EPA staff assessment report on application APP202601
To import and release a genetically modified live-attenuated vaccinia virus for use in a Phase 3 clinical trial to examine safety and efficacy in patients with hepatocellular carcinoma.
September 2015
ADVICE TO THE DECISION MAKER 2
EPA staff assessment report for application APP202601
Executive summary and recommendation
On 16 September 2015, Clinical Network Services Pty Ltd lodged an application to import and release a genetically modified live-attenuated vaccinia virus (Pexa-Vec; also known as JX-594) for use in a Phase 3 clinical trial to examine safety and efficacy in patients with hepatocellular carcinoma. The application was made on behalf of SillaJen Biotherapeutics Inc (the applicant), pursuant to section 34 of the Hazardous Substances and New Organisms (HSNO) Act 1996 (the “HSNO Act”).
Section 38I of the HSNO Act provides for a rapid assessment of applications received under section 34, if the application seeks the release of a qualifying organism. A qualifying organism is, in part, a new organism (including a genetically modified organism) that is a medicine or is contained in a medicine.
Based on the information in the application and other readily available sources, we found that it is highly improbable that the dose and route of administration of Pexa-Vec will have significant adverse effects on the health of the public or any valued species. Moreover, we found that it is highly improbable that Pexa- Vec could form a self-sustaining population and have significant adverse effects on the health of the public, any valued species, natural habitats, or the environment.
Therefore, we recommend that the application be approved subject to the proposed controls.
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Table of contents
Executive summary and recommendation ...... 2 Table of contents ...... 3 Purpose of this document ...... 4 Application summary ...... 4 The organism: Pexa-Vec ...... 4 Information from other agencies ...... 13 Legislative criteria to be considered ...... 13 Conclusion and recommendation ...... 15 References ...... 17 Appendix 1: MoH comments ...... 20 Appendix 2: MPI comments ...... 22 Appendix 3: MPI proposed controls and EPA responses ...... 26
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Purpose of this document
1. This Staff Assessment Report has been prepared by EPA staff to assist the decision-maker in considering application APP202601. It contains information from the applicant and other readily available sources, and it sets out the statutory criteria applicable to considering this application under the HSNO Act. Application summary
2. On 16 September 2015, Clinical Network Services Pty Ltd lodged an application under section 34 of the HSNO Act (on behalf of SillaJen Biotherapeutics Inc, the applicant) seeking approval to import and release a genetically modified live-attenuated vaccinia virus (Pexa-Vec; also known as JX-594). The applicant intends to use Pexa-Vec in a Phase 3 clinical trial to examine safety and efficacy as a therapeutic oncolytic vaccine immunotherapy in patients with hepatocellular carcinoma (ie, a form of liver cancer).
3. The applicant intends to conduct the Phase 3 clinical trial at various sites in New Zealand. The areas where Pexa-Vec will be used include public hospitals and associated facilities (such as pharmacies and laboratories) where Pexa-Vec will be transported, stored and prepared for intratumoural injection into patients with liver cancer. These sites will include laboratories where specimens from treated patients will be analysed to monitor patient safety during the clinical study. Private organisations (such as laboratories, courier companies and centralised vaccine storage and distribution centres) may also be contracted to provide services (section 5 of the application).
4. Pexa-Vec treated patients will be allowed to return to their homes after Pexa-Vec is intratumourally administered. The organism: Pexa-Vec
5. The organism Pexa-Vec (also known as Pexastimogene Devacirepvec, or JX-594) is a genetically modified live-attenuated vaccinia virus. The vaccinia virus strain used to create Pexa-Vec is the Wyeth strain1.
Vaccinia virus
6. The first medical application of vaccinia virus was as a vaccine against smallpox at some time before the 1930s (Fenner et al. 1988). Vaccination against smallpox using live vaccinia virus was effective because vaccination with vaccinia virus generates antibodies that cross-react with smallpox. The vaccinia virus vaccine was key to the Intensified Smallpox Eradication Programme
1 DryvaxTM, from which Pexa-Vec virus was prepared, is a mixed population of Wyeth vaccinia strains (Nalca et al. 2010). During the manufacturing process of Pexa-Vec virus, one Wyeth strain was selected (LVB Clone 1; (Bergonie 2014)).
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established in 1966 by the World Health Assembly, which culminated in the global eradication of smallpox in 1980 (Fenner et al 1988).
7. Four vaccinia strains, namely EM-63, Lister, New York City Board of Health (also known as the Wyeth strain), and Temple of Heaven were the strains most widely used in the many millions of vaccinations administered during the global smallpox eradication programme (Fenner et al. 1988).
8. Vaccinia virus has the following taxonomic classification:
Family: Poxiviridae (ie, viruses that cause “pockmarks” on the skin (Fenner et al. 1988));
Subfamily: Chordopoxvirus (ie, poxviruses that infect vertebrates); Genus: Orthopoxvirus;
Species: Vaccinia virus
9. Vaccinia virus is an enveloped poxvirus that contains a linear double-stranded DNA genome. Upon infection of the host, the virus spreads through the blood, manifesting as leucocyte-associated viraemia2 (Fenner et al. 1988; Chahroudi et al. 2005). From the blood, the virus spreads to epidermal tissues (Thorne et al. 2007) where it replicates within the cytoplasm of infected cells. Mature vaccinia virus particles (virions) are released when the infected epidermal cell (ie, skin and mucous membranes) undergoes virus-induced disintegration (lysis) (Fenner et al. 1988).
10. Following vaccination with vaccinia virus, a papule3 typically develops within three to five days at the site of injection, which then becomes a pustule4. A scab then forms, which eventually peels away leaving a pitted vaccination scar typically by three weeks post-vaccination (Fenner et al. 1988; Lane et al. 2003). Vaccination produces a mild generalized infection in humans (swelling, tenderness of the draining lymph nodes), and viraemia is sometimes detectable between three to 10 days post-vaccination. Sometimes, vaccinia virus can be isolated from swabs of the respiratory tract following vaccination (saliva from swabbed tonsils, pharyngeal swabs etc.) (Fenner et al. 1988).
11. Transmission of vaccinia virus from vaccinated individuals to unvaccinated individuals is rare (recorded as occurring 20-60 times for every million primary vaccinations administered in the 1950s and 1960s), and generally requires intimate physical contact5 (Lane et al. 2003).
12. Additional biological characteristics of vaccinia virus, and clinical observations following vaccination with vaccinia virus, are discussed where applicable in subsequent sections of this document.
2 Viraemia is the presence of virus/viruses in the bloodstream. 3 A papule is a solid elevation of skin with no visible fluid, varying in size from a pinhead to 1 cm. 4 A pustule is a small bump on the skin that is filled with fluid or pus. 5 The evidence for respiratory/airborne spread of vaccinia virus is scant (Lane et al. 2003).
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The genetic modifications used to create Pexa-Vec
13. Pexa-Vec (Pexastimogene Devacirepvec, also known as JX-594) is a live-attenuated vaccinia virus that contains three genetic modifications: 1) disruption of the viral thymidine kinase gene by, 2) insertion of the gene for human granulocyte macrophage-colony stimulating factor (hGM- CSF), and 3) insertion of the gene for the β-galactosidase enzyme (LacZ).
14. These modifications were achieved by the co-transfection of mammalian cells with unmodified vaccinia virus (ie, the Wyeth strain) and the plasmid pSC65/hGM-CSF (which carries the genes for hGM-CSF and LacZ) ((Kim et al. 2006); section 3.1 of the application).
