Practical and Biosafety Considerations Associated with Gene Therapy

Webinar: Considerations for the Use of In Vivo AAV-Based Gene Therapies

An overview of the biological risks and containment practices for use of AAV-based gene therapies

Chris Jenkins

Principal Partner and Chief Gene Therapy Biosafety Officer at Clinical Biosafety Services

Chris Jenkins

Principal Partner and Chief Gene Therapy Biosafety Officer at Clinical Biosafety Services

Dr. Chris Jenkins is the Principal Partner and Chief Gene Therapy Biosafety Officer at Clinical Biosafety Services, a regulatory firm specializing in administering Institutional Biosafety Committees for biosafety risk assessment review of gene transfer trials at academic medical centers, hospital systems, and clinics. He has worked 10+ years in the fields of human protections, gene therapy, and biosafety compliance fields in academic, private research, and clinical settings. Dr. Jenkins received his Doctorate of Philosophy in Public Health, with a focus on Biosecurity through the Saint Louis University School for Public Health and Social Justice. He holds academic appointments at the Saint Louis University School for Public Health and Social Justice, and The University of Texas Health Science Center at Houston (UTHealth) School of Public Health in Austin.

My name is Chris Jenkins. I’ll be with you all today from the East Coast and West Coast. Good afternoon and good morning for our webinar from the Gene Therapy Network, Practical Considerations for the Use of In Vivo AAV-Based Gene Therapies focused on healthcare providers.

As I mentioned earlier, my name is Chris Jenkins. I’m a founder, as a disclosure, of a for-profit clinical research organization supporting gene and cell therapy. A few items that we’re going to cover today as we enter into a new era of gene and cell therapy, drugs, and drug development and now into the world of FDA-approved drugs. We’re encountering a new field of individuals, healthcare providers, nurses, doctors, pharmacists who are encountering the challenges of utilizing these drugs in situations with live biologics that have previously not been encountered. This webinar will provide an overview of gene therapy, the biological risks associated with those gene therapies and the containment practices and policies when working with adeno-associated viral vectors.

First, we’re going to go with a brief overview of gene therapy for those health care providers and those on the line. First, gene therapy as a novel treatment option has been discussed for several decades. This is not a brand new science, it’s brand new in the sense that we’re just now getting to the realization of the hope and promise of gene and cell therapy products to treat and hopefully cure numerous diseases from infectious disease, oncology, rare disease and beyond. A few items to start off with for the consideration of those attending is when we say gene therapy, what exactly do we mean? Gene therapy as we’re describing today involves the introduction or removal or genetic material or the modification of gene expression to alter the biological function of a person’s genetic code in an effort to treat the disease.

Recent developments in gene delivery techniques and technologies including the development of non-integrating viral vectors such as the recombinant adeno-associated virus, which we’ll discuss in more detail today, has improved the safety and efficacy of these gene therapies. This has led to a dramatic increase in the number of gene therapy clinical trials that have been approved worldwide with over 200 clinical trials approved in 2018. In fact to date, there have now been several virus-based gene therapies that have received regulatory approval from the FDA as well as outside of the US and the European Union and China. Those drugs for those unfamiliar are Amgen’s Imlygic, that’s the recombinant herpes simplex virus for metastatic melanoma. That’s the Novardis Kymriah for two indications. The Kite Pharma Yescarta for one indication. Spark Therapeutic’s Luxturna, an AAV-based product for retinal disease as well as the more recently approved Novartis Zolgensma SMA AAV9-based product.

In addition to the worldwide clinical trials, the current state inside of the United States for those watching from inside of the USA, the recently increasing number of clinical trial INDs has vastly increased. This is realizing the potential, especially over the last two years. You can see on this graph that the field had flatlined around 50 to 60 initiated INDs from 1989 through to about 2011 with an increase beginning to occur. Then as recently as 2017, over 100 initiated INDs as well as doubling to 200 in 2018. As recently as the American Society of Gene & Cell Therapy Policy Summit, the FDA has indicated that for 2019 that number is now above the 350 to 400 mark indicating the J curve continues to increase on the number of clinical trials initiated.

