- Email: [email protected]
Bacteriophage therapy: Fast-forward to the past lessons identified from the advanced therapy regulation
burns 42 (2016) 11–12
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/burns
Editorial
Bacteriophage therapy: Fast-forward to the past lessons identified from the advanced therapy regulation
Since 1987, the Burn Wound Centre of the Queen Astrid Military Hospital (Brussels, Belgium) has been producing cultures of human epithelial cells (keratinocytes) as an additional surgical tool to treat its critically burnt patients. Initially, the production environment of keratinocyte grafts at the Burn Wound Centre as well as other important aspects that guarantee the safe use of these products on patients (e.g. the donor- and release testing) were regulated solely by national legislation and national quality guidelines. Production units and cell banks were licensed and inspected only by the Belgian national health authorities. In 2004, the European Tissues and Cells Directive 2004/23/EC on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells [1] was published and later transposed into Belgian Law. For the Burn Wound Centre, implementing this new law meant increased production costs and no significant increase in final quality and/or safety of the produced grafts. In 2007, Europe published Regulation (EC) No 1394/2007 on Advanced Therapy Medicinal Products [2], amending Directive 2004/23/EC. Overnight, the keratinocytes cultured at the Burn Wound Centre became (arguably) ‘‘Advanced’’ Therapy Medicinal Products (ATMPs) to be produced as medicinal products for human use. The practical impact of this amendment was (and still is) considerable. A similar development appears imminent in bacteriophage therapy. Bacteriophages are bacterial viruses that can be used for tackling the problem of bacterial resistance development to antibiotics. Therapeutic natural bacteriophages have been in clinical use (including in Europe) for almost 100 years. Regulators today are framing the re-introduction of (natural) bacteriophage therapy into ‘‘modern western’’ medicine as biological medicinal products (BMPs), also subject to stringent regulatory medicinal products requirements. Parallels can be seen between the regulatory history of keratinocytes and current developments in the re-introduction of (natural) bacteriophage therapy. Since 2007, the Burn
Wound Centre of the Queen Astrid Military Hospital sporadically applies bacteriophage therapy in patients infected with antibiotic-resistant bacteria. The first therapeutic use of bacteriophages in the centre was conducted in a small clinical trial in which bacteriophages were sprayed on the patients’ wound. Ten bacteriophage applications were performed on 9 patients. This trial was approved by the Leading Medical Ethical Committee of the University Hospital of the Free University of Brussels (UZ Brussel). After the trial, patients in the Burn Wound Centre continued to receive sporadic spraybased and drain-based treatments with natural therapeutic bacteriophages. These treatments were performed under Article 37 of the 2013 Helsinki Declaration [3] and all patients (or their legal representative) signed an informed consent document. Protocols for the production of natural therapeutic bacteriophages have been increasingly optimised much as keratinocyte production protocols have been optimised over the years. The results of these efforts were published open access (without patent protection) in 2009. Bacteriophage production activities at the hospital are actually not performed in a pharmaceutical GMP environment and the produced natural bacteriophage cocktails are not compliant with the Medicinal Product Legislation. The classification of therapeutic natural bacteriophages as biological medicinal products is disadvantageous because the actual BMPs legal framework does not provide for a hospital exemption procedure, while big pharmaceutical companies are no longer interested in investing in the development of small-spectrum antibacterial products. The Queen Astrid Military Hospital does not experience the Medicinal Product Legislation as an adequate tool for bringing natural therapeutic bacteriophages to patients in a sustainable and tailored way. Hospitals working under a ‘‘yet-to-bedefined’’ BMPs ‘‘hospital exemption’’ should have access to a specific European Bacteriophage Therapy Legislative Frame that guarantees quality and safety for these therapeutic
12
burns 42 (2016) 11–12
bacteriophage products. Today’s European Medicinal Product Legislation needs to be reworked to ensure the sustainable (larger-scale) re-introduction of natural bacteriophage therapy in Europe. Defining a hospital exemption under the actual Biological Medicinal Products Legislation is crucial and needs to target the ‘‘in-hospital’’ use of natural bacteriophages, tailored to the patient’s needs and taking into account the co-evolutionary aspects of what natural bacteriophage therapy really stands for. Hospitals that have obtained the hospital exemption status should have access to tailored and bacteriophagespecific quality and safety guidelines. Efficacy and safety of the treatments need to be documented but not necessarily in the format of a clinical trial which exists for the testing and development of new medicinal products. Specific quality and safety requirements should be elaborated to guarantee patients’ safe access to efficient bacteriophage therapy products and to facilitate research. One could contend that the tailored use of natural bacteriophages produced in-hospital for use on the in-house patients does not constitute a market placement of these tailored therapeutic bacteriophage products and, for these reasons, places these products outside of the scope of European Medicinal Product Directive 2001/83/EC [4]. This again is a motive to publish (urgently) a European bacteriophage therapy specific quality, safety and efficacy Directive.
references
[1] ECTD 2004. European Cell- and Tissue Directive 2004/23/EC of the European Parliament and of the council of 31 March 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells; 2004, http://eurlex.europa.eu/LexUriServ/LexUriServ. do?uri=CELEX:32004L0023:EN:HTML. [2] ATMP 2007. Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on Advanced Therapy Medicinal Products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004; 2007, http://eur-lex.europa.eu/LexUriServ/LexUriServ. do?uri=OJ:L:2007:324:0121:0137:en:PDF. [3] Helsinki 2013. WMA Declaration of Helsinki – ethical principles for medical research involving human subjects. Fortaleza, Brazil: 64th WMA General Assembly; 2013, http:// www.wma.net/en/30publications/10policies/b3/.
