When external controls collide with the FDA: two recent cases and what they teach us

When trials don’t use a traditional control — What the FDA guidance says

In the usual drug-development pathway, regulators expect a trial where patients are randomly assigned either to receive the investigational drug or a comparator (placebo or active treatment). This randomized-controlled-trial (RCT) design is the “gold standard” for showing that a drug works (i.e., that the benefit is due to the drug not to other factors). For NDA/BLA approvals, FDA issued two guidance documents:

• Demonstrating Substantial Evidence of Effectiveness for  Human Drug and Biological Products
• Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence

However, there are settings—rare diseases, rapidly progressive conditions, or severe unmet need—where recruiting a traditional randomized control arm is difficult or ethically questionable. In those settings, sponsors may propose to compare patients treated under an investigational protocol against a group of patients drawn from an outside dataset (e.g., prior trials, patient registries, real-world data) who did not receive the investigational drug. Such a comparison group is often called an external control (sometimes “synthetic control” or “historical control”).

In this design:

• The treatment arm is prospective, treated under a defined protocol.

• The control arm comes from a separate dataset (regardless of when or how collected) and did not receive the investigational product under the same protocol.
  Because the groups were not randomized together, there are extra risks of bias and confounding. The key question is: can the FDA rely on such evidence to reach its statutory standard of “substantial evidence of effectiveness”?
  In February 2023 the FDA issued a draft guidance for industry titled “Considerations for the Design and Conduct of Externally Controlled Trials for Drug and Biological Products”. 

Here are some of the most important take-aways from that guidance:

• The guidance explicitly recognizes that externally-controlled trials may, in some circumstances, serve as an adequate and well-controlled investigation to support approval of a drug or biologic. 

• But the guidance is cautious: it states that in many cases “the likelihood of credibly demonstrating the effectiveness of a drug of interest with an external control is low.” 

• The guidance puts heavy emphasis on using patient-level data (not just summary published numbers) for the external control. 

• It emphasizes key threats: unmeasured confounding, bias, differences in assessment or follow-up, intercurrent events, immortal time bias, and temporal changes in standard of care or diagnostics. 

• It recommends early and frequent communication between sponsor and FDA if an external control design is under consideration. 

• It doesn’t endorse a single statistical adjustment method (propensity scores, Bayesian modelling, etc.). Instead, it says the analytic plan must be prespecified, transparent, and justified in the context of the specific trial. 

• The guidance makes clear this is not the default approach—it remains a specialized tool rather than the standard route.

In short: the FDA is signaling openness to external controls in selected settings—but the bar remains high.

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How this ties to the two recent cases

Here’s how the guidance connects to the two real-world situations.

Case 1: uniQure and AMT-130 in Huntington’s disease

• uniQure reported a treated cohort using AMT-130 (a one-time gene therapy) and compared outcomes to a natural-history/external cohort.

• The agency essentially pushed back: although the signals were strong, the design raised concerns (especially given the lack of randomization, external control issues) and the company reported that pre-BLA discussions did not confirm a clean path.

• Under the FDA external-control guidance, the concerns would include: are the treated and external groups sufficiently similar (baseline disease features, prior therapies, timing)? Was the index date (“time zero”) aligned? Are the outcome assessments the same, and is the follow-up and endpoint definition comparable? Are missing data or unmeasured confounders plausibly influencing the result? The guidance states that if any of these are weak, the design may not credibly distinguish drug effect from other influences. 

• The uniQure case illustrates: even with promising effect size, the agency may conclude that uncertainties tied to external control reduce confidence in the evidence.

Case 2: Biohaven Pharmaceuticals and Vyglxia (troriluzole) in Spinocerebellar ataxia

• Biohaven’s NDA included a large externally-controlled dataset (real-world evidence for the control arm) reporting disease-slowing.

• The FDA issued a Complete Response Letter (CRL) citing concerns with the external-control-based evidence (e.g., bias, data‐quality, missing/unmeasured information). According to Biohaven, the agency rejected its drug, called troriluzole, due to issues that can be "inherent to real-world evidence and external control studies, including potential bias, design flaws, law of pre-specification and unmeasured confounding factors."

• According to the guidance, when the anticipated treatment effect size is modest, an externally controlled trial is less likely to be acceptable unless the design is very strong. 