For those unfamiliar, an investigational new drug, or IND, is the application that’s submitted by researchers to the FDA prior to clinical testing in human subjects for authorization to administer an investigational drug into humans. As those numbers have increased with the hope towards FDA approvals, we use that as background for those healthcare providers who may have not been a part of those clinical trials, but are now encountering these drugs in their hospitals, in their institutions, inside of their clinics as this field continues to expand into broader areas. It’s an exciting time right now.

There’s really two ways that we can get gene therapy or cellular therapy into our human subject, into the person that we’re treating. You can do that outside the body or inside the body. That’s ex vivo and in vivo. The ex vivo delivery involves the modification of patient’s own cells, or cells have from a standardized bank, outside of the body, followed by the readministration of those cells into the patient. In contrast, the in vivo delivery method involves the direct transfer of a therapeutic gene that is packaged like a vehicle into a delivery mechanism like a virus into the patient. Since the ex vivo delivery system involves the administration of cultured cells, the handling procedures generally are not as stringent as they are for in vivo delivery methods that are using live viruses in many cases. This webinar is going to focus primarily on the handling procedures of gene therapies that are delivered in vivo.

As a brief introduction to the idea of the viral vector, the car, the vehicle that’s bringing the gene into the individual being treated, we call it a viral vector. The viral vectors are the most extensively studied gene delivery system with approximately 70% of gene therapy trials and all of the approved agents currently in the US by the FDA utilizing a viral vector to deliver the therapeutic transgene. These are naturally occurring viruses that have then been modified by the pharmaceutical company or a laboratory in a way that involves the replacement of their original viral genes with the desired transgene. In addition, removal of the replication components within the viral genome prevents the viral vector from replicating and hence is less likely to trigger an immune response compared with their wild type counterpart.

As we dive a little bit deeper into the types of viral vectors, there are a number of different viruses that have been investigated over the years as potential tools for the delivery of these genes for use in gene therapy. In the initial years from the 90s and 2000s, adenoviruses were among the most thoroughly and first studied viruses that were proposed for the use in gene therapy. However because of side effects, complexity of systemic administration, large genome size, the complexity of design, adenoviruses are used a bit less than gene therapy today, although they’re still in a number of indications for infectious disease vaccines as well as in oncology indications. More recently, we’ve seen an uptick or increase in the utilization of viral vectors including retroviruses, of which lentivirus is a derivative, as well as adeno-associated viruses. Retroviruses and lentiviruses are viruses that can integrate into the genome. Whereas adenoid-associated viruses are useful because they are generally nonintegrating and persist in the cell nucleus predominantly as in extra chromosomal episomes.

In this webinar, we’ll be focusing again on adeno-associated viral vectors and how they can be approached from a healthcare provider perspective by your pharmacies and clinics and institutions in a post FDA-approved world. But before we go into that detail, we need to cover a little bit of the biological risk that’s currently the mechanisms and guidance on how do we assess those risks of these gene therapies when no real guidance for post-FDA approval exists? That overview I would like to go through in a bit more detail now.

Gene therapies are utilizing a biological agent. These are classified as a biohazard. That requires in the US that they undergo what’s called a risk assessment based on their hazards inherent to the viral vector itself, the nature of the genetic modifications that have been made and the inserted gene construct, as well as the processes involved in their manufacturing formulation of the agent and the route of administration of that gene therapy. Typically in the United States, that involves the review and approval of that assessment by a convened group called the Institutional Biosafety Committee. That’s on the clinical trial side.

Once you get into the FDA-approved status, then that committee is no longer required under the current requirements in the United States. This information will be useful for those pharmacists, nurses, and clinicians who are handling these types of products for the first time, but without a clear regulatory guidance as we’ll discuss in upcoming slides. After this risk assessment is conducted, what is utilized is a system of containment. You’ll hear the term biosafety levels frequently when handling and utilizing these gene therapy vectors. That must be maintained to include both the physical containment of the gene therapy agent, which I like to think of is like the onion rings around the agent, as well as the handling practices of the pharmacists and their technicians and the nurses, as well as the clinician infusing or operating room staff that are administrating this drug into the patients receiving the product.

