International Journal of Research in Pharmacy 

and Allied Science (IJRPAS)

Published by Ideal Publication

 Available at https://ijrpas.com/

 

Regulatory Overview: Clinical Trial Application Process in Europe, USA and India

Akshatha¹, Chandan B.V.*²

1 Pharm D Intern, TVM College of Pharmacy, Ballari, Karnataka.

2 Regulatory Associate, Bengaluru, Karnataka.

 

*Correspondence: jethawapalak@gmail.com; Tel.: +91-8128617182

DOI: https://doi.org/10.71431/IJRPAS.2025.4804

Article Information		Abstract
Review Article Received: 30/08/2025 Accepted: 31/08/2025 Published: 31/08/2025   Keywords Clinical trials; Investigational New Drug (IND); Clinical Trials Information System (CTIS); SUGAM portal; Clinical Trials Registry-India (CTRI); Clinical Trial Application (CTA);		Clinical trials serve as the cornerstone for advancing medical knowledge, ensuring patient safety, and enabling the approval of new therapies across the globe. However, the regulatory frameworks governing clinical trials vary significantly across regions, reflecting differences in healthcare systems, legal requirements, and regulatory authorities. This article provides an overview of clinical trials and the clinical trial application (CTA) process from a regulatory perspective in Europe, the United States, and India. It highlights the role of key regulatory bodies such as the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA), and the Central Drugs Standard Control Organization (CDSCO), and compares the processes, timelines, and documentation requirements across these jurisdictions. By examining both the similarities and unique aspects of each system, the article aims to provide a comprehensive understanding of the global clinical trial landscape and its implications for drug development and approval.

 

INTRODUCTION

Clinical trials are essential components of medical research, designed to evaluate the safety and efficacy of new treatments, including drugs, biologics, and medical devices in human participants. These trials play a critical role in the development of new medical treatments and the advancement of clinical practice by determining the therapeutic value and potential risks associated with new interventions.

Clinical trials are essential for advancing medical knowledge, improving patient care, and ensuring the safety of new treatments before they become widely available. They are regulated by government agencies and ethical review boards to protect participants and maintain scientific integrity.¹

 

History of clinical trial

Clinical trials have a rich history, evolving significantly over the years to improve medical research and address various challenges related to ethics, logistics, and scientific rigor. The development of clinical research has followed a lengthy and intriguing path. The earliest documented clinical trials can be traced back to biblical accounts from 500 BC. This journey progressed from dietary treatments, such as legumes and lemons, to the use of medications. After the fundamental principles of clinical trials were outlined in the 18th century, efforts were directed towards enhancing the design and statistical components. Subsequently, there were shifts in the regulatory and ethical landscape.²

1.      Nuremberg Code: Created in response to the unethical medical experiments conducted on concentration camp prisoners, without their consent by Nazi doctors during World War II. The Nuremberg Code emphasizes voluntary consent, the necessity to avoid unnecessary suffering, and the requirement that experiments should yield fruitful results for society. This code forms the foundation of modern bioethics and emphasizes that the welfare of the participant should take precedence over the interests of science or society.³

Figure 01: Defendants in their dock at the Nuremberg Trials ⁴

2.      Thalidomide Study: Thalidomide was a drug used in the late 1950s for morning sickness in pregnant women, later found to cause severe birth defects (eg Phocomelia). The tragedy underscored the importance of robust pre-marketing drug testing, particularly concerning the effects on unborn children. This crisis led to stricter drug regulations and the establishment of guidelines ensuring that drugs undergo thorough testing before being made available to the public.⁵

Figure 02: children born with birth defects ⁶

3.      Nazi Trials: The trials of war criminals post-World War II addressed heinous crimes, including unethical medical experiments conducted without consent. These trials highlighted the need for clear ethical standards in research involving human subjects, resulting in international responses towards formulating ethical guidelines.³

4.      Tuskegee Syphilis Study: This infamous study involved African American men with syphilis who were left untreated to observe the natural progression of the disease, specifically looking for racial differences in the disease's manifestations. This study Conducted without informed consent, it persisted from 1932 to 1972, raising serious ethical questions and resulting in public outrage. This led to significant changes in U.S. law and ethics concerning medical experiments, particularly the establishment of informed consent protocols and oversight.³

