Institutional Preparedness

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John Petrich (00:00):

The resources and guidelines available to help prepare institutions to handle gene therapy are listed for you here. A few key resources shown here include the Biosafety in Microbiological and Biomedical Laboratories and the National Institutes of Health Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules.

Also, incorporating the biosafety guidance of these two documents into the pharmaceutical standards of the US Pharmacopeia’s General Chapter 800 called Hazardous Drugs — Handling in the Healthcare Settings will help establish viral gene therapy handling guidelines in a health system pharmacy.

Additional resources that are available are shown on the slide. They include websites such as the Gene Therapy Network and the American Society of Health-System Pharmacists (ASHP) Resource Center on gene therapy. The Hematology/Oncology Pharmacy Association and ASHP also have additional guidelines that you can garner from their websites.

Resources listed in video:

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John Petrich (00:00):

The importance of a multidisciplinary biosafety committee cannot be understated. Its role is to develop safe handling protocols and evaluate approved gene therapy products. The biosafety committee should comprise a pharmacist, physician, nurse, biosafety officer or environmental safety health officer, occupational health officer, and waste services personnel. Some centers are also considering the inclusion of a specialized gene therapy pharmacist on the biosafety committee.

Theresa Mays (00:37):

I think important components of a clinical biosafety committee include several PhD scientists who have experience in working with gene therapy agents, viral agents, and viral vectors, as they can provide information to a clinical site based on their experience in a laboratory setting and maybe help us supply that from a laboratory setting to our clinical setting.

And I have found in working with our independent biosafety committee that I was more at ease with handling these agents because of the questions I could ask them and the answers I could receive. Our independent biosafety committee had several — they had about five additional members that were PhD scientists, who had worked with not only viral agents but also with gene therapy across a multitude of institutions. And they were quite a resource for us when we were going through and getting ready to set up our study.

Now, it is my understanding that a lot of larger institutions —  I am talking about more academic hospital-based institutions — had their own clinical biosafety committees on hand already. So, this may be a resource that you already have access to. However, I want smaller institutions and groups to know that there are these independent committees out there that can help you, and they are a great resource. And maybe the best thing about it is, if you are participating in a clinical trial, you can bill their fees back to your sponsor for the trial.

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Jeff Wagner (00:00):

Texas Children’s may be a unique example in this, in that we do not have a clinical biosafety committee. We do have an environmental health and safety team as well as an infection control team that do deal with issues such as the reagents that are used in a laboratory, where those reagents are stored, how those reagents are handled, and ensuring the appropriate safety data sheets are available when a spill or otherwise exposure occurs and can be dealt with appropriately.

Not having a formal committee does not necessarily create a barrier to introducing gene therapy within a particular facility. And I think institutions who only practice clinically should be familiar with infection control and environmental health and safety teams within their everyday work to be able to address the potential concerns of introducing gene therapy within a particular institution.

And then the issues discussed should not be unfamiliar to many institutions. These are requirements from Centers for Medicare & Medicaid Services, the National Institute for Occupational Safety and Health or NIOSH, and others that do require that you have safety data sheets available for the chemicals and reagents that are used within your institution or facility. And an example of this would be, if you use certain gases in your operating room that require flammable storage, that they are stored in a flammable cabinet to protect the institution and other areas from potential exposure.

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John Petrich (00:00):

A gene therapy risk assessment is carried out using a risk identification decision tree, such as the one pictured here. Gene therapy properties that should be considered and are included in this decision tree include those related to the vector. This includes the vector type, whether it is a nonviable type, such as a plasmid, or a viable type, such as a virus, its ability to replicate, and whether or not it integrates into the host genome.

Properties related to the transgene should also be considered. This includes the toxicity and oncogenicity of the transgene.

Brian Yarberry (00:46):

You should definitely look at the product itself, what vector is being used, any information from clinical trials as far as the adverse effects, the effects that will associate with the product itself, and then compile that into a risk assessment.

The US Pharmacopeia’s Chapter 800, which is USP 800, actually makes you carry out a clinical assessment on each new product that you bring in. So, if you follow that same format, you will be following the same —  you will be introducing a gene therapy product, just like you would with any other hazardous agent.

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Brian Yarberry (00:00):

There are definitely some policies that you will want to have in place within your pharmacy as far as the preparation, anything related to the storage, and dispensing of the product. For example, how are you going to store it? Where are you going to receive it in? And what areas are you going to have it on your shelf?

Policies around the training of your staff are also very important. For example, how are you going to train your staff to make sure they are competent in the preparation of gene therapy? In the beginnings of your gene therapy program, you are probably not going to be doing these products very often, so how are you going to keep your preparation staff competent in how to handle these medications?

Outside of the pharmacy, you will definitely want to work with your nursing unit, where these products will be administered. You need to make sure they know how to handle the product itself, any precautions they need to take to protect themselves, and how to dispose of anything that was used to administer the product.

