An area of some confusion and lack of clarity remains EU Risk Management Plans.
Although they have been in existence for several years, the new Good PV Practices Module 5 released by the EMA in July 2012 (https://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129134.pdf) made significant changes in the requirements and in how the RMP is prepared. This is clearly a very complex document running 80 pages.
In addition there are 14 guidances and templates on how to prepare each section of the RMP available on this website both individually and as an integrated version (https://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/11/WC500134743.doc).
Note that there is an old template also available on the website from 2006. This is out of date and should not be used any longer. Rather the templates in the individual guidances/integrated version is to be used.
In August 2013, the EMA made two significant changes to the 2012 requirements (https://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000360.jsp&mid=WC0b01ac058067a113). These are addressed at the end of Part 2.
This seems to be a good time to do a quick review of what the RMP contains and the changes just announced. This posting is a very brief overview and anyone preparing RMPs must be familiar with Module 5 and the integrated guidance. Even though this is “billed” as a brief overview the document is so complex that this posting will be done in two parts. This is Part I.
In the EU, the RMP is a required part of the marketing authorization (MA) application for all products using the Centralized Authorization procedure (which is almost all new products). Note that in some instances, additional safety measures may be required in which case a Risk Minimization Plan (NOT abbreviated RMP) will be required.
There are seven parts to the RMP but part II, the safety specification, contains eight modules so in fact there are 14 sections to the document. Not all sections must be done in all RMPs, particularly abbreviated RMPs for generics. See the website above for the generic guidance. An overview of the sections is shown below (Figure V.2) from Module 5.
I will make comments where appropriate (representing my own feelings on RMPs and certainly not those of the EMA or any other organization) in italics and prefaced by the word Comments.
Module 5: Risk Management Plans
When is an RMP needed? The EMA is fairly direct about this:
- When a new MA is submitted for a new active substance, a similar biological, a generic or hybrid where a safety concern has been identified, when a pediatric use is requested
- When there is a significant change in an MA such as a new indication, dosage form, route of administration, new manufacturing process of a biotechnology product etc.
- On request from the EMA or a member state
- On the initiative of the company
- Other situations at any point during the lifetime of the product when safety issues arise
Comments: This looks deceptively simple! Although it looks relatively short and straightforward it is not. Every product (nearly) needs to have an RMP; however, not every product needs all seven parts. All products must have the first three parts: overview, safety specification and PV plan. Only certain products need parts IV, V and VI. Thus “routine” products without any particular need for minimization measures or surveillance beyond the routine need only complete parts I, II and III plus the summary sections in VI and VII. Every product thus needs a safety specification and a PV Plan but may not need special or additional measures.
As you go through this note the comparison to the US FDA REMS both in terms of philosophy and contents. The two are light years apart. The US risk management plan is rather simple and straightforward and is required for very few products (there are only about 80 in place right now and most are only MedGuides and Dear HCP letters or education requirements). The RMPs are complex medical documents slicing and dicing the risk in many ways.
Part I: Product Overview
This section includes:
- The name(s) of the product, the authorization procedure, a description of the chemical class, summary of the mode of action and information on its composition.
- Indications: current and proposed
- Dosing and route of administration: current and proposed
- Pharmaceutical forms: current and proposed
- First worldwide and EEA approval and launch date & whether the product is subject to additional monitoring in the EU
Comments: This is the most straightforward part and is modular. Parts of this can be used in PSURs, DSURs, RMPs and other regulatory documents.
Part II: Safety Specification
Comment: This section has as its origin ICH E2E. This part of the document establishes the safety profile of the disease(s), the drug and the patients as best as they can be known. As with most parts of the RMP much is asked for but much cannot be supplied.
This is complex section with eight modules:
- Module SI: Epidemiology: There should be a separate discussion for each indication, men and women (unless targeted only at one sex) and the target populations and subpopulations:
- Incidence & prevalence, demographics, risk factors for the disease, treatment options, disease morbidity, mortality and natural history
- Concomitant medications used frequently in the target population (e.g. anti-hypertensives are often used with hypoglycemic drugs)
- Important comorbidities in the target population (e.g. coronary artery disease is seen with increased incidence in rheumatoid arthritis patients)
Comment: Much of this may be very hard to obtain and may vary from region to region, group to group etc. Obviously, the EMA is most interested in this information on Europeans.
