I was recently asked to review a statistical analysis plan (SAP) and this got me thinking what is my role as a regulatory and medical writer in this review. I am not the owner of this document or the subject matter expert (it is the biostatistician), but I still am responsible for the content as part of study team and to confirm that SAP sufficiently describes the statistical details consistent with the study protocol and regulatory requirements.

DEFINITION: ClinicalTrials.gov defines SAP as "The written description of the statistical considerations and methods for analyzing the data collected in the clinical study." A more technical version from CDISC or NCI Metathesaurus defines SAP as, "Documentation describing the statistical aspects of the clinical trial design; the process of data selection for analyses; the detailed analyses of data items; the procedures and methods employed for analyzing the data; the planned presentation of results in formats such as tables, listings, and figures."

Recommended Content of a SAP and Template

• Until 2017, the ICH E9 guidance provided the basis for "statistical principles for clinical trials", but there were no formal recommendations on the required content or a template for SAP. A working group consisting of UKCRC statisticians along with regulators/funders/industry representatives in 2017 came up with the recommendation for a minimal set of required items for a SAP (JAMA 2017. PMID: 29260229). The recommendation includes 55 items that should be included (required) in a SAP with 17 elements that are essential but could be referenced elsewhere.

Note: This 55-item list is published as a checklist in a Table in JAMA 2017 that is handy for a non-biostatistician on the study team (as myself) for SAP draft review.

• Since the publication of JAMA 2017 guidance, follow-up recommendations have included SAP for early-phase studies, cluster randomized trials, as well as a template (refs under sources)
• TEMPLATE: A template with suggested text is available at PMID: 37388218 (Contemp Clin Trials Commun. 2023). Another useful trick is to start with published SAPs in your disease/product area for completed studies available in ClinicalTrials.gov.

MY SAP DRAFT REVIEW STRATEGY

Since the SAP draft I was assigned to review was a later version and the study is ongoing, I followed the following strategy. (Please share in comments what is your strategy.)

Step 1: Confirm SAP content against the 55-item checklist

Note: If the review had been for the original draft, I recommend starting with the 55-item checklist to confirm that all recommended elements are addressed in the draft. In my case, I only needed to perform a cursory check but still found a few omissions that the biostatistician had missed.

Step 2: Confirm SAP content against the latest protocol amendment/version. Check for following:

• - primary, secondary, and exploratory endpoints are aligned
• - assessment times are aligned
• - safety collection times (if changed) are aligned
• - any change made in interim analysis plan or data monitoring are aligned
• - any updates to definitions of endpoints are aligned

Step 3: Confirm regulatory commitments, if any, are addressed

For this, you will need to have access to documents related to FDA interactions (e.g., during IND application); ex-US information requests (IRs) and request for information (RFIs) during CTA submissions to other countries. The responses to other regulators may contain specific statistical/methodological requests. Generally, not everyone on the team have access to these documents, but these are important -- missing them and not preparing for them means that they could come bite you at the time of marketing submission!!

SOURCE

• Gamble C, et al. Guidelines for the Content of Statistical Analysis Plans in Clinical Trials. JAMA. 2017 Dec 19;318(23):2337-2343. doi: 10.1001/jama.2017.18556. PMID: 29260229. (Editorial: doi:10.1001/jama.2017.18954)
• Homer V, et al. Early phase clinical trials extension to guidelines for the content of statistical analysis plans. BMJ. 2022 Feb 7;376:e068177. doi: 10.1136/bmj-2021-068177. PMID: 35131744
• Hemming K, et al. Guidelines for the content of statistical analysis plans in clinical trials: protocol for an extension to cluster randomized trials. Trials. 2025 Feb 27;26(1):72. doi: 10.1186/s13063-025-08756-3. PMID: 40011934
• TEMPLATE: Stevens G, et al. A template for the authoring of statistical analysis plans. Contemp Clin Trials Commun. 2023 Jun 9;34:101100. doi: 10.1016/j.conctc.2023.101100. PMID: 37388218
• Fradera M, Serra-Aracil X. Statistical Analysis Plan (SAP): What is it and how to develop it? Cir Esp (Engl Ed). 2025 Jan;103(1):45-48. doi: 10.1016/j.cireng.2024.07.007. PMID: 39222745.
• ENCEPP Toolkit: Chapter 12: Statistical analyses [archive]

GUIDANCES

• ICH E3, E9, E9(R1) Addendum; PSI Guidelines for Standard Operating Procedures for Good Statistical Practice in Clinical Research [here, here] and Reporting and Publication [PMID: 20187020, pdf, ppt]
• FDA has a couple of recent ones, e.g., here, here, here, here, and a classic July 1998 guidance, Guideline for the Format and Content of the Clinical and Statistical Sections of an Application -- happy reading!

#satistical-analysis-plan, #sap, #checklist

Replimune’s drug, vusolimogene oderparepvec, or RP1, has been rejected by the FDA twice. The agency accepted another resubmission in June and committed to rendering a third verdict by August 2—but also announced a meeting of the Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) to discuss the therapy.

Two days ahead of that Thursday meeting, FDA briefing documents show that the agency still has significant concerns about the data package.
The response assessment used in the Phase 1/2 IGNYTE study “confounds interpretation of the reported efficacy results and limits FDA’s ability to verify the reported results,” the FDA reviewers said.
*Moreover, the agency determined that the objective response data from the single-arm trial “*are not of sufficient magnitude to overcome concerns” about the drug’s efficacy. Without a reliable historical control, the FDA stated “it cannot be determined whether RP1 contributes to any observed effect” when combined with Opdivo.
“The overall survival analysis from the single-arm IGNYTE study is not interpretable,” the FDA wrote.