[4] EMPD 2001. European Directive 2001/83/EC of the European parliament and of the council on the Community code relating to medicinal products for human use of 6 November 2001; 2001L0083 – EN – 16.11.2012 – 011.001 – 1 (Compiled); 2014, http://www.ema.europa.eu/docs/en_GB/ document_library/Regulatory_and_procedural_guideline/ 2009/10/WC500004481.pdf.
G. Verbekena,b,c,* Queen Astrid Military Hospital, Burn Wound Centre, Laboratory for Molecular and Cellular Technology, Bruynstraat 1, 1120 Brussels, Belgium b KU Leuven, Faculty of Pharmaceutical and Pharmacological Sciences, Herestraat 49, 3000 Leuven, Belgium c Royal Military Academy, Department of Behavioural Sciences, Renaissancelaan 30, 1000 Brussels, Belgium a
I. Huysa,b KU Leuven, Centre for Intellectual Property Rights, Minderbroedersstraat 5, 3000 Leuven, Belgium b KU Leuven, Faculty of Pharmaceutical and Pharmacological Sciences, Herestraat 49, 3000 Leuven, Belgium a
C. Ceulemans Royal Military Academy, Department of Behavioural Sciences, Renaissancelaan 30, 1000 Brussels, Belgium S. Jennes Queen Astrid Military Hospital, Burn Wound Centre, Bruynstraat 1, 1120 Brussels, Belgium D. De Vos J.P. Pirnay Queen Astrid Military Hospital, Burn Wound Centre, Laboratory for Molecular and Cellular Technology, Bruynstraat 1, 1120 Brussels, Belgium *
Corresponding author at: Queen Astrid Military Hospital, Burn Wound Centre, Laboratory for Molecular and Cellular Technology, Bruynstraat 1, 1120 Brussels, Belgium. Tel.: +32 2 264 4856; fax: +32 2 264 4833 E-mail address: [email protected] (G. Verbeken) http://dx.doi.org/10.1016/j.burns.2015.10.022 0305-4179/# 2015 Elsevier Ltd and ISBI. All rights reserved.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/burns
Editorial
Bacteriophage therapy: Fast-forward to the past lessons identified from the advanced therapy regulation
Since 1987, the Burn Wound Centre of the Queen Astrid Military Hospital (Brussels, Belgium) has been producing cultures of human epithelial cells (keratinocytes) as an additional surgical tool to treat its critically burnt patients. Initially, the production environment of keratinocyte grafts at the Burn Wound Centre as well as other important aspects that guarantee the safe use of these products on patients (e.g. the donor- and release testing) were regulated solely by national legislation and national quality guidelines. Production units and cell banks were licensed and inspected only by the Belgian national health authorities. In 2004, the European Tissues and Cells Directive 2004/23/EC on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells [1] was published and later transposed into Belgian Law. For the Burn Wound Centre, implementing this new law meant increased production costs and no significant increase in final quality and/or safety of the produced grafts. In 2007, Europe published Regulation (EC) No 1394/2007 on Advanced Therapy Medicinal Products [2], amending Directive 2004/23/EC. Overnight, the keratinocytes cultured at the Burn Wound Centre became (arguably) ‘‘Advanced’’ Therapy Medicinal Products (ATMPs) to be produced as medicinal products for human use. The practical impact of this amendment was (and still is) considerable. A similar development appears imminent in bacteriophage therapy. Bacteriophages are bacterial viruses that can be used for tackling the problem of bacterial resistance development to antibiotics. Therapeutic natural bacteriophages have been in clinical use (including in Europe) for almost 100 years. Regulators today are framing the re-introduction of (natural) bacteriophage therapy into ‘‘modern western’’ medicine as biological medicinal products (BMPs), also subject to stringent regulatory medicinal products requirements. Parallels can be seen between the regulatory history of keratinocytes and current developments in the re-introduction of (natural) bacteriophage therapy. Since 2007, the Burn
Wound Centre of the Queen Astrid Military Hospital sporadically applies bacteriophage therapy in patients infected with antibiotic-resistant bacteria. The first therapeutic use of bacteriophages in the centre was conducted in a small clinical trial in which bacteriophages were sprayed on the patients’ wound. Ten bacteriophage applications were performed on 9 patients. This trial was approved by the Leading Medical Ethical Committee of the University Hospital of the Free University of Brussels (UZ Brussel). After the trial, patients in the Burn Wound Centre continued to receive sporadic spraybased and drain-based treatments with natural therapeutic bacteriophages. These treatments were performed under Article 37 of the 2013 Helsinki Declaration [3] and all patients (or their legal representative) signed an informed consent document. Protocols for the production of natural therapeutic bacteriophages have been increasingly optimised much as keratinocyte production protocols have been optimised over the years. The results of these