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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March and July 2017

Scheduling medicines and poisons

15 September 2017

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2.1 Plasmid DNA Vaccine

Referred scheduling proposal

An application was submitted by the Australian Pesticides and Veterinary Medicines Authority (APVMA) to create a new entry for plasmid DNA (rE. coli DH5α pINGhT) in Schedule 4 of the Poisons Standard, with no exemption cut-off.

Scheduling application

This was a general application. The APVMA's proposed amendments to the Poisons Standard are:

Schedule 4 – New Entry

PLASMID DNA (rE. coli DH5α pINGhT).

The applicant's reasons for the request are:

  • The proposed new product contains a new active constituent, plasmid DNA
  • (rE. coli DH5α pINGhT) that expresses the gene coding for the full-length sequence of human tyrosinase. It is designed to stimulate an immune response targeted at canine melanoma cells expressing tyrosinase. It is proposed for the vaccination of dogs with Stage II or III oral melanoma, for which local disease control has been achieved, to aid the extension of survival time.
  • No specific toxicity studies or associated data on either the active constituent or the formulated product were submitted with the application. However, some relevant studies from published literature were submitted in response to questions from the APVMA. These studies involved the administration to both humans and other animal species, of vaccines that were the same as or similar to the proposed product. Additionally, there were studies on other relevant DNA vaccines. Data from these studies suggested that the proposed product vaccine is unlikely to be associated with any significant toxic effects in humans
  • The product is a therapeutic vaccine that is applied by a spring powered device that does not require the use of needles. This technology has the potential to make the administration of medicine safer as well as efficient and convenient. Post-application exposure is likely to be negligible. Any residual vaccine on the skin surface is likely to very small. The needle free device means that there are no needles that require disposal. However, the use of this canine transdermal device requires trained personnel.
  • As the amounts of DNA injected are small (about 110 µg), treatment is systemic (IM administration), the DNA will not replicate in the body of the injected animal or be excreted intact, no exposure is anticipated to occur during re-handling. As DNA is a normal component of the body, its breakdown products are not toxic, so urine/faeces of the injected animal will not contain hazardous substances arising from vaccination.
  • The applicant has requested scheduling as Schedule 4 Prescription animal remedy because of precedence of other vaccines in the Poisons Standard.

Current scheduling status and relevant scheduling history

Plasmid DNA (rE. coli DH5α pINGhT) is not specifically captured in the current Poisons Standard. The proposed use for Plasmid DNA (rE. coli DH5α pINGhT) is as an active in a veterinary vaccine for canine melanoma. The Poisons Standard has a Schedule 4 entry for veterinary live virus vaccines as follows:

Schedule 4

VACCINES, veterinary live virus except:

  1. poultry vaccines;
  2. pigeon pox vaccine; or
  3. scabby mouth vaccine.

Plasmid DNA (rE. coli DH5α pINGhT) is not captured by any group entry (including the entry for vaccines, veterinary live viruses above) as it is not a live virus and does not meet the exemptions for the Schedule 4 entry for veterinary live viruses.

Australian regulatory information

Plasmid DNA vaccine has not been previously considered for scheduling. Therefore, a scheduling history is not available.

International regulations

USA

The USDA Animal and Plant Health Inspection Service approved the canine melanoma vaccine in the USA in March 2007.
In November 2007, FDA issued a guidance document, "Guidance for Industry: Considerations for Plasmid DNA Vaccines for Infectious Disease Indications" to assist the developers of DNA vaccines. This document supersedes the 1996 "Points to Consider on Plasmid DNA Vaccines for Preventive Infectious Disease Indications" document, which delineated the manufacturing, preclinical, and clinical issues relevant to the development of DNA vaccines, and described potential safety concerns that the Centre for Biologics Evaluation and Research (CBER) recommended vaccine developers address prior to the initiation of phase 1 clinical studies. The recommendations involving DNA vaccine manufacture and testing provided in that document were based on experience with other types of vaccines and DNA-based products, including gene therapy agents.

In this time, the FDA has permitted the initiation of phase 1 clinical studies of DNA vaccines for a number of infectious diseases indications including malaria, hepatitis B, and human immunodeficiency virus (HIV). The initiation of phase 1 clinical studies is predicated on the manufacturers and/or sponsors of vaccine clinical studies documenting the quality and consistency of plasmid manufacture, combined with extensive preclinical safety studies. Considerable preclinical and clinical experience on plasmid DNA vaccines has been accumulated since the issuance of the 1996 Points to Consider document. This experience was taken into consideration in revising recommendations concerning preclinical testing of DNA vaccines.

