Anand Pharmacy College.
The regulatory landscape governing the lifecycle of new molecular entities plays a pivotal role in drug development and market access. This study meticulously examines the regulatory perspectives across divers regions, including the USA, Europe, Brazil, India and other row countries. Key Focus Areas: 1. Approval Pathways: A comparative analysis of the approval pathways elucidates the distinct requirements, timelines, and evaluation criteria in each region. Understanding these nuances is crucial for successful NME launches. Clinical Trial Regulations: The study delves into clinical trial regulations, encompassing patient safety, ethical considerations, and data integrity. Variations in trial design, endpoints, and reporting standards are explored. Post-Marketing Surveillance: Robust post-marketing surveillance mechanisms are essential for monitoring NME safety and efficacy. We explore pharmacovigilance practices, adverse event reporting, and risk management strategies. Pricing and Reimbursement: Navigating pricing and reimbursement policies is pivotal for market access. We analyze pricing negotiations, health technology assessments, and affordability considerations. Intellectual Property: Intellectual property protection significantly impacts NME commercialization. Patent laws, data exclusivity, and market exclusivity periods are dissected. Emerging Markets: Brazil, India, and other ROW countries present unique challenges and opportunities. We delve into their evolving regulatory frameworks and market dynamics.
The pharmaceutical sector has been experiencing decreased growth and profit margins in recent years due to factors such as generic competition, a fast-evolving healthcare market, and diminishing productivity in research and development. Drug development in the past has prioritized the management and results of clinical studies. However, the industry is now looking at more all-encompassing strategies to enhance the procedures for bringing new products to market, strategies that can both reduce operating costs and speed up product development. The pharmaceutical industry has many obstacles, but there are also opportunities in this fiercely competitive market for creative businesses seeking to reinvent themselves for growth and profitability. Improved company performance and competitive differentiation await companies who effectively navigate the transformation process to meet these challenges. While promoting novel therapeutic areas, businesses aim to expedite the process by which new products pass from the development stage to commercialization.
1.1 New chemical entities
With its substantial contribution to economic systems, new pharmaceuticals are an indication of a robust pharmaceutical sector and have much to offer in terms of improving patient care. Significant funding is needed for the study and development of new medications, and this investment is repaid in a variety of ways.
Different countries define a New Chemical Entity (NCE) in different ways. As per Unted States Food and Drug Association (USFDA), an NCE is defined as “A New Chemical Entity (NCE) is a drug that does not contain any active moiety that has been approved by the United States Food and Drug Administration (USFDA) with any other application.” The EMA calls the New Chemical Entity as New Active Substance (NAS) which is defined as: “A chemical active substance that is not previously authorized in a medicinal product for human use in the European Union and that is from a chemical structure point of view not related to any other authorized substances should be considered as a NAS.” 1.2 Pharmaceutical product life cycle management Product lifecycle management, or PLM, is the process of controlling a product's whole existence, from inception to design and production to servicing and disposal.
Product Life Management includes the following Technical Activities Pharmaceutical Development:1
? Drug substance development
?Formulation development (including container/closure system)
? Manufacture of investigational products
? Delivery system development (where relevant)
? Manufacturing process development and scale up
? Analytical method development
? Technology Transfer
? New product transfers during development through manufacture
? Transfers within or between manufacturing and testing sites for marketed products
? Commercial Manufacturing
? Acquisition and control of materials
? Provision of facilities, utilities, and equipment
? Production (including packaging and labeling)
? Quality control and assurance
? Release
? Storage
? Distribution
1.2.1 Goals of PLM
Product Lifecycle Management has the following goals:
• Describe the benefits to all parties concerned in PLM.1
• Choose to satisfy your clients over optimising.1
• Avoid giving everyone in the group the same response.in the organization concurrently.
1.2.2 Challenges in the pharmaceutical product life cycle management
To effectively carry out the various tasks connected with lifecycle management, leaders need to have a solid grasp of the key concerns. appropriately managing the lifetime. The management lifecycle method is always evolving as a result of several elements include modifications to regulations and growth into emerging markets.
Following are the challenges associated with the pharmaceutical product life cycle management:1
• Growing Intricacy on the Inside and Outside
• Lack of a Single Source of Data for Products and Related Information
• Enhancement of Research and Development
• Transfer of Technology
• Combined Risk and Quality Control
• All-inclusive Packaging
• International Product Registration
• Portfolio of Intellectual Property
• Handling Intricate Joint Venture Management networks.
