Center for Health System Sustainability

Factors influencing the timing of regulatory submission for new drugs across countries are poorly understood. We identified all new drugs approved by the Food and Drug Administration (FDA) or European Medicines Agency (EMA) during the period 2014–18 and tracked their regulatory submissions to the US, the European Union, Canada, Japan, and Australia through 2022. We assessed whether disease area, orphan status, therapeutic value, market size, and launch price were associated with submission delays. The FDA received the highest proportion of first submissions (70 percent). Median submission delays ranged from zero months (FDA) to 18.5 months (Australia). The range of median regulatory review times was small (9.2–14.1 months) compared with the range of median submission delays. Drugs with moderate-to-high therapeutic value were associated with a six-month earlier submission time compared to drugs with low therapeutic value, on average. Higher-price drugs were associated with earlier submission, on average. Overall, cross-national differences in drug availability largely reflected differences in submission, not regulatory review, times. Although the US had greater and faster availability of novel therapeutics, the difference was smaller for drugs that offered moderate-to-high therapeutic value.

More than 75% of cancer drugs are approved by the US Food and Drug Administration (FDA) through expedited regulatory programs,(1) the use of which often leaves clinical uncertainties that may arise from issues related to trial design, conduct, analysis, or reporting—such as unvalidated end points, limited long-term data, or approval based on a single trial—about drug efficacy and safety.(2) Communicating these uncertainties is important, as clinicians may otherwise be unaware and overestimate a drug’s benefits and underestimate its risks.(3)

Although the FDA describes these uncertainties in detail in its benefit-risk assessments,(2) these documents are not widely read by clinicians. Instead, clinicians often rely on journal publications and guidelines. It is unclear whether clinical trial uncertainties about newly approved cancer drugs are reported in these sources.

Uncertainties about the benefits and harms of new drugs are common at the time of drugs’ approval. It is unclear to what extent the Food and Drug Administration (FDA) communicates these uncertainties in the FDA-approved prescribing information (the drug label), which is the primary channel of communication between the FDA and physicians. Although physicians might not regularly consult the drug label for prescribing decisions, other information sources used by physicians either index or incorporate information from the label. We searched FDA review documents for uncertainties identified by FDA reviewers with new cancer drugs. We considered the subset of uncertainties highlighted in the FDA’s Benefit-Risk Framework as important to the FDA’s approval decision. During the period 2019–22, the FDA approved fifty-two new cancer drugs. In review documents, FDA reviewers identified a total of 213 clinical trial uncertainties with new cancer drugs, 50 percent of which were considered to be important uncertainties to the FDA’s approval decision. Labels for physicians reported information on 26 percent of all uncertainties and 48 percent of uncertainties that were important to the FDA’s approval decision. Communicating uncertainties about the evidence of drugs in the label is essential for informing physicians about drugs’ safe and effective use.

We appreciate the responses to our Article, which suggest that the health cost of paying for new pharmaceuticals in the National Health Service (NHS), estimated at £1·25 million quality-adjusted life-years (QALYs) lost between 2000 and 2020, might be justified by the benefits of incentivising future innovation, attracting industry funding, or prioritising certain populations—we disagree.

Since 1999, the National Institute for Health and Care Excellence has weighed costs against benefits to help the NHS decide what it should buy. The institute’s boss, Sam Roberts, calls it a mindful “health-care innovation shopper”. Within a fixed budget, every new drug it buys risks squeezing essentials like GPs or ambulances among existing health-care services.

Health systems experience difficult trade-offs when paying for new drugs. In England, funding recommendations by the National Institute for Health and Care Excellence (NICE) for new drugs might generate health gains but inevitably result in forgone health as the funds cannot be used for alternative treatments and services. We aimed to evaluate the population health impact of NICE recommendations for new drugs during 2000–20.