FEATURE
Once a dossier for a new drug has been submitted , the EMA allocates rapporteurs ( French for “ reporters ”) from two of its member states to complete a primary assessment . The dossier then goes back to the CHMP . At that stage , all member states have a chance to comment on the initial dossier or pose questions about the report . This list of questions , often long , is then returned to the drug ’ s sponsor . 9
“ The company then has the option to ‘ stop the clock ’ and take its time to properly consider all of these questions , so that adds a bit of time onto the standard duration of EMA approval ,” Dr . Bowen said .
The EMA also has accelerated pathways to drug approvals , but they are still slower than the FDA ’ s . The EMA ’ s priority review process can shorten the typical approval time from just over 12 months to just under 10 , but the timeframe is not guaranteed . Even in scenarios in which drug sponsors are seeking approval without randomized controlled trial ( RCT ) data available , the FDA is quicker to reach a decision . From 1999 to 2014 , the FDA granted 60 unique indications for drugs without RCT results , whereas the EMA approved 44 . 10 Of the 44 applications that were made to both agencies that had comparable review packages , the FDA granted 43 approvals , but the EMA approved just 35 . In addition , the FDA took an average of 8.7 months to review the products , compared with 15.5 months by the EMA .
“ Unlike the EMA , the FDA has a prevailing attitude to take risks in order to guarantee quicker access to new treatments .”
Pricing Problems
A similarity between the agencies is that pricing is not a factor for determining whether to approve a drug .
“ Neither a drug ’ s potential price nor the price of a similar drug product plays a role in the approval process ,” Jeremy Kahn , a trade press officer and spokesman for the FDA , told ASH Clinical News . “ The FDA does not have the authority to regulate drug prices .” Instead , in the U . S ., manufacturers , distributors , and group-purchasing organizations determine drug prices .
In Europe , pricing and reimbursement decisions about an investigational drug are made only after the EMA has granted its approval . Then , each EU member state determines its own pricing or reimbursement plan .
For instance , in the UK , NICE establishes prices by running cost-effectiveness analyses on certain drugs , including all newly licensed cancer drugs . “ At NICE , our objective is to start the review process during the EMA marketing authorization assessment process , on the assumption that the drug is going to get a license ,” said Dr . Bowen . “ This means that there is not a long time between the point of licensing and the point at which a decision is made about whether the drug is cost-effective for use in the National Health Service ( NHS ) and patients may or may not have routine access to the drug .”
Once a license is granted by the EMA , NICE aims to decide within three months whether the drug is cost-effective enough for use by the NHS . To reach this decision , the NICE appraisal committee relies on academic information , models , and discussion in what Dr . Bowen called a “ challenging , rigorous ” process .
“ At the end of the day , there ’ s a set figure , and if the drug falls below that figure , it is deemed costeffective and will be routinely commissioned by the NHS for use ,” he explained . “ If it falls above that figure , it won ’ t be commissioned and there is no mechanism for a patient to be treated with the drug within the NHS because the drug is not deemed to represent effective use of NHS resources , compared with other pressures on the fixed NHS budget .”
Other member states rely on alternative methods from the NICE process . For instance , French and German agencies use comparative-effectiveness analyses to decide whether a drug should receive marketing authorization . Reviewers examine the novel drug and its associated data , then score it against the current standard treatment to determine an appropriate price . They can then enter negotiations with the drug company to set a market price .
“ The heterogeneity of systems and criteria used by health technology assessment and reimbursement bodies among the EU member states often leads to serious discrepancies in pricing , reimbursement , and patient access across countries ,” Dr . Tafuri noted .
Seeking Public Input
Mr . Kahn indicated that interacting with patients , caregivers , and advocates has long been a priority of the FDA . “ In this tradition , the FDA intends to enhance future patient engagement by providing a more transparent , accessible , and robust experience for patient communities ,” he said , adding that the agency is even considering adding a new Office of Patient Affairs .
Drs . Tafuri and Trotta also highlight the high value the FDA places on seeking public input . “ All FDA respondents considered patient input ‘ highly valuable ,’ though they still thought the FDA ought to make regulatory decisions based on independent scientific grounds ,” they wrote . “ FDA respondents stressed that their agency has been increasing its transparency and interaction with the outside world over time , integrating the perspectives of patients , physicians , and healthcare system specialists at all levels .” 5
Some FDA regulators interviewed for the study identified public input as a leading factor contributing to the divergence in decision-making between the EMA and FDA .
