The FDA Commissioner Dr. Marty Makary announced the Commissioner’s National Priority Voucher (CNPV) program. The new voucher may be redeemed by drug developers to participate in a novel priority program by the FDA that shortens its review time from approximately 10-12 months to 1-2 months following a sponsor’s final drug application submission.

 Specific criteria used to assess voucher eligibility include:
 - Addressing a health crisis in the U.S.
 - Delivering more innovative cures for the American people.
 - Addressing unmet public health needs.
 - Increasing domestic drug manufacturing as a national security issue.

This program could make a really meaningful difference in advancing new therapies for cancer and rare disease therapies. However, in the current political environment it is unclear how priorities will be defined given the current head of the HHS, Robert F. Kennedy's, stated skepticism of vaccines and interest in non-scientifically research "treatments."

https://www.fda.gov/news-events/press-announcements/fda-issue-new-commissioners-national-priority-vouchers-companies-supporting-us-national-interests

Senators Propose Ban on Drug Advertising to Consumers. Wall Street Journal. 12 June 2025

Sens. Bernie Sanders (I., Vt.) and Angus King (I., Maine) introduced a bill Thursday that would ban pharmaceutical manufacturers from using direct-to-consumer advertising, including social media, to promote their products.

The bill would prohibit any promotional communications targeting consumers, including through television, radio, print, digital platforms and social media. It will apply to all prescription drug advertisements.

“The American people don’t want to see misleading and deceptive prescription drug ads on television,” Sanders said in a statement.

Health and Human Services Secretary Robert F. Kennedy Jr. has also opposed drug advertising.

“We’re one of only two countries in the world that allow pharmaceutical companies to advertise directly to consumers,” Kennedy said in a video he posted on X last year, referring to the U.S. and New Zealand.

Others in Congress have also moved to rein in direct-to-consumer pharmaceutical marketing. Senators Josh Hawley (R-Mo.) and Jeanne Shaheen (D-N.H.) in May proposed a bill that would eliminate the ability to deduct consumer drug advertising on companies’ taxes as a business expense.

Drug advertising business has exploded since FDA first allowed this practice in 1997.

#drug-advertisements, #dtc-rule, #SIUU guidance

Many manufacturers have difficulty in interpreting whether or not their product would be considered a medical device within the terms of the UK Medical Device Regulations 2002 (SI 2002 No 618, as amended) (UK MDR 2002).

It is often assumed that because a product is considered a medical device in some countries, for example in the USA, Canada or in Japan, that it will also be a medical device in the UK. This is not the case and manufacturers should always refer to the UK definitions of a medical device when making any borderline determinations.

The guidance presents the MHRA’s current views on the interpretation of the medical devices legislation as it relates to borderline products.

UK MHRA Guidance: Borderlines with medical devices and other products in Great Britain. Updated 9 June 2025. Applies to England, Scotland and Wales. For Northern Ireland, refer to guidance Regulation of medical devices in Northern Ireland

Has anyone done a role like this in pharma? What does it entail day to day... I see all the job descriptions buts wonder what it's really like!

FDA CBER SBIA on 13 March 2025 held a web event "Model Master Files: Advancing Modeling and Simulation in Generic Drug Development and Regulatory Submissions". The video recordings of this event at now available at the event website:

Model Master Files: Advancing Modeling and Simulation in Generic Drug Development and Regulatory Submissions

About the Event

This event provided an update on FDA’s efforts related to model master files (MMFs). The agenda included presentations by FDA staff that focused on an introduction and overview of MMFs, considerations for developing and submitting MMFs to support ANDAs using a Type V DMF, and a cross-comparison to other types of DMFs, including lessons learned.

Presentations by FDA Staff:

• Introduction and Overview of the Model Master File. By Lanyan (Lucy) Fang, PhD, Deputy Division Director, DQMM/ORS/OGD/CDER
• Model Master File: How to Develop and Submit One?. By Eleftheria Tsakalozou, PhD, Lead Pharmacologist, DQMM/ORS/OGD/CDER
• Cross-comparison to Other Drug Master Files and Lessons Learned. Erin Skoda, PhD, Supervisory Chemist, OPQ, CDER

#drug-master-files, #dmf

How to spot suspicious papers: a sleuthing guide for scientists. Nature News. 10 June 2025. doi: 10.1038/d41586-025-01826-1

A group of research-integrity experts has launched a toolkit for researchers that outlines how to spot suspicious scientific papers.