15. These modifications confer three specific properties on Pexa-Vec relative to vaccinia virus. First, deactivation of the viral thymidine kinase gene results in a diminished capability of Pexa-Vec to replicate within all but the most rapidly dividing cells (ie, cancer cells) because only these cells express sufficiently elevated levels of thymidine kinase to allow Pexa-Vec to replicate. This characteristic has been described in numerous peer-reviewed publications as ‘selective replication’ within cancer cells. Like vaccinia virus, Pexa-Vec causes replication-dependent cell lysis, which is the mechanism for its cancer cell-lysing (oncolytic) property. Second, expression of hGM-CSF stimulates systemic anti-tumour immunity (ie, mechanism for the vaccine immunotherapy property). Third, the β-galactosidase enzyme provides a marker for viral replication in tumour biopsies, and in potential shedding or transfer of Pexa-Vec to caregivers (see section 3.1 of the application).
Intended use of Pexa-Vec
16. The applicant states that they intend to administer Pexa-Vec intratumourally to patients with hepatocellular carcinoma (a form of liver cancer) who are enrolled in a Phase 3 clinical trial. In a previous clinical trial, some patients received up to eight separate doses of Pexa-Vec (Park et al. 2008).
17. Control 1 is proposed to limit the use of Pexa-Vec to intratumoural administration of patients enrolled in a Phase 3 clinical trial (see paragraph 67). That means that Pexa-Vec cannot be used for any other purpose without a further HSNO Act approval.
18. In accordance with proposed Control 2 (see paragraph 67), the EPA and MPI will be notified of the location of the clinical trial sites.
Potential benefits from Pexa-Vec use
19. The incidence of liver cancer in New Zealand is approximately 180 new cases per year (Torre et al. 2015). The disease is approximately three times more prevalent among men than women; and compared with non-Māori, Māori men have nearly five times the rate of liver cancer, and Māori women have three times the rate of liver cancer (Chamberlain et al. 2013).
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20. Data from previous clinical trials support Pexa-Vec as a promising candidate therapy for liver cancer (Liu et al. 2008; Park et al. 2008; Heo et al. 2011; Heo et al. 2013)6. As such, the potential immediate benefits of Pexa-Vec to the patients recruited to the applicant’s Phase 3 clinical trial include tumour shrinkage, alleviation of cancer symptoms and improved quality of life, cancer remission and prolonged survival (section 5 of the application).
21. Pexa-Vec also has the potential to benefit the wider New Zealand community with liver cancer, subject to positive results from the Phase 3 clinical trial described and regulatory approval for commercial release.
Potential adverse effects from Pexa-Vec use
22. Flu-like symptoms are common following Pexa-Vec treatment (Liu et al. 2008; Park et al. 2008; Breitbach et al. 2011; Heo et al. 2013). Other side effects experienced include: transient platelet deficiency in the blood (this causes bruising and other symptoms) (Park et al. 2008), fever, chills, nausea, vomiting, anorexia (Breitbach et al. 2011; Heo et al. 2013), rigors, low white blood cell count (Heo et al. 2013), fatigue, headache, high and low blood pressure, rapid heart rate, and muscle pain (Breitbach et al. 2011).
Potential clinical complications of Pexa-Vec treatment based on the vaccination history of vaccinia virus 23. As described previously, vaccination with vaccinia virus usually produces a mild generalized infection in humans (swelling, tenderness of the draining lymph nodes) (see paragraph 10). However, vaccination with vaccinia virus is not without very low risk of the following significant clinical complications:
Eczema vaccinatum is a severe, widespread infection of the skin that could occur in vaccinated or unvaccinated contacts who have eczema (frequency rate: 66 cases (no deaths) among approximately 14.1 million US vaccine recipients, and 60 contact-acquired cases (one death), for the year 1968 (Fenner et al. 1988));
Progressive vaccinia is a severe, potentially fatal illness characterised by progressive necrosis at the site of vaccination that could occur in vaccinated individuals who suffer from a deficient immune system (frequency rate: 11 cases (four deaths) among approximately 14.1 million US vaccine recipients for the year 1968 (Fenner et al. 1988));
Generalized vaccinia is characterised by a vesicular rash that sometimes covers the entire body. The rash is self-limiting and little or no therapy is administered (frequency rate: 141 cases
6 Vaccinia virus exhibits an inherent tropism for tumour cells, replicating to higher levels in the tumour cell lines than in the normal cells (Thorne et al. 2007; Heo et al. 2011).
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(no deaths) among approximately 14.1 million US vaccine recipients, and two contact-acquired cases, for the year 1968 (Fenner et al. 1988));
Accidental infection of a body part away from the inoculation site (eyelid etc.) is a common complication of vaccination with vaccinia virus (frequency rate: 149 cases (no deaths) among approximately 14.1 million US vaccine recipients, and 44 contact-acquired cases, for the year 1968 (Fenner et al. 1988));
Postvaccinial encephalitis is a neurological complication of vaccination with vaccinia virus (frequency rate: 16 cases (four deaths) among approximately 14.1 million US vaccine recipients for the year 1968; (Fenner et al. 1988)).
24. The New York City Board of Health strain (also known as the Wyeth strain), which was one of the vaccines used during the smallpox eradication programme, had a somewhat lower pathogenicity, in terms of the frequency of clinical complications (Fenner et al. 1988; Nalca et al. 2010).
25. Vaccinia virus is a Risk Group 2 microorganism7, meaning it is unlikely to be a serious hazard to laboratory personnel, the community, animals, or the environment, and it presents a limited risk of infection spread. Further, there are effective treatments and preventive measures with respect to any infections that it may cause (outlined below; see paragraph 42).
26. There are no reports of Pexa-Vec inducing the aforementioned clinical complications, but they are still theoretical concerns regarding Pexa-Vec use. However, considering that Pexa-Vec is an attenuated strain of vaccinia virus, it is highly unlikely that the aforementioned clinical complications will develop following Pexa-Vec treatment.
Capacity of Pexa-Vec to replicate within cancer cells over normal cells
27. Thymidine kinase is an enzyme involved in DNA synthesis. Rapidly proliferating cancer cells commonly express elevated levels of thymidine kinase, but levels are extremely low (almost undetectable) in resting/non-proliferating normal cells (Hengstschlager et al. 1994; Hengstschlager et al. 1998; Parato et al. 2012; Heo et al. 2014). As such, Pexa-Vec should selectively replicate within cancer cells (ie, high levels of cellular thymidine kinase) because Pexa-Vec contains a deactivated thymidine kinase gene.
28. In a clinical trial that involved intratumoural administration of Pexa-Vec to 14 liver cancer patients, tumour reduction was detected in some treated patients, and no healthy-organ toxicity was noted (Park et al. 2008) – a result that suggests Pexa-Vec replication is highly selective for cancer cells. Breitbach et al. (2011) have shown that Pexa-Vec selectively replicates within tumour tissue (colon, endometrial and rectal) over normal tissue in vitro (ie, most tumours had high-intensity staining for
7 As Risk Group 2 is defined in the Australian/New Zealand Standard Safety in laboratories. Part 3: Microbiological aspects and containment facilities (AS/NZS 2243.3.2002).
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Pexa-Vec whereas normal tissues did not (Breitbach et al. 2011)). Further, Parato et al. (2012) have shown that while Pexa-Vec replicated in a variety of cancer cell types in vitro, eight normal tissues displayed either no apparent susceptibility to Pexa-Vec (normal tissue types: brain, lung, ovarian, cervical, vulvar, endometrial and renal), or less sensitivity to Pexa-Vec infection (one of three normal colon/rectal cell samples) (Parato et al. 2012).