• Also the guidance emphasizes that outcome ascertainment, timing, and data source differences between arms are key threats. The Biohaven case appears to reflect those issues.

• This case reinforces that external controls are not a way to bypass rigorous design—they still demand high‐quality data, pre-specification, and detailed justification.

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What this means for patients, clinicians and developers

• For patients & clinicians: When you see a newly approved drug whose pivotal evidence is based on an external control rather than a randomized trial, ask: how comparable were the groups? How solid was the external data (patient-level, good follow-up, similar measurement)? Has a confirmatory trial been required or planned?

• For developers: If you plan to rely on an external control, start very early: identify and curate the external dataset, lock the eligibility and analytic plan, engage FDA in frequent meetings, anticipate the agency will probe data quality, comparability, missing data and bias. Treat the external control design as a rigorous undertaking—not a shortcut.

• For the field of rare diseases and high-unmet-need areas (for example your interest area of pulmonary arterial hypertension): External controls offer a promising option when randomization is infeasible—but you must make the case strongly. The FDA’s guidance gives you the checklist: patient­-level data, alignment of arms, clear index date, consistent endpoint measurement, robust analytics. If you can’t satisfy those, a randomized or concurrent control may still be needed.

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Final thoughts

The FDA’s external‐control guidance is a signal that regulators recognize the realities of these challenging settings—but it does not mean external controls are easy, or will automatically yield approval. The recent uniQure and Biohaven cases are a clear reminder: you may have impressive effect size or compelling unmet need—but the agency will still closely scrutinize design, data source, comparability, missing data, and bias.

FDA Commissioner's National Priority Voucher (CNPV) program versus Priority Review Voucher (PRV)

FDA created a new voucher program called "Commissioner's National Priority Voucher (CNPV) Pilot Program" to accelerate Drug Review for Companies Supporting U.S. National Interests. The CNPV pilot program offers an unprecedented opportunity to reduce drug and biological product application or efficacy supplement (ES) review times from 10-12 months to just 1-2 months. Announced in June 2025, this innovative program uses a collaborative tumor board style review process to accelerate approvals for companies aligned with critical U.S. national health priorities.

On October 16, 2025, FDA Awards First-Ever National Priority Vouchers to Nine Sponsors. The following 9 products were selected:

• Pergoveris for infertility
• Teplizumab for Type I diabetes
• Cytisinicline for nicotine vaping addiction
• DB-OTO for deafness
• Cenegermin-bkbj for blindness
• RMC-6236 for pancreatic cancer
• Bitopertin for porphyria
• Ketamine for domestic manufacturing of a critical drug for general anesthesia
• Augmentin XR for domestic manufacturing of a common antibiotic 

On November 06, 2025, FDA Awards Second Batch of National Priority Vouchers. The following 6 products were selected following external applications and internal nominations from FDA review divisions:

• Zongertinib for HER2 lung cancer
• Bedaquiline for drug-resistant tuberculosis in young children
• Dostarlimab for rectal cancer
• Casgevy for sickle cell disease
• Orforglipron for obesity and related health conditions
• Wegovy for obesity and related health conditions

The new voucher program was criticized in this NEJM article “Flaws in the FDA’s New Priority Voucher Program” by Carpenter, Hwang, and Kesselheim. The authors argue that while the program seeks to promote innovation and address public health needs, it has significant shortcomings. They note that regulatory review already represents a small portion of total drug-development time and that past voucher programs have shown little evidence of spurring innovation while straining FDA resources. The paper warns that the CNPV program, created without congressional authorization and with vague eligibility criteria, risks politicizing FDA decisions, fostering conflicts of interest, and undermining public trust. Moreover, the compressed review timelines could compromise drug safety and overburden staff. The authors suggest that if implemented, the program should focus on generic drugs where expedited review could have tangible benefits, and should incorporate strong transparency, conflict-of-interest safeguards, and legislative oversight to maintain the integrity of the FDA’s regulatory process.