Canada

In 2011, the Canadian Centre for Veterinary Biologicals (CCVB), based on assessment of available information, concluded that the importation and use of Canine Melanoma Vaccine in Canada would not be expected to have any significant adverse environmental effect when manufactured and tested, and used according to label directions.

The Permit to Import Veterinary Biologics was amended to allow the importation and distribution of a product containing plasmid DNA in Canada.

The Canine Melanoma Vaccine, DNA - Environmental Assessment is available on the Canadian Food Inspection Agency website.

Substance summary

DNA vaccines are defined by the Canadian Food Inspection Agency as highly purified plasmid preparations containing one or more DNA sequences capable of inducing and/or promoting an immune response against a pathogen. Typically, these plasmids possess DNA sequences necessary for selection and replication in bacteria. Additionally, these contain eukaryotic promoters and enhancers as well as transcription termination/-polyadenylation sequences to promote gene expression in vaccine recipients, and may contain immunomodulatory elements.[4]

Table 2.1.1: Chemical information for Plasmid DNA Vaccine
Property Plasmid DNA Vaccine
Plasmid map of pING/hT plasmid used in ONCEPT Plasmid map of pING plasmid used for generation of human tyrosinase DNA vaccine given to nine dogs with advanced malignant melanoma.
IUPAC and/or common and/or other names Plasmid DNA (rE. coli DH5α pINGhT)

Acute toxicity

No specific toxicity studies or associated data on either the active constituent were submitted with the application.

The applicant contends that both the non-living and highly purified nature of the plasmid constituent make it unlikely to be of toxicological concern.

The vaccine does not contain a living organism/infectious agent and therefore does not suffer the issues that might be associated with a live attenuated vaccine.

Furthermore, given the highly purified nature of the plasmid constituent means there will not be toxicological issues associated with residual endotoxin, RNA, genomic DNA, protein, antibiotics or residual solvent.

Other potential safety issues associated with a DNA vaccine, including toxicity of the plasmid DNA, toxicity associated with expression of the encoded protein (including autoimmune disease), and the potential for a transformation event resulting from the integration of the plasmid DNA into chromosomal DNA, have been studied for various DNA vaccines.

Repeat-dose toxicity

Parker et al., (1999)[5] conducted a GLP repeat dose study on a plasmid DNA vaccine for malaria, VCL-2510, by the IM route (right thigh) in 7-week old CD-1 mice (10/sex/dose). VCL-2510 was administered at dose levels of 1, 10 and 100 µg DNA (50 µL dose volume) twice weekly for 4 weeks. Control mice (10/sex) received injections of phosphate buffered saline (PBS) (50 µL). Two additional (satellite) groups of 10 mice/sex received doses of 0 or 100 µg DNA and were used only for the analysis of anti-nuclear antibodies (ANA) and antibodies to double-stranded (ds) DNA. Half the main study animals and half the satellite animals were killed at 48 hours after the last dose, while the remaining half (‘recovery animals') were killed at 30 days after the last dose. Animals were examined twice daily for morbidity and mortality, once daily for clinical signs of toxicity, while a more thorough (hands-on) examination was conducted once weekly throughout the study. Food intake and body weight were also monitored (presumably weekly). Ophthalmological examinations were conducted pre-dosing, and in the main study high dose and control groups on the day before sacrifice (i.e. 24 hours and 29 days post the last dose). Injection sites (main study animals) were examined pre-dosing and daily throughout the study and scored for erythema and eschar formation using a modified Draize scoring system of 1-3, and for oedema using a similar modified Draize scoring system of 0-3 (the site was shaved weekly to facilitate scoring). At each of the 2 sacrifice times, clinical chemistry, haematology, ANA, antibodies to dsDNA, gross necropsy (including organ weights) and histological examination (full range of tissues, but histological examination only on control and high dose animals) were conducted. The analysis for ANA used 2 pools of nuclear antigens:

  1. single-stranded DNA, SSA, SSB and Jo-1; and
  2. dsDNA, ribonucleoprotein, histones, Sm, and Scl-70.

There were no treatment-related deaths and no clinical signs were observed. Food consumption and body weight gains were not affected by treatment. Ophthalmological examination and clinical chemistry and haematology analyses did not reveal an effect of treatment. There were no treatment-related necropsies or histopathological findings or changes in organ weights. In particular, there was no indication of an inflammatory response that was suggestive of induction of autoimmune disease. Also suggesting a lack of immune pathology was the lack of an effect of treatment on ANA and dsDNA antibodies, although large standard deviations were observed for the results of these parameters (including for control animals). No irritation (erythema or oedema) was observed by Draize scoring at the injection sites (Draize scores of 0 at all time points in all animals). Inflammation was observed histologically at the injection site in 3 treated (high dose) animals.

