'Femi Fajimi

Understanding Pre-Clinical Modules of the CTD – A Dermalexiin Case Study 

By Femi Fajimi | 02 July 2025  

Introduction: The CTD and Its Pre-Clinical Modules 

Regulatory medical writers often encounter the Common Technical Document (CTD) format when preparing submissions for new medicines. The CTD is organised into five modules, where Module 4 compiles all pre-clinical (nonclinical) study reports. These include the in vitro and animal studies that assess the pharmacology and safety of an investigational product. In simple terms, Module 4 is the “safety module” of the CTD, encompassing pharmacology, pharmacokinetics, and toxicology data for a drug candidate. (Module 2, by contrast, contains summary documents like the Nonclinical Overview and Summaries, which distil the detailed data from Module 4 into a clear narrative for reviewers.) 

In this post, I’ll explain the purpose and typical content of each section of the CTD’s pre-clinical module with an emphasis on Module 4. To make it concrete, I’ll use a fictional investigational product – Dermalexiin, a hypothetical topical dermatological cream – as an illustrative case. (Dermalexiin is an invented example for educational purposes.) We’ll describe the information that goes into the Pharmacodynamics, Pharmacokinetics (ADME), and Toxicology sections of Module 4 and show how these data support a Clinical Trial Application (CTA). Along the way, I’ll include sample excerpts in a style consistent with regulatory documentation, to give early-career medical writers a flavour of how such content is written. 

Overview of CTD Module 4 (Pre-Clinical Study Reports) 

CTD Module 4 is dedicated to Nonclinical Study Reports, which demonstrate the pre-clinical pharmacology and safety profile of a drug. The structure and content of Module 4 are defined by ICH guidelines (M4 “Safety” module). Module 4 is divided into three primary sections: 

• Pharmacology (4.2.1): This includes pharmacodynamics studies; how the drug works and its effects on the body (both intended effects and any off-target effects), as well as safety pharmacology studies of critical organ systems. 

• Pharmacokinetics (4.2.2): This section contains studies of Absorption, Distribution, Metabolism, and Excretion (ADME) of the drug in animals, plus any nonclinical drug interaction or toxicokinetic studies. 

• Toxicology (4.2.3): This compiles all toxicity studies, from acute and repeat-dose toxicity in animals to genotoxicity, reproductive toxicity, carcinogenicity (if required), local tolerance, and any other special toxicology studies. 

Each of these sections in Module 4 would include complete study reports or detailed summaries of the experiments performed. The goal is to provide regulators with evidence that the investigational product has been sufficiently tested for safety before it is given to humans. The nonclinical program is designed according to international guidelines, for example, ICH M3(R2) outlines the recommended battery of studies needed to support human trials. Generally, before conducting first-in-human trials, the nonclinical package must include: pharmacodynamic evaluations, safety pharmacology studies, general toxicity studies (acute and repeat-dose in two species), toxicokinetic/pharmacokinetic studies, and genotoxicity tests. Other studies (e.g. carcinogenicity, reproductive toxicity, phototoxicity, or immunotoxicity) are conducted as needed, depending on the product’s characteristics and intended use. It’s worth noting that for biotechnology-derived products (biologics), ICH S6 provides a tailored framework for pre-clinical safety testing; however, in this post, I focus on a small-molecule example (Dermalexiin). 

Below, I delve into each subsection of Module 4, explaining what it contains and providing examples from the fictional Dermalexiin dossier. 

Pharmacodynamics: Demonstrating How Dermalexiin Works (Module 4.2.1) 

Pharmacodynamics (PD) studies describe the biochemical and physiological effects of the drug and its mechanisms of action. In Module 4, the pharmacology section is typically broken down into primary PD, secondary PD, and safety pharmacology: 

• Primary Pharmacodynamics: Studies that show the drug’s intended therapeutic effects and mechanism of action. This often includes in vitro assays (e.g., receptor binding or enzyme inhibition) and in vivo efficacy models that demonstrate the drug produces the desired effect in a disease-relevant system. For Dermalexiin (a dermatological anti-inflammatory cream), primary PD might involve assessing its anti-inflammatory or antipruritic effects in skin models. 

• Secondary Pharmacodynamics: Investigations of the drug’s effects other than the primary therapeutic aim, for example, effects on other receptor systems or organs. This helps identify any potential off-target activities. A Dermalexiin example could be tests to see if it affects receptors unrelated to skin inflammation (to evaluate possible side effects). 

