The silent epidemic of substandard and falsified medicines in low- and middle-income countries: heed lessons from the tragic deaths of children in Indonesia

Dear Editor,

‘There is no universal health coverage (UHC), no health security without access to quality medicine’ said Tedros Adhanom Ghebreyesus, WHO’s Director-General. Substandard and falsified medical products (SFMPs) are a global public health scourge – especially in low- and middle-income countries (LMICs) – that affects patients and their families, ruins public interest in health systems, and impacts economic growth. The regional prevalence was estimated to be 18.7% in Africa and 13.7% in Asia1. The heart-wrenching deaths of at least 195 children due to substandard (contaminated) cough and fever syrups in Indonesia is a ‘human disaster’2. Further probing revealed that the deaths occurred due to acute kidney injury caused by the consumption of syrups tainted with ethylene glycols [(mono)ethylene glycol (EG) and diethylene glycol (DEG)]. Reportedly, unacceptable levels of EG/DEG were found in the syrups/drops identified in the recent Indonesian tragedy2. Of note, the United States Pharmacopoeia allows only up to 0.2% of the sum of EG and DEG in polyethylene glycols – an additive used to enhance drug solubility. The European Pharmacopoeia allows only up to 0.1% of DEG in glycerol and 0.4% of the sum of EG and DEG in polyethylene glycols. But there is no such specification for EG/DEG limit in the Indonesian Pharmacopoeia.

HIGHLIGHTS

• The menace of substandard and falsified medical products (SFMPs) is an often overlooked, “silent” epidemic in low- and middle-income countries.

• Substandard syrups tainted with ethylene glycols (mono/diethylene glycols) have claimed the lives of about 195 children in Indonesia.

• Extending the political will into action is highly critical for devising a pragmatic and reliable approach to combat the SFMPs problem.

The incidence of pediatric deaths caused by mass poisoning due to EG/DEG has occurred in several countries including the USA, Bangladesh, Haiti, India, Nigeria, etc.3. It is worth mentioning that the Elixir Sulfanilamide disaster of 1937, the world’s first documented incident of mass poisoning by DEG (which claimed 107 American lives), was an eye-opener for US regulators and this bitter experience was the foundation stone for the enactment of the 1938 Federal Food, Drug, and Cosmetic Act, which required proof of safety before marketing a pharmaceutical product. But a more agonizing concern is that even after several EG/DEG mass poisoning catastrophes spanning more than eight decades, LMICs are still grappling with such events due to SFMPs. Hence, the current Indonesian calamity should be considered the cornerstone to drawing appropriate regulations and enforcing them effectively.

Our lament begs the question, ‘What can we do about it?’ We must foster a deeper understanding of the causes and devise appropriate strategies to prevent, detect, and respond to such tragic events. In 2017, the WHO listed various causal factors underpinning the manufacturing and trade of SFMPs and recommended steps to combat this menace4. Accordingly, the factors driving the production and circulation of SFMPs are grouped into three comprehensive categories: constrained access to quality medicines, fragile governance, and limited technical capacity. However, recent seminal research published by Pisani et al. 5 proposed that, in addition to these immediate drivers listed by the WHO, specific political and economic factors must be considered to limit the production, circulation, and consumption of SFMPs in middle-income countries.

Indonesia is a lower-middle-income country with the world’s fourth-largest population currently marching toward UHC. The swift but underfunded scale-up of national health insurance to accomplish UHC, compounded by medicine procurement and reimbursement reforms, political and economic policies, have a negative impact on the profits of pharmaceutical companies, distributors, and healthcare providers6. Squeezed profits drive them to produce poor-quality medicines. In this viewpoint, we discuss the learnings and future implications of the current tragedy to effectively forestall and manage such catastrophic events.

Using cost-effective, rapid, reliable, and simple methods like Fourier transform infrared and near-infrared spectroscopic techniques over expensive gas chromatographic techniques could be preferred to boost widespread testing. Postdeployment support systems for testing equipment, funded training and refreshment programs, and subsidization for micro, small, and medium-scale enterprise (MSME) pharmaceuticals are the strategies that encourage regular testing.

