Geography of Drug Approvals
it ’ s relatively straightforward compared to the complexity of the EMA ’ s regulatory processes .
“ The EMA is the coordinating hub for the network of EU member state – specific regulatory agencies called national competent authorities ,” explained Giovanni Tafuri , PhD , a senior heath technology assessment officer at the Italian Medicines Agency , one of the national competent authorities working within the European medicines regulatory network . ( Dr . Tafuri offered his own personal views based on his research in this area and noted that they do not reflect the views of the Italian Medicines Agency .)
Similar to the FDA ’ s use of medical experts as special government employees to serve on advisory committees , the national competent authorities supply thousands of European experts to serve on EMA ’ s special committees , working parties , and other groups . 2 However , Dr . Tafuri noted , “ at the FDA , the assessment is more internalized .”
Typically , drug manufacturers seek approval through the EMA ’ s centralized procedure , which allows applicants to obtain marketing authorization that is valid throughout the EU . This process involves a number of committees , including the Committee for Medicinal Products for Human Use ( CHMP ).
The CHMP , which is charged with developing a scientific opinion on a drug , comprises an elected chair , one member , and an alternate nominated from each of the 28 EU member states , as well as a member and alternate nominated by Iceland and Norway . 3 Member states and the EMA can also nominate as many as five additional members to join the committee . The members ( who serve 3-year terms ) convene monthly to conduct initial assessments of applications and to review marketing authorizations .
“ At the end of this rather complex process of evaluation that involves many , many parties , the committee sends its scientific opinion to the European Commission , which converts the opinion into a decision that allows companies to market the drug in the EU , Norway , and Iceland ,” added Francesco Pignatti , MD , head of the EMA ’ s Oncology , Haematology , and Diagnostics division .
National competent authorities are also responsible for reviewing products that do not pass through the EMA ’ s centralized procedure , but are instead submitted for review in individual member states .
This is “ an infrequently used process ,” noted David Bowen , MD , a consultant hematologist at the Leeds Teaching Hospital in the United Kingdom ( UK ), a recent Seconded National Expert at EMA ,
“[ It is a ] question of where the bar for certainty about the presented evidence is . What is the level of uncertainty that your country or your organization is prepared to accept ?”
— DAVID BOWEN , MD
and a member of the UK ’ s National Institute for Health and Care Excellence ( NICE ) appraisal committee . “ This process is probably mostly used for drugs for which the evidence base is quite marginal and also where there may be a specific unmet need in one country .”
Once approved in one member state , the drug can be reviewed under a Mutual Recognition Procedure for consideration of approval in other member states that choose to evaluate the product .
Am I Seeing What You ’ re Seeing ?
As an example , when the antibody-targeted chemotherapy agent gemtuzumab ozogamicin ( GO ) was being reviewed for the treatment of acute myeloid leukemia ( AML ), the FDA and the EMA handled its approval much differently . 4
In the United States , the FDA granted accelerated approval to GO in 2000 but the manufacturer voluntarily withdrew the drug from market in 2010 because it failed to meet post-marketing requirements . ( Note : On July 12 , 2017 , the FDA ’ s Oncologic Drugs Advisory Committee recommended GO for approval for the treatment of adult patients with previously untreated , CD33-positive AML .) Japan approved GO as an orphan drug in 2005 and opted to extend its approval in 2010 . The EMA , however , failed to approve the drug in 2008 because of a lack of randomized clinical trial data .
What drove the regulatory bodies to reach such varied decisions ?
“ Internationally , we all agree on the value of certain endpoints . We all prefer to see differences in overall survival ( OS ),” said Dr . Pignatti . The divergence occurs when those data are not available . Then , agencies turn to other efficacy endpoints , such as progressionfree survival ( PFS ) or – occasionally in the case of hematologic malignancies – response rates .
In a recent study of the EMA and FDA decision processes for anti-cancer drugs , Dr . Tafuri and Francesco Trotta , PhD , a senior pharmaco-epidemiologist at the Department of Epidemiology of Lazio Regional Health Service in Italy , interviewed regulators from each agency to determine the formal and informal factors that ultimately drove decision-making . 5
“ Most respondents attributed the divergence in decision-making to a different evaluation of clinical endpoints ,” said Dr . Trotta .
He added that EMA regulators tend to identify PFS as a clinical benefit , whereas FDA respondents are more likely to consider it a surrogate endpoint to be confirmed by OS .
The study also revealed that the agencies handle risk differently . “ Unlike the EMA , the FDA has a prevailing attitude to take risks in order to guarantee quicker access to new treatments ,” Dr . Trotta said . Dr . Bowen agreed , explaining that it is probably more common for the FDA to approve a drug , whereas the EMA might err on the side of caution .
“ That comes down to the question of where the bar for certainty about the presented evidence is . What is the level of uncertainty that your country or your organization is prepared to accept for a drug to be licensed ?” he said , noting that it is difficult to define the exact criteria either organization uses to make decisions .
Another important distinction is that the datasets the two agencies base their decisions on aren ’ t exactly the same . The FDA examines raw data ( the actual clinical data collected from a study ), and the EMA relies on an analysis of data provided by the company seeking drug approval .
“ This gives the FDA the capability to initiate its own independent analysis , which we don ’ t have ,” said Dr . Pignatti . “ It also ensures that companies are diligent in analyzing their data , which is more difficult for us to check .”
Although neither agency designs clinical trials for investigational products , they do provide guidance for drug sponsors initiating such studies . Manufacturers can even get advice from both organizations at the same time .
The FDA seems to play a more active role in shaping the clinical trial pathway , though . Before phased clinical trials can begin , drug sponsors are required to submit an investigational new drug application to the FDA that outlines initial animal testing results , the drug ’ s composition and manufacturing , and the plan for testing the drug in humans .
Time to Approval
As one would expect , each review method results in different timelines to approval , with the EMA typically taking longer to reach a decision . The advantage of the EMA system – the large diversity of opinions included in the process – puts the agency at a disadvantage when it comes to efficiency .
“ In the European [ example ], pharmaceutical legislation has been about harmonizing the requirements among the countries ,” Dr . Pignatti said . “ This type of set-up ensures that all countries have an equal say in these decisions .”
It also means that the FDA boasts faster time to approval . Bringing safe , effective , innovative drugs to market more quickly has long been a stated goal of the FDA leadership . In 2002 , legislators amended the 1992 Prescription Drug User Fee Act ( PDUFA ) to establish specific goals for both standard and priority reviews , requiring that standard reviews be completed within 10 months and priority reviews be completed within six months . 6
According to the 2016 PDUFA Performance Report , 95 percent of the drug applications in the 2015 fiscal year were acted on within the set goal . 7
The EMA has a maximum of 210 days to carry out its assessment , according to the agency ’ s 2016 annual report , but its time to approval is nearly universally slower than the FDA ’ s . 8
“ The fundamental reason for this difference is related to the process by which the EMA comes to its decision ,” Dr . Bowen said , which includes multiple rounds of review .
36 ASH Clinical News August 2017