Consideration for Clinical Requirements for Investigational Drug

AE.............................................Adverse Event

BE.............................................Bioequivalence

CTCAE.............................................Common Terminology Criteria for Adverse Events

DLT.............................................Dose-Limiting Toxicity

FiH.............................................First-in-Human Study

GCP.............................................Good Clinical Practice trials.

HED.............................................Human Equivalent Dose.

ICH.............................................International Council for Harmonisation

IDMC.............................................Independent Data Monitoring Committee

MTD.............................................Maximum Tolerated Dose

OBD.............................................Optimal Biological Dose

PD.............................................Pharmacodynamics

PK.............................................Pharmacokinetics

PMCs.............................................Post Marketing Commitments

PMRs.............................................Post Marketing Requirements.

PREA.............................................Pediatric Research Equity Act

PROs.............................................Patient-Reported Outcomes

PSP.............................................Pediatric Study Plan

QbD.............................................Quality by Design

RP2D.............................................Recommended Phase II Dose

SFDA.............................................Saudi Food and Drug Authority

SMP.............................................​Safety Monitoring Plan​

Biomarker:  Biological characteristic used as an indicator of pharmacologic response, disease state, or treatment outcome.

Dose Escalation:  The process of increasing doses stepwise to identify the MTD or OBD.

Dose Increment / Decrement:  The percentage increase or decrease between successive dose levels.

Dose–Efficacy Curve:  Describes the relationship between drug dose and probability of therapeutic efficacy.

Dose–Toxicity Curve:  Represents the relationship between drug dose and likelihood of experiencing toxicity.

Starting Dose:  The initial dose selected for the first cohort in a Phase I trial.

Surrogate Endpoint:  A substitute for a clinical endpoint that predicts clinical benefit 

Target Toxicity Level:  Maximum acceptable probability of experiencing a DLT in a trial

Therapeutic Index:  ​Ratio of toxic dose to effective dose, indicating the drug’s safety margin.

1.1. Purpose 

This guideline is intended to support clinical investigators and applicants in investigating the efficacy and safety of new drugs. it provides guidance throughout the clinical trial lifecycle, encompassing every stage of drug development.

1.2. Scope and applicability 

This guideline applies to all investigational drug applications submitted to the Saudi Food and Drug Authority (SFDA) for interventional clinical trials involving investigational drugs intended for human use, including, but not limited to, new chemical entities and biological drugs.

1.3. Regulatory framework and objectives  

The Saudi Food and Drug Authority (SFDA) evaluates investigational drug applications with the primary objective of ensuring the safety of clinical trial participants and the scientific validity of the trial objectives, design, and conduct. The assessment also focuses on whether the efficacy of the investigational drug is sufficient to support a comprehensive evaluation of the submitted application.

All clinical trials are expected to be designed and conducted in a manner that safeguards the safety and well-being of participants, while ensuring the reliability and credibility of the generated data. This approach serves to uphold the quality and integrity of clinical trials and to promote their ethical and scientific conduct. All clinical trials must be conducted in alignment with ethical principles rooted in the declaration of Helsinki and in accordance with SFDA Guideline for Good Clinical Practice (GCP) and applicable regulatory requirements

The information presented in this document is not applicable to veterinary or herbal product submissions. This guideline is intended to assist applicants in ensuring the availability of minimum clinical data necessary to establish the safety and efficacy of the investigational product. The SFDA encourages applicants to engage in early discussions with the regulatory authority.

1.4. Relevant Documents 

This guideline should be read in conjunction with: 

• Data requirements for human drugs submission 

• Regulatory framework for drugs approval 

• Guideline for bioequivalence 

• Clinical considerations for vaccines 

• Guidelines on Biosimilar Products: Quality Considerations 

• Guidance for presenting the labeling information, Summary of product characteristic (SPC) and Patient information leaflet (PIL). 

International Council for Harmonization (ICH) guidelines: 

• ICH E1: The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions

• ICH E3: Structure and Content of Clinical Study Reports

• ICH E4: Dose-Response Information to Support Drug Registration

• ICH E5: Ethnic Factors in The Acceptability of Foreign Clinical Data

• ICH E6: Good Clinical Practice 

• ICH E7: Studies in Support of Special Populations: Geriatrics 

• ICH E8: General Considerations for Clinical Studies 

• ICH E9: Statistical Principles for Clinical Trials 

• ICH E10: Choice of Control Group and Related Issues in Clinical Trials 

• ICH E11: Clinical Investigation of Medicinal Products in The Pediatric Population 

• ICH E17: General Principles for Planning and Design of Multi-Regional Clinical Trials

• ICH E19: A Selective Approach to Safety Data Collection in Specific Late-Stage Pre-Approval Or Post-Approval Clinical Trials​

​​The nature of the therapeutic modality (e.g., small molecule, biological drug, pharmacological mechanism of action, novelty of the product and unmet medical needs) determines the specific studies that are both necessary and anticipated to support the initiation of first-in-human (FiH) clinical trials.

The assessment of investigational drugs serves not only to meet regulatory requirements but also facilitate a deeper understanding of both on-target and off-target pharmacological effects, thereby reducing translational risks to clinical trials participants.