• Safety Pharmacology: Focused studies to examine whether the drug has adverse effects on vital organ systems, typically cardiovascular, respiratory, and central nervous system, at therapeutic or higher exposures. These studies are mandated by guidelines, such as ICH S7A, to ensure that no critical organ functions are dangerously impaired. Even for a topical drug with low systemic exposure, key safety pharmacology assays (such as hERG binding or blood pressure and CNS observation studies in animals) are usually conducted to rule out unexpected hazards. 

In a CTA, the pharmacodynamics data are used to justify why the drug is being developed and to support the proposed therapeutic approach. Efficacy data in animals (or relevant models) provide proof-of-concept that the drug has the intended biological activity. For a medical writer, it’s essential to clearly describe the results in Module 4 and related summary documents, highlighting the drug’s mechanism and any dose-response relationships observed in nonclinical studies. 

Example excerpt from Dermalexiin’s Nonclinical Overview (fictional): 

Pharmacodynamics: Dermalexiin (DMLX-1) is a novel topical anti-inflammatory agent. In primary pharmacodynamic studies, Dermalexiin demonstrated significant efficacy in reducing skin inflammation in a murine model of allergic contact dermatitis. Daily application of Dermalexiin 1% cream to mice’s ears led to a 75% reduction in oedema and erythema compared to vehicle controls, indicating potent anti-inflammatory activity at the site of application. The mechanism of action is attributed to inhibition of pro-inflammatory cytokine release (Dermalexiin-treated skin showed >50% lower TNF-α and IL-6 levels than controls). Secondary pharmacodynamic assays revealed no significant off-target binding at 100 known receptors and enzymes, suggesting a high degree of selectivity. In safety pharmacology studies, Dermalexiin had no notable effects on CNS behaviour in mice or cardiovascular function in telemetered rats at doses yielding systemic exposure ~20-fold above the anticipated human exposure. No QT prolongation was observed in a hERG channel assay at concentrations up to the solubility limit. 

This excerpt illustrates how PD results might be summarised. It shows Dermalexiin’s intended effect (anti-inflammatory action in skin), provides quantitative outcomes (e.g. “75% reduction in oedema”), explains the putative mechanism, and reports any off-target findings or safety pharmacology outcomes (in this case, none significant). All these details would be documented in Module 4, with full study reports appended and summarised in Module 2. Importantly, these pharmacology data support the rationale for testing Dermalexiin in humans – they suggest that Dermalexiin works as intended (justifying moving into clinical trials) and that it does not have obvious pharmacological liabilities at relevant exposures. 

Pharmacokinetics (ADME): How Dermalexiin Behaves in the Body (Module 4.2.2) 

Pharmacokinetics – often abbreviated as PK- describes how the drug is absorbed, distributed, metabolised, and excreted in animals. It corresponds to the ADME studies in Module 4.2.2, which typically include: 

• Absorption: Does the drug get absorbed into systemic circulation? For oral medications, this could be related to gut absorption; for Dermalexiin (a cream), the focus is on dermal absorption. Studies might measure plasma levels after topical application to estimate systemic exposure. 

• Distribution: Once absorbed, how does the drug distribute through the body? These studies measure drug concentrations in different tissues. A plasma protein binding assay and tissue distribution study (possibly using a radiolabeled compound) could be done to determine if Dermalexiin remains in the skin or distributes widely. 

• Metabolism: How is the drug chemically broken down in the body? In vitro studies (e.g. liver microsomes or hepatocyte incubations) can identify metabolic pathways and metabolites. If Dermalexiin is absorbed, researchers would identify its metabolites in plasma or excreta. They might also check whether it inhibits or induces major drug-metabolising enzymes. 

• Excretion: How is the drug (and its metabolites) eliminated – via urine, faeces, or other routes? For a topical with minimal absorption, excretion may be limited; however, if absorbed, one would examine biliary versus renal excretion. 

• Other PK studies: This can include toxicokinetic measurements (drug levels in animals during toxicity studies to correlate exposure with toxic effects) and any PK drug interaction studies in animals or in vitro (e.g. cytochrome P450 inhibition assays). 