29. Although gut crypt epithelial cells are highly proliferative, neither viral replication nor gut toxicity have been reported in normal colorectal tissue following Pexa-Vec treatment (Park et al. 2008; Breitbach et al. 2011).
30. Consistent with intratumoural replication and subsequent leakage into the systemic circulation through lysis of the cancer cells, Pexa-Vec has been detected in the blood of some treated patients up to five weeks post-administration in clinical trials (Park et al. 2008; Heo et al. 2013). However, although blood cells are highly proliferative, Breitbach et al. (2011) and Parato et al. (2012) have demonstrated in vitro that peripheral blood mononuclear cells (PBMCs) are highly resistant to Pexa- Vec replication (Breitbach et al. 2011; Parato et al. 2012).
31. Epidermal skin cells are rapidly proliferating cells, and as is to be expected, based on the biological properties of vaccinia virus (see paragraph 10), skin lesions have been reported following Pexa-Vec treatment (outlined in the following section of this document).
Capacity of Pexa-Vec to spread from treated patients
32. Some of the Pexa-Vec clinical trials have reported that one to two patients developed small skin pustules a few days after Pexa-Vec administration (approximately 5-10% of treated individuals; from one to 10 pustules per patient), but the pustules later cleared without complication (Breitbach et al. 2011; Heo et al. 2013). Specifically, Heo et al. (2013) observed skin pustule formation on the extremities, forehead and trunk, which cleared in approximately six weeks (Heo et al. 2013).
33. Similarly, the applicant states that of the patients treated with Pexa-Vec (over 300 patients with advanced cancer have been treated with Pexa-Vec (Breitbach et al. 2015))8, 23% of Pexa-Vec treated patients develop pustules following treatment (69/300), and 6% of all treatment administrations (72/1200; individuals are treated more than once; frequency rates include intravenous and intratumoural administration). The Pexa-Vec-induced pustules are similar in appearance and size (<10 mm in diameter) to pustules that have been observed after administration of vaccinia virus for vaccination purposes. However, the Pexa-Vec pustules generally tend to remain intact and be less prone to ulceration than vaccinia vaccine pustules. Further, all Pexa-Vec pustules have been self-limiting and cleared without complications or the need for specific anti-viral treatment, in trials to date. Onset of pustules is typically within one week of Pexa-
8 The Pexa-Vec clinical trials conducted in the USA are described on ClinicalTrials.gov (https://www.clinicaltrials.gov/).
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Vec administration, with resolution within the following two to three weeks. Most patients with skin pustules developed one to five pustules (section 3.1 of the application).
34. Of note, in all 14 patients treated only via intratumoural administration of Pexa-Vec, no throat swabs were found to be positive for Pexa-Vec ((Park et al. 2008); section 6.2 of the application).
Capacity for Pexa-Vec to shed from treated patients to untreated individuals and induce significant adverse effects 35. Pexa-Vec transmission from treated individuals to untreated individuals has not been reported (see section 3.1 of the application), meaning Pexa-Vec transmission is currently only a theoretical concern based on the rare occurrence of vaccinia transmission from vaccinated individuals to close contacts (see paragraph 11).
36. A lack of evidence for Pexa-Vec transmission can likely be credited in part to the applicant instructing treated individuals on how to avoid contact with pustules, before they are treated, should they form following treatment. This includes covering pustules with a non-occlusive dressing until a scab forms and peels away, laundering textiles and fabrics in hot water (71°C) with detergent and hot air drying, and instructing treated individuals not to touch their pustules or let anyone come into direct contact with them (section 6.2 of the application).
37. Considering vaccinia virus is completely inactivated within 60 minutes at 55°C (within 90 minutes at 50 °C), and is inactivated when exposed to sunlight (Fenner et al. 1988; Sagripanti et al. 2013), Pexa-Vec transmission via contaminated surfaces is highly unlikely. Disrupting the thymidine kinase gene does not confer any trait that would make Pexa-Vec less sensitive to UVB radiation (ie, sunlight; section 6.2 of the application).
38. We note that Pexa-Vec treated individuals will be permitted to leave the clinical setting following Pexa-Vec administration, and may be required to cover pustules in non-clinical settings (their homes). Therefore, we propose Control 3 and Control 4.
39. Control 3 requires all individuals who are treated with Pexa-Vec be educated about the potential for Pexa-Vec transmission, and instructed on pustule management practices, before treatment (see paragraph 67).
40. Control 4 requires all individuals who are treated with Pexa-Vec to be provided with a biohazard container for disposal of used pustule dressings at home. These containers must be returned to the clinical trial site for medical waste disposal (see paragraph 67). This will provide for the appropriate disposal of dressings and other waste material that may carry Pexa-Vec.
41. In light of the aforementioned Pexa-Vec pustule management practices, and poor survival of the modified host when exposed to heat and sunlight, we consider that Pexa-Vec transmission from a treated individual to an untreated individual is highly unlikely. If transmission did occur, the level of exposure via pustular lesions is predicted to be low compared to the doses received by Pexa-Vec treated individuals, and low compared to doses of vaccinia virus used in previous smallpox
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vaccination programmes (ie, the doses associated with the clinical complications described in paragraph 23). In the highly unlikely event of a Pexa-Vec infection resulting from the exposure of an untreated individual to a Pexa-Vec treated individual, the exposed individual would most likely clear attenuated Pexa-Vec rather than experience a significant adverse reaction because Pexa-Vec replication is significantly impaired or non-existent in healthy tissue.
42. Therefore, we consider that the likelihood of an untreated individual being infected with attenuated Pexa-Vec and developing a significant adverse reaction is highly improbable. Regardless, if an untreated individual was to demonstrate virus-associated toxicity (confirmed by assaying for β- galactosidase; see paragraph 15), therapy could be initiated with vaccinia immunoglobulin (VIG) and/or cidofovir (anti-viral agents shown to inhibit vaccinia virus replication (Thorne et al. 2007; Nalca et al. 2010)). A local stock of VIG and cidofovir will be held in Singapore by the applicant and can be dispatched overnight to any New Zealand hospital if requested (see section 6.2 of the application).
Ability of Pexa-Vec to infect and replicate in animal hosts
43. In the unlikely event of Pexa-Vec transmission from a treated individual to a contacted animal, attenuated Pexa-Vec is not expected to replicate within the healthy tissue of the animal because Pexa-Vec replication exhibits selectivity for tumours. Kim et al. (2006) have demonstrated Pexa-Vec tumour selectivity in a rabbit animal model with minimal or no virus detected in the normal tissues (including lung, liver, ovary, kidney, spleen, heart, skeletal muscle, bone marrow and colon tissue) (Kim et al. 2006).
44. The EPA did not identify any pre-clinical Pexa-Vec studies that involved avian species. Of note, no reports of vaccinia virus ever infecting birds during its long use as a vaccine were identified either.
45. Therefore, we consider that the likelihood of untreated animal species being infected with attenuated Pexa-Vec and developing a significant adverse reaction is highly improbable.
Genetic stability of Pexa-Vec and capacity to recombine with other poxviruses
46. Double-stranded DNA viruses, such as vaccinia virus, typically have very low rates of mutation from one cellular passage to the next (Nalca et al. 2010).