In a previous post, the FDA's Priority Review Voucher (PRV) programs were discussed. Here’s a side-by-side comparison table summarizing the key similarities and differences between the Commissioner’s National Priority Voucher (CNPV) and the Priority Review Voucher (PRV) programs such as the Rare Pediatric Disease PRV:

Feature	Commissioner’s National Priority Voucher (CNPV)	Priority Review Voucher (PRV) – e.g., Rare Pediatric Disease
Origin / Authorization	Created by the FDA Commissioner in 2025 as a pilot program without explicit congressional authorization.	Created by Congress through legislative action (e.g., the 2012 FDA Safety and Innovation Act for rare pediatric diseases).
Purpose	To accelerate review for drugs aligned with U.S. national health priorities, including unmet needs, national security, innovation, and affordability.	To incentivize development of drugs for neglected or rare conditions (e.g., tropical or rare pediatric diseases).
Review Time Benefit	Shortens FDA review time for selected drugs to 1–2 months, much faster than any existing program.	Converts a standard 10-month review to a priority 6-month review for another drug application.
Eligibility Criteria	Broad and somewhat opaque—drugs must align with “national priorities,” such as public health crises or domestic manufacturing.	Clearly defined by statute—applies to drugs for designated rare pediatric diseases (or other legislatively defined conditions).
Voucher Transferability	Nontransferable (can only be used by the same sponsor; valid if company ownership changes).	Transferable—can be sold or traded to another company, often for hundreds of millions of dollars.
Voucher Expiration	Expires after 2 years if unused.	Does not expire.
Selection and Oversight	Controlled by the FDA Commissioner’s office, raising concerns about political influence and conflicts of interest.	Statutory oversight and criteria limit discretion; implementation and tracking are agency-administered but legislatively mandated.
Scope / Eligible Products	Focused on drugs supporting U.S. national interests (innovation, security, affordability).	Focused on drugs addressing specific rare or neglected diseases.
Impact on FDA Workload	Could significantly burden FDA staff due to extremely short review timelines and unfunded mandates.	Adds workload but within a manageable 6-month priority window, and user fees help fund FDA resources.
Pilot Structure / Limits	Initially limited to five awardees in the first year; long-term limits unclear.	Ongoing statutory program with defined eligibility and reporting mechanisms.
Evidence of Effectiveness	No evidence yet; experts predict limited impact on overall development time and potential risks to review quality.	Empirical studies show limited evidence of incentivizing innovation but measurable market and financial impacts.
Key Concerns	Politicization, conflicts of interest, safety risks from rushed reviews, lack of transparency, and legal vulnerability due to lack of statutory basis.	Limited innovation incentive, windfall profits for some sponsors, and added workload, but more transparent and regulated.
Suggested Improvements	Apply to generic drugs, establish clear criteria, ensure independent review, legislative authorization, and transparency.	Better alignment between voucher incentives and public health impact; continue to monitor postmarket safety.

While both CNPV and PRV programs aim to accelerate access to important therapies, the CNPV is a politically driven, non-statutory pilot emphasizing national priorities, with potentially risky acceleration timelines and limited oversight. In contrast, the PRV system—though imperfect—has a clear legislative framework, defined eligibility, and established oversight mechanisms that maintain greater regulatory transparency and accountability.

Industry-Sponsored N-of-1 Trials in Orphan Drug Development

N-of-1 clinical trial is often mentioned as one of the approaches to address the challenging issues in orphan drug development. at one point, FDA rolled out more guidance on 'N of 1' gene therapies including the guidance on "Individualized Antisense Oligonucleotide Drug Products for Severely Debilitating or Life-Threatening Diseases". AHRQ had a publication "Design and Implementation of N-of-1 Trials: A User’s Guide". Recent "baby KJ's story" was touted by the FDA as a success story for individualized treatment for a N-of-1 disease condition "FDA Cell & Gene Therapy Roundtable: Putting Every Patient Within Reach of Innovation". Nature magazine had an article "A framework for N-of-1 trials of individualized gene-targeted therapies for genetic diseases"

We would like to check the reality to see how many drugs or biological products were approved by the US FDA based on the evidence from N-of-1 clinical trials. 

