Drug Regulatory Systems in Comparative Perspective: A Tri-National Study of the United States, the Philippines, and Ghana

Pharmaceutical regulation is a critical component of national healthcare systems, ensuring that medicines are safe, effective, and of high quality. While the core objectives of drug regulation are consistent worldwide, the strategies and capacities for achieving them vary considerably between high-income and low- and middle-income countries. In the United States, the Food and Drug Administration (FDA) administers a robust and scientifically rigorous regulatory framework, including defined pathways such as the Investigational New Drug (IND), New Drug Application (NDA), and Abbreviated New Drug Application (ANDA). The U.S. FDA also holds a prominent role in international regulatory harmonization through its participation in organizations such as the International Council for Harmonisation (ICH) and the Pharmaceutical Inspection Cooperation Scheme (PIC/S) ^[1]. In contrast, through its Food and Drug Administration under the Department of Health, the Philippines is actively modernizing its regulatory system. As a member of the Association of Southeast Asian Nations (ASEAN), the country is adopting the ASEAN Common Technical Dossier (ACTD) format to promote regional harmonization. Nevertheless, challenges persist, including limited infrastructure, regulatory enforcement capacity, and workforce development. Ghana, under the oversight of the Food and Drugs Authority (FDA Ghana), has made significant strides by achieving WHO maturity level recognition and participating in regional initiatives such as the African Medicines Regulatory Harmonization (AMRH) ^[2]. Despite these advancements, Ghana continues to face obstacles related to technical capacity, funding, and infrastructure.

Pharmaceutical registration guidelines in the United States: Regulatory Framework and Process:

Drug Regulatory Authority:

Pharmaceutical regulation in the United States is overseen by the Food and Drug Administration (FDA), operating under the authority of the Federal Food, Drug, and Cosmetic (FD&C) Act. This act serves as the principal legal framework governing the approval, regulation, and marketing of pharmaceutical products.

Legal and Regulatory Basis:
The U.S. pharmaceutical regulatory system is built upon key federal legislation, including:

• The Federal Food, Drug, and Cosmetic Act (FD&C Act) – Establishes the FDA’s authority to oversee drug development, approval, and marketing.
• The Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Act) Facilitates the approval of generic drugs through the Abbreviated New Drug Application (ANDA) process.

These statutes are further operationalized through comprehensive regulations found in Title 21 of the Code of Federal Regulations (CFR).

Regulatory Structure and Responsibilities:
Within the FDA, the Centre for Drug Evaluation and Research (CDER) plays a central role in drug regulation. Its core functions include:

• Reviewing Investigational New Drug (IND) submissions to permit clinical trials.
• Evaluating New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs) for market approval.
• Conducting post-marketing surveillance to ensure continued drug safety and efficacy.
• Inspecting drug manufacturing sites to enforce Good Manufacturing Practice (GMP) standards.^[3]

Types of Application ^[5]

• Investigational New Drug (IND)
• New Drug Application (NDA)
• Abbreviated New Drug Application (ANDA)
• Over-the-Counter Drug (OTC)
• Biologic License Application (BLA)

INDA:

An FDA application is submitted before human testing begins. It thoroughly examines the chemistry, manufacturing processes, and quality assurance. The following details must be included in the Investigational New Drug (IND) application:

• Toxicology and pharmacology studies in animals
• Information about clinical investigators and procedures
• Data on the manufacturing process

After submitting the IND, the sponsor must wait 30 days before starting any clinical trials. During this period, the FDA has the authority to assess the IND for safety to ensure it is secure. The requirements for the content and format of an IND application are outlined in Section 312 of the 21 Code of Federal Regulations. ^[6]

Key FDA Forms for Clinical Drug Development

• FDA Form 1571, Investigational New Drug Application (IND): This is the primary submission form used to initiate an IND. It contains detailed information about the drug sponsor, the investigational product, the clinical trial phase, and the components of the submission.
• FDA Form 1572, Statement of Investigator: This form must be completed by each clinical investigator involved in a trial. It provides documentation of the investigator’s credentials, details about the study site, and their commitment to adhere to regulatory standards.
• FDA Form 3674, Certification of Compliance: This form certifies that the trial sponsor fulfills legal obligations to register clinical trials and disclose results on ClinicalTrials.gov, in accordance with U.S. legislation. ^[7]

NDA:

To market a new drug in the United States, a New Drug Application (NDA) must be submitted. The NDA includes all the data provided in the Investigational New Drug (IND) application, along with the results from clinical trials demonstrating the drug's safety and efficacy. The FDA will begin reviewing the application 60 days after submission, following a non-disclosure agreement for NDA format and contents, which is prepared in two sets. The application is divided into two parts:

• Archival Copy
• Review Copy

Archival Copy: This contains copies of clinical trial case report forms and tabulations, serving as a reference for FDA reviewers who may need additional details not included in the review copy.

