joy Campbell expressed disappointment, highlighting the negative impact on research institutions and public health. Industry experts emphasize the long-term consequences of reduced diversity-focused research, potentially widening healthcare disparities and stalling progress in clinical trials targeting minority groups.

The Supreme Court has ruled 5-4 to allow the Trump administration’s NIH funding cuts to continue, impacting more than 1,700 medical research grants in areas including heart disease, HIV/AIDS, Alzheimer’s disease, and mental health.

Sirj Goswami, PhD, and Jason Rizzo, MBA

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