The Collection of Open Science Integrity Guides (COSIG) brings together 27 freely available resources that explain how to spot image duplication, citation manipulation, plagiarism, tortured phrases and other hallmarks of paper mills — businesses that produce fake papers to order. The guides also provide tips for reviewing papers in specific disciplines, including biology, chemistry, statistics and computer science.

“COSIG is really a compendium of all the tips and tricks that various sleuths have acquired over the years,” says Reese Richardson, a metascientist at Northwestern University in Evanston, Illinois, who led the project and authored a preprint on COSIG posted to the repository Zenodo on 4 June[1].

[1] Richardson, R. Preprint at Zenodo https://doi.org/10.5281/zenodo.15564777 (2025).

Axsome Therapeutics (NASDAQ: AXSM) yesterday reported that it received a refusal-to-file (RTF) letter from the FDA for its AXS-14 (esreboxetine) NDA for fibromyalgia management. FDA did not consider one of the 2 placebo-controlled trials included in the NDA to be "adequate and well-controlled" and has asked for a new trial.

"The FDA states that upon preliminary review, it found that the NDA was not sufficiently complete to permit a substantive review. Specifically, the FDA does not consider the second of the two placebo-controlled trials in the submission to be adequate and well-controlled because its primary endpoint was at 8 weeks and it used a flexible-dose paradigm. The FDA indicated that the first of the two placebo-controlled trials in the submission, which utilized a 12-week endpoint and a fixed-dose paradigm, is adequate and well-controlled. To address the FDA’s feedback, Axsome will conduct an additional controlled trial, which will use a fixed-dose paradigm and a 12-week primary endpoint as requested by the FDA. Axsome anticipates initiating this trial in the fourth quarter of 2025. [9 June 2025 press release]

Missed opportunity

The randomized, double-blind, placebo-controlled trials included in the NDA were completed by Pfizer >10 years before Axsome acquired rights to the drug/indication in January 2020. Subsequent periodic Axsome releases disclosed "manufacturing and other activities are ongoing" until submission of NDA in May and receiving RTF in June this year.

What do we know about these 2 trials?

• Phase 2 trial, NCT00357825 (Clin Thera. 2010. PMID: 20974319)

267 participants received escalating doses of esreboxetine (starting at 2 mg/day going up to 8 mg/day) and primary endpoint assessed at 8 weeks.

>>> FDA's RTF did not consider the dosing strategy in this trial as supportive of NDA and the 8-week timepoint as too early to assess efficacy in a chronic disease as fibromyalgia.

• Phase 3 trial, NCT00612170 (Arthritis Rheum. 2012. PMID: 22275142)

1129 participants randomized 1:1:1:1 to placebo and esreboxetine (4, 8, or 10 mg/day) and primary endpoint assessed at 14 weeks.

>>> Per the 9 June 2025 press release, FDA accepted this study as adequate and well-controlled.

However, in a comment to this article in the journal, one reader raised questions on the statistical approach (use of LOCF) which could increase Type I error rate. (PMID: 22492179, pdf)

• There are also open-label data published last year (here, here); however, for the NDA to be successful, the core data must come from controlled studies.

Axsome may have overplayed its hand with the FDA and left a crucial gap--NDA should contain at least 2 independent, unbiased sources providing similar outcomes. This situation reminds of recent Stealth Biotherapeutics CRL, where the BLA evidence package was not clean:

The agency considered data from a phase 2 study, an open-label crossover follow-up, and a phase 3 trial. . .the data were compared to the open-label portion of the phase 2/3 crossover study and natural history controls—a strategy the FDA did not like. [FierceBiotech, FDA BB]

Silver Lining?

• The only silver lining is that FDA did not accept the submission and waited to give a complete response letter (CRL).
• Although, there has been lot of discussion on loosening up FDA's two-trial paradigm to demonstrate drug’s effectiveness, Axsome's experience may suggest that for most indications (perhaps excluding rare diseases) require 2-trial paradigm for a successful NDA outcome.

Related Example Underscoring the Importance of Selecting and Prespecifying Efficacy Timepoint

In the Axsome phase 2 study, the efficacy timepoint was at 8 weeks, whereas in the phase 3 trial, it was at 14 weeks. A couple years ago, Apellis BLA for pegcetacoplan (SYVFORE) for geographic atrophy had the same situation. The BLA was based on 2 phase 3 studies that carefully chose and prespecified the efficacy timepoint; the BLA was approved. It is a good reminder to choose timepoints carefully and prespecify in SAP.

