Organizational Challenges

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Jeff Wagner (00:00):

There are several key stakeholders to engage when establishing gene therapy within an institution.

The primary group to engage is the pharmacy and therapeutics (P&T) committee that likely should already be established if following the Centers for Medicare & Medicaid Services requirements and standards to have a program in place to manage formulary. The P&T, as many would be aware, is comprised of medical staff, pharmacists, nurses, administrators, and other professionals who participate in the medication use process and oversee many of those policies and procedures that are associated. That committee generally would follow drug development in the pipeline and be aware of when new approvals were coming about via the Food and Drug Administration or the FDA. And I think a question that many pharmacy and therapeutic committees should ask is: “Do we have the appropriate medications available to our patients who seek care within our institution in the scope of care that we provide?” And I think that is one of the routine questions that we get, particularly with gene therapy, of great importance, in that many of these patients with some unique conditions do require access to gene therapies. And then, what patient population would that be intended for, and do you serve that population within your facility? And it is also important to monitor, as these drugs develop; kind of another piece is, would it be valuable for the institution to consider participation in the research for these therapies coming to market over the course of time?

Another key stakeholder to engage would be someone in finance or the Chief Financial Officer. Usually, the reason for engaging someone kind of on the level of finance for new therapies that are coming to market that are gene therapies is that typically they have larger expenses than most other therapies. And it would be a good question for them too or a good value to them to be participatory in the process to understand and assess various things as they come to market, so that they understand the financial implications of adding these therapies to formulary and having them available for patients. Another key consideration with the financial services team is to consider whether the payers, the commercial payers, or even the managed Medicaid services have payer sheets for the therapies that have been approved by the FDA to appropriately cover and seek reimbursement for those therapies. That also includes kind of the managed care contracting team that would be aware of drugs in development. In the case where a payer sheet may not exist, there is an opportunity for the managed care contracting team to create single-case agreements to ensure that they are covering reimbursements as the therapies get used or available to patients.

Another key person to engage would be the Pharmacy Director or the Executive of the Pharmacy Services. It is primarily their responsibility to control or oversee the medication use process, and it would be important for them to be engaged to understand the various aspects of having that therapy available and what it would take, operationally, to dispense and provide it to patients.

So, in conclusion, it will certainly vary by institution, but there are several key stakeholders to engage throughout the process, including physician leadership as part of the P&T committee, typically someone from finance or managed care contracting team as well as pharmacy.

Theresa Mays (03:58):

So, in my mind, the main stakeholders an institution would need to engage when looking at gene therapy are very similar to those who were involved in the recent updates to the US Pharmacopeia’s General Chapter 800, otherwise known as USP 800, which recently changed how we handle chemotherapy, currently more accurately referred to as hazardous therapy, in our clinical settings. It affected pharmacy, nursing, and waste-disposal streams.

So, some of those key stakeholders are nursing administration, one to two key nursing individuals, pharmacy administration, one or two other individuals in the pharmacy itself, probably environmental services, as well as a physician champion who could help lead the charge to get gene therapy started in an institution. In addition, depending on what type of gene therapy agents you may be conducting, you may also need somebody from laboratory services. And this could include not only the general laboratory at your facility but also a cellular laboratory, if you do have access to one in your institution.

John Petrich (05:12):

C-suite members are key stakeholders when requesting resources such as capital and space. The role of the Chief Pharmacy Officer or the Pharmacy Director is key to getting institutional buy-in and convincing the C-suite to commit resources to this therapeutic area. Once this is accomplished, the institutional biosafety committee and the institutional review board should be engaged.

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Theresa Mays (00:00):

So, depending on who you have identified as your key stakeholders, I think your first question or problem to solve is how much education and background do they have in gene therapy? And if this is like most of us, where there is not a lot of background, then maybe just start with the basics and have a discussion as to what that entails. So, some of that would be discussing the types of gene therapies that are available and how they actually work in the human body, and additionally reviewing and explaining why gene therapy is important and why an institution needs to be prepared to administer these now and in the future.

Additionally, a discussion of the different types of vectors and the types of gene therapies that the institution may be administering is important as well as discussing biosafety levels and potential risks to the staff versus benefits to the patients and how these agents could be safely handled.

