https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM346564.pdf?source=govdelivery
In April 2013 FDA issued a brief guidance entitled Providing Postmarket Periodic Safety Reports in the ICH E2C(R2) Format (Periodic Benefit-Risk Evaluation Report). This document summarizes FDA’s position on accepting the new format EU/EMA PSURs known as PBRERs (pronounced “pee-bers”).
New & Old PSURs
A brief review of the new and old PSUR situation. The PSURs (Periodic Safety Update Report) have been around for many years. They are standardized and accepted by most health authorities (including FDA, Health Canada, the EU). A PSUR covers one entity (all indications, dose forms, routes of administration and regimens). They include an analysis and evaluation of new or changing safety data received during the period covered by the PSUR which includes:
- Analysis of ADRs & lack of efficacy cases,
- An interval data review. Minimal cumulative overviews
- Safety data from studies
- Other relevant safety information
- Pregnancy experiences
- Increased frequency where meaningful
- Follow up of any Risk Management Plans in place
- Timing of submission was rigid (in the EU: every 6 months for 2 years, yearly for 2 years then every 3 years forever).
They are meant to be critical, medical analyses unlike the Annual Safety Reports they replaced which were more data dumps than analyses.
The new PSUR (which is still officially and confusingly called a PSUR but is unofficially called a PBRER) came into effect in the EU in January 2013 and is based on ICH E2C. It is an analytical document covering “all available data” – both interval data and cumulative data. It covers the items above but has much more including a review of market uptake and off-label use. A big change is that it now views risk in the context of benefits. That is, risk is no longer reviewed in isolation (as in the old PSURs) without considering whether the drug is used for a benign set of symptoms (e.g. anti-histamines for seasonal allergic rhinitis) or for deadly diseases (cancer, infections) and without considering whether the drug really has benefits or not. New relevant interval data is reviewed in the context of cumulative information and how it impacts on the integrated benefit-risk assessment. The timing of its submission is no longer the same for all drugs but is rather determined by the regulators in the EU based on the drug, disease etc. Frequency of submission is now published in the European Union Reference Date List and the agencies may change the timing at any point if they feel it to be appropriate.
So in the EU at least, the new PSUR is to be used. There are complicated interval/interim rules in place and not all health authorities are quite ready to handle these new reports but nonetheless, everyone is now transitioning to them and by year end or so the process will presumably be smoother. There are still outstanding issues that the EMA/member states must clarify (e.g. what is to be in the efficacy section) and this too will work itself out over the next year or two.
Some problems arise outside the EU. Most of the rest of the world requires the old format PSUR often with local additions (e.g. the FDA requires additional US data) and sometimes with timing that differs from the old EU timing. Nonetheless, after nearly two decades of PSURs everyone has gotten comfortable with them around the globe.
Now, with a new document going to the EU, the question is what will the rest of the world accept. Will other countries accept the new EU format with its efficacy section and much more safety data? And what about the EU specific sections such as the review of EU risk management plans which may or may not be germane in other countries. In effect, should Australian TGA or the US FDA be sent information on EU risk management plans?
Another complicating factor is that the EU changed the contents of its PSUR by getting rid of most of the line listings of individual cases that formed the voluminous appendices in the old PSURs? Why did they do this? Because in the EU now, companies must submit all serious and non-serious post-marketing cases in 30 and 90 days respectively. Thus the EU gets (essentially) all the cases in near real time, not just expedited reports, and doesn’t have to wait months or years to get the serious and non-serious AES in PSUR line listings. They already have them in EudraVigilance by the time the new PSUR is submitted.
This is NOT the case in the rest of the world where the old expedited (15 day reports) requirements still remain in place and real time ICSR reporting is not done. It’s not clear that other non-EU countries will want or be able to handle the continuous reporting of all cases as the EU now does (well sort of – EudraVigilance is still transitioning too and many of the member states – broke and bailed out – may not be able to handle them either. Not clear the US could handle them as we are nearly broke and sequestered too).
So now, if other countries just get the PBRERs without line listings, they won’t have received all the cases (serious non-expedited and non-serious). So they will probably still require the old-style line listings thus creating another “flavor” (version) of the new PSUR which is a hybrid of the old and new.
Other countries may not accept the EU’s timing. In fact, the EU has (sort of) said that some old and “safe” drugs won’t even need PSURs and generic drugs also may not need PSURs. It is unlikely that other countries will accept the EU’s new requirements. This is the continuing slow ending of harmonization (or at least whatever harmonization we have now).