efforts were published open access (without patent protection) in 2009. Bacteriophage production activities at the hospital are actually not performed in a pharmaceutical GMP environment and the produced natural bacteriophage cocktails are not compliant with the Medicinal Product Legislation. The classification of therapeutic natural bacteriophages as biological medicinal products is disadvantageous because the actual BMPs legal framework does not provide for a hospital exemption procedure, while big pharmaceutical companies are no longer interested in investing in the development of small-spectrum antibacterial products. The Queen Astrid Military Hospital does not experience the Medicinal Product Legislation as an adequate tool for bringing natural therapeutic bacteriophages to patients in a sustainable and tailored way. Hospitals working under a ‘‘yet-to-bedefined’’ BMPs ‘‘hospital exemption’’ should have access to a specific European Bacteriophage Therapy Legislative Frame that guarantees quality and safety for these therapeutic
12
burns 42 (2016) 11–12
bacteriophage products. Today’s European Medicinal Product Legislation needs to be reworked to ensure the sustainable (larger-scale) re-introduction of natural bacteriophage therapy in Europe. Defining a hospital exemption under the actual Biological Medicinal Products Legislation is crucial and needs to target the ‘‘in-hospital’’ use of natural bacteriophages, tailored to the patient’s needs and taking into account the co-evolutionary aspects of what natural bacteriophage therapy really stands for. Hospitals that have obtained the hospital exemption status should have access to tailored and bacteriophagespecific quality and safety guidelines. Efficacy and safety of the treatments need to be documented but not necessarily in the format of a clinical trial which exists for the testing and development of new medicinal products. Specific quality and safety requirements should be elaborated to guarantee patients’ safe access to efficient bacteriophage therapy products and to facilitate research. One could contend that the tailored use of natural bacteriophages produced in-hospital for use on the in-house patients does not constitute a market placement of these tailored therapeutic bacteriophage products and, for these reasons, places these products outside of the scope of European Medicinal Product Directive 2001/83/EC [4]. This again is a motive to publish (urgently) a European bacteriophage therapy specific quality, safety and efficacy Directive.
references
[1] ECTD 2004. European Cell- and Tissue Directive 2004/23/EC of the European Parliament and of the council of 31 March 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells; 2004, http://eurlex.europa.eu/LexUriServ/LexUriServ. do?uri=CELEX:32004L0023:EN:HTML. [2] ATMP 2007. Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on Advanced Therapy Medicinal Products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004; 2007, http://eur-lex.europa.eu/LexUriServ/LexUriServ. do?uri=OJ:L:2007:324:0121:0137:en:PDF. [3] Helsinki 2013. WMA Declaration of Helsinki – ethical principles for medical research involving human subjects. Fortaleza, Brazil: 64th WMA General Assembly; 2013, http:// www.wma.net/en/30publications/10policies/b3/.
[4] EMPD 2001. European Directive 2001/83/EC of the European parliament and of the council on the Community code relating to medicinal products for human use of 6 November 2001; 2001L0083 – EN – 16.11.2012 – 011.001 – 1 (Compiled); 2014, http://www.ema.europa.eu/docs/en_GB/ document_library/Regulatory_and_procedural_guideline/ 2009/10/WC500004481.pdf.
G. Verbekena,b,c,* Queen Astrid Military Hospital, Burn Wound Centre, Laboratory for Molecular and Cellular Technology, Bruynstraat 1, 1120 Brussels, Belgium b KU Leuven, Faculty of Pharmaceutical and Pharmacological Sciences, Herestraat 49, 3000 Leuven, Belgium c Royal Military Academy, Department of Behavioural Sciences, Renaissancelaan 30, 1000 Brussels, Belgium a
I. Huysa,b KU Leuven, Centre for Intellectual Property Rights, Minderbroedersstraat 5, 3000 Leuven, Belgium b KU Leuven, Faculty of Pharmaceutical and Pharmacological Sciences, Herestraat 49, 3000 Leuven, Belgium a
C. Ceulemans Royal Military Academy, Department of Behavioural Sciences, Renaissancelaan 30, 1000 Brussels, Belgium S. Jennes Queen Astrid Military Hospital, Burn Wound Centre, Bruynstraat 1, 1120 Brussels, Belgium D. De Vos J.P. Pirnay Queen Astrid Military Hospital, Burn Wound Centre, Laboratory for Molecular and Cellular Technology, Bruynstraat 1, 1120 Brussels, Belgium *
Corresponding author at: Queen Astrid Military Hospital, Burn Wound Centre, Laboratory for Molecular and Cellular Technology, Bruynstraat 1, 1120 Brussels, Belgium. Tel.: +32 2 264 4856; fax: +32 2 264 4833 E-mail address: [email protected] (G. Verbeken) http://dx.doi.org/10.1016/j.burns.2015.10.022 0305-4179/# 2015 Elsevier Ltd and ISBI. All rights reserved.