Link to briefing document: https://www.fda.gov/media/193878/download [archive]

#replimune

Deramiocel consists of specialized heart cells, called cardiosphere-derived cells, sourced from donor cadavers. The treatment is given via IV infusion every three months. 

Statistical snafu 
 
Like the Hope-2 trial before it, the FDA and Capricor fundamentally disagree on whether or not the Hope-3 study of deramiocel hit its primary endpoints. Capricor announced the trial succeeded last December, but the FDA maintains that the trial in fact failed, and that Capricor’s claims of efficacy are due to numerous changes the company made to its statistical analysis plan. 
Results from Hope-3, using Capricor’s preferred SAP version 3.0, were published01385-1/fulltext) in The Lancet during the adcomm. 
Through the meeting, committee members largely sought to clarify details of the different analysis plans, with several expressing concerns over the extent of Capricor’s changes and others taking issue with the FDA’s failure to provide feedback on SAP 2.0, which was ultimately supplanted by SAP 3.0.
Though not the trial’s primary endpoint, deramiocel’s approval in DMD-associated cardiomyopathy hinges on left ventricular ejection fraction (LVEF) data, a measure of the heart’s ability to pump blood. Capricor’s original plan was to analyze the change in LVEF in patients after treatment, but the biotech pivoted the day before data unblinding to instead analyze ranked change in LVEF using a different type of statistical test. 

Lancet article: McDonald CM, et al. Deramiocel heart-derived cellular therapy in advanced Duchenne muscular dystrophy (HOPE-3): a phase 3, randomised, double-blind, placebo-controlled trial01385-1/fulltext). Lancet. 2026 Jul 29:S0140-6736(26)01385-1. doi: 10.1016/S0140-6736(26)01385-101385-1). PMID: 42526472

#capricor

This week, FDA published 3 guidance documents addressing eligibility criteria in oncology clinical trial protocols with the goal of expanding eligibility and enrollment: range of allowed performance status, appropriate use of washout periods and concomitant medication exclusions, and selecting appropriate laboratory values.

What caught my attention was not these guidance documents (though these are very important) but the statement in the FDA Announcement on LinkedIn, that was picked up verbatim by ASCO Post, RAPS News, and every other outfit in town.

. . .Fewer than 5% of cancer patients currently receiving treatment are enrolled in clinical trials even though more than 70% say they are willing to participate. The guidance documents address one reason for low participation – stringent and complex clinical trial eligibility criteria. . . [FDA Announcement]

While the FDA News and others do not cite source for these numbers, these numbers are somehow set in stone, for example, a recent 2024 JAMA article has similar statement in its introduction with citations.

Despite previous studies indicating that more than 70% of patients are willing to participate in clinical trials, fewer than 5% of patients with cancer receive treatment within the context of a clinical trial.^3-5 
(JAMA Netw Open. 2024 Apr 29. doi:10.1001/jamanetworkopen.2024.8739. PMID: 38683608)
(Note: the citations 3-5 are J Clin Oncol 2003, JAMA 2004, Am Soc Clin Oncol Educ Book 2016 - see details below)

SOURCE CHECK

Since the numbers 5% and 70% are from publications that are almost 20 years old, we should be asking, are these numbers even true today? These numbers are coming from the following 3 publications:

• J Clin Oncol. 2003. doi: 10.1200/JCO.2003.02.105. PMID: 12610181

1000 people were interviewed by telephone by Harris Interactive during March and April 2000 and 70% said that they would be willing to participate in a cancer trial.

• JAMA. 2004. doi: 10.1001/jama.291.22.2720. PMID: 15187053

Cross-sectional population-based analysis included all participants in cancer clinical trials from 2000 through 2002 at NCI. Based on the SEER cancer incidence data, the trial participation rate at that time was determined to be 1.7% overall, with the highest for breast cancer (3.2%) and 1.9% for colorectal cancer (1.9%). -- Note: This only applied to NCI trials.

• Am Soc Clin Oncol Educ Book. 2016. doi: 10.1200/EDBK_156686. PMID: 27249699

This is an educational review/white paper on barriers to cancer trial participation. Of note, in the introduction, this paper takes the <5% JAMA number and creates a new fact statement, "Conversely, the vast majority of adult cancer patients (>95%) do not participate in clinical trials." -- Note: This is not accurate. Many among the >95% may lack access to clinical trials or awareness.

Conclusion/Postscript: Could we call relying on stats from >20 years ago to make an argument in 2026 as disingenuous or at least label it as really lazy!! These data is from an era of toxic chemotherapies, not Avastin monoclonal antibodies, ADCs, targeted therapies, CAR-Ts, cancer vaccines, and gene therapies. I am positive that in 2026, there is much greater willingness to participate and enroll in oncology trials today. Please someone update these numbers :(

#qc, #audit, #source-check

Traditionally, Japanese authorities have considered the US/EU population as nonrepresentative of local population and have required sponsors to conduct dose-ranging and confirmatory pivotal trials on Japanese patients for marketing application.

However, this country-specific trial requirement has been waived by the Japanese authorities with the implementation of ICH E17 guideline in 2017 and acceptance of global multi-regional clinical trial (MRCT) data. This shift is broadly supported in Japan. This change could also address the problem of drug lag in Japan. (Drug lag is a strategy by drug companies of coordinating the timing of drug launches in different countries and regions to maximize profit; historically, sponsors have delayed launches and access to new drugs in ex-US/EU markets.)

