Comparative Study of Regulatory Requirements for Drug Approval (USFDA vs. EMA vs. INDIA)

Different nations are required to adhere to their own regulatory standards for the approval of new medications. Achieving a unique regulatory strategy for the Marketing Authorization Application (MAA) across multiple countries is quite challenging. Consequently, it is important to understand the official requirements for Marketing Authorization Application specific to each nation. Even post-approval, the government continues to oversee the drug's safety during Phase IV.[1] While approval processes vary by country, this study compares regulations from the USFDA, EMA, and CDSCO. It also highlights advances and challenges in cell therapy development. The clinical trial process consists of three distinct phases executed according to the guidelines. In the USA, the approval and regulation of novel drugs are based on the New Drug Application. Since 1938, every novel drug must receive NDA approval before being sold in the USA. The NDA process allows drug companies to request FDA authorization to market and sell a pharmaceutical product. A New Drug Application is a request submitted to a country's regulatory bodies to get permission for selling a novel drug (an innovative medicine). To get this approval, the company developing the drug provides data from lab tests, animal studies, and human trials, along with details about how the drug is made.[2]       

Stages of Drug Testing

• Preclinical Study – Testing on animals and in labs to check basic safety and effects.
• Phase I (Clinical Trial) – Small-scale testing on healthy volunteers to check safety and dosage
• Phase II (Exploratory Trial) – Testing on a small group of patients to see how well the drug works.
• Phase III (Confirmatory Trial) – Extensive testing on numerous patients to verify efficacy and observe adverse effects.
• Phase IV (Post-Marketing Trial) – Post approval, ongoing monitoring of the drug in real-world use.[24]

Figure 1 Drug Approval Process.[13]

USFDA (United States Food and Drug Administration)

In the globe, the USA has some of strictest laws governing medication approval of USA drug regulation started in 1820 with the initiation of the U.S. Pharmacopoeia.[5] The Food and Drugs Act of 1906 set guidelines for the potency and quality of drugs. Following the sulfanilamide tragedy in 1937The Federal Food, Drug, and Cosmetic Act of 1938 mandated that pharmaceutical products must be demonstrated as safe prior to being sold on the market. The Kefauver-Harris Amendment of 1962 added the requirement for evaluate of both safety as well as efficacy. The FDA is responsible for the drug approval process, which includes Clinical Trials and the approval of New Drug Applications. NDAs, now submitted in electronic Common Technical Document format, ensure the safety and efficacy of products, starting with an Investigational New Drug application.[5] The FDA oversees the safety and effectiveness of the food supply, prescription medications, medical equipment, cosmetics, products that emit radiation, animal products, and the manufacturing of tobacco in the USA. It implements the Act FDCA is established in 1938 to protect the public health. Pharmaceutical companies are required to adhere to rigorous regulations. before they can market their products. The agency is managed by a commissioner who is designated by the president and approved by the Senate.[7]

Here are the major milestones in U.S. drug laws in simple terms:

The Food and Drugs Act mandated that medications must comply with established standards for both potency and quality of drugs. The Federal Food, Drug, and Cosmetic Act of 1938 was established as a reaction to a major pharmaceutical crisis, mandating that a drug's safety must be proven before it is made available to the public. The Kefauver-Harris Amendment established in 1962 was a response to a birth defect crisis linked to a medication, necessitating that pharmaceutical companies provide evidence that a drug is not only safe but also effective, in addition to reporting any side effects to the FDA. The Orphan Drug Act of 1973 encouraged drug companies to create treatments for rare conditions by offering tax benefits.[8]

Drug Approval Process in USFDA

The USA Food and Drug Administration is a federal agency operating under the Department of Health and Human Services, in control of protecting public health by ensuring the safety, efficacy, and security of a wide range of products. These products encompass medications for both humans and animals, biological products, medical devices, the nation’s food supply, cosmetics, and items that emit radiation. Furthermore, the FDA oversees the manufacturing, marketing, and distribution of tobacco products to promote public health and decrease tobacco use among young individuals.[7]