The types of anticipated clinical trials in the submitted investigational drug applications are as follow: 

I. Human pharmacology: Phase I, FiH, Bioequivalence and others, such as Phase 0 

II. Therapeutic exploratory: Phase I and phase II integrated clinical trial, Phase II 

III. Therapeutic confirmatory: Phase II and phase III integrated clinical trial, Phase III 

The investigational drug should be thoroughly described, including its dosage, dose and route of administration. This encompasses details regarding the dosage form, packaging, and labelling. 

2.1. Protocol

A clinical trial protocol serves as the foundational document for the design, conduct, and evaluation of a study. It must be scientifically robust, operationally feasible, and clearly articulated to ensure compliance with regulatory expectations and the generation of reliable data. The SFDA requires that protocols submitted for investigational drug applications adhere to ICH standards and provide comprehensive details to guide the evaluation process. 

The essential components expected in a clinical trial protocol. These include:

 Study Title: A concise and descriptive title that reflects the study's purpose and scope.

 Protocol Summary: A brief overview of the study design, objectives, and key elements.

 Background and Rationale: A detailed explanation of the scientific basis for the study, including nonclinical and prior clinical data supporting the investigational drug's development. 

 Objectives: Clearly defined primary and secondary objectives that align with the study endpoints.

 Study Design: A description of the methodology, including randomization, blinding, and control measures, tailored to the study's objectives.

 Study Population: Inclusion and exclusion criteria, along with justification for the selected population.

 Endpoints: Definitions of primary and secondary endpoints, supported by a rationale for their selection.

 Safety Monitoring: A plan for assessing and managing adverse events, including stopping rules and escalation criteria. 

 Statistical Analysis Plan: Pre-specified methods for analyzing data, consistent with ICH E9 statistical principles. 

 Operational Details: Information on study sites, investigator responsibilities, and logistical considerations. 

The protocol should be structured to enable investigators to design and submit studies that meet SFDA expectations. Additionally, the subsequent sections provide detailed guidance on specific protocol components, such as study design, population, endpoints, and safety monitoring. This ensures a cohesive understanding of the requirements and facilitates the development of high-quality submissions.

2.2. Types of clinical trials and their objectives 

When planning clinical trials for new drugs, applicants are required to ensure that adequate safety and efficacy data are available to justify human exposure. These data should be derived from nonclinical studies, prior clinical investigations, and/or real-world evidence. The justification must address the intended route of administration, the proposed dosage regimen, the planned duration, and the target trial population. 

Human Pharmacology Trials (Phase I)

Applicants must design human pharmacology trials, to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of investigational drugs. These trials are foundational for subsequent therapeutic exploratory and confirmatory studies. Applicants are expected to tailor the design of these trials to their specific objectives, which may include, but are not limited to:

• First-in-Human (FiH) Studies: To assess initial safety, tolerability and PK in humans. 

• Single Ascending Dose (SAD) Studies: To evaluate the safety and PK of increasing single doses. 

• Multiple Ascending Dose (MAD) Studies: To assess safety, tolerability, and PK/PD of repeated doses. 

• Drug Interaction Studies: To investigate potential interactions with other drugs.

• Bioequivalence Studies — comparability across formulations, where relevant

Applicants are adequately required to justify the choice of study design and ensure that the trials are conducted in compliance with regulatory and ethical standards. 

Therapeutic Exploratory Trials (Phase II) Trials

Exploratory trials must be designed to evaluate the preliminary safety, efficacy, and pharmacological activity of investigational drugs in a defined patient population. These trials are critical for identifying optimal therapeutic doses, establishing dose-response relationships, and refining the drug's safety profile to inform subsequent confirmatory trials. 

Applicants are encouraged to employ flexible and adaptive designs to maximize the understanding of the drug's effects while minimizing risks to participants. Examples of such designs include:

• Dose-Ranging Studies: To explore the relationship between dose and response. 

• Biomarker-Driven Approaches: To identify subpopulations likely to benefit from the drug. 

• Stratified or Titrated Dosing Strategies: To optimize dosing for individual participants or subgroups. 

• Phase I/II Integrated Designs: to combine dose-finding and preliminary efficacy assessment within a single study.

The data generated from exploratory trials must be used to shape the design and objectives of later-phase confirmatory studies, ensuring a rational and efficient progression in drug development. Applicants are expected to provide a clear rationale for their chosen designs and demonstrate how the data will support the transition to confirmatory trials. 

Confirmatory Trials

Confirmatory trials, which are commonly designed as blinded, placebo-controlled studies, must meet rigorous regulatory expectations to ensure the meaningful interpretation of clinical benefit. Applicants are required to:

• Define clear endpoints that align with the trial's objectives and regulatory standards. 

• Develop robust statistical analysis plans to ensure the reliability and validity of the results. 

• Specify appropriately defined populations that reflect the intended use of the drug. 

Additionally, the nonclinical, clinical, and clinical pharmacology data generated in earlier phases must be sufficient to support the progression to large-scale trials. These confirmatory studies are pivotal in demonstrating the drug's efficacy and safety for regulatory approval and subsequent use in the target population. 