Theresa Mays (00:59):

I think some key policies and SOPs an institution needs to have are going to be, and the first decision you have to make is: "Are you going to try to make these global, or are they going to be study specific?"

At our site, we ended up — because of our independent biosafety committee and how they like to do their protocols — we actually have a study-specific SOP on how we are going to handle our investigational agent. So, normally, this would include receiving and storage, but in our case, this will be handled by a secondary site. It outlined how we would prepare the agent, how it will be administered, and how we will deal with emergency situations, such as if there is a spill of the study agent or if a staff member or someone else has an occupational exposure to the study agent. So, that will be specific to that particular study and then, if we open any other gene therapy protocols, their preference is to individually do an SOP for each and every gene therapy that we open.

We also created an exposure control plan, and this will be a global plan, so we will not have to update this as we open additional studies. And this basically outlines what would happen in the event of a needle stick or an exposure. It also outlines what type of engineering controls we have available at our site, how we will use our personal protective equipment, how we will clean, and how this will affect our housekeeping team. And then finally, provision of the hepatitis B vaccine if needed.

In addition, outside of safe handling for these agents, sites need to plan on how to handle infusion-related reactions, and the most common ones that you see with these agents are cytokine release syndromes. And so, sites need to outline how they would handle that in their clinic. For us, we do not have a specific SOP for that. Instead, we have what we call a hypersensitivity guideline that outlines the various types of infusion-related reactions or cytokine release-type reactions a patient could have and how we would manage them in our facility.

Jeff Wagner (03:17):

The policies and SOPs that an institution shall put in place when establishing gene therapy should align with the established policies and procedures for hazardous drug handling and can commonly be applied for handling gene therapy.

Many of the unique policies and procedures may be related to the balancing side, the financial aspects of gene therapy as well as reimbursement, rather than actual operations and handling. So, gene therapies may not use a facility’s conventional billing formula processes. An approach may be required to evaluate that against established policies and procedures to make sure that the appropriate billing and reimbursement is sought for gene therapies. The reimbursement team certainly may want to consider seeking single-case agreements each time with a payer, until a more formal agreement or payer coverage policy has been established.

The cleaning requirements for gene therapies after they are prepared in a particular area may be a little bit unique, but they could be added typically as an addendum to an established hazardous drug cleaning procedure. The addendum would include the required cleaning after gene therapy preparation and the length of time that the hood or biological safety cabinet should be run, both before and after the cleaning procedure has been performed, before it can be used again, as is recommended by the National Institute for Occupational Safety and Health or NIOSH.

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John Petrich (00:00):

The existing institutional policies that can be used as a basis for the creation of gene therapy policies are your institutions’ policies on hazardous compounding. They can be a foundation for your gene therapy-specific policies and SOPs.

Hazardous SOPs around personal protective equipment receipt, storage, and disposal will be similar to gene therapy SOPs.

Brian Yarberry (00:28):

A lot of times, you can utilize the hazardous medication or hazardous drug preparation policies and practices that you have in place. They are very similar to those that you will be utilizing for gene therapy. So, with a little bit of tweaking, you will be able to filter through those and have a gene therapy protocol and policy in place.

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Jeff Wagner (00:00):

For institutional training, the key recommendation is to increase awareness of the safe handling of gene therapies, and in general it follows much of what already exists for the handling of hazardous drugs as well as chemotherapy within a particular institution. And a unique consideration that may be in place for gene therapy is accidental exposure. And providing context and feedback from infection control related to the handling of gene therapy and its safety is important to address this.

For caregiver training, a unique consideration of gene therapy is that families often have a very young baby and may not have experience in the healthcare environment, and education will be centered around one infusion rather than multiple doses, as is in the case for chemotherapy. So, getting a family up to speed on the safety of a particular therapy may be a little more difficult in a one-time scenario, as is the case for gene therapy, as opposed to an ongoing therapy, as we have today with chemotherapy. And so, again, in this scenario, education may be a little bit more challenging for one-of-a-kind event infusion and ongoing care rather than the multistep chemotherapy process. Home education would certainly be similar to what is needed for patients who do undergo chemotherapy and treatments with other hazardous drugs. The burden actually may be lesser than that of chemotherapy in that the risks certainly would be less, and the primary recommendations, as it stands for the therapies available on the market today, are to do gloves, diaper changes, and that certainly may be easier than handling other aspects of treating a patient that is undergoing complex chemotherapy that will be well beyond just the handling of diapers.

John Petrich (02:05):

My recommendations for institutional and caregiver training related to gene therapy are that healthcare professionals involved in gene therapy handling should be trained with gene therapy molecular biology principles. Caregivers should be trained with product-specific information, such as administration issues, waste handling, viral shedding, immune response, seroconversion, and potential further safety testing. The training should be documented and repeated at regular intervals, and training should be individualized to professional practice.

