Patient Safety: All data represents my current thinking, no reference to my current or past employers
What is PADER?
Why is it needed?
When is it needed?
MAH must submit Quarterly PADER within 30 days of the close of the quarter beginning from first quarter from date of approval.
MAH must submit Annual report within 60 days of the anniversary date of approval of the application.
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=314.80
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PSUR/PBRER (Periodic Benefit Risk Evaluation Report)
If you ask anyone what they want to do next in PV? Most certainly if they have just started PV career and /or in ICSR the answer is aggregate reports.
PBRER/PSUR is one important aggregate report. Let’s look at
template of PSUR in this blog and sections. PBRER (Periodic Benefit Risk
Evaluation Report) and PSUR (Periodic Safety Update Report) are interchangeably
used, but the both are different. PSUR is simple template than PBRER accepted by many health authorities and especially for established products.
Below is template of PBRER as per E2C (R2) step 3 Guideline:
|
Section in PSUR |
Name of section |
|
Part I |
Title Page |
|
Part II |
Executive Summary |
|
Part II |
Executive Summary |
|
Part II |
Executive Summary |
|
Part II |
Executive Summary |
|
1 |
Introduction |
|
2 |
Worldwide Marketing Authorization Status |
|
3 |
Actions Taken In the reporting interval for
Safety Reasons |
|
4 |
Changes to Reference Safety Information |
|
5 |
Estimated Exposure and Use Patterns |
|
5.1 |
Cumulative Subject Exposure in Clinical Trials |
|
5.2 |
Cumulative and Interval Patient Exposure from
Marketing Experience |
|
5.3 |
Post
Approval use in Special Population |
|
5.3 |
Other post approval use |
|
6 |
Data in Summary Tabulations |
|
6.1 |
Reference information |
|
6.2 |
Cumulative summary tabulations of serious adverse
events from clinical trials |
|
6.3 |
Cumulative and interval summary tabulations from
post-marketing data sources |
|
7 |
Summaries of significant findings from clinical
trials during the reporting interval |
|
7.1 |
Completed clinical trials |
|
7.2 |
Ongoing
clinical trials |
|
7.3 |
Long-term follow-up |
|
7.4 |
Other
therapeutic use of medicinal product |
|
7.5 |
New safety data related to fixed combination
therapies |
|
8 |
Findings from non-interventional studies |
|
9 |
Information from other clinical trials and
sources |
|
9.1 |
Other clinical trials |
|
9.2 |
Medication errors |
|
10 |
Non-clinical Data |
|
11 |
Literature |
|
12 |
“Other
periodic reports” |
|
13 |
“Lack of efficacy in controlled clinical trials |
|
14 |
PSUR section “Late-breaking information” |
|
15 |
“Overview of signals: new, ongoing, or closed |
|
16 |
Signal and risk evaluation |
|
16.1 |
Summary of safety concerns |
|
16.2 |
Signal evaluation |
|
16.3 |
Evaluation of risks and new information |
|
16.4 |
Characterisation of risks |
|
16.5 |
Effectiveness of risk minimisation |
|
17 |
Benefit evaluation |
|
17.1 |
Important baseline efficacy and effectiveness
information |
|
17.2 |
Newly identified information on efficacy and
effectiveness |
|
17.3 |
Characterisation of benefits |
|
18 |
“Integrated benefit-risk analysis for authorised
indications |
|
18.1 |
Benefit-risk context - medical need and important
alternatives |
|
18.2 |
Benefit-risk analysis evaluation |
|
19 |
Conclusions and actions |
|
20 |
Appendices to the PSUR |
The section regarding worldwide market authorisation status is usually available with regulatory affairs or marketing department. It is regarding the status of approval of the product in different countries. This ensures that there is dialog between PV and regulatory affairs and consequently other affiliates in each country where the product is approved regarding its status. If there was any change in authorisation etc ,PSUR stands as a good check periodically in knowing such changes.
In the next section, there is section wherein such changes in the regulatory status due to actions taken by MAH or actions directed by regulatory authority due to safety reasons are enlisted. One example would be if the product labelling was updated due to safety reasons then this will be included herein.