Applicants must ensure that the design of confirmatory trials reflects regulatory expectations and supports meaningful interpretation of clinical benefit. This includes aligning endpoints and statistical plans with the trial’s objectives and ensuring that the study population is appropriately defined to represent the intended use of the drug. By meeting these requirements, confirmatory trials provide the critical evidence needed for regulatory approval and subsequent commercialization.

2.3. Study population 

2.3.1 Healthy volunteers vs. patients:

When enrolling healthy volunteers, an upper age limit should be applied to minimize risks associated with comorbidities and the influence of concomitant medications prevalent in older populations. This approach ensures the safety of participants and the reliability of pharmacokinetic and pharmacodynamic data. 

In therapeutic areas where enrolling healthy volunteers is ethically inappropriate or scientifically unjustified patients should be enrolled instead. This ensures the study population is relevant to the investigational drug's intended use. 

Special attention must be given to vulnerable participants, including pediatric participants, older adults, individuals with hepatic or renal impairment, and diverse ethnic groups.  Robust ethical and regulatory safeguards must be implemented to protect their rights and welfare. Applicants are required to obtain pharmacokinetic data in sub-populations that may exhibit altered drug metabolism or excretion.  

This includes individuals with hepatic or renal impairment, older adults, pediatric populations, and diverse ethnic groups. Such data are critical for understanding the drug's behavior and ensuring accurate labeling for safe and effective use.

In therapeutic confirmatory trials, the selection of the study population is critical to achieving the trial's objectives. Applicants must define and justify the inclusion and exclusion criteria to ensure alignment with the trial's goals. This includes considerations for disease characteristics, comorbidities, and demographic factors. 

Furthermore, applicants are required to obtain pharmacokinetic data in sub-populations that may exhibit altered drug metabolism or excretion. This includes, but is not limited to, individuals with hepatic or renal impairment, older adults, pediatric populations, and diverse ethnic groups. Such data is essential for understanding the drug's behavior in these populations and ensuring that the product label accurately reflects relevant information for safe and effective use. 

Failure to provide adequate data for these sub-populations may result in limitations or exclusions in the product label for these groups. Applicants are strongly encouraged to proactively address these requirements during trial planning and execution.

2.4. Endpoints

2.4.1. Primary & Secondary Endpoints 

The selection and definition of study endpoints are essential to ensure that clinical trials generate meaningful and interpretable data. Applicants are required to specify the primary endpoint clearly in the study protocol, ensuring it is clinically relevant, robust, and capable of addressing the primary objective of the trial.  This aligns with the principles outlined in ICH E9 (Statistical Principles for Clinical Trials), which emphasize the importance of endpoints that provide reliable evidence for regulatory decision-making.

 Primary Endpoints

• Requirement: The primary endpoint must be explicitly defined and justified in the protocol. It should reflect the therapeutic benefit of the investigational drug and be acceptable to regulatory authorities across regions, particularly in multi-regional clinical trials (MRCTs). 

• Examples: For oncology trials, endpoints such as progression-free survival (PFS) or overall survival (OS) are commonly used, as they provide measurable and clinically significant outcomes. In other therapeutic areas, endpoints may include disease-free survival (DFS) or patient-reported outcomes (PROs), depending on the trial's objectives. 

 Secondary Endpoints

• Requirement: Secondary endpoints should support the primary objective or evaluate additional effects aligned with secondary objectives. These endpoints must also be clearly defined in the protocol to ensure consistency in data collection and interpretation. 

• Examples: Secondary endpoints may include biomarkers, toxicity measures, or health-related quality of life (HRQoL) assessments, particularly in trials where patient-centric outcomes are critical

Applicants are requested to provide a clear and scientifically justified rationale for the selection of all endpoints. The justification should explain how each endpoint is relevant to the investigational drug, its mechanism of action, and the intended target population. Where applicable, applicants should also address potential cultural or regional differences in endpoint interpretation, in alignment with the principles outlined in ICH E17 for multiregional clinical trials.Applicants should specify, within the study protocol, the detailed methods and timing of endpoint assessments. For example, oncology trials should utilize validated assessment criteria such as RECIST when evaluating tumor response. All measurement tools and evaluation criteria should be appropriately validated and standardized to ensure the reliability and reproducibility of results.

2.4.2. Biomarker Assessment

In early-phase clinical studies, biomarkers shall be utilized when traditional clinical endpoints are insufficient to adequately inform study objectives.  Applicants are required to employ appropriate and validated biomarkers to support dose selection, enhance mechanistic understanding, and enable risk stratification.  The selection and validation of biomarkers must be justified in the study protocol, ensuring their relevance to the investigational drug and alignment with regulatory expectations.

2.4.2.1.Role of Biomarkers in Early-Phase and FIH Studies

The roles of biomarkers shall be clearly categorized based on their intended function and supported by appropriate justifications, as outlined in section 2.4.2.2 of this guideline. Applicants are required to ensure that the selection and use of biomarkers align with the study objectives and regulatory expectations. Specifically:

• Pharmacodynamic Biomarkers: Biomarkers may be utilized to demonstrate target engagement or pathway modulation, providing mechanistic insights into the investigational drug's activity. 

• Predictive and Prognostic Biomarkers: Predictive and prognostic biomarkers shall be employed to identify patient subpopulations likely to benefit from the investigational drug or experience adverse effects. Their use must be justified with evidence supporting their relevance to the study population and therapeutic area. 