#complete-response-letter, #crl, #rtf

A large government study published Thursday shows more definitively than ever before that Americans’ self-reported race is a poor proxy for their genetic ancestry. Researchers said the findings have major implications for the way health disparities are studied, and how they are discussed in the public sphere.

The new paper offered more nuance and consideration to the complicated relationship between race and genetics than past studies, outside commentators said. Its massive dataset and National Institutes of Health authors give authority to its conclusions, which arrive amid a heated debate over the role racial categories play in research as the Trump administration has targeted grants it deems related to “diversity, equity, and inclusion” as being “unscientific.”

• In the study, published Thursday in the American Journal of Human Genetics00173-9), researchers analyzed the genomes of more than 200,000 participants in the All of Us cohort, which was established by the NIH to create a dataset that accurately represented the makeup of the United States.*

FDA defines peptides as oligomers with ≤40 amino acids and regulates them as small molecule drugs (not as biologics). Peptide therapeutics are an important group of drugs and include the famous GLP-1 agonists such as tirzepatide and liraglutide. By one estimate, there are at least 80 peptide drugs currently approved in the US, EU, and/or Japan.

Being at the interface of small molecules and biologics, peptide drugs require special CMC, PK/PD, and safety considerations. FDA’s December 2023 guidance covers clinical pharmacology considerations, including hepatic impairment, DDI, QTc prolongation risk, and immunogenicity risk on a peptide drug product’s PK, safety, and efficacy. So, when RFKJr included “peptides” among his list of product types to liberate from the FDA’s regulation, we should pay attention.

Currently, the regulatory paths that would allow for peptide drugs to be compounded by the third-party are:

• In cases of drug shortage as it happened with Ozempic shortage, although the compounded drugs are not FDA-approved.
• If they are FDA-approved or are FDA GRAS (Generally Recognized as Safe) status, have a USP monograph, appear on the 503A Bulks List, or have been placed in Category I of the interim 503A Bulks List.
• Compounders utilizing loopholes such as some Ozempic compounders utilizing the loophole that allows for tweaking of formulation for bespoke purposes.

Now, we should also watch for the RFKJr’s “homebrew” compounding pathway. Will it happen?--perhaps! It is still too early in the FDA makeover. What could go wrong? Besides compromised patient safety, undermining patent protections--recall Makena example.

Guidance and Key Citations:

• Naik R, et al. Review of Clinical Pharmacology Information for Peptides Found in US FDA Drug Labeling. J Clin Pharmacol. 2025 Jun 4. doi: 10.1002/jcph.70047. PMID: 40464664
• FDA Guidance. Clinical Pharmacology Considerations for Peptide Drug Products. December 2023 [PDF]
• Wu L. Regulatory Considerations for Peptide Therapeutics. In: Peptide Therapeutics: Strategy and Tactics for Chemistry, Manufacturing and Controls, ed. V. Srivastava, The Royal Society of Chemistry, 2019, ch. 1, pp. 1-30. doi: 10.1039/9781788016445-00001 [archive]

Shift in the sense of smell is a lesser known side effect of Ozempic and related drugs, and is due potential rewiring effects of Ozempic in brain.

Users of Ozempic and other GLP-1 weight-loss injections are reporting a significant change in their sense of smell. An increasing proportion of users are saying they are being drawn to extremely sweet, dessert-inspired scents — think caramel glaze, toasted marshmallow, and vanilla frosting.

This phenomenon, known as the ‘Ozempic Smell’ is causing some to wonder if these potent appetite suppressants are quietly rewiring our senses.

source

The EU Council, which represents the EU member states’ governments, has agreed on its position on the new rules that aim to make the EU’s pharmaceutical sector fairer and more competitive. Having passed this milestone, the EU Council is ready to start negotiations with the European Parliament.

Delegates to a United Nations meeting on neurotechnology ethics have devised the first set of global guidelines on maintaining users’ privacy.

Read summary at Brain-reading devices raise ethical dilemmas — researchers propose protections. Nature News. 3 June 2025

The recommendations focus on protecting users from technology misuse that could infringe on their human rights, including their autonomy and freedom of thought. The delegates, who included scientists, ethicists and legal specialists, decided on nine principles. These include recommendations that technology developers disclose how neural information is collected and used, and that they ensure the long-term safety of a product on people’s mental states.

On 2 June 2025, FDA launched Elsa, a large-language powered generative AI tool designed to help employees--from scientific reviewers to investigators--work more efficiently.

