Bart’s Corner: Update on EMA Risk Management Plans (RMPs)
In April of this year the EMA announced the first public summary of an RMP, in this case for the drug Neuraceq [florbetaben (18F)]
The EMA also published an update of their webpage on RMPs, which noted that the revision to the Good PV Practice RMP module – Module V – came into effect on 28 April 2014.
In the US, REMS (the first or perhaps second cousin of the EU RMPs) are public documents. They can be found on FDA’s website. Note that REMS are rather unusual and that there are very few (under a hundred) currently open and in place in the US.
The EU RMPs are far more common and are required for all new products and for most, if not all, products when there is a change in the MA. An RMP must be done even if the drug only requires routine pharmacovigilance. So every drug will eventually have a detailed and ongoing review of risks and safety matters. See more below in the RMP Webpage comments.
With the publication of the EU RMPs, the EMA is continuing its move to more transparency and public access. The RMPs complement (to use EMA’s word) other information on drugs that is available on the website of European Public Assessment Reports (EPARs).
The Neuraceq RMP
The Neuraceq RMP is available here. What is interesting here is what the EMA is making public in terms of risk. The document is five pages long. Having prepared RMPs, I suspect the actual RMP is much longer. Neuraceq is an imaging agent used to determine if beta-amyloid plaques are present in the brain. These plaques have been found in patients with Alzheimer’s Disease (AD) and are used now as a diagnostic marker.
The format of this document, not surprisingly, parallels the actual contents of the RMP. Key sections (without the duplication found in the RMP) are summarized. The first section covers an Overview of the Disease, in this case dementia. The next section outlines the Treatment Benefits – in this case aid in diagnosing AD. Next is the Summary of Safety Concerns:
- Important identified risks: There are two. Reactions around the injection site and risk due to contact with radiation from the product.
- Important potential risks: There are five. Reactions to the alcohol content of the injection, injection of the medicine outside a vein, hypersensitivity, PET scan interpretation errors and off-label use.
Next is Missing Information: There are three areas noted. Safety in patients with reduced kidney function, safety in patients with reduced liver function and disulfiram drug-drug interaction.
The next section is a summary of the Risk Minimisation Measures by safety concern. For this product the “routine” PV measures are in place as well as some special conditions and restrictions and the reader is referred to the EPAR for Neuraceq for further information. The risk minimization measure included here is a healthcare professionals’ educational program to minimize PET scan interpretation errors.
Finally the Planned Post-Authorisation Development Plan and Studies which are a Condition of the MA are described in tables. This includes two post-authorisation safety studies and an on-going clinical trial. For each study, the objective, the safety or efficacy issue addressed, the status and the planned end and submission dates are noted.
Most of the data is in short paragraphs or tables. It is easy to read and more or less in lay-language.
This is an excellent, short summary of the RMP. It is clearly meant to be updated as the final section is a Summary of Changes to the RMP over Time. There are none yet for this product. If one reads this along with the EPAR one will have a good feel for the drug, its efficacy, safety and risks to date. This does indeed seem to meet the EMA’s transparency and openness objectives. One hopes they will update the document frequently as risks are found, verified or ruled out.
This document also shows some differences in philosophy with FDA. The EMA requires this risk evaluation for all products and that these risks be made clear (in tables) and tracked. The FDA obviously also requires risk evaluation and tracking but does not require a formal risk document like the RMP prepared by the NDA holder/sponsor/MA holder as the EU does. Rather FDA looks at signals and requires the NDA holder to actively look for and track signals. The EMA requires the same but, again, in a more formal manner. This seems to be a difference in philosophy and transparency.
The Neuroceq product is a good example of this divergence. The EU is requiring a healthcare professionals’ educational program to minimize PET scan interpretation errors. The FDA is not requiring this or any other special program judging the risks to be similar to those of other radiopharmaceutical products.
In the US, the CDER Risk Management review group concluded that the safety profile of this product is similar to that of other radiopharmaceuticals and that no additional surveillance or REMS are required.
So the real question here is which philosophy is better or preferable? There is no clear answer to this and it is unlikely that one will ever be found. Firstly, it is not clear anyone is asking the question. Secondly, even if one were to ask the question, it’s not at all clear how one could measure empirically which methodology is superior.
For the EMA method, one could argue that more information is better in all cases. The US method, one might argue, prevents information overload particularly for drugs which don’t seem to have any particularly elevated risk.
The Updated RMP Webpage
This page has a brief summary of what is included in an RMP:
- a medicine’s safety profile;
- how its risks will be prevented or minimised in patients;
- plans for studies and other activities to gain more knowledge about the safety and efficacy of the medicine;
- risk factors for developing side effects;
- measuring the effectiveness of risk-minimisation measures.
The hyperlink to Module V on RMPs is included as well as the documents on the three RMP formats available: the full format and the abridged format for generic medicines.
The changes that are noted include amendments to definitions, changes in the “Summary of activities in the RMP” part VI, changes in variation applications, changes in the cited references and some clarification of phrasing throughout the document. The actual changes compared to the previous version are not highlighted making it hard to actually see what has changed without doing a direct word-by-word comparison here. Nonetheless, the changes do not appear to be major.
Overall, the major impact of these two documents is the first publication of an RMP for a particular product. This is a very positive change.
Nonetheless, we now see that there is less and less information that remains proprietary and not revealed to the public. Obviously, preparers of RMPs should keep this in mind, particularly in regard to phrasing. One should eschew obfuscation (avoid lack of clarity)!
Tags: drug safety, ema, EU, Pharmacovigilance, regulations, REMs, Risk Management Plans, RMP, RMPs