• Surrogate Biomarkers (Endpoints): Surrogate biomarkers may be accepted when they provide early evidence of efficacy or biological response. Applicants must validate surrogate biomarkers by presenting robust evidence of their reliability and relevance, including data demonstrating their correlation with clinical outcomes

2.4.2.2.Selection and Validation of Biomarkers

The selection of biomarkers shall be based on their biological relevance to the investigational drug’s mechanism of action or the underlying disease pathway. This relevance must be supported by translational evidence derived from preclinical models, ensuring that the biomarker is scientifically justified and aligned with the study objectives. Furthermore, biomarkers must be supported by validated bioanalytical methods to ensure their reliability and reproducibility. Practical considerations, such as sample collection, stability, storage, and processing, shall be addressed and documented comprehensively in the study protocol. 

The qualification of a biomarker for use in drug development is contingent on selecting a biomarker that is suitable for its defined context of use (COU). This selection must ensure high-quality measurement methods, and there must be a demonstrable, reliable correlation between the biomarker and the relevant clinical outcome. Supporting evidence must include both clinical validation (demonstrating that the biomarker’s relationship with the outcome of interest is robust and acceptable for the proposed COU) and analytical validation (confirming the precision and reliability of the measurement method). 

A biomarker submission must clearly define the following factors:

a) Intended Purpose: Specify the biomarker’s role, such as:

• Prognostic biomarker for patient enrichment. 

• Safety biomarker for detecting drug-induced toxicity.

• Pharmacodynamic biomarker for assessing target engagement or pathway modulation.

• Surrogate biomarker (endpoint) for providing early evidence of efficacy or biological response.

b) Stage of Drug Development: Identify the phase or study in which the biomarker will be applied, such as Phase 1 clinical trials or nonclinical safety studies. 

c) Clinical Trial Population or Model System: Provide a detailed description of the population or model system, including characteristics such as age, disease stage, comorbidities, or relevant animal models.

d) Therapeutic Mechanism of Action (MOA): Detail the MOA for which the biomarker is intended, ensuring that the MOA is biologically relevant and consistent with the biomarker’s pathway and intended utility.

Applicants should provide a comprehensive explanation of the biomarker’s known role within the biological or disease process of interest. This includes identifying any existing gaps in the understanding of the disease pathophysiology or molecular mechanisms, as well as outlining the biomarker’s position within the disease pathway to support its biological plausibility. 

The level of evidence required to qualify a biomarker is contingent upon its COU. In instances where the potential benefits of a biomarker substantially outweigh its associated risks, and where effective risk mitigation strategies are established, a lower level of supporting evidence may be deemed acceptable. Conversely, where the benefits marginally exceed the risks, a higher level of supporting evidence will be required to ensure safety and efficacy.

2.5. Safety monitoring

2.5.1. Data Collection and Monitoring

Robust safety data collection is a fundamental requirement for early-phase clinical trials to ensure participant protection and generate reliable and interpretable safety profiles for investigational drugs. Applicants are required to establish and maintain procedures that ensure the prompt reporting of all serious adverse events, irrespective of the investigator’s assessment of causality. These procedures must comply with applicable regulatory requirements and Good Clinical Practice (GCP) standards.

2.5.2. The scope and frequency of safety assessments shall be proportionate to the risk associated with the investigational drug and aligned with its mechanism of action, pharmacologic class, and anticipated toxicity profile. Applicants are encouraged to incorporate patient-reported outcomes (PROs) to provide complementary insights into tolerability, particularly in the context of dose modifications or adverse drug reactions. When PRO instruments are utilized, they must be validated and demonstrated to be fit for purpose within the trial context.

​2.5.3. Safety Monitoring Plans
Applicants are required to develop a comprehensive Safety Monitoring Plan (SMP) for all early-phase clinical trials. The SMP should clearly describe how safety will be proactively monitored, managed, and reported throughout the study to ensure the protection of trial participants and the integrity of safety data. 

The plan must include a detailed schedule of safety evaluations, specifying the timing, frequency, and methods of data collection. These planned safety assessments should encompass all relevant parameters necessary to detect potential adverse effects or emerging safety concerns at the earliest possible stage. 

Applicants should also provide a clear description of the data flow and responsibilities within the SMP. This section must delineate the roles and responsibilities of all parties involved in safety data collection, analysis, and reporting, ensuring that accountability and communication pathways are well defined. 

In addition, the SMP must include predefined thresholds for intervention, outlining the specific criteria used to identify safety signals and determine when immediate actions or modifications to the trial are warranted.

For trials involving long-term follow-up or where sustained efficacy and safety are critical, extended monitoring must be implemented to evaluate delayed or cumulative adverse effects and the durability of clinical benefit. The SMP should address the specific requirements for long-term safety monitoring, including the collection of data on late-onset adverse events.

In studies involving significant safety uncertainty, high-risk populations, or complex trial designs, the establishment of an Independent Data Monitoring Committee (IDMC) is strongly recommended. IDMCs provide objective oversight to safeguard participant safety and support the scientific integrity of the trial. The necessity for an IDMC must be determined during study planning, based on the trial’s risk profile and regulatory expectations. The SMP should include provisions for IDMC operations, including the frequency of meetings, reporting requirements, and decision-making processes.

