Special Report For reprint orders, please contact:
[email protected]
Regulation of nanomedicines in the EU: distilling lessons from the pediatric and the advanced therapy medicinal products approaches As the market for nanomedicines in the EU is growing, the development of regulatory guidance in this area assumes priority. Currently, the nanomedicine market is poised at a critical stage wherein clear regulatory guidance is imperative in providing for clarity and legal certainty to manufacturers of nanomedicine. The regulation of the pharmaceutical sector in the EU has witnessed several developments and innovations guided by the philosophy of single market and balancing the principle of ensuring high public health protection and safety of medicines. Both the pediatric and the advanced therapies medicinal products (ATMP) regimes offer important regulatory guidance that could be adopted for the regulation of nanomedicines in the EU. KEYWORDS: advanced therapy medicinal products n efficacy n internal market n market authorization n nanomedicine n pediatrics n safety regulation
The EU internal market has witnessed the launch of several medical applications using nanotechnology or nanomedicines as they are generally referred to as in regulatory literature [1] . There is, however, a lack of consensus on what is the range of applications that constitutes nanomedicines [2] . The RIVM (Dutch National Institute for Public Health and Environment) report in 2005 was the first exhaustive study of the range of medical applications that were using some aspects of nanotechnology [101] and it identified surgery, therapy, diagnostics, imaging, implant technology, bionics, bioactive surfaces, tissue engineering, textiles, actuators and delivery systems as areas in which products containing nanomaterials are being developed. The European Medicines Agency (EMEA) Reflections Paper on nanotechnology-based medicinal products for human use specified that these authorized medicinal products containing nanoparticles are in the form of liposomes (Caelyx®, Myocet®), protein conjugates (PegIntron®, Somavert ®), polymeric substances (Copaxone®) or suspensions (Rapamune ®, Emend®) and nanoparticles (Abraxane®) [102] . In the case of the USA, reports [103,104] have suggested that the number of nanomedicine authorizations by the US FDA stand between 12 and 18, and that there are several new products in the pipeline that will be launched in the near future. It also identified drug delivery and in vivo imaging as the most active areas. FDA-approved ‘nanoscale’ therapeutics products include gadolinium chelates for MRI (Gd-DTPA dimeglumine), iron-oxide
particles for MRI (Feridex®), liposomes (Doxil®, DaunoXome®), microemulsions (cyclosporine) and albumin-bound nanoparticles (Abraxane) [3] . Silver nanoparticles for antibacterial wound dressing, engineered calcium phosphate (NanOss™, duplicates microstructure, composition and performance of human bone) and nanoparticle dental restorative (3M™ ESPE™ Filtek™) are some of the nanoscale devices that have received regulatory approval. Given the number of sectors and the wide spectrum of applications that use nanotechnology, it is important to raise the question of whether it is possible or even desirable to evolve a definition of nanomedicines to illustrate this growing and rapidly diversifying sector. Bringing all the different applications of nanotechnology under one definition viz. nanomedicine could provide some unity, thus forming the basis for developing regulatory guidance in a cogent and comprehensive manner [105] . However, given the range of applications, the search for a definition could result in something synthetic and unreflective of market realities. Nevertheless, it is important to underline that a regulatory trigger would have to be identified at some stage and it is a prerequisite for the development and implementation of any regulatory guidance in this sector.