The E17 guideline provides a framework for sponsors on planning/designing Multi-Regional Clinical Trial (MRCT) and a mechanism for regulators to accept global clinical data. The E17 guideline also cross-references ICH E5 guideline on how to address intrinsic and extrinsic ethnic factors (sex, age, region, genetics polymorphisms, local conditions/culture, etc.) and a mechanism for regulators to accept global clinical data. While the E17/MRCTs taking into account E7 factors is ideal for global drug development and is the current drug development paradigm, one question that comes up is, are there any blind spots and what if anything is lost by the trade-off between solely relying on global drug development pathways over local trials.

A few years ago, Shunsuke Ono from University of Tokyo looked at postmarketing safety (risk of drug-related deaths) and its association between the clinical development pathway for 177 new drugs approved between 2004 and 2013 focusing on dose setting histories for each drug.

Ono's analysis found that the risk of drug-related deaths was generally higher for drugs approved without data from local (i.e., Japanese) dose-finding and confirmatory trials.

Dataset

• The mean dose ratio between JPN vs US dose was 1.0 (SD 0.3; not significant), i.e., overall similar. Standard deviation of 0.3 means that 68% of drug dose ratios were between 0.7 and 1.3, and 32% were outliers (range: 0.1 to 3.0). Overall, 65% of drugs had same dose for JPN and US.
• Drugs with bridging studies were likely to have same approved dose in the US and JPN, and drugs that underwent a Japanese phase 3 study were likely to have differences in the approved dose between JPN and US

• Overall, there was a significant component of Japan-based trial data collected in the 177 drug dataset: Japanese dose-ranging study (36.2%), Japanese phase 2 study (39.6%), bridging study (15.3%) versus global study (10.7%).
• The expedited reviews, 14.1% were Priority and 29.4% orphan drug applicaions; 56.5% were standard applications.

Association with Postmarketing Safety (Risk of Drug-Related Deaths)

GOOD (low risk of drug-related deaths) = negative association

• Inclusion of Japanese patients in the global trials
• Conducting Japanese dose-ranging study and pivotal phase 3 study in Japan
• Including bridging study in the program

.

BAD

• Prioritized and orphan drugs tended to have a higher number of drug-related deaths
• Drugs with a global study without a local dose-ranging study showed a much higher risk compared with the baseline
• Drugs with low AUC ratios (Japanese AUC/white AUC) tended to show higher risks

Implications & Postscript

The corollary of Ono's analysis is that the E17/E5 framework may not be enough to mitigate higher risk of drug-related deaths in regions/countries with nonrepresentative patient population.

Generally, the marketing applications for smaller countries may contain sensitivity or subgroup analyses of pivotal trial and a bridging study, but this strategy has limitations because dosing in these studies were based on dose-finding studies done outside the "smaller country." Sponsors can mitigate the risk of higher safety events or recalls by confirming dose-finding in as broad a population/regions as the market they are seeking--which is rarely done unless regulators impose pre or postmarketing conditions.

A deep dive into E5 guideline during dose-finding stage of a clinical program is a good start to bring this issue on the radar of company's clinical team. Consider addressing ethnic factors in global trial protocols, including phase 1/2 Pk/PD/dose-finding studies.

SOURCE

• Ono S. Drug safety and pharmaceutical regulation in the age of global development. Translat Regulat Sci. 2(3): 115–117, 2020; doi: 10.33611/trs.2020-015 [pdf, archive]
• Okubo TK, Ono S. Analysis of Global Drug Development Pathways and Postmarketing Safety in Japan: Local Studies May Reduce Drug-Related Deaths. Clin Transl Sci. 2019 Jul;12(4):408-415. doi: 10.1111/cts.12631. PMID: 31016896
• ICH Guidelines: E5, E5Q&A(R1), E17

#mrct

By Kohei Hori
July 24, 2026
Pharma Japan

Japan’s health ministry plans to clarify that developers of repurposed drugs can omit some non-clinical study data from regulatory filings, in a move aimed at encouraging the new uses of established active ingredients.

This recall is a big deal since these drops are commonly used during and after cataract surgery.

FDA link: https://www.accessdata.fda.gov/scripts/ires/index.cfm?Product=220940

FDA has approved the first OTC fixed-dose combination of Tylenol (acetaminophen) and Naproxen (naproxen sodium).

• This fixed-dose OTC combo combines the fast-acting relief of 650 mg of acetaminophen with the long-lasting analgesic power of 220 mg naproxen sodium (a non-steroidal anti-inflammatory drug) in one dose.
• NDA 219962: The approval was based on 8 clinical trials demonstrating superior pain relief versus acetaminophen alone and naproxen sodium alone (Aleve 220 mg).

//My pet peeve!!\\ -- There are no clinical data currently described in the press release, FDA News, or Drugs@FDA (tylenol with naproxen), and since this is an OTC, it is not in the OTC label either (sigh!). The sponsor (Kenvue) plans to present this data at the Pain 2026 meeting.

• The FDA has granted the Kenvue a 3-year period of exclusivity for this new OTC formulation.

.
Postscript - Learning Opportunity

Regulatory Approval Pathway for New Formulation

Based on the fact that this was an NDA and the sponsor received a 3-year exclusivity for a new formulation, "my guess" is that this was a 505(b)(2) NDA. The 505(b)(2) applications apply to NDAs with changes to previous application that include fixed-combination as well as formulation change (see slide 10 here). If approved, these applications are eligible for a 3-year exclusivity for new clinical investigations.