​​3.1. Dose selection and escalation 

Defining an appropriate dose range is a critical element in the design and execution of early-phase clinical trials. Dose selection should be grounded in a comprehensive integration of nonclinical data—including pharmacology, toxicology, and pharmacokinetics—and any relevant clinical data, particularly from agents with similar mechanisms of action (MOA).

To ensure participant safety, a suitable safety factor should be applied to the human equivalent dose (HED) derived from animal studies, thereby minimizing the risk of adverse effects from the initial human dose.

3.1.1. Factors influencing starting dose selection  

The selection of a safe and scientifically justified starting dose for early phase trials is a foundational decision in the clinical development of investigational drugs. This process must integrate robust nonclinical evidence with mechanism of action and drug-specific considerations. 

3.1.1.1.Preclinical data

All these factors should be comprehensively assessed to ensure both participant safety and the potential for therapeutic benefit. A thorough nonclinical program is essential to inform the design of early-phase clinical trials. 

Critical preclinical objectives include characterization of systemic and target organ toxicities, including reversibility and dose-dependence, establishment of exposure–response relationships, based on toxicokinetic data, evaluation of pharmacological selectivity and off-target effects and identification and validation of safety biomarkers, which can be monitored in clinical trials.

3.1.1.2.Mechanism of action 

A clear understanding of the drug’s mechanism of action is critical for determining an appropriate starting dose. This includes a description of the pharmacological effects and the underlying biological pathways through which the drug exerts its activity, as demonstrated in nonclinical models, target expression and engagement profiles as well as potential for immune activation or suppression.

While comparisons to compounds with similar MOAs can provide a useful reference point, differences in potency, PK, biodistribution, and formulation must be considered. Cross-reactivity studies and species specificity assessments for example in biologics, where the relevance of animal models may be limited.

3.1.1.3.Therapeutic Window

The therapeutic window is the range between the minimum effective dose and the dose at which toxicity becomes unacceptable. Its estimation is fundamental for selecting a safe and informative starting dose and shaping dose-escalation strategy

For compounds with a narrow therapeutic window, a conservative approach to dose escalation is essential to minimize the risk of adverse events. In contrast, investigational drugs with a wider therapeutic margin may permit more flexible or accelerated dose-escalation strategies. A clear understanding of the therapeutic window, informed by preclinical data and mechanistic insights, supports safer and more efficient clinical development.

3.1.1.4.Dose escalation   

 Sentinel dosing

Sentinel dosing is a risk mitigation strategy employed to enhance participant safety during early-phase clinical trials, including single ascending dose (SAD) and multiple ascending dose (MAD) studies.  This approach involves the staggered administration of the investigational drug to one or two participants at a specific dose level, followed by a predefined observation period before dosing the remainder of the cohort.  The use of sentinel dosing, including the number and treatment allocation of sentinel participants, should be prospectively specified and scientifically justified. The duration of the observation period should be based on the expected onset and duration of adverse events, informed by the pharmacology, pharmacokinetic, and pharmacodynamic profiles of the investigational product. The protocol should further specify predefined criteria for proceeding with dosing of the remaining participants in the cohort, including safety, tolerability, pharmacokinetic and, where relevant, pharmacodynamic data that must be reviewed and considered acceptable before further dosing is authorized. 

While sentinel dosing is typically implemented during the initial dose levels, it may be continued or reintroduced at later dose levels or study stages where warranted by the evolving risk profile of the investigational product. Relevant circumstances may include a steeper dose-response or exposure-response relationship, disproportionate increases in systemic exposure, a narrowing safety margin relative to nonclinical toxicity thresholds or emerging clinical findings indicating an increased likelihood or adverse reactions with further dose escalation. Similarly, investigational products associated with a high level of uncertainty such as those with novel mechanisms of action, limited preclinical safety data, or unpredictable toxicity profiles and may require ongoing sentinel dosing to mitigate risks effectively. 

 Dose-stopping criteria

Dose-stopping criteria are predefined thresholds that trigger cessation of further dose escalation based on safety concerns. It is recommended that protocols incorporate explicit stopping rules to prevent surpassing known or predicted exposure and toxicity limits. When reviewing emerging data in relation to this criterion, the maximum exposure observed in individual subjects within a cohort rather than the mean exposure should be taken into account.

Stopping rules in early phase clinical trials are predefined criteria within the clinical trial protocol that require an immediate halt to dosing under certain conditions. These rules should be clearly defined for each of the following situations:

• Final stop to dosing and termination of the trial.

• Stopping dosing for an individual subject at any time during the trial.

• Stopping dosing within a cohort, including:

 When subjects in a cohort are dosed in a staggered manner.

 During multiple dosing phases.

• Stopping before progression to the next part of the trial.

• Stopping during any dose escalation parts of the trial.

Stopping rules for healthy volunteer trials should include, but not be limited to: 

• One ‘serious’ adverse reaction in one subject.

• Two ‘severe’ non-serious adverse reactions occurring in the same cohort, regardless of whether they affect the same or different system-organ classes.