PK/ADME data in Module 4 serve several purposes for a CTA. Firstly, they help predict human pharmacokinetics. For instance, if Dermalexiin is minimally absorbed in animals, one might expect low systemic exposure in humans as well, which could influence the safety monitoring plan. The PK studies also inform dose selection: understanding the relationship between dose, blood levels, and time helps estimate a dosing regimen for human trials. Additionally, knowing how the drug is metabolised and cleared can alert clinicians to potential drug-drug interactions or accumulation issues. 

For medical writers, it’s important to clearly describe the key PK findings. This may include numerical values such as bioavailability, half-life, C_max (peak concentration), and AUC (area under the curve) exposure from animal studies, as well as any cross-species differences. It’s also customary to note if the exposure achieved in animal studies covers the expected human exposure (i.e. safety margins). 

Example excerpt from Dermalexiin’s Nonclinical Summary (fictional): 

Pharmacokinetics (ADME): The systemic absorption of Dermalexiin through the skin was low across the tested species. In a rat dermal absorption study, only ~5% of the applied dose was absorbed into circulation (bioavailability ~5%). The peak plasma concentration (C_max) at the highest tested topical dose (equivalent to 10 mg/cm²) was 50 ng/mL, occurring ~2 hours post-dose, and exposure was dose-proportional. Tissue distribution studies with radiolabeled Dermalexiin demonstrated that radioactivity was primarily confined to the application sites and regional lymph nodes, with negligible levels in other organs. Dermalexiin was rapidly metabolised via phase II conjugation pathways; the primary metabolite in plasma was a glucuronide conjugate. Excretion was chiefly biliary/faecal – in rats, >80% of the absorbed Dermalexiin-derived radioactivity was recovered in faeces, with <5% in urine. The plasma elimination half-life was approximately 3 hours in rats, indicating no tendency for bioaccumulation with once-daily dosing. In vitro cytochrome P450 inhibition assays revealed no significant inhibition of major CYP isoforms at concentrations up to 10 µM, suggesting a low risk of metabolic drug–drug interactions. 

In this fictional summary, we see how one would report the ADME characteristics: low absorption (only 5% through the skin), limited distribution (mostly at the site of application), rapid metabolism (via glucuronidation), and elimination routes. For Dermalexiin, the low systemic exposure is a reassuring point for safety, and a medical writer would likely highlight that the drug’s limited absorption may reduce systemic side effects. We also included a note on the lack of CYP enzyme inhibition, which is relevant for later clinical use (indicating Dermalexiin likely won’t cause drug–drug interactions via CYP inhibition). All these details support the design of the clinical trial – for example, knowing the half-life (3 hours in rats) might hint that twice-daily application in humans could be necessary if the effect duration is similar, although human PK could differ. More importantly, the animal PK data are used in toxicology interpretations, which we turn to next. 

Toxicology: Ensuring Safety of Dermalexiin (Module 4.2.3) 

The toxicology section of Module 4 is typically the largest, as it encompasses all the safety studies that assess the potential harm the drug may cause. These studies adhere to regulatory standards (ICH “S” series guidelines) to ensure that a new drug is thoroughly tested. Key components of the tox package include: 

• Single-Dose Toxicity (Acute Toxicity): Studies where a single high dose of the drug is given to animals (usually two species, e.g. rodent and non-rodent) to observe immediate toxic effects and determine approximate lethal dose levels. For Dermalexiin, an acute dermal toxicity study may involve applying a high-concentration cream to rats and rabbits once and monitoring for any acute systemic or local adverse effects. 

• Repeat-Dose Toxicity: These studies assess subacute, subchronic, and chronic toxicity by administering the drug regularly (e.g., daily) over a specified period (2 weeks, 1 month, 3 months, etc.) to evaluate cumulative toxic effects. Regulatory guidelines stipulate that the duration of animal studies should cover the intended length of human exposure. For example, a 2-week study in two species can support a clinical trial up to 2 weeks long, whereas for chronic use, longer studies are required (ICH S4 recommends 6-month rodent and 9-month non-rodent studies to support chronic administration in humans). In Dermalexiin’s case, since it’s a topical for potentially chronic dermatological use, subchronic 3-month dermal toxicity studies in a rodent (rat) and a non-rodent (often minipigs are used for dermal products) would likely be conducted. These studies aim to assess any organ toxicity, general health effects, and reversibility after discontinuation of dosing. Toxicokinetic data (drug levels in the animals during the study) are collected to relate any toxicity to systemic exposure. 

