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Pink Sheet
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Pink Sheet
Article PackReal World Evidence Benefits, Limits Explored In US FDA
Demonstrations
Executive Summary Reproducing Clinical Trial Results With Real
FDA’s Jacqueline Corrigan-Curay lists three demonstrations World Data
now underway that are aimed at looking at different A second demonstration is being conducted with Brigham
aspects of generating real world evidence and may inform and Women’s Hospital and Harvard Medical School, led by
the agency’s evaluation of the data and methods. Harvard epidemiology professor Sebastian Schneeweiss.
It will use a scalable analytics platform with Medicare and
The US FDA is sponsoring demonstration projects to commercial claims databases to replicate the findings of
explore different applications of real world evidence in the 30 Phase III/IV clinical trials using real world data.
regulatory process and patient care, according to Center
for Drug Evaluation and Research Office of Medical Policy “Empirical” findings from the research should also be
Director Jacqueline Corrigan-Curay. available by the fall of 2020, an FDA spokesperson told the
Pink Sheet.
“We’re funding some demonstration projects … around
what do we know about how the data can be used,” A third demonstration is being conducted by FDA’s
she told a meeting on real world evidence sponsored by Sentinel prescription drug post-market electronic data
the International Society for Pharmacoeconomics and system and the Clinical Trial Transformation Initiative,
Outcomes Research (ISPOR) and the International Society a public-private partnership designed to advance
for Pharmacoepidemiology (ISPE) in Washington, D.C. Oct. improvements in the design and conduct of clinical trials.
20. The demonstration is aimed at evidence generation.
The meeting was held to discuss recently-released ISPOR/ Known as IMPACT-Afib, the study is the first interventional
ISPE recommendation on good practices for conducting clinical trial conducted in the Sentinel system, which had
studies using real world data. (Also see “Observational only been used for post-market safety surveillance. (Also
Studies Should Get Safe Harbor For Preregistering Protocols see “Sentinel’s “IMPACT” Beyond Safety: Anti-Coagulant
– Humana” - Pink Sheet, 30 Oct, 2017.) Study Is Early Test” - Pink Sheet, 10 Mar, 2016.)
Corrigan-Curay mentioned three demonstration projects, The prospective, randomized, open-label interventional
each looking at different aspects of generating real world trial will evaluate the effect of an educational intervention
evidence from real world data. The projects are part of on patients with atrial fibrillation who are not currently
a broader effort at the agency to develop a framework treated with anticoagulants. Results are expected to
for more widely incorporating real world evidence into inform future interventional studies designed to use
regulatory applications. Other activities have included a existing health care data.
series of public workshops held in September. (Also see
“Real-World Evidence: Advice, Principles And Examples Preliminary results will be available on the intervention’s
Emerge From FDA” - Pink Sheet, 7 Oct, 2017.) effectiveness by late 2019, “but there are insights into the
process of leveraging the Sentinel system for this types of
The first demonstration, which is designed to assess data research that likely will be available earlier,” the agency
“fitness,” is being conducted in collaboration with the spokesperson noted.
Duke Clinical Research Institute and GlaxoSmithKline PLC.
Dubbed “Harmony,” the project is an ancillary study to FDA is involved in other activities related to exploring the
GSK’s ongoing cardiovascular outcomes trial for its GLP-1 utility of real world data as well. The agency’s Oncology
agonist Tanzeum (abiglutide). Center for Excellence has a collaboration with health
care technology and services company Flatiron Health
Using a subset of research sites, FDA plans to assess the to examine how real world data can be used to gain
ability of electronic health records to facilitate recruitment, insights into the safety and effectiveness of new cancer
populate baseline characteristics and identify clinical treatments.
endpoints. Researchers will also explore whether they can
“get the outcomes in a reliable manner if you just draw FDA has a partnership with CancerLinQ, the American
those out of the EHRs,” Corrigan-Curay said. Results are Society for Clinical Oncology’s big data initiative. The
expected in the fall of 2020. partners will use real world, aggregated, de-identified
2 / November 2017 © Informa UK Ltd 2017 (Unauthorized photocopying prohibited.)patient care data from oncology practices to understand Institute’s (PCORI’s) National Patient-Centered Clinical
a variety of issues related to the use of newly-approved Research Network to address barriers in working across
drugs. The initial focus will be on immunotherapy agents networks. The project is intended to create an open
approved for melanoma. source interoperable service that allows data partners
to participate in multiple data research networks, query
And FDA will pilot a cross-network directory service using across networks, and share analytic capabilities and
Sentinel and the Patient-Centered Outcomes Research knowledge.