B

A

Figure 03 (A, B): A U.S. public health worker drawing blood from a man as part of the Tuskegee syphilis study in Macon County, Alabama.^7,8

5.      The Belmont Report: Initiated following the Tuskegee Study scandal, the Belmont Report (issued in 1979 by the National Commission) outlines essential ethical principles for conducting research on human subjects of Biomedical and Behavioral Research. It introduces core principles such as respect for persons, beneficence, and justice, which guide institutional review boards (IRBs) and ensure that ethical standards are upheld in all human research ventures.⁹

6.      The Declaration of Helsinki: Adopted by the World Medical Association in 1964, it provides ethical guidelines specifically for physicians conducting biomedical research with human participation. The Declaration emphasizes principles such as the right to self-determination and the need for physicians to consider ethical standards beyond mere compliance with laws or regulations. It has undergone multiple revisions to accommodate evolving ethical challenges in medical research.¹⁰

 

Phases of Clinical Trials:

Clinical trials are divided into several phases, each with specific objectives. Phases 0 to IV encompass the entire clinical trial process:

Figure 04: Phases of clinical trials ¹¹

Preclinical Studies

Before a drug reaches humans, it undergoes preclinical studies involving in vitro (cell culture) and in vivo (animal) experiments. These studies evaluate the drug’s basic efficacy, toxicity, and pharmacokinetics (absorption, distribution, metabolism, and excretion). Researchers test a wide range of doses to identify possible therapeutic effects and safety concerns. The data from preclinical work helps decide whether the drug has enough scientific merit to proceed to human trials, which requires filing an Investigational New Drug (IND) application with regulatory authorities.¹²

Phase 0 – Microdosing Studies

Phase 0 is a relatively new stage, introduced under the US FDA’s 2006 exploratory IND guidelines. It involves administering a single, very small (sub-therapeutic) dose of the drug to a small number of volunteers usually between 10 and 15 to study its pharmacokinetic (how the body processes the drug) and pharmacodynamic (how the drug affects the body) properties it also provides early data on the drug's interaction with the human body. Because the doses are too low to produce therapeutic effects, Phase 0 does not assess safety or efficacy. Instead, it helps researchers decide which drug candidates should move forward to further testing based on how they behave in the human body.¹³

Phase I – Safety and Dose Ranging

Phase I marks the first stage of testing in humans, focuses on assessing the safety, tolerability, and pharmacokinetics of a drug through gradual dose escalation in a small group of healthy volunteers or patients typically involving 20 to 100 healthy volunteers, though in some cases patients with the target condition may be included. The main goals are to evaluate safety, tolerability, and detailed pharmacokinetic/pharmacodynamic profiles. Studies are often conducted in specialized clinical units with around-the-clock medical supervision.¹² Two main designs are used: Single Ascending Dose (SAD), where increasing doses are tested in new volunteer groups until the maximum tolerated dose (MTD) is found, and Multiple Ascending Dose (MAD), where participants receive multiple doses over time to study drug accumulation and effects. Data from this phase identifies safe dosage ranges and potential side effects.¹³

Phase II – Therapeutic Exploratory

Phase II trials aim to evaluate the efficacy and side effects of the intervention in a larger patient group, often through randomized controlled studies. It helps determine the optimal dose and treatment regimen. It expands testing to 100 to 300 patients who actually have the condition the drug is meant to treat. The purpose is to evaluate whether the drug works (efficacy) while continuing to monitor safety. This phase often includes genetic or biomarker testing if differences in metabolism are suspected. Phase II is split into Phase IIa, focusing on dose optimization, and Phase IIb, concentrating on confirming therapeutic effectiveness. These studies are usually conducted in hospitals or university medical centers. Phase II is also known for having the highest attrition rate only about one-quarter of drugs advance to Phase III because many fail to demonstrate sufficient benefit or reveal unexpected safety issues.¹³

