E-DRUG: Two recent articles about the importance of regulatory agencies
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[Long message! Richard has included the complete articles here. Thank you Richard BS]
Hi E-Druggers,
I was struck by two recent articles about the importance of national regulatory agencies.
The first in the recent edition of the Journal of Pharmaceutical Policy and Practice is by three international authors who work for the MSH MTaPS program. They make the case for National Regulatory Agencies.
The second is by Andy Gray from South Africa describing how the South African regulatory agency functions.
Recently regulatory agencies all over the world have faced political pressures to do more or to do less, to be quicker or be more careful.
What these two articles tell me is that the NRAs are important and deserve support. Both are well written, short and are useful resources.
My congratulations to the authors.
Richard Laing
Retired Professor
BUSPH
"Laing, Richard" <richardl@bu.edu>
Making the investment case for national regulatory authorities
Gloria Twesigye, Tamara Hafner & Javier Guzman
Journal of Pharmaceutical Policy and Practice volume 14, Article number: 16 (2021)
https://joppp.biomedcentral.com/articles/10.1186/s40545-021-00299-7
Abstract
Well-functioning national regulatory authorities (NRAs) ensure access to safe, effective, quality-assured, and affordable medical products. However, the benefits of their work are often unseen and difficult to attribute, thereby making NRAs undervalued and under-resourced, particularly in low- and middle-income countries. This paper offers three key arguments NRAs and other stakeholders can use to advocate for greater investment in regulatory systems strengthening-medical products regulation effectively safeguards public health; effective regulation improves health system's efficiency by increasing access to affordable medical products, contributing to universal health coverage; and robust regulation strengthens local pharmaceutical manufacturing and bolsters pharmaceutical trade. NRAs' critical role in health systems is indisputable, yet they need to better promote their value to receive the requisite resources to function effectively.
Introduction
As part of its proposed strategy for strengthening regulatory systems to support good quality, wholesome food and safe, effective medical products globally, the National Academies of Sciences, Engineering, and Medicine (NASEM) recommended that national regulatory agencies (NRAs) should address the "ways regulation improves quality, safety, and access, using different strategies to convey this information to government leaders, regulated industry, and the public" [1]. NRAs tend to be in the spotlight during highly visible public health crises. The benefits of their work, when done well, are diffused, difficult to attribute, and hidden from the public [1].
The World Health Organization (WHO) estimates that only 30% of NRAs have the capacity to effectively and efficiently regulate medical products in their countries and that one-third of the world's population lacks timely access to quality-assured medicines [2]. Systems strengthening is resource-intensive and requires a long time commitment [3]. Further, the evidence base on what systems strengthening interventions are effective has been historically weak [3]. With the development of the Global Benchmarking Tool (GBT) Revision VI, the first globally accepted tool for objectively assessing and strengthening NRAs, countries now have a tool to formulate an institutional development plan with realistic standards and well-defined interventions to systematically strengthen their system [4]. The availability of a globally agreed-upon benchmark for regulatory systems underscores the need for increased national-level commitments to strengthening NRAs [3].
Prompted by the NASEM's recommendation for better communication, we propose three arguments for greater investment in regulatory systems strengthening. These arguments are particularly salient in low- and middle-income countries (LMICs) where many NRAs are chronically underfunded and lack the necessary legal mandate and resources to effectively control the safety, efficacy, and quality of medical products being imported, manufactured, or used in their jurisdictions [1]. Weak NRAs also affect the affordability of medical products, as they influence market competitiveness, and the availability of substandard and falsified medicines and underuse of generic medicines, two of the highest sources of inefficient health spending [5]. NRAs' inability to conduct core regulatory functions negatively affects population health and wellbeing, the efficiency and sustainability of health systems, and the robustness of local pharmaceutical industry and trade.
