The Global Medicines Agency Charter

The Global Medicines Agency Charter: Comparison

Please note this is a comparison between Version 2 by Camila Xu and Version 1 by Sarfaraz K. Niazi.

The charter of the Global Medicines Agency (GMA) is based on learning from the working of these agencies to enable reaching the goal by bringing clarity, rationality, and practicality to the registration of drugs to overcome their accessibility issues.

biosimilars
Arab states
regulatory guideline
harmonization
centralized approval
EMA
FDA
Global Medicine Authority (GMA)

1. Introduction

Medical anthropology teaches that health and medicine’s social, cultural, and political dimensions do not favor developing countries, and this disparity grows as newer high-cost drugs enter the market, particularly biotechnological drugs or biologics that are derived from living organisms or containing components of living organisms. Biologics can be composed of sugars, proteins, nucleic acids, or complex combinations of these substances, or may be living entities such as cells and tissues. Biologics are isolated from various natural sources, such as human, animal, or microorganism, and may be produced by biotechnological methods and other cutting-edge technologies ^[1]. Gene-based and cellular biologics, for example, are often at the forefront of biomedical research and may be used to treat untreatable diseases. Biologics are complex molecules that are not easily characterized; examples include vaccines that are centuries old such as powdered scab inoculations against smallpox that were used in China as early as the 10th century ^[2]. As these products expanded, a new terminology became necessary to differentiate them from chemical drugs in the early 20th century. This led to a rush to standardize their definition, production, and quality, ultimately resulting in the Biologics Control Act, which the US Congress passed in 1902 ^[3]. Soon after, biological drugs were expanded to include products made by a biological process or containing a biological entity. This led to therapeutic proteins and genomic medicines, but their production controls have resulted in an exponential increase in development and production costs.

Genomic medicine has dramatically matured in terms of its technical capabilities; however, its accessibility worldwide faces significant barriers beyond mere access to technology. Development strategies for global genomic medicine should recognize an individual country’s pressing public health priorities and disease burdens. Therefore, it is more pragmatic to transfer technology at different stages, from the bottom up, instead of the top down. An à la carte model of global innovation and development strategy offers multiple entry points into the global genomics innovation ecosystem for developing countries, regardless of whether extensive and expensive discovery infrastructure is already in place. [4,5]^[4][5]

More than half of the projected increase in global spending on medicines, which is expected to reach approximately USD 2 trillion in 2027 from an estimated USD 1.5 trillion today [6^[6][7],7], is attributed to biological drugs such as vaccines, blood, blood components, allergenic, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins.

As the number and variety of biologics increased throughout the 20th century, so did our ability to produce them. In 1949, researchers at Boston Children’s Hospital successfully used an in vitro system to produce Lansing Type II poliovirus using a human tissue cell culture. This development pave the way for the creation of modern biologics. However, the emergence of genetic engineering in the late 1970s and early 1980s created new opportunities for the research and manufacturing of biologics. Researchers could alter existing agents’ DNA sequences to increase their stability, safety, and effectiveness. These modifications may also affect the targeting specificity of the agent, broadening the applicability of some agent types, including antibodies. Finally, genetic engineering has provided scientists with a broader range of feasible production models. Before the development of transfection and transduction, the ability to create a cellular factory was constrained by the production cell’s genome or, in the case of viral production, by the virion’s susceptibility to persistent but non-lethal infection. However, theoretically, any cell could now be made to produce any molecular or protein-based agent. CRISPR technology, for instance, can modify recombinant cell lines to create proteins with specific properties ^[8].

Since the 1980s, there has been a significant increase in biologics research and production, leading to notable advancements in the creation of novel therapeutic strategies for diseases, including cancer, immunological disorders, and rare genetic illnesses, among others ^[6]. The creation, manufacturing, and synthesis of a wide variety of complex designer molecular, protein, gene, cell, and tissue-based agents capable of highly selective targeting have expanded the scope of science, which was once limited to the extraction of naturally occurring chemicals ^[9].

New drug development costs now run into billions of dollars ^[10], leading to their high prices for at least 12 years for new biological drugs during the exclusivity period ^[8]. The increased development cost comes from more stringent SRA guidelines necessitated by knowledge about their potency and side effects ^[11], resulting in the high price of these products (Table 1) to amortize the investment cost. These drugs should be the first focus for securing their entry into developing countries. This applies to both types of drugs, one that can be copied as biosimilars and other biologics, such as vaccines and gene therapy, for which there is no guideline to produce copies. The latter class is more relevant for manufacturing these products in non-SRA countries. While many recent gene therapy products can cost millions of dollars, therapeutic proteins, a type of drug allowed to have biosimilars, may still cost hundreds of thousands of USD. The latter category is, therefore, most suitable for domestic manufacturing. Notably, the GMA will not approve a new drug of any type that has not been approved in an SRA country.