 Rule-based Designs 

Rule-based dose (e.g., 3+3 design) escalation designs utilize predefined algorithms to guide dose increases or decreases based on the occurrence of specific safety events, such as dose-limiting toxicities. These designs specify fixed dose levels in advance and adjust dosing decisions according to observed safety outcomes.

 Model approaches to inform dosing

Model-based approaches to dose selection and optimization are increasingly recognized as essential tools for enhancing the efficiency, safety, and scientific rigor of early-phase clinical trials.  These approaches leverage advanced statistical and mechanistic modeling techniques to inform decisions across all stages of dose selection, including starting dose determination, dose escalation, and dose optimization.  Applicants are encouraged to employ state-of-the-art modeling methodologies to ensure robust and scientifically justified dose selection strategies.

The selection of the starting dose might be informed by advanced modeling approaches in addition with other evidence, including but not limited to:

• Physiologically-Based Pharmacokinetic (PBPK) Models: Mechanistic models that simulate drug absorption, distribution, metabolism, and excretion based on physiological and biochemical parameters. 

• Allometric Scaling: Approaches that extrapolate dose from preclinical species to humans based on body size, metabolic rates, and other scaling factors. 

• Population Pharmacokinetics (PopPK): Models that account for variability in drug exposure across diverse populations, including age, sex, disease state, and genetic factors. 

• Pharmacokinetic/Pharmacodynamic (PK/PD) Models: Models that integrate drug exposure and response data to predict therapeutic and toxic effects.

Applicants should adequately justify the choice of modeling approach based on the investigational drug’s mechanism of action, preclinical data, and anticipated clinical use.  The starting dose should minimize risks to participants while ensuring sufficient exposure to generate meaningful pharmacokinetic and pharmacodynamic data.

Dose escalation beyond the starting dose could be guided by real-time modeling approaches that integrate emerging human PK/PD data, safety signals, and pharmacodynamic markers. Mechanism-informed modeling techniques, such as exposure-response modeling, systems pharmacology, and hybrid approaches, should be employed to refine dose escalation strategies and identify the recommended phase 2 dose (RP2D). These approaches allow for:

• Identification of the Maximum Tolerated Dose (MTD): Determining the highest dose that can be administered without unacceptable toxicity. 

• Optimization of the Optimal Biological Dose (OBD): Identifying the dose that achieves the desired therapeutic effect with minimal toxicity.

Applicants are encouraged to utilize evolving modeling methodologies and not limit themselves to the models explicitly mentioned. As new modeling techniques emerge—such as advanced machine learning algorithms, artificial intelligence-driven simulations, or hybrid models combining PBPK and PopPK—these should be considered to enhance dose selection and optimization. 

3.2. First-in-Human (FiH) Studies

First-in-Human studies represent the initial administration of an investigational drug to human subjects, following completion of an adequate nonclinical program (pharmacology, toxicology, and pharmacokinetics) sufficient to justify safe translation from animal models to humans. The primary objective is to assess safety and tolerability at a carefully derived starting dose, while generating preliminary pharmacokinetic (PK) data and, where feasible, pharmacodynamic (PD) data.

These studies are typically conducted in healthy volunteers, except in specific cases,  such as highly cytotoxic agents (e.g., oncology) or products with a high-risk mechanism of action, where they may instead be conducted directly in patients with the target condition. Refer to Section 3.1 (Dose Selection and Escalation) for starting dose determination.

3.3. Single Ascending Dose (SAD) Studies

Evaluate the safety, tolerability, and pharmacokinetics of a single dose administered to successive cohorts at progressively increasing dose levels. Traditionally the first component of FiH development, dose escalation between cohorts is guided by cumulative review of safety, PK, and PD data from preceding levels, with staggered (sentinel) dosing applied at initial dose levels. Refer to Section 3.1 for starting dose determination and escalation principles.

3.4. Multiple Ascending Dose (MAD) Studies

Assess the safety, tolerability, and PK/PD of repeated administration across ascending dose levels, typically initiated once SAD data confirm an acceptable safety margin. Dose and duration are constrained by the supporting repeat-dose nonclinical toxicology package. As with SAD, staggered dosing, pre-defined stopping rules, and continuous safety review apply. Refer to Section 3.1 for escalation methodology.

3.5. Drug Interaction Studies

Investigational drugs should be assessed for drug-drug interaction (DDI) potential progressively throughout development. This assessment should address pharmacokinetic interactions in both directions: how the investigational drug's exposure may be affected by co-administered drugs (as an object of interaction), and how the investigational drug may in turn affect the exposure of other concomitant medications (as a precipitant).

3.6. Bioequivalence Studies

​Where a different formulation of the investigational drug is used during development, its relative bioavailability compared to the original formulation should be assessed in accordance with SFDA bioequivalence guideline.

​​​​Exploratory studies play a critical role in the rational development of new therapeutic agents. It is important to maintain the conventional distinction between Phase I/II exploratory trials and Phase III confirmatory trials.

In these trials, the focus shifts from the safety profile of the drug, as seen in early phase studies, to identifying the optimal therapeutic dose that balances both efficacy and safety and to determine the optimal dose for subsequent therapeutic confirmatory trials:

 Dose-ranging studies

Dose-ranging studies systematically evaluate different dose levels to characterize the dose-response relationship for both efficacy and safety. The primary aim is to identify a dose range that offers the best therapeutic benefit with an acceptable safety profile, including identification of the minimum effective dose, the point at which the therapeutic effect begins to plateau, and the dose or exposure at which adverse effect become clinically unacceptable. These findings are critical for selecting and justifying the dose or dose regimen to be evaluation in subsequent confirmatory trials such as phase III trials. 