Governments should regulate medical products effectively to safeguard public health
Regulation is indisputably a public health good because it ensures access to safe, quality-assured, and affordable medical products. A 2018 meta-analysis revealed that 13.6% of essential medicines in LMICs were substandard and falsified, including 18.7% in Africa and 13.7% in Asia [6]. Models estimate poor-quality medicines cause approximately 70,000 excess deaths from childhood pneumonia and 8500 to 20,000 malaria deaths in sub-Saharan Africa annually [7]. Weak NRAs have limited capacity to detect and prevent the sale and consumption of substandard and falsified medicines. This contributes to poor health outcomes by prolonging disease, increasing mortality and adverse events, and hastening antimicrobial resistance [7]. Without a functional NRA, a government cannot verify whether the medical products being imported or manufactured locally meet approved quality standards or that those standards are stringent enough to protect consumers. Likewise, the public cannot be confident that the products they use are safe and effective and may lose confidence in both the health system and the government [1].
The public health argument has been strengthened by the COVID-19 pandemic as NRAs are essential in addressing the unique challenges associated with deploying new medical products during a public health emergency. With new vaccines and medicines, oversight of clinical trials is crucial to ensure they are appropriately designed and patients' rights and safety are protected. Similarly, the expedited registration of new products-including medical devices, diagnostics, and personal protective equipment-must guarantee product safety, efficacy, and quality assurance. As these new products enter the market, vigilance to detect and address adverse events will be equally critical.
Effective regulation improves health systems' efficiency, increases access to medical products, and contributes to achieving universal health coverage
The significant economic costs of substandard and falsified medicines directly hamper progress towards universal health coverage (UHC), a target of Sustainable Development Goal (SDG) 3 [5]. WHO estimates that expenditures on falsified and substandard medicines in LMICs are approximately US$ 30 billion [7]. Importantly, patients bear the brunt of the economic costs through increased out-of-pocket expenses to pay for health services and medical products, as well as forgone earnings and lost productivity due to prolonged illness. Reducing the proportion of large household expenditures on health as a share of total household expenditures is a key indicator in measuring progress towards UHC (SDG Indicator 3.8.2); however, progress will be limited unless NRAs can reduce the availability of falsified and substandard medicines [8].
In many LMICs, prices for generic and brand medicines are often higher relative to high-income countries, and quality-assured generics remain unavailable and underutilized [5, 9]. Prioritizing the entry and use of generic medicines can have considerable cost savings. Strong regulatory systems allow for a fair and competitive market, removing low-priced, substandard products from the market. Cameron and Liang found that 17 countries could reduce expenditures for 18 medicines by an average of 60% solely by switching to generic medicines, saving an average of US$ 31.3 million in 1 year [9]. In Mexico, reforms initiated in 2011 to strengthen the Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS), the regulatory body, resulted in a 77% increase in the use of generic medicines over 2 years [10]. Increasing market penetration of quality-assured generic medicines while removing substandard products further enables the inclusion of an affordable basket of quality-assured essential medicines in health insurance schemes, promoting equitable access to medicines [11].
Robust regulation strengthens local manufacturing and bolsters pharmaceutical trade
Effective regulation improves the quality of locally manufactured products and facilitates entry in international markets, thereby strengthening the local pharmaceutical industry and boosting trade. Patients and governments also benefit from greater competition and lower prices. Manufacturers from countries with strong regulatory authorities often receive preferential treatment in regional markets. After the COFEPRIS reforms, for example, PAHO recognized COFEPRIS as a reference authority, expanding the export market and the potential for expedited assessments in the Americas [10]. Additionally, strengthening COFEPRIS eliminated a backlog of approximately 4500 applications and led to an estimated 13.2% growth in the local Mexican pharmaceutical market between 2011 and 2014 [10]. El Salvador's 2012 regulatory system reforms reduced case backlogs and increased competition in the market and the availability of quality-assured generics, contributing to an average 20-25% reduction in medicines prices and an approximate US$ 60 million annual savings in out-of-pocket medicines expenditures [12].
