Are UK hospital pharmacy departments ready for the rise of gene therapy medicinal products?

ABSTRACT

Introduction: The first gene therapy medicines are licensed and National Institute for Health and Care Excellence approved for use in the NHS. UK Hospital pharmacy departments will need to work with multidisciplinary colleagues to ensure that there are facilities available to handle this new group of medicines.

Areas Covered: UK licensed and National Institute for Health and Care Excellence gene therapy medicinal products (GTMP) and requirements for handling. Review of pharmacy facilities and implementation of advanced therapy medicinal products (ATMP) in the UK.

Expert Opinion: Most hospital pharmacy departments do not have aseptic facilities for the reconstitution of gene therapy medicines, or have the appropriate freezers in place. Staff do not have the understanding or training of these products unless they are experienced in using them in clinical trials. Chief Pharmacists will need to ensure that governance process are in place as they will ultimately be responsible for the implementation and safe handling of these product. Therefore, work needs to continue to highlight the importance of pharmacy departments and their role in the implementation of this new group of medicines. As more GTMPs are licensed and become standard medicines being handled in pharmacy departments, there will be more hospital pharmacy departments ready to handle them. Initially it will just be the centers of excellence, ATMP centers, and research centers with the expertise and facilities. In the long-term, other hospitals will plan and build the facilities they require.

KEYWORDS:

• Gene therapy
• hospital pharmacy
• advanced therapy medicinal products
• genetically modified organisms

Gene Therapy Medicines are classified as Advanced Therapy Medicinal Products (ATMPs). ATMPs are a new class of biological medicines that are classified as one of, or a combination of, three categories of medicines:

1. Gene Therapy Medicinal Product (GTMP)

2. Somatic Cell Therapy (SCT)

3. Tissue Engineered Product (TEP) [1,2].

A GTMP is a biological medicine, which contains or consists of genes, to prevent, treat, diagnosis, or cure disease. Gene therapy medicines can be genetically modified organisms. A Genetically Modified Organisms (GMO) is defined as an organism whose genes have been artificially altered to modify their characteristics[3].

GTMPs used in clinical trials in the UK are regulated by the Health and Safety Executive (HSE) Guidance on GMO, and the Medicines and Healthcare products Regulatory Agency (MHRA), in addition to clinical trial and ethics regulations. The hospital Trust Genetic Modification Safety Committee (GMSC) has to approve all gene therapy clinical trials [3–5].

However, the HSE GMO guidance does not apply to licensed GTMPs following market authorization. UK hospitals will need to put governance procedures in place for the implementation of this new class of licensed products, as they are regulated by the European Medicines Agency and are not regulated by the HSE.

GTMPs consist of a vector (a genetically modified virus or plasmid), and genetically modified genes, which target cells in the human body. GTMPs can, for example, replace defective genes in hereditary diseases, or add genes to code, for example, for an enzyme that would convert a prodrug to an active drug. The resulting protein expressed in the human body as a result of the GTMP is not genetically modified. GTMPs can be administered ‘in vivo’ by injection, or inhalation (in cystic fibrosis trials). The possible routes of GTMP injection are intramuscular, subcutaneous, intra-nodular, and intravenous. There is also ‘ex vivo’ gene therapy, where a patients’ cells are removed, incubated with the gene therapy vector, and the genetically modified cells are reintroduced into the patient.

The aim of the GTMP is for the vector to transport the therapeutic gene to the nucleus of the host cell, where the product encoded by the gene is produced. For some gene therapies used for cancer, not only cells transduced with the GTMP will be affected, but the product encoded by the gene will also affect surrounding cells. Some of the viruses that have been used in GTMPs include adenovirus, adeno-associated viurs, lentivirus, herpes simplex virus, all of which have been genetically modified so that they do not cause disease. GTMPs can be replication incompetent, or replication competent under specific conditions or in specific cell types.

GTMPs are classified according to their potential to cause disease, so biosafety class 1 GTMPs do not cause human disease and are of negligible or low risk, biosafety class 2 GTMPs have a low risk of causing human disease. All GTMPs have additional precautions for handling[5].

