Medicines regulation and law
Substandard and falsified medicines: global and local efforts to address a growing problem
Abstract: Substandard and falsified medicines need to be acknowledged as everyone’s problem, whether on street markets in rural Africa or in illegal online pharmacies in the UK. Poor-quality medicines have a detrimental impact on health, mainly when found among antimicrobials used to treat infectious disease in high-burden populations.
Often, discussions around substandard and falsified medicines include causal factors or consequences in isolation and may be presented with regional focuses and minimal global harmonisation. There are ongoing efforts to combat substandard and falsified medicines through legislation, manufacturing practices and supply chain management, as well as detection and reporting methods. Alongside these efforts, from a social perspective, we should optimise the resourceful positioning of pharmacists in all industries, as well as public health education and engagement.
This article provides a rounded and comparative insight into substandard and falsified medicines for healthcare professionals and summarises the limitations to our knowledge and their effect on public health in high-income countries and low-to-middle-income countries.
Key words: falsified medicines; regulators; substandard medicines; supply chain.
Original submitted: 1 October 2018; Revised submitted: 17 December 2018; Accepted for publication: 14 February 2019; Published online: 8 May 2019.
Source: Alamy Stock Photo
- Substandard and falsified medicines are a global problem, and being aware of the threat is the first step in addressing this.
- Knowledge and awareness of the barriers to treating disease such as substandard and falsified antimicrobials are as vital as the cure.
- Implementing the consistent use of the new terminology for substandard and falsified medicines would improve measurements of trends, root cause analysis, coherent literature and global harmonisation.
- Educating healthcare professionals, especially pharmacists, around medicine quality, needs to be implemented initially during university studies, and built on during post-graduate years as part of continuing professional development.
- An approach to overcoming substandard and falsified medicines should reflect the problems encountered in different regions. This further emphasises that no ‘one size fits all’ approach can be used to tackle this issue effectively.
- More comprehensive insight is needed, relative to regions and economic status to determine the best approach to tackle this global problem in a localised manner.
Unsafe medicines reach patients when there are breaches in regulation, legislation and monitoring, and can be obtained from illegal online pharmacies to street markets in rural Africa. Substandard and falsified medicines commonly reported in high-income countries (HICs) include novel medicines, such as hormones, steroids, and supplements, while low-to-middle-income countries (LMICs) have become targets of substandard and falsified antimicrobials, essential for the treatment of life-threatening diseases, such as malaria, tuberculosis, HIV and AIDS.
With the introduction of the Falsified Medicines Directive (FMD) in February 2019, pharmacists and healthcare professionals need to understand how substandard and falsified medicines affect pharmacy practice and their detrimental effects on global health.
In response to the global threat posed by substandard and falsified medicines, the 70th World Health Assembly introduced new terminology and definitions for the category of ‘substandard/spurious/falsely-labelled/falsified/counterfeit’ (SSFFC). The new terms ‘substandard’, ‘falsified’ and ‘unregistered medicines’ were proposed to exclude ‘counterfeit medicines’ (the infringement of intellectual property) from the category. The introduction of global standardised definitions can be considered a crucial step towards developing and advocating interventions to combat substandard and falsified medicines.
The World Health Organization (WHO) defines a substandard medicine as an authorised medical product that does not meet quality standards or specifications, produced by a known manufacturer with no intent to fool or defraud the patient. Substandard medicines enter the legitimate supply chain and reach patients when the technical capacity to enforce good manufacturing practices (GMP) and good distribution practices (GDP) is limited.
The WHO defines a falsified medicine as a medical product that is deliberately and fraudulently mislabelled concerning identity and source. Falsified medicines are produced in unsanitary and unregulated conditions by an unknown manufacturer. They can contain incorrect quantities of the active pharmaceutical ingredient (API), inert ingredients and dangerous contaminants. The packaging of falsified medicines is nearly always identical to the original medicine, making it challenging to identify without running a series of detection tests on the contents of the medicine.