Typically, a parallel-group design is used, often randomized and controlled, with 3 to 5 fixed dose arms, this enables the comparison of various dose levels and provides data on both safety and efficacy at each dose level as well as pharmacokinetics (PK/PD) as secondary endpoint.

In PK/PD-guided dosing, it incorporates pharmacokinetic and pharmacodynamic data to inform and refine the dosing strategy.  While in biomarker-driven dose selection, the dosing strategy is informed by specific validated biomarkers that can be used to track the drug's biological effect, such as target engagement, receptor occupancy, or changes in gene expression. The applicant might use model-based approaches, when possible, to integrate biomarker, pharmacokinetic and pharmacodynamic data and support dose selection​

The approach is particularly important in therapeutic areas like oncology or immunotherapy, where surrogate markers are often available. The identification of specific biomarkers, where validated, allows for dose optimization based on the biological response in the target population, ensuring that the drug is being administered to those most likely to benefit.

Stratified designs are often used to identify subpopulations with the most favorable risk-benefit profiles. This enables precision dosing, tailoring the treatment to those most likely to experience therapeutic effects while minimizing adverse events. In a fixed dosing strategy, all participants receive the same predetermined dose level, this approach is simpler and is commonly used when there is a clear therapeutic window or when variability between patients is low.

Titrated dosing involves adjusting the dose based on individual patient factors, such as clinical response or side effects. This approach is highly relevant for investigational products with narrow therapeutic indices or high inter-patient variability, the optimal dose may differ significantly between individuals. Titrated dosing is preferred in trials where personalized medicine is important, as it allows for a tailored approach that can maximize therapeutic benefit and minimize adverse effects for each individual. 

 Stopping rules: 

Phase 2 trials primarily assess efficacy and safety in a larger group of patients with the target condition. The stopping rules are also predefined in the protocol.

These rules should include:

• Safety-related criteria similar to Phase 1, such as serious or severe adverse events possibly related to the investigational product.

• Efficacy-related stopping rules, for example:

- when interim analyses indicate that the trial is unlikely to demonstrate efficacy (futility). However, implementing futility stopping rules requires careful planning and consideration of factors such as the timing of interim analyses, the choice of statistical methods and the interpretation of results.

- When interim analyses indicate sufficient evidence of efficacy (early stopping for efficacy).​

​A comprehensive review of safety findings from all early phase trials is essential to ensure the investigational drug's risk profile is well characterized. As well as the justification of dose selection for Phase 3 according to previously mentioned considerations based on pharmacokinetics, pharmacodynamics, and observed tolerability. When applicable, pediatric development must be considered early.​

Applicant must also identify any additional studies or analyses needed to support claims related to efficacy, safety, or labeling. Long-term follow-up may be necessary for trials aiming for curative outcomes or for instant, when assessing vaccine durability.

The design of clinical trials is a cornerstone in the development of medicinal drugs and directly impacts the interpretability, reliability, and regulatory acceptability of study outcomes, the need for well-structured, scientifically justified clinical trial designs becomes even more critical by time.

This section outlines the essential considerations that applicants and investigators must address when planning and conducting clinical trials. Additionally, it highlights strategies to minimize bias and confounding, ensure rigorous statistical analysis, and appropriately handle missing data, factors vital to maintaining the trial's scientific credibility.

6.1. Minimizing Bias and Confounding

Applicants are expected to proactively incorporate bias-reduction strategies into trial design, conduct, and analysis, in line with international regulatory standards. The primary techniques used in trial design are blinding and randomization, which should be standard features of most controlled trials supporting marketing applications.

In double-blind trials, treatments are pre-packed and labeled to conceal allocation from both participants and investigators. Where double-blinding is not feasible, single-blind or open-label designs may be used with additional safeguards such as centralized randomization and blinded outcome assessors. The protocol should justify the level of blinding and describe procedures for maintaining the blind and handling any unblinding events.

Randomization reduces selection bias and promotes balance across treatment groups. Applicants should use secure, reproducible randomization schedules. Blocking and stratification may enhance group comparability, especially in small or multicenter trials. 

Dynamic allocation methods can be applied to maintain balance across multiple factors, provided randomization is preserved and centrally controlled. The randomization schedule should be securely maintained, and its access controlled throughout the trial.

6.2. Control of Confounding in the analysis 

Confounding arises when an extraneous variable is associated with both the exposure and the outcome, potentially distorting the effect estimate. Strategies to reduce confounding include stratified randomization, eligibility criteria, determine a pre-specified subgroup analysis and applying multivariable statistical adjustment. 

6.3. Data integrity, Compliance, and Quality assurance

Implementing and maintaining quality assurance and quality control systems is the responsibility of the applicant to ensure that data generation, documentation, and reporting in line with the protocol, Good Clinical Practice (GCP) and applicable regulatory requirements.