47. Pexa-Vec could revert its genome back to that of the unmodified vaccinia virus (ie, the Wyeth vaccinia strain) by eliminating the genes inserted in the thymidine kinase gene (ie, genes for hGM- CSF and LacZ, and regulatory elements). However, genetic stability studies of Pexa-Vec have not detected spontaneous revertants (section 3.1 of the application). Specifically, screening for β- galactosidase expression within Pexa-Vec infected cells is used for the evaluation of Pexa-Vec
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genetic stability (ie, expressing plaques9 appear blue; non-expressing plaques appear as white colourless “holes” in the cellular monolayer). More than 500 plaques have been evaluated for β- galactosidase expression from two clinical lots of Pexa-Vec, and the results show that the genetic stability is comparable from one clinical lot to another (Institut Bergonie).
Recombination in orthopoxviruses 48. Horizontal gene transfer (HGT) is the stable transfer of genetic material from one organism to another without reproduction or human intervention. For viruses, HGT can occur via genetic recombination between replicating viruses within a co-infected cell (Keese 2008) – such events have the potential to generate a novel virus with altered pathogenic properties.
49. Genetic recombination between vaccinia virus strains in vitro has been reported (Fenner et al. 1958; Yao et al. 2003). Genetic recombination has also been reported to occur between other species of orthopoxviruses in vitro, within laboratory animals and in nature (Gershon et al. 1989). However, the EPA did not identify any examples of vaccinia recombinants having arisen under natural conditions (ie, no reports of recombination between vaccinia strains, nor reports of recombination between vaccinia strains and other orthopoxviruses or closely related parapoxviruses10, under natural conditions).
50. The likelihood that administered Pexa-Vec (or shed Pexa-Vec) will recombine with other poxviruses within treated individuals (or within infected untreated individuals or animals) and yield recombinant poxviruses of concern (ie, an undesirable self-sustaining population), is unlikely given that: In the long history of mass vaccination against smallpox using vaccinia virus, there is not one reported instance of a transmissible vaccinia strain taking hold and spreading through a vaccinated region (within people or animals); If a Pexa-Vec viral recombinant was generated within a treated individual, the recombined virus would likely remain within the individual, because Pexa-Vec transmission from a treated individual has never been reported (Pexa-Vec is only a theoretical concern based on the vaccination history of the unmodified host); If an untreated individual or animal infected with a poxvirus were exposed and subsequently infected with Pexa-Vec, genetic recombination could only occur in the short period where any poxviruses were viraemic, or when the replicating poxviruses co-infect a cancerous cell (Pexa- Vec replication is highly impaired or non-existent in normal cells).
51. Therefore, we consider the likelihood of a virulent recombinant Pexa-Vec virus forming is highly improbable.
9 As the virus replicates and spreads within a cell culture, it generates regions of cell destruction known as plaques. 10 Parapoxviruses infect sheep, goats, cattle and deer in New Zealand (McFadden et al. 2012).
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Information from other agencies
52. The Department of Conservation (DOC), the Ministry for Primary Industries (MPI) and the Ministry of Health (MoH) were given the opportunity to comment on the application.
53. DOC noted that they agree that Pexa-Vec is unlikely to be able to form a self-sustaining population in the environment, and don’t expect that there would be any adverse environmental effects from this release application.
54. MoH noted that they consider this release application presents a minimal public health risk for the following reasons: Pexa-Vec transmission will be minimised when standard infection prevention and control procedures are applied effectively, shed Pexa-Vec is unlikely to infect and replicate within healthy people because it exhibits tumour selectivity (if it did manage to infect a healthy person, the resulting infection would be minor in most people), Pexa-Vec is genetically stable and viral recombination with other poxviruses is unlikely.
55. MoH also acknowledged that there is an increased risk of complications in immunocompromised people (see paragraph 23), and for this reason, Pexa-Vec recipients should be treated in isolation from other cancer patients and should avoid contact with immunocompromised people while pustules are present11. However, MoH commented that the minimal risk of harm to people is far outweighed by the potential benefits of Pexa-Vec treatment (see Appendix 1 for full comments received from MoH).
56. MPI noted that they agree the environmental risk from this release application is negligible (including risk to animals and primary production; see Appendix 2 for full comments received from MPI). MPI’s proposed controls have been addressed in Appendix 3. Legislative criteria to be considered
57. Section 38I of the HSNO Act provides for the rapid assessment of applications that seek to release qualifying organisms. A qualifying organism is, in part, a new organism that is or is contained in a medicine (as defined in section 3 of the Medicines Act 1981).
58. Pexa-Vec is a medicine as it is “for administering to 1 or more human beings for a therapeutic purpose” (in accordance with section 3 of the Medicines Act 1981).
59. In order to be approved for release as a qualifying organism, section 38I(3) of the HSNO Act requires that the decision-maker be satisfied that, taking into account all the controls that will be imposed (if any), it is highly improbable that: (a) the dose and routes of administration of the medicine would have significant adverse effects on- (i) the health of the public; or
11 There is also an increased risk of complications in people with eczema (see paragraph 23).
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(ii) any valued species; and (b) the qualifying organism could form an undesirable self-sustaining population and would have significant adverse effects on- (i) the health and safety of the public; or (ii) any valued species; or (iii) natural habitats; or (iv) the environment.
60. In doing so, the effects of the medicine or qualifying organism in the person who is being treated with the medicine are not to be taken into account as per section 38I(4) of the HSNO Act.
61. In the first instance, we have assessed the organism against these criteria. This assessment is set out in the following section of this report.
62. If the organism does not meet these criteria, the applicant may request that the application be considered under section 38, or section 38A.
Assessment of the risk of Pexa-Vec conditional release against legislative criteria
63. It is highly improbable that the dose and intratumoural administration of Pexa-Vec to individuals with hepatocellular carcinoma will have significant adverse effects on the health of the public or any value species, given that: Pexa-Vec transmission from treated individuals to untreated individuals/animals has not been reported, and transmission of unmodified strains of vaccinia virus from vaccinated individuals to unvaccinated individuals/animals is rare; In the highly unlikely event of a Pexa-Vec infection resulting from the exposure of an untreated individual/animal to a Pexa-Vec treated individual, an exposed individual/animal would most likely clear attenuated Pexa-Vec rather than experience an adverse reaction because Pexa-Vec replication is significantly impaired or non-existent in healthy tissue.
64. Moreover, it is highly improbable that Pexa-Vec could form an undesirable self-sustaining population that would have significant adverse effects on the health and safety of the public, any valued species, natural habitats or the environment, given that: Pexa-Vec replication is significantly impaired or non-existent (attenuated) in healthy tissue due to deactivation of the thymidine kinase gene; Pexa-Vec attenuation is genetically stable; Formation of a self-sustaining Pexa-Vec/poxvirus recombinant is highly unlikely because genetic recombination could only occur in the short period where the poxviruses were viraemic, or if the replicating poxviruses co-infected a cancerous cell.
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Conclusion and recommendation
65. Based on the intrinsic properties of vaccinia virus and the specific properties of attenuated Pexa- Vec, we consider that it is highly improbable that Pexa-Vec will have any significant adverse effects on the health and safety of the public, any valued species, natural habitats or the environment if Pexa-Vec is used in a Phase 3 clinical trial for patients with hepatocellular carcinoma.
66. We acknowledge that all clinical trials in New Zealand are expected to be conducted in accordance with the standards set out in the Note for Guidance on Good Clinical Practice (Medsafe 2015); and that all New Zealand clinics and hospitals are expected to follow New Zealand Health and Disability Services (Infection Prevention and Control) Standards (NZS 8134.3.3:2008)12.