Substandard and falsified antimicrobials
One major area of concern is the growing number of substandard and falsified antimicrobials. The WHO Global Surveillance and Monitoring System reported that 42% of the 1,500 cases of substandard and falsified medical products reported between 2013 and 2017 were from the Africa region. Antibiotics and antimalarials were most commonly reported, representing around 36% of all the products reported by member states.
The presence of poor-quality antimicrobials on the market poses a considerable risk in areas where malaria is often endemic and is the leading cause of childhood mortality. In Africa, the WHO estimates that up to 169,000 children die each year from pneumonia and up to 158,000 children die from malaria owing to the administration of substandard and falsified antimicrobials, although it is difficult to determine whether disease progression or deaths have a direct link to the administration of a substandard or falsified antimicrobial.
Substandard antimicrobials have a reduced antimicrobial potency (owing to API degradation), altered antimicrobial bio-availability (owing to excipient degradation) or poor formulation (e.g. the antibiotic tetracycline is often found to be substandard owing to enhanced chemical degradation resulting from poor storage conditions in tropical climates).
Falsified antimicrobials have been found to contain poisonous or toxic ingredients, but most commonly they are found to be inert, containing ingredients such as chalk, flour or talc; consequently, they show no therapeutic effect. They can also contain ingredients that mask the clinical symptoms of the infectious disease. For example, one study reported the detection of falsified artemisinin, an antimalarial that only contained paracetamol. In this study, after administration of falsified artemisinin, patients presented with a reduced fever, suggesting successful treatment; in reality, it was a short-term symptom relief from paracetamol. This delayed treatment may lead to disease progression and, in some cases, death.
A sub-therapeutic dose of an antimicrobial will selectively kill susceptible strains, reducing reproductive competition and allowing more resistant strains to multiply, thus contributing to the development of antimicrobial resistance (AMR). For healthcare professionals in HICs, it is often understood that causes of AMR often relate to patient adherence to treatment and the over-prescribing of antimicrobials. Recent focus on antibiotic prescribing practices and increasing the public’s awareness of AMR have been undertaken to reduce the burden of infections with resistant bacteria. However, poor-quality medicines and dangerous prescribing behaviour undermines efforts to promote antimicrobial stewardship, creating increased pressure on newer and more expensive classes of antimicrobials. The presence of substandard and falsified antimicrobials is a growing societal problem, where individual harm leads to harming others, which in turn contributes to further complications and the development of multidrug-resistant infections, such as tuberculosis (TB).
Limitations to our understanding of the problem
Under-reporting of incidence
The importance of collecting reliable and robust data around substandard and falsified medicines should not be understated. Data collection contributes to the determination of high-risk medicines, affected geographical regions and vulnerable patient populations, as well as the measurement of patterns in drug resistance and the impact of substandard and falsified medicines on patient morbidity and mortality. Part of the difficulty of reporting and data collection is the lack of consensus and ambiguity around the definitions for SSFFC, which are often subject to different interpretations, leading to variations in recorded numbers.
Coverage of substandard and falsified medicines in the media and literature tends to be sporadic and accumulates after a “major events”, such as the seizing of £12m worth of counterfeit medicines in the UK. In turn, it has become a grey area within the literature as a vast number of occurrences are unaccounted for and many events go unreported. The WHO reported that estimates of prevalence are likely to represent only a small fraction of the total problem as many cases may be going unreported,. Inaccurate estimations neglect the magnitude of the global burden and hold back international cooperation and public discourse.
Poor detection methods
Making sure that suitable detection technologies are available to healthcare professionals and pharmaceutical companies is a huge challenge. When selecting the most appropriate technique for detecting substandard and falsified medicines, it is important to consider the purpose of testing; whether it is for regulatory or healthcare bodies, and where the testing site will be (where further considerations include consistent electrical supply and staff training). For example, sophisticated laboratory equipment that requires a high level of technical expertise (e.g. gas chromatography) will not be appropriate in all settings, such as a LMIC or location where there is no access to electricity; in this instance, a portable device that requires little training (e.g. paper chromatography test cards) might be more suitable.