Brian Yarberry (01:02):

My recommendations for getting stakeholders invested in establishing gene therapy within your institution would start with an explanation of what the product is, what is the disease state you are treating, and how this will impact the children and their health. Most of the time, these products are very limited, the diseases they treat are rare, and a lot of people do not understand what these disease states manifest as and what the morbidity and mortality associated with them are.

Following that, you can give your stakeholders information on how these products affect the disease states, and moving forward, you can give them clinical trial data that show them the outcomes of what these products can provide.

Also, the greatest thing to have is examples from your own patient population. So, if you have treated patients or you have patients locally that have been treated, have videos or information about what the effect has been on their life — it is great to show those to your key stakeholders.

John Petrich (02:02):

Physicians also play a key role in helping to get stakeholders invested, as they will bring funding along with the spotlight to attract new patients. Also, engaged physicians want to participate in gene therapy trials because they will potentially give them additional treatment options, particularly in rare diseases.

An added advantage in trial participation is that, once a gene therapy is FDA approved, a site will already have a level of expertise around the drug, and the P&T process will be less arduous if they are involved in the process in the early phases.

Jeff Wagner (02:38):

It is a change from kind of the common question of: “Should we make this work?” to “How do we make this work?” I think, with these therapies, it is our imperative to work to help make these as widely available as possible across the marketplace so that patients do have access to the care that they need.

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Theresa Mays (00:00):

I think the specific concerns that an institution will have are primarily, number one, how is this going to affect my team or my department? Then we also have to think about who is going to be responsible for training all of the staff? Who is going to prepare it? Who is going to store it? Who is going to administer it? And how is it going to be disposed of?

For preparation standpoint, is this something that the pharmacy is going to be responsible for, or is a cellular laboratory or another type of laboratory setting going to handle the agent?

When the agent is administered, do the patients receiving the agent need to be segregated from the general population? What is the safest way to administer the agent? And what are the resources that we currently have available to implement the use of gene therapy?

What additional resources may we need in the future? And how do we appropriately budget it so we can provide gene therapy in the future at our institution?

John Petrich (01:01):

The concerns that an institution may have about gene therapies as a therapeutic class are uncertainties around safety. I think that is the major concern. A robust campaign to educate the stakeholders on risk evaluation and the proper handling and administration is the key.

Other concerns are the unknowns regarding proper facilities and engineering controls. And finally, some clinicians are hesitant to adopt gene therapy into their practice due to negative past publicity.

Jeff Wagner (01:35):

Certainly, there is a lot of misconceptions around gene therapies that are available in the market, including their safety, the type of genetic modifications that they may create, and whether they will change your inherent DNA or RNA structure. If a viral vector is used, the common question is: “Is there a potential for it to infect or cause harm to people that are exposed to the virus or the viral vector itself?”

And I think these concerns around the safety may be greater now, when more awareness across the public of viral transmission with things, particularly COVID-19, has become more prevalent. And I think once that information is shared, people will understand that gene therapies utilize noninfectious viral vectors that do not change your inherent DNA structure, and it would be important for people to better understand and eliminate any misconceptions that may exist.

Another consideration is certainly the long-term consequences. So, once gene therapy is administered, what are the potential long-term consequences? Many of these gene therapies have been researched in the past decade or so, and so there is not a great understanding of the long-term outcomes of these therapies in patients, although there are several that have had patients been monitored for certainly that time, or even longer. And I think there is limited information in determining the long-term consequences of gene therapy administration, but know that we do understand it well and that the researchers understand well how these therapies do work. And the positive outcomes that they do have, that have been studied and proven to date, have been certainly beneficial.

And then, developing confidence around the available safety information is important to addressing specific concerns. And it would be in the best interest of the institution and people that are concerned about these things and have kind of understood or heard some of these misconceptions to better research and understand the knowledge that is out there, for the safety of gene therapies as well as the viral vectors that are used for the most common gene therapies available today. In addition to some of the safety concerns that might exist around the gene therapies themselves or long-term outcomes, as well as the viral vectors that are used, there may also be financial concerns that may be more prominent at smaller institutions.