As NRAs mature and participate in regional harmonization and convergence initiatives, they increasingly collaborate to systematically rely on decisions and actions of NRAs recognized as reference authorities. For example, joint dossier reviews through regional regulatory harmonization initiatives shortened timelines for medicines registration for countries in the East African Community and the Southern African Development Community [13]. In the Caribbean Community, abbreviated dossier reviews helped streamline the process for generics through reliance on reference authorities [13]. Increased efficiencies in the medicines registration process reduce delays and costs to manufacturers, increase trade opportunities, and allow NRAs to redirect their limited resources to other essential regulatory functions, such as vigilance.
Conclusion
Given NRAs' indisputable, though largely invisible, role in national health systems and pharmaceutical markets, it is critical for NRAs to communicate the health and economic benefits of their work to the government, industry and the public. However, analyzing the health and economic impact of regulatory policies is challenging because of the time lag and indirect causal pathway. Some NRAs' inability to generate evidence about the regulatory environment compounds the challenge. An implicit issue raised by this paper is the need for more systematic analyses of the health and economic benefits of medical products regulation, particularly in LMICs. Regardless, the COVID-19 pandemic has brought into sharp relief the need to invest in regulatory systems strengthening to ensure timely access to safe, effective, quality-assured, and affordable medical products. A strong regulatory system helps facilitate a robust response to pandemics and other health emergencies, as opposed to initiating an emergency response without the requisite systems in place.
Availability of data and materials
Not applicable.
Abbreviations
COFEPRIS: Comisión Federal para la Protección contra Riesgos Sanitarios
GBT: Global Benchmarking Tool
LMIC: Low- and middle-income country
NASEM: National Academies of Sciences, Engineering, and Medicine
NRA: National Regulatory Authority
SDG: Sustainable Development Goal
UHC: Universal health coverage
WHO: World Health Organization
References
1. National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Global Health; Committee on Stronger Food and Drug Regulatory Systems Abroad. Stronger food and drug regulatory systems abroad. In: Woteki CE, Buckley GJ, editors. Washington (DC): National Academies Press (US); 2020. http://www.ncbi.nlm.nih.gov/books/NBK555797/. Accessed 19 Nov 2020.
2. WHO. WHO essential medicines and health products: annual report 2017: towards access 2030. Geneva: World Health Organization; 2018. Report No.: WHO/EMP/2018.01. https://apps.who.int/iris/handle/10665/272972. Accessed 13 July 2020.
3. Hafner T, Banda M, Kohler J, Babar Z-U-D, Lumpkin M, Adeyeye MC, et al. Integrating pharmaceutical systems strengthening in the current global health scenario: three "uncomfortable truths." J Pharm Policy Pract. 2020;13:38.
4. WHO. WHO Global Benchmarking Tool (GBT) for evaluation of national regulatory systems of medicines and vaccines. WHO. World Health Organization. http://www.who.int/medicines/regulation/benchmarking_tool_version_vi/en/. Accessed 19 Nov 2020.
5. WHO. Health systems financing: the path to universal coverage. Geneva: World Health Organization; 2010. http://www.who.int/whr/2010/en/. Accessed 26 May 2020.
6. Ozawa S, Evans DR, Bessias S, Haynie DG, Yemeke TT, Laing SK, et al. Prevalence and estimated economic burden of substandard and falsified medicines in low- and middle-income countries. JAMA Netw Open. 2018;1(4):e181662.
7. WHO. A study on the public health and socioeconomic impact of substandard and falsified medical products. Geneva: World Health Organization; 2017. http://www.who.int/medicines/regulation/ssffc/publications/se-study-sf/en/. Accessed 26 May 2020.
8. WHO. Tracking universal health coverage: 2017 Global Monitoring Report. Geneva: World Health Organization; 2017. http://www.who.int/healthinfo/universal_health_coverage/report/2017/en/. Accessed 26 May 2020.
9. Cameron A, Mantel-Teeuwisse AK, Leufkens HGM, Laing RO. Switching from originator brand medicines to generic equivalents in selected developing countries: how much could be saved? Value Health. 2012;15(5):664-73.