• Genotoxicity: A standard battery of tests to check if the drug can cause genetic damage (mutations or chromosomal abnormalities). This typically includes an in vitro bacterial mutagenesis test (Ames test), an in vitro assay in mammalian cells (such as a chromosomal aberration or micronucleus test), and an in vivo genotoxicity test (often a rodent micronucleus assay). For Dermalexiin, these studies would determine whether it poses any risk of DNA damage, an essential consideration before human exposure. 

• Reproductive and Developmental Toxicity: If the drug is intended for use in women of childbearing potential or long-term use, studies on fertility, embryofetal development, and prenatal/postnatal development in animals are needed (per ICH S5). These assess whether the drug could affect reproduction or cause congenital disabilities. Dermalexiin’s development program might include such studies if it were planned for use by pregnant women or in adults broadly. However, these are often completed before Phase III, if not done before the first-in-human study. 

• Carcinogenicity: For drugs intended for long-term use, rodent carcinogenicity studies (often 2-year studies in rats and mice) may be required to evaluate cancer risk. However, these are usually not required until later stages (e.g. before marketing). Dermalexiin, being a topical with potentially limited systemic exposure, might be exempt or might undergo a shorter-term carcinogenicity assessment if needed. 

• Local Tolerance: Essential for topical products, local tolerance studies assess the drug’s potential for irritation or sensitisation at the site of application. Dermalexiin would be tested for dermal irritation (e.g. Draize test in rabbits) and for allergenic potential (e.g. a guinea pig maximisation test or murine local lymph node assay to detect skin sensitisation). If Dermalexiin were intended for use with sun exposure, a phototoxicity test might also be done to ensure it doesn’t cause photochemical skin reactions. 

• Other toxicology studies: Depending on the drug, additional studies could include immunotoxicity (e.g. effects on immune function), juvenile animal toxicity (if the drug is for pediatric use), or abuse liability studies (for drugs acting on the CNS). These are done as applicable. 

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The collective toxicology data in Module 4 underpin the safety rationale for human trials. Regulators will scrutinise this section to ensure that: (1) No unexpected, severe toxicity emerged at exposures comparable to those proposed in humans; (2) there is a comfortable safety margin between the doses causing no harm in animals and the starting dose in humans; and (3) potential risks are identified and can be monitored or managed in the clinic. For example, if Dermalexiin caused mild reversible liver enzyme elevations in animals, the CTA would need to discuss this and propose liver function monitoring in the clinical trial. ICH guidelines note that the nonclinical safety studies should characterise toxic effects, target organs, dose dependence, and the relationship to exposure. This information is used to estimate a safe starting dose for human trials and to identify potential adverse effects to monitor clinically. 

Let’s see how some of Dermalexiin’s fictional toxicology results might be reported: 

Example excerpt from Dermalexiin’s Investigational’s Brochure – Toxicology section (fictional): 

Toxicology: Dermalexiin has been evaluated in a comprehensive nonclinical toxicology program. In single-dose toxicity studies, Dermalexiin showed a high margin of safety – no mortality or severe toxicity was observed in rats or minipigs even at the limit dose of 1000 mg/kg (dermal application). Only transient mild erythema at the application site was noted at these high doses. In repeated-dose dermal toxicity studies (28-day and 90-day duration), Dermalexiin was well tolerated at daily doses up to 50 mg/kg in rats and 20 mg/kg in minipigs. There were no drug-related systemic toxicities or organ damage findings. The primary findings were limited to dose-dependent local skin changes: slight erythema and dryness at the application sites, which were reversible upon a 2-week recovery period. Importantly, no significant changes in clinical pathology parameters were noted; for instance, liver enzymes remained within normal ranges, indicating no hepatic toxicity. The no-observed-adverse-effect level (NOAEL) was established as 50 mg/kg/day in the 90-day rat study (highest dose tested with no adverse effects). This NOAEL provides an approximate 10-fold safety margin over the maximum anticipated human dose (on a mg/m² basis). Dermalexiin also tested negative for genotoxicity in a standard battery of tests. No mutagenic activity was detected in the Ames bacterial assay, and no clastogenic effects were observed in an in vitro micronucleus test in human lymphocytes. An in vivo mouse micronucleus test also showed no evidence of chromosomal damage at exposures greater than 25 times the expected clinical exposure. In reproductive toxicity screening studies, no impairment of fertility or early embryonic development was seen in rats at dermal doses up to 20 mg/kg/day. Embryo-fetal development studies in rabbits revealed no teratogenic effects; only minor skeletal variations were noted at doses that caused maternal skin irritation. Additionally, Dermalexiin did not induce contact sensitisation in a guinea pig maximisation test. Overall, these nonclinical findings support a favourable safety profile for Dermalexiin, with skin-localised effects as the primary observed drug-related changes and wide safety margins for systemic toxicity. 