We identified a few ultra-rare disease cases in the past decade where industry or institutional sponsors conducted single-patient (“N-of-1”) trials of experimental therapies. Notably, no drug or biologic approved in the last 10 years appears to have relied on N-of-1 clinical trial data for its FDA approval. The only FDA approval historically based in part on N-of-1 evidence was danazol for hereditary angioedema in the 1980s. Below we summarize key examples of N-of-1 trials involving drugs/biologics and rare indications:

Drug/ Biologic	Orphan Indication	Sponsor (Company/Institution)	N-of-1 Trial Design & Results	Regulatory Outcome
Milasen (custom ASO)	CLN7 Batten disease (Infantile neuronal ceroid lipofuscinosis)	Boston Children’s Hospital (Timothy Yu’s lab)	Single-patient, customized antisense oligonucleotide. FDA cleared an IND for Mila in late 2017, and she received serial intrathecal doses. Her seizure frequency fell dramatically (from ~30/day to <10/day) and her neurologic decline stabilized during treatment.	Investigational (IND only; no FDA marketing approval)
Custom ASO for A-T (no trade name)	Ataxia-Telangiectasia	Boston Children’s Hospital / A-T Children’s Project (Dr. Yu)	Personalized splice-modulating ASO for one AT patient. FDA granted an IND in 2020 for an N-of-1 trial. The child began receiving the ASO (via intrathecal delivery) later in 2020; detailed clinical outcomes have not yet been published.	Investigational (IND only; ongoing treatment)
CRD‑TMH‑001 (CRISPR-based gene therapy)	Duchenne muscular dystrophy (specific exon 1/promoter mutation)	Cure Rare Disease (nonprofit biotech)	Single-patient CRISPR/Cas9 gene-editing therapy. FDA cleared an IND in August 2022 for a one-person trial. The only enrolled patient (the sponsor’s founder’s brother) was dosed but later died (cause under review). As a result, efficacy remains unknown.	Investigational (IND only; trial suspended)
Danazol	Hereditary angioedema	Original developer (Searle/Pfizer)	Historical example: A multi-crossover N-of-1 trial (9 patients, 47 treatment periods) was reported in 1976. This small trial of danazol demonstrated reversal of HAE symptoms and formed part of the FDA approval record.	Approved (for HAE; orphan indication) https://www.fda.gov/media/87621/download section 5.2.4

Each case is discussed in more detail below.

Milasen for Batten Disease (CLN7)

• Drug & Sponsor: Milasen is a one-off antisense oligonucleotide (ASO) developed at Boston Children’s Hospital by Dr. Timothy Yu’s team. It was designed for an 8‑year-old patient (“Mila”) with a unique retrotransposon mutation in the CLN7 gene causing Batten disease.
• N-of-1 Design & Results: After rapid sequencing and preclinical work, the FDA granted an IND to trial milasen in late 2017. Mila then received intrathecal milasen injections every 3 months under an N-of-1 protocol. Over ~9 months of treatment, Mila’s seizure frequency fell from ~30/day to under 10/day, and her neurological decline notably stabilized. No significant adverse effects were reported, and her condition improved in several clinical measures. These results were published in the New England Journal of Medicine (2019).
• Regulatory Outcome: Milasen remains an investigational therapy given under an IND. It was not submitted for FDA marketing approval (and Mila later died in early 2021). Thus, no FDA approval was sought or granted for milasen.

Customized ASO for Ataxia-Telangiectasia

• Drug & Sponsor: A patient-specific splice-switching ASO (unnamed) was developed by Dr. Yu’s group (supported by the A-T Children’s Project) for a young girl with ataxia-telangiectasia (AT). The ASO was tailored to correct her particular ATM gene splicing defect.
• N-of-1 Design & Results: The FDA granted IND approval for this one-off ASO treatment in 2020actionforat.org. The affected child began receiving the ASO via intrathecal infusion that year, under a single-patient trial protocol. (To our knowledge, no detailed efficacy data from this N-of-1 trial have yet been published.)
• Regulatory Outcome: This custom AT therapy is in the investigational stage (IND only). No FDA marketing approval has been sought or obtained.

CRD‑TMH‑001: CRISPR Therapy for Duchenne Muscular Dystrophy

• Drug & Sponsor: CRD‑TMH‑001 is a one-time, custom CRISPR/Cas9 gene-editing therapy developed by Cure Rare Disease (a nonprofit “n=1” biotech) to target a specific exon 1/promoter mutation in the DMD gene. Cure Rare Disease’s founder (motivated by his brother’s illness) sponsored the program.
• N-of-1 Design & Results: In mid-2022, the FDA cleared a first-in-human IND for CRD-TMH-001. The trial was explicitly a single-patient study: one eligible DMD patient (age 27, the sponsor’s brother) was treated. The therapy was infused intrathecally as planned. Tragically, the patient died several months later; a causality review is ongoing. To date, no efficacy data (or definitive safety findings) from this N-of-1 trial have been published.
• Regulatory Outcome: CRD-TMH-001 remains purely investigational under the IND. No further patients have been treated and no FDA approval has been pursued.