10. Arriola Peñalosa MA, Cavazos Cepeda R, Alanis Garza M, Lumpkin MM. Optimized medical product regulation in Mexico: a win-win for public and economic health. Ther Innov Regul Sci. 2017;51(6):744-50.
11. Wirtz VJ, Hogerzeil HV, Gray AL, Bigdeli M, de Joncheere CP, Ewen MA, et al. Essential medicines for universal health coverage. Lancet Lond Engl. 2017;389(10067):403-76.
12. Yamagiwa TJ. The New Law on Medicines and its implementation. Geneva: World Health Organization; 2015. http://www.who.int/health_financing/documents/Efficiency_health_systems_El_Salvador/en/. Accessed 6 Aug 2020.
13. Preston C, Chahal HS, Porrás A, Cargill L, Hinds M, Olowokure B, et al. Regionalization as an approach to regulatory systems strengthening: a case study in CARICOM member states. Rev Panam Salud Publica Pan Am J Public Health. 2016;39(5):262-8.
Acknowledgements
The authors thank Susan Gillespie for reviewing an earlier draft of this manuscript.
Funding
This work is made possible by the generous support of the US Agency for International Development (USAID) under contract number (7200AA18C00074). The contents are the responsibility of the authors and do not necessarily reflect the views of USAID or the US Government.
Affiliations
USAID Medicines, Technologies, and Pharmaceutical Services (MTaPS) Program, Management Sciences for Health, Arlington, VA, USA
Explainer: how South Africa regulates medicines and vaccines
Andy Gray Senior Lecturer, Division of Pharmacology, University of KwaZulu-Natal February 10, 2021 5.
https://theconversation.com/explainer-how-south-africa-regulates-medicines-and-vaccines-154843
COVID-19 has raised public awareness about the role of national medicines regulatory authorities in enabling access to safe, effective and quality-assured medicines. This includes vaccines.
In South Africa, the pandemic has also exposed a number of important misperceptions, among the public and health professionals.
The South African Health Products Regulatory Authority is responsible for monitoring, evaluating, investigating, inspecting and registering all health products. These include medicines for human and animal use, medical devices and diagnostic tests. The authority is an independent structure, located outside the Department of Health and the public service. Funded by a combination of user fees and fiscal allocation, with a small contribution from donors, it is accountable to the Minister of Health.
Regulatory bodies vary around the world, but the structure of the South African authority is now closer to those of other major regulators. The decision-making power is vested in the Chief Executive Officer (CEO). The CEO can appoint a range of technical advisory committees to make recommendations to inform regulatory decisions. Members of the advisory committees are drawn from academia and private practice.
Examples of regulatory decisions include:
* Registration of a medicine or vaccine. Registration is required before a medicine can be marketed.
* Approval to conduct a clinical trial in human volunteers of an investigational vaccine.
* Approval of compassionate access to an unregistered medicine. This is done on the basis of motivation by an authorised prescriber or the Department of Health.
National medicines regulatory authorities can also be proactive. For example, they can provide advice on regulatory standards. The authorities can also engage with applicants as they develop new products. For example, regulators have communicated in advance about the targets for the efficacy of COVID-9 vaccines.
The South African authority has also contributed to global regulatory efforts. And it is doing rolling reviews of two COVID-19 vaccines (Novavax; Johnson and Johnson) and is assessing a dossier for another (Pfizer). It has also approved imports of the vaccine (Oxford/AstraZeneca) which is being manufactured in India even though it hasn't yet been registered. It's awaiting submission of a full dossier on the vaccine.
South African authority
By law, the South African Health Products Regulatory Authority is constrained to consider only three factors when it makes decisions: quality, safety and efficacy.
Quality refers to the batch-to-batch reliability of the regulated product. This takes into account how it is made, packaged and distributed. Quality must be demonstrated at the time of registration. It must also be assured throughout the lifecycle of the health product. Lifecycle refers to the entire time that a product is marketed.