This detailed fictional excerpt mirrors how a real regulatory document might summarise toxicology findings. We see the critical outcomes: identification of a NOAEL (50 mg/kg/day) with a stated safety margin for human dosing, the absence of systemic toxicity, and characterisation of the limited local effects. This is precisely the kind of information regulators look for to decide if a first-in-human trial can proceed safely. The excerpt also notes that all genotoxicity results were negative, which reassures that Dermalexiin isn’t likely to be carcinogenic or mutagenic (important for allowing human exposure). By performing toxicity studies in two species for up to 3 months, the developers of Dermalexiin have satisfied the guideline requirements to support clinical trials of similar or shorter duration. The favorable nonclinical results would be used to justify the proposed starting dose in the CTA, typically by applying a safety factor to the animal NOAEL to calculate a safe human dose. For example, suppose the NOAEL in rats corresponds to a human-equivalent dose of (say) 100 mg. In that case, the sponsor might propose a starting dose of around 10 mg in humans (a 10-fold safety margin), aligning with regulatory recommendations for first-in-human dose selection. 

From Lab to Clinic: Using Module 4 Data to Support a CTA 

How do all these pre-clinical data come together to support a Clinical Trial Application? In essence, the Module 4 studies provide the evidence base that it is reasonably safe and scientifically justified to administer the investigational product to humans. Early-phase clinical trials (such as a Phase I study) are typically designed based on the findings of the nonclinical program: 

• Safety Justification: The toxicology studies inform the risk assessment. Regulatory guidelines emphasise that animal data should be integrated to define the safety profile of the drug and to predict potential human risks. For Dermalexiin, the lack of systemic toxicity in animals, combined with the wide safety margins, provides confidence that human volunteers are unlikely to experience serious adverse effects at the planned dose levels. Any target organs of toxicity seen in animals (in Dermalexiin’s case, none major aside from local skin irritation) would be specifically monitored in the clinical trial. For instance, if high-dose animals had shown kidney changes, renal function tests would be included in trial safety monitoring. In our example, local skin irritation is the primary concern, so the CTA would outline measures to monitor application site reactions in participants. 

• Starting Dose and Dose Escalation: Nonclinical data guide the selection of a safe starting dose in humans. As noted, typically the NOAEL in the most sensitive animal species is used to calculate a maximum recommended starting dose, applying conservative safety factors. With Dermalexiin, if the NOAEL is 50 mg/kg in animals, the CTA might propose a starting dose that is a fraction of the animal exposure at NOAEL (e.g. 1/10th of the human-equivalent dose). The PK data (showing low systemic exposure) also feed into this decision, suggesting that even at relatively high topical doses, systemic levels remain low, which is reassuring. The clinical protocol would reference these calculations to justify why the starting dose and escalation schedule are safe. 

• Dosing Interval and Route: Pharmacodynamic and pharmacokinetic results help determine the optimal dosing interval and route for administering the drug in the trial. For example, Dermalexiin’s animal PK indicated a 3-hour half-life, suggesting that twice-daily application might maintain its effect. However, if the primary PD model in animals demonstrates an anti-inflammatory, prolonged impact, perhaps once-daily application could be sufficient. The CTA would use this rationale (e.g. “once daily topical dosing is proposed based on sustained local efficacy in animal models and the convenience for patients”). The route of administration in the trial (topical dermal) is, of course, the same as that tested in animals, which is essential. Administering to animals via the intended clinical route (when feasible) ensures that the safety assessment is relevant. 