Regulatory Scope of the FDA

The regulatory authority of the FDA covers a diverse range of products:

• Foods: This section encompasses items like dietary supplements, bottled water, food additives, infant formulas, and various food products. Nonetheless, certain components of meat, poultry, and egg products are overseen by the U.S. Department of Agriculture.
• Drugs: The FDA is responsible for both prescription medications and OTC drugs.
• Biologics: This category encompasses vaccines, blood and blood derivatives, cellular and gene therapy products, tissue products, and allergenic materials.
• Medical Devices: The FDA ensures that medical devices, from simple tools like tongue depressors to complex systems like pacemakers, are safe and effective.
• Radiation-Emitting Products: Items such as microwave ovens, X-ray machines, laser products, and ultrasonic therapy devices are regulated to manage radiation exposure.
• Cosmetics: Although the FDA regulates cosmetics, these products and their ingredients do not need FDA approval prior to being marketed, except for color additives.
• Tobacco Products: The FDA regulates the production, marketing, and distribution of tobacco products to safeguard public health.[9]

FDA Leadership

The FDA is headed by the Commissioner, who is appointed by the President of the USA with the Senate's advice and approval. This individual is responsible for overseeing the agency's operations and ensuring that its aim to ensure safe public health is fulfilled.[5]

Foundational Legislation: The FD&C Act of 1938

The Federal Food, Drug, and Cosmetic Act (FD&C Act) of 1938 is the foundation of the FDA's regulatory power. This legislation establishes the legal basis for the agency to supervise the safety and efficacy of food, pharmaceuticals, and cosmetics. Over time, the FD&C Act has been revised to broaden the FDA's jurisdiction to encompass medical devices, biological products, and tobacco. [9]

Centers for Drug and Biologic Evaluation

Within the FDA, two main centers are tasked with the assessment and approval of pharmaceutical and biological products

• Center for Drug Evaluation and Research (CDER): CDER guarantees that safe and effective medications are accessible to enhance the health of individuals in the United States. It reviews new drugs prior to their market entry and continues to monitor them for safety concerns after they are sold.
• The Center for Biologics Evaluation and Research (CBER): is responsible for regulating biological products intended for human use, such as vaccines, blood products, and cellular therapies, while ensuring their safety and effectiveness.[24]

The Drug Approval Process

Before a new medication can be sold in the U.S., it must go through a thorough approval process to prove its safety and effectiveness:

1. Preclinical Testing: Initial laboratory and animal studies are performed to collect preliminary information regarding efficacy, toxicity, and pharmacokinetics.
2. Investigational New Drug Application (IND): If preclinical testing results are favorable, the sponsor files an IND with the FDA that details the drug's formulation and production while proposing the clinical trial plan.
3. Clinical Trials: These trials occur in three distinct phases to evaluate the drug's safety and effectiveness in human subjects:
4. Phase 1: The drug is administered to a small group (cohort) of healthy volunteers to determine its safety and efficacy of appropriate dosage.
5. Phase 2: A larger group of patients is involved to examine effectiveness and side effects.
6. Phase 3: Conducted on a sizable patient population to verify efficacy, observe adverse effects, and compare the drug against standard treatments.
7. New Drug Application (NDA): After successfully done clinical trials, the sponsor submits the report of an NDA to CDER, presenting extensive report on the drug's safety and efficacy.
8. FDA Review: A group of physicians, statisticians, chemists, pharmacologists, and other experts from CDER evaluates the NDA. If the advantages of the drug surpass its known risks, the FDA grants it approval for marketing.[7]

It is crucial to understand that new medications are not considered safe or effective until they have undergone appropriate testing and received FDA approval.[13]

Figure 2 Drug Approval Process - United States. [7,8]

New Drug Application

A New Drug Application (NDA) is a request made to the relevant regulatory body getting permission to sell a novel medication. Each country has specific regulatory criteria that must be met to obtain approval for a new drug within its borders. Pursuing a uniform regulatory strategy for drug approval across various nations can be challenging. To obtain this authorization, a sponsor must provide preclinical and clinical trial report for evaluating the information of the novel drug along with details regarding the manufacturing processes.[23]

Different Phases of clinical trials Preclinical study.

