Ten years after the development of the conditional marketing authorization (CMA) pathway, European Medicines Agency (EMA) on Monday said the program is working as intended, and has led to earlier patient access to 30 drugs, nearly half of which were for orphan indications, and 80% of which target seriously debilitating or life-threatening conditions.
Additionally, EMA says that the majority of products granted conditional marketing authorization were either for indications where there were no satisfactory alternative treatments (11/30) or improved on treatment effect and/or safety compared to available treatments (9/30).
Background: Conditional Marketing Authorization
The pathway for conditional marketing authorization was developed as a means of speeding access to new medicines in areas of unmet or serious need by allowing sponsors to market a product based on incomplete clinical data until the sponsor is able to provide more comprehensive data.
The legal basis for conditional marketing authorizations in the EU is laid out in Article 14(7) of Regulation (EC) No. 726/2004, which establishes that EMA can grant marketing authorization on an annual basis subject to specific obligations.
The concept is further defined in Commission Regulation (EC) No. 507/2006, which establishes the criteria and requirements a product must meet to qualify for conditional marketing authorization.
EMA Report: 10 Years In
Of the 30 products granted conditional marketing authorization so far, 11 have gone on to receive standard authorization, EMA said in touting the program's success.
Furthermore, EMA says that only two of the products have been withdrawn for commercial reasons, both pandemic influenza vaccines, and no conditionally authorized medicines have been revoked or suspended.
EMA also notes that the average time to conversion to full authorization is four years.
Figure 1. Status of Conditional Marketing Authorizations (2006-2016)
Since 2006, EMA says it has received a total of 52 applications that were reviewed for conditional marketing authorization. Of those, 30 were granted conditional authorization, while the other 22 were not conditionally authorised.
Despite some dips from year-to-year, EMA says that interest in conditional marketing authorization has increased over time, with the average number of applications per year increasing since the pathway's initiation in 2006. The agency also reports a dramatic jump in the number of requests for scientific advice or protocol assistance for submissions for conditional marketing authorization in recent years.
Figure 2. Submissions for Conditional Marketing Authorization
Figure 3. Number of Requests for Scientific Advice or Protocol Assistance
However, despite increasing interest in conditional authorization, EMA says that fewer than half (14/30) of the products granted conditional authorization requested conditional authorization in their initial submission.
For the remaining conditional authorizations, EMA says the proposal for conditional authorization was made during its review for 14 of the submissions, while the remaining two were made during the re-examination phase.
"This likely indicates a certain reluctance of applicants to proactively propose a conditional authorisation type already in the initial application," EMA writes.
EMA also points out that conditional marketing authorization has only made an impact in four therapeutic areas (oncology, infectious disease, neurology and ophthalmology), while other areas, such as cardiovascular disease, endocrinology, respiratory medicine and rheumatology have yet to see any conditionally authorised products.
In its report, EMA recommends that sponsors engage early with the agency and prospectively plan their submissions for conditional marketing authorization as reviews took longer when the proposal was made later in the product's review.
According to EMA, this could not only lead to a more efficient assessments, but "could also facilitate prompt completion of additional studies and timely availability of comprehensive data" after receiving conditional marketing authorization.
"Unsurprisingly, later consideration of conditional marketing authorisation was linked with longer total duration of the assessment procedure (including clock-stops)," EMA writes.
On average, EMA says that submissions initially requesting conditional marketing authorization were completed in 347 days, while submissions where conditional authorization was proposed during EMA's assessment took 423 days and submissions where conditional authorization was proposed during re-examination took 484 days.
Clinical Studies and Obligations
When it comes to the data provided to support a conditional marketing authorization, EMA says the majority of applications identified Phase II (including Phase I/II, II and IIb) and/or Phase III studies as the main/pivotal assessment of the product. However, some applications pointed to Phase I studies as the main/pivotal study for the submission.
"On the product level, half (15/30) of products had provided results from at least one phase III study (even if interim results). This proportion was similar across therapeutic areas, apart from ophthalmology," EMA writes.
As for obligations imposed on sponsors as a condition of marketing authorization, EMA says it generally required two additional studies, "typically open label Phase II, III or IV studies, either randomized or single arm, and the majority had a primary endpoint different from that used in the main/pivotal studies for the initial authorisation."
"The number of measures that have been imposed as specific obligations had varied, ranging from one to 16 activities. In particular, the number has shown a tendency to stabilize – the average number of activities has decreased, and during the last three years conditionally authorised products have each had only one to four activities imposed as specific obligations," EMA writes.
Most of these obligations related to submitting final results from clinical studies (77/107), with other obligations, such as submitting interim results or conducting additional analysis making up the remaining ones.
Over time, EMA says that the type of specific obligations for conditionally authorized products has focused more heavily on the submission of final results from clinical studies, while in earlier years other obligations were more common.
EMA also reports that it generally received data from follow-up studies from sponsors on time. "The due dates for submission of data from specific obligations were generally observed and often (20/61) data were submitted more than a month early."
EMA Press Release