• The CAPA System (Corrective and Preventive Action)
• Systems Validation Burden
1.2.3 Phases of PLM
PLM has mainly 4 phases namely:1
? Phase 1: conceive [imagine, specify, plan, innovate]
? Phase 2: design [describe, define, develop, test, analyze and validate]
? Phase 3: realize [manufacture, make, build, procure, produce, sell and deliver]
? Phase 4: service [use, operate, maintain, support, sustain, phase-out, retire, recycle and disposal]
1.3 Stages in the life cycle of a New Molecular Entity From discovery to approval, the average drug's lifecycle extends between ten to twelve years. The length of time varies based on prior knowledge and experience obtained by resemblance to a licensed and approved drug product already on the market, as well as the kind of regulatory approval process the drug product undergoes. FDA-approved pharmaceutical medicines are only 8–10% of preclinical drug developments. The ultimate objective is to provide potential patients with access to safe and efficient medications. The stages from drug discovery to the approval and post marketing is shown in the table below.
Table 1: Stages in the life cycle of a New Chemical Entity
|
Stage – 1 |
Drug Discovery |
|
Stage – 2 |
Drug Development |
|
Stage – 3 |
Pre – Clinical Research |
|
Stage – 4 |
Clinical Research |
|
Stage – 5 |
Regulatory Approval |
|
Stage – 6 |
Market Launch |
|
Stage - 7 |
Post - Market Activities |
Life cycle of an NME in the USA Market
4 United States of America
North America is home to the United States of America (USA), also referred to as the United States (U.S.) or America. It is made up of nine Minor Outlying Islands, five large unorganized territories, a federal district, and fifty states.23
4.1 United States Food and Drug Administration (USFDA)
The Department of Health and Human Services houses the FDA. The Food and Drug Administration (FDA) is in charge of ensuring the security, safety, and efficacy of pharmaceuticals for humans and animals, biological products, medical equipment, food supplies in the country, cosmetics, and radiation-emitting goods in order to safeguard public health. The public is also given accurate, scientifically based health information by the FDA.24
4.2 Regulatory Requirements during the entire life cycle of the New Medical Entity
Table 9: Life cycle stage wise regulatory requirement
|
Stage |
Title |
Regulatory Requirements |
|
I |
Drug Discovery |
Good Laboratory Practices |
|
II |
Drug Development |
|
|
III |
Pre–Clinical Research |
|
|
IV |
Clinical Research |
Clinical Trial Application |
|
V |
Regulatory Approval |
Marketing Authorization Procedures |
|
VI |
Market Launch |
|
|
VII |
post approval |
|
Life cycle of an NME in the Brazil Market
6.1 Brazil
Brazil, or the Federative Republic of Brazil as it is formally known, is the largest and most eastern nation in Latin America and South America. Brazil is the seventh most populous and fifth-largest country in the world in terms of area. São Paulo is the most populated city, and Brasília serves as its capital. The Federal District and the 26 states together make up the federation. Portuguese is the only official language of only one nation in the Americas. Because of more than a century of widespread immigration from all over the world, it is the most populated nation with a majority of Roman Catholics and one of the most cosmopolitan and ethnically varied countries.58
6.2 Brazilian Health Regulatory Agency (ANVISA)
The full form of Anvisa is: “Agência Nacional De Vigilância Sanitária”. As the coordinator of the Brazilian Health Regulatory System (SNVS), which is implemented across the nation, the Brazilian Health Regulatory Agency (ANVISA), an autarchy associated with the Ministry of Health, is a component of the Brazilian National Health System (SUS). ANVISA's mission is to safeguard public health by enforcing hygienic controls over the manufacturing, distribution, and use of goods and services that are governed by health regulations. These controls include those over associated settings, procedures, materials, and technologies, as well as those over ports, airports, and borders.59