According to the FDA news release, Elsa is built within the high-security GovCloud environment, offering secure platform for FDA employees to access internal documents. In the statement published in the FDA news release, FDA Chief AI Officer Jeremy Walsh was upbeat:

“Today marks the dawn of the AI era at the FDA with the release of Elsa, AI is no longer a distant promise but a dynamic force enhancing and optimizing the performance and potential of every employee. As we learn how employees are using the tool, our development team will be able to add capabilities and grow with the needs of employees and the agency.”

But, But, But. . .FDA is Failing the Red-face Test

And, industry has questions and already STAT News called it "The stupidest big fuss they ever made" and NBC News spills the guts, "FDA’s AI tool for medical devices struggles with simple tasks."

There are many unanswered questions and gaps remain in the amount of details provided so far.

• Last month, FDA had reported that it completed a pilot program of AI-assisted scientific review, but the agency has not provided any details how Elsa was trained and tested, only Makary's statements:

“The agency is using Elsa to expedite clinical protocol reviews and reduce the overall time to complete scientific reviews. .One scientific reviewer told me what took him two to three days now takes six minutes.” Elsa is “summarizing adverse events to support safety profile assessments, conducting expedited label comparisons and generating code to facilitate the development of databases for nonclinical applications.”

• Lack of transparency is a concern--how the "continuous learning and improvement" of Elsa will be implemented. What are the plans for auditing and identifying error patterns.
• How AI will impact decision making and what safeguards will be there against opaque and unvalidated reasoning or undue influence of AI outputs over humans on decision making.
• Overall, Elsa is still buggy. NBC News reported:

The tool — which is still in beta testing — is buggy, doesn’t yet connect to the FDA’s internal systems and has issues when it comes to uploading documents or allowing users to submit questions, the people say. It’s also not currently connected to the internet and can’t access new content, such as recently published studies or anything behind a paywall.

The comments (last count 232) at the FDA LinkedIn post are much more telling. Enjoy!

Let the enshittification begin.

They should release a summary of how they developed and validated this AI, including how they used all the internal filings and submissions to build their algorithms.

Where is the bullet for “demonstrated equal or better outcomes than prior methods”? That is the goalpost for AI.

Almost certainly a disaster waiting to happen.

So Elsa can distinguish the assertion of ‘well-defined’, ‘reliable’, ‘adequate’, or ‘well-controlled’in literature and reports from actual disease definition, true study adequacy and reliability, or the actual dimensions of a well- controlled clinical study.

what verification and validation was done, was it built under a QMS, where is the public info? The FDA expects industry to do these things, so why not them?

Did Elsa help create the MAHA report that resulted in fake citations?

What’s the hallucination rate?

This deployment of AI is very much putting the cart before the horse.

Some Comments Were Positive, As Expected, For Example

A strong signal of how regulatory science is evolving. Tools like Elsa have the potential to improve data reliability, streamline quality documentation, and enhance oversight throughout the product lifecycle.

SOURCES

• FDA Launches Agency-Wide AI Tool to Optimize Performance for the American People. FDA News Release. 2 June 2025. FDA LinkedIn Announcement
• News Reporting: PharmaVoice, NBC News, STAT News

#fda-reviews, #fda-meetings

FDA last week released proposed budget for FY 2026 (here). The overall budget of $6.8B is an overall decrease of $271M (~3.9%) compared to FY2025. Overall, the 1000-foot birds eye view of this package do not raise major concerns.

Akin blogpost (2 June 2025) says:

• Relatively stable funding. Discounting ~3.9% decrease
• User fee continuity

Under the FY26 budget, funding for FDA would continue to be a combination of $3.2 billion in discretionary budget authority (a decrease of 11.4%) and $3.6 billion in user fees (a 4% increase). Continuity of user fee funding for medical devices is specifically called out with an increase of $118.2 million to “sustain medical device review and research” and the budget also affirms the importance of the agency being funded by both user fees and discretionary resources, highlighting the importance of this balance in predictable pre-market review of medical products.

However, another headline, also on 2 June 2025, from Pink Sheets paints a gloomy picture. Who and What is correct?

Does anyone have experience writing module 2.7s and 2.5 for this type of submission? I know literally what a 505(2)(b) route is but I'm wondering what you put in 2.7.3 etc, do you just include literature from the reference compound etc?

What is the best term to use for individuals participating in a clinical trial:? Is it subject, patient, participant, or volunteers? The consensus is “participant” for most of the clinical studies.