3 / November 2017 © Informa UK Ltd 2017 (Unauthorized photocopying prohibited.)Brexit Already Affecting UK Regulator’s Role In Marketing
Authorizations
Executive Summary appointment, and was co-rapporteur in 13% of cases.
A recent stakeholder meeting at the EMA heard that
because of Brexit, the UK will soon no longer be able It was suggested earlier this year that the MHRA had
to play the role of rapporteur for initial EU marketing asked the EMA not to stop appointing it as rapporteur
authorization applications. Meanwhile, the EMA is working in the run-up to Brexit, and that this could be enabled
with the other 27 EU member states to ensure an “orderly via a multi-year transitional arrangement after Brexit to
redistribution” of the work currently done by the UK allow more time to reallocate products where the UK had
regulator, the MHRA. acted as rapporteur. (Also see “Massive Reallocation of
UK Rapporteurships Likely As EMA Plans For Future; UK’s
Brexit is already taking its toll on the UK as a key player in Interim Role Uncertain” - Pink Sheet, 11 May, 2017.)
the EU regulatory network after the European Medicines
Agency confirmed that the UK will now only be considered But with the slow pace of negotiations and growing
as rapporteur for initial centralized approval applications uncertainty over whether the UK and the EU will manage
if the evaluation procedure can be completed before the to negotiate a Brexit deal in time, the EMA will need to
country leaves the EU at the end of March 2019. proceed on the assumption that there will be no such
arrangements.
Given that it can take around more than a year to
complete a new drug evaluation procedure, this would The EMA stresses that the MHRA and UK experts are still
suggest that at some point before March 2018 the UK will engaged in other EMA activities “and will continue to do
no longer be deemed eligible to act as rapporteur. so until the UK withdraws from the EU,” and that there
is “regular high level communication with MHRA around
Following a meeting with industry stakeholders held Brexit preparedness activities.”
earlier this month, the European Medicines Agency, which
allots rapporteurships for new drug applications, said Redistribution Of Work
that rapporteurs are appointed in a way that allows “the In the meantime, the agency is working with the other 27
use of the best and available expertise in the EU in the EU member states to ensure an “orderly redistribution” of
relevant scientific area. In the current context, ‘available’ the regulatory and scientific work that is currently done by
is interpreted as being available also beyond 30th March the MHRA.
2019” (i.e., the day after the official Brexit date of March
29, 2019). This includes the distribution of initial MAAs (including
the reassignment of procedures that have not yet
“As the average length of a centralised evaluation for started but have been assigned to the UK), licenses for
initial MAAs is more than 1 year, it was noted that this approved drugs for which the UK acted as rapporteur
is already starting to take effect with regards to UK or co-rapporteur, scientific advice, procedures at the
rapporteur appointments for new medicines,” the EMA agency’s Pharmacovigilance Risk Assessment Committee,
commented in a report on the meeting. inspections, and so on.
A spokesman for the agency said: “EMA is working on the Action on these issues is being led by the EMA’s working
basis of the scenario that the UK withdraws from the EU groups on operational preparedness (covering human and
by the end of March 2019 and becomes a third country. veterinary medicines), which are due to meet in November
Notwithstanding the ongoing [Brexit] negotiations, this to discuss redistribution scenarios for legacy products
means that UK rapporteurs are still being appointed and make some recommendations to be agreed by the
for those marketing authorisation applications that are network and the EMA management board in December.
expected to be finalised by the end of March 2019.”