6.3 Regulatory Requirements during the entire life cycle of the New Medical Entity
Table 19: Regulatory Requirements during the entire life cycle of the New Medical Entity
|
Stage |
Title |
Regulatory Requirements |
|
I |
Drug Discovery |
Good Laboratory Practices |
|
II |
Drug Development |
|
|
III |
Pre–Clinical Research |
|
|
IV |
Clinical Research |
Clinical Trial Application |
|
V |
Regulatory Approval |
Marketing Authorization Procedures |
|
VI |
Market Launch |
|
|
VII |
Post-Approval |
|
Life cycle of an NME in the India Market
7.1 Central Drugs Standard Control Organization
The National Regulatory Authority (NRA) of India is the Central Drugs Standard Control Organization (CDSCO), which is housed inside the Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India. FDA Bhawan, Kotla Road, New Delhi 110002 is home to the organization's headquarters. In addition, there are nine zonal offices, seven sub zonal offices, eighteen port offices, seven central laboratories, and six mini labs. The drugs and Cosmetics Act of 1940 and the Rules of 1945 have assigned central and state regulators a number of duties related to the regulation of pharmaceuticals and cosmetics. It calls for the uniform application of the Act's provisions and the Rules issued under them to regulate pharmaceuticals and cosmetics and safeguard patients' rights, safety, and wellbeing. The CDSCO is consistently striving to enhance transparency, accountability, and standardization in its offerings to guarantee the safety, effectiveness, and caliber of medical products that are produced, imported, and dispersed throughout the nation.73 The Drugs and Cosmetics Act assigns CDSCO the following duties:74
• Regulatory control over the import of drugs
• Meetings of Drugs Consultative Committee (DCC) and Drugs Technical Advisory Board (DTAB),
• Approval of certain licenses as Central License Approving Authority.
• Approving drugs,
• Conducting clinical trials,
• Setting standards for drugs,
• Monitoring the quality of drugs imported into the nation, and
• Coordinating the efforts of state drug control organizations by offering professional advice in an effort to standardize the enforcement of the drugs and cosmetics act.
Additionally, CDSCO and state regulators work together to provide licenses for specific specialized categories of important drugs, including vaccines, blood and blood products, IV fluids, and serum.
7.2 Regulatory Requirements during the entire life cycle of the New Medical Entity
Table 23: Regulatory Requirements during the entire life cycle of the New Medical Entity
|
Stage |
Title |
Regulatory Requirements |
|
I |
Drug Discovery |
Good Laboratory Practices |
|
II |
Drug Development |
|
|
III |
Pre–Clinical Research |
|
|
IV |
Clinical Research |
Clinical Trial Application |
|
V |
Regulatory Approval |
New Drug Application |
|
VI |
Market Launch |
|
|
VII |
Post-Approval |
|
Life cycle of an NME in the REST OF WORLD
(ROW) Market
8. Rest Of World (ROW) Countries
The majority of countries in the emerging market are those in the Gulf, Africa, Latin America, and Asia Pacific. These nations vary from one another not only in terms of geography but also in numerous other areas, such as pharmaceutical regulation, the use of distinct guidelines for registration, fees associated with registration, requirements for maintaining registration, length of registration, patent regulation, and drug legislation.82, 83
ROW market is divided into the following regions:
• Asia: (Sri-Lanka, India, Bangladesh, China, Pakistan, Bhutan, Nepal).
• ASEAN: 10 Countries group - Philippines, Vietnam Singapore, Malaysia, Thailand, Indonesia, Laos, Cambodia, Brunei Darussalam, and Myanmar.
• African countries: (Algeria, Zambia, Ethiopia, Ghana, Kenya, Malawi, Mozambique, Namibia, Nigeria, Sierra Leone, Tanzania, Zimbabwe etc.)