10.2217/NNM.09.91 © 2010 Future Medicine Ltd
Nanomedicine (2010) 5(1), 135–142
Nupur Chowdhury Department of Legal & Economic Governance Studies, School of Management & Governance, University of Twente, Institutenweg, T-201, PO Box 217, NL-7500 AE Enschede, The Netherlands Tel.: +31 53 489 5482; +31 53 489 3260; Fax: +31 53 489 2159;
[email protected]
Key regulatory issues: questions for nanomedicines in Europe The market reality is that nanotechnology applications in the pharmaceutical and medical devices sector are not only spread across a ISSN 1743-5889
135
Special Report
Chowdhury
number of sectors but that, increasingly, products combine multiple modes of actions, thereby making strict and clear categorization difficult [4] . Furthermore, given the rapidly evolving nature of the sector, any such definition would soon become redundant. It is therefore not necessary to define and develop a single product category for all applications of nanotechnology in the medical sector. A case-by-case approach where there is lack of data to develop regulatory guidance would be prudent at the initial stages. However, the question of whether applications of nanotechnology across sectors such as medicinal products, medical devices and advanced therapies medicinal products (ATMP) should be regulated in a similar manner and at the same level still remains. The essential regulatory issue is, therefore, whether there should be equivalence or parity in the standard of care that manufacturers/applicants (of marketing authorization) are to maintain across sectors. Or should regulatory obligations relating to safety, efficacy and quality for manufacturers of nanomedicines be equivalent in the case of medicinal products and medical devices. Equivalence in this case refers to substantial parity in terms of standard setting in safety and efficacy testing and not mirroring of regulatory procedures in terms of institutional structures. Currently, the regulatory pathways for medicinal products and medical devices are well differentiated. The regulation of medical devices involves conformity assessment and selfregulation and is squarely situated in the ‘New Approach’ policy of the European Commission. On the contrary, medicinal products reflect a traditional ‘command and control’ approach that is more stringent and based on penalties [5] . However, the problem arises in the case of borderline products, which include elements of both medicinal products and medical devices and which combine multiple modes of action in which neither of the modes are seconda ry to each other [106] . The criteria of the primary mode of action for the determination of product category in such cases may run into difficulty. The legislative response to such cases can be divided into two categories. First, if the borderline product falls into a category of an ATMP, the centralized procedure for grant of marketing authorization is followed wherein notified body’s opinion as to the conformity to the safety requirements for the ‘device’ part of the product is taken into account by the EMEA. Second, in all other cases the assessment depends upon the nature and extent to 136
Nanomedicine (2010) 5(1)
which the product combines its ‘product’ and ‘device’ parts. As a general rule, a medical device intended to administer a medical product is governed by the relevant medical device directives (93/42/EEC or 90/385/EEC [107,108]) with the caveat that the medical product to be administered would have to fulfil the requirements laid down under the medical products directive (2001/83/EC) [109] . However, if the device and medical product form a single integral unit, then the authorization procedures under 2001/83/EC [109] will be followed with the caveat that the ‘device’ part would have to conform to the safety and performance related standards as provided under the medical devices directive. Essentially, provisions of both sets of directives (medical products and medical devices) apply concurrently and simultaneously to combined products, with the only difference being the path followed for authorization of the product. It is in such cases that manufacturers face uncertain regulatory environment vis-àvis preauthorization responsibilities and the regulatory pathways to be adopted. In 2004, the amending directive 2004/27EC [110] made the clarification that in doubtful cases directive 2001/83/EC [109] would apply.
Problem of identifying the primary mode of action The introduction of nanomedicines has further complicated the identification of the primary mode of action as the basis for establishing whether it is a medicinal product or medical device. Herein, it is important to point out that medical devices using immobilized nanostructures are considered by regulatory agencies to be ‘substantially equivalent’ to the existing devices [6] . The EMEA has acknowledged that the commercial applications focus on drug delivery and better targeting and bioavailability of medicinal substances [7] . However, nanomedicines in the pipeline are expected to exhibit complex mechanisms of action, “combining mechanical, chemical, pharmacological and immunological properties and combining diagnostic and therapeutic functions” [7] . Examples include substances such as ‘nanobubbles’ [8] composed of diblock copolymers that gather around tumors owing to their enhanced permeability and retention effect. They form microbubbles, which in turn activate a strong echo in the ultrasound imaging, thereby releasing the encapsulated drug (doxorubicin). The nanomedicine, therefore, simultaneously functions as a drug, a drug carrier and a diagnostic tool. This is only future science group
Regulation of nanomedicines in the EU
one such example that illustrates the difficulty in identifying the primary mode of action. The obvious next question, therefore, is whether regulatory parity should be established for all medical applications that utilize free nanoparticles and structures and whether it is in the form of a medical device or a medical product. It is an accepted fact that the authorization procedures reflect a more restrictive safety evaluation framework for medical products in comparison to medical devices based on the reasoning that the latter is only used externally on the body through mechanical action. This differentiation is being increasingly challenged in the face of the current developments in nanomedicines.