Systems of quality assurance and quality control should be in place to ensure the quality of the data. If used, the clinical study report appendices should contain documentation of inter-laboratory standardizing techniques and quality assurance processes. 

The applicant should establish a monitoring plan outlining the strategy, responsibilities, approaches, and justification for monitoring. Depending on a systematic, prioritized, risk-based approach, monitoring could take place on-site, centrally, or using a combination.

In cases where non-compliance is identified, the applicant is expected to respond promptly. If the issue has a significant impact on participant safety or the reliability of the trial results, a root cause analysis should be performed. Based on this, appropriate corrective and preventive actions should be implemented to address the issue and prevent recurrence. All data handling related activities have to be performed under validated systems with sufficient backup, security, and audit trails. Essential records must be kept in line with relevant criteria and data transformations have to be traceable to original data.

6.4. Handling of Missing Data

Trial designs should proactively aim to minimize the occurrence of missing data through rigorous follow-up procedures, continued data collection post-treatment discontinuation, and patient retention strategies. Collection of post-dropout outcome data and treatment information (e.g., rescue medication, switch therapy) should be prioritized, particularly when these influence the interpretation of treatment effect.

Understanding the mechanism of missingness is essential, as it directly influences the choice of appropriate handling and analysis methods.

The primary method for handling missing data must be clearly defined in the statistical analysis plan, including rationale and assumptions, acceptable methods should minimize bias and reflect uncertainty accurately. 

Single Imputation Methods are simple but often inappropriate for primary analysis due to potential for bias and underestimation of variability. Multiple Imputation (MI) generates several datasets by replacing missing values using a stochastic model that reflects the uncertainty inherent in the missing data. Lastly different approaches are available for Model-Based Methods. Sensitivity analysis are essential to test the robustness of results under different missing data assumptions.

6.5. Innovative Clinical Trial Design

 Innovative clinical trial designs are reshaping drug development by offering greater flexibility, efficiency, and potential for regulatory acceleration. These designs aim to address the limitations of traditional randomized controlled trials, such as high cost, long timelines, and limited adaptability to emerging data, particularly in settings with high unmet medical needs or where rapid evidence generation is crucial.

From a regulatory perspective, innovative clinical trial designs offer the potential to make drug development more agile, efficient, and responsive to emerging data. When properly designed and executed, these approaches can shorten development timelines, enhance patient recruitment and retention, and facilitate adaptive decision-making based on accumulating evidence. Their successful implementation, however, requires robust scientific rationale, rigorous methodological planning, and comprehensive pre-specification of adaptations in the protocol and statistical analysis plan. Moreover, strict control of the Type I error rate and measures to mitigate operational bias such as appropriate blinding and independent data monitoring are essential to preserve trial integrity and interpretability.

Common modern clinical trial designs include, but are not limited to:

• Adaptive Designs: Permit pre-specified modifications such as sample size re-estimation, early stopping, dropping or adding arms, or dose-finding adjustments.

• Seamless Phase Trials: Combine development stages (e.g., Phase I/II or II/III) under a single protocol to streamline progression and reduce redundancy.

• Basket Trials: Evaluate a single investigational treatment across multiple disease indications that share a molecular target or biomarker.

• Umbrella Trials: Test multiple therapies in a single disease population, stratified by distinct biomarkers or genetic mutations.

• Platform Trials: Utilize a continuous, multi-arm structure that allows for dynamic addition or removal of treatments, often using a shared control group.

Each of these designs introduces statistical and operational complexities that must be carefully addressed. For inferentially seamless or adaptive trials, advanced statistical methods such as combination testing procedures, α-spending functions, or stage-wise analysis are acceptable approach to ensure the validity of conclusions across stages or adaptations. Sponsors are encouraged to consult with regulatory authorities early in development when planning the use of these novel designs.​​

​Effective risk mitigation is essential to ensure the safety of participants, the integrity of trial data, and the overall quality of clinical development programs. Applicants are expected to adopt a structured, proactive, and continuous approach to identifying, evaluating, and managing potential risks throughout the investigational drug lifecycle.

7.1. Integrated Safety Surveillance and Risk Management

Applicants must establish a comprehensive safety surveillance system beginning in early-phase development and continuing through all phases of clinical investigation.

Safety surveillance should be informed by both clinical and nonclinical findings, as well as by pharmacovigilance data from similar compounds or therapeutic classes. Applicants must be prepared to adapt study protocols, pause enrollment, or modify dose regimens in response to new safety information.

7.2. Quality by Design (QbD) and Risk-Based Trial Oversight

Adopting a Quality by Design (QbD) approach allows applicants to identify and control factors critical to participant safety and data reliability from the outset of clinical development. ​

7.3. Risk-Proportionate Monitoring Studies 

Risk-proportionate monitoring ensures that monitoring intensity is commensurate with the level of risk identified. The goal is to optimize resource allocation while ensuring timely detection and mitigation of issues that could compromise study outcomes.

7.4. Post marketing and Post-Approval Risk Management

In certain cases, post marketing requirements (PMRs) or post marketing commitments (PMCs) may be necessary to further characterize the benefit-risk profile of the drug. Such strategies should be aligned with findings from the investigational phases and should be clearly described in regulatory submissions, including Risk Management Plans (RMPs) where applicable