• Middle East countries (Gulf Co-operation Council countries): i.e. Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, UAE
• Latin America (Mexico, Brazil, Panama, Peru, Guatemala, Argentina, Chile, Dominican Republic)
• CIS: (common wealth of independent states): There are nine member states of the Commonwealth of Independent States. These CIS states are Armenia, Azerbaijan, Belarus, Kazakhstan, Kyrgyzstan, Moldova, Russia, Tajikistan, and Uzbekistan)
8.1 Association of South East Asian Nations (ASEAN) Region
One of the world's most successful regional organizations is the Association of Southeast Asian Nations, or ASEAN. Known as the "Balkans of the East," this region was formed in 1967 by a group of small and medium-sized states with a troubled past from post-colonial Southeast Asia. They overcame mistrust and animosity to create an organization that would handle interstate conflicts and advance political and economic cooperation in the region.84
Table 24: ASEAN Member States with their Regulatory Authorities86
|
Country |
Drug Regulatory Authority |
Ministry of Health |
|
Brunei |
|
Ministry of Health |
|
Cambodia |
Department of Drugs and Food |
Ministry of Health |
|
East Timor |
|
Ministry of Health |
|
Indonesia |
National Agency of Drug and Food Control |
Ministry of Health |
|
Laos |
Food and Drug Department |
Ministry of Health |
|
Malaysia |
National Pharmaceutical Regulatory Agency (NPRA) |
Ministry of Health |
|
Myanmar |
Food and Drug Administration |
Ministry of Health and Sports |
|
Philippines |
Food and Drug Administration |
Department of Health |
|
Singapore |
Health Sciences Authority |
Ministry of Health |
|
Thailand |
Food and Drug Administration |
Ministry of Public Health |
|
Vietnam |
Drug Administration of Vietnam |
Ministry of Health |
8.2 Gulf Cooperation Council (GCC) Region
Saudi Arabia, Kuwait, the United Arab Emirates, Qatar, Bahrain, and Oman are the six Middle Eastern nations that make up the Gulf Cooperation Council (GCC), a political and economic partnership. In May 1981, the GCC was founded in Riyadh, Saudi Arabia. The Gulf Cooperation Council (GCC) aims to unite its members via shared goals and comparable political and cultural identities derived from Islamic and Arab traditions. The council president alternates yearly.86, 87
8.2.1 Organization Structure
The Ministerial Council, the Secretariat General, and the Supreme Council make up the GCC's organizational structure. The city of Riyadh is home to the Secretariat. The GCC's constitution accurately represented the significance of looking for measures to bring about the unification of the Arab States. In terms of economic, social, and cultural matters, the organization was mandated by the constitution to offer "the means for realizing coordination, integration, and cooperation."87
The heads of state of the six GCC members make up the Supreme Council, which is the organization's highest authority. The Supreme Council convenes in regular session once a year. The leaders of any two Member States may call emergency meetings at any moment. Every Member State takes turns holding the position of Supreme Council chairperson. A majority vote is required to pass a resolution. The Ministerial Council or the Secretariat General may submit suggestions to the Supreme Council for approval, and the Council is ultimately in charge of deciding the GCC's overarching policy.88 The six member nations' foreign ministers make up the Ministerial Council. In regular session, the Ministerial Council convenes once every three months. Any two Member States' foreign ministers may call emergency sessions at any moment. The Ministerial Council formulates policies and offers suggestions for fostering coordination and collaboration between Member States in the domains of the economy, society, and culture.88
For the GCC, the Secretariat General creates studies, budgets, reports, and accounting. In addition to drafting laws and regulations, it is in charge of supporting Member States in carrying out decisions made by the Ministerial and Supreme Councils. On the Ministerial Council's suggestion, the Supreme Council appoints the Secretary General to a three-year term that is renewable.88
8.3 Commonwealth of Independent States (CIS) Region December 1991 saw the creation of the Commonwealth of Independent States (CIS); following official confirmation of the implementation, the union's members formally announced their membership (equality of sovereignty). There are currently 13 countries that make up the CIS. The leaders of the CIS countries established the Single Economic Space (1993) on the basis of free movement of capital, products, labor, and services. The corporation received approval to include the management of economic movement regulation into a business agreement. Additionally, the agreement offers beneficial requirements for the expansion of direct production connections.89 Four nations—Russia, Kyrgyzstan, Kazakhstan, and Belarus—as well as the Union of the Sovereign Republic was founded in 1995 with the goal of establishing Russia and Belarus as relevant coordinating entities to advance future integration. With the Council of Four countries' announcement in 1999, Tajikistan was admitted as a full member of the CIS. The agreement on the establishment of the Eurasian Economic Community (2000) was approved by the leaders of five nations: Kazakhstan, Kyrgyzstan, Tajikistan, Russia, and Belarus. The Eurasian Economic Union granted observer status to Moldova, Armenia, and Ukraine. Uzbekistan made its announcement entered the organization in 2005. As indicated in Table 1, an agreement was reached in 2003 by the four nations (Belarus, Kazakhstan, Ukraine, and Russia) to establish the Common Economic Space (CES). Legislative, executive, and CIS industrial cooperation bodies are the coordinating entities that bring nations together to form the Commonwealth of Independent States.90
Table 25: CIS Member States89
|
Name Of Country |
Regulatory Authority |
|
Armenia |
Scientific centre of drug and Medical technology expertise |
|
Azerbaijan |
Analytical expertise center |
|
Belarus |
Ministry of health |
|
Georgia |
Georgia drugs and narcotics Agency |
|
Kazakhstan |
national center for medicines, medical devices and medical equipment expertise |
|
Kyrgyzstan |
Medical equipment department of Drug supply |
|
Moldova |
Agency for medicines and medical Devices (Amed) |
|
Russia |
Federal service for surveillance In healthcare |
|
Tajikistan |
Ministry of health |
|
Turkmenistan |
Ministry of health of the republic Of Turkmenistan |
|
Ukraine |
Ministry of health |
|
Uzbekistan |
Ministry of health protection of the republic of Uzbekistan |
8.4 Regulatory Requirements during the entire life cycle of the New Medical Entity
Table 26: Regulatory Requirements during the entire life cycle of the New Medical Entity
|
Stage |
Title |
Regulatory Requirements |
|
I |
Drug Discovery |
Good Laboratory Practices |
|
II |
Drug Development |
|
|
III |
Pre–Clinical Research |
|
|
IV |
Clinical Research |
Clinical Trial Application |
|
V |
Regulatory Approval |
Marketing Authorization Procedures |
|
VI |
Market Launch |
|
|
VII |
Post-Approval Activities |
|
8.1 Stage – 1 and Stage – 2 Regulatory Requirements
8.5.1 Personnel.
Each individual engaged in the conduct of or responsible for the supervision of a nonclinical laboratory study shall have education, training, and experience, or combination thereof, to enable that individual to perform the assigned functions. 28 Each testing facility shall maintain a current summary of training and experience and job description for each individual engaged in or supervising the conduct of a nonclinical laboratory study. 28
There shall be a sufficient number of personnel for the timely and proper conduct of the study according to the protocol. 28 Personnel shall take necessary personal sanitation and health precautions designed to avoid contamination of test and control articles and test systems.328 Personnel engaged in a nonclinical laboratory study shall wear clothing appropriate for the duties they perform. Such clothing shall be changed as often as necessary to prevent microbiological, radiological, or chemical contamination of test systems and test and control articles.28 Any individual found at any time to have an illness that may adversely affect the quality and integrity of the nonclinical laboratory study shall be excluded from direct contact with test systems, test and control articles and any other operation or function that may adversely affect the study until the condition is corrected. All personnel shall be instructed to report to their immediate supervisors any health or medical conditions that may reasonably be considered to have an adverse effect on a nonclinical laboratory study. 28
8.5.2 Testing facility management.
For each nonclinical laboratory study, testing facility management shall: 28
• Designate a study director before the study is initiated.
• Replace the study director promptly if it becomes necessary to do so during the conduct of a study.
• Assure that there is a quality assurance unit.
• Assure that test and control articles or mixtures have been appropriately tested for identity, strength, purity, stability, and uniformity, as applicable.
• Assure that personnel, resources, facilities, equipment, materials, and methodologies are available as scheduled.
• Assure that personnel clearly understand the functions they are to perform.
• Assure that any deviations from these regulations reported by the quality assurance unit are communicated to the study director and corrective actions are taken and documented.
8.5.3 Study director.
For each nonclinical laboratory study, a scientist or other professional of appropriate education, training, and experience, or combination thereof, shall be identified as the study director. The study director has overall responsibility for the technical conduct of the study, as well as for the interpretation, analysis, documentation and reporting of results, and represents the single point of study control. The study director shall assure that: 28
• The protocol, including any change, is approved and is followed.
• All experimental data, including observations of unanticipated responses of the test system are accurately recorded and verified.
• Unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study are noted when they occur, and corrective action is taken and documented.
• (d) Test systems are as specified in the protocol.
• (e) All applicable good laboratory practice regulations are followed.
• (f) All raw data, documentation, protocols, specimens, and final reports are transferred to the archives during or at the close of the study.