There are resources out there to help those healthcare providers. The ones I would point folks to there’s the backbone document for that committee I mentioned earlier, the Institutional Biosafety Committee, called the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules. As I mentioned earlier, that document and those requirements don’t apply to an FDA-approved product, but we want to mention that there’s a lot of good guidance in there. In addition, there’s materials and guidance from the Centers of Disease Control with a document called Biosafety and Microbiological and Biomedical Laboratories, the World Health Organization’s Laboratory Biosafety Manual, the European Association of Hospital Pharmacists and in addition to other resources including the USP 797, USP 800 and other guidance including some recently published articles.

When we talked about the classification of these agents, the guidance that currently exists in the clinical trial world that I would recommend would be applied into the post-FDA approved world is utilizing a terminology called risk groups. What is the risk group of your viral vector or your agent for that’s carrying this gene. The guidance from the NIH guidelines and World Health Organization have recommended classification to four groups. This is geared towards laboratory use in animal research and has been applied in both the United States and elsewhere in the clinical realm as well.

These are subdivided into groups one, two, three and four. Those groups are based on the risk to the individual and the risk to the community with one being the lowest risk and risk group four being the highest risk. Risk group one agents, as you might expect, are those not associated with disease and healthy adult humans, those are the lowest-risk agents. Risk group two includes agents that are associated with human disease, but that is rarely serious and for which there are preventative or therapeutic interventions often available.

As a note, most viral vectors and therapeutic compounds that you will see both in clinical trials and in a post FDA-approved status will be from these two risk groups, risk group one or risk group two. Risk group three will include agents that are associated with serious or lethal human disease for which

… Preventative or therapeutic interventions may or may not be available and has a high individual risk but a low community risk. And then finally, risk group four includes the agents that are likely to cause serious or lethal human disease for which preventative therapeutic interventions are not usually available. So this risk group has the highest individual risk as well as the highest community risk. Expanding further on risk groups, each of the resources that we mentioned earlier are available for establishing the risk and containment procedures for these types of biological agents. So the Appendix of the NIH guidelines goes into detail on the different risk groups. The Center for Disease Control BMBL goes into some information, especially on high-risk pathogens. In addition, the Public Health Agency of Canada and the World Health Organization provides information, and I really like the Public Health Agency of Canada’s, they have risk group information specific for infectious agents geared, if you’re familiar with material safety data sheets, they have them as pathogen safety data sheets. So instead of an MSDS, they’re called a PSDD. You can find that at the Public Health Agency of Canada’s webpage.

Once you know the risk group of the agent that you’re handling, the approved FDA product, whether it’s an adeno associated virus or a herpes simplex virus, like from Amgen and Novartis and other organizations, then as an institution you need to apply the standards around what’s called a bio safety level, and similar to the risk groups there are four bio-afety levels, but they are not always one to one. So just because an agent is risk group one doesn’t necessarily mean it’s bio-safety level one.

The World Health Organization and CDC established this expansive set of standards. So if you have not run across these standards, there’s a whole field of biological safety professionals. Infection control deals with this area of bio-safety levels, and they encompass really three main areas of facilities, practices and engineering controls that would be utilized in a pharmacy, for example, like a biological safety cabinet for drawing up this product. The bio-safety levels are utilized to handle those products safely. So if you’re utilizing a biological safety cabinet that means that the assessment of the risk is that you would need to protect the individual, the environment as well as provide product sterility. So each level builds on those facilities of your pharmacy or where you’re drawing up the drug, the practices of the people, the pharmacy and the pharmacy techs and the nurses and the doctors who will ultimately touch that drug in your institution as well as the engineering controls that they’ll use. So whether it’s a biological safety cabinet, whether it’s a closed system transfer devices, whether it’s safety sharps, whether it’s infusion pumps, anything that touches that product, everyone would need to be communicated as to what that hazard is.

The biggest challenge for, and you’ll hear multiple times throughout this webinar, is what I would call institutional readiness, especially for those institutions that are outