There are lots of sources to learn how to prepare a PSUR/PBRER. In particular the EU Good PV Practices Module VII (https://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/04/WC500142468.pdf) covers the EU requirements in detail.
As PADERs usually have
What is not explained though is how to review the safety sections of the PSUR. How should companies review the document and how will the health agencies review and respond to the PSUR? Not much is written about that.
First, just a quick comment on how the medical review of the PSUR should be done by the sponsor/Marketing Authorization Holder (MAH). First there should be a quality review to be sure that the mechanical and operational aspects are correct (pagination, references to tables, column totals etc.).
There should also be a review by an experienced medical person who knows the drug and who knows drug safety. Often but not always a physician. This review should encompass quality too though you probably don’t want the senior reviewer making sure columns add up correctly. However, in small companies where personnel wear many hats, the senior MD or final reviewer may indeed do this.
What to do
First pull out all the old PSURs/PADERs/PBRERs from the files. Particular attention should be paid to the most recent ones. All promises and commitments made to the health agencies (HAs), whether in the PSUR itself or in accompanying emails or communications should be noted. Obviously, any promises made must be fulfilled. If that means more data in the PSUR, the reviewer should ensure that the data are included. If something has not been done, it should be asap. If that is not feasible, a plan must be put in place to get it done and this should be communicated to the HA in the appropriate way – perhaps in the PSUR or perhaps in a separate communication. It is clearly unwise to have the HA call the company to complain that a promise was not kept.
Make sure you have in hand the appropriate labels (CCSI, national labeling etc.).
Some of the obvious operational details should be checked (again) such as the periodicity of the PSUR (especially in the EU where periodicity is now described drug by drug in the Union Reference List. The duration covered should also be verified to be correct (6 months, 1 year etc.).
The reviewer should be aware of any current concerns from other sources that might influence the review but which may not be specifically included in the PSUR. For example, are there any social media or internet issues, adverse or favorable publicity for the product or competitors or other drugs in the class? Any active patient groups either for or against? Have there been new or removed indications? Is patient exposure rising inappropriately (or appropriately)?
Have there been any actions taken for safety reasons by the company or another health agency? Any label changes for safety reasons anywhere in the world?
Next there will be a careful review of the AEs:
– All AEs/SAEs
– Spontaneous reports
– Clinical trial reports
– Solicited reports (patient support programs)
– Other “special” reports (named patient, compassionate use etc.)
– Non-serious AEs: Any “hidden” serious AEs?
Under the new format of PBRERs, there are no line listings submitted with the PSUR because the cases have been sent in either in 30 or 90 days. Nonetheless, the HAs and the companies do need to review line listings, case series etc. So the agencies will prepare their own line listings from the data sent in by the companies or, for non-EU countries taking PBRERs, they will require that the companies continue to send the line listings as they did with the old PSURs. Thus, bottom line, there will be line listings and the company should review them and be aware of what is in them. In particular, the non-serious AEs should be scrutinized to be sure there are no “hidden” serious AEs that might have been missed or misclassified when first received and first reviewed.
Then various questions will be asked such as:
- In which SOCs have most SAEs occurred?
- Any surprises or signals in the listed AEs?
- Any surprises or signals in the unlisted AEs? If yes, did the company pick the signal up or did the HA? If the HA, there will be a question as to whether the company is doing adequate review.
- Any surprises or issues in the fatal SAEs?
- Are there capsule summaries for all the fatal AEs? If not, why not?
- Look for new signals especially in light of labeled AEs, warnings, precautions etc. Be sure to look at both serious and non-serious AEs. For example, mild allergic reactions may be in the non-serious listing but be sure to look for serious allergic or possible allergic reactions too. Adding them together (serious + non-serious) may put you over the “threshold” to create a signal.
- Are there any findings in specific patient populations as defined by disease, age, comeds, vulnerable groups etc?
Literature cases will be reviewed. For old drugs or generic drugs where there are few or no clinical trials and perhaps few spontaneous reports, the bulk of the reporting will cover cases from the medical literature. This is a special group of cases, since most if not all the cases will have an implied or stated causality due to the drug. If there were no likely causality there would usually be no reason to publish the paper in the first place. So these cases must be carefully scrutinized and analyzed for signals. A serious review of these cases should occur with consideration of a signal workup or even label changes must be evaluated.
Clinical trials (if done) are next. Are there any new signals or new safety information? Anything touching on the already approved labeling and indications?
Next the company will address newly identified signals or issues, risk factors, targeted populations, previous signal commitments etc. This is the area where the company is concerned and contemplating changes in the product labeling and use. For these issues, the company should do a clear-headed analysis of how they think the health agencies will respond to these safety issues. Does the company anticipate that one or more of the HAs will propose or require an action by the company? If the company itself proposes new actions (new AEs, warnings, precautions etc.), will these be sufficient or will the HAs proposed tougher requirements? The company should have a Plan B ready if they truly believe that what the HA proposes is excessive based on the evidence presented. Do not discount the possibility that the HA has more or different information from other sources than the company. Surprises do occur.
Is there any evidence of missed signals or signals that were “downplayed” or ignored? Is there any evidence of non-compliance with regulations? Is there follow up for important cases left open or as yet unresolved in the last PSUR?
Are there any REMS (US) or RMPs (EU and elsewhere) in place with specific requirements or promises due? Are the RMPs covered in the PSUR?
If the document is a PBRER, rather than the old style PSUR, the efficacy/effectiveness analysis should be reviewed (at least briefly by the safety reviewer) and then benefit-risk analysis should be reviewed in detail to be sure that the conclusions are appropriate. Since we have, to date, little experience with PBRERs, the efficacy/effectiveness remains something of an unknown quantity and it is not clear how the benefit-risk analysis will be viewed by the HAs.
Are there any late breaking issues that have popped up since the data lockpoint and the submission of the PSUR?
The bottom line here when the company is reviewing its document is to put oneself in the shoes of the reviewer at the Health Agency. That reviewer will have a different point of view from that of the company. He or she will have a different professional experience goal set. Of course, the company must concern itself with public health but there is also the overlay of protecting the product and the company’s income. This is the nature of the system. The HA has different sets of goals including, again of course, protecting the public health. But separate from that there is no reason to “protect” the drug or the company and there may be many other reasons to approach the scientific analysis differently from the company. The reviewer has likely seen the PSURs from competitors and other drugs in the class and may have a much broader overview of the drug and the class than the company. This may alter his or her thinking. Are there any politicians or patient groups “breathing down the reviewer’s neck”? Broadly speaking, the company will presume a drug is “innocent until proven guilty” whereas the HA may take the view that the drug is “guilty” (that is, there is a signal or danger or safety issue) until proven innocent.
So, finally, the company in preparing the document must take a broad and high level point of view in addition to the detailed view needed in preparing the document. The reviewer should try to understand how the HA will look at the document.
On the other side, the HA should understand all of the issues involved in preparing the report. They will look at the company’s track record, reputation and how the data are handled and interpreted. This may color their thinking.