For many years , the EMA overlooked patient involvement , but a recent push by the agency opened up the discussion to patients and other external stakeholders . “ For several years now , we have had a framework for patient interaction ,” said Dr . Pignatti . “ Patients are not members of the committee , but we do call on them as experts in advisory committee meetings . We also have working groups of patients to whom we can address communication questions , for instance .”
Patient opinion is now also considered when the CHMP is making decisions , though the meetings
— FRANCESCO TROTTA , PhD remain closed to the public . “ The opportunity for patients to voice their views during different stages of the EMA regulatory processes are much greater than they have been in the past ,” Dr . Tafuri noted . However , EMA regulators in his study expressed mixed opinions on the value of holding public hearings and incorporating patient advocacy groups in the process .
“ Even respondents who agreed in principle to the establishment of public hearings in Europe were afraid that [ adding ] steps to the decision-making process could further slow … the approval of new anti-cancer medicines ,” the authors wrote . 5
Working Together
Despite their differences , both agencies have a close relationship and rely on each other during the approval process . “ One of our most valuable collaborators is the EMA ,” said Mr . Kahn .
Since 2004 , the FDA and EMA have collaborated in groups called “ clusters .” “ We have formed [ clusters ] that focus on treatments for children , establish effective measures for the development and use of biosimilar medications , evaluate new treatments for patients with cancer , set standards to help develop medicines personalized to a patient ’ s genetic makeup , and much more ,” he said .
Dr . Pignatti said six organizations ( the FDA , the EMA , Health Canada , the Australian Government Department of Health , the Pharmaceuticals and Medical Devices Agency in Japan , and Swissmedic ) also participate in monthly , confidential calls to discuss methodology and ongoing evaluations . Dr . Tafuri explained that those interactions are typically part of an effort to “ exchange information , not necessarily to find convergence on decisions .” This scheduled communication also helps to foster global collaboration , which will become a larger part of drug review and approval in the coming years .
As drugs become more complex and therapies become more individualized , collaboration will be essential to providing safe and effective medications across the globe , Dr . Tafuri said . “ In a globalized world , international cooperation among different agencies – none excluded – is key .”— By Jill Sederstrom ●
REFERENCES
1 . U . S . Food and Drug Administration . Drug Approval Process . Accessed May 16 , 2017 , from https :// www . fda . gov / downloads / drugs / resourcesforyou / consumers / ucm284393 . pdf .
2 . European Medicines Agency . How We Work . Accessed May 16 , 2017 , from http :// www . ema . europa . eu / ema / index . jsp ? curl = pages / about _ us / general / general _ content _ 000125 . jsp & mid = WC0b01ac0580028a46 .
3 . European Medicines Agency . CHMP Members . Accessed May 16 , 2017 , from http :// www . ema . europa . eu / ema / index . jsp ? curl = pages / contacts / 2010 / 02 / people _ listing _ 000002 . jsp & mid = WC0b01ac0580028c7c .
4 . Tanimoto T , Tsubokura M , Mori J , et al . Differences in drug approval processes of 3 regulatory agencies : a case study of gemtuzumab ozogamicin . Invest New Drugs . 2013 ; 31:473-8 .
5 . Tafuri G , Stolk P , Trotta F , et al . How do the EMA and FDA decide which anticancer drugs make it to the market ? A comparative qualitative study on decision makers ’ views . Ann Oncol . 2014 ; 25:265-9 .
6 . U . S . Food and Drug Administration . Frequently Asked Questions about the FDA Drug Approval Process . Accessed May 17 , 2017 , from https :// www . fda . gov / drugs / resourcesforyou / specialfeatures / ucm279676 . htm .
7 . U . S . Food and Drug Administration . FY 2016 PDUFA Performance Report . Accessed May 21 , 2017 , from https :// www . fda . gov / AboutFDA / ReportsManualsForms / Reports / UserFeeReports / PerformanceReports / ucm548126 . htm .
8 . European Medicines Agency . Annual Report 2016 . Accessed May 17 , 2017 , from http :// www . ema . europa . eu / docs / en _ GB / document _ library / Annual _ report / 2017 / 05 / WC500227334 . pdf .
9 . European Medicines Agency . Marketing Authorisation : The Evaluation Process . Accessed May 18 , 2017 , from http :// www . ema . europa . eu / docs / en _ GB / document _ library / Presentation / 2009 / 10 / WC500004235 . pdf .
10 . Hatswell AJ , Baio G , Berlin JA , et al . Regulatory approval of pharmaceuticals without a randomised controlled study : analysis of EMA and FDA approvals 1999-2014 . BMJ Open . 2016 ; 6 : e011666 .
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