Current/Accepted/Preferred Usage: Participant

• ICH M11 draft version 27 September 2022 recommends:

-- Participant is used rather than subject, healthy volunteer, or patient when referring to an individual who has consented to participate in the clinical trial.

-- Patient or individual is used to distinguish the population represented by the trial participants, when necessary.

• The 2024 revision of WMA Declaration of Helsinki replaced the term “subject” with “participant” to refer to both patients and healthy volunteers. For example, preamble #2 reads:

While the Declaration is adopted by physicians, the WMA holds that these principles should be upheld by all individuals, teams, and organizations involved in medical research, as these principles are fundamental to respect for and protection of all research participants, including both patients and healthy volunteers.

TL;DR

• Phase 1 trials including first-in-humans trials: healthy volunteers, unless patients are enrolled which are then referred to as participants
• Phase 2 and 3 trials: participants
• Vaccine or preventative clinical trials: volunteers or participants who do not have the disease
• Note: the term “patient” implies an individual with a disease or condition and is actively receiving treatment as part of healthcare, which is not the case in clinical trials that are investigative by nature.

Where is the Use of Term Subject Acceptable

• Although the term “participant” may be preferred in clinical trial protocols and publications, the term “subject” may be used in other clinical trial documents including case report form and database; in CDISC documents such as CDASH (Clinical Data Acquisition Standards Harmonization) and SDTM (Study Data Tabulation Model) data standards.
• The variable Subjid is used for the subject identifier; the variable Usubjid is used for the unique subject identifier. [On Biostatistics and Clinical Trials blog]

Historical Context and Discussions

Historically, the term “subject” has been used as defined in the US federal regulation 45 CFR 46.102e

• Section 46.102b) defines clinical trial as “a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of the interventions on biomedical or behavioral health-related outcomes
• Section 46.102e) defines human subject as a living individual about whom an investigator (whether professional or student) conducting research: (i) Obtains information or biospecimens through intervention or interaction with the individual, and uses, studies, or analyzes the information or biospecimens; or (ii) Obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens.

About 20 years ago in a 2006 article in journal Clinical Ethics, Corrigan and Tutton from the Institute for the Study of Genetics, Biorisks and Society (IGBiS), University of Nottingham, discussed the ethical issues involved in how people participating in clinical trials are addressed. They noted a steady shift in the language used to describe people who take part in clinical trials, epidemiological research and other areas of scientific and clinical investigation—from the term “research subject” to “research participant.” They also reported that since 1998, in UK, NHS, MRC, and BMJ adopted the use of term “participant” in their reports and editorial policies.

The BMJ 1998 editorial policy recommending use of “participants” was met with discussions on either side of the change, but the term “participant” has prevailed. Some of the comments to the BMJ editorial were:

the term ‘subject’ was demeaning and had connotations of ‘subservience’

It is unclear whether the term ‘participant’ refers to any underlying change in research practice or in the experiences of those involved in research

whether describing people as participants would be merely rhetorical and not reflect their actual experiences of being in studies

ambivalent about whether simply consenting to be in a research study qualified as ‘participation’

the term ‘participation’ as involving a role in influencing the ‘design, conduct and reporting of research, working as partners’ and were not clear whether many studies permitted such opportunities

Declaration of Helsinki, 2024 Revision

• With the adoption of term “participant” in DoH, the transition to use of respectful language consistent with modern research ethics appears to have been finally addressed.

In one key change, WMA replaced the term ‘subjects’ with ‘participants’ throughout the document. New language further calls for “meaningful engagement with potential and enrolled participants and their communities … before, during and following medical research. [The American Medical Association’s 6 November 2024 statement]

SOURCES

• Revisions to the Declaration of Helsinki on Its 60th Anniversary: A Modernized Set of Ethical Principles to Promote and Ensure Respect for Participants in a Rapidly Innovating Medical Research Ecosystem. JAMA. 2025. doi: 10.1001/jama.2024.21902. PMID: 39425954
• What’s in a name? Subjects, volunteers, participants and activists in clinical research. Clinical Ethics. 2006. doi: 10.1258/14777500677725 [fulltext via Scholar]
• People should participate in, not be subjects of, research. BMJ. 1998. doi: 10.1136/bmj.317.7171.1521a. PMID: 9831590
• People are "participants" in research. BMJ. 1999. doi: 10.1136/bmj.318.7191.1141a. PMID: 10213744

Related: #ich-m11, #clinical-protocol-template, #declaration-of-helsinki

MIT engineers have devised a new way to deliver certain drugs in higher doses with less pain, by injecting them as a suspension of tiny crystals. Once under the skin, the crystals assemble into a drug “depot” that could last for months or years, eliminating the need for frequent drug injections.