Changes to safety information section would talk about the changes in the reference safety information section of CCDS,USPI,SmPC or IB.
Patient exposure data is generally available with sales team/marketing department. This data is important to understand the age group (pregnancy/breastfeeding etc) and the total product distributed.
The section 6 is about ICSR, and should provide only summary tabulation. If presenting a case is required usually this are SUSARs (Serious unlisted cases) and Fatal cases in section 16. In case of low volume a decision to include short narrative of all cases can be taken. Overall, good idea is to present only relevant cases of that review period. Presentation of cases is usually in a form of short narrative with only information that is relevant to medical assessment of case.
In the section about studies, data regarding ongoing, completed ,company sponsored or non sponsored studies is evaluated and presented.
The sections about overall safety evaluation is summary of all safety information presented in PSUR and how it affects the safety profile of product.
The most time consuming section is section of risk and benefit. Characterizing risk is very important step which should be derived from RMP or USPI/SmPC when writing for first time. Usually the idea is to only describe risk that are important identified, potential risk and missing information. The risks definitions and signal definition can be referred in GVP modules. One good starting point is the risks that are mentioned in contraindications, warnings and precautions, and important adverse reactions ,class actions in potential risk. Not all risk qualify as important, those that have higher severity, impact, risk minimization measures are loosely considered as identified. Writing benefits section will depend on current approved indications and usage and should summaries the current profile of product.
Conclusion will give an presentation regarding if the data in PSUR will led to any action in terms of changing label of product, change in RMP etc.
Generally this PSUR template which is more concise is accepted by rest of the world authorities (Non-EU) E.g. DCGI, Russia ,Malaysia etc and generally for generic products.
Frequency of PSUR: Each regulatory authority has different requirements with respect to timelines of PSUR. As an example for CDSCO -India's regulatory authority below is standard:
PSURs shall be submitted every six months for the first two years from the approval of product and annually for the subsequent two years, and it must be submitted within 30 calendar days of the last day of the reporting period.
If you are author, compiler or reviewer, in addition to PSUR you need to be aware of baseline safety profile of product, competitors USPI/CCDS, Regulatory status on signals or any communications. You should also have other skills and tool to manage this document- word, time management, project management etc.
I hope, I could summarize key points regarding PSUR in this blog.
Reference:
E2C R2
RMP GVP V
PSUR GVP VII
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What skills are important in PV other than
PV?
Many of us who are SME (Subject matter experts) are always under impression than knowing my domain and being hardworking will help me in my career and i don't need anything else. I was under the same rock, being a nerd my whole life (off course i am doctor) i was huge believer of this myth at least for a year or two in my new job.
Fortunately, i had great mentors, bosses, colleagues and leaders who bust my myth and helped me build whatever career i wanted to achieve one step, one skill and one learning and one training at a time.
It never too late for us to shift from what my favorite author says "knower to learner". SO lets dive in what other skills you need apart from sound and working PV knowledge.
Yes, if you don't have PMP certificate its ok, but working knowledge is must. Because PBRER, DSUR, PSUR, Signal reports, RMP, PSMF -they are projects.
They have multiple writers, compilers, reviewers
and they have strict external timelines. So dust your skills on what it means
to have RACI matrix, KPI, KOM. Even a SUSAR is project with 15day/7 day
timelines and you have data entry, medical review or quality review from
different people that needs to happen on time with quality
and final step is submission.
How do you handle this projects? will you be their
manager ? nope, not always and even if you are then you have
more responsibility . This are individual tasks given to you if you
have team or not. So you need to learn how to clear accountable,
responsible delegation, expectation setting and tracking to deliver this.
2. Communication skills:
You work in
strictly regulated environment and strict timelines, asking for what
you need and giving what you promised needs clear communication with
who, when, what and how and also why.
3. Time management:
Time management skills, which I like to say is time utilization is to use your time effectively to deliver expected results. These means allocate your time properly and accomplish tasks efficiently.
When you have SUSAR, a section in PSUR and signal
report due in one week, how do you allocate time? If you are a manager add to
this list, performance reviews, unexpected sick leaves and so on. Learning how
to allocate time is must.