Table 1.

Top ten most expensive treatment costs till June 2023 ^[12].

Rank	Drug	Manufacturers	Indication	Cost
1	Hemgenix	CSL Behring, uniQure	Hemophilia B	$3.5 million/dose
2	Skysona	Bluebird bio	Cerebral adrenoleukodystrophy	$3 million/dose
3	Zynteglo	Bluebird bio	Transfusion-dependent thalassemia	$2.8 million/dose
4	Zolgensma	Novartis	Spinal muscular atrophy	$2.25 million/dose
5	Myalept	Chiesi Farmaceutici	Leptin deficiency	$1.26 million/year
6	Zokinvy	Eiger BioPharmaceuticals	Hutchinson-Gilford progeria syndrome and processing-deficient progeroid laminopathies	$1.07 million/year
7	Danyelza	Y-mAbs Therapeutics	Relapsed or refractory high-risk neuroblastoma	$1.01 million/year
8	Kimmtrak	Immunocore	Uveal melanoma	$0.97 million/year
9	Luxturna	Spark Therapeutics	Biallelic RPE65-mediated inherited retinal disease	$0.85 million/treatment
10	Folotyn	Acrotech Biopharma	Relapsed or refractory peripheral T-cell lymphoma	$0.84 million/year

Global health disparities: Analyzing the implications of global health disparities in the distribution and availability of biotechnology drugs. They investigate the power dynamics between developed and developing countries, pharmaceutical companies, and regulatory bodies and their impact on access to these medications.
Ethical considerations: Examining the ethical dimensions of developing, testing, and distributing biotechnology drugs in developing countries. This includes exploring issues of informed consent, clinical trials, and the involvement of vulnerable populations;
Domestic manufacturing: The cost of establishing the manufacturing of biotechnology drugs keeps developing countries from becoming self-sufficient in their supply. However, this option applies only to those drugs that can be copied in the SRA countries; an example is biosimilars.

The proposed plan to establish a GMA has the following objectives:

To make these drugs available in developing countries by simplifying the registration process of novel SRA country products;

2. The GMA Charter

While new drugs have significantly helped affluent countries, the accessibility of these products remains limited in most developing countries for several reasons:

Access and affordability: Individuals and communities face challenges in accessing biotechnology drugs in resource-limited settings. This includes analyzing factors such as cost, availability, distribution, and the role of pharmaceutical companies and government policies;
Cultural and social dimensions: How biotechnology drugs are perceived, understood, and utilized within specific cultural contexts. This involves exploring local beliefs, practices, and values related to health, illness, and treatment options, as well as the influence of social and cultural factors on the acceptance and use of these drugs;
To encourage SRA originators and domestic developers by making a large market population with a single registration;
To ensure data integrity by not requiring all countries to acquire registration dossiers.
To ensure the safety and efficacy of products manufactured in non-SRA countries by adopting a rational and practical registration process.

However, the idea of the GMA is not new, as several agencies have been formed with similar goals in the past. Still, the disparity in accessibility of biotechnology drugs and many chemical drugs remains in place. The charter of the GMA is based on learning from the working of these agencies to enable reaching the goal by bringing clarity, rationality, and practicality to the registration of drugs to overcome their accessibility issues.

2.1. Regulatory Agencies

The European Medicines Agency (EMA) is responsible for the scientific evaluation, supervision, and safety monitoring of medicines, particularly biotechnology drugs and medicines. However, countries within the EU/EEA can also have their own national regulatory authorities that evaluate and approve medicines for their specific jurisdictions. These national regulatory authorities work with the EMA and may require additional steps for local registration, such as translation, labeling adaptations, or specific national requirements. Some medicines, especially those under national procedures or certain categories, may undergo decentralized or mutual recognition procedures, where individual countries review and grant marketing authorizations based on common assessments and agreements. [https://www.ema.europa.eu/ (accessed on 15 July 2023)].