Central versus decentralized authorization procedure Another related issue is whether all nanomedicines should be regulated at the community level and subjected to the central authorization procedure involving a single scientific evaluation of the quality, safety and efficacy of the product by the EMEA. The central authorization procedures are mandatory for a host of product categories including recombinant DNA technology, controlled gene expression, AIDS, cancer, diabetes, orphan medical products and ATMP. Article 3(2) of Regulation EC/726/2004 specifies the optional scope of the procedure [111] . It identifies three thresholds for the application of the procedure to medicinal products, in other words, when there is presence of a new active substance, when it constitutes significant therapeutic, scientific or technical innovation or when it is in the interest of patients at the community level. In such cases, the manufacturer may approach the EMEA and request for the application of the optional procedure. In the case of nanomedicines, there exists sufficient rationale for its inclusion in the mandatory list. It is a new and rapidly developing sector and, therefore, there is a real interest in overcoming the scarcity of expertise in the community [112] and ensuring a high level of scientific evaluation of these medicinal products in the community. Harmonization of evaluation techniques would also facilitate market access for these cutting edge innovative products. This, however, is not easy given the variety of nanomedicines and given that there is an altogether separate (and much less stringent) regulatory framework existing for medical devices. In the case of combination products involving nanotechnology, it is critical to put into place regulatory triggers, which would make it obligatory for notified bodies to future science group
Special Report
consult the EMEA and competent authorities of member states to harmonize decision-making standards and regulatory guidance.
Horizontal regulatory guidance for nanotechnologies The larger regulatory issue for nanotechnology applications, in general, is whether all nanotechnology applications across sectors (e.g., cosmetics, electronics and textiles) should be regulated at the same level or should sector-specific regulatory frameworks be developed for applications of nanotechnology? Currently, the developments seem to indicate that each sector is developing regulatory guidance specific to the applications in that area [9] . It is important to realize that nanotechnology is, primarily, a platform technology and, therefore, enables processes and applications across a number of sectors and manufacturing processes. Therefore, proposals to regulate all applications of nanotechnology or nanomaterials in general are impractical and unviable, given different kinds of applications and the fast pace of developments in each of the subsectors. Regulatory policy has to be tailored to address the specific challenges and developments in a particular sector. It should be noted that, overall, the pharmaceutical sector has the highest level of safety and environmental care standards as compared with the other sectors such as cosmetics, textiles and electronics in which nanotechnology is also being used to develop new product applications. In that sense, standard setting and regulatory developments in the nanomedicine sector in Europe would lead the way in providing guidance for regulations in other neighboring sectors [113] . Lessons from the ATMP & pediatrics approach The regulatory framework for medical products has witnessed several innovations over the last few decades. From the creation of specific product sectors to that of detailed guidance in clinical trials, manufacturing practices and pharmacovigilance, all have contributed to the goal of ensuring a high quality and standard of medicines and accessibility through a single market [10] . Both the pediatrics [114] and ATMP [115] regimes were established in the last few years to create an additional framework [109] of institutional arrangements and information disclosure requirements that would, with an objective of securing a higher level of patient safety, provide a clear regulatory pathways for authorization of new and innovative pharmaceutical products www.futuremedicine.com
137
Special Report
Chowdhury
in Europe. These regulatory regimes can act as regulatory reservoirs by providing options of designs, mechanisms and approaches that could be applied in the case of nanomedicines. In this context, the pediatrics and the ATMP regulatory framework is of special interest because it instrumentalized several institutional, legal and technical innovations, which could be useful to consider at this stage of regulatory policy formulation in nanomedicines. These innovations relate to information disclosure obligations, institutional measures, advisory support and pharmacovigilance. The Medical Products For Pediatric Use Regulation (EC/1901/2006) (Pediatric Regulation) [114] was passed by the European Parliament in 2006 and entered into force in January, 2007. The objective of the regulation is to improve the availability of information of medicines being used for the pediatric population and ensure high-quality medication through appropriate authorization procedures. The underlying concern was that a heightened level of safeguard should be provided for medicinal products that were being used for children and to minimize clinical trials on children by ensuring access to clinical data of similar products investigations. The ATMP regulation was legislated with the aim of clarifying regulatory procedures for all biological products and tissueengineered products across the community. In the following paragraphs certain aspects of the regulatory framework that could be adopted for nanomedicines in order to secure the same benefits and ensure adequate protection of public health are discussed.