Efficient detection technologies improve detection rates; minimise the entry of poor-quality medicines into the community; and curtail the trade in falsified and substandard medicines. In addition, the use of efficient detection methods can help generate accurate estimates of the magnitude of the problem and improve incident reporting. However, it must be accepted that ultimately, no detection technology can replace stringent medicine regulation in the fight against substandard and falsified medicines.
Lack of global harmonisation
The problem of substandard and falsified medicines is not limited to LMICs alone; it should be recognised as a worldwide phenomenon that has spread to highly regulated countries. Stronger collaborative forces are needed between national medicine regulatory authorities, along with the WHO and non-governmental organisations, to effectively prevent the production and spread of falsified medicines.
One limitation to global harmonisation is that policies based on medicine quality and access to medicines are decided upon by HICs, which take time to filter down to where they have most impact: LMICs. When introducing legislation or guidance on a policy level, outcomes are often not applicable to LMICs and are challenging to implement in these countries. One example is the WHO Good Manufacturing Practices certification, which is primarily used in LMICs. These guidelines are often adjusted to fit local conditions and their implementation is challenging because the strict enforcement of the guidance might lead to significant barriers to the growth of domestic companies.
Preventative measures taken against substandard and falsified medicines cannot be implemented by one organisation or one country working alone. For example, Rwanda has been successful in reducing falsified products in its supply chain by prohibiting the sale of TB and malaria therapies in private sectors, and instead bringing them into the publicly funded health system. However, the maintenance of this is dependent on regional co-operation. The lack of co-operation between neighbouring countries hinders the effectiveness of the policies Rwanda has set in place. In attempts to overcome this, a regional law against falsified medicines is being created for member states in East Africa, particularly advocating the need for adjusting to the definitions distinguishing between generic and falsified medicines.
Although substandard and falsified medicines are a more significant problem in LMICs, their presence is not limited to countries with poor regulatory controls or weak pharmaceutical governance; these medicines have infiltrated medicine supply chains in countries of all economic levels. In April 2014, the European Medicines Agency published a warning for nine batches of trastuzumab vials stolen from Italian hospitals that later appeared in Finland, Germany and the UK. These vials had been intentionally compromised so that the API was absent or diluted and/or vial integrity was damaged causing a loss of sterility.
In addition to this, the instances of EU customs seizing falsified medicines are increasing. In the UK alone, there were 15 known incidents reported from 2005 to 2011, 7 of which were seized before reaching patients. Nine were recalled, but the proportion of those medicines actually returned is unknown; it is thought that over 500,000 medicine packs remained in the hands of patients in one incident alone.
A prevailing view among healthcare professionals in HICs is that substandard and falsified medicines are not a problem that affects them directly, even though there is evidence to suggest otherwise. This “dissociated approach” may be a result of little or no exposure to the problem in their workplace or their time in education. This results in a reduced perceived need to learn and promote awareness among colleagues and the public.
Other misconceptions about falsified medicines are that they only present as novel medicines, such as Viagra (Pfizer, UK), steroids or supplements,. The presence of falsified medicines on the market is dependent on demand for it. By comparison, substandard medicines are bound by manufacturing and storage practices. It is essential for healthcare professionals to acknowledge how medicines become substandard, perhaps owing to the inadequate storage of fridge items, dispensing expired medicines or using medicine compliance trays.
Preventing substandard and falsified medicines
Before discussing methods to prevent substandard and falsified medicines entering the supply chain, we need to acknowledge the difference between them regarding causal factors, which in turn affects how these problems are resolved.
On a national and global scale, the previous lack of standardised definitions concerning poor-quality medicines posed problems regarding legislation, policy-making and prosecution. The previously used term, ‘counterfeit medicine’, refers legally to a product that infringes on a registered trademark or intellectual property; the definition does not protect or serve health. However, generally speaking, counterfeit medicines were commonly associated with poor-quality medicines or medicines made with intentional deceit. It is hoped that the introduction of the new terms by the WHO will lead to a standardisation of definitions across the legislative bodies, to allow for more robust prosecutions that may have been previously restricted by loopholes in the system.