“The changes are not expected to come into effect before
Losing its rapporteurships will be a blow to the UK Q3 2018 with adequate time foreseen for knowledge
Medicines and Healthcare products Regulatory Agency, transfer,” the report says. To facilitate product transfer,
which has been a key player in the assessment of new marketing authorization holders should play “an
EU centralized drug applications. Between January 2015 important role,” for example in meeting with the new
and December 2016, for example, the UK was chosen rapporteur’s team.
as rapporteur for 15% of products that came up for
4 / November 2017 © Informa UK Ltd 2017 (Unauthorized photocopying prohibited.)The EMA also stresses the importance of transparency feed back on these ideas, it was agreed to organize follow-
in communications: “It will be key for industry to keep up discussions on the following topics:
EMA well informed of any foreseen changes to the timing • Regulatory marketing authorization holder transfers:
of initial MAA submissions and to better share post- transfer versus variation, timelines etc.
authorisation lifecycle submission planning,” particularly • Manufacturing and supply chain: good manufacturing
for products with UK rapporteurs. practice status, batch testing, acceptance of UK
qualified person testing beyond March 30, 2019.
Industry Concerns Raised • Pharmacovigilance: changes relating to the qualified
The industry viewpoint was put at the meeting by Alan person for pharmacovigilance (QPPV), access etc.
Morrison of the European industry federation EFPIA and its • Cross-project activities such as telematics.
European Biopharmaceutical Enterprises group, on behalf
of the other industry bodies representing biotech, generic, Future Plans
vaccine and OTC drug companies. Thenext phase of the EMA’s Brexit preparedness business
continuity plan, which will be launched on Jan. 1, 2018,
A “hard-Brexit scenario” was “clearly not the preferred is currently under discussion and more information will
option” for industry, the report says, noting that concerns be released after the December management board
were voiced around business continuity and supply chain meeting. The first phase of the business continuity plan,
disruptions, with industry stakeholders saying an early which was released earlier this month, deals with all
decision on the future UK-EU relationship and a long Brexit-related affecting the EMA, including its relocation
transition period were needed to mitigate such issues from the UK to another member state; the new location is
and ensure the necessary changes, such as technology to be decided on Nov. 20.
transfers, could be undertaken.
In the meantime, an industry-wide survey across the
Companies would also have to make the necessary trade associations is under way with a view to gathering
legal and regulatory arrangements for batch testing, insights into “short- and long-term company impact and
certification and release of products, the meeting heard. timing of decision making.” Depending on what emerges
In light of the high number of regulatory submissions that from this, the EMA may conduct its own survey to collect
would need to be made in a short timeframe, together more detailed information on issues like supply and
with the issues raised by the EMA’s relocation, industry availability of products.
called for “simplification and flexibility” around timelines
and administrative requirements “where at all possible.” In addition, industry stakeholder meetings or webinars
will be scheduled every two to three months to discuss
Before the meeting, industry stakeholders had put Brexit-related matters, and regular procedural guidance
together a list of detailed questions to highlight areas and updates of the EMA’s question and answer document
where more clarity is needed. As it was thought that the will be released.
meeting was not the appropriate forum to discuss and
5 / November 2017 © Informa UK Ltd 2017 (Unauthorized photocopying prohibited.)US FDA Recognizes Eight EU Authorities, Triggers Mutual
Recognition Provisions
Executive Summary as FDA recognizes them. It is unclear when these
US FDA recognizes the drug regulatory authorities for eight recognitions will occur or to what extent they will be
of the European Union’s 28 member states by a Nov. 1 announced.
deadline, triggering key provisions of the landmark mutual
recognition agreement. Agency Leaders Laud Milestone
Agency leaders on both sides of the Atlantic provided
The US FDA has named the first eight European drug written statements lauding the latest development.
regulatory authorities that it is recognizing under a US/EU
mutual recognition agreement reached in March. FDA Commissioner Scott Gottlieb emphasized the
importance of the agreement in enabling the agency to
It will now be the exception rather than the rule for FDA to focus more inspectional resources on higher-risk countries,
inspect pharmaceutical manufacturing facilities in these while Guido Rasi, executive director of the European
countries: Austria, Croatia, France, Italy, Malta, Spain, Medicines Agency, noted that this is the EU’s sixth such
Sweden and the UK. agreement with third-country parties. Dara Corrigan,
FDA’s acting deputy commissioner for global regulatory
FDA will henceforth determine compliance status based operations and policy, and a chief architect of the
on domestic inspection findings of authorities in those agreement, called it an “unprecedented and significant
countries. However, the determinations it makes based step.”