• Phase I - Clinical trial
• Phase II - Exploratory trial
• Phase III - Confirmatory trial
• Phase IV - Post marketing trial

Before initiating clinical trials, approval from the appropriate authority is necessary. These trials consist of four phases aimed at evaluating safety, effectiveness, and dosage in human subjects. If the trials yield positive results, a Marketing Authorization Application (MAA) is filed, and the drug is granted approval if its advantages outweigh any potential risks. In the USA, the regulation and oversight of novel drugs have been based on the New Drug Application (NDA). Since 1938, every novel drug has required approval through the NDA process prior to commercialization in the U.S. An NDA is submitted for regulatory assessment, containing preclinical, clinical, and manufacturing information.[23]

Clinical Trial Phases:

• Pre-clinical – Animal testing
• Phase I – Initial human trials
• Phase II – Effectiveness testing
• Phase III – Confirmatory trials
• Phase IV – Post-marketing safety monitoring

After submission, the NDA undergoes technical screening Possible outcomes:

• Not Approvable – Lists deficiencies
• Approvable – Requires changes or post-approval studies Approval – Drug is approved
• For "not approvable" or "approvable" decisions, applicants can discuss deficiencies with the agency.[27]

Drug Approval Process in Europe

The European Medicines Evaluation Agency (EMEA), established in 1995, oversees drug evaluation and supervision in the EU. It ensures that medicines meet safety, efficacy, and quality standards before reaching the market. A clear and structured process was established for developing, reviewing, finalizing, and implementing pharmaceutical guidelines. In European countries, drug approval happens in two main stages:

• Clinical Trials – Testing the drug on volunteers to assess its safety and effectiveness.
• Marketing Authorization – Official approval to sell and distribute the drug based on trial results.[16]

EEA (European Economic Area)

Market Authorization in the EEA (European Economic Area) To sell a medicinal product in the EEA (which includes the EU and countries like Norway, Iceland, and Liechtenstein), manufacturers need market authorization. This can be obtained through:

• National Authorization – Approval in just one country.
• Union Authorization – Approval for the whole EU through a central process.[18]

process follows these key steps:

1. Research & Preclinical Testing

Before human trials, a drug undergoes preclinical studies (lab and animal testing) to assess toxicity and biological effects.

Clinical Trials (Human Testing).[12]

2. Clinical development occurs in three phases:

• Phase 1 – Small group (20–100 people), focuses on safety and dosage.
• Phase 2 – Larger group (100–500 people), evaluates efficacy and side effects.
• Phase 3 – Large-scale trials (1,000+ people), compares drug effectiveness with existing treatments.[12]

Types of Market Authorization

National Authorization:

If a drug is approved in one country, but the manufacturer wants to sell it in other countries, they can use: Mutual Recognition: The drug is approved in one country and then other countries recognize that approval.

1. Centralized: This procedure enables an applicant to secure marketing approval for their product throughout the entire EU. The European Medicines Agency (EMA) generally requires around 210 days to evaluate the product before sending it to the European Commission for final approval, following a review by the Committee for Medicinal Products. Centralized authorization is mandatory for specific types of drugs, such as genetically modified drugs, orphan drugs, and treatments for conditions including HIV, cancer, neurological disorders, autoimmune diseases, and diabetes. [13]
2. Decentralized: This approach is used for medications that do not fall under the category of essential centralized drugs. Companies usually choose this pathway to gain approval for products (which have yet to be authorized in any member state) across multiple EU member states by submitting applications to each member state and including a reference member state (RMS) number with every application to the corresponding member state (CMS). This ensures the consistency of the dossier presented by the applicant across all member states. Feedback from the RMS and CMS is assessed, after which market authorization can be granted. This process also takes 210 days.[13]