Various other countries are now making PBRER policy.
The FDA PBRER Policy
The FDA has just issued its policy as a guidance: non-binding recommendations. Since the US regulations actually do not require PSURs (even the old kind) but still require a Periodic Adverse Drug Experience Report (PADER/PAER), the FDA requires that companies must obtain a waiver from FDA to submit PSURs. FDA has been giving (if not encouraging) these waivers for many years and they are usually easily granted. The waiver procedure continues. Even with a waiver though, companies must still provide the contents of the PADER as defined in the federal regulations:
- Copies of all non-expedited individual case safety reports (ICSRs) received during the PSUR reporting interval must be submitted.
- A narrative that identifies any changes made to the approved U.S. labeling based on new information in the PSUR
- The data lock point may be changed to harmonize with international birthdates but no gaps in reporting are permitted
- Reporting frequency essentially remains the standard US requirements (every 3 months for two years and then yearly forever). If PSURs are submitted using ICH (or EU) timing, then the 3 month and annual reports must be submitted either as PSURs or PADERs/PAERs. In other words, something has to be submitted every three months for 3 years and then yearly. Some or all of these can be PSURs.
So in this guidance, FDA indicates that if a company/sponsor/applicant already has an old style PSUR waiver they do not need to submit a new waiver request. If there are no changes in the data lock point or frequency of reporting, the sponsor does not need to tell FDA but can simply send the PBRERs. If there are “substitutions” in the waiver (e.g. submitting some PADERs and some PSURs), the new PBRER can be used. It is not stated, but it probably is wise to speak to FDA to be sure the new PBRER is ok. Of course, the new PBRERs still have to have the US specific data as required in the old PSURs.
If there are changes in the data lock point and/or frequency of reporting, the FDA should be contacted and a “notification” should be submitted noting the changes. As always, no gaps in reporting are permitted.
If the plan is to submit the PBRER less frequently than is permitted in the current waiver, FDA needs to be notified and the measures taken to ensure that the usual US reporting requirements.
Interestingly, FDA indicates that “if you are on a quarterly reporting schedule but with to report every 6 months without submitting a quarterly PADER/PAER in the intervening quarters” this may be requested. This is most interesting. FDA does not, in this document, give criteria for when this might be acceptable.
Getting a New Waiver
If a sponsor does not have a waiver and wishes to get one, this document indicates what needs to be submitted and where to submit. Each NDA/application must have a waiver though a single waiver request can cover multiple applications. In the waiver, the company must indicate:
- The product name(s) and application number(s).
- A brief description of the justification for the request.
- The U.S. approval date for the product(s) and current reporting interval used.
- The reporting interval of the last PADER/PAER submitted for the product(s).
- The data lock point you intend to use for each PBRER. If you propose a data lock point other than one aligned to the U.S. approval date, you should describe how you will ensure there are no gaps in reporting intervals.
- The frequency with which you intend to submit reports.
- The PBRER may be used with US specific appendices
- Submission may be in the 70/90 day timelines in the ICH guideline
Implications
This is the author’s view (not FDA’s).
Does the company really want to give more information to the FDA than is required? This may be a good thing but it may also raise more questions than it answers. Each company must decide.
The workload at the company many increase if the company still submits PADERs (which are usually easier to compile) than PBRERs which must be customized for the EU and for the US and for which the timing may vary. It might be that the company will write a US specific PBRER that does not get submitted to the EU or an EU style PBRER that doesn’t get submitted to FDA. Companies may have to produce PADERs, PSURs and bridging reports. This may produce a series of “one-offs” whereby each product is handled differently making the life of the drug safety and regulatory folks rather complicated. In spite of harmonized birth dates, there may be multiple submissions for each product each year around the world.
Complex drugs with high volume ICSRs or drugs with complex safety problems or REMS will become complicated. Companies must ensure that they say the same thing to every regulator.
My personal preference is to try to minimize operational headaches, particularly if report preparation is outsourced or fragmented (e.g. multiple CROs or groups within a large company preparing reports). The people and groups involved, the more approvals, the more formats, the greater is the chance for something to get inadvertently messed up.
As always, it is not clear that this new report will improve public health and minimize patient adverse events. That remains to be seen (if we choose to actually measure whether safety has improved 5 or ten years down the road).