Institutional structure for regulation In terms of institutional structure, the Pediatric Committee was created within the EMEA with the responsibility of scientific assessment and authorization of pediatric investigation plan overseeing the system of waivers and deferrals, and also providing scientific advice and assistance to the EMEA for the various support activities to the applicant. Article 4 of the Pediatric Regulation further provides that the final composition of this Pediatric Committee will include representatives from all the relevant scientific areas. Similarly, the ATMP regime also created the Committee for Advanced Therapies (CAT) for preparation of opinions on quality, safety and efficacy for all ATMP. It is also to be consulted in the evaluation of any other medicinal product that requires specific knowledge and expertise in this area. The setting up of a dedicated committee within the EMEA has, 138
Nanomedicine (2010) 5(1)
therefore, been a standard response in the case of development of specific product regimes in pharmaceuticals. The obvious question is whether it is required in the specific case of nanotechnology applications in medicinal products at this stage? Currently, the EMEA has set up a nanoexperts group within the Innovation Task Force to assist and advise the applicants and assist the Committee on Medical Products for Human Use (CHMP) facing scientific and regulatory challenges in developing nanomedicines [116] . This experts group could be institutionalized into a full fledged Nanomedicine Committee (NC) within the functioning apparatus of the EMEA. In terms of representation, such a committee should consist of experts from scientific relevant areas such as drug delivery, pharmacovigilance, medical devices for diagnostics and regenerative, genomics, ATMP, ethics, public health and environmental health risk disciplines. Furthermore, an institutional linkage should be established between the NC and the Medical Devices Expert Group. Like the CAT and the Pediatric Committee, the NC could advise the CHMP on the quality, safety and efficacy aspects of the nanomedicines. This will ensure that standardized guidance is available across medicinal products and medical devices sectors. In this case the notified bodies in the case of medical devices should have to refer applications for scientific advice to the NC.
Information disclosure for innovative medicinal products Information disclosure is another critical area in the case of new and innovative medicinal products as it fulfils two objectives. It enables regulatory authorities to track product development at an early stage and fashion appropriate regulatory responses. In return, manufacturers/applicants are able to benefit from scientific advice and seek guidance in designing postauthorization activities and, thus, ensuring regulatory conformity. The Pediatric Regulation enables early-stage consultation between the manufacturer and the regulator through the submission of a pediatric investigation plan. The ninth recital of the Pediatric Regulation states that the plan will include detailed information of the “timing and the measures proposed to demonstrate the quality, safety and the efficacy of the medical product in the pediatric population”. It is to be submitted prior to the submission of the application for marketing authorization with the purpose of establishing communication and dialog between the committee and the applicant. future science group
Regulation of nanomedicines in the EU
Ensuring flexibility, the plan can be modified at a later stage, given a change of circumstances, in consultation with the committee. This is an important step in ensuring that there is transparency between the applicant and the regulatory authority. Such a measure (e.g., a nanomedicine investigation plan) is ideal in the short term given that at this stage many applicants are considering approaching the EMEA or the competent authorities of the member states. This would secure several benefits for both the applicant and the regulatory authorities, including ensuring early communication on the various scientific and regulatory challenges. This would provide an important source of product development information and enable authorities to keep abreast of the range of applications being considered by manufactures and also to ensure regulatory compliance at the preclinical stage. It will also provide a mechanism to coordinate regulatory responses between the EMEA and the competent authorities of the member states. However, prior to developing such a mechanism, the EMEA would have to either define nanomedicine as a product category or identify specific characteristics of such applications in order to provide guidance to the manufacturer in establishing that they have such a responsibility. Such consultation or advice should be made free of charge as an incentive for applicants. The EMEA currently clarified in public forums and on their website that manufacturers should consult them at an early stage of development of applications involving nanotechnology [117] . Another important aspect of the Pediatric Regulation is that it establishes an optional procedure for obtaining a single community-wide opinion for a nationally authorized medical product in cases where the pediatric investigation plan formed part of the marketing authorization application. This procedure relates to the referral of opinion of the CHMP and its adoption via a community-authorized decision on the use of the medical product and its inclusion in all national product information. Adoption of such an optional procedure for nanomedicines will ensure a coordinated approach, especially in a situation where producers could apply for authorization via either the centralized (if they are able to prove that the product is innovative) or mutual recognition procedure. This is especially important at the current stage where there is considerable confusion and a lack of guidance as to the regulatory procedures to be adopted for applications involving nanotechnology. This is also a strategy to ensure that there is uniformity future science group
Special Report
in decision-making between the competent authorities of the member states and at the level of the EMEA.