on those findings won’t necessarily mirror the decisions of
foreign authorities. Ellen Morrison, assistant commissioner for medical
products and tobacco operations in FDA’s Office of
FDA’s recognition of the eight countries on Oct. 31 meets Regulatory Affairs, Oct. 31 told the annual meeting of
a Nov. 1 deadline that triggers key provisions of the the International Society for Pharmaceutical Engineering
agreement, most notably the EU’s recognition of FDA’s in San Diego, California, “we are excited about this. The
domestic inspection findings. However, EU inspectorates agreement will allow regulators to use inspection reports
already had begun to defer US inspections in anticipation to help determine whether facilities are making high-
that FDA would meet the deadline. (Also see “EU To quality drugs.”
Defer US GMP Inspections Ahead Of Mutual Recognition
Agreement Becoming Operational In November” - Pink In response to a question, Morrison said FDA’s addition
Sheet, 27 Jun, 2017.) of Germany to the agreement is “still under discussion.”
Corrigan and others have called attention to the
The EU had recognized FDA in June and added the complexity of evaluating Germany due to the provincial
agency to its list of recognized authorities on Aug. nature of its inspectorate. Morrison said, “we hope it’s
11. A separate Aug. 23 agreement with the European going to be this year.”
Commission enabled FDA to share commercially
confidential information with its European counterparts. Key Provisions Triggered
No longer will the agency have to redact such information Some aspects of the revised mutual recognition
from inspection reports before sharing them with agreement took effect March 2, the day after its signing
EU authorities. (Also see “EU, US Commit To Sharing was completed. (Also see “EU, US Finally Agree On Mutual
Full Inspection Reports To Supplement GMP Mutual Recognition Of GMP Inspections” - Pink Sheet, 2 Mar,
Recognition” - Pink Sheet, 24 Aug, 2017.) 2017.)
FDA must recognize the other 20 EU member states by Other aspects took effect Nov. 1, when the agreement
July 15, 2019, for the mutual recognition agreement to became operational, such as the cessation of routine
remain in effect. inspections by EU authorities in the US and routine FDA
inspections in the first eight EU countries the agency has
The agreement will apply to each European country recognized.
6 / November 2017 © Informa UK Ltd 2017 (Unauthorized photocopying prohibited.)By meeting the Nov. 1 deadline, FDA triggered four key based on input from members of its inspection team.
articles of the agreement, which was incorporated as
an amended pharmaceutical sectoral annex to a 1998 Article 10: transmission of official GMP documents. This
mutual recognition agreement between the US and the article sets forth a process for sharing GMP documents.
EU. (Also see “Why Now Is The Right Time For Mutual It gives an exporting country’s authority 30 days to share
Recognition” - Pink Sheet, 3 Mar, 2017.) such documents with the importing country, if requested.
If the importing country determines, based on its review
These articles require the parties to accept each other’s of the GMP documents, that a new inspection is in order, it
inspection findings, though with some exceptions, as can request one per Article 11.
well as share GMP documents, request inspections, and
continue to assess each other. Article 11: requests for pre-approval and post-approval
inspections. This article sets forth a procedure for
Article 8: recognition of inspections. This article requires requesting pre-approval and post-approval inspections.
the parties to accept “official GMP documents” concerning
domestic facilities of recognized authorities, which means An authority that receives such a request gets 15 days
relying on the document’s factual findings. to say whether it will do the inspection. Such requests
would most likely arise in the context of an application for
However, there are exceptions. An authority can decline marketing approval or of information warranting for-cause
to accept GMP documents because an inspection inspections.
report appears to have “material inconsistencies or
inadequacies,” or is overshadowed by evidence of quality If the requested authority believes it has relevant GMP
defects or consumer safety issues arising from post- documents, it should alert the requesting authority and
market surveillance or complaints. provide the documents upon request.
The declining authority must explain why it won’t accept Article 12: maintenance. This article calls for regular
the report and request clarification. The authority that audits or assessments of each authority to make sure it
produced the GMP documents must respond, typically continues to merit recognition.
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