How a drug gets approved

Most candidate drugs do not make it

This is the single most useful thing to internalise, and it is not cynicism. Of the compounds that enter human testing, only a minority are ever approved, and the attrition is heaviest in exactly the diseases where the need is greatest — neurodegenerative conditions, where the biology is complex and change happens too slowly to measure easily.

Which means: a promising phase 1 result is not close to a treatment. A drug entering phase 3 is still more likely than not to fail. This is worth knowing before reading a press release, because press releases are written to be encouraging and are not lying when they are.

Why rare diseases are harder

Every part of the process assumes something that rare disease breaks.

• Not enough participants. A trial detects an effect by comparing groups, and small groups make small effects statistically invisible. When only a few thousand people in a country have the condition, and only some are eligible, the study may struggle to give a clear answer regardless of whether the drug works.
• Slow change is hard to measure. Detecting a difference over one or two years in a condition that unfolds over decades demands very sensitive measurement, and developing measures that sensitive is itself a research problem.
• Placebo groups are ethically fraught. Asking people with a progressive untreated condition to spend years knowingly possibly receiving nothing is a genuine cost, which pushes sponsors towards designs that avoid it — and those designs are harder to interpret.
• Commercial logic is thin. Development costs roughly the same regardless of how many people will use the result. Orphan drug incentives exist precisely to offset this.

Regulators have tools for this, and limits

Orphan drug designation, Fast Track and Priority Review all exist to make rare disease development more feasible. Two things about them are commonly misread. Priority Review shortens the review clock; it does not lower the evidence bar. And a designation is an incentive to develop a drug, not a statement that the drug works.

What a Complete Response Letter is

A Complete Response Letter is the FDA saying it will not approve an application in its current form, with reasons. It is not a finding that a drug is dangerous, and not necessarily the end — a company can address the issues, sometimes with additional studies, and resubmit.

If you are following a programme that has received one, the company’s regulatory filings are a better guide to what happens next than its press releases. Filings carry legal accountability that press releases do not, and they tend to be more candid about what a setback actually requires.