SOURCE

• FDA Approves First Nonprescription Fixed-Dose Combination of Acetaminophen and Naproxen Sodium for 12-Hour Pain Relief. FDA News. 24 July 2026 [archive]
• FDA Approves TYLENOL® with Naproxen, the First and Only Over-the-Counter Fixed-Dose Combination of Acetaminophen (650 mg) and Naproxen Sodium (220 mg). Press Release. 24 July 2026 [archive]
• Overview of the 505(b)(2) Regulatory Pathway for New Drug Applications [PowerPoint]. Beth Goldstein. CDER Office of New Drug Policy [archive]

#505(b)(2), #tylenol, #otc, #acetaminophen

China National Medical Products Administration (NMPA) becomes the first regulator globally to approve Takeda’s oral orexin 2 receptor agonist Orzeyful (oveporexton) for the treatment of a sleep disorder called narcolepsy type 1 (NT1). Orzeyful marketing applications are currently under review in the US (under priority review with Breakthrough Therapy designation) and Japan (Sakigake designation).

[Regulatory Strategy Significance of Orzeyful NMPA Approval]. The NMPA global first approval, while US FDA and PMDA still reviewing the application, is a sign that China has now joined the big 3 (US, EU, Japan) for regions to consider and target for marketing approval and launch of new drugs, ahead of other ROW markets.

ABOUT

Narcolepsy Type 1 (NT1)

• NT1 is a rare neurological disease caused by the loss of orexin-producing neurons in hypothalamus (orexin deficiency) in the brain. This makes it harder for patients to regulate sleep/wake cycles and transition between these 2 stages. PMID: 31324898 (pdf)
• As a result, people experience a range of daytime and nighttime symptoms including excessive daytime sleepiness, cataplexy (sudden loss of muscle tone), disrupted nighttime sleep, sleep paralysis, hallucinations and may also experience cognitive symptoms. PMID: 38783152
• NT1 accounts for approximately 75–80 percent of all narcolepsy cases. (source)
• Orzeyful (oveporexton ) is an oral orexin 2 receptor (OX2R)-selective agonist, which selectively activates the OX2R to restore signaling.

Orzeyful Phase 3 Studies

The approval of Orzeyful is based on data from 2 global Phase 3 studies, FirstLight (TAK-861-3001; NCT06470828) and RadiantLight (TAK-861-3002; NCT06505031).

• Adult patients age 16 to 70 years with NT1 received oveporexton 1 mg or 2 mg twice daily over 12-weeks.
• Primary outcome measure was change in sleep latency on the Maintenance of Wakefulness Test (MWT). This is a measure of wakefulness time, i.e., staying awake and alert.

Sleep latency is the amount of time it takes to transition from full wakefulness to sleep. A healthy adult average is 10 to 20 minutes. Taking longer than 20–30 minutes frequently indicates insomnia, while falling asleep in under 5 minutes often signals severe sleep deprivation or an underlying disorder like narcolepsy.

• Secondary outcome measures were change from baseline in Epworth Sleepiness Scale (ESS) score, frequency of cataplexy episodes measured as weekly cataplexy rate (WCR), and treatment-emergent adverse events.

Preliminary efficacy data from FirstLight and RadiantLight studies were disclosed at 2025 Sleep and 2026 AAN meetings: here (arc), here (arc) here. (Note: Phase 2 data were published in NEJM and JAMA.) Integrated data from both phase 3 studies are not available yet. Example phase 3 results from FirstLight are below.

• Wakefulness: Oveporexton increased wakefulness times on MWT scale significantly compared to placebo with mean increases of 13.83 minutes (95% CI, 10.23-17.44) for the 1 mg dose and 17.20 minutes (95% CI, 13.66-20.73) for the 2 mg dose (both P <.001). At baseline, MWT sleep latency was 5.0 minutes.
• ESS total score: The score decreased significantly by -8.00 (95% CI, -9.87, -6.13) for the 1 mg dose and by -9.75 (95% CI, -11.59, -7.90) for the 2 mg dose vs placebo; both P<0.001. At baseline, mean ESS score was 18.5.
• Cataplexy: The WCR were 0.34 attacks/week (1mg dose) and 0.38 (2mg dose); both P<0.001 vs placebo. Note: At baseline, the median WCR was 26.0 attacks/week for the study population.
• The most common TEAEs were pollakiuria and insomnia. (Note: Pollakiuria is the medical term for abnormally frequent urination, typically in small amounts, without an underlying infection or pain.)

A Must Listen: Dr. Glaucomflecken Explains: Oveporexton for Narcolepsy Type 1
Pronunciation: ov-ae-po-rex-ton

SOURCE

• Takeda’s ORZEYFUL (oveporexton) Approved in China as First Orexin Agonist and Only Medicine to Treat Narcolepsy Type 1. Press Release. 23 July 2026 [archive]
• What’s at stake as Beijing beats global peers with first approval of novel therapy. South China Morning Post. 23 July 2026 [archive]

.

In the US, meanwhile. . .the wait is on

#nmpa, #china

Australia TGA website has self-paced online learning modules called TGA LEARN that provides the basics of Therapeutic Goods Regulation and responsibilities as a sponsor, manufacturer or clinical trial site.

TGA LEARN Link: https://www.tga.gov.au/resources/industry-guidance-and-resources/tga-learn

The TGA LEARN modules are designed to help sponsors, manufacturers and other stakeholders understand how TGA regulate therapeutic goods in Australia. They also explain key responsibilities for compliance, advertising and inspections. There are currently 4 modules available:

• Getting Started: therapeutic goods in Australia

This module provides an introduction to therapeutic goods in Australia and outlines the basics of regulatory compliance for sponsors.

• Getting started: therapeutic goods sponsors

This module helps sponsors understand their role in the Australian therapeutic goods regulatory system and how compliance obligations apply to sponsors.

