I might be misunderstanding your question, but I’m wondering where you heard/read that only drugs with a proven mortality benefit should/will be approved (?) This is not the case. In fact, very few of the drugs physicians prescribe every day (e.g., antacids, pain medications, antidepressants, inhalers, antibiotics…) will have a proven mortality benefit. Medications for many acute or chronic conditions (e.g., antihistamines for hives, NSAIDs for musculoskeletal pain, loperamide for IBS-associated diarrhea) would not be expected to reduce mortality, since the underlying conditions they are meant to treat are not inherently life-threatening. Therefore, the trials that led to their approval would have been unlikely to include mortality as an endpoint.
Specifying composite endpoints will increase the number of “events of interest” that are captured in each treatment arm during a trial, thereby increasing the trial’s power to detect an effect of therapy, if it exists. But including mortality in a composite endpoint would only make sense in specific clinical contexts. This is because only a subset of all trials would be expected to record more than a very small number of deaths (if any). Unless trials involve very sick people or enrol very large numbers of subjects or follow subjects for a very long time, the number of deaths recorded during a trial is going to be small.
It’s challenging to interpret the effect of a treatment on mortality when death is included as part of a composite endpoint but the trial captures only a small number of deaths. This issue was discussed in a thread started during the pandemic:
Interpretation of the REGEN-COV trial
It seems like it would be most important to get a handle on a therapy’s effect on mortality if one or more things are true:
- The sponsor is trying to show that the treatment reduces mortality;
- The therapy has recognized, potentially life-threatening toxicities related to its mechanism of action (e.g., immunosuppression, bleeding, clotting, hemodynamic or metabolic/electrolyte effects);
- The therapy is going to be used in a medically precarious population (i.e., a population already at increased risk of death by virtue of their illness), especially if use is expected to be prolonged (e.g., therapies for heart failure, cognitive impairment, cancer).
If a trial doesn’t record enough deaths to allow us to infer a mortality benefit reliably, sometimes the best we can do is to ensure that there’s no adverse mortality signal (i.e., a between-arm imbalance in mortality that favours placebo/standard of care over the new treatment). Such an imbalance would always be a red flag for drug regulators.
Don’t know if any of this is helpful…