8.5.4 Quality assurance unit.
A testing facility shall have a quality assurance unit which shall be responsible for monitoring each study to assure management that the facilities, equipment, personnel, methods, practices, records, and controls are in conformance with the regulations in this part. For any given study, the quality assurance unit shall be entirely separate from and independent of the personnel engaged in the direction and conduct of that study. The quality assurance unit shall: 28
• Maintain a copy of a master schedule sheet of all nonclinical laboratory studies conducted at the testing facility indexed by test article and containing the test system, nature of study, date study was initiated, current status of each study, identity of the sponsor, and name of the study director.
• Maintain copies of all protocols pertaining to all nonclinical laboratory studies for which the unit is responsible.
• Inspect each nonclinical laboratory study at intervals adequate to assure the integrity of the study and maintain written and properly signed records of each periodic inspection showing the date of the inspection, the study inspected, the phase or segment of the study inspected, the person performing the inspection, findings and problems, action recommended and taken to resolve existing problems, and any scheduled date for reinspection. Any problems found during the course of an inspection which are likely to affect study integrity shall be brought to the attention of the study director and management immediately.
• Periodically submit to management and the study director written status reports on each study, noting any problems and the corrective actions taken.
• Determine that no deviations from approved protocols or standard operating procedures were made without proper authorization and documentation.
• Review the final study report to assure that such report accurately describes the methods and standard operating procedures, and that the reported results accurately reflect the raw data of the nonclinical laboratory study.
• Prepare and sign a statement to be included with the final study report which shall specify the dates inspections were made and findings reported to management and to the study director.
The responsibilities and procedures applicable to the quality assurance unit, the records maintained by the quality assurance unit, and the method of indexing such records shall be in writing and shall be maintained. These items including inspection dates, the study inspected, the phase or segment of the study inspected, and the name of the individual performing the inspection shall be made available for inspection to authorized employees of the Food and Drug Administration. 28
(d) A designated representative of the Food and Drug Administration shall have access to the written procedures established for the inspection and may request testing facility management to certify that inspections are being implemented, performed, documented, and followed-up in accordance with this paragraph. 28
8.5.5 Equipment design.
Equipment used in the generation, measurement, or assessment of data and equipment used for facility environmental control shall be of appropriate design and adequate capacity to function according to the protocol and shall be suitably located for operation, inspection, cleaning, and maintenance. 28 Maintenance and calibration of equipment. Equipment shall be adequately inspected, cleaned, and maintained. Equipment used for the generation, measurement, or assessment of data shall be adequately tested, calibrated and/or standardized. 28 The written standard operating procedures shall set forth in sufficient detail the methods, materials, and schedules to be used in the routine inspection, cleaning, maintenance, testing, calibration, and/or standardization of equipment, and shall specify, when appropriate, remedial action to be taken in the event of failure or malfunction of equipment. The written standard operating procedures shall designate the person responsible for the performance of each operation. 28 Written records shall be maintained of all inspection, maintenance, testing, calibrating and/or standardizing operations. These records, containing the date of the operation, shall describe whether the maintenance operations were routine and followed the written standard operating procedures. Written records shall be kept of nonroutine repairs performed on equipment as a result of failure and malfunction. Such records shall document the nature of the defect, how and when the defect was discovered, and any remedial action taken in response to the defect. 28