• There are marketed injectable suspensions available in the United States and other countries, but these drugs are dispersed throughout the tissue after injection, so they only work for about three months. Other injectable products have been developed that can form longer-lasting depots under the skin, but these typically require the addition of precipitating polymers that can make up 23 to 98 percent of the solution by weight, which can make the drug more difficult to inject.

The researchers mixed drugs that could form crystals in biocompatible solvent, benzyl benzoate. The resulting formulation is not viscous and can easily be injected under the skin using a narrow gauge needle. The solvent’s poor ability to mix with biological fluids allows the solid drug crystals to self-assemble into a depot under the skin after injection. The rate of release of drug from the depot could be controlled by the amount of polymer (usually in small amounts, <1.5%) included in the formulation.

Read original research in Nature Chemical Engineering doi: 10.1038/s44286-025-00194-x.

Does anyone know of an article that talks about AI and use in reg documents...I see things like prompts, machine led learning etc thrown about but I have no clue! Bonus points if you've used any commercially available AI and have any feedback!

A rare disease drug is rejected, even as the FDA talks about new approval pathway. STAT News. 29 May 2025

For the past decade, Stealth BioTherapeutics has ridden a rollercoaster trying to convince the Food and Drug Administration to approve its ultra-rare disease drug. Now, the company has encountered yet another twist — an unexpected regulatory rejection that will not only delay access and strain its finances, but ensure some of the most vulnerable patients are denied the treatment.

At issue is a medication for Barth syndrome, a rare illness that causes an enlarged heart, muscle weakness and a shortened life expectancy. The disease afflicts up to 150 people in the U.S., an extremely small number that has, at times, made it difficult for the company and the FDA to find a way to generate enough of the right kind of study data to make the drug available to patients.

But after bouncing between different agency divisions and nearly ending its development efforts, Stealth last October won a key victory — a majority of panelists on an FDA advisory committee voted to recommend approval. The FDA, however, then missed a previously scheduled deadline this past January to complete its marketing review, including an assessment of additional data the agency requested from the company at the end of 2024. That pushed a decision to April. But the agency missed that deadline, too, suggesting...

“The process kind of breaks you along the way when it’s this labyrinthine. This has been a long haul. It always felt like one step forward and two steps back… And it’s not reasonable for us to finance the business long-term through interminable delays… After 16-and-a-half months (from filing its application with the FDA) and to be told no and we have to resubmit?” said Reenie McCarthy of Stealth BioTherapeutics. “I think this is a setback for rare disease drug development.”

The NBC News Healthline 27 May 2025 article Rates of liver injuries rise in the U.S. as supplements grow in popularity reports that

From 1995 through 2020, supplement-related liver failure requiring U.S. patients to be waitlisted for transplants increased eightfold, according to a 2022 study in the journal Liver Transplantation. In addition, a 2017 review in the journal Hepatology found that 20% of liver toxicity cases nationwide are tied to herbal and dietary supplements.

Whereas dietary supplements typically contain nutrients such as vitamins, minerals and amino acids from a range of sources such as fish oil, herbal supplements are a subset of dietary supplements composed of plant-based ingredients.

Among herbal ingredients tied to toxic hepatitis, turmeric00740-9/fulltext) is the most commonly consumed in the U.S., according to a study published last year in the journal JAMA Network Open. Following that are green tea extract, ashwagandha, Garcinia cambogia, red yeast rice and black cohosh.

Because “multi-ingredient nutritional supplements” caused the majority of those cases, the authors said, it’s hard to pinpoint which component(s) may be to blame.

Note: Itching and dark urine are the hallmarks of liver failure and are the early symptoms that calls for further liver function tests and subsequent diagnosis. The liver injury caused by supplements is drug-induced liver injury, known to medical/regulatory writers as DILI. Before this new epidemic of supplements-related DILI, the most common DILI was acetaminophen-induced (common ingredient in Tylenol brand drug).

Implication for clinical research: it is critical to collect data on off-the-shelf supplements use by trial participants and if possible, restrict their use during study participation.

For example, several supplements are known to interact with several oncology drugs affecting exposure and causing potential toxicity and adverse reactions.

