ࡱ> []\` F?bjbjss .\F7j j j j T  $hTsss s  s  j c0>w>>l,ojssssj j  MHRA Seminar: Working with the New Medicines Legislation and New Regulatory Pathways February 5, 2007 Reviewed by Andrew Pegg, Unicus Regulatory Services Limited Key words: MHRA, Marketing Authorisation, MRP, DCP, CMD(h), CHMP, harmonisation. This was one of a series of seminars being run in parallel by the Medicines and Healthcare products Regulatory Agency (MHRA) at the Queen Elizabeth Conference Centre in London. A number of the other seminars and workshops are reported elsewhere. The seminar was intended to provide an update on the implementation of the revised European Union (EU) medicines legislation from the MHRAs point of view. Working with the New Medicines Legislation Prof Kent Woods (Chief Executive, MHRA) gave an overview of working with the revised legislation for the 15 month period since its introduction. The points of significance highlighted by Prof Woods included the introduction of risk management planning, which demonstrates a shift from a reactive to a proactive approach to risk management. The formal legislative status afforded to the Coordination Group for Mutual Recognition and Decentralised Procedures human (CMD(h)) was specifically aimed at reducing inconsistencies in interpretation between Member States (MS) during these procedures. Encouragement of greater use of Scientific Advice earlier in the development process is also seen as a method of stimulating EU- based pharmaceutical research. Improving levels of data protection in order to reward innovation and the reduction in administrative burden by, for example, reducing the need for 5 year renewals, were intended to improve the competitiveness of the EU-based pharmaceutical industry. With the enlargement of the EU, it was necessary to change the composition of the Committee for Medicinal Products for Human Use (CHMP) to reduce the delegates per MS from 2 to 1. The provision is still there to co-opt up to 5 additional scientific experts, which would enable CHMP to pull in expertise felt lacking in the MS delegation. The new procedures for resolving differences of opinion between MS during Mutual Recognition Procedures (MRP) and Decentralised Procedures (DCP) and the clarification of rules for generic medicines are significant examples of the intention to rationalise and simplify the procedures. Fifteen months after the legislation come into force Prof Woods considers that good progress has been made. For example, the CHMP, CMD(h) and the Pharmacovigilance Working Party have demonstrated a great deal of effort and goodwill to make the new procedures work in practice. Also, all structural changes to committees have been made, most of the guidelines for revised procedures are in place and the Notice to Applicants (NTA) has been revised. Transparency provisions (Article 126b of Directive 2001/83/EC as amended) provide some challenges for competent authorities with a requirement to make agendas and records of its meetings publicly accessible, including all decisions taken. The issue is how to strike a balance between the obligation to maintain commercial confidentiality whilst complying with this legislation. In particular, the timing of publication of meeting agendas and their contents could breach commercial confidentiality with respect to products being discussed at the meeting. It was also pointed out that making information publicly available is likely to mean more than just publishing the information on the competent authority website. So, how effective has the new legislation been in meeting its aims? In terms of enhancement of health protection, there remains a lack of harmonisation for adverse event reporting, with several MS imposing additional requirements. Completion of the internal market with enhanced competitiveness still has a number of issues, and time will tell whether the legislation has been effective. Meeting the challenges of the enlargement of the EU seems to have been largely successful so far, though the larger and more established EU MS still dominate as Reference Member States (RMS) and in Rapporteurships, which needs to change. The regulatory systems in the EU remain relatively complex despite the aim of the new legislation to rationalise and simplify these, and there is increasing pressure for further simplification. Looking specifically at