The same authors also conducted a GLP repeat dose study by the IM route (right thigh) in 15-19-week old New Zealand White rabbits (8/sex/dose) in which VCL-2510 was administered at dose levels of 0.15 and 0.45 mg DNA (0.5 mL dose volume) once weekly for 6 weeks. Control rabbits (8/sex) received injections of PBS (0.5 mL). Half the animals were killed at 48 hours after the last dose, while the remaining half ('recovery animals') were killed at 30 days after the last dose. Monitoring was as described for the mouse study, except that ophthalmological examination was not conducted on the recovery animals, clinical chemistry and haematology analyses were conducted on days 15, 30, 43 and 57, in addition to the days of sacrifice (38 and 66), and analyses for ANA and antibodies to dsDNA were conducted on the main study animals.

There were no treatment-related deaths, and no clinical signs were observed. Food consumption was not affected by treatment. Body weight gains were significantly increased in high-dose males over the study but this was not considered to be biologically significant. Clinical chemistry and haematology analyses did not reveal an effect of treatment, although there were increases (significant at some time points) in white blood cell count and lymphocytes in high-dose females that may have been indicative of an immune response to the malaria sporozoite protein. There were no adverse treatment-related ophthalmological effects, and no treatment-related necropsy or histopathological findings or changes in organ weights. In particular, there were no findings suggestive of induction of autoimmune disease. There was no effect of treatment on ANA or dsDNA antibodies, although (as with mice) large standard deviations were observed for the results of these parameters (including for control animals). No treatment-related irritation was observed by Draize scoring at the injection sites, although slight erythema and slight oedema (Draize scores of 1) were observed at similar incidences in the control and treated animals. Inflammation was observed histologically at the injection site at the 48 hour sacrifice in 3/10 treated animals and 1/10 control animals. Observation in humans Wolchok et al., (2007) conducted a clinical trial of human and mouse tyrosinase DNA vaccines in a total of 18 human patients with stage III/IV melanoma. The human tyrosinase DNA vaccine was either the same or comparable to the proposed product. Half the patients received 3 mouse tyrosinase DNA injections followed by 3 human tyrosinase DNA injections, while the remaining half received the same vaccines in the opposite sequence. The vaccines were given by IM injection in either the deltoid or gluteus muscles (using a needle-free delivery system) every 3 weeks, with injection sites rotated for each immunisation. Three dose levels (100, 500 and 1500 µg DNA/injection) were used, with patients in 3 dose cohorts (no intra-patient dose escalation). The use of both syngeneic and xenogeneic gene vaccines was chosen based on nonclinical observations in which the injection of a xenogeneic gene vaccine for priming, followed by the syngeneic gene vaccine as a booster, yielded better immune responses compared with a xenogeneic gene vaccine for all injections (Weber et al., 1998). The mouse and human cDNAs were cloned and inserted in the pING vector. Injection site examinations, haematology and clinical chemistry analysis, and assessment of adverse events were conducted, but no further details were provided. However, no significant toxicities were observed, i.e. no patient developed a dose-limiting toxicity, defined as any event specified in the National Cancer Institute Toxicity Criteria (CTC v2) at grade 3 or 2 allergic/immunologic toxicity. Most toxicities were grade 1 injection site reactions. Fourteen patients (78%) had injection site reactions.

Positive CD8+ T-cell responses, measured using 2 methods, were observed in 7 of 18 patients at one or more post- vaccination time points by either method. Positive responses were observed at all 3 dose levels, generally in the period at least 3-weeks after the last vaccination, and did not appear to be affected by the sequence of xenogeneic/syngeneic vaccination.

IgG antibodies against tyrosinase were not detected (2 methods used), nor was any persistent elevation of anti-DNA antibodies observed.

Public exposure

The chance of accidental exposure in humans is low.

The main persons likely to be exposed to the proposed product would be qualified veterinarians who are experienced/trained in the administration of veterinary drugs, including the use of needle-free devices. The vaccine is packaged in single dose vials and will be administered under controlled conditions.

The proposed product is not for use in food producing animals, so there will be no exposure of the public to residues in food. From a risk assessment based on the provided data, in conjunction with an exposure assessment which indicated low potential exposure of humans to the vaccine, the APVMA concluded that the proposed use of the product would not be an undue health hazard to humans.

Pre-meeting public submissions

No public submissions were received.

Summary of ACCS-ACMS advice to the delegate

The committee recommended that a new Schedule 4 entry be created in the Poisons Standard for VACCINES – PLASMID DNA and a cross-reference in the Index to Plasmid DNA (rE. coli DH5α pINGhT) as follows:

Schedule 4 – New Entry

VACCINES – PLASMID DNA for animal use except when separately specified in these Schedules.