For a small hospital, certainly, the kind of investment to purchase a high-cost therapy with, maybe, some question or hesitation about its reimbursement and essentially who is responsible or at risk for payment in a scenario like that may be more difficult than a large institution who might have a lot of kind of working operational capital or funds to be able to purchase and provide therapies.

Although many of these therapies will consume or take a big part of the entire monthly drug budget on a one-dose-for-one-patient basis with the gene therapies that are available today, for small institutions that would be, certainly, more significant. For large institutions, one gene therapy or one dose for one patient may be a drop in the bucket in the overall scheme of things. It will still be important, certainly, to seek reimbursement and to make sure that the costs are appropriately covered for the therapy that is provided, but there might be institutional variance in the financial concerns as well.

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John Petrich (00:00):

Some of the considerations that are dependent on a gene therapy’s properties are — one consideration is viral shedding. A shed vector may be infectious, which raises the possibility of transmission of the virus to untreated individuals, such as close contacts and healthcare professionals.

For viral vectors that are replication deficient, such as the adeno-associated virus or AAV, safety concerns are extremely low regarding viral shedding. However, safety concerns associated with vector shedding are a potential concern for replication-competent viral vectors. Replication-competent vectors may have a longer shedding period than replication-incompetent viral vectors.

Vector immunogenicity also plays a role. Gene therapies that are derived from viruses that elicit a strong immune response may be cleared from the circulation more rapidly than less immunogenic therapies.

And another consideration is tropism. Tropism of the gene therapy product can influence the route through which a vector is shed. Gene therapy products that are engineered to carry tropism-modifying genes or mutations may exhibit a shedding profile that is different from the parent virus because of re-targeting of the product to a different tissue or organ. The altered tropism can influence the type of clinical samples used to study vector shedding.

So, these are just a few examples of the biological characteristics of vectors to consider.

Jeff Wagner (01:42):

So, there are certain considerations and key considerations related to viral vectors that focus largely around safety and education. And safety associated with accidental exposure to a provider or caregiver is important, and it depends on the particular viral vector that is used.

And as gene therapies are developed, knowledge around the different vectors and how they will work will certainly increase, and, over time, vector types may become a larger consideration. However, I do not think that the viral vector type affects the addition of gene therapy to formulary as they stand today.

The consideration related to the transgene is the effect of the therapy and how it works, and I think the key question around this is: “Does the expression of the transgene have a limited effect or potential to change the entire host genome?”

And we understand with the therapies that are available today that the entire host genome is not changed. It is a somewhat limited effect for a particular expression of a protein or substance that otherwise the patients are deficient in that the vectors work to help create.

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Brian Yarberry (00:00):

So, what information do we utilize to get stakeholders or decision-makers on board with supporting the introduction of gene therapy in our institution?

We started with an explanation of the whole process to them just so they had a good understanding of the baseline of the disease state that we were trying to treat.

Secondly, we explained what these products would do, how often they would be given, and what the adverse effects are.

And third, we explained what the literature would show as far as the outcomes of what these products can do to enhance the lives of the patients that they are treating with them.

We compile together information, and we present it in an organized fashion on a level that our financial staff, our administrative staff, and physicians could understand. They all have different levels of understanding what the disease process is, but making that more applicable to their understanding made them see the benefits of these products.

John Petrich (00:56):

First, the projections made by industry and the FDA about the rapidly increasing numbers of gene therapies and then, second, their potential impact in treating devastating illness — those were our two keys to success. Specifically, the FDA commissioner predicted that, by the year 2025, the FDA will be approving 10 to 20 cell and gene therapy products a year.

And then the game-changing nature of some gene therapies is impossible to resist, and it is pivotal toward convincing stakeholders that this is a train you need to be on board.

Jeff Wagner (01:34):

The other information will be part of kind of the desire and need for patients to be administered therapy within their institution from both patient and family networks. And these networks often connect, are aware of products in the pipeline, and know well in advance of their approval, and just kind of a groundswell of support from the public or patients with these conditions to which they do seek information and kind of gather together to know when new therapies are coming.

And it is important to communicate as a facility that maybe you have a process to consider the availability of that gene therapy within your institution as well as evaluating the availability of payers and the information on coverage and reimbursement that will be important.