the UK, Prof Woods confirmed that the Department of Health was committed to a 25% reduction in the administrative burden on industry by 2010. He suggested that as far as medicines were concerned, this would be largely achieved by rolling back some of the regulatory burden, and focussing on the areas of higher risk to the patient and the country at large. In addition, the MHRA have restructured the pre and post licensing functions into therapeutic groups, with the aim of joining things up functionally. Selected findings from a recent Ipsos MORI survey conducted on behalf of MHRA were also presented. In particular, the survey showed that there was a wish amongst the general adult public to know more about the medicines they receive both in terms of the benefits and the risks. The survey also revealed a lack of trust in some important information sources such as Package Leaflets. Prof Woods concluded that there was a need to ensure competent authorities are seen by the general public as trusted communicators of the facts. Finally, the future directions for medicines regulation in the EU were highlighted. These included the continuing drive to meet unmet therapeutic needs, and sustaining innovation by ensuring proportionate rather than overburdening regulation is in place. Pharmacovigilance was noted as an area where it should be possible to obtain far more relevant data by having a coordinated approach across the 27 MS and over 400 million people, and that these data would give pointers not only with respect to treatment risks, but also benefits. The Sunset Clause Margaret Jackman (Group Manager European Medicines Policy, MHRA) gave a presentation which looked in detail at the Sunset Clause incorporated into the revised medicines legislation. The focus was on Marketing Authorisations (MAs) obtained via the MRP and DCP routes which have an impact on MS competent authorities, although the legislation also applies to Centralised MAs (in this case, notifications and correspondence would be with European Medicines Agency (EMEA)). The basic provisions are for the MA holder (MAH) to notify the competent authority when the product is marketed and give two months notice if the product ceases to be on the market temporarily or permanently (exempt in exceptional circumstances). In addition, the MAH of any product which is not placed on the market within three years of authorisation of the application or not marketed for three consecutive years will cease to be valid. Exemptions can be granted on justified public health grounds. The interpretation of the term placed on the market is key to implementation of this provision. MHRA define this as the date of the first transaction whereby the product is placed in the distribution chain. The term present on the market is taken to mean just one packaging presentation being available. Ms Jackman accepted that this interpretation could allow product still to be under the control of the manufacturer if they are responsible for the import into the MS or the distribution chain. As the intention of this interpretation was that the product would have left the control of the manufacturer, MHRA will reconsider this issue. The interpretation of the term ceasing to be placed on the market is more straightforward. One presentation remaining on the market is sufficient, but MHRA require notification if any authorised presentation ceases to be available. There is no requirement to notify MHRA where a product ceases to be available as a result of normal seasonal manufacturing arrangements e.g. for cold and flu treatments, though this interpretation may not be applied in other MS. Exemption from invalidation after 3 years in exceptional circumstances will be applied on a case by case basis, considering the implications for patients and public health. An example of this might be where a product is voluntarily withdrawn whilst safety concerns are considered. Exemption for duplicate MAs to be used for other purposes would also be considered on a case by case basis. There are also some principles agreed by the MS at CMD(h) which apply to exemptions, particularly the need to consider the implication of invalidation in the RMS when the product remains marketed in Concerned Member States (CMS) and for an MA which is held for the purposes of export to third countries. Failure to notify a cessation or