67. We recommend that this application to import and release Pexa-Vec (JX-594) be approved subject to the following controls:
Control 1 - The organism (Pexa-Vec; JX-594) must only be intratumourally administered to individuals with hepatocellular carcinoma who are enrolled in a Phase 3 clinical trial to examine the safety and efficacy of Pexa-Vec in patients with hepatocellular carcinoma.
Control 2 - The EPA and MPI must be notified, in writing, of the location of the clinical trial site before this approval is used at the site for the first time.
Control 3 - Individuals who are treated with the organism must be educated about the potential for Pexa-Vec transmission to untreated individuals and animals, and instructed on pustule management practices, before treatment.
Control 4 - Individuals who are treated with the organism must be provided with a biohazard container for disposal of used pustule dressings at home. These containers must be returned to the clinical trial site for medical waste disposal.
Control 5 - Any occurrence of Pexa-Vec-induced adverse effects resulting from Pexa-Vec transmission from Pexa-Vec treated individuals to untreated individuals or animals must be reported to the EPA and MPI as soon as possible. In the event of this occurring, the EPA may consider reassessing the approval.
Control 6 – A report that shows compliance with the above controls must be submitted to the EPA and MPI on or before 30 June every year from the commencement of the clinical trial to the conclusion of the clinical trial.
12 General practices are expected to operate in accordance with Australian/New Zealand Standard (AS/NZS): Office- based health care facilities - Reprocessing of reusable medical and surgical instruments and equipment, and maintenance of the associated environment (AS/NZS 4815:2006). Laboratories are expected to adhere to various standards, including AS/NZS 2243.3:2010: Safety in laboratories - Microbiology safety and containment.
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68. The EPA, Clinical Network Services Pty Ltd and SillaJen Biotherapeutics Inc recognise that an approval granted under section 38I of the HSNO Act is not an approval to use a qualifying medicine until the medicine has been approved for use under the Medicines Act 1981.
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References
Bergonie, I. (2014). JX-594: Summary Notification Information Format For The Release of Genetically Modified Organisms Other Than Higher Plants In Accordance With Article 11 Of Directive 2001/18/EC.
Breitbach, C. J., J. Burke, D. Jonker, J. Stephenson, A. R. Haas, L. Q. M. Chow, J. Nieva, T.-H. Hwang, A. Moon, R. Patt, A. Pelusio, F. L. Boeuf, J. Burns, L. Evgin, N. D. Silva, S. Cvancic, T. Robertson, J.-E. Je, Y.-S. Lee, K. Parato, J.-S. Diallo, A. Fenster, M. Daneshmand, J. C. Bell and D. H. Kirn (2011). Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. Nature Medicine 477(99-103).
Breitbach, C. J., K. Parato, J. Burke, T.-H. Hwang, J. C. Bell and D. H. Kirn (2015). Pexa-Vec double agent engineered vaccinia: oncolytic and active immunotherapeutic. Current Opinion in Virology 13: 49- 54.
Chahroudi, A., R. Chavan, N. Koyzr, E. K. Waller, G. Silvestri and M. B. Feinberg (2005). Vaccinia Virus Tropism for Primary Hematolymphoid Cells Is Determined by Restricted Expression of a Unique Virus Receptor. Journal of Virology 79(16): 10397-10407.
Chamberlain, J., D. Sarfati, R. Cunningham, J. Koea, J. Gurney and T. Blakely (2013). Incidence and management of hepatocellular carcinoma among Māori and non-Māori New Zealanders. Australian and New Zealand Journal of Public Health 37(6): 520-526.
Fenner, F. and B. M. Comben (1958). Genetic studies with mammalian poxviruses: I. Demonstration of recombination between two strains of vaccinia virus. Virology 5(3): 530–548.
Fenner, F., D. A. Henderson, I. Arita, Z. Jezek and I. D. Ladnyi (1988). Smallpox and its Eradication. World Health Organization Geneva.
Gershon, P. D., R. P. Kitching, J. M. Hammond and D. N. Black (1989). Poxvirus Genetic Recombination during Natural Virus Transmission. Journal of General Virology 70: 485-489.
Hengstschlager, M., M. Knofler, E. W. Miillner, E. Ogris, E. Wintersberger and E. Wawra (1994). Different Regulation of Thymidine Kinase during the Cell Cycle of Normal Versus DNA Tumor Virus-transformed Cells*. The Journal of Biological Chemistry 269(19): 13836-13842.
Hengstschlager, M., M. Pfeilstocker and E. Wawra (1998). Thymidine Kinase Expression: A Marker for Malignant Cells. Purine and Pyrimidine Metabolism in Man IX, Plenum Press.
Heo, J., C. J. Breitbach, A. Moon, C. W. Kim, R. Patt, M. K. Kim, Y. K. Lee, S. Y. Oh, H. Y. Woo, K. Parato, J. Rintoul, T. Falls, T. Hickman, B.-G. Rhee, J. C. Bell, D. H. Kirn and T.-H. Hwang (2011). Sequential Therapy With JX-594, A Targeted Oncolytic Poxvirus, Followed by Sorafenib in Hepatocellular Carcinoma: Preclinical and Clinical Demonstration of Combination Efficacy. Molecular Therapy 19(6): 1170-1179.
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Heo, J., T. Reid, L. Ruo, C. Breitbach, S. Rose and M. Bloomston (2014). New Frontier in Liver Cancer Treatment: Oncolytic Viral Therapy. Hepatology 59(1): 343-346.
Heo, J., T. Reid, L. Ruo, C. J. Breitbach, S. Rose, M. Bloomston, M. Cho, H. Y. Lim, H. C. Chung, C. W. Kim, J. Burke, R. Lencioni, T. Hickman, A. Moon, Y. S. Lee, M. K. Kim, M. Daneshmand, K. Dubois, L. Longpre, M. Ngo, C. Rooney, J. C. Bell, B.-G. Rhee, R. Patt, T.-H. Hwang and D. H. Kirn (2013). Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nature Medicine 19(3): 329–336.
Keese, P. (2008). Risks from GMOs due to Horizontal gene Transfer. Journal of Environmental Biosafety Research 7: 123-149.
Kim, J. H., J. Y. Oh, B. H. Park, D. E. Lee, J. S. Kim, H. E. Park, M. S. Roh, J. E. Je, J. H. Yoon, S. H. Thorne, D. Kirn and T. H. Hwang (2006). Systemic Armed Oncolytic and Immunologic Therapy for Cancer with JX-594, a Targeted Poxvirus Expressing GM-CSF. Molecular Therapy 14(3): 361-370.
Lane, J. M. and V. A. Fulginiti (2003). Transmission of Vaccinia Virus and Rationale for Measures for Prevention. Clinical Infectious Diseases 37: 281–4.
Liu, T.-C., T. Hwang, B.-H. Park, J. Bell and D. H. Kirn (2008). The Targeted Oncolytic Poxvirus JX-594 Demonstrates Antitumoral, Antivascular, and Anti-HBV Activities in Patients With Hepatocellular Carcinoma. Molecular Therapy 16(9): 1637-1642.
McFadden, A. and T. Rawdon (2012). Parapoxviruses in domestic livestock in New Zealand. Surveillance 39(2): 14-16.
Medsafe (2015). Guideline on the Regulation of Therapeutic Products in New Zealand. Part 11: Clinical trials - regulatory approval and good clinical practice requirements.
Nalca, A. and E. E. Zumbrun (2010). ACAM2000™: The new smallpox vaccine for United States Strategic National Stockpile. Drug Design, Development and Therapy 4: 71-79.
