WHO shapes priorities for medicines? An analysis of the applicants and decision makers within the historical evolution of the WHO Model Lists of Essential Medicines.

WHO recently announced a process to review and potentially update the procedures for selecting essential medicines. This announcement presents an opportunity to reflect on the evolution of the WHO Model Lists of Essential Medicines (EML), including the composition of the stakeholders that shape priorities. We contextualised our findings within the broader history of the WHO EML to support future reforms to improve access to essential medicines. The current system allows individuals to propose a medicine for the WHO EML. This makes the EML reactive to applicant priorities. Almost all medicines (687/700; 98·1%) proposed to the WHO EML between 2003 and 2023 came from applicants in high-income countries. Most applications (210/700; 30·0%) were submitted by universities and research institutions, followed by non-governmental organisations (159/700; 22·7%), the UN system (158/700; 22·6%), professional associations (98/700; 14·0%), and the pharmaceutical industry (75/700; 10·7%). Between 1977 and 2023, over half of the Expert Committee members were from low-income and middle-income countries, with an increasing proportion in recent EML updates. Mainly, UN agencies acted as observers between 1977 and 2023. One central question emerges when evaluating whether applicants' geographical distribution translates to the WHO EML's intended purpose: for whom is the EML intended? Over the years, the geographical applicability has blurred. Defining a strategic vision for the WHO EML, including articulating a target audience and structured selection process, would strengthen decision-making processes by providing additional clarity, including to those implementing the guidance, mostly in low-income and middle-income countries.

Regulatory Review Duration and Differences in Submission Times of Drugs in the United States and Europe, 2011 to 2020.

The speed of drug regulatory agencies in the United States and Europe is often a source of discussion. The objective of this research was to assess regulatory review duration of first and supplementary indications approved between 2011 and 2020 in the United States and Europe (European Union [EU] and Switzerland) and differences in submission times between the United States and Europe. Descriptive statistics were applied to review times between the jurisdictions and across the therapeutic areas. A regression analysis was done to estimate the association between approval agency and review times. The primary analysis cohort included 241 drugs approved in the United States, the EU, and Switzerland. Of these, 128 drugs had supplemental indications (331 in total) in the United States and 87 had supplemental indications (206 in total) in the EU. Overall median review duration from submission to approval subtracting the clock stop period was 39 weeks in the United States, 44 weeks in the EU, and 44 weeks in Switzerland. When review times within each drug were compared, the European Medicines Agency took a median of 3.7 weeks (IQR, -6.7 to 14.9 weeks) longer than the U.S. Food and Drug Administration and Swissmedic a median of 0.3 weeks (IQR, -10.6 to 15.3 weeks) longer. Median total review duration for supplemental indications was 26 weeks in the United States and 40 weeks in the EU. Applications were submitted a median of 1.3 and 17.9 weeks later in the EU and Switzerland, respectively, than in the United States. The regression analysis showed small differences in submission times between the United States and the EU (-2.1 weeks [95% CI, -11.7 to 7.6 weeks]) and larger differences between the United States and Switzerland (33.0 weeks [CI, 23.1 to 42.8 weeks]). It would be beneficial for patients if differences in submission times between the United States and Europe continue to be minimized.

Approval and therapeutic value of gene therapies in the US and Europe.

Gene therapies are a fast-growing area of innovation and hold promise for the treatment of many diseases currently with unmet medical need. To better understand the clinical importance of the current landscape of approved gene therapies, we conducted a systematic analysis of the approved gene therapies and their added therapeutic value. Through December 2022, 13 gene therapies have been approved in the US, 15 in the EU, and 9 in Switzerland. Nine gene therapies have been approved in all three jurisdictions, and 11 in both the US and EU. Among the 11 gene therapies approved in more than one jurisdiction, there were differences in the approved indications among the regulatory agencies, mostly the European drug agencies (EMA and Swissmedic) being more restrictive. Among the gene therapies with available therapeutic ratings, approximately two-thirds had high added therapeutic value, which is substantially higher than the average prevalence of high added therapeutic value ratings among new drugs and biologics (approximately one-third). However, therapies with high added therapeutic value will not be useful for patients if excessive prices limit access to them. Drug pricing reforms should address gene therapies to ensure access to new gene therapies that can offer important therapeutic value to patients.

Defining 'therapeutic value' of medicines: a scoping review.

