Essential Medicines

Essential medicines are defined by the World Health Organization (WHO) as those pharmacological agents, biologics, and vaccines that satisfy the priority healthcare needs of a population, selected with due regard to disease prevalence, rigorous epidemiology and clinical trial evidence of efficacy and safety, and comparative cost-effectiveness. Within public health and universal health coverage systems, essential medicines are intended to be available within functioning healthcare facilities at all times, in appropriate dosage forms, of assured pharmaceutical quality, and at a price that both the individual patient and the public health budget can afford.

Pioneered under WHO Director-General Halfdan Mahler and adopted in October 1977 with the publication of the first WHO Model List of Essential Drugs (containing 208 active substances), the essential medicines paradigm transformed global pharmacology. Rather than leaving national hospital formularies to unregulated commercial marketing of thousands of duplicative brand-name products of variable efficacy, the WHO Model List established an evidence-based methodology—updated every two years by an independent Expert Committee—to guide national procurement, supply-chain logistics, and health equity.

The Core List vs. The Complementary List and the Square Box Symbol

Since 2007, the WHO has published both the Model List of Essential Medicines (EML) for adults and a dedicated Model List of Essential Medicines for Children (EMLc) tailored to pediatric pharmacokinetics, dispersible oral tablet formulations, and child weight bands to reduce infant mortality. Every biennial edition of the WHO EML partitions approved therapeutic agents into two structural tiers:

1. The Core List: Presents a list of minimum medicine needs for a basic healthcare system, listing the most efficacious, safe, and cost-effective medicines for priority conditions. Priority conditions are selected on the basis of current and estimated future public health relevance (such as maternal mortality from postpartum hemorrhage, malaria, tuberculosis, HIV/AIDS, cardiovascular disease, diabetes, and priority cancers) and the potential for safe and cost-effective treatment in primary and secondary facilities.
2. The Complementary List: Presents essential medicines for priority diseases for which specialized diagnostic or monitoring facilities, specialist medical care, or specialist clinical training are required (such as targeted monoclonal antibodies, cytotoxic antineoplastics, or reserve-line anti-tuberculosis drugs for multidrug-resistant tuberculosis). In case of doubt, medicines may also be listed on the Complementary List on the basis of consistently higher cost or less attractive cost-effectiveness in specific settings.
3. The Square Box Symbol (▢) and Therapeutic Equivalence: Throughout the WHO EML, a square box symbol (▢) preceding an International Nonproprietary Name (INN, or generic chemical name) indicates that the listed drug is a representative example of a pharmacological class within which multiple drugs exhibit comparable clinical efficacy and safety (for instance, ▢ enalapril representing angiotensin-converting enzyme [ACE] inhibitors, or ▢ simvastatin representing HMG-CoA reductase statins). National formulary committees use the square box rule to invite competitive generic tenders across all therapeutically equivalent molecules in that class, driving down procurement costs.

Evidence-Based Selection Criteria and Evolution from Cost to Clinical Effectiveness

During the initial decades of the EML (1977–1999), low unit acquisition cost was often treated as a precondition for inclusion. However, during the global HIV/AIDS crisis of the late 1990s and early 2000s, high patent prices initially excluded life-saving triple antiretroviral therapy (ART) from resource-limited formularies. In 2002, the WHO revised its methodological charter: absolute unit price is never a reason to exclude a medicine from the Model List if it meets the criteria of public health relevance, clinical efficacy, and comparative cost-effectiveness within its therapeutic class. Instead, listing a high-cost patented medicine (such as HIV antiretrovirals in 2002, direct-acting antivirals like sofosbuvir/velpatasvir for hepatitis C in 2015, or PD-1 immune checkpoint inhibitors and long-acting GLP-1 receptor agonists in the 2020s) serves as a global regulatory catalyst to trigger generic licensing, pooled procurement, and price reductions.

Access, Watch, and Reserve Tiers to Curb Antimicrobial Resistance

To combat the global rise of multidrug-resistant bacteria driven by horizontal gene transfer of beta-lactamases and carbapenemases, the WHO Expert Committee introduced the AWaRe (Access, Watch, Reserve) Classification inside the 2017 revision of the Essential Medicines List as a quantitative cornerstone of global antimicrobial stewardship:

By tracking the ratio of Access-to-Watch consumption via Defined Daily Doses (DDDs) per 1,000 inhabitants per day, national ministries of health detect inappropriate empirical overprescribing of broad-spectrum Watch antibiotics (such as oral fluoroquinolones and third-generation cephalosporins for viral upper respiratory infections) that select for extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae.