interruption in supply by the MAH is considered a criminal offence. MHRA requires all notifications in connection with these provisions to be made by email, though this will evolve toward use of the Sentinel system with time. Other future activities in connection with this provision will be a need to obtain confirmation of the products and packaging presentations which are not marketed for each MA, so that those not marketed can be deleted from 30th October 2008. Finally, the question was raised as to whether UK parallel import MAs could be issued for products where the MA for the product in the UK has ceased to be valid. No definitive answer could be provided by the MHRA staff present, so it is possible that this is another area MHRA will be reviewing in terms of interpretation of the Sunset Clause provisions. Coordination Group for Mutual Recognition and Decentralised Procedures - human Shirley Norton (Deputy Director of the Vigilance and Risk Management of Medicines Division, MHRA, and UK representative on CMD(h)), provided some background to the relevant legislation, the role and function of CMD(h) and feedback on referrals to CMD(h) since the legislation was implemented 15 months ago. The purpose of the CMD(h) is to examine any questions relating to the MA of a medicinal product in two or more MS in accordance with the DCP or MRP. The CMD(h) comprises one representative from each MS, and representatives may be accompanied to meetings by experts in order to enhance the scientific assessment process. The functions of the CMD(h) are to aim for consensus and avoid referrals to CHMP other than in exceptional circumstances, ensure consistency of standards and decision-making across the EU, provide a harmonised view on interpretation of legislation, and promote the harmonisation of Summaries of Product Characteristics (SmPCs) of national MAs. In the first 15 months of operation, the CMD(h) referrals procedure has used a considerable resource from national agencies in meeting the above functions. The most problematic areas have been the approval of generics, and the interpretation of potential serious risk to public health. It was noted that the referral procedure applies to all applications and renewals, but not variations, where arbitration is handled directly by CHMP. The CMD(h) has issued guidance on referral procedures, including guidance on oral explanations as well as participation in seminars and meetings with interested parties to clarify requirements. The referral procedure was described, and the consequences of withdrawal were clarified. Withdrawal during Assessment Step I of the DCP can be made without consequences, but if withdrawal is made during Assessment Step II, the application will still be referred to CMD(h) by a CMS if there is considered to be a serious risk to public health. Of the 511 MRP and 57 DCP which ended positively in 2006, approximately 20% and 2% of procedures were referred to CMD(h), respectively. Agreement was reached on 71% of referrals, with the remaining 29% being referred on to CHMP. The vast majority of referral cases were for generic applications, with the main issues being bioequivalence and SmPC harmonisation. The Heads of Medicines Agencies (HMA) has a strategic interest in making the DCP a success, and there has been considerable liaison between HMA and CMD(h) in order to agree action to improve the procedure. The first area for improvement is the validation procedure. The CMD(h) is also working to improve the referral rate by improving the guidance available to both applicants and competent authorities. As already stated, the definition of potential serious risk to public health remains a problematic area. There is already a guideline on this subject in Volume 1 of the NTA, and there is also a negative list contained in an Annex to Volume 2C of NTA. The CMD(h) will continue to focus on the concepts within the main guideline. Another area worked on to improve referral rates is that of generic applications, particularly those where there are a different number of indications compared to the reference product in the CMS. The CMD(h) has issued guidance in this area as this is currently a common scenario, which allows for the RMS to provide supplementary data in order to provide the basis for approval (http://heads.medagencies.com/mrfg/docs/generics/generic_indications.pdf.) Other