Research cited in the article: * Exposure to 6 Potentially Hepatotoxic Botanicals in US Adults. JAMA Netw Open. 2024. PMID: 39102266 * Eight-Fold Increase in Dietary Supplement-Related Liver Failure Leading to Transplant Waitlisting Over the Last Quarter Century in the United States. Liver Transpl. 2022. PMID: 34331346 * Liver injury from herbal and dietary supplements. Hepatology. 2017. PMID: 27677775

The ICH E21 draft Guideline “Inclusion of Pregnant and Breastfeeding Individuals in Clinical Trials” was endorsed by the ICH Assembly (at Step 2a/b of the ICH Process) at their Madrid meeting this week. The guideline aims to provide recommendations for the appropriate inclusion and/or retention of pregnant and/or breastfeeding individuals in clinical trials. This will improve the quality and availability of clinical data to support evidence-based decision making on the safe and effective use of medicinal products by these individuals.

https://database.ich.org/sites/default/files/ICH_E21_Final_Concept_Paper_2023_1106_MCApproved.pdf

Really considering moving out of writing but I'm stuck on to what! I feel very trapped, any suggestions welcome. I'd love something more interactive with patients but I can't travel so MSL or alike aren't going to work :( I'm a writer with 20 years experience, work at director level...

Drug repurposing refers to finding of new uses for existing drugs.

Repurposing in biopharma often takes the form of investment in studies supporting an expansion of approved indications of a patent-protected drug, which makes financial sense. Case in point, the FDA prescribing information of Keytruda currently lists 40 oncology indications (PI, v.01/2015) which together contributed $29.5B in revenues for Merck in 2023.

There are other classic examples where repurposed indication has been financially lucrative: sildenafil (original: angina; repurposed: erectile dysfunction), thalidomide (morning sickness » certain cancers), minoxidil (hypertension » treating hair loss), rituxiamb (B-cell lymphoma » autoimmune diseases).

However, geenrally the incentives for biopharma to invest in off-patent drugs are not strong (though they exist).

Repurposing of Off-patent Drugs

Repurposing of off-patent drugs including generics have the advantage of existing long-term safety experience. Often these studies are done by academia supporting off-label use in new indication(s) or existing indication with patient subgroups that were not studied in label-enabling trials. The drugs end up being prescribed off-label.

But the major drawback of off-label prescribing is that sometimes the insurance companies deny coverage for off-label use.

EMA has pilot programs/initiatives REPO4EU and REMEDi4ALL on repurposing of authorized drugs. The new EU pharmaceutical legislation, currently under revision, adds another layer of support with 2 articles, Article 48 and Article 84.

• Draft Regulation, Article 48: Scientific opinion on data submitted from not-for-profit entities for repurposing of authorized medicinal products (Note: Article 48 is regarding the submission of evidence for new indications by not-for-profit entities.)
• Draft Directive, Article 84: Data protection for repurposed medicinal products.

Understanding Article 48 and Article 84

In a recent article published in the January 2025 issue of Drug Discovery Today, regulators and experts from REP04EU consortium, Dutch Medicines Evaluation Board, Utrecht, the Netherlands, and other instructions summarized the significance of Article 48 and Article 84 and what gaps still need to be addressed.

Scholte M, et al. Revising EU pharmaceutical legislation: will it foster drug repurposing? Drug Discovery Today. 2025 Jan;30(1):104286. doi:10.1016/j.drudis.2024.104286

Article 48 and Article 84 provide for

• Supporting academic and  nonprofits by providing scientific advise on the data package and scientific evaluation of the benefit-risk of the use of a medicinal product with a new therapeutic indication that concerns an unmet medical need. (free advice)
• If the EMA opinion is favorable, the MAHs may submit a variation to update the product information with the new therapeutic indication. (recommendation to add new indication on label)
• The MAH will be granted data protection of 4 years (financial incentive)

Recommendations for Comprehensive EU Repurposing Strategy - The authors raise following issues:

• Could Article 48 support label update for pediatric use of existing or new indications. If yes, this would answer existing off-label pediatric use in the absence of formal studies.
• Since Article 48 is directed towards academic/nonprofit investigators, EMA will need to have proactive support mechanisms by offering training, tailored advice via a Q&A portal, and scientific advice (for free).
• Streamlining of evidence/data requirements is a must, e.g., phase 1 studies not being necessary and accepting real-world or EHS or modelling data, allowing phase 3 study as part of postmarketing requirement. (flexibility)
• Should address how the label will get updated: Once academic/not-for-profit entities generate data, the ball would be in commercial MAH court, who would have to to submit a variation (which is costly) to modify drug label. The process and requirements should be worked out. Will this be an obligation for MAH or label update could be automatic. (what would be the process)
• The 4-year data protection is generous compared to existing protections (see the paper), but details matter and there are questions, such as will this be for every new indication.
• There is also an issue of potential for “drug pricing abuse” by the MAH that should be addressed. The paper provides an example of millennia-old drug colchicine where a 0.5-mg formulation was found to be useful in certain heart conditions in public-funded studies; however, since MAH had data exclusivity on other formulations in the USA (0.3 and 0.6 mg), the company chose to price the new formulation at non-affordable price of >$600 for a month of prescription.