Pan American Health Organization (PAHO)—PAHO serves as the regional office for the Americas and collaborates with regulatory authorities across the region to facilitate the approval and regulation of medical products; it serves as the regional office for the Americas under the umbrella of the World Health Organization (WHO). Its role includes promoting health, preventing diseases, and improving healthcare systems across its member countries in the Americas. PAHO consists of 35 member countries, including all countries in the Americas (North, Central, and South America, as well as the Caribbean). Each member country has an independent healthcare system and regulatory authority responsible for overseeing the approval and regulation of medicines within their respective territories. PAHO’s role primarily focuses on providing technical cooperation, guidance, and support to member countries in public health. It works closely with national health authorities, sharing information, expertise, and best practices to strengthen healthcare systems and address public health challenges. While PAHO does not have a centralized approval system for medicines like the European Medicines Agency (EMA), it provides guidance and recommendations on various health topics, including regulating and using medicines. [https://www.paho.org/ (accessed on 15 July 2023)].

The Pharmaceutical Inspection Co-operation Scheme (PIC/S) is an international organization that harmonizes Good Manufacturing Practice (GMP) standards and inspects pharmaceutical manufacturing facilities. Its primary objective is to ensure medicinal products’ quality, safety, and efficacy. The PIC/S operates through a collaborative framework involving regulatory authorities from multiple countries. The participating regulatory authorities exchange information, share expertise, and work together to establish common standards and guidelines for GMP inspection. The organization aims to promote consistency and quality in pharmaceutical manufacturing practices across borders. The PIC/S has 54 participating regulatory authorities from countries worldwide, including various European countries, Australia, Canada, Switzerland, Singapore, and others. Each member country is responsible for implementing and enforcing the GMP standards within its jurisdiction based on the guidelines and recommendations established by PIC/S. [https://www.picscheme.org/ (accessed on 15 July 2023)].

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a global organization that brings together regulatory authorities and the pharmaceutical industry to develop and promote harmonized guidelines for the registration, quality, safety, efficacy, and multidisciplinary evaluation of pharmaceutical products. The ICH aims to advance regulatory harmonization, streamline drug development, and registration processes, and facilitate global access to high-quality, safe, and efficacious medicines. The guidelines developed by the ICH provide a framework for consistent and efficient regulatory practices, allowing for more effective collaboration and information sharing among member countries and stakeholders in the pharmaceutical industry. The guidelines apply to the territories of the countries part of the ICH. These countries include the United States, European Union member states, Japan, Canada, Switzerland, and Australia. It is important to note that individual member countries may adopt and implement the ICH guidelines following their own regulatory frameworks and legal requirements. [https://www.ich.org/home.html (accessed on 15 July 2023)].

The World Health Organization (WHO) is a specialized agency of the United Nations (UN), the leading global authority on international public health. It operates to promote health, prevent diseases, and address health-related challenges on a global scale. The decisions and recommendations made by the WHO apply to all 194 member countries. Each member country is expected to align its national health policies and practices with the guidelines and recommendations put forth by the WHO. However, it is important to note that the WHO’s decisions and recommendations are not legally binding. Member countries can implement and adapt the WHO’s guidelines according to national contexts, legal frameworks, and health priorities. Nonetheless, the WHO’s guidance carries significant influence and is considered authoritative in global health, often shaping national health policies and practices worldwide. https://www.who.org (accessed on 15 July 2023).

The Gulf Cooperation Council (GCC) is a regional political and economic organization comprising six Arab states in the Arabian Gulf region. The GCC member countries are Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates (UAE). The organization collaborates on various fronts, including healthcare, and has established a drug registration and regulatory framework. The GCC Central Committee for Drug Registration (GCC-DR) is the body responsible for overseeing the drug registration processes among member countries. The GCC-DR facilitates cooperation and harmonization in evaluating, registering, and post-marketing surveillance of pharmaceutical products across the GCC region. This process involves the formation of expert committees comprising representatives from member countries, who collectively review and evaluate the safety, quality, and efficacy data submitted by pharmaceutical companies. Once a pharmaceutical product is approved by one member country, it can be recognized and accepted by other member countries, thereby facilitating market access across the region. The GCC-DR has established guidelines, standards, and technical requirements for drug registration and regulation in member countries. Pharmaceutical companies seeking to register their products in the GCC region must comply with these guidelines and meet the specified requirements. https://www.gcc-sg.org/en-us/Pages/default.aspx (accessed on 15 July 2023).