Pharmacovigilance Finally, pharmacovigilance is critical in addressing the specific challenges of collecting safety data on the possible long-term effects given the range of potential risks that both in vivo in vitro studies seem to suggest [11] . The longterm effects of any drug cannot be addressed only by using preclinical studies and are generally ascertained postmarketing and after a product has been in use for a considerable period of time. This problem is especially critical since pediatric safety is paramount. As such, any procedural or methodological advances that enable long-term safety evaluation of products destined for the treatment of pediatric patients will most certainly improve the safety of adult patients. Efficacy within the targeted population of nanomedicine users is another aspect that may need additional study following authorization. In the case of the Pediatric Regulation, in addition to studies being conducted in compliance with the pediatric investigation plan, applicants shall also be obligated to state the preparations made for ensuring the long-term follow up of possible adverse reactions to the use of the medical product and efficacy in the pediatric population. This should also be made mandatory for applicants of all kinds of medical applications using nanotechnology. It should be made obligatory for the applicant to submit and operationalize a riskmanagement system along with the performance of specific postmarketing studies as a condition of marketing authorization. Conclusion In conclusion, a few points need to be reiterated. Currently, developments within the medical products sector seem to indicate that there are a number of applications in the pipeline that use nanocomponents as enabling agents. Given that there have been several EU-level expert committees that have commented on the need to develop regulatory guidance, this seems to be an opportune moment to take stock and identify specific regulatory gaps that could be addressed via multiple mechanisms in the short to medium term. The necessary first step should be to take a decision on whether all nanotechnology applications in both the medicinal products and the medical devices sectors need to be regulated in a similar manner. At this point in time, given the still limited understanding of the full extent www.futuremedicine.com
139
Special Report
Chowdhury
of toxicity effects of all forms of nanoparticles and nanomaterials being used and those under development, it is advisable that the current risk– benefit analysis disciplines in both the medicinal products and the medical devices should aim for comparable equivalence. This would ensure that regulatory disciplines across both these sectors are matched, thus minimizing the incentive for taking advantage of the systemic product categorization issues that are embedded in the regulatory regime. There is also an urgent need to institutionalize procedures in order to ensure transparency and legal certainty for manufacturers. Pending any decision as to whether nanomedicines should follow the centralized authorization procedure, mechanisms need to be established at the earliest possible stage to ensure systematic coordination between the notified bodies, competent authorities of the member states and the EMEA. This is critical in ensuring that uniformity is maintained in the authorization procedures of applications for nanomedicines received by the centralization procedures and the mutual recognition procedure. This exchange of information will also contribute to the building of a database of regulatory actions that would be an important resource for developing more detailed guidelines on this area at a later stage. Furthermore, there is a need to provide guidance as to the obligations at the preauthorization and pharmacovigilance stages for the application for marketing authorization. At the preauthorization stages, the regulatory authorities need to make early-stage (at the investigational stage) consultation mandatory for manufacturers of medicinal products and medicinal devices that use nanotechnology. The thresholds for such an obligation need to be fixed. This consultation mechanism would ensure that regulatory authorities are able to guide manufacturers in ensuring regulatory conformity. The regulatory authorities should also guide holders of marketing authorization in developing risk-management systems in such cases as a precautionary measure. In this context, the procedures and practices followed within the pediatric and ATMP regulatory regime, viz. submission of an investigational plan for early review, optional procedure for central ized authorization and dedicated technical committee for coordinating authorizations and lending advisory support, could be adopted in nanomedicine regulation in Europe. There has been considerable debate on the (in)adequacy of the current pharmaceutical and medical devices framework to regulate the wave 140
Nanomedicine (2010) 5(1)