8.5.6 Standard operating procedures.
A testing facility shall have standard operating procedures in writing setting forth nonclinical laboratory study methods that management is satisfied are adequate to ensure the quality and integrity of the data generated in the course of a study. All deviations in a study from standard operating procedures shall be authorized by the study director and shall be documented in the raw data. Significant changes in established standard operating procedures shall be properly authorized in writing by management. 28 Each laboratory area shall have immediately available laboratory manuals and standard operating procedures relative to the laboratory procedures being performed. Published literature may be used as a supplement to standard operating procedures. 28 A historical file of standard operating procedures, and all revisions thereof, including the dates of such revisions, shall be maintained. 28
8.5.7 Reagents and solutions
All reagents and solutions in the laboratory areas shall be labelled to indicate identity, titre or concentration, storage requirements, and expiration date. Deteriorated or outdated reagents and solutions shall not be used. 28
8.6 Stage – 3 Regulatory Requirements
Once a possible drug has been found in the lab, preclinical testing can start. Preclinical testing entails laboratory and animal research to assess the pharmacologic and toxic effects of the medication. The Good Laboratory Practices (GLP) for Nonclinical Laboratory Studies, of all the countries, also apply to preclinical studies. Minimum requirements are outlined in the GLP regulations for staff, facilities, equipment, and operations. Preclinical trials encompass the pharmacokinetic analysis, which delves into the drug’s journey within living systems. This involves scrutinizing the absorption, distribution, metabolism, and excretion—collectively known as ADME—to verify the drug’s effective delivery to the target area and its appropriate passage out of the body. Concurrently, chemical evaluations are performed to ascertain the drug’s purity, stability, and longevity. Additionally, production assessments are carried out to gauge the large-scale manufacturability of the drug, alongside considerations for dosage, packaging, and composition.90
8.7 Stage – 4 Regulatory Requirements
A Clinical Trial Application (CTA) represents a formal request submitted to the appropriate National Regulatory Authorities to secure permission for executing a clinical trial within a particular nation. It encompasses a dossier filled with critical data regarding the investigational medicinal products. The objective of a CTA is to furnish comprehensive information about the clinical trial to the health officials, thereby facilitating the approval of the product.91
8.7.1 Contents of a CTA81
• Administrative Documents
• Chemistry, Manufacturing & control documents
API DMF Open part – Following data should be available in Open Part
? Nomenclature.
? General Properties.
? Name of the Manufacturer and Site of manufacture.
? Route of Synthesis, flow diagram in brief.
? Structural Elucidation
? Impurities.
? Specifications and Method of Analysis
? Container Closure System
? Stability testing Retest period & Storage
? API Specification and Method of Analysis & COA of API by the Applicant.
Drug Product
? Formulation Development
? Overages
? Impurities
? Analytical Procedures
? Batch Analysis
? Finished product Specification
? Stability Data and Stability Protocol
? Packing Material
? Container Closure System
• Pharmacological, Toxicological data (pre-clinical)
8.8 Stage – 5 Regulatory Requirements
A Marketing Authorization Application should be submitted to the national Regulatory Agency to market a drug in any ROW country. The contents of the Marketing Authorization Application are as below:91
• Administrative Documents
API DMF Open part – Following data should be available in Open Part
? Nomenclature.
? General Properties.
? Name of the Manufacturer and Site of manufacture.
? Route of Synthesis, flow diagram in brief.
? Structural Elucidation.
? Impurities.
? Specifications and Method of Analysis
? Container Closure System
? Stability testing Retest period & Storage
? API Specification and Method of Analysis & COA of API by the Applicant.
Drug Product
? Formulation Development
? Overages
? Impurities
? Analytical Procedures
? Batch Analysis
? Finished product Specification
? Stability Data and Stability Protocol
? Packing Material
? Container Closure System
•Pharmacological, Toxicological data (pre-clinical)
•Bioequivalence
8.9 Stage – 7 Regulatory Requirements
Throughout a pharmaceutical product’s lifecycle, the marketing authorization holder bears the responsibility for the marketed product. They must also consider ongoing technical and scientific advancements and implement any necessary modifications. These changes ensure that the pharmaceutical products can be produced and verified using widely recognized scientific techniques. All such modifications require the approval of the Drug Regulatory Authority.92
Table 27: ASEAN Variation Catogaries92
|
MIV-N |
Minor Variation (Notification) |
|
MIV-PA |
Minor Variation (Prior Approval) |
|
MAV |
Major Variation |
Table 28: GCC Variation Catogaries93
|
Type – IA |
Minor Variation |
|
Type – IB |
|
|
Type - II |
Major Variation |
DISCUSSION AND CONCLUSION
A comprehensive understanding of regulatory variations empowers pharmaceutical companies, regulators, and healthcare stakeholders to optimize NME development, enhance patient access, and foster global health innovation.
ACKNOWLEDGEMENT
The authors would like to thank, Anand pharmacy college for extending their facilities.
Conflict Of Interest
The authors attest that they are free of any known financial or personal conflicts of interest that could taint this study's findings.
Informed Consent
Using websites, review articles, and other sources to produce research content.
REFERENCES
Jignasha Dabhi*, Jay Patel, Hitesh Raval, Tejal Gandhi, Study of Regulatory Perspectives in The Lifecycle of a New Molecular Entity in USA, Europe, Brazil, India and Row Countries, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 1, 400-418. https://doi.org/10.5281/zenodo.14608515
10.5281/zenodo.14608515