As many times, what happens in the marketplace with therapies that have been approved is that they are approved by the FDA, but it takes months for various payers to develop policies and payer sheets around the therapies that are available, and that delay certainly can cause some frustration to patients and families as the process is kind of streamlined.

But I think, short of that, another opportunity for institutions to consider is to create a single-case agreement while that policy is being developed.

And it is important to keep patients and families engaged in the timeliness — timeline of the release and availability of these therapies within your particular institutions.

And then I think another consideration to help get stakeholders on board is providing information on handling, which is available from the National Institute for Occupational Safety and Health or NIOSH or well-experienced safety experts, to instill confidence that the handling of these gene therapies is safe and ultimately helps provide a need to the patients that will be seeking those therapies.

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John Petrich (00:00):

The space and cost requirements will be driven by the volume of gene therapies to be prepared. This is dependent on the size and type of facility, for example, a hospital, infusion clinic, small family health center, etc.

A properly engineered clean room with Biosafety Level 2 (BSL-2) capabilities can be a seven-figure cost consideration. The more volume your gene therapy program generates, the more BSL-2 space you will eventually need.

I learned from experience that one 10 x 10 negative pressure room will not be sufficient for a growing gene therapy program at a large center. Volume will eventually outstrip capacity at some institutions, according to expert opinion. So, when planning, space considerations should factor in volume projections for 10 years down the road.

Theresa Mays (00:54):

When you are preparing and manipulating gene therapies, you have to understand that, if you only have one biological safety cabinet to compound in, then you basically will shut down all other compounding. You have to decontaminate that biological safety cabinet, prepare your product, and then decontaminate your biological safety cabinet a second time before you can resume preparing other medications in it.

So, therefore, your questions are going to be volume. Is it something we are going to do daily? Is it something we are going to do weekly? Is it going to be monthly or much less frequent? And that will help you decide if you need to create a specific area to prepare these agents.

Another big issue or question for me is storage. A lot of these agents require liquid nitrogen storage. This is not something we are very familiar with in a pharmacy. In my institution, I have -20°C freezers, and I have a -80°C freezer available to me, but I do not have the potential, right now, to store liquid nitrogen.

And it is going to be difficult to decide, do I need another space to store these agents? So, currently, with USP 800, we have to segregate our hazardous drugs from our nonhazardous drugs. And this has resulted in two storage areas for almost everything we have on site.

So, are we now going to be looking at having a third storage area for gene therapy? That may not be as big of an issue if all gene therapy agents are stored the same way, but we know, even with medications, some agents are stored at room temperature, some are stored under refrigeration, and some are stored frozen.

Some other considerations are, what equipment do you need to purchase? And this may include those storage tanks for liquid nitrogen and how to monitor that storage. And you may also need to purchase a water bath to thaw out the agents before administering, and finally, the space to put all of these items in your institution.

Brian Yarberry (03:00):

So, as far as space planning from a budgetary standpoint, these therapies have to be accounted for outside of your normal budgetary means.

We look at them on an individual basis, and we have separate accounts that we put them in to keep track of what the cost associated with those agents are and the reimbursement associated with them.

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Jeff Wagner (00:00):

It’s important that institutions understand that gene therapies are going to become part of the standard of care in the future and should be a critical part of the pipeline and strategic plan today.

So, putting the appropriate facilities and operations in place should certainly be a part of every institutional pharmacy as well as overall organizational strategic plan.

It is important to develop a process for the introduction of gene therapy early on that would detail who should be engaged in that process of approval and awareness within the institution as well as the level of approvals that are required in order to purchase the therapy, given their expense.

I think the cutting edge of gene therapy is going to be in the pediatric hospital environment in our particular settings.

And the particular focus for hospitals will be creating a gene therapy approach and a standard process to introduce new gene therapies on formulary and allow them to be ordered for patients that are served by a particular institution to also ensure that they are looking toward the future, so you would be able to keep up with the patient demand and overall need for therapies.