Historical FDA Approval: Danazol for Hereditary Angioedema

• Drug & Indication: Danazol is a synthetic steroid used to prevent attacks of hereditary angioedema (HAE), a rare genetic edema disorder.
• N-of-1 Trial Evidence: In 1976, a classic FDA review noted that the approval of danazol for HAE was supported in part by an N-of-1 multiple-crossover trial of nine patients (47 treatment periods). In that study, each subject alternated between danazol and placebo in random sequence, demonstrating clear reversal of clinical and biochemical abnormalities on danazol. This case was cited in section 5.2.4 of the FDA's Good Review Practice: Clinical Review of Investigational New Drug Applications
• Regulatory Outcome: Danazol was approved for HAE prevention (an orphan indication) and remains an approved drug (marketed as DANOCRINE). This case shows that the FDA has historically accepted single-subject crossover data in rare diseases. However, it is an older example; no similar approvals based on N-of-1 data have emerged in the past decade. The N-of-1 study of Danazol in HAE was published in New England Journal of Medicine in 1976 "Treatment of Hereditary Angioedema with Danazol — Reversal of Clinical and Biochemical Abnormalities"

Summary

In summary, we found only a handful of “N-of-1” clinical trials over the past 10 years involving investigational drugs for very rare diseases. These include two custom antisense oligonucleotides (Mila’s milasen for Batten disease, and an ASO for one AT patient) and one CRISPR gene therapy for Duchenne MD. All were “approved” only under individual INDs and have shown promising signals but remain experimental; none has led to FDA marketing approval. Apart from the historical example of danazol (approved via N-of-1 data in the 1970s), our searches of FDA databases, ClinicalTrials.gov, and published literature did not identify any new orphan drugs approved based on N-of-1 trial evidence. Thus, while N-of-1 trials are an emerging tool for ultra-rare diseases, they have not yet changed the landscape of FDA approvals in the last decade.

Steroid Tapering Design in Action - Failed

In a previous post, I discussed steroid tapering design clinical trials. In these trials, the primary efficacy endpoint is the reduction in steroid dose. Efficacy is demonstrated if patients receiving the experimental treatment are able to reduce their steroid dose significantly more than those in the placebo group.

Steroids remain highly effective for many conditions, particularly those involving chronic inflammation or an overactive immune system. However, long-term or high-dose steroid use is associated with numerous side effects. Therefore, it is highly desirable to develop therapies that allow for steroid dose reduction—or even complete steroid sparing—while maintaining disease control.

One of these diseases is sarcoidosis or lung sarcoidosis. Sarcoidosis is an inflammatory disease in which the immune system overreacts, causing groups of cells to form clusters of inflamed tissue called "granulomas" in one or more organs of the body. The most affected organ is lung. Sarcoidosis symptoms can be treated using corticosteroids, or prednisone, which turn down the immune system's activity to reduce inflammation.

A sponsor, aTyr Pharma, conducted a phase 3, confirmatory trial to investigate if their experimental drug efzofitimod is effective in treating the pulmonary sarcoidosis. The study "Efficacy and Safety of Intravenous Efzofitimod in Patients With Pulmonary Sarcoidosis" was designed as steroid tapering with the primary efficacy endpoint being "Change from baseline in mean daily oral corticosteroid (OCS) dose at Week 48".

This morning, the sponsor issued a press release announcing Topline Results from Phase 3 EFZO-FIT™ Study of Efzofitimod in Pulmonary Sarcoidosis. Study did not meet primary endpoint in change from baseline in mean daily oral corticosteroid (OCS) dose at week 48, although clinical benefit for efzofitimod observed across multiple study parameters.

The change from baseline in mean daily OCS dose reduced to an average of 2.79 mg for the high dose of efzofitimod versus 3.52 mg for placebo, resulting in an insignificant treatment difference. The sponsor blames the unexpected placebo response.

aTyr flunks phase 3 lung disease trial, deflating stock, but still plans talks with FDA

The steroid tapering design offers important clinical advantages by directly addressing the need to reduce long-term steroid exposure, a major source of morbidity in many chronic inflammatory and immune-mediated diseases. The steroid tapering design and the change from baseline in steroid dose is accepted by the regulatory agencies. It provides a patient-centered and easily quantifiable endpoint that demonstrates whether an investigational treatment can maintain disease control while allowing for a lower steroid dose. 