GTMPs have been used in clinical trials for a variety of diseases, including cancer, HIV, cystic fibrosis, and genetically inherited conditions for more than 20 years. Most UK pharmacy departments have not been actively involved in handling GTMPs in clinical trials, which then opens the debate as to whether hospital pharmacy departments are ready for the rise in gene therapy medicines? The first GTMPs are now available as licensed medicines.

The first licensed GTMP in Europe (and hence in the UK), was Alipogene Tiparvovec (Glybera) in 2012. Alipogene Tiparvovec was an adeno-associated virus viral vector that delivered a copy of the human lipoprotein lipase gene to muscle cells. It was licensed to treat a rare inherited disorder of lipoprotein lipase deficiency. The product was withdrawn in 2017 due to lack of demand[6].

Talimogene Laherperepvec (Imlygic), was the first cancer GTMP licensed in Europe. It has been approved by the National Institute for Health and Care Excellence (NICE) in England for treating malignant melanoma skin cancer[7]. The Summary of Product Characteristics [8] states that this is a GTMP and should be handled in line with institutional guidelines on handling GTMPs. There are also details on the risk management of this product[9] available. However, many institutions will not have institutional guidelines in place for handling GTMPs, unless they have the experience of handling them in clinical trials.

NICE has issued final draft guidance recommending gene therapy for children with the genetically inherited disease, ADA-SCID, which is a severe immunodeficiency disorder in which babies are born with adenosine deaminase deficiency, which makes them vulnerable to infection and so have to be isolated in order to survive [10]. Patients with this deficiency usually have delays in development, chronic diarrhea, recurrent infections, and issues with thriving. ‘Strimvelis’ is the gene therapy treatment that is licensed, where patients will have to receive treatment in Milan. The treatment is an ‘ex vivo’ gene therapy treatment in which bone marrow cells from the patient are incubated with the gene therapy to genetically modify them so that they produce a correctly working ADA enzyme. The genetically modified cells are returned to the patient via an infusion. NICE is also reviewing how they will be assessing and appraising regenerative medicine and cell therapy products[11].

GTMPs are medicines, so they are subject to the same requirements as other medicinal products. This means that as medicines pharmacy departments are responsible for all steps of the GTMP from procurement through to administration to the patient, as well as the clinical governance pertaining to these products. Chief Pharmacists are ultimately responsible for medicines management in hospitals. Standard operating procedures (SOPS) should be in place for handling GTMPs[2].

The role of hospital pharmacy departments is to oversee the governance arrangements and to ensure that GTMPs used are of the appropriate quality for their intended use. GTMPs may require specialist handling and expertise, which may not be available in Pharmacy Departments. For example, ex vivo GTMPs also fall under the Human Tissue Authority regulations, and staff outside of pharmacy trained to handle these products would need to be involved. Pharmacy will have to have oversight of these products, even if colleagues in other departments are procuring, handling and delivering them.

All licensed medicines in UK hospitals need to be approved by hospital Medicines Management and Therapeutics Committees prior to implementation in a hospital, to ensure cost-effectiveness, NHS funding, place in therapy, and any other practical issues. GTMPs may be subject to additional approvals, for example they may need to be reviewed by Technology Advisory Groups or the Trust GMSC. Many Trusts may not have the local expertise available to appropriately assess the practical issues of product handling and containment for licensed GTMPs before their introduction for use. Trusts may need to review their clinical governance arrangements and procedures for introducing GTMPs into their Trusts, and decide which Governance committee(s) will be responsible to review and approve this group of medicines. Many hospitals are unlikely to have procedures in place for the approval and implementation of this new group of licensed medicines.

GTMPs are usually stored at or below −80°C and can have very short shelf lives at room temperature. Many pharmacy departments do not have the appropriate freezers available, so these would need to be procured, with appropriate temperature monitoring and in appropriate space. GTMP handling and reconstitution requires separate facilities to those readily available in aseptic units. Most hospitals would not have the aseptic facilities required, unless they were involved in gene therapy clinical trials. Consideration then needs to be made as to whether the gene therapy medicine can be drawn up and administered at the patient bedside, dependent on the gene therapy medicine classification, risk assessment, and whether multiple dilutions are required. Currently in the UK, if pharmacy departments do not have gene therapy aseptic facilities, the GTMP is defrosted and drawn up by nursing staff at the bedside prior to administration, following the gene therapy SOPs.