• Clinical Monitoring and Risk Mitigation: All notable findings from pre-clinical studies are carried forward into the risk management for the trial. For Dermalexiin, the CTA would mention the potential for mild skin irritation. Thus, the informed consent for volunteers would state the possibility of redness or rash, and the trial investigators would be instructed to check the application sites regularly. Suppose any organ had a mild, non-adverse effect in animals (e.g., a slight, non-progressive increase in liver weight in rats without clinical pathology changes). In that case, the sponsor might still monitor that organ’s function in humans (e.g., perform liver enzyme tests periodically) out of caution. Nonclinical pharmacology might also suggest specific efficacy biomarkers to measure, for instance, if Dermalexiin lowered skin TNF-α in animal studies, an exploratory endpoint in the trial could be changes in inflammatory markers in skin biopsies. 

From a regulatory medical writing perspective, crafting the CTA involves summarising the nonclinical findings clearly in documents like the Investigator’s Brochure (IB) and the Nonclinical Overview (Module 2.4). These summaries must interpret the data for regulators and investigators, explaining how the animal data support the proposed human trial. The writer must ensure that the conclusions are well-supported by the data (with references to Module 4 studies) and that any uncertainties or risks are transparently discussed with plans to manage them. According to ICH M4 guidance, the Nonclinical Overview should integrate the pharmacology, pharmacokinetics, and toxicology results and “arrive at logical, well-argued conclusions supporting the safety of the product for the intended clinical use”. In other words, by the end of the overview, the reader should be convinced that it’s appropriate to proceed to human trials, given the pre-clinical evidence. 

In my Dermalexiin example, the bottom line of the nonclinical package might be: “Dermalexiin has shown the desired pharmacological activity in nonclinical models, a favourable pharmacokinetic profile with low systemic exposure, and no significant toxicity in animal studies at exposures greatly exceeding those expected in humans. The primary identified risk, mild skin irritation, is monitorable and manageable. Therefore, the nonclinical data support the initiation of a Phase I clinical trial of Dermalexiin in human subjects.” This would be conveyed in the concluding section of the Nonclinical Overview and echoed in the Risk Assessment section of the Investigator’s Brochure. 

Conclusion 

Pre-clinical modules (Module 4 of the CTD) form the scientific backbone of any Clinical Trial Application. They provide regulators with evidence that a new investigational drug has been thoroughly tested in the laboratory and animal models for both efficacy and safety. For early-career regulatory medical writers, understanding the content and purpose of each part of Module 4 is crucial. Pharmacodynamics studies show why the drug should work (and help anticipate therapeutic effects), Pharmacokinetics studies reveal how the drug behaves in a biological system (influencing dosing and interaction considerations), and Toxicology studies demonstrate the safety margins and inform risk mitigation for human trials. All three areas are interlinked and must be interpreted together to paint a complete picture of the drug’s profile. 

Using the fictional case of Dermalexiin, I illustrated how a Module 4 might look for a topical drug and how that data would be utilised in a CTA. In real-world scenarios, the specific studies and data will vary depending on the nature of the drug (for example, a biologic therapy would have a different set of studies, as per ICH S6(R1), or a cytotoxic oncology drug might require specialised studies). However, the overarching principles remain the same. The CTD’s pre-clinical module is there to ensure that when a new drug advances to human testing, it does so on a foundation of sound science and safety evidence. 

As a medical writer, your role is to communicate that foundation clearly and accurately. By structuring the documents well (following the CTD format) and citing key findings (with references to study reports and guidelines), you help regulators navigate the data effectively. Ultimately, a well-prepared Module 4 (and its summaries in Module 2) helps instil confidence that the investigational product, whether it’s Dermalexiin or a real new drug, is ready for the critical step of being tested in humans, with patient safety as the foremost priority. 

References & Guidelines: In preparing Module 4 content, writers often refer to ICH guidelines for requirements and format. Key references include the ICH M4 guideline for CTD organisation, ICH M3(R2) for the recommended scope of nonclinical studies before trials, and various ICH “S” series guidelines for specific study types (e.g. S1–S5 for tox, S7A for safety pharmacology, etc.). Ensuring compliance with these guidelines and citing them where appropriate not only strengthens the submission’s credibility but also demonstrates to the reviewer that the nonclinical program adheres to global regulatory standards. By mastering both the science and the regulatory framework, early-career medical writers can make a significant contribution to the success of a CTA and, ultimately, to the safe development of new therapies.