Recently, a lawsuit was filed by the Indonesian Consumer Organization against the Indonesian regulatory body, the Food and Drug Monitoring Agency (BPOM) for allegedly misleading the public about tainted-cough syrups on various grounds: lack of rigorous quality testing of syrups, weak surveillance of substandard syrups, and the delegation of obligatory quality testing to the pharmaceutical companies itself7. In a House of Representatives (DPR) Hearing, Penny K. Lukito, Head of the BPOM said that ‘PG and PEG are not entered through the BPOM but through the Ministry of Trade. Therefore, it’s not through BPOM’s import certification.’ Hence, improving the surveillance of imported goods used as pharmaceutical raw materials, streamlining inconsistent or inappropriate labeling of excipients sourced from different manufacturers (e.g. labeling industrial-grade glycerin as pharmaceutical grade), and expanding access to affordable quality testing points are obligatory.

Although there is inexorable growth of e-pharmacies in Indonesia, only a dozen (out of thousands) online pharmacies possess an online license, while others are illegal e-stores with a high potential to sell SFMPs. Besides, there is no government-approved pharmacy on any popular e-commerce platform. Consumers consider online pharmacies safe and fall prey to apps not approved by Indonesia’s food and drug authority. In addition, queues, administrative difficulties, and distrusted medicine quality at the puskesmas (government-run clinics) compound the problem of purchasing SFMPs from unapproved online pharmacies. Hence, a significant overhaul of the digital regulatory framework is critical.

Proposals to collaborate with the United Nations International Children’s Emergency Fund (UNICEF) and other such children welfare-focused global bodies – could offer financial support and incentives to encourage the manufacturers of pediatric medical products to implement global standards in terms of Good Manufacturing Practice (GMP). Indonesia was not proactive and hence obtained the antidote (fomepizole) from Singapore and Australia due to the lack of adequate stock within the country. A recent publication based on the current exploratory work in the Indonesian market proposed a proactive approach to target four sentinel groups of substandard medical products: irrationally cheap essential medicines, contract-manufactured medicines, poor regulatory history, technically vulnerable products (which require high investment in quality assurance)8. The lack of proactive measures in this milieu is a setback for preventing, detecting, and timely managing mass poisoning.

As the Lancet Commission on Essential Medicines emphasized, any aspiring country should understand that it is impossible to accomplish UHC with poor-quality medicines9. Harnessing the power of digital technologies not only helps in the rapid and effective tracking and tracing of medical products, but they could be a valuable tool for prompt recalls, identification and management of outbreak hotspots. Particularly blockchain technology – through secured interfacing with other cutting-edge technologies like Internet-of-Things (IoT), cloud computing, artificial intelligence (AI), Radio Frequency Identification (RFID), Global Positioning System (GPS), and others – provide multilayered security, real-time information and lend well to effective provenance, track and trace solutions to tackle the SFMPs scourge.

Although mass poisoning due to EG/DEG is an uncommon epidemic, it is not sporadic and could happen again until Indonesia, or other LMICs learn from the history and this current catastrophe. We opine that, in addition to the factors outlined by the WHO and research groups4–6,8, scale-up of laboratory resources, creating a robust regulatory framework (especially pertinent to the digital platforms), increasing the funding capacity through collaborations, developing proactive action plans, and espousal of advanced track and trace technologies are critical to change the bleak outlook on the regulatory system of Indonesia and other LMICs. Above all, extending the political will into action is the key to curbing the prevalence of SFMPs and the associated tragic outbreaks in these countries.

Ethical approval

Not applicable.

Sources of funding

None.

Authors’ contribution

A.S.M.S., B.K.P., A.M., S.S., and R.S. conceived, drafted, critically reviewed, and approved the final manuscript.

Conflicts of interest disclosure

The authors declare that they have no financial conflict of interest with regard to the content of this report.

Research registration unique identifying number (UIN)

None.

Guarantor

ArunSundar MohanaSundaram.