Figure 3 Shows Centralized Procedure.[13]

Figure 5 National Procedure.[13]

INDIA

The Indian government established the Drug and Cosmetics Act of 1940 along with its Rules in 1945 to oversee the import, production, distribution, and sale of pharmaceuticals and cosmetics within the country.[20] To manage this, the Central Drugs Standard Control Organization (CDSCO) was formed, headed by the Drugs Controller General of India (DCGI). In 1988, the government added Schedule Y to the Drug and Cosmetics Rules, which outlines the regulations for conducting clinical trials.[25] These guidelines were revised in 2005 to align with international standards. Companies seeking to manufacture or import a new drug must apply for authorization from the DCGI. This involves submitting Form 44 along with data according to Schedule Y. To confirm that the drug is safe and effective for the Indian population, the company must carry out clinical trials in accordance with Schedule Y's regulations. The outcomes of these trials must be presented in the specified format for evaluation. The approval process adheres to established rules (122A, 122B, and 122D) under Schedule Y, which outlines the protocols for clinical trials.[20] Companies must submit their application in a Common Technical Document (CTD) format, with one hard copy and three soft copies. Even if a drug's active ingredient (API) is already approved, a new product must still provide bioequivalence study data to prove its safety and effectiveness. If a drug is discovered in India, it must go through all trial phases. However, if a drug is already approved in another country, India may waive some trials if it benefits public health, but the company must submit full trial data from that country.[21]

The approval of a new drug in India happens in two main phases:

1. Clinical Trial Permission (INDA – Investigational New Drug Application)
2. Market Authorization (NDA – New Drug Application)

Phase 1: Getting Permission for Clinical Trials

5. The organization files an Investigational New Drug Application (INDA) with the Central Drugs Standard Control Organization (CDSCO), overseen by the Drug Controller General of India (DCGI). This submission contains information regarding the drug's composition, production processes, quality assurance, and results from animal studies.
5. A copy of the application is also forwarded to the Ethics Committee for evaluation.
5. The new drug is examined and evaluated.
5. The IND Committee reviews the application and submits a report to the DCGI.
5. Based on the reports from the IND Committee and Ethics Committee, the DCGI makes a decision.
5. If approved, the DCGI gives permission to start clinical trials on humans.[18]

Phase 2: Market Authorization for Selling the Drug

5. The medication goes through three stages of clinical trials to evaluate its safety and efficacy in humans.
5. Subsequently, the company presents a New Drug Application (NDA) that includes clinical and non-clinical data formatted according to the Common Technical Document (CTD).
5. The DCGI and CDSCO review and evaluate the submitted data.
5. If everything is complete and satisfactory, a license is granted for marketing the drug in India. If there are any issues, a deficiency letter is sent to the company for corrections.[18]

Registration Requirement

Form 44 must be submitted along with a fee of ?50,000.

New Drug Approval Process in India

1. For all manufacturers who wish to manufacture new API or New Drug formulations for retail or distribution, a license is mandatory from the Zonal FDA and CDSCO.
2. To receive CDSCO's approval, this process is necessary.
3. Complete form CT-10 to seek permission for manufacturing ND for testing and analysis using form CT-11.
4. File a second Form 30 application with the state FDA to obtain a license for ND manufacturing (Form 29).
5. Submit your CT-21 application through the SUGAM portal along with the required supporting documents and relevant government fee.
6. The CDSCO will assess the application and may raise questions if it finds any concerns. Additionally, CDSCO will issue an IPC test letter.
7. Send your samples to IPC laboratories, and after receiving the IPC report, submit the application using form CT-21 to obtain approval in CT-22 (API)/CT-23 (Formulation).
8. After acquiring CT-22/CT-23, submit Form 25 to the state FDA requesting further product approval. Generally, the license processing is completed within 90 days, and manufacturers will receive their license.[22]

Table 1: Principle differences between US, EU & INDIA.[11]

Table 2: Administrative Requirements.[13]

Table 4: Manufacturing & Control Requirements.[14]