Index – New Entry

VACCINES – PLASMID DNA
cross reference: PLASMID DNA (rE. coli DH5α pINGhT)

Schedule 4

The committee also recommended an implementation date of 1 February 2018.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice were:

  • The vaccine is used in dogs with stage II or III oral melanoma. Melanomas account for 4% of the tumours seen in dogs. The prognosis for dogs with stage II or III oral melanoma is poor. Administration of the vaccine increase life expectancy for dogs with oral melanoma.
  • The dosage of plasmid DNA (rE. coli DH5α pINGhT) in the vaccine is low, 110 µg per 0.4 mL dose and the number of doses administered is small.
  • The vaccine is well tolerated by dogs.
  • There is no evidence of dog-to-dog transmission of plasmid DNA (rE. coli DH5α pINGhT).
  • Use of the vaccine is not expected to significantly contribute to the dissemination of genetic material encoding antibiotic resistance.
  • The vaccine is not intended for use in food producing species.
  • The vaccine plasmid is unable to replicate autonomously in a eukaryotic host cell.
  • Published studies of bio-distribution of DNA vaccines indicate that intramuscular delivery does not result in long-term persistence of plasmid at ectopic sites.
  • Adverse events seen in dogs treated with the vaccine include injection site reactions and transient hyperthermia.
  • Toxicity to humans is not expected as it is likely there would be minimal exposure to the plasmid DNA during administration of the vaccine. There is even less chance of exposure when re‑handling a dog that received the vaccine. There does not appear to be a significant risk of immune-system related adverse events.
  • The vaccine does not contain an adjuvant.
  • The vaccine would be administered using a needle-free device by veterinary practitioners who are familiar with this method of administration. The risk of adverse events related to unintentional exposure in humans (inadvertent self-injection or through handling a dog that has received the vaccine) is low.

Delegate's considerations

The delegate considered the following regarding this proposal:

  • Scheduling proposal
  • ACCS-ACMS advice
  • Section 52E of the Therapeutic Goods Act 1989
  • Scheduling Policy Framework (SPF 2015)
  • Other relevant information

Delegate's interim decision

The delegate's interim decision is to create a new Schedule 4 entry in the Poisons Standard for vaccines – plasmid DNA with a cross-reference in the index to plasmid DNA (rE. coli DH5α pINGhT). The proposed Schedule entry is:

Schedule 4 – New Entry
VACCINES – PLASMID DNA for animal use except when separately specified in these Schedules.

Index – New Entry

VACCINES – PLASMID DNA

cross reference: PLASMID DNA (rE. coli DH5α pINGhT)

Schedule 4

The proposed implementation date is 1 February 2018, as this is the earliest possible implementation date.

The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the interim decision are:

  • The vaccine is used in dogs with stage II or III oral melanoma. Melanomas account for 4% of the tumours seen in dogs. The prognosis for dogs with stage II or III oral melanoma is poor. Administration of the vaccine may result in an increase in life expectancy for dogs with oral melanoma.
  • The dosage of plasmid DNA (rE. coli DH5α pINGhT) in the vaccine is low, 110 µg per 0.4 mL dose and the number of doses administered is small.
  • The vaccine is well tolerated by dogs.
  • There is no evidence of dog-to-dog transmission of plasmid DNA (rE. coli DH5α pINGhT).
  • Use of the vaccine is not expected to significantly contribute to the dissemination of genetic material encoding antibiotic resistance.
  • The vaccine is not intended for use in food producing species.
  • The vaccine plasmid is unable to replicate autonomously in a eukaryotic host cell.
  • Published studies of bio-distribution of DNA vaccines indicate that intramuscular delivery does not result in long-term persistence of plasmid at ectopic sites.
  • Adverse events seen in dogs treated with the vaccine include injection site reactions and transient hyperthermia.
  • Toxicity to humans is not expected as it is likely there would be minimal exposure to the plasmid DNA during administration of the vaccine. There is even less chance of exposure when re‑handling a dog that received the vaccine. There does not appear to be a significant risk of immune-system related adverse events.
  • The vaccine does not contain an adjuvant.
  • The vaccine would be administered using a needle-free device by veterinary practitioners who are familiar with this method of administration. The risk of adverse events related to unintentional exposure in humans (inadvertent self-injection or through handling a dog that has received the vaccine) is low.

Footnotes

  1. Guidance for Industry: Considerations for Plasmid DNA Vaccines for Infectious Disease Indications (Centre for Biologics Evaluation and Research, Food and Drug Administration).
  2. Parker, S.E., et al.. (1999) Plasmid DNA malaria vaccine: tissue distribution and safety studies in mice and rats. Human Gene Ther. 10: 741-758.

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