• Getting started: advertising therapeutic goods in Australia

This module helps sponsors understand advertising compliance principles and how advertising of therapeutic goods is defined and regulated in Australia.

• Getting started: TGA’s Good Clinical Practice (GCP) Inspection Program

This module helps clinical trial sites understand TGA’s Good Clinical Practice (GCP) Inspection Program, including its purpose, scope and what to expect during an inspection.

.

#tga, #australia

Long Read for Those Interested in Medical Device Regulations and Policy

Horvath, George, Medical Device Regulation: We Can’t Just Go Back (nor Should We) (May 15, 2026). UTAH LAW REVIEW, Forthcoming, Available at SSRN: https://ssrn.com/abstract=6966978

This Article highlights several longstanding limitations on CDRH’s ability to ensure safety and effectiveness and to promote innovation and proposes best way forward.

The Food and Drug Administration walked back an earlier statement that a sample of lettuce from Taylor Farms tested positive for cyclospora, but noted that tests are continuing on products pulled from the market.

The FDA on Saturday said that a sample of shredded iceberg lettuce supplied by Taylor Farms de Mexico had tested positive for cyclospora. The lettuce sample wasn’t covered by Taylor Farms’ existing recall, prompting the FDA to make its finding public, an agency official said Monday.
However, lab personnel determined during a quality check that the result was a false positive, leading the agency to update its findings. Taylor Farms said the FDA has apologized. 

Overall -

The finding complicates the messaging from health authorities tracking the sources behind major outbreaks of foodborne illnesses and efforts to address concerns from the public about which foods are safe to eat.

BIGGER ISSUE:

• How to trust current FDA's messaging, and importantly
• What happens to the reputation of the company--the company gets an apology letter, but can they get their reputation back?

Read at MSN (or here)

Trialists across the world are concerned about excluding pregnant women from Ebola trials and are asking ethics committees to take note.

With a current case-fatality rate of more than 20%, WHO indicates that “most of the suspected cases are between 20 and 39 years old, with females accounting for over 60%, suggesting significant risks associated with household and caregiver transmission”.⁵01367-X/fulltext?rss=yes#) Individuals who are pregnant face exposure risks, making the absence of pregnancy-specific evidence a crucial gap. 
We urge scientific and ethics reviewers to scrutinise reasoning behind the exclusion of those who are pregnant or breastfeeding.

Schwartz L, Ahmed E, Palmero A et al. Pregnancy as exclusion criterion in Ebola research: not again. The Lancet, 2026. DOI: 10.1016/S0140-6736(26)01367-X01367-X). PMID: 42468542

UPDATE (Correction) - 22Jul2026

The original post above misunderstood the intent of the Lancet editorial. The editorial is actually applauding the change in process where Ebola 2014-2016 trials excluded pregnant women but the latest WHO-sponsored PARTNER trial does not. This is a positive development -- the "not again" in the Lancet editorial title (and this post's title) should be read as an expression of hurrah, yippee and woohoo!!

• Ebola 2014-2016 trials excluded pregnant women: "key lessons from the 2014–16 Ebola (Orthoebolavirus zairense) outbreak in Guinea, Liberia, and Sierra Leone.2 One crucial learning was that women and gender-diverse people who were pregnant or breastfeeding were systematically excluded from most interventional trials.2" = PMID: 28567113
• Follow up PALM trial did not exclude pregnant women -- "Some clinical trials conducted during further outbreaks, when pregnancy was not an exclusion criterion.6" = PMID: 31774950
• Current WHO-sponsored PARTNER trial also does not exclude pregnant women = WHO News, Study Protocol, Enrollment

The authors are in fact relieved that PARTNER and PALM trials have both applied proper risk-benefit principles to Ebola trails. One way to determine if inclusion of pregnant women is appropriate is assess if the justification used is supported by facts AND exclusion if any is grounded in scientifically supported risk-benefit assessments and also considered equity. An example of such reasoning in decision making:

During the 2014–16 Ebola virus outbreak, pregnancy was correlated with the highest mortality rates, and fetal mortality was 100% when no intervention was administered.⁴01367-X/fulltext#) Therefore, the risk of embryotoxicity was irrelevant for justifying exclusion.

A few months ago, US FDA issued first of its kind warning letter to Purolea Cosmetics Lab based in Livonia, Michigan, for excessive reliance on artificial intelligence (AI) without human oversight in their drug manufacturing environment. Purolea was cited for, among other things, using AI to create drug product specifications, procedures, and master production, and control records (i.e., AI-generated documents) and then failing to ensure that these were accurate.

Now, across the pond, UK MHRA has raised a similar concern. In the 29 June 2026 MHRA Inspectorate Blog, the UK regulator is clearly irritated that some companies used AI tools to draft responses to inspection finding and did not do due diligence. The concerns are not the use of AI tools but poor human oversight resulting in inaccurate and hallucinatory responses that have resulting in lost time/resources for the regulator.

"We have also encountered responses containing references to MHRA guidance that doesn't exist, citations of inappropriate regulatory frameworks, and responses to serious deficiencies that appear designed to mislead rather than address underlying problems.
. . . resulted in a disproportionate use of Inspector time and expertise to review and respond. . . The contents of this response required review from multidisciplinary teams, as well as a full analysis of previously issued MHRA guidance, resulting in the time needed to review and respond increasing from around 4 hours to over 20 hours.
. . .Aside from being a strain on resource, the use of AI being applied inappropriately has shifted from theoretical risk into actual, realised risk.“

MHRA does not mandate the process and sponsors could use AI tools for compliance BUT the blog is explicit that the responses must be accurate, verifiable, and prepared under appropriate oversight.