of new nanomedicines that are under development [118] . As discussed earlier, the debate needs to identify specific regulatory objectives in the short, medium and long term and chart clear regulatory pathways for the use of nanomedicines in Europe. As a precautionary measure, until tailored and specific guidance is developed for the different groups of nanomedicines, it is essential that the principle of equivalence is followed in the authorization procedures for nanomedicines that fall either in the medicinal products or medical devices regime. Until that is done, this sector will continue to be plagued by regulatory discontinuities that could become a serious impediment to the twin objectives of safeguarding public health and ensuring access of innovative nanomedicines to the internal market.
Future perspective The pipeline of nanomedicines seems to offer a much wider range of more complex multifunctional products. Nanoshells that combine imaging and drug-delivery systems and nanoparticles that use magnetic properties to administer drugs along with real-time monitoring facilities are all examples in which multiple modes of action are concurrently combined. In 5–10 years, the products will be in the process of being launched and this will no doubt create additional regulatory challenges. The important thing to note, however, is that how we react today will determine, to a large extent, how prepared we are to address the regulatory challenges that those new-generation nanomedicine will pose in 10 years time. Tackling structural issues such as the definition of nanomedicines, its location within either the medicinal products or medical devices, the creation of a specific regime and the level of standard of care to be adopted are some of the important foundational aspects that are critical in laying down clear regulatory pathways that would secure legal certainty for manufacturers of nanomedicines both now and in the future. Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. future science group
Regulation of nanomedicines in the EU
Special Report
Executive summary The market reality is that nanotechnology applications in the pharmaceutical and medical devices sector are not only spread across a number of sectors but that, increasingly, products combine multiple modes of actions, thereby making strict and clear categorization difficult. It is not necessary to define and develop a single product category for all applications of nanotechnology in the medical sector. A caseby-case approach, where there is a lack of data to develop regulatory guidance, would be prudent at the initial stages. The question is whether applications of nanotechnology across sectors such as medicinal products, medical devices and advanced therapies medicinal products should be regulated in a similar manner and at the same level. The essential regulatory issue is, therefore, whether there should be equivalence or parity in the standard of care that manufacturers/applicants (of marketing authorization) are to maintain across sectors. Another related issue is whether all nanomedicines should be regulated at the community level and subjected to the central authorization procedure, involving a single scientific evaluation of quality, safety and efficacy of the product by the European Medicines Agency (EMEA). There are several innovative procedures and practices that have been adopted within the ATMP and the pediatric regulatory frameworks that could be worth exploring for adoption in nanomedicine regulation in Europe. The setting up of a dedicated committee within the EMEA has been a standard response in the development of specific product regimes in pharmaceuticals. The nano-experts group within the Innovation Task Force could be institutionalized into a full fledged Nanomedicine Committee within the functioning apparatus of the EMEA. Information disclosure is another critical area in the case of new and innovative medicinal products. This is an important step in ensuring that there is transparency between the applicant and the regulatory authority. Such a measure (e.g., a nanomedicine investigation plan) is ideal in the short term given that at this stage many applicants are considering approaching the EMEA or the competent authorities of the member states. Pharmacovigilance is critical in addressing the specific challenges of collecting safety data on the possible long-term effects given the range of potential risks that both in vivo and in vitro studies seem to suggest. Efficacy within the targeted population of nanomedicine users is another aspect that may need additional study following authorization. There has been considerable debate on the adequacy of the current pharmaceutical and medical devices framework to regulate the wave of new nanomedicines that are under development. The debate needs to identify specific regulatory objectives in the short, medium and long term and chart out clear regulatory pathways for the use of nanomedicines in Europe.