Phase III –Therapeutic Confirmatory

Phase III trials are large-scale studies involving 1,000 to 3,000 or more patients, often across multiple countries. They aim to confirm the drug’s efficacy, compare it with existing standard treatments or placebo, and gather a more comprehensive safety profile. These studies are usually randomized and controlled, and due to their size and duration, they are the most expensive and complex to run. Positive Phase III results form the foundation of the application for regulatory approval to market the drug. Detailed reports include manufacturing methods, formulation details, and complete clinical data. If significant adverse effects are discovered at this stage, the drug may be withdrawn from development.¹³

Phase IV – Post-Marketing Surveillance

Conducted after the intervention is marketed to gather information on long-term effects and additional benefits. Once a drug is approved and available on the market, Phase IV studies monitor its performance in the general population over an extended period. This phase, also called post-marketing surveillance or pharmacovigilance, is crucial for detecting rare or long-term adverse effects that may not appear in earlier trials. It also helps identify new therapeutic uses or populations that could benefit from the drug. Phase IV can be initiated by regulatory agencies or the sponsoring company, and findings can sometimes lead to changes in labeling, usage recommendations, or even market withdrawal.¹³

Table 01: Phases of clinical trials ¹²

 

Clinical Trial Application Process in Europe (EMA)

Clinical trials in the EU and EEA are governed by the Clinical Trials Regulation (Regulation (EU) No 536/2014) which came into application on 31 January 2022.

The EU has made a significant stride by implementing the Clinical Trial Regulation (EU) 536/2014 (CT Regulation), which replaces the old Clinical Trials Directive 2001/20/EC (CT Directive).

The regulation of clinical trials aims to ensure that the rights, safety and well-being of clinical trial participants are protected, and the results of clinical trials are reliable and informative.¹⁴

·         Clinical trial sponsors can use this website to apply for permission to run a clinical trial anywhere in the EU/EEA including in multiple countries, provide updates to national regulators about a trial, and submit trial results.

·         EU/EEA national regulators can use it to process clinical trial applications collaboratively, request further information, authorise or refuse a trial and oversee an authorised trial.

·         Anybody can use it to view information on clinical trials in the EU and EEA from 31 January 2022.

Clinical trial sponsors and EU/EEA national regulators work in the Clinical Trials Information System (CTIS).¹⁴

Clinical Trials Information System (CTIS) streamlines the process for evaluating and overseeing clinical trials across the EU. A unified clinical trial application (CTA) with a core dossier is submitted for approval, reaching all European national competent authorities and ethics committees and ensuring the trial is registered in a public database.

Before CTIS, clinical trial sponsors needed to submit separate applications to national competent authorities and ethics committees in each country to obtain trial approval. The new CTIS system tackles issues like the fragmentation and complexity of clinical trials, lack of transparency, administrative burdens, slower approval processes, and the limited harmonization seen under the previous CT Directive.

Transition period: Starting on Jan. 31, 2022, the CT Regulation replaced the CT Directive, marking the beginning of a three-year transition period that concluded on 30 Jan 2025.¹⁵

Submission Process and requirements:

For a clinical trial, three types of applications can be submitted through CTIS:

1.      Initial CTA: A request to conduct a clinical trial that includes comprehensive information about the trial for evaluation by the Member State Concerned (MSC).

2.      Additional MSC: A request by the sponsor to extend an authorized clinical trial to one or more additional MSCs.

3.      Substantial Modification: A request by the sponsor to make changes to the clinical trial that could significantly impact the safety or rights of the participants or the reliability of the generated data.

Sponsors can also submit non-substantial modifications during an ongoing clinical trial. These modifications are not considered applications, as they are not evaluated by the MSCs.¹⁵

Submitting an Initial CTA:

Creating a new CTA involves completing the following 4 steps:¹⁶

        I.            Forms: This section includes administrative information such as a cover letter and proof of payment.

·         This section of the Applications contains different structured data, which will vary depending on the type of application (i.e: IN, AMSC, SM, non-SM).

·         Among others, it may contain the cover letter, proof of payment and trial category sections.

 

     II.            MSC: This section includes information related to the MSCs and the number of subjects targeted for each member state.