Parato, K. A., C. J. Breitbach, F. L. Boeuf, J. Wang, C. Storbeck, C. Ilkow, J.-S. Diallo, T. Falls, J. Burns, V. Garcia, F. Kanji, L. Evgin, K. Hu, F. Paradis, S. Knowles, T.-H. Hwang, B. C. Vanderhyden, R. Auer, D. H. Kirn and J. C. Bell (2012). The Oncolytic Poxvirus JX-594 Selectively Replicates in and Destroys Cancer Cells Driven by Genetic Pathways Commonly Activated in Cancers. Molecular Therapy 20(4): 749–758.
Park, B.-H., T. Hwang, T.-C. Liu, D. Y. Sze, J.-S. Kim, H.-C. Kwon, S. Y. Oh, S.-Y. Han, J.-H. Yoon, S.-H. Hong, A. Moon, K. Speth, C. Park, Y.-J. Ahn, M. Daneshmand, B. G. Rhee, H. M. Pinedo, J. C. Bell and D. H. Kirn (2008). Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. The Lancet Oncology 9: 533-542.
Sagripanti, J.-L., L. Voss, H.-J. Marschall and C. D. Lytle (2013). Inactivation of Vaccinia Virus by Natural Sunlight and by Artificial UVB Radiation. Photochemistry and Photobiology 89: 132–138.
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Thorne, S. H., T.-H. H. Hwang, W. E. O’Gorman, D. L. Bartlett, S. Sei, F. Kanji, C. Brown, J. Werier, J.-H. Cho, D.-E. Lee, Y. Wang, J. Bell and D. H. Kirn (2007). Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963. The Journal of Clinical Investigation 117(11): 3350-3358.
Torre, L. A., F. Bray, R. L. Siegel, J. Ferlay, J. Lortet-Tieulent and A. Jemal (2015). Global Cancer Statistics, 2012. CA: A Cancer Journal for Clinicians 65: 87-108.
Yao, X.-D. and D. H. Evans (2003). High-Frequency Genetic Recombination and Reactivation of Orthopoxviruses from DNA Fragments Transfected into Leporipoxvirus-Infected Cells. Journal of Virology 77(13): 7281–7290.
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Appendix 1: MoH comments
We expect clinical trials to comply with the principles of GCP [Good Clinical Practice] but there is not a specific NZ standard or audit processes. Here is the link to the Clinical trial guidelines on the Medsafe website http://www.medsafe.govt.nz/regulatory/Guideline/GRTPNZ/Part11.pdf
We are also not sure that negative pressure rooms need to be used for the conduct of the clinical trial. We note that the transmission of vaccinia virus by contact has been described and therefore consider that infection prevention and control for Pexa-Vac should focus on minimising contact and standard precautions for control of infectious particles. The use of negative pressure room for test subjects is therefore not necessary, unless further evidence shows that airborne transmission may occur.
We do suggest that the applicant needs to consider the disposal of the dressings used to cover the pustules. These should either be removed/changed by a clinic or test subjects should be provided with appropriate containers for containment of used dressings prior to correct disposal of medical waste. Although the risk to the public is low, we think this is appropriate for the public perception of responsible management of clinical trials using live microorganisms.
We also think it is pertinent to mention other standards that are designed to for infection prevention and control in a clinical setting.
Clinics and hospitals are all expected to follow NZS 8134.3.3:2008 Health and Disability Services (infection Prevention and Control) Standards which include infection prevention and control standards. GP practices should be using AS/NZS 4815:2006 Office based healthcare facilities - Reprocessing of reusable medical and surgical instruments and equipment, and maintenance of the associated environment. Laboratories are also supposed to adhere to standards, including regarding microbiology safety and containment (As/NZS 2243.3:2010)
We would like to comment that from an MoH view it is considered that there is minimal public health risk to the community because:
The disruption of the thymidine kinase gene in the live, attenuated recombinant Vaccinia virus (LArV) results in the LArV selectively infecting and replicating in cells that over express thymidine kinase (such as tumor cells). While normal cells are mostly unaffected by the LArV, there have been examples of infection and pustule formation in the epidermis and mucosal lines of the respiratory tract of some treated patients. It is assumed that these pustules shed LArV. In considering the potential risk to public health the Ministry has considered the possibility of virus being shed from these pustules.
The transmission of vaccinia virus by contact has been described, therefore IPC for LArV should focus on contact and standard precaution. If the standard IPC processes are applied effectively, transmission of the virus will be minimised. There is little evidence to suggest that airborne transmission occurs but this should be confirmed with the applicant.
The shed virus is very unlikely to infect healthy people because it cannot easily replicate in normal cells. It is unlikely that the LArV virus can naturally infect the epidermis or mucosal membranes of a secondary host. If it does the results of an infection will be minor in the majority of people.
the virus does not exhibit unstable genetics meaning reversion is at a low frequency. This means it is unlikely that the LArV will revert to an infectious strain. Even if it did, the strain is a low pathogenic strain
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used to vaccinate against small pox. During the WHO vaccination campaign no reports of outbreaks of a pox disease were reported.
the virus is unlikely to undergo reassortment to express pathogenicity. Small pox has been eradicated so the virus cannot obtain small pox pathogenicity genes. To obtain other pox virus genes the LArV would need to be actively replicating together with another pox virus. This is very unlikely to occur. Again, during the WHO campaign no reports of reassortment were reported.
There is a increased risk of complications in immunocompromised people. For this reason, test subjects should be treated in isolation from other cancer patients and should avoid contact with immunocompromised people while pustules are present and appropriate infection prevention and control measures should be applied.
The minimal risk of harm to people is far outweighed by the benefits in the treatment of solid tumors suggested by this medicine.
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Appendix 2: MPI comments
General . MPI understands that applicant is wishing to import and release a genetically modified (GM) vaccinia virus, known as ‘Pexa-Vec’. Pexa-Vec is a replicative oncolytic live attenuated vaccina virus derived from the extensively used commercial vaccine Wyeth strain.
. The purpose of the importation and release is to assess the effectiveness and safety of Pexa-Vec as a therapeutic treatment in patients with liver cancer as part of a Phase III clinical trial.
. Pexa-Vec will be administered to patients with liver cancer and enrolled in the Phase III clinical trial program. Storage, preparation and administration of Pexa-Vec will occur in up to 5 public hospitals and clinical settings offering oncology services. Following Pexa- Vec administration, patients will be permitted to go home. In some cases, patients may develop pustules which may ulcerate and shed live virus. The applicant is proposing to mitigate the potential of shedding through covering the skin pustule with a bandage and not allowing other people or the patient themselves to have direct contact with it or any potentially contaminated material.
Section 5 - Risks . The applicant has identified a number of risks associated with Pexa-Vec and its use related to the proposed activity. Most of these risks relate to the organism itself, the likelihood of spread through use and potential changes to the organism during use (e.g. reversion). The applicant has also indicated that the risks to the environment, including animals and primary production, are negligible.
. MPI supports this contention and cannot provide any information to the contrary.
. An area of risk that MPI considers has not been well addressed is the political risk from the use of a GM organism in humans and its outside of a containment facility. Being the first application of its kind, the public interest, particularly from anti-GM interest groups, cannot be underestimated, despite the probable negligible biological risks. In this respect, the applicant need to be seen to be aware of these risks and to take steps to manage them. As the enforcement agency for the new organism provisions of the HSNO Act, MPI needs to ensure that such steps are enforceable and are effective.