You can achieve more when you start dedicating time to the right things. But how do you know what those things are? Eisenhower's principle explains this nicely, which you can google. What it means is in PV everything can feel like its urgent, so use your SME skills, know what are timelines for SUSAR, PSUR, DSUR etc so you know which to prioritise. In addition, some tasks may simply don’t have defined timelines, then also you need to know how to prioritise them.
As PV SME, you may work for CRO/Vendor or MAH. When you are working in service side, you will be required to know how to do business capability presentations, upsell, crossell, pricing for ICSR, SUSAR, PADER etc. You will be required to negogiate, engage and finalise business agreements with partners, clients etc. Even if you are working for MAH/Pharma you need to know what is strategy for my product, what is the revenue, what are the plans and how PV can support that product to ensure its thriving in market.
Many people believe that as PV SME they just need to know safety database, literature database and maybe few signal database and that’s the only tools they need to know. Yes we will spend majority of our time in the PV systems, but we will need to use word (author, compile, review) PSUR ,DSUR, RMPs so you need to know how to use word ( insert footnotes, bibliography, TOCs, hyperlinks and more complex commands). You need to know excel- how to calculate number of case, events, present cases by patient age, gender in pivot table, create signal reports etc. We also need to know power point, leading, contributing to kick of meetings for aggregate reports, RMP, PSMF, Signals etc.
This are very few that i have listed, and yet i am still developing them. The goal is to keep learning and implementing.
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Signal
detection is the most extensive and critical topic in PV. While it is almost
impossible to cover it in one simple blog, we can try to introduce it at least.
Definition of Signal: New potentially causal association, or a new
aspect of a known association between a medicinal product and an
event or set of related events which may require some action for ensuring
patient safety. A signal may only be relevant for a particular medicinal
product or a whole class of medicinal products.
1. Sources of Signal detection:
1. ICSRs
2. Clinical trial data ,
Spontaneous data, Scientific literature
3. Experimental and/or
non-clinical findings which has a significant impact on human exposure
4. Databases with larger
datasets when the signal was detected from national or marketing authorization
holder-specific databases (Eudravigilance)
5. Healthcare databases that may
provide information on characteristics of exposed patients and medicines
utilization patterns (VigiBase-WHO, FAERS)
6. Information from other
regulatory authorities worldwide
2. Steps
in Signal detection:
2. 1. Detection:
Using signal sources ,
first step is to detect signal by using any of the below methods as per the disease, product portfolio and RA requirements.
2. 2.Validation:
Once a signal is
identified, validating it with different methodologies, and assessing if a true causal link is present between the event and drug.
2. 3. Analysis and prioritization:
Once we validate that a signal is indeed present, the next step is
to analyze if the identified signal (event) is serious, severe,
reversible, irreversible and its impact on public. A event that causes a irreversible damage
or requires a very risky and expensive treatment obviously needs
high prioritization. Based on this there is definition of signal, High,
medium and low priority signals.
2.4. Assessment and recommendation for action:
Once we prioritize a signal, we need to ensure there is action taken to minimize the impact of the signal. E.g. if a signal is identified as drug induced liver injury, then we may have to inform HCPs via USPI/training to monitor the liver enzymes of patients
3. Signal detection methods:
3.1. Quantitative: High volumes e.g. EVDAS,
Vigibase then Computational and statistical, Data mining algorithms, Disprotionality
and eRMR
3.2. Qualitative: Low volumes e.g. Company
safety database then ICSR from safety database, Aggregate safety data, Literature
and AESI
3.3. Semi-quantitative: Both together then
Qualitative for safety database with low volumes and Statistical methods
for high volumes from HA database
4.Examples of actions to be taken:
4. 1. Urgent Dear Health Care
Professionals Communication warning of potentially increased risk of adrenal
crisis during the swap over the period, with the risk theoretically being highest
in youngest patients, and those with least adrenal reserve or other comorbidities.
4. 2. An update to the
reference safety information.
4. 3. An update to the EU RMP
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