Bibliography
6
Papers of special note have been highlighted as: n of interest nn of considerable interest 1
nn
2
Wagner V, Dullart A, Bock A-K, Zweck A: The emerging nanomedicine landscape. Nat. Biotechnol. 24(10), 1211–1217 (2006). Good overview of the market size and variety of nanomedicines that have been launched in Europe and the USA, gathered from patent filings data. Moghimi SM, Hunter AC, Murray JC: Nanomedicine: current status and future prospects. FASEB J. 19, 311–330 (2005).
Paradise JK, Diliberto G, Tisdale A, Kokkoli E: Exploring emerging nanobiotechnology drugs and medical devices. Food Drug Law J. 63(2), 415 (2008).
7
Wagner V, Dullart A, Bock A-K, Zweck A: The emerging nanomedicine landscape. Nat.Biotechnol. 24(10), 1214 (2006).
8
Rapoport N, Gao Z, Kennedy A: Multifunctional nanoparticles for combining ultrasonic tumor imaging and targeted chemotherapy. J. Natl Cancer Institute 99(14), 1095–1106 (2007).
9
Bhogal N: Regulatory and scientific barriers to the safety evaluation of medical nanotechnologies. Nanomedicine 4(5), 495–498 (2009).
Sadrieh N: FDA considerations for regulation of nanomaterial containing products. Conference presentation: Nanotechnology: Impact on Health and Regulation. Organized by the Medicines and Health Products Regulatory Agency, UK (2005).
nn
4
Warren, CW Chan: Research Highlights. Nanomedicine 4(5), 507–508 (2009).
10
5
Jefferys B: The regulation of medical devices and the role of the Medical Devices Agency. Br. J. Clin. Pharmacol. 52, 229–235 (2001).
Abraham J, Lewis G: Regulating Medicines in Europe: Competition, Expertise and Public Health. Routledge, London, UK, 207–212 (2000).
11
Bellucci S, Chiaretti M, Cucina A, Carru GA, Chiaretti AI: Multiwalled carbon nanotube buckypaper: toxicology and biological effects in vitro and in vivo. Nanomedicine 4(5), 531–540 (2009).
3
n
Good comparative study on the differences between the regulation and institutional framework in the medicinal devices and the medicinal products sector in the UK.
future science group
Good overview of the regulatory developments in Europe and the USA and the scientific barriers in the evaluation of medical nanotechnologies.
www.futuremedicine.com
Websites 101 Roszek B, de Jong W, Geertsma R:
Nanotechnology in medical applications: state-of-the-art in materials and devices. RIVM report. 265001001. www.nano.org.uk/nanomednet/images/ stories/Reports/nanotechnology%20 and%20medical%20applications_ netherlands.pdf (Accessed 9 August 2009) nn
Exhaustive study of the range of applications of nanomaterials in medical technology.