. Further areas of risk relate to MPI, as the enforcement agency. This firstly relates to any controls that may be placed upon the application, if approved, which may not be able to be adequately enforced by MPI (e.g., the ability to ensure patients comply with instructions relating to contact with other persons and management of pustules in their own home). MPI does not have the ability to enter private dwellings without the consent of the inhabitant or without a search warrant. This could potentially limit its ability to ensure controls are being complied with. Secondly, if inadvertent spread of the organism did occur and MPI had not been charged with ensuring spread was minimised or prevented (e.g. through absence of a control requiring spread to be minimised or prevented), MPI could be criticized for not preventing spread, despite the fact that it had no legal mandate to do so.
. While MPI is aware that the applicant has a number of regulatory hurdles to pass, particularly with the Ministry of Health, if all these are achieved, the only enforcement agency with a legislative mandate to act proactively is MPI, under both the Biosecurity Act and the HSNO Act.
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Section 6A . The applicant is conscious of the need to minimise potential risks from spread of Pexa- Vec and has proposed measures to manage this through the effective management of the following:
1. Storage and preparation;
2. Administration to patients;
3. Spread from areas where the virus is stored, prepared and administered;
4. Spread from shedding; and
5. Spread from waste.
. MPI is supportive of measures that minimise spread of the organism and considers that if the EPA approves the application, it should include controls addressing this. At this point in time, and despite the likelihood that the biological risks are most likely negligible, the uncontrolled spread of a GM organism in the NZ environment is not a good way to give confidence to the NZ public that such organisms present other risks and to generate social acceptance of GM organism use. However, as noted earlier, such controls need to be enforceable and effective.
. The applicant is proposing some specific measures related to:
1. The clinical setting where administration will occur;
2. The containers used to hold Pexa-Vec and the labelling of these;
3. Who is responsible for the use and administration of Pexa-Vec to patients;
4. The use and decontamination of the biological safety cabinet used to prepare Pexa- Vec for injection;
5. Decontamination of material by chemical sterilization, incineration and/or autoclaving
6. The training of staff involved in the handling, administration and disposal of Pexa-Vec and potentially contaminated materials as well as material not dedicated to the clinical trial;
7. Decontamination of hospital/clinical areas where patients injected with Pexa-Vec have been as well as areas where administration has occurred; and
8. Management of spills and inadvertent exposure to potentially infected materials.
. Because this is an application for release, even if controls are imposed, MPI is aware that the EPA is not required to impose a control requiring the work to be conducted within a containment facility. This is particularly relevant because patients will be permitted to leave the hospital/clinical setting and return home, taking the organism with them.
. To all intents and purposes, however, and as the applicant is suggesting through proposing measures to limit spread, there is an intention to manage Pexa-Vec as if it were in a containment facility. Accordingly, we are proposing controls that, to a large extent, mirror those that we would expect to be applied if the organism was required to be held in a containment facility.
. As noted earlier, while MPI would likely have limited ability to adequately enforce any controls directly imposed on patients and private dwellings, controls could be placed on the applicant, requiring them to minimise spread from patients through a variety of means. Even these, however, would not be without difficulty unless permission to enter private
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dwellings was granted and patients freely agreed to comply with conditions of the clinical trial.
Proposed controls . If the application is approved, the approval should adequately describe the ‘approved organism’ so there is no confusion as to what is being referred by use of the term. For example, the ‘approved organism’ is the oncolytic and immunotherapeutic vaccinia virus JX-594, also known as Pexa-Vec (Pexastimogene Devacirepvec).
. Taking the above considerations into account, MPI suggests the following controls if the application is approved (in no particular order of priority or importance):
1. Areas where the approved organism are to be held, stored, prepared, administered to patients and disposed of must be identified and documented. Such areas must be inspected by MPI prior to the approved organism being received
2. Contingency plans must be prepared and documented for effectively managing the risks associated with escape of the approved organism from the identified areas or through suspected loss, spill, natural disaster, fire and/or misadventure. Such contingency plans must be able to be implemented and be implemented when a contingency event occurs.
3. An individual must be identified within each registered hospital, and/or place receiving samples from individuals administered with the approved organisms, that has overall responsibility for all activities relating to the secure storage and safe use, preparation, administration, decontamination and disposal of the approved organisms and any materials and equipment associated with it. This individual must be in a position to make and implement decisions relating to such activities, to direct staff having responsibilities related to those activities and expend resources for activity management.
4. All activities related to secure storage and safe use, preparation, administration, decontamination and disposal of the approved organisms and any materials and equipment associated with it must be documented, be able to be verified as effective and evidence provided to that effect.
5. The approved organism must only be intratumourally administered only to individuals with hepatocellular carcinoma who are enrolled in a Phase III clinical trial.
6. The approved organism must only be administered within a registered hospital.
7. All activities involving the use of the approved organism in the Phase III clinical trial must be in accordance with the New Zealand Clinical Trial Guidelines (Part 11).
8. All individuals having responsibilities for the secure storage and safe preparation, administration, decontamination and disposal of the approved organisms and any materials and equipment associated with it must be deemed competent to do so by the individual in overall charge of the approved organisms in each registered hospital and received and understood the requirements of this approval and how the controls are to be effected.
9. The EPA, MPI and Medsafe must be notified in writing before this HSNO Act approval is used in each registered hospital for the first time.
10. Individuals administered with the approved organism must be instructed on, understand, and agree to comply with, pustule management requirements prior to administration occurring.
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11. Individuals administered with the approved organism must be provided with sealable biohazard containers for the disposal of pustule clinical waste.
12. Any occurrence or suspected occurrence of transmission of the approved organism from individuals administered with it to individuals not administered with it must be reported to the EPA, MPI and Medsafe as soon as practicable and within 24 hours of becoming aware of such an occurrence.
13. Any occurrence or suspected occurrence of adverse effects in individuals administered with the approved organism must be reported to the EPA, MPI and Medsafe as soon as practicable and within 24 hours of becoming aware of such an occurrence.
14. Any occurrence or suspected occurrence of escape, loss and/or spill of the approved organism must be reported to the EPA, MPI and Medsafe as soon as practicable and within 24 hours of becoming aware of such an occurrence.
15. All places receiving samples from individuals administered with the approved organism must comply with the requirements of this approval.
16. The movement of the approved organisms and any material containing or potentially containing the approved organism must be authorised by MPI prior to that movement occurring.
17. Documented records relating to storage, preparation, administration, and disposal of the approved organism must be maintained and made available to MPI on request.
18. MPI must ensure that this approval is complied with.
19. Any organisation involved in using the approval must agree to pay MPI the costs associated with enforcement, as per the Biosecurity (Costs) Regulations 2015 or any subsequent amendments to those Regulations.
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Appendix 3: MPI proposed controls and EPA responses
MPI proposed control (in no particular order of priority EPA response or importance)
1 Areas where the approved organism are to be held, Pexa-Vec treated individuals will be permitted to stored, prepared, administered to patients and leave the clinical trial site following Pexa-Vec disposed of must be identified and documented. administration. For that reason, this report has Such areas must be inspected by MPI prior to the assessed the environmental risk associated with approved organism being received. Pexa-Vec release into the environment via treated individuals. 2 Contingency plans must be prepared and Based on the information in the application and other documented for effectively managing the risks readily available sources, we concluded that it is associated with escape of the approved organism highly improbable that Pexa-Vec will have any from the identified areas or through suspected loss, significant adverse effects on the health and safety of spill, natural disaster, fire and/or misadventure. Such the public, any valued species, natural habitats or the contingency plans must be able to be implemented environment if Pexa-Vec is used in a Phase 3 clinical and be implemented when a contingency event trial for patients with hepatocellular carcinoma. occurs. Imposing MPI inspection controls on the clinical trial sites was deemed unnecessary considering that clinical trials in New Zealand are expected to be conducted in accordance with Good Clinical Practice (Medsafe 2015), and New Zealand clinics and hospitals are expected to follow New Zealand Health and Disability Services (Infection Prevention and Control) Standards. Furthermore, Medsafe administers a Clinical Trial Site Self-Certification scheme covering sites which have study participants in residence while the clinical trial medicines are administered. The self- certification is site-specific and provides a description of the site’s facilities and procedures for dealing with any emergencies and a list of key personnel (Medsafe 2015).