Training is required for all staff before gene therapy products are handled. Specific risk assessments are required. The European Association of Hospital Pharmacy guidance[12] is available for pharmacists on handling licensed GTMPs. The European Guidance on Good Manufacturing Practices for ATMP’s outlines requirements for thawing and reconstitution[13].

To investigate whether UK hospital pharmacy departments are ready to handle GTMPs, we developed a questionnaire based on the European Guidance for hospital pharmacists on handling licensed GTMPs[12]. A survey monkey questionnaire was sent out to hospital pharmacy departments across the UK via the British Oncology Pharmacy Association membership list (900 members from up to 500 hospitals) and the NHS Pharmaceutical Aseptic Services Group (PASG) (540 members from up to 301 hospitals). A total of 84 responses from 73 hospitals were collected. 79 were from pharmacists and 3 from pharmacy technicians. The results identified that there are 14 hospitals already providing biosafety class 1 and biosafety class 2 GTMPs in clinical trials, with five hospitals having aseptic facilities specifically to provide GTMPs. There are issues with staffing, training, a lack of knowledge about handling these products, and a lack of hospital pharmacy facilities. There are a minority of hospitals that already provide GTMPs in clinical trials, and are prepared to handle GTMPs. Most hospitals will require further funding to develop their staff and the aseptic facilities to enable them to safely provide GTMPs to their patients.

A further survey of UK hospitals was undertaken to assess the implementation of the gene therapy, talimogene laherparepvec. Only seven hospitals have this medicine on their formulary to date. These initial results suggest that the majority of hospitals are not prepared to handle viral gene therapy. Further research is necessary with a larger sample size to accurately represent all UK hospitals and gain a better understanding of how prepared hospitals are in providing GTMPs.

UK Hospital pharmacy departments are not ready to handle GTMPs. They do not have aseptic facilities for the reconstitution of GTMPs, or have the appropriate freezers in place. They will need to work with multidisciplinary colleagues to horizon scan and plan for the aseptic facilities required for pharmacy handling of these products. This will include a need for business cases and bids for NHS capital funding. Outsourced providers will not be in a position to prepare GTMPs. There needs to be up to date guidance available for the requirements for pharmacy aseptic provision for ATMPs.

Pharmacy departments will be unable to handle ‘ex vivo’ GTMPs, as they will not have the expertise of cellular therapies. Pharmacists will need to work closely with expertise in handling tissue therapy, and ensure GTMP governance is in place. This will be a new way of working for pharmacy departments.

Most will Staff will not have the understanding of these products or the training required unless they are experienced in using them in clinical trials. Chief Pharmacists will need to ensure that governance process are in place as they will ultimately be responsible for the implementation and safe handling of these product. Therefore, work needs to continue to highlight the importance of pharmacy departments and their role in the implementation of this new group of medicines. Guidance needs to be available nationally to support staff in implementing GTMPs.

There has been very little research done so far to assess whether UK hospital pharmacy departments are ready to handle GTMPs. The only data available has been presented here, and the sample was not comprehensive. NHS Improvement should include this information in their model hospital dashboard to ensure there is a more robust set of data on UK hospital pharmacy readiness for handling GTMPs. A robust research study should be undertaken to assess the readiness of hospital pharmacies across Europe and the rest of the world to handle GTMPs. This could be undertaken by an international pharmacy working group as a collaborative research project.

The published work to date has concentrated on research required to license GTMP products, and pharmacy departments have not always engaged in this new technology. The UK ATMP working group is now established to ensure that information is disseminated, and that Chief Pharmacists are aware of their responsibilities. The ultimate goal is to ensure that Pharmacy departments are ready to handle ATMPs, and have all the information they require to enable them to do this. The biggest challenge in this goal being achieved is educating the profession in the new technology, and the appropriate dissemination of the information. The UK advanced therapy treatment centers have been initiated and funded to take forward this agenda.

As more GTMPs are licensed and become standard medicines being handled in pharmacy departments, there will be more hospital pharmacy departments ready to handle them. Initially it will just be the centers of excellence, ATMP centers, and research centers with the expertise and facilities. In the long-term, other hospitals will plan and build the facilities they require.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.