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Brian Yarberry (00:00):

You can develop your own in-house training program, developed specific to meet your needs. It is nice to reach out though to other facilities that have already handled these gene therapy products to get their information on their training and their standards of practice. The healthcare world is very willing to share their processes with you, so it is really easy to reach out to centers where these products are already being administered and get their take on what you will need to do it in your facility. So, I would say reach out to others but know that most places are going to have something that is tailored to their institution. You can take their information and tailor it to yours.

Jeff Wagner (00:44):

I would say this depends on what training exists and the assessment of the current competencies within the team. And I think, to address that, we attempt to use the best resources that are available.

For complex products, manufacturers are often better at providing the training versus an individual institution to try to recreate the wheel every time that a new therapy comes out — that manufacturers generally are better at creating kind of the standard training for very complex products. And we would use a teach-back method to make sure that the team members and caregivers are confident that they understand the training and awareness around a particular competency for handling and use of gene therapies for patients that we do serve. And if there are no existing resources, then certainly we are kind of up to develop our own to the best we can with the resources that we create internally.

John Petrich (01:45):

Yes. My institution develops its own training programs. There is global training for pharmacy personnel involved in handling commercial gene therapy products and protocol-specific training for research personnel handling investigational gene therapies. The training is valid for 1 year.

Theresa Mays (02:03):

For institutional training, I think this is going to be essential for anybody handling gene therapy, and a person or persons are going to have to be identified to do this. At my institution, I have been nominated to be the gene therapy trainer. So, what I have thought about is how am I going to train, and how am I going to make this applicable to all the different departments? And basically, I have decided I am going to have to kind of do focused training with three different key groups. One group will be my investigational pharmacy staff, another group will be our treatment room nurses, who are administering the agent, and then our third group will be our housekeeper.

So how I plan on approaching this is to come up with a background handout that will kind of go over the types of gene therapies that are available, biosafety levels and what they mean, how to safely handle different biosafety levels, and then what types of personal protection equipment, etc., does one need to use?

And I am kind of thinking due to time constraints and just being able to sit with a group of people for 30 minutes, which is quite challenging in our environment, that this definitely would be a handout or something that I would put on our website for people to view. Then as we get closer to opening our study, I would do about a 30-minute in service, specifically related to that study, and in that we would delve into what type of viral vector is being used for our gene therapy and then what this means for everything I just discussed. How we would use personal protective equipment, how we will safely administer, and how we would handle any spills or any accidental exposure to the agents. Then I would kind of tailor those specifically for, like I said, pharmacy, nursing, and our housekeeper, so everybody was comfortable and willing to go ahead with treating patients with this agent.

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John Petrich (00:00):

Yes, definitely. Only those who are trained and certified are allowed to access the clean rooms and to handle gene therapies. Sterile product competency must be demonstrated yearly by all who enter the clean room. And for research purposes, only those individuals who are trained and authorized and delegated by the principal investigator are allowed to handle investigational gene therapies for clinical trials.

Brian Yarberry (00:28):

This is something you are going to have to address in your standards and practices within your institution. But yes, the kind of practice we utilize in my institution is we only allow those that are trained and certified to utilize these products in the preparation and dispensing. Once they have been trained and signed off, they know how to handle the product itself — they are allowed to either prepare it or handle it for dispensing.

Theresa Mays (00:53):

In my opinion, yes, only those who are trained and certified should be allowed to have access to clean rooms and to handle gene therapies, as gene therapies are definitely going to require specialized handling. At the moment, I am not aware of any certification programs for pharmacies or for nursing handling and administering these agents, so I think each institution is going to have to develop their own ways of certifying and approving people to handle these agents.

Jeff Wagner (01:25):

Within our Department of Pharmacy at Texas Children’s Hospital, we have over 550 people, and every pharmacist and technician that we employ is certified for the preparation of sterile products, which is maybe a little bit of a unique scenario and consideration. But this means that they can prepare and work in the hoods and clean room, successfully. And I would say that it would make sense for institutions that have kind of entry-level technicians, potentially, who do not handle or prepare our sterile hazardous drugs and not be given access to handle the therapies. But, certainly, it would depend on institutional policy on who should handle and be able to manipulate therapies within a particular environment.

And there also may be state-specific requirements. Certain certification or training may exist based on various requirements. For example, our state in Texas has requirements on sterile products handling. In addition, it would include sterile product and hazardous drug preparation, hood cleaning, and even gloved fingertip testing to validate the competency of the person in handling sterile products.

We do not really do much differently for gene therapies other than ensuring that staff understand the procedure for hood cleaning. That is a little bit unique. That can differ from and does differ from hazardous drug preparation hood cleaning. We do have our own institutional program for sterile products preparation for our pharmacy staff, and it comprises 20 hours of training for pharmacists and 40 hours of training for technicians during their orientation as well as annual maintenance of those requirements. And this is followed by a validation test that comprises both a practical with broth and media, with a written test to ensure appropriate competency by the staff. The high-risk compounders that work in our compounding and packaging area that do make sterile products from nonsterile powders are actually recertified to perform their responsibilities every 6 months, while all other staff are recertified on a yearly basis.