Most HICs have strict laws in place concerning the manufacturing, supply, distribution and dispensing of medicines, making it less likely that substandard medicines are produced or that falsified medicines penetrate the supply chain. Unfortunately, when looking at LMICs, a sufficient healthcare system is not in place; instead, they have weak regulatory bodies that cannot cope with the burden of poor-quality medicines. Illegal organisations will gravitate towards countries where these systems are the weakest.
Current regulatory and legislative leniency in LMICs is likely to be a function of outdated laws; these require updating with more stringent prosecution methods and stricter penalties. To be able to introduce new laws and enforce penalties, more robust medicine regulations, surveillance and law enforcement need to be implemented.
Legislation should effectively manage the risks to patients, while simultaneously promoting access to affordable medicines, and stimulating innovation in new and better products relative to each country.
Good manufacturing practice and good distribution practice
GMP is defined as the minimum standard that a medicines manufacturer must meet in their production processes. GDP highlights that medicines are to be obtained from the licensed supply chain and are consistently stored, transported and handled under suitable conditions.
When such practices are compromised, the production of substandard medicines is more likely to occur. The pharmaceutical industry in LMICs face many challenges including limited access to finance and skilled human resources; local production is therefore often blamed for the manufacture of “substandard medicines”. Some argue that local production should not be underestimated when performed ethically. If stricter guidelines were set and implemented by overseeing organisations such as the WHO, it could result in driving up the cost of medicines and deterring local production. Instead, other more realistic approaches should be taken, such as managing storage conditions and monitoring medicines expiry. Falsified medicines do not meet GMP and GDP requirements as they have not passed through the appropriate quality, safety and efficacy checks.
Supply chain regulation and reporting methods
The Global Surveillance and Monitoring System is available for use by National Regulatory Authorities of member states and international procurement agencies. Reports of substandard and falsified medicines can be submitted via an electronic rapid alert form. Alerts are then distributed worldwide, promoting better prevention, detection and response to substandard and falsified medicines, which protects public health. The system allows for the collection of accurate data concerning possible substandard and falsified medicines, and more accurately assesses the scope, scale and harm caused by substandard and falsified medical products.
In Nigeria — a LMIC — there are more than 200 registered pharmaceutical companies, unlike other African LMICs, where there are none. Similarly, there is a wide divergence in the level of regulatory oversight among these countries. A WHO survey of 26 African countries found that many regulatory authorities could not fulfil the essential functions required for the adequate protection of the public.
As previously discussed, the problem of falsified medicines is not limited to LMICs and has become widespread: the WHO estimates that less than 1% of sales in HICs are counterfeit. With around 2 billion items dispensed each year in the UK, falsified medicines could represent up to 200,000 medicine packs. In addition, the Medicines and Healthcare products Regulatory Agency (MHRA) seized 6.2 million medicine doses and medical devices worth £15.8m in 2015.
The Falsified Medicines Directive
In attempts to combat the global problem, the EU has introduced the FMD, which came into force in February 2019 as a form of supply chain management that aims to eliminate the entry of falsified medicines into the supply chain. The EU commission describes a falsified medicine as “often disguised as authentic medicines but may contain ingredients of harmful or toxic quality, or in the wrong dosage”.
The original directive, which was published in 2011, suggested the need to introduce a definition of “falsified medicinal product” to distinguish these from medical products with unintentional quality defects resulting from manufacturing or distribution errors (“substandard”) and from products infringing intellectual property rights. However, this has not been addressed and the EU commission is yet to adopt the definitions set by the WHO.
The FMD requires all medicines sold in the EU to have tamper-evident features on the pack and a unique identifier (a 2D data matrix code) that will be scanned at fixed points along the supply chain. Users will be able to scan medicine packages to a National Medicines Verification System, which will alert them with the current status of the product.