·         This section, the Member States Concerned, contains the same structured data in all applications.¹⁶

 

  III.            Part 1: This section includes details concerning the trial, sponsor, product, and all trial-specific documents.¹⁶

 

  IV.            Part 2: This section includes country-specific details such as trial sites, facilities, and recruitment details in each MSC.¹⁶

 

Response to RFI (Request for Information):

RFI is a Request for Information sent by a Member State Concerned (MSC) or the Reporting Member State (RMS) to a clinical trial sponsor. It is a formal query for additional data, clarification, or modifications to a submitted clinical trial application (CTA) during the validation or assessment phases. Sponsors must respond to RFIs within a set timeframe to avoid the application lapsing.

Sponsor may be requested for information through the RFI functionality. Each RFI can be related to the validation, assessment Part I and/or assessment Part II.¹⁷

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Timelines of Initial CTA in CTIS:¹⁸

a)    Initial CTA

Day 55 (+31 days if RFI Was issued)

Day 10 (+15 days if RFI Was issued)

Day 60

                                           

Assessment part I

                       10 days                                    45 days                            5 days

Decision

Assessment part II

RFI response (if applicable)

RFI response (if applicable)

RMS Selection

RFI response (if applicable)

Validation

 

 

 

 

 

              Member states responsibilities

               Sponsor’s responsibilities

      RFI= Request for Information

      RMS= Reference Member State

 

b)  

Day 0

Substantial Modification

Day 45 (+31 days if RFI Was issued)

Day 6 (+15 days if RFI Was issued)

Day 50

                                           

Assessment part I *

                       6 days                                      38 days                            5 days

Decision

Assessment part II *

RFI response (if applicable)

RFI response (if applicable)

RMS Selection

RFI response (if applicable)

Validation

 

 

 

 

 

              Member states responsibilities

               Sponsor’s responsibilities

*Step in the process that may occur depending on the CTA submitted. An SM CTA include Part I and Part II, Part I only or Part II only.

 

C)   Additional MSC

Day 47 (+31 days if RFI Was issued)

Day 0

Day 52 (+31 days if RFI Was issued)

 

                                           

Assessment part I *

                          47 days                            5 days

Assessment part II *

RFI response (if applicable)

Decision

RFI response (if applicable)

 

 

 

 

 

              Member states responsibilities

               Sponsor’s responsibilities

*Step in the process that may occur depending on the CTA submitted. For an MSC CTA users may raise considerations for Part I, but the conclusion cannot be modified.

 

Clinical Trial Application Process in the United States of America (USFDA)

For conducting clinical trials across the United States (US) with an Investigational New Drug or drugs that are not approved for intended use, the sponsor must submit an Investigational New Drug Application (IND) to the US FDA which is known as IND Filing and obtain FDA’s acceptance before the drug is transported or distributed across the US for use in the clinical program.

An IND is a request for authorization from the Food and Drug Administration (FDA) to administer an investigational drug or biological product to humans.

An IND must be authorized prior to interstate shipment and administration of any new drug or biological product that is not the subject of an approved New Drug Application or Biologics/Product License Application.¹⁹

Types of IND:²⁰

·         An Investigator IND is submitted by a physician who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed.  A physician might submit a research IND to propose studying an unapproved drug, or an approved product for a new indication or in a new patient population.

·         Emergency Use IND allows the FDA to authorize use of an experimental drug in an emergency situation that does not allow time for submission of an IND in accordance with 21CFR , Sec. 312.23 or Sec. 312.20.  It is also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist.

·         Treatment IND is submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.

Categories of IND:²¹

·         Commercial – Permits sponsor to collect data on clinical safety and effectiveness needed for application for marketing in the form of NDA

·         Research (non-commercial) – Permits the sponsor to use drug in research to obtain advanced scientific knowledge of new drug (No plan to market the product).

Contents of IND application: (3 broad areas)¹⁹

a)      Animal Pharmacology and Toxicology Studies - Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans.  Also included are any previous experience with the drug in humans.

b)     Manufacturing Information - Information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product.

c)      Clinical Protocols and Investigator Information - Detailed protocols for proposed clinical studies, information on the qualifications of clinical investigators, informed consent from the research subjects, to obtain review of the study by an institutional review board (IRB), and to adhere to the

IND regulations.

Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any clinical trials.  During this time, FDA has an opportunity to review the IND for safety to assure that research subjects will not be subjected to unreasonable risk.²⁰

 

Resources for IND Applications:²¹

1.      Pre-IND Consultation Program - CDER's Pre-Investigational New Drug Application (IND) Consultation Program fosters early communications between sponsors and new drug review divisions to provide guidance on the data necessary to warrant IND submission.

2.      Guidance Documents for INDs – The guidance documents provide FDA review staff and applicants/sponsors with guidelines to the processing, content, and evaluation/approval of applications and also to the design, production, manufacturing, and testing of regulated products. They also establish policies intended to achieve consistency in the Agency's regulatory approach and establish inspection and enforcement procedures. To find guidance documents to help prepare INDs, go to Guidances (Drugs) and use "investigational" in the search box.

3.      Laws, Regulations, Policies and Procedures - The mission of FDA is to enforce laws enacted by the U.S. Congress and regulations established by the Agency to protect the consumer's health, safety, and pocketbook.  The Federal Food, Drug, and Cosmetic Act is the basic food and drug law of the U.S. The law is intended to assure consumers that foods are pure and wholesome, safe to eat, and produced under sanitary conditions; that drugs and devices are safe and effective for their intended uses; that cosmetics are safe and made from appropriate ingredients; and that all labeling and packaging is truthful, informative, and not deceptive.

 

4.      Code of Federal Regulations (CFR) - The final regulations published in the Federal Register (daily published record of proposed rules, final rules, meeting notices, etc.) are collected in the Code Of Federal Regulations (CFR). 

The CFR is divided into 50 titles that represent broad areas subject to Federal regulations.  The FDA's portion of the CFR interprets the The Federal Food, Drug, and Cosmetic Act and related statutes.  Section 21 of the CFR contains most regulations pertaining to food and drugs.  The regulations document all actions of all drug sponsors that are required under Federal law.

The following regulations apply to the IND application process:²²

 

Guidance documents to help prepare INDs include:²³

·         Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs — General Considerations

·         Content and Format of INDs for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products. Questions and Answers

·         Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products

·         Current Good Manufacturing Practice for Phase 1 Investigational Drugs 

·         Drug Master Files: Guidelines

·         Exploratory IND Studies

·         FDA IND, NDA, ANDA, or Drug Master File Binders

·         IND Exemptions for Studies of Lawfully Marketed Drug or Biological Products for the Treatment of Cancer 

·         Safety Reporting Requirements for INDs (Investigational New Drug Applications) and BA/BE (Bioavailability/Bioequivalence) Studies 

IND Application Procedures: Overview ²⁴

When submitting original IND applications, sponsors are expected to send their applications in triplicate (one original and two copies).

Each application should be accompanied by:

·         Form 1571 (IND application cover),

·         Form 1572 (Investigator’s statement), and

·         Form 3674 (certification requirement & mandatory registration and reporting of results for applicable clinical trials through ClinicalTrials.gov.) 

While IND application sponsors are not required to submit information regarding clinical investigators’ financial interests or arrangements in the original IND applications, they are expected to collect this information before a clinical investigator participates in a clinical study.

Upon receipt of an IND application, FDA will notify the sponsor of the date it receives the application through an IND acknowledgment letter.²⁴

An IND application may go into effect:

·         30 days after FDA receives the application, unless FDA notifies the sponsor that the investigations described in the application are subject to a Clinical Hold; or

·         on earlier notification by FDA that the clinical investigations in the IND may begin. 

Once an IND application is in effect, a drug manufacturer may ship the investigational new drug to the investigator(s) named in the application. An investigator may not administer an investigational new drug to human subjects until the IND application goes into effect.

 

IND Review Process: ²⁴

 

Clinical Trial Application Process in India (CDSCO)

The clinical trial application process in India, overseen by the Central Drugs Standard Control Organization (CDSCO), is regulated by the New Drugs and Clinical Trials (NDCT) Rules, 2019. The process requires approval from the CDSCO and an institutional ethics committee, with all applications submitted online through the SUGAM portal. 