Review Copy: Each technical section is bound separately within folders as part of the review copy. These sections should include an index, FDA Form 356h (copy), A duplicate of the cover letter, and authorization letters. A copy of the application summary.

The FDA will meet with the sponsor at least twice: once after the conclusion of phase 2 clinical trials and again before the NDA is filed, known as the pre-NDA meeting. The analysis committee will review the study findings and determine whether to accept the application. ^[8]

NDA Forms:

When submitting an NDA to the U.S. Food and Drug Administration (FDA), several specific forms must be included as part of the complete application. These forms provide critical regulatory, administrative, and technical information.

Overview of Key FDA Forms Used in Drug Applications

• FDA Form 356h serves as the primary application document for seeking approval to market a new drug, biologic, or antibiotic for human use. It contains essential information about the product, the applicant, and the type of regulatory submission being made.
• FDA Form 3397, known as the User Fee Cover Sheet, is submitted alongside payment for user fees required under the Prescription Drug User Fee Act (PDUFA). It ensures proper processing of fees associated with New Drug Application (NDA) submissions.
• FDA Form 3331, the New Drug Application Field Report, is utilized to report field alerts such as adverse events or product quality issues after a drug has been submitted or approved. This form supports the FDA’s post-marketing surveillance and safety monitoring efforts. ^[9]

ANDA
An ANDA is submitted to the U.S. FDA’s Centre for Drug Evaluation and Research (CDER), specifically the Office of Generic Drugs, to obtain approval for marketing a generic version of an already authorized brand-name drug. Upon approval, manufacturers are permitted to produce and distribute the generic product, which must match the innovator drug in dosage form, strength, route of administration, quality, performance characteristics, and intended use. Approved generics and their reference products are listed in the FDA’s Orange Book, which includes therapeutic equivalence evaluations. Unlike New Drug Applications (NDAs), ANDAs are termed “abbreviated” because they do not generally require preclinical or clinical trial data to establish safety and efficacy. Instead, applicants must scientifically demonstrate that their product is bioequivalent to the reference listed drug (RLD). Bioequivalence is typically assessed in 24 to 36 healthy volunteers by comparing the rate and extent of absorption (bioavailability) of the active ingredient with that of the brand-name drug. Regulatory provisions for ANDAs were introduced under the 1984 Drug Price Competition and Patent Term Restoration Act, also known as the Hatch-Waxman Act. ^[10]

Patent Certification Requirements under the Hatch-Waxman Act:
All ANDA submissions must include one of the following patent certifications:

• Paragraph I: Indicates that no patents are listed for the RLD in the Orange Book, allowing the application to proceed directly to review.
• Paragraph II: Indicates that all listed patents have expired, permitting immediate approval and marketing.
• Paragraph III: Acknowledges existing patents and agrees to delay marketing until patent expiry; the FDA may grant tentative approval in the interim.
• Paragraph IV: Challenges the validity or enforceability of a listed patent, triggering a 45-day period for potential litigation by the NDA holder. If litigation occurs, final approval is delayed for up to 30 months. The first applicant to file a successful Paragraph IV certification may receive 180 days of marketing exclusivity. ^[11]

Table 1: Common Technical Components of NDA and ANDA Submissions ^[12]

Dossier format:

To facilitate regulatory review in international drug development, an eCTD format with standardization was launched, consistent with ICH guidelines for Technical Requirements for Pharmaceuticals for Human Use. The U.S. Food and Drug Administration (FDA) favors the use of ICH-based standards as the standard and preferred format for regulatory submissions in the nation. It was ordered in May 2017 that New Drug Applications (NDAs), Abbreviated New Drug Applications (ANDAs), and Biologics License Applications (BLAs) have to be filed in the form of eCTD. This is followed by all the Investigational New Drug Applications (INDs) from the commencement of May 2018 onwards. ^[13]

Drug Application Review Process

• Submission: Applicants submit New Drug Applications (NDAs) or Abbreviated New Drug Applications (ANDAs) electronically via the FDA’s Electronic Submission Gateway (ESG) NEXGEN platform.
• Filing Review: The FDA conducts an initial 60-day screening to determine if the application is sufficiently complete to warrant a full scientific review.
  • For NDAs, this culminates in a “Day 74 Letter” notifying the applicant of acceptance for review.
  • For ANDAs, the FDA assesses the application’s “receivability.”
    If essential information is missing or regulatory criteria are unmet, the FDA may issue a “Refuse to Receive” (RTR) letter, halting further evaluation.
• Scientific Review: The Center for Drug Evaluation and Research (CDER) evaluates the application, including Chemistry, Manufacturing, and Controls (CMC), safety, efficacy, and bioequivalence data.
• Labeling and Facility Inspections: The FDA conducts inspections of manufacturing and testing facilities to verify compliance with current Good Manufacturing Practices (cGMP).
• Approval or Complete Response Letter (CRL): Upon completing the full review, the FDA either grants approval or issues a Complete Response Letter detailing deficiencies that must be addressed before approval can be considered.