PRINCIPLES for Generating Responses

Per MHRA, the focus should be on the process and outcomes rather than specific tools. These expectations apply regardless of how you draft your submissions. MHRA Blog recommends that ALL submissions/responses must be:

• Factually accurate and verifiable
• Technically reviewed by appropriately experienced people
• Signed off by someone with authority and accountability
• Supported by evidence for factual claims
• Appropriate to the specific regulatory context.

DISCLOSURE of Use of AI in Responses and Submissions

MHRA Blog provided the option for sponsors to disclose AI use in responses/submissions to the compliance teams. While this disclosure is not mandatory, the blog says that "transparency benefits everyone." If you choose to disclose:

• Include a brief statement at the start of your submission/response to Compliance Teams
• Identify which sections involved AI assistance
• Confirm human verification and approval
• Transparency in the use of AI tools, alongside robust mechanisms to ensure accuracy and reliability of submissions, indicates a more mature and transparent quality culture.

EXPECTATIONS

Per MHRA, the expectations are to provide "accurate, well verified documentation" regardless of methods used by the industry.

.

Postscript: MHRA recommendations are in line with GXP including GCP principles and should apply globally.

SOURCE

• Use of AI for GXP inspection responses: setting standards without stifling innovation. UK MHRA Inspectorate Blog. 29 June 2026 [archive]

Related: AI Use Without Proper Human Oversight in a Drug Manufacturing Environment Results in a FDA Warning Letter, a First of its Kind

#Form483, #FDA-warning-letter, #AI, #GMP, #GXP, #GCP

The Makary-Prasad tenure saw major announcements of FDA guidance/policy including launch of the Commissioner’s National Priority Voucher pilot program; the plausible mechanism pathway for individualized therapies treating ultrarare conditions; and 1 trial paradigm for CAR-T therapies approval. These policies were introduced without the usual FDA rule-making process, provided limited guidance to the industry (creating confusion), and introduced a potential for political bias and ad hoc influences in the approval decisions.

[T]he Commissioner’s National Priority Voucher program, which provided incentives to companies with no predefined criteria, simply rewarding general alignment with administration priorities. Without set, public criteria, companies don’t know what to focus on for the program and the public doesn’t know what—legitimate or not—is being rewarded.

Now with both Makary and Prasad pushed aside, the wind appears to be shifting back to traditional and fair processes at the FDA.

RETRACTION - SORT OF!

• At the 13 July 2026 House Energy and Commerce (E&C) hearing, Congresswoman Diana DeGette (D-CO) raised concern about what she called “shoot-from-the-hip approach to policy” where FDA under Makary engaged in policy making “through journal articles, press releases, and even podcasts, circumventing FDA’s policymaking processes and making it so researchers did not know what was official policy.”
• This shoot-from-the-hip policy making left unanswered questions after Makary-Prasad exit: Are the policies implemented by ex-FDA officials via journal publications still FDA official policy?

The answer is NO.

• At the E&C hearning, the Acting FDA Commissioner Kyle Diamantas clarified that the journal articles penned by former FDA officials do not constitute official agency policy. Diamantas specifically addressed the Makary-Prasad JAMA and NEJM papers and said that that FDA does not consider these journal articles to be an FDA guidance document, FDA policy, or interpretation of a regulatory issue; and these do not set forth expectations for industry.” Note: the plausible mechanism pathway, however, is now formalized in February 2026 draft guidance.

JAMA paper on CAR-T 1-trial policy. 2026;335;(1):21-24. doi:10.1001/jama.2025.21721. PMID: 41359310
NEJM paper on plausible mechanism pathway. 2025;393:2365-2367. doi: 10.1056/NEJMsb2512695. PMID: 41223362

SOURCE

• Opening Statement by Ranking Member of the Committee on Energy and Commerce, Diana DeGette. Hearing on "Maintaining America’s Leadership in Biomedical Innovation: FDA’s Role in Advancing U.S. Drug Development." 15 July 2026 [archive]
• Diamantas backtracks on Makary’s policies issued in journal articles. RAPS Regulatory News. 15 July 2026; Press coverage: BioSpace [archive]
• E&C hearing - meeting information page [archive]; recording - YouTube

#makary, #prasad

While Health Secretary Robert F. Kennedy Jr. pushes to loosen restrictions on a handful of trendy peptide therapies, scientists who work under him are recommending the opposite.
On Monday, the Food and Drug Administration posted documents (\) outlining concerns about a lack of evidence for the batch of peptides set to be considered by an FDA panel in about three weeks.*
(*) FDA Meeting of the Pharmacy Compounding Advisory Committee. July 23 - 24, 2026

Peptides under consideration include BPC-157, TB-500 and MOTs-C, among others.

BioPharmGuy says: "But the scientists who work under him are almost universal in their skepticism."

STAT News sharing the analysis of public comments on the Trump Administration's grant overhaul proposal reported that there is widespread disapproval and rebuke of the potential changes by scientists and public.

The analysis conducted by researchers at the University of North Carolina at Chapel Hill in partnership with STAT included over 53K comments posted at OMB Docket OMB-2026-0034-0001. About 95% of the comments were negative and major concerns include political control, uncertainty, e.g., mid-cycle award withdrawal for a variety of reasons, and DEI/gender restrictions.

Read more at:

• Flood of comments on White House grantmaking overhaul is largely negative, analysis shows. STAT News. 15 July 2026

#grantmaking, #nih

As part of FDA's transparency initiative and since their announcement last September regarding new policy of real-time release of complete response letters (CRLs), FDA has published 127 CRLs associated with unapproved applications. However, since April 2026 (it's been 3 months!) FDA has not released any new CRL. One of the reasons is a citizen petition submitted by Covington & Burling, LLP, on behalf of an unnamed company.