For small facilities, while there are certain initial financial considerations that are associated with gene therapy, many are now being appropriately reimbursed, and that should offer significant opportunities for them to introduce it on formulary as well as to balance, both through return on investment, for allowing other treatments to be established within that facility. If smaller facilities are a little bit behind in gene therapy, patients — and we have seen this — will kind of go elsewhere for treatment. And that certainly would be a concern on the opposite end of not having a strategy to introduce gene therapies within your facility. At Texas Children’s main campus, we have planned for the future, and 4 out of our 13 pharmacy satellites do have clean rooms with multiple hoods that are suitable for preparing gene therapy or biological safety cabinets, and some of those cabinets and hoods are yet to be used.

John Petrich (02:21):

The way institutions adapt their infrastructure to prepare for the expected rapid increase in gene therapies will depend on the size of the institution and the volume their program generates. Hospitals will need to invest in large-scale infrastructure right from the start. Ideally, we would like to handle most, if not all, gene therapies using BSL-2 precautions. But here is a common example of my recommendation to a center whose volume has outstripped current capacity and is working toward expanding their footprint but is not quite there yet. In the short term, I recommend a risk-based approach to gene therapy handling, using the decision tree found on the Gene Therapy Network website (https://genetherapynetwork.com/practical-considerations/handling-gene-therapy-in-clinical-settings/), to route as many gene therapies down the BSL-1 pathway as possible. This includes some adeno-associated virus-based therapies, specifically those not manufactured with any virus and derived from nonhuman sources. This will temporarily alleviate some of the burden on your BSL-2 facility until your expansion is complete.

Brian Yarberry (03:29):

This is a great area of expansion within medicine. Going forward, what is our plan going to be? And how are we going to have a strategic plan associated with how we handle these medications? If you are planning spaces, you definitely need to reserve areas for the storage and preparation of gene therapy products in the future. The process right now will probably not require dedicated areas, but in the future, when these products grow and become more the mainstay of therapy for various disease states, having an area that is dedicated for the preparation of gene therapy products and storage will be to the benefit of the institution.

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Theresa May (00:00):

So, what I would provide to my staff in the beginning would be a very basic review of what gene therapy is and then to get them to understand the terminology. Then I would also discuss the various biosafety levels, what that meant for risk to them, and how we would handle them separately than how we handle our other medications that we work with. And then, finally, we would look at the differences between handling these agents to other agents. And the big one, there is highlighting how we handle spills and how we decontaminate the area. Now, what we have to remember is that most of these agents are going to be considered biohazardous versus hazardous drugs. So, most references recommend using a 10% bleach solution to clean up spills in different areas, which is very different from what we do with hazardous drugs.

After my staff has kind of reviewed that background information and I have answered those questions, if they had additional questions that I could not answer, that is where I would reach out to our biosafety committee for additional help. And then, finally, once we had a specific protocol identified and we are getting ready to open it, I would do a second round of training and really focus on that agent and how it works and what type of viral vector it has to deliver the gene therapy. I recently did attend our first meeting of our independent biosafety committee for our study that we are getting ready to open, and the chair presented a very nice, three-page summary handout to the board to discuss how the agent worked, how the viral vector worked, what other viral vectors are being studied or looked at in the population, and then what the risks were to staff and to the patient themselves. And they put it in very clear language that made it very nice to understand. So, I plan on using some information from that handout when I train my staff on the agent.

Finally, what I like to do for all of my investigational drugs is, the day before we prepare our first dose, we go through our compounding steps. I make individual sheets that kind of outline how the drug should be compounded. I would review this with my technicians and my pharmacists, and then we would go through and answer any questions or concerns they would have. And then, on the day of the actual preparation, I would ask my technician, do they want me to be present in the intravenous (IV) room when they compound to handle questions, or are they comfortable in doing it themselves, and we remotely monitor them from afar.

John Petrich (02:53):

My experience with addressing staff concerns also expands to other colleagues across the country. And if I get questions from other centers on this, the first thing I ask them is: “Are you mixing chemotherapy?” If the answer is yes, I would highlight that they are already handling drugs that are just as dangerous, if not more dangerous, in their pharmacy than gene therapy.

I would also evaluate each viral vector individually and go through their properties to assess their risk and required biosafety handling precautions. Also, engage your biosafety committee. I found concerns can be minimized, but not necessarily eliminated, when educating personnel on proper BSL-2 precautions and on using a closed-system transfer device.