Pharmaceutical Registration Guidelines in the Philippines: Regulatory Framework and Processes:
Pharmaceutical regulation in the Philippines is managed by the Food and Drug Administration (FDA) under the Department of Health (DOH). Its authority is established by Republic Act No. 3720 (Food, Drug, and Cosmetic Act) and strengthened by Republic Act No. 9711 (FDA Act of 2009), which enhanced the agency's autonomy and regulatory powers. The FDA operates regional field offices to serve the archipelagic structure of the country, while the Center for Drug Regulation and Research (CDRR) leads pharmaceutical oversight and regulatory compliance. ^[14]

Drug registration and Licensing:

Companies involved in the import, export, or distribution of pharmaceuticals must obtain a License to Operate (LTO) from the FDA. The LTO is required before applying for a Certificate of Product Registration (CPR), which authorizes market distribution. Both applications are submitted through the Public Assistance, Information, and Receiving (PAIR) system using the Integrated Application Form (IAF), as outlined in FDA Circular No. 2014-003. The IAF also accommodates applications for:

• Promotional and advertising permits
• Free Sale Certificates (FSC)
• Certificates of Pharmaceutical Product (COPP)
• Export Certificates
• GMP compliance documentation
• Generic labeling exemptions

A step-by-step overview of the drug application process using the IAF. ^[14]

FDA Philippines Drug Application Process (Using Integrated Application Form - IAF)

1. Download
   Get the IAF (XLS/XLSX) from the FDA website; used for product registration, licensing, and certifications.
2. Fill Up Form

Complete all required fields until the green “PROCEED” message appears.

3. E-mail

Email fdac@fda.gov.ph using the content from the ‘Email’ worksheet of the IAF. Do not attach the form. Limit: 10 applications per email.

4. Scheduling

Receive a Document Tracking Number (DTN) and submission schedule within 2 working days. No specific date requests allowed.

5. Pay

Pay fees at Land Bank or FDAC cashier. Present printed DTN and IAF. Payment DTN must match IAF.

6. Check

Ensure all documents are accurate, complete, and saved in PDF. Save soft copies and payment slip on a malware-free USB.

7. Submission

Submit only on the assigned schedule. No hard copies required. Missed schedules require email rescheduling.

The Integrated form is categorized into six sections:

• General Information
• Establishment Information
• Product Information
• Supporting Documents
• Sources and Clients
• Applicant Information

It’s important to note that Part 3: Product Information is required only when the applicant selects "Product Registration" as the purpose. This section is not applicable for License to Operate (LTO), only applications. Upon submission, the Centre for Drug Regulation and Research (CDRR) evaluates the product dossier to ensure it complies with established standards of safety, efficacy, and quality. If approved, the FDA issues a Certificate of Product Registration (CPR) that remains valid for five years. However, if the evaluation reveals deficiencies, the FDA may issue a Notice of Deficiency (NOD) or a Letter of Disapproval (LOD), depending on the nature and severity of the issues found. ^[38]

Applications may be rejected for various reasons, including:

• Failure to meet regulatory or technical requirements
• Submission of false or misleading information or omission of critical data
• Significant discrepancies in the registration documents,
• Inadequate responses to concerns raised in the NOD
• Inconsistencies between compliance documents and the original submission.

Additionally, an existing LTO may be revoked if the company does not apply for renewal within 120 days after its expiration date. To renew an LTO, the applicant must submit a completed application form along with a signed Declaration and Undertaking and pay the corresponding fees. ^[15]

Types of Applications Managed by the Philippine FDA

The Philippine Food and Drug Administration (FDA) manages several categories of drug registration applications, including:

• Initial Registration: This applies to new drug products under monitored release, established pharmaceuticals, and fixed-dose combination drugs.
• Generic Drug Registration: Applications for multisource or generic drugs must demonstrate bioequivalence to an approved reference innovator product. Such submissions require bioequivalence study data alongside comprehensive quality documentation.
• Renewal of Registration: Renewal applications are required for products holding Certificates of Product Registration (CPR) nearing expiration. These applications must be submitted within 90 to 180 days before the CPR expires. The renewal process generally involves fewer documentation requirements compared to initial registration. However, delayed submissions may result in penalties or suspension of the CPR.
• Extension for Monitoring/Release: Applications for extension of monitoring or release are submitted for drugs that have received CPR extensions to allow additional time for the submission of supporting documents, particularly clinical trial data related to monitored release dosage forms.