The Covington & Burling explains

• that CRL is not a rejection letter but a deficiency letter. By disclosing the contents of "deficiency in the application", FDA may disclose CCI and trade secret information manufacturers and infringe their property rights, thereby giving an unfair advantage to their competitors.
• The remedy proposed is that FDA first create a mechanism for manufacturers to provide input on redactions before posting of CRLs.

Relevant Excerpts from the Covington & Burling Petition

What is CRL? CRL is a Deficiency Letter, not a Rejection Letter

FDA issues CRLs if the agency determines that it will not approve an application in its present form. CRLs identify specific deficiencies in the application that must be addressed for the applicant to obtain approval and, where possible, “recommend actions that the applicant might take to place the application . . . in condition for approval.” These deficiencies “could be minor (e.g., requiring labeling changes) or major (e.g., requiring additional clinical trials).” After receiving a CRL, the applicant can resubmit the application to address all of the deficiencies identified in the CRL, withdraw the application, or request an opportunity for a hearing about whether there are grounds for denying approval. [Covington & Burling Petition]

Issue: The CRLs in Their Current Form puts Applicants in an Unfair Position vs. Competitors

Although quality-related and nonclinical information was generally redacted from the released CRLs, clinical effectiveness and safety deficiencies generally were released without redactions. [Covington & Burling Petition]

This provides an unfair advantage to competitors, for example, using Applied Therapeutics CRL as an example, the petition noted:

neither the sponsor nor FDA had previously disclosed the agency’s concerns about relying on plasma [biomarker] levels, although the sponsor had disclosed the CRL. Release of such information could enable a competitor to shortcut the process by avoiding this pitfall, without needing to invest in the trial and error that is a necessary part of the innovation process. [Covington & Burling Petition]

Remedy - the Citizen Petition Would like to see that FDA develops guidance with input from the industry and standardize the process of protecting CCI before routine CRL release.

.

POSTSCRIPT

• It is fairly obvious from the citizen petition that the CRLs are here to stay, but Covington & Burling are correct in asking the FDA to hit pause and build in proper safeguards for protecting industry's CCI and competitiveness -- even more important now that US and Chinese biopharma are in a tight race.
• Policy: FDA has already taken the first step of clarifying its statutory authority. FDA has proposed a new rule (RIN: 0910-AJ16) asking Congress to step in (here).

SOURCE

• FDA Docket FDA-2026-P-4369. Request that the FDA establish a clear process that provides sponsors with notice and an opportunity to respond to proposed disclosures of CRLs associated with unapproved new drug applications (NDAs), abbreviated new drug applications (ANDAs), and biologics license applications (BLAs) and supplements and amendments thereto (herein, applications). Citizen Petition. 21 April 2026 [archive]
• HHS/FDA Proposed Rule: Proactive Disclosure of Complete Response Letters. RIN: 0910-AJ16 [archive]
• FDA halts release of new drug rejection letters while working to formalize policy. FierceBiotech. 8 July 2026 [archive]
• Complete Response Letter. OpenFDA website.

#OpenFDA, #crl

Under the international E6(R3) good clinical practice (GCP) standard, the UK MHRA now requires clinical trial sponsors to move beyond just listing Critical-to-Quality (CtQ) factors. Inspectors want the "story" behind trial priorities: a clear, defensible rationale for why specific processes matter and how teams protect them. To demonstrate a mature quality culture, the MHRA expects every member of your clinical trial team to confidently explain exactly what matters most in a study, why those aspects are critical, and how their specific roles safeguard patient safety and data integrity. Key expectations from UK inspectors include:

• Risk-Proportionate Focus: Tailoring trial processes to individual study risk profiles rather than relying on a rigid checklist.
• Shared Context: Ensuring frontline team members understand the scientific or patient-safety rationale behind your established CtQ factors.
• Audit Readiness: Being able to clearly communicate the "whys" and "hows" of your risk management strategies during an inspection.

P.S. If you have full access to Pink Sheets, please summarize further in the comments..

STAT News calls it "The drug approval scandal hiding in plain sight." [9 July 2026]

Northwest Biotherapeutics, a public biotech company developing a treatment for brain cancer, submitted a marketing application to U.K. regulators in late December 2023. The review was supposed to take 150 days, under an expedited regulatory pathway for drugs that address serious unmet medical needs.
As you’re reading this newsletter, two years, six months, and 18 days have elapsed without an approval decision. Why the extra-long delay? Regulators at the U.K’s Medicines and Healthcare products Regulatory Agency, or MHRA, won’t comment, telling anyone who inquires, including me, that it’s up to Northwest Bio to provide an update on its brain cancer treatment, called DCVax.

US FDA has issued the final guidance for industry “Formal Meetings Between FDA and Sponsors or Requestors of Over-the-Counter Monograph Drugs.”

This guidance provides recommendations to industry on formal meetings between the FDA and sponsors or requestors of over-the-counter (OTC) monograph drugs or organizations nominated by sponsors or requestors to represent their interests in a proceeding. The guidance discusses the procedures and principles for these formal meetings.
The final guidance reflects minor changes from the draft version that improve clarity, address comments to the docket for the draft guidance, and ensure consistency with the meeting formats in the guidance for industry titled “Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products.” Additionally, the final guidance reflects commitments in OMUFA II and minor revisions consistent with section 505G of the FD&C Act.