The Doha Declaration (2001), Compulsory Licensing, and the Medicines Patent Pool

When the World Trade Organization (WTO) Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) took effect in 1995, it mandated minimum 20-year pharmaceutical product and process patents across signatory nations, restricting the ability of generic manufacturers (notably in India and Brazil) to reverse-engineer patented medicines. At that time, triple antiretroviral therapy for HIV cost more than 10,000 USD per patient per year, placing treatment out of reach across sub-Saharan Africa.

In response, WTO member states adopted the Doha Declaration on the TRIPS Agreement and Public Health (November 2001), affirming that the TRIPS Agreement "can and should be interpreted and implemented in a manner supportive of WTO members' right to protect public health and, in particular, to promote access to medicines for all." The Doha Declaration codified three legal TRIPS flexibilities:

• Compulsory Licensing (TRIPS Article 31 and Article 31*bis*): Authorizes a national government to license a domestic generic manufacturer (or import from an foreign generic producer under Article 31*bis*) to produce a patented essential medicine without the consent of the patent holder in exchange for a reasonable royalty, including fast-track issuance during public health emergencies.
• Parallel Importation (Exhaustion of Rights, TRIPS Article 6): Permits a nation to import a patented pharmaceutical product from another country where the patent holder markets it at a lower tiered price, without requiring the patent holder's authorization.
• Rigorous Patentability Standards and Bolar Exceptions: Allows generic manufacturers to conduct bioequivalence studies and submit regulatory dossiers to national drug authorities (and the WHO Prequalification of Medicines Programme, established in 2001) prior to patent expiration so that quality-assured generics launch on the day a patent expires, while barring "evergreening" patents on minor salt or polymorph variations lacking enhanced therapeutic efficacy.

To complement compulsory licensing with collaborative voluntary technology transfer, Unitaid founded the Medicines Patent Pool (MPP) in 2010. Through the MPP, originator pharmaceutical companies voluntarily license patents on essential medicines—such as dolutegravir (HIV), glecaprevir/pibrentasvir and sofosbuvir (hepatitis C), and nirmatrelvir/ritonavir—into a central pool that sub-licenses multiple generic manufacturers across low- and middle-income countries (LMICs). Combined with pooled procurement through the Global Fund, PEPFAR, and UNICEF (supported by cold chain distribution and heat-stable formulations like oral rehydration therapy co-packaged with zinc), competition among WHO-prequalified generic suppliers reduced the annual cost of first-line HIV antiretroviral therapy (tenofovir + lamivudine + dolutegravir, TLD) from over 10,000 USD per year to under 45 USD per patient per year, averting more than 20 million premature deaths and tens of millions of years of potential life lost.

1. World Health Organization (1977). The Selection of Essential Drugs: Report of a WHO Expert Committee (WHO Technical Report Series, No. 615). Geneva: World Health Organization. https://iris.who.int/handle/10665/41272
2. Laing, R., Waning, B., Gray, A., Ford, N., & 't Hoen, E. (2003). "25 years of the WHO essential medicines lists: progress and challenges." The Lancet, 361(9370), 1723–1729. https://doi.org/10.1016/S0140-6736(03)13375-213375-2)
3. Sharland, M., Pulcini, C., Harbarth, S., Zeng, M., Gandra, S., Mathur, S., & Magrini, N. (2018). "Classifying antibiotics in the WHO Essential Medicines List for optimal use—be AWaRe." The Lancet Infectious Diseases, 18(1), 18–20. https://doi.org/10.1016/S1473-3099(17)30724-730724-7)
4. Wirtz, V. J., Hogerzeil, H. V., Gray, A. L., Bigdeli, M., de Joncheere, C. P., Ewen, M. A., Gyansa-Lutterodt, M., Jing, S., Luiza, V. L., Mbindyo, R. M., Möller, H., Moucheraud, C., Pécoul, B., Rägo, L., Rashidian, A., Ross-Degnan, D., Stephens, P. N., Teerawattananon, Y., 't Hoen, E. F., Wagner, A. K., Yadav, P., & Reich, M. R. (2017). "Essential medicines for universal health coverage." The Lancet, 389(10067), 403–476. https://doi.org/10.1016/S0140-6736(16)31599-931599-9)
5. 't Hoen, E., Berger, J., Calmy, A., & Moon, S. (2011). "Driving a decade of change: HIV/AIDS, patents and access to medicines for all." Journal of the International AIDS Society, 14, 15. https://doi.org/10.1186/1758-2652-14-15