The Association of Southeast Asian Nations (ASEAN) promotes economic, political, and social cooperation among its member countries in Southeast Asia. In drug regulation, the ASEAN has implemented a framework known as the ASEAN Common Technical Dossier (ACTD) and the ASEAN Common Technical Requirements (ACTR) for registering and regulating pharmaceutical products. The ASEAN member countries include Brunei Darussalam, Cambodia, Indonesia, Laos, Malaysia, Myanmar, the Philippines, Singapore, Thailand, and Vietnam. The ASEAN member countries have adopted a decentralized approach to drug registration. Each member country has a national regulatory authority responsible for evaluating and approving pharmaceutical products within its jurisdiction. However, the ACTD and ACTR provide a common framework that facilitates the mutual recognition of product approvals among member countries. Once a product is approved by one member country, it can be recognized and accepted by other member countries, enabling easier access to markets across the region; however, the member countries retain the autonomy to implement and enforce regulations according to their specific national requirements and legal frameworks. https://asean.org/ (accessed on 15 July 2023).

2.2. Functions of the GMA

The idea of a joint regulatory agency assisting multiple countries in expanding the availability of drugs is not new. Yet, none of these agencies listed above perform the functions anticipated by the proposed GMA charter that overcomes all constraints from a structured plan:

Legally binding registration across member countries, regardless of their geography;
No dossier sharing with member countries;
Allows local labeling requirement compliance;
Does not engage in price negotiations;
The product must be registered in the country of origin;
Automatic registration of SRA-approved products if they are also distributed in the country of origin;
Rapporteur-based evaluation of registration dossiers from non-SRA countries;
Third-party cGMP audit and testing sample surveillance;
Centrally operated international scientific, legal, and technical expertise.

However, to make this proposal a success, a sponsor must set a role-model example that is difficult to find because states do not always agree with each other due to the differences in their perspective, their misunderstanding, and the desire for political independence. It is well exemplified by existing agencies that could meet the proposed GMA charter, but would not. However, if a model agency is established with an allowance for open membership, it can grow into the world’s most significant regulatory agency that focuses on biotechnological products.

References

What Are “Biologics” Questions and Answers. Available online: https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/what-are-biologics-questions-and-answers (accessed on 14 July 2023).
Von Schwerin, A.; Stoff, H.; Wahrig, B. (Eds.) Biologics: An introduction. In Biologics, a History of Agents Made from Living Organisms in the Twentieth Century; Pickering & Chatto: London, UK, 2013; pp. 1–33.
Gross, C.P.; Sepkowitz, K.A. The myth of the medical breakthrough: Smallpox, vaccination, and Jenner reconsidered. Int. J. Infect. Dis. 1998, 3, 54–60.
CooperDavid, N.; ReichardtJürgen, K.V.; AliBassam, R.; PatrinosGeorge, P. Which Strategies Should Developing Countries Employ to Invest in Precision Medicine? A New “Fast-Second Winner” Strategy. OMICS J. Integr. Biol. 2017, 21, 647–657.
Spök, A.; Twyman, R.M.; Fischer, R.; Ma, J.K.; Sparrow, P.A. Evolution of a regulatory framework for pharmaceuticals derived from genetically modified plants. Trends Biotechnol. 2008, 26, 506–517.
Kalkan, A.K.; Palaz, F.; Sofija, S.; Elmousa, N.; Ledezma, Y.; Cachat, E.; Rios-Solis, L. Improving recombinant protein production in CHO cells using the CRISPR-Cas system. Biotechnol. Adv. 2023, 64, 108115.
Global Spending on Medicines in 2010, 2022, and a Forecast for 2027. Available online: https://www.statista.com/statistics/280572/medicine-spending-worldwide/ (accessed on 14 July 2023).
Andrews, L.; Ralston, S.; Blomme, E.; Barnhart, K. A snapshot of biologic drug development: Challenges and opportunities. Hum. Exp. Toxicol. 2015, 34, 1279–1285.
Casadevall, N.; Flossmann, O.; Hunt, D. Evolution of biological agents: How established drugs can become less safe. BMJ 2017, 357, j1707.
Wouters, O.J.; McKee, M.; Luyten, J. Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009–2018. JAMA 2020, 323, 844–853, Erratum in: JAMA 2022, 328, 1110. Erratum in: JAMA 2022, 328, 1111.
Schlander, M.; Hernandez-Villafuerte, K.; Cheng, C.-Y.; Mestre-Ferrandiz, J.; Baumann, M. How Much Does It Cost to Research and Develop a New Drug? A Systematic Review and Assessment. Pharmacoeconomics 2021, 39, 1243–1269.
Priciest Drugs in 2023. Available online: https://www.fiercepharma.com/special-reports/priciest-drugs-2023 (accessed on 14 July 2023).