Every medicine is associated with desired and undesirable effects. The safety assessment relates to the undesired, adverse effects, and whether they are proportional to the proposed use. For example, a treatment for a severe and potentially fatal disease may be associated with serious adverse effects. But, on balance they may be considered acceptable.
On the basis of safety considerations, medicines can be restricted to prescription-only access, or pharmacist-initiated sale, or placed on the market for general sale.
In some cases, a formal post-registration obligation is placed on the applicant. Examples include research on use in children. But most post-registration safety data comes from spontaneous reporting by health professionals and patients. Anything reported to the manufacturer must be reported to the regulator.
Efficacy data describe whether the medicine achieves its proposed purpose in preventing or treating a disease or symptom. The data also shows whether there are important differences in effect between patient groups. For example, it is affected by age or sex.
Importantly, there are certain things the regulator is excluded from factoring in. These include:
* the price of a medicine
* its cost-effectiveness to the health system, or
* its affordability.
This responsibility lies with the Minister of Health and a pricing committee.
The process
In the case of medicines and vaccines, the starting point for the regulator's assessment is the dossier submitted by the applicant. This is a comprehensive and exhaustive submission of the evidence of quality, safety and efficacy.
After initial screening, the elements of the common technical document are referred to specific evaluators. These are often external people, or technical advisory committee members. Their assessments, after peer review and sometimes committee deliberations, inform the eventual regulatory decisions.
The final decision to issue a certificate of marketing authorisation is accompanied by:
* specific conditions,
* approval of the professional information and patient information leaflets, and
* an approved proprietary (brand) name for the product.
Lastly, each batch of biological medicines, such as vaccines, is tested at the National Control Laboratory for Biological Products.
Many of the assessments conducted by the South African regulator may have been done by one in another country. To avoid duplication, and speed up decision-making, regulators engage in what is called "reliance". They enter into agreements to share information and co-operate in making regulatory decisions.
In a minority of applications, South Africa's regulator can "rely" on prior decisions taken by well-resourced and mature regulators, and focus its efforts only on issues that are specific to circumstances in the country.
The South African Health Products Regulatory Authority's response to COVID-19 has been questioned.
Advocates for medicines that are unregistered in South Africa have accused the body of not being proactive in bringing such products to market and approving their use. But an applicant is needed to provide a quality-assured product and to be held accountable for meeting those standards. The authority can't approve a product in the absence of an appropriate applicant.
The body has also been criticised for not conducting the necessary clinical trials to provide the needed evidence of safety and efficacy. Again, its role is to regulate such trials, not to conduct or fund them.
Meeting mandates
National medicines regulatory authorities are gatekeepers that protect the public from unnecessary harm from health products. They do so in the best tradition of the injunction to "do no harm". But in doing so, regulators must necessarily restrict the freedom to make, sell or use such products.
As prominent political scientist Daniel Carpenter described, the most powerful of these agencies, the US Food and Drug Administration
"is venerated in one corner and bemoaned in another; it is targeted for expansion by one voice, for evisceration by a second."
The South African Health Products Regulatory Authority is no less buffeted in a time of extraordinary clinical need and risk. It can only respond by being true to its mandate, transparent in its decision-making and scrupulously reliant on the scientific evidence.
Disclosure statement
Andy Gray serves on three technical advisory committees at SAHPRA and also reviews proposals for funding submitted to UNITAID. He is a member of the Pharmaceutical Society of South Africa and the International Pharmaceutical Federation.
Partners
University of Kwa-Zulu Natal
University of Kwa-Zulu Natal provides funding as a partner of The Conversation AFRICA.
The Conversation is funded by the National Research Foundation, eight universities, including the Cape Peninsula University of Technology, Rhodes University, Stellenbosch University and the Universities of Cape Town, Johannesburg, Kwa-Zulu Natal, Pretoria, and South Africa. It is hosted by the Universities of the Witwatersrand and Western Cape, the African Population and Health Research Centre and the Nigerian Academy of Science. The Bill & Melinda Gates Foundation is a Strategic Partner.