102 EMEA, 2006. Reflection Paper
on Nanotechnology-Based Medicinal Products for Human Use, EMEA/CHMP/79769/2006. www.emea.europa.eu/pdfs/human/ genetherapy/7976906en.pdf (Accessed 2 August 2009) 103 Market survey report on Medical
Nanotechnology Markets: Trends, Industry Participants, Product Overview and Market Drivers, pegs the number of authorizations at 18 (Trimark Publications, 2008). www.trimarkpublications.com/samples/ mednanosample.pdf (Accessed 2 August 2009)
141
Special Report
Chowdhury
104 Darin Y Furgeson: Nanotools for toxicity
assessments of nanomedicines; to the FDA, puts the number as 12 (2008). www.fda.gov/ohrms/DOCKETS/ac/08/ slides/2008-4370s1-05-Guest-Furgeson.pdf (Accessed 9 August 2009) 105 Duncan R: Polymer Therapeutics as
Nanomedicines. Presentation at the EMEA First Ad Hoc Expert Group on Nanomedicines, London, UK (2009). www.emea.europa.eu/pdfs/conferenceflyers/ nanotech_workshop/ruth_duncan.pdf (Accessed 2 August 2009) 106 Lebourgeois C: Device and Drug
Combination Products: a New Regulatory, Reimbursement and Marketing Challenge. Lifescience Online (2008). www.lifescience-online.com/articles.html?por talPage=Lifescience+Today.Articles&a=1014 (Accessed 17 August 2009) 107 OJ L 169, 12.7.1993. Council Directive
concerning medical devices. http://eur-lex.europa.eu/LexUriServ/site/en/ consleg/1993/L/01993L0042-20031120-en. pdf (Accessed 2 August 2009) 108 O J L 189. 20.7.1990. Council Directive on
the approximation of the laws of the Member States relating to active implantable medical devices. http://eur-lex.europa.eu/LexUriServ/ LexUriServ. do?uri=CELEX:31990L0385:en:HTML (Accessed 2 August 2009)
109 The framework has been understood as
‘additional’ in the sense of it being an add on to the existing legal framework of Directive 2001/83/EC and Regulation EC/726/2004. See Recital 6 of Regulation EC/1394/2007. http://ec.europa.eu/enterprise/ pharmaceuticals/eudralex/vol-1/ reg_2007_1394/reg_2007_1394_en.pdf (Accessed 9 August 2009)
113 Jong WH, Roszek B, Geertsma R:
Nanotechnology in medical applications: possible risks for human health. RIVM report. 265001002/2005, 34. www.rivm.nl/bibliotheek/ rapporten/265001002.pdf (Accessed 2 August 2009). 114 OJ L 378/1, 27.12.2006. Regulation
EC/1901/2006 on medicinal products for paediatric use. http://ec.europa.eu/enterprise/ pharmaceuticals/eudralex/vol-1/ reg_2006_1901/reg_2006_1901_en.pdf (Accessed 9 August 2009)
110 OJ L 136/34, 31.3.2004. Directive of the
European Parliament and of the Council amending Directive 2001/83/EC on the Community code relating to medicinal products for human use. http://eur-lex.europa.eu/LexUriServ/ LexUriServ.do?uri=OJ:L:2004:136:0034:00 57:EN:PDF (Accessed 9 August 2009)
115 OJ L 324/121, 10.12.2007. Regulation
EC/1394/2007 on advanced therapy medicinal products. http://ec.europa.eu/enterprise/ pharmaceuticals/eudralex/vol-1/ reg_2007_1394/reg_2007_1394_en.pdf
111 OJ L 136/1, 30.4.2004, p.1 Regulation of the
European Parliament and of the Council laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency, as amended by Regulation EC/1901/2006. http://ec.europa.eu/enterprise/ pharmaceuticals/eudralex/vol-1/ reg_2004_726/reg_2004_726_en.pdf (Accessed 2 August 2009)
116 European Medicines Agency: Medicines and
Emerging Science. www.emea.europa.eu/htms/human/mes/ emergingtechnologies.htm#Nanotechnology (Accessed 2 August 2009) 117 Papaluca-Amati M: Nanotechnology: “Safety
for Success” Guidance in the Medical Area, Presentation made at the 2nd Annual Nanotechnology Workshop, Brussels (2008). www.mmmc.be/sanco/nano/ Presentations2008/M%20PapalucaAMAti%20Nanomedicines%20Oct%20 2008%20Brussels%20-MPA.pdf (Accessed on 2 August 2009)
112 Rationale for centralized authorization
procedure, Recital 9 of Regulation EC/1394/2007 on advanced therapy medicinal products. http://ec.europa.eu/enterprise/ pharmaceuticals/eudralex/vol-1/ reg_2007_1394/reg_2007_1394_en.pdf (Accessed 2 August 2009)
nn
Good overview of the ongoing activity in the EMEA on nanomedicines.
118 D’Silva J, Van Calster G: Taking
temperature – a review of European Union regulation in nanomedicine (2008). http://ssrn.com/abstract=1285099 (Accessed 2 August 2009)
142
Nanomedicine (2010) 5(1)
future science group