3 An individual must be identified within each The applicant of a clinical trial under Section 30 of registered hospital, and/or place receiving samples the Medicines Act (also known as the New Zealand from individuals administered with the approved sponsor following approval) is made by the person organisms, that has overall responsibility for all legally responsible for the trial in New Zealand activities relating to the secure storage and safe use, (Medsafe 2015). preparation, administration, decontamination and disposal of the approved organisms and any materials and equipment associated with it. This individual must be in a position to make and implement decisions relating to such activities, to direct staff having responsibilities related to those activities and expend resources for activity management.
4 All activities related to secure storage and safe use, Medsafe administers a Clinical Trial Site Self- preparation, administration, decontamination and Certification scheme covering sites which have study
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MPI proposed control (in no particular order of priority EPA response or importance) disposal of the approved organisms and any participants in residence while the clinical trial materials and equipment associated with it must be medicines are administered. The self-certification is documented, be able to be verified as effective and site-specific and provides a description of the site’s evidence provided to that effect. facilities and procedures for dealing with any emergencies and a list of key personnel (Medsafe
2015).
5 The approved organism must only be intratumourally See EPA proposed control 1 (paragraph 67). administered only to individuals with hepatocellular carcinoma who are enrolled in a Phase III clinical trial.
6 The approved organism must only be administered Medsafe administers a Clinical Trial Site Self- within a registered hospital. Certification scheme covering sites which have study participants in residence while the clinical trial medicines are administered. The self-certification is site-specific and provides a description of the site’s facilities and procedures for dealing with any emergencies and a list of key personnel (Medsafe 2015).
7 All activities involving the use of the approved All clinical trials in New Zealand are expected to be organism in the Phase III clinical trial must be in conducted in accordance with the standards set out accordance with the New Zealand Clinical Trial in the Note for Guidance on Good Clinical Practice Guidelines (Part 11). (Medsafe 2015); and New Zealand clinics and hospitals are all expected to follow New Zealand
Health and Disability Services (Infection Prevention and Control) Standards (NZS 8134.3.3:2008)13.
8 All individuals having responsibilities for the secure The applicant of a clinical trial under Section 30 of storage and safe preparation, administration, the Medicines Act (also known as the New Zealand decontamination and disposal of the approved sponsor following approval) is made by the person organisms and any materials and equipment legally responsible for the trial in New Zealand associated with it must be deemed competent to do (Medsafe 2015). so by the individual in overall charge of the approved organisms in each registered hospital and received and understood the requirements of this approval and how the controls are to be effected.
9 The EPA, MPI and Medsafe must be notified in See EPA proposed control 2 (paragraph 67). writing before this HSNO Act approval is used in each registered hospital for the first time.
13 General practices are expected to operate in accordance with Australian/New Zealand Standard (AS/NZS): Office- based health care facilities - Reprocessing of reusable medical and surgical instruments and equipment, and maintenance of the associated environment (AS/NZS 4815:2006). Laboratories are expected to adhere to various standards, including AS/NZS 2243.3:2010: Safety in laboratories - Microbiology safety and containment.
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MPI proposed control (in no particular order of priority EPA response or importance)
10 Individuals administered with the approved organism See EPA proposed control 3 (paragraph 67). must be instructed on, understand, and agree to comply with, pustule management requirements prior to administration occurring.
11 Individuals administered with the approved organism See EPA proposed control 4 (paragraph 67). must be provided with sealable biohazard containers for the disposal of pustule clinical waste.
12 Any occurrence or suspected occurrence of See EPA proposed control 5 (paragraph 67). transmission of the approved organism from individuals administered with it to individuals not administered with it must be reported to the EPA, MPI and Medsafe as soon as practicable and within 24 hours of becoming aware of such an occurrence.
13 Any occurrence or suspected occurrence of adverse The New Zealand sponsor (who must be a person in effects in individuals administered with the approved New Zealand) is responsible for reporting adverse organism must be reported to the EPA, MPI and events (Medsafe 2015). Medsafe as soon as practicable and within 24 hours However, consideration of potential Pexa-Vec- of becoming aware of such an occurrence. induced effects on the treated individual is outside the scope of the HSNO Act (in accordance with section 38I(4)).
14 Any occurrence or suspected occurrence of escape, Medsafe administers a Clinical Trial Site Self- loss and/or spill of the approved organism must be Certification scheme covering sites which have study reported to the EPA, MPI and Medsafe as soon as participants in residence while the clinical trial practicable and within 24 hours of becoming aware medicines are administered. The self-certification is of such an occurrence. site-specific and provides a description of the site’s facilities and procedures for dealing with any emergencies and a list of key personnel (Medsafe 2015).
15 All places receiving samples from individuals All clinical trials in New Zealand are expected to be administered with the approved organism must conducted in accordance with the standards set out comply with the requirements of this approval. in the Note for Guidance on Good Clinical Practice (Medsafe 2015); and New Zealand clinics and hospitals are all expected to follow New Zealand Health and Disability Services (Infection Prevention and Control) Standards (NZS 8134.3.3:2008)14.
16 The movement of the approved organisms and any Medsafe administers a Clinical Trial Site Self- material containing or potentially containing the Certification scheme covering sites which have study participants in residence while the clinical trial
14 General practices are expected to operate in accordance with Australian/New Zealand Standard (AS/NZS): Office- based health care facilities - Reprocessing of reusable medical and surgical instruments and equipment, and maintenance of the associated environment (AS/NZS 4815:2006). Laboratories are expected to adhere to various standards, including AS/NZS 2243.3:2010: Safety in laboratories - Microbiology safety and containment.
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MPI proposed control (in no particular order of priority EPA response or importance) approved organism must be authorised by MPI prior medicines are administered. The self-certification is to that movement occurring. site-specific and provides a description of the site’s facilities and procedures for dealing with any
emergencies and a list of key personnel (Medsafe 2015).
17 Documented records relating to storage, preparation, Medsafe administers a Clinical Trial Site Self- administration, and disposal of the approved Certification scheme covering sites which have study organism must be maintained and made available to participants in residence while the clinical trial MPI on request. medicines are administered. The self-certification is site-specific and provides a description of the site’s facilities and procedures for dealing with any emergencies and a list of key personnel (Medsafe 2015).
Further, the New Zealand sponsor, who must be a person in New Zealand, is responsible for the preservation of records (Medsafe 2015).
18 MPI must ensure that this approval is complied with. MPI’s role as the enforcement agency for the provisions of the HSNO Act in respect of new organisms is set out in section 97A of the HSNO Act.
19 Any organisation involved in using the approval must Section 97A(4A) of the HSNO Act states that “the agree to pay MPI the costs associated with enforcement agency’s costs of enforcing this Act in enforcement, as per the Biosecurity (Costs) respect of new organisms are to be treated as if they Regulations 2015 or any subsequent amendments to were costs of administering the Biosecurity Act those Regulations. 1993…”
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Level 10, 215 Lambton Quay, Wellington 6011, New Zealand