OBJECTIVES: In recent years, discussions on the importance and scope of therapeutic value of new medicines have intensified, stimulated by the increase of prices and number of medicines entering the market. This study aims to perform a scoping review identifying factors contributing to the definition of the therapeutic value of medicines. DESIGN: Scoping review. DATA SOURCES: We searched the MEDLINE, CINAHL, Embase, Business Source Premier, EconLit, Regional Business News, Cochrane, Web of Science, Scope and Pool databases through December 2020 in English, German, French, Italian and Spanish. ELIGIBILITY CRITERIA: Studies that included determinants for the definition of therapeutic value of medicines were included. DATA EXTRACTION AND SYNTHESIS: Data were extracted using the mentioned data sources. Two reviewers independently screened and analysed the articles. Data were analysed from April 2021 to May 2022. RESULTS: Of the 1883 studies screened, 51 were selected and the identified factors contributing to the definition of therapeutic value of medicines were classified in three categories: patient perspective, public health perspective and socioeconomic perspective. More than three-quarters of the included studies were published after 2014, with the majority of the studies focusing on either cancer disorders (14 of 51, 27.5%) or rare diseases (11 of 51, 21.6%). Frequently mentioned determinants for value were quality of life, therapeutic alternatives and side effects (all patient perspective), prevalence/incidence and clinical endpoints (all public health perspective), and costs (socioeconomic perspective). CONCLUSIONS: Multiple determinants have been developed to define the therapeutic value of medicines, most of them focusing on cancer disorders and rare diseases. Considering the relevance of value of medicines to guide patients and physicians in decision-making as well as policymakers in resource allocation decisions, a development of evidence-based factors for the definition of therapeutic value of medicines is needed across all therapeutic areas.

Therapeutic value of first versus supplemental indications of drugs in US and Europe (2011-20): retrospective cohort study.

OBJECTIVE: To analyze the therapeutic value of supplemental indications compared with first indications for drugs approved in the US and Europe. DESIGN: Retrospective cohort study. SETTING: New and supplemental indications approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) between 2011 and 2020. MAIN OUTCOME MEASURES: Proportion of first and supplemental indications rated as having high therapeutic value using ratings from the French and German national, independent health authorities. RESULTS: The cohort study included 124 first and 335 supplemental indications approved by the FDA and 88 first and 215 supplemental indications approved by the EMA between 2011 and 2020; the largest subset was for cancer disorders. Therapeutic ratings were available for 107 (86%) first and 179 (53%) supplemental indications in the US and for 87 (99%) first and 184 (86%) supplemental indications in Europe. Among FDA approved indications with available ratings, 41% (44/107) had high therapeutic value ratings for first indications compared with 34% (61/179) for supplemental indications. In Europe, 47% (41/87) of first and 36% (67/184) of supplemental indications had high therapeutic value ratings. Among FDA approvals, when the sample was restricted to the first three approved indications, second indication approvals were 36% less likely to have a high value rating (relative ratio 0.64, 95% confidence interval 0.43 to 0.96) and third indication approvals were 45% less likely (0.55, 0.29 to 1.01) compared with the first indication approval. Similar findings were observed for Europe and when weighting by the inverse number of indications for each drug. CONCLUSIONS: The proportion of supplemental indications rated as having high therapeutic value was substantially lower than for first indications. When first or supplemental indications do not offer added therapeutic value over other available treatments, that information should be clearly communicated to patients and physicians and reflected in the price of the drugs.

Therapeutic Value of Drugs Granted Accelerated Approval or Conditional Marketing Authorization in the US and Europe From 2007 to 2021.

Importance: The number of drugs approved through the accelerated approval or conditional marketing authorization pathways has increased with unclear evidence of their therapeutic value. Objectives: To assess the therapeutic value of drug indications granted accelerated approval in the US or conditional marketing authorization in the European Union (EU) overall and for cancer indications. Design, Setting, and Participants: This cohort study used the public databases of the US Food and Drug Administration and the European Medicines Agency to identify all drugs (initial and supplemental indications) granted accelerated approval in the US or conditional marketing authorization (initial indications only) in the EU between January 1, 2007, and December 31, 2021. Therapeutic value ratings were obtained from national health authorities in Germany, France, and Canada. Main Outcomes and Measures: Descriptive statistics were used to assess the proportion of accelerated approvals and conditional marketing authorizations overall and for cancer vs noncancer indications rated as having high added therapeutic value. Results: The cohort included 146 drug indications (94 first indications, 52 supplemental indications) in the US and 58 (all first indications) in the EU. Most drugs were approved for cancer (122 [83.6%] in the US; 40 [69.0%] in the EU). Therapeutic value ratings were available for 90 drug indications (61.6%) in the US and 56 (96.6%) in the EU. Overall, 35 drug indications granted accelerated approval (38.9%) and 21 granted conditional marketing authorization (37.5%) had high added therapeutic value in the US and EU, respectively, at the time of approval. The proportions of indications rated as having high added therapeutic value were 36.0% (27 of 75) for cancer vs 53.3% (8 of 15) for noncancer indications in the US and 30.8% (12 of 39) for cancer vs 52.9% (9 of 17) for noncancer indications in the EU. Conclusions and Relevance: In this cohort study, among new drug indications approved through the accelerated approval or conditional marketing authorization pathways in the US and Europe from 2007 to 2021, 38.9% and 37.5%, respectively, demonstrated high therapeutic value. A substantially lower proportion of cancer indications than noncancer indications were rated as having high therapeutic value. Policy makers and regulators should increase enforcement of timely postapproval study completion for drugs qualifying for these pathways.