Since 2017, all applications to conduct clinical trials are submitted online through the CDSCO's SUGAM portal. The sponsor must submit Form CT-04 and the required documentation. The portal provides step-by-step instructions for the submission process.²⁵

Key regulatory bodies:

·         Central Drugs Standard Control Organization (CDSCO): The national regulatory body that approves new drugs and clinical trials.

·         Drugs Controller General of India (DCGI): The head of the CDSCO, who grants the final permission for a clinical trial.

·         Institutional Ethics Committee (IEC): An independent committee that reviews and approves the trial protocol to ensure the rights, safety, and well-being of participants are protected.

·         Clinical Trials Registry-India (CTRI): A mandatory registry for all clinical trials conducted in India. Trials must be registered prospectively, before the enrolment of the first participant.²⁶

Stages of approval:²⁶

·         Ethics Committee (EC) approval: Before submitting to the CDSCO, the clinical trial protocol must be approved by a registered Institutional Ethics Committee (IEC). The EC must be local to the trial site.

·         CDSCO application: The sponsor must submit the application in Form CT-04 through the SUGAM portal, along with the necessary documentation and fees.

·         Regulatory review: The CDSCO and its expert committees, such as the Subject Expert Committee (SEC), review the application.

·         Issue of permission: If the application is approved, the CDSCO grants permission in Form CT-06

Compliance and post-approval: ²⁷

·         Clinical trial registry: Once permission is granted, the trial must be registered with the Clinical Trials Registry-India (CTRI).

·         Sponsor responsibilities: The sponsor is responsible for monitoring the trial, submitting safety reports (like Development Safety Update Reports), and providing medical management and compensation for any trial-related injuries.

·         Post-trial availability: The NDCT Rules, 2019, include provisions for post-trial access to the investigational drug for patients who benefited from it.

How to apply: ²⁸

 

Fee involved: ²⁹

CDSCO charges a fee for the issuing of a license.

·         Phase I: INR 300,000

·         Phase II: INR 200,000

·         Phase III: INR 200,000

·         Phase IV: INR 200,000

 

Key application documents needed are mentioned as follows: ³⁰

·         Administrative and legal records (COPP, market and EC approvals, status of drug regulation, etc.).

·         Manufacturers' information

·         CMC data, which provides precise chemical and pharmaceutical details about drug substances and drug formulations.

·         Sufficient reports and summaries of preclinical studies.

·         Clinical research (study reports, protocol, CRF, ICF, undertakings, etc.)

·         Detailed list of documents as mentioned in Global Clinical Trial (GCT checklist);

o   Module 1 - ADMINISTRATIVE SECTION

o   Module 2 - SUMMARIES

o   Module 3 – CMC DATA

o   Module 4A - ANIMAL TOXICOLOGY DATA

o   Module 4B - ANIMAL PHARMACOLOGICAL DATA

o   Module 5 - CLINICAL DATA

o   Module 6 - TRIAL RELATED DOCUMENTS

 

Approval timelines: 90 days

Approval process for application submitted through online Sugam Portal with respect to Global

Clinical Trials Division:³⁰

Form CT-04:

Query

If any deficiency in document

If all the documents are in order

SUGAM Portal: ³⁰

 

 

Conclusion

The regulatory landscape for clinical trials varies across Europe, the United States, and India, each with its own unique processes and requirements. In Europe, the Clinical Trials Regulation (EU) No 536/2014 has streamlined the application process through the Clinical Trials Information System (CTIS), allowing for a unified submission across member states. The United States, under the oversight of the FDA, requires sponsors to submit an Investigational New Drug (IND) application, which undergoes a 30-day review period before clinical trials can commence. India's process, governed by the Central Drugs Standard Control Organization (CDSCO), involves online submission through the SUGAM portal and requires approval from both the CDSCO and an institutional ethics committee. While all three regions prioritize patient safety and scientific integrity, they differ in their specific documentation requirements, review timelines, and post-approval obligations. These regulatory frameworks reflect the ongoing efforts to balance the need for rigorous scientific evaluation with the imperative to facilitate medical innovation and improve global health outcomes.

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