- Module SII: Non-Clinical Matters: This includes important safety findings in the toxicity, carcinogenicity and pharmacology studies as well as mechanisms for drug interactions. It should conclude with a list of safety concerns:
- Important identified risks confirmed by clinical data
- Important potential risks
- Missing information
- Module SIII: Clinical Trial Exposure: Tables of pooled:
- Randomized, blinded trial patients
- All clinical trial populations
Additional tables should be provided with:
- Duration of exposure by indication and total exposure including persons and person-time values
- By dose for each indication & total population
- By age group & gender by indication
- By ethic or racial origin by indication
- Special populations by indication (pregnant women, lactating women, renal impairment, hepatic impairment, cardiac impairment, subpopulations with genetic polymorphism, immunocompromised)
- Module SIV: Populations Not Studied in Clinical Trials: A discussion of the limitations of the data in relation to the ability to predict the safety in the market place
- Limitations of ADR detection in the development program such as ADRs that are rare, seen only with long exposure or due to cumulative effects or have a long latency period till they appear
- Effect of exclusion criteria in the development program noting which exclusion criteria will be contraindications and which will not be proposed as contraindications
- Limitations due to under-represented populations: children, elderly, pregnant or breast feeding women, hepatic or renal impaired patients, patients with other relevant co-morbidities, patients with disease severity different from that in the trials, subpopulations with relevant polymorphisms, racial & ethic origin patients
- Conclusions on the populations not studied and other limitations on the trial data regarding safety concerns due to limitations of the trial program
Comments: Conceptually this is a good idea and is less stressed by FDA though they are now looking at this concept also. Missing data must now be thought about, acknowledged and addressed – even if it is to say that such data is not likely to ever be obtained (e.g. use in pregnant women).
- Module SV: Post-Authorization Experience:
- Actions taken by regulatory authorities or the MAH: A discussion of marketed data including labeled and off-label uses, special populations, observational studies etc. Significant actions taken to update safety information should also be provided with a listing of actions taken by regulatory authorities or the MAH for safety reasons.
- Post-marketing exposure. Indicate the number of persons exposed, the method used to calculate this with exposure for each indication by age, gender, route of administration, dose and country
- Post-marketing use in populations not studied in clinical trials (pediatric, elderly, pregnant/lactating women, hepatic/renal impairment, other use)
- Post-marketing off label use
- Epidemiologic study exposure. A table by study should be given with the study title, objectives, population studied, length of study, number studied and comments
Comments: This is where EMA begins to make the distinction between efficacy (data obtained from clinical trials) and effectiveness (data that is obtained in the “real world” of post-marketing use) which are not necessarily the same thing. Another good concept which acknowledges that clinical trials done on narrow patient populations are not necessarily representative of the way the drug will be used in the “real world” after marketing.
- Module SVI: Additional EU Requirements:
- Potential of harm from overdose
- Potential for transmission of infectious agents
- Potential for misuse for illegal purposes
- Potential for medication errors including any that might have occurred during the clinical trials
- Preventive measures against errors for the marketed product
- Effect of device failure (if a device is involved)
- Reports of medication errors with the marketed product
- Potential for off-label use
- Pediatric issues including:
- Issues identified in Pediatric Investigation Plans
- Potential for pediatric off-label use
- Overall safety concerns from this module
Comments: This is highly speculative and difficult to know in many cases before marketing. Obviously some drugs do have misuse or off-label use that is fairly easy to predict and that should be discussed here. For example, long-acting oral opioids have a high likelihood of misuse and abuse and there is data on this available. Immunomodulators approved for a narrow indication (e.g. inflammatory bowel disease) may well be tried off-label for use in other inflammatory diseases such as rheumatoid arthritis and these should be discussed. Pediatric use is a conundrum that all the agencies and most physicians have been trying to deal with for years. Few studies are done on children and fewer on babies yet adult medications are given to kids usually using data extrapolated from adults. As the saying goes, children are not small adults and such extrapolation may not be appropriate. But lacking better data, what is to be done?
At this point, we will stop and continue in Part 2 next week.