Pharmaceutical products regulated by the Philippine FDA are categorized into three primary groups:

• Prescription Medicines
• Over-the-Counter (OTC) Products
• Drugs listed on the Essential Drug List (EDL), which are prioritized for addressing critical healthcare needs.

Submission in dossier format:

The ASEAN Common Technical Dossier (ACTD) outlines a standardized format for preparing CTD applications to be submitted to ASEAN regulatory authorities for the registration of medicinal products intended for human use. This format is designed to minimize the time and resources needed for application preparation and, in the future, will support the transition to electronic submission. By using a unified structure, it also streamlines regulatory review and enhances communication between regulators and applicants. The ASEAN Common Technical Document (ACTD) is organized into four parts as follows:

Part I: Administrative Data and Product Information

Part II: Quality Document

Part III: Non-clinical Document

Part IV: Clinical Document ^[16]                

Post–approval changes:

A Marketing Authorization Holder (MAH) is eligible to request Post-Approval Changes (PAC) if:

• They hold a valid License to Operate (LTO); and
• The pharmaceutical product has an active Certificate of Product Registration (CPR).

Types of post approval changes in the Philippines FDA

The Philippine Food and Drug Administration (FDA) classifies post-approval changes to pharmaceutical products under FDA Circular No. 2014-008 into several categories, depending on their potential impact on product quality, safety, and efficacy. The main types include:

• Major Variation – MaV-PH
• Minor Variation

• Prior Approval (MiV-PH)
• Notification (MiV-PH-N)

The Food and Drug Administration (FDA) maintains the authority to modify the classification of a post-approval change (PAC) application if it is determined that the initial categorization does not conform to the established guidelines. In the event of such a reclassification, the application may be considered unsatisfactory. Consequently, the FDA will issue an official notice, and the Marketing Authorization Holder (MAH) will be obligated to submit a new application, which will be assigned a new Document Tracking Number (DTN). ^[17]

Pharmaceutical Registration Guidelines in Ghana: Regulatory Framework and Processes
The Food and Drugs Authority (FDA) Ghana, established under the Public Health Act, 2012 (Act 851), regulates the safety, quality, and efficacy of medicines. Formerly the Food and Drugs Board, it is now recognized as a Regional Centre of Regulatory Excellence (RCORE) by NEPAD and AMRH for drug registration.

Legal Framework:

• Public Health Act, 2012 (Act 851)
• FDA Guidelines for Registration of Allopathic Medicines
  All medicines must be registered before being marketed in Ghana.

Types of Applications:

• Generic Application: Required for new products; separate applications for differing actives, strengths, dosage forms, or brand names. Similar products differing only in pack size or packaging can be submitted under one application.
• Renewal Application: Submitted at least 3 months before expiry; includes updated safety data, samples, and fees.
• Variation Application: Required for changes to registered products.

Table 2: Review Timelines for Different Application Types ^[18]

Dossier Format:

In Ghana, the Food and Drugs Authority (FDA) mandates that application dossiers be presented using the Common Technical Document (CTD) format. Common Technical Document (CTD) is a standardized common format established by the International Conference on Harmonization (ICH) to organize technical documentation systematically, helping to reduce the time duration for the registration of medicinal products. The Common Technical Document (CTD) comprises 5 Modules, each with a further granularity section containing all the relevant documentation for registering a drug product.

Module 1: Regional Administration Information

Module 2: Quality Overall Summary

Module 3: Quality

Module 4: Non-Clinical Study Reports

Module 5: Clinical Study Reports ^[19]

Table 4: Comparative analysis of regulatory frameworks in the US, Philippines, and Ghana

Stability conditions in the United States, Philippines, and Ghana:

Stability refers to the ability of a pharmaceutical product to maintain its physical, chemical, and microbiological properties within specified limits over time, when stored in its designated container-closure system. The primary purpose of conducting stability studies is to ensure that no unacceptable levels of degradation products are formed throughout the product's shelf life. Countries like the United States, the Philippines, and Ghana adhere to internationally recognized guidelines for stability testing. The United States, as a member of the International Council for Harmonization (ICH), follows the ICH Q1A (R2) guideline. The Philippines and Ghana, as WHO member states, comply with the WHO guideline titled “Stability Testing of Active Pharmaceutical Ingredients and Finished Pharmaceutical Products” along with the ICH Q1A (R2), where applicable. According to the WHO and ICH, the world is divided into four climatic zones (I–IV) based on environmental conditions to determine appropriate long-term stability testing requirements.

Stability data plays a critical role in providing the necessary quality and safety information for dossier submission. If the available long-term stability data does not fully support the proposed re-test period at the time of application, a post-approval stability protocol and a commitment to continue long-term studies throughout the re-test period must be submitted.

Table 8: Comparison of Pharmacovigilance Requirements and Practices in the US, Philippines, and Ghana