However, this design also has limitations. Variability in tapering schedules, risk of disease flares, and ethical concerns regarding aggressive tapering in placebo groups can complicate interpretation. In addition, results may be less generalizable to steroid-naïve patients, and regulatory acceptance of steroid-sparing endpoints as stand-alone primary outcomes remains uncertain. Careful planning and standardization are therefore essential to balance the scientific value with patient safety and trial credibility.

ICH E21 "Inclusion of Pregnant and Breastfeeding Individuals in Clinical Trials"

US FDA has just endorsed the draft guideline of ICH E21 "Inclusion of Pregnant and Breastfeeding Individuals in Clinical Trials". E21 Training Material can also be found at ich.org. 

The ICH E21 guideline aims to provide recommendations for the appropriate inclusion and retention of pregnant and breastfeeding individuals in clinical trials. This is crucial because historically, these populations have been largely excluded, leading to a significant lack of data on the safety and efficacy of medicinal products during pregnancy and lactation.

For clinical trialists, the guideline emphasizes:

• Proactive Planning: Sponsors should consider strategies to generate data on medicinal product use in pregnancy and breastfeeding from early stages of development, including nonclinical studies through post-approval.

• Risk-Benefit Evaluation: A thorough assessment of potential risks and benefits for both the pregnant or breastfeeding individual and the fetus/breastfed infant is essential.

• Ethical Considerations and Informed Consent: The guideline stresses the importance of obtaining truly informed consent, ensuring clear communication of potential risks and benefits, and avoiding any undue influence or coercion. Efforts should be made to reduce the burden of study procedures on these participants.

• Study Design and Implementation: It provides practical guidance for designing clinical trial protocols, including considerations for data collection, safety monitoring, and follow-up for both mother and child. This also includes pharmacokinetic (PK) and dosing considerations, as physiological changes during pregnancy can impact drug pharmacokinetics.

• Addressing Unmet Medical Need: The inclusion of pregnant and breastfeeding individuals is particularly important for conditions where there is a high unmet medical need for treatment in pregnancy or while breastfeeding, though the guideline's scope is not limited to these scenarios.

• Data Generation: The overarching objective is to facilitate the generation of robust clinical data that allows for evidence-based decision-making on the safe and effective use of medicinal products by these individuals and their healthcare providers.

The ICH E21 guideline is a significant step towards improving the evidence base for prescribing medications during pregnancy and lactation, ultimately aiming for better patient outcomes for these underserved populations.

Just several weeks ago, I wrote a blog post on this same topic "Managing Pregnancies in Clinical Trials: Regulatory Guidance and Best Practices", which offered a comprehensive overview of the historical exclusion of pregnant women from clinical trials, the reasons behind this, and the evolving regulatory landscape advocating for their inclusion. The article emphasized a balanced approach, highlighting FDA's shift towards diversity in trials and the ethical imperative to gather data on drug use in pregnancy to ensure evidence-based care. It delved into practical aspects like informed consent, pre-screening procedures, managing pregnancies discovered during trials (including stopping drug, unblinding, and re-consenting), and the importance of detailed data collection and specialized safety monitoring. The blog post also strongly argued for the ethical benefits of inclusion, asserting that systematic exclusion leads to greater harm by forcing healthcare providers and patients to make decisions without adequate evidence. 

The newly endorsed ICH E21 guideline directly aligns with various FDA guidance described in the blog post and significantly reinforces the "balanced approach" and the ethical arguments. 

• ICH E21 provides a more harmonized, international standard for how this inclusion should be achieved proactively throughout drug development. 
• ICH E21 offers detailed recommendations on study design, ethical considerations, pharmacokinetic and dosing adjustments, safety monitoring, and data collection specifics for pregnant and breastfeeding individuals, directly addressing the "when and how" question you pose at the end of your article. 
• ICH E21 reiterates the need for IRBs with maternal-fetal expertise, suggesting consultation with specialists for study design and safety monitoring. 
• ICH E21 highlights the critical importance of robust informed consent and ongoing safety monitoring for both the mother and the child. 
• ICH E21 essentially provides the detailed, internationally agreed-upon framework, moving the industry further towards systematic and responsible inclusion rather than historical exclusion.