Pre-approval access to investigational medicines

Expanded access — named-patient supply, compassionate use, managed access — lets a patient with a serious or life-threatening condition receive an investigational medicine outside a clinical trial, when no satisfactory alternative exists and enrolment is impossible. The clinical case for it is immediate. The reason it is regulated rather than simply permitted is that each such treatment interacts with the evidence base that decides whether the drug reaches everyone else.

Data that cannot answer the question it appears to answer

A patient treated under expanded access generates an observation, not a result. There is no randomisation, no control arm, no prespecified endpoint and frequently no protocol-defined assessment schedule. Selection runs in both directions and neither is measurable: physicians request access for patients they judge might benefit, and the patients who obtain it are also those with the information, mobility and support to pursue it. Confounding by indication is therefore built in, and an apparent response rate from a cohort assembled this way cannot be compared with anything.

This matters in the other direction too. Serious adverse events in expanded-access patients are reportable in the same safety system as trial events, and these are patients with advanced disease and failed prior therapy, in whom deterioration is expected and attribution to the drug is unresolvable. The regulatory record indicates such events have rarely halted development programmes, but the asymmetry is real: the programme absorbs interpretive risk from patients whose outcomes cannot contribute evidence of benefit.

Expanded-access data can support a regulatory decision, but only where it was collected as if it were evidence — prespecified outcomes, consistent ascertainment, a defensible external comparator. Retrospective assembly of a case series does not become real-world evidence by being called one.

The trial is the resource being spent

Two scarce things compete. The first is patients. Where access is available outside a trial, the incentive to enrol in a randomised study — with its chance of the control arm — falls, and slower recruitment delays the answer for the whole future population. This is the field’s central ethical tension: it is not compassion against caution, but one identified patient now against many unidentified patients later.

The second is supply. Pre-approval manufacturing runs at clinical scale, and for autologous cell and gene therapies the constraint is literal: a manufacturing slot used for one patient is a slot not used for another. A sponsor’s refusal to supply is often a capacity statement rather than a judgement about the applicant.

Why the calculus changes when there is no alternative

Tolerance for uncertainty is not fixed; it is set by the counterfactual. Where an approved therapy exists, an unquantified risk is compared against a known benefit and access is hard to justify. Where the alternative is untreated progression, the same uncertainty is weighed against a near-certain outcome, and the balance moves.

What does not move is the expectation of benefit. Response rates for agents still in early-phase development are low, and an investigational drug is investigational precisely because whether it works is unknown. The US Right to Try route bypasses regulatory review but creates no obligation on a sponsor to supply, so the decisive constraints remain supply and evidence rather than permission.