Exceptional circumstances: marketing authorisation without comprehensive data

The legal basis is Article 14(8) of Regulation (EC) No 726/2004 for centrally authorised products and Article 22 of Directive 2001/83/EC for national ones, with the criteria in Annex I, Part II, section 6 of the Directive. The applicant must show that it cannot provide comprehensive data on efficacy and safety under normal conditions of use because the indications are so rare that full evidence cannot reasonably be collected, because the present state of scientific knowledge does not allow it, or because collecting the data would be contrary to generally accepted principles of medical ethics.

The authorisation is granted subject to specific obligations, which may include a programme of studies, restrictions on supply such as prescription by named specialists or use in hospital, and a requirement that the package leaflet and other information draw the attention of prescribers to the shortcomings of the evidence. The holder reports on the obligations each year and the authority reassesses the benefit-risk balance annually. Unlike a conditional marketing authorisation, an authorisation under exceptional circumstances is not expected to become a standard authorisation, because the missing data are not expected to become available.

The route is used for very rare diseases, for some ATMPs and for products such as antidotes and vaccines against agents that cannot be studied in trials. Orphan medicines are frequent candidates, and the EPAR and SmPC state the basis of the authorisation so that prescribers understand the evidence behind it. Where a product could qualify for both routes, EMA's guidance steers applicants towards a conditional authorisation whenever the missing data can realistically be generated.

What goes wrong: applicants who choose exceptional circumstances to avoid a confirmatory trial that could in fact be done, which the CHMP will reject in favour of a conditional authorisation; annual reassessment reports that repeat the previous year without new analysis; obligations that are quietly dropped when a study proves infeasible, instead of being renegotiated with the authority; and product information that does not explain the limits of the data as the authorisation requires.

Under the new pharma package (not yet in force), marketing authorisations become valid for an unlimited period by default, but authorisations granted in exceptional circumstances stay at five years; see MA validity changes.