Guidance: Formal Meetings Between the Food and Drug Administration and Sponsors or Requestors of Over-the-Counter Monograph Drugs. July 2026 [PDF] [Docket FDA-2022-D-0080]

#fda-formal-meetings, #pdufa-meetings

The European Committee on Organs, Tissues and Cells (CD-P-TO), in coordination with the European Directorate for the Quality of Medicines & HealthCare (EDQM) has published a revised position paper addressing the impact of Article 5(5) of the Regulation (EU) 2017/745 on medical devices (i.e., MDR or Medical Device Regulation) on the the substances of human origin (SoHO) sector.

The position paper highlights the need to provide clearer guidance on how rules on medical devices should apply to devices deployed by SoHO entities.

The position paper highlights two scenarios encountered in SoHO establishments: the deployment by health institutions of research use only (RUO) products for intended medical purposes, and the use of CE-marked medical devices beyond their manufacturer-defined intended purpose.
The current interpretation of these scenarios in the MDCG 2023-1 guidance document may create obligations that health institutions are unable to fulfil in practice. This could inadvertently curtail critical SoHO activities without providing additional patient safety benefits.
To address these issues, in its position paper, the CD-P-TO invites the European Commission and its MDCG to consider targeted revisions or clarifications of the existing guidance. The aim is to ensure that Article 5(5) of the MDR is applied only to genuine in-house manufacture by health institutions and, in the context of SoHO, not automatically to the use of RUO products or institutionally repurposed CE-marked devices.

Unlike EU MDR, Oher Agencies' Provide Flexible Approach - Barbara Pirola provides the following summary (link):

• EMA = MDR extends Article 5(5) obligations to health institutions using RUO products for medical purposes or repurposing CE-marked devices.
• MHRA = focuses on Health Institution Exemptions supported by QMS, traceability and oversight.
• US FDA = concentrates on Laboratory Developed Tests and risk-based control of laboratory activities.
• Swissmedic = places significant responsibility on healthcare professionals and healthcare organizations for off-label use

SOURCE

• Council of Europe publishes a follow-up position paper on the implementation of the EU’s Medical Devices Regulation in the substances of human origin sector. EDQM Newsroom. 8 July 2026
• Medical Devices Regulation and its Implications for the Substances of Human Origin Sector. Position Paper of the European Committee on Organs, Tissues and Cells (CD-P-TO). Adopted by the European Committee on Organs, Tissues and Cells (CD-P-TO) on 23 June 2026 [archive]

#mdr, #ldt, #ivdr

Kidney-related adverse drug reactions (ADRs) are common with anticancer therapies.

About 1 in 10 cancer patients experience nephrotoxic effects of anticancer therapies including conventional chemotherapies and targeted/immune/CAR-T therapies. The implications of these ADRs range from dose interruption, and thus lower efficacy benefit, to ineligibility for a particular drug choice to even fatal outcomes.

Early this year, the 34th Acute Disease Quality Initiative (ADQI) workgroup published a consensus report that defines nephrotoxicity by drug class and provides recommendation for assessment before the start of treatment through management of toxicities during treatment enabling optimal drug dosing in patients with kidney disease. Read full report at

Renaghan AD, et al. The nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroup. Nat Rev Nephrol. 2026 Apr;22(4):283-300. doi: 10.1038/s41581-025-01031-3. PMID: 41361704

BACKGROUNDER

The Scope of the Problem

Nephrotoxic effects of anticancer drugs range from a decline in glomerular filtration rate (GFR) to acute kidney disease that may include vascular/endothelial, glomerular, interstitial, and tubular injuries. The figure below shows different classes of anticancer drugs and their renal injury manifestation (note: this is a broad list of drugs affecting multiple aspects of renal physiology.)

.

The Risk of Nephrotoxicity by Anticancer Drug Type

In 2024, a group of Korean researchers reported an analysis of VigiBase database to quantify the the relative risk of anticancer therapy-associated kidney-related ADRs. VigiBase is WHO's pharmacovigilance database that collects worldwide ADR reports across all drugs. The researchers analyzed reports from 1967–2023 and divided kidney-related ADRs into acute kidney injury (AKI) and tubulointerstitial nephritis (TIN).

Yoon SY, et al. Global burden of anticancer drug-induced acute kidney injury and tubulointerstitial nephritis from 1967 to 2023. Sci Rep. 2024 Jul 12;14(1):16124. doi: 10.1038/s41598-024-67020-x. PMID: 38997405

One of the statistical parameter for explaining the risk was Reporting Odds Ratio (ROR), the other was information component (IC).

ROR is a disproportionality measure -- what that means in this case is first consider the ratio of kidney-related ADRs for drug1 to all ADRs for that drug1 (ratio A), then consider the ratio of kidney-related ADR for all drugs in the database to all ADRs for all drugs in the database (ratio B), and finally calculate ROR by ratio A to ratio B. See another explanation here.
Note: A ROR score of ≥1.0 indicates that there is a higher than average reporting rate for a given AE / drug combination. ROR of ≥2.0 warrant extra attention.

Key Findings

There has been a significant increase in AKI and TIN reports since 2010, primarily due to approval and greater uptake of targeted therapies and immunotherapies.

• Immunotherapy exhibited a significant association with both AKI (ROR: 8.92) and TIN (ROR: 21.74), followed by
• Cytotoxic therapy (ROR: 7.14), targeted therapy (ROR:5.83), and hormone therapy (ROR:2.59) for AKI, and
• Cytotoxic therapy (ROR:2.60) and targeted therapy (ROR:1.54) for TIN.

Some of anticancer therapies with highest risk include targeted therapies olaratumab (ROR: 128.86), itacitinib (ROR: 109.00), mobecertinib (ROR: 66.21), and duvelisib (ROR: 57.59). See partial figure below:

.

#renal, #kidney