activities ongoing to improve referral rates are the use of CHMP working parties to clarify guidance where differing interpretation exists. The CMD(h) SmPC harmonisation subgroup is progressing Article 30 (of Directive 2001/83) divergent decision referral cases. Shirley Norton also pointed out that applicants can make the whole process of referrals run more smoothly or even prevent them altogether by working closely with the RMS and CMD(h), by making use of breakout sessions with CMD(h) members and by having people empowered to make decisions regarding changes to the SmPC etc present at CMD(h) meetings. Overall, CMD(h) was considered to have proved its success in its first full year of operation. These presentations provided a useful overview of the progress achieved with some aspects of the new medicines legislation. Several areas where problems are still to be resolved were highlighted, particularly with respect to the interpretation of the sunset clause. TU_bght6 T U n o p t u A P Q R T U y { ƸδδδάΠhghWx5hghx5hNhx>*hNh XR>*h0h<hxh(OhghO vh hP)6 h6hh6h XRhh<5 hP)5hhx5hhj5hh05hhg51UVgh L M $a$gdgF?  K L M   ' - . 7 : ; = > +,RSȾȷ۩ӥۡ۝ӝӝӝh4 h X@h4 h X@h1^h1^hWxhO v hO vhO v h3Nh6^ h3Nh@h3NhzhWx h3NhzhzhghU3h6^hxh:hghx5hghWx5hghg56,2OQ_`=?GfijnZchiwn .cd*6 h X@hXhXh&Y= h X@hWxh4h6@NB*ph h X@hg h X@h6@Nh\"h6@Nh"h:hO vh1^hgF6>HlnLHI[@Tcdbh 01FXYh./֟hNhh>*hNhN>*hWx h X@h$= h X@hWx h X@h`h\"h: h\"h` h\"hhhhhO vh__h%hgh&Y=hX h X@hX h X@h4823 ! !##%%V'W' * *++,,g-h---.0/0?3@344Z5/0123CDElmrst     C K N Q U W o x !!!!.!;!!!!!""O"U"^"k"s"~"""#6$@$A$J$v$w$}$ŽŽŽŹŹŽŽŹŹɱ h X@h`h`hDC5hLh$=hO vhghNh1Mhghg5hgh1M5hghN5 hN>* h0>*hNh__>*hNhX>*A}$$$$%c%%%%%%R'T'())))))))))))*E*P*~**++++, ,,$,*,2,5,F,I,t,,,,,,,,.-H-M-N-T-U-h-------hhetp5hLh hDC5>*h h`>* h>*h h >*hXjh h`h`H*h\"hO vh`h9h1MhhDC5 h X@hDC5@--- . ..... .9.:.;.=.>..........//x/z////////////30<0G0H0I0J0K0R0H1O1R1m1n1o1p1q1t1u111112b2i2|2}222ǿһһֳַַַ֯h-Vh=rhjh@hoaeh`B*ph hh`hO vh#^hhetphHhhetp5 hB5hh5hhH5C222 3 33>3@3D3G3H3I3J3M3N344n4y4~4444444445555@5A5h5i55555555555366666666666666E7F7]7^7_7`77777777777777h h h X@h` h X@h8JhjhBh8JhNh-Vhht hthth=rMZ5[56677~<<==;><>F? 777^88888888888889 9 92939^9b9e9f9g9h999 ::p:t:w:x:y:z::%;';n;o;p; < < < <<<C<v<0=1=2=3=8=`=a=b=c=d=l=================:><>h#h/A hHhHhHh-Vh'jh* h hBhhhO<>E?F? hNh* hB ,1h. A!"#$% @@@ NormalCJ_HaJmH sH tH DAD Default Paragraph FontRiR  Table Normal4 l4a (k(No List HH $= Balloon TextCJOJQJ^JaJB'B $=Comment ReferenceCJaJ<< $= Comment TextCJaJ@j@ $=Comment Subject5\F7\UVghLM  23  VW " "##$$g%h%%%.(/(?+@+,,Z-[-..//~4455;6<6H7h0h0h0h0h0h0h0h0h0h0h0h0h0h00000000000000000000000000000000000000000000000000000000 6/}$-27<>F? #$%'()*,-Z5F?!&+F?"8@0(  B S  ?@t @|v @y@u@\l @ @Tl @ @d @Dd@@c@ @\A @l@..U/n23H7 8 *urn:schemas-microsoft-com:office:smarttagsdate8*urn:schemas-microsoft-com:office:smarttagsCityB*urn:schemas-microsoft-com:office:smarttagscountry-region9*urn:schemas-microsoft-com:office:smarttagsplace?*urn:schemas-microsoft-com:office:smarttags stockticker  10200830DayMonthYear o)t)H7  ;>!!''''))D+H+ ----Z/^///b1f1t2x24 4-51555H73333333333333333333UH7b*e*y*{*,,--////00l5o5H7*2k+jg n 9T 7 gB=rl wwfH g9C^3N M,$V$qc$ %b%ln&Z'n,g.]34DC5$=&Y=F>w?@@ X@/AlcADDEF8JhJN6@N^(O(O XR-V Z1^#^6^E^__&eoaeie'jckkvl2]oetpmru(uO vCvwwWxzSAX:]dQP)\8#Ax%"f7`9~_(\"6F@pshXInB U+qtB X7G`- ]6wd"c3* yB:U3zaDh81M<Xj0%/G{\\KjL/<6H7@H_F7P@UnknownGz Times New Roman5Symbol3& z Arial5& zaTahoma"qh&&:F ?/d?/d24d*7*72QHX?02FWorking with the New Medicines Legislation and New Regulatory Pathways Administrator AdministratorOh+'0 , DP p |  HWorking with the New Medicines Legislation and New Regulatory PathwaysAdministrator Normal.dotAdministrator2Microsoft Office Word@d@4T@ @ ?/՜.+,0L hp  + Unicus Regulatory Services Ltdd*7 GWorking with the New Medicines Legislation and New Regulatory Pathways Title  !"#$%&'()*+,-.012345689:;<=>?@ABCDEGHIJKLMOPQRSTUXRoot Entry F ZData /1Table7>WordDocument.\SummaryInformation(FDocumentSummaryInformation8NCompObjq  FMicrosoft Office Word Document MSWordDocWord.Document.89qRoot Entry F4 `Data /1Table7>WordDocument.\  !"#$%&'()*+,-.012345689:;<=>?@ABCDEGHIJKLM_^ itle4 $, SummaryInformation(FDocumentSummaryInformation8CompObjq  FMicrosoft Office Word Document MSWordDocWord.Document.89q՜.+,D՜.+,L hp  + Unicus Regulatory Services Ltdd*7 GWorking with the New Medicines Legislation and New Regulatory Pathways T