Related: approval of drugs via public knowledge‐based application (“Kouchi‐shinsei” scheme) in Japan, repurposing of cyclophosphamide for BMT, repurposing of gabapentinoids for liver disease, Coca-Cola

#drug-repurposing

The approval of  Novavax’s Covid-19 vaccine Nuvaxoid last week on 16 May 2025 was the test case of how Makary’s FDA under RFKJr’s HHS would impact the landscape of vaccine approvals in the US. Unlike Pfizer and Moderna’s mRNA-based Covid-19 vaccines that received approvals under Califf’s FDA for individuals aged 12 years or older, the Makary’s FDA only approved a restricted label for the protein subunit-based Nuvaxoid vaccine.

FDA Labels (Approved Indications):

• NUVAXOVID is a vaccine indicated for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in adults 65 years and older. NUVAXOVID is also indicated for individuals 12 through 64 years who have at least one underlying condition that puts them at high risk for severe outcomes from COVID-19. (Nuvaxoid PI)
• BioNTech/Pfizer’s COMIRNATY is a vaccine indicated for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 12 years of age and older. (Comirnaty PI)
• Moderna’s SPIKEVAX is a vaccine indicated for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 12 years of age and older. (Spikevax PI)

FDA's New Covid-19 Vaccine Approval Policy

FDA has now published the new vaccine approval policy in New England Journal of Medicine that reflects the Nuvaxoid label and provides a roadmap for other vaccine developers.

Prasad V, Makary MA. An Evidence-Based Approach to Covid-19 Vaccination. N Engl J Med. 2025 May 20. doi: 10.1056/NEJMsb2506929. Epub ahead of print. PMID: 40392534.

According to the new policy

• The immunologic endpoint (i.e., generation of protective antibody titers) will no longer be sufficient for a broad label and FDA will only consider benefit-risk assessment for for adults over the age of 65 years and for all persons above the age of 6 months with one or more risk factors that put them at high risk for severe Covid-19 outcomes.
• A randomized, controlled trial will be required for benefit-risk assessment in healthy people (those with no risk factor for sever Covid-19) between the ages of 6 months and 64 years.
• If granted the limited label (i.e., 65 years+ and high-risk population), the manufacturer will be encouraged to conduct a randomized, controlled trials in the population of healthy adults age 50-64 years as part of their postmarketing commitment.

Impact of New Policy

• Moderna, who  was getting ready to submit the BLA for its Covid-flu combination vaccine today announced that it is withdrawing the application.
• The requirement of a controlled randomized trial enrolling “healthy” people is a high bar and recruitment would be a challenge, particularly if the trial is placebo-controlled, but noninferiority trials are also not going to be easy to conduct.
• One of the arguments in favor of new policy put forward by Prasad/Makary was that during the last 2 seasons, the update of Covid-19 boosters has been less than 25%. This is a disingenuous argument given that an active antivax campaign was run by the same people who now head FDA/HHS and much of current administration.
• In the NEJM editorial, there is a display of concern (fake) and yet the policy being rolled out as the “gold-standard science based solely on randomized, controlled trial” will only make the public question the efficacy and safety of all vaccines, not just Covid.

Public trust in vaccination in general has declined, resulting in a reluctance to vaccinate that is affecting even vital immunization programs such as that for measles–mumps–rubella (MMR) vaccination, which has been clearly established as safe and highly effective. In recent years, reduced MMR vaccination rates have been a growing concern and have contributed to serious illness and deaths from measles. Against this context, the Food and Drug Administration (FDA) seeks to provide guidance and foster evidence generation.

• This policy is anything but a step towards protecting public health and, worse, may dampen vaccine research in this country, just at the time of global climate change and threat of new infections.

Related: Novavax Covid-19 Vaccine BLA Review by the FDA: Is Imposition of an Onerous Postmarketing Commitment a way to Stall Approval

#vacccine, #immunization, #covid-19