Pink Sheet is part of the Informa Intelligence Division of Informa PLC

This site is operated by a business or businesses owned by Informa PLC and all copyright resides with them. Informa PLC’s registered office is 5 Howick Place, London SW1P 1WG. Registered in England and Wales. Number 8860726.

This copy is for your personal, non-commercial use. For high-quality copies or electronic reprints for distribution to colleagues or customers, please call +44 (0) 20 3377 3183

Printed By


The Value of Reviewing Existing EU Risk Management Plans

This article was originally published in SRA

Executive Summary

Cheryl Key, Barry Mulchrone and Karen Wai describe an electronic database for tracking RMPs for drugs approved in the European Union and explain why it is crucial for sponsors submitting marketing applications to have a thorough knowledge of safety plans already required for similar products.

Risk management plans have been a mandatory requirement of most new drug marketing authorisations in the European Union since November 2005 and are part of the common technical document1.

An RMP is a complex document and calls for sponsors to have not only knowledge of the product itself but also an appreciation of regulatory authority expectations for that therapeutic area and product type. Developing an RMP for any given product needs to be carried out with reference to other products not only in its pharmacotherapeutic group but also to those with similar indications and/or risks.

However, as yet, there is not an easily accessible point from which sponsors of future submissions can obtain an overview of risk minimisation measures being requested for all therapeutic groups for newly licensed products.

In this article we look at a snapshot of RMPs with risk minimisation activities relating to erythropoietins and illustrate the complexity and value of reviewing other products when considering the first steps in an RMP. The development of a good RMP that will meet key stakeholder expectations will be based on many different factors, but knowing what has already been required for similar products in the past should be a starting point.

We describe our development of an electronic database system that enabled us to review all RMPs approved for erythropoietin products licensed via the European centralised authorisation system since the implementation of the new legislation in 2005, in particular those requiring risk minimisation activities. Additional risk minimisation activities may be warranted if it is considered that a risk may not be adequately addressed by routine risk minimisation activities, such as warnings in the product labelling, for example.

Whilst this article deals with EU RMPs, it is worth mentioning that in the US, the Food and Drug Administration also requires certain applicants to have a medicines safety plan – ie a risk evaluation mitigation strategy (REMS). Essentially, if a product’s labelling alone is considered sufficient to ensure that the benefits of a product outweigh its risks, a REMS is generally not required.

A proactive and robust plan

Companies are required to have an RMP for any product containing a new active substance, a similar biological medicinal product and generic/hybrid medicinal products where a safety concern requiring additional risk minimisation activities has been identified for the reference medicinal product. A risk management plan is also required with applications for paediatric use marketing authorisation.

A product can be approved only when its risk:benefit profile is considered positive for the target population and the RMP will play a large part in this overall evaluation. It is well known that not all actual or potential risks will have been identified at the time of authorisation. The RMP outlines the means by which the marketing authorisation holder intends to identify, measure, monitor and manage these risks.

The optimal way of doing this for any specific risk can be a matter of debate and opinion and in some cases the marketing authorisation holder and the regulatory authority may not agree as to what is the best approach. There is always a need for compromise between the ideal solution and the realities of post-marketing surveillance and factors that need to be considered include finances, the limitations of spontaneous reporting methods and signal detection, incidence of any given adverse event, distinguishing from the symptoms of the disease being treated itself and potential market exposure of the product. The risk management plan will be the outcome of this compromise and will have aimed to reach a realistic and workable plan for all parties.

Given the importance of the RMP, therefore, a great deal of thought, time and effort goes into devising an effective plan that will be acceptable to the regulatory authority. A proactive and robust plan that addresses all potential concerns and issues will do a great deal to demonstrate that the marketing authorisation holder is diligent and responsible in taking the risks of its products as seriously as its potential benefits and sales.

Methods: RMP tracker and statistics

The European Medicines Agency routinely makes public on its website, assessment reports for the evaluation of the marketing authorisation applications – ie European Public Assessment Reports – for products approved via the centralised system. Within this public document an outline of the RMP can now be found.

In order to obtain an overview of RMPs it is necessary to access each of the EPARs individually. To facilitate review of the RMPs of interest, we developed an electronic database. Initially, the database was populated with all the basic information about the medicinal products of interest, as provided on the EPAR section of the EMA’s website. Subsequently, the product’s records were tagged electronically to provide us with search functionality. Examples of tags are orphan medicinal products, International Classification of Diseases (ICD)-10 categorisation2 for indication of use and drugs with additional risk minimisation plans. Thus, in order to search for cardiovascular drugs with additional risk minimisation plans, those two parameters were entered into the database and the relevant drugs were listed in a report. The database can be updated monthly with new approvals or any other changes relevant to the drugs.

As of 21 August 2009, since the legislation requiring RMPs came into force there have been 260 positive RMP opinions, of which 188 led to approved RMPs and 37 required additional risk minimisation activities. Commenting on the number of RMPs, the EMA has stated3: “When you consider that products using the centralised procedure are the most innovative and technically advanced products, this is relatively few and we feel in proportion.”


Figure 1 illustrates the RMPs we identified for medicinal products licensed via the centralised system that have required additional risk minimisation activities. The products have been classified according to the indication for which they are licensed rather than pharmacotherapeutic area and this was determined via ICD-10 (online version as of 15 August 2009).

At first glance it would appear that the products used to treat diseases of blood and blood forming organs are the most likely to require risk minimisation activities. However, the numbers need to be reviewed in the context of the types of products that have been submitted and licensed in the centralised system. In addition, the results are skewed for this product group due to the presence of a biosimilar product that had been submitted by three different marketing authorisation holders.

The products in this group were as follows: Novoseven (eptacog alfa (activated)), Siklos (hydroxycarbamide – orphan indication), Soliris (eculizumab – orphan indication), Nplate (romiplostim – orphan indication), Mircera (methoxy polyethylene glycol-epoetin beta), Silapo (epoetin) and the recombinant human erythropoietin alfa products, Abseamed, Epoetin alfa hexal and Binocrit.

Figure 2 stratifies the group into further subcategories. The majority of these drugs fell into the category of anaemia in chronic diseases that are treated by epoetins. Of the four other indications, three are orphan indications (idiopathic thrombocytopaenia, paroxysmal nocturnal haemaglobinuria and sickle cell disorders).

Erythropoietin is responsible for the stimulation of red blood cell production, and epoetin-containing medicinal products are currently indicated for several conditions such as anaemia in patients with chronic renal failure, chemotherapy-induced anaemia in cancer patients and for increasing the yield of autologous blood from patients in a pre-donation programme. In recent years there have been concerns surrounding the safety of these compounds4,5. In the US, the FDA has reviewed the safety of this class of compounds6. The EMA has issued draft guidance providing guidelines on the non-clinical and clinical development of compounds containing recombinant erythropoietin7.


Of the five products summarised in Table 1, there are clear differences in the RMPs, even though they all belong to the same pharmacotherapeutic group and might be expected to have the same risks.

Certainly there are risks that are common to all five products; these include pure red cell aplasia, thrombotic vascular events and risks associated with off-label subcutaneous use in chronic renal disease.

Four of the products are authorised under legislation for biosimilars and three are the same product but licensed to three different marketing authorisation holders.

However, there are significant differences in the licensed indications for these products, with the recombinant erythropoietin alfa having the most comprehensive indications and Mircera the most restricted, which has had an impact on the RMP. Mircera differs from erythropoietin through formation of a chemical bond between an amino group present in erythropoietin beta and methoxy polyethylene glycol (PEG) butanoic acid. As compared to epoetin beta, Mircera shows a different activity at the receptor level and this provides different pharmacological characteristics, which might be expected to account for a different safety profile. The risk management plan includes follow-up for adverse events of hypertension, decreased platelet count and GI bleeding, which do not feature for the other products.

There is a difference in the post-marketing activities for the products, which might be accounted for by gaps and differences in the clinical development programme as well as the pharmacological profile of the products themselves.


The spectrum of RMPs outlined in this small snapshot for what might appear to be similar products shows not only the complexity and variability of RMPs and their evaluation but also helps to illustrate the different strategies that are available and accepted for each individual product, even when the risks initially may seem likely to be the same.

Risk management and pharmacovigilance continues to evolve and incorporates not only risk detection but also risk minimisation activities. Following authorisation, the RMP is not a static document and, like the product information, will change over the life-cycle of the medicine as more knowledge accumulates, new populations and new indications are studied and new risks are found or mitigated.

An awareness of additional risk minimisation measures being requested for all therapeutic groups for newly licensed products will provide a sound understanding of what may be needed for any future submissions. Pharmaceutical companies, prescribers and patients will ultimately benefit by having a consistent approach to recommended risk minimisation activities. At present, the EMA does not collect statistics on the number of post-authorisation studies included in product pharmacovigilance plans. While it can be a laborious process to track this manually, in the long term we believe this may well be a worthwhile activity for pharmaceutical companies and regulators alike.


1. Volume 9A of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Human Use (September 2008) in accordance with Article 106 of Directive 2001/83/EC as amended and Article 24 of Council Regulation (EEC) No 2309/93,

2. International Statistical Classification of Diseases and Related Health Problems, 10th Revision Version for 2007,

3. Email communication from Stella Blackburn, 20 August 2009, response to general enquiry email to the EMA

4. Bennett CL, Silver SM, Djulbegovic B, Samaras AT, Blau CA, Gleason KJ, Barnato SE, Elverman KM, Courtney DM, McKoy JM, Edwards BJ, Tigue CC, Raisch DW, Yarnold PR, Dorr DA, Kuzel TM, Tallman MS, Trifilio SM, West DP, Lai SY, Henke M, Venous Thromboembolism and Mortality Associated With Recombinant Erythropoietin and Darbepoetin Administration for the Treatment of Cancer-Associated Anemia, JAMA, 2008;299(8):914-924

5. Bennett CL, Cournoyer D, Carson KR, Rossert J, Luminari S, Evens AM, Locatelli F, Belknap SM, McKoy JM, Lyons EA, Kim B, Sharma R, Costello S, Toffelmire EB, Wells GA, Messner HA, Yarnold PR, Trifilio SM, Raisch DW, Kuzel TM, Nissenson A, Lim LC, Tallman MS, Casadevall N, Long-term outcome of individuals with pure red cell aplasia and antierythropoietin antibodies in patients treated with recombinant epoetin: a follow-up report from the Research on Adverse Drug Events and Reports (RADAR) Project, Blood, 15 November 2005;106(10):3343-7, Epub, 11 August 2005

6. Tuma S, Amid Health Concerns, FDA Reviews Safety of Several Heavily Used Anemia Drugs, J Natl Cancer Inst, 16 May 2007;99(10):746-7, 753

7. Guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant erythropoietins (Revision), 23 July 2009, EMEA/CHMP/BMWP/301636/2008,

8. H-725-en6 Binocrit European Public assessment report – Scientific discussion (MAA 28 August 2007),

9. H726-en6 Epoetin alfa hexal European Public assessment report – Scientific discussion (MAA 28 August 2007),

10. H727-en6 Abseamed European Public assessment report – Scientific discussion (MAA 28 August 2007),

11. H739-en6 Mircera European Public assessment report – Scientific discussion (MAA 20 July 2007),

12. H760-en6 Silapo European Public assessment report – Scientific discussion (MAA 18 December 2007),

Cheryl Key is medical director, medical & scientific services, drug safety group at Quintiles, in Bracknell, Berkshire, UK.Barry Mulchrone is senior pharmacovigilance program manager at Quintiles, Dublin, Ireland.Karen Wai is director, medical & scientific services, European lead for drug safety group at Quintiles, Dublin, Ireland. Email:




Ask The Analyst

Please Note: You can also Click below Link for Ask the Analyst
Ask The Analyst

Your question has been successfully sent to the email address below and we will get back as soon as possible. my@email.address.

All fields are required.

Please make sure all fields are completed.

Please make sure you have filled out all fields

Please make sure you have filled out all fields

Please enter a valid e-mail address

Please enter a valid Phone Number

Ask your question to our analysts