The introduction of the FMD has raised many questions, particularly in hospital settings, such as who will be scanning the barcode to decommission — the pharmacist on supplying the medicine or a nurse on administrating it? Other questions involve providing stock without verification in emergencies and dealing with returned medicines. More information concerning the frequently asked questions in secondary care services and the FMD can be found on the Specialist Pharmacy Service website. More recently, the MHRA announced that regulations coming into force as part of the FMD would not apply to the UK if it leaves the EU without a deal, which was still undecided at the time this article was published. This may halt progress towards eliminating falsified medicines; however, there is still hope as the Department of Health and Social Care suggests it would be reasonable to create a UK version of the FMD.
Pharmacy professionals must use and stay up to date with reporting methods; one example discussed is the Global Surveillance and Monitoring System. The Yellow Card Scheme run by the MHRA in the UK can also be used to report suspected falsified medicines.
Healthcare professional awareness and education
The introduction of the FMD has created a shift towards educating pharmacy professionals on the global issue of falsified medicines. Previous guidance on the topic published by the Royal Electronicjuice and the MHRA discussed the causes and consequences of counterfeiting, providing pharmacists with practical advice on detecting and reporting suspected counterfeit medicines. However, resources like these will need to be updated to incorporate the more recent terms of substandard and falsified medicines. The National Pharmacy Association has created a brief guide to FMD, a checklist for compliance and template standard operating procedures (SOPs), to provide support for its members during this transitional phase.
Although the FMD is widely applicable to many HICs, it is limited in its applicability to other regions; it will not be feasible to introduce in African and Asian LMICs owing to the limited use of technology, lack of infrastructure and regulatory support. In these situations, regulating and optimising the role of pharmacists can curtail the sale of poor-quality medicines; falsified medicines enter the legitimate supply chain and circulate through inadequate supervision of the supply and distribution network. Healthcare settings lacking professional training and monitoring are the most vulnerable to substandard and falsified medicines. In LMICs like India, Egypt and sub-Saharan Africa, community pharmacies do not require a pharmacist to be on the premises; instead, it is usually run by counter assistants.
Patient and public awareness
What is often neglected in the debate of substandard and falsified medicines is the loss of the public’s confidence in healthcare systems as a result of treatment failure. Poor-quality medicines further undermine already weak confidence in public health, especially in many African LMICs. Victims of substandard or falsified medicines are usually unaware; instead, they assume they are not responding well to the treatment, creating mistrust in pharmacies and medicines.
Over the past few years, there has been an increase in the number of people using the internet to self-diagnose and self-prescribe. Initially, online sales of medicines included novel medicines. However, it is now more often prescription-only medicines, such as antibiotics and cardiovascular medicines.
Patients need to be aware that medicines obtained through unregulated online pharmacies may not be subjected to the normal controls on manufacture and may not be of suitable quality or may even be falsified. The probability of obtaining fake or substandard medicines is significantly increased when the standard, regulated system is bypassed.
Studies show that there has been an increase in public awareness of the existence of substandard and falsified medicines and this proves to be an effective prevention method in HICs. A survey conducted by the EU Alliance for Safe Online Pharmacy explored consumers’ perceptions of online pharmacies and showed promising results. It was found that a 70% change in consumers’ attitudes towards online pharmacies when associated with falsified medicines, deterring them from purchasing medicines online. Patients should be advised to avoid self prescribing, and the importance of seeing a pharmacist or GP should be emphasised to promote the regulated and safe administration of medicines.
Combatting substandard and falsified medicines falls under the United Nations Sustainable Development Goals, which strive for access to safe, effective, quality and affordable essential medicines. However, this goal seems to be unachievable in the near future, especially in LMICs, owing to limitations posed by several contributing factors. An active movement to reduce the harm that substandard and falsified medicines pose should aim to engage and encourage collaboration among all stakeholders. The International Federation of Pharmaceutical Manufacturers and Associations places raising awareness at the centre of the movement, which should be supported by technology/product protection and a robust regulatory framework.
Financial and conflicts of interests disclosure
The author has no relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. No writing assistance was used in the production of this manuscript.
Citation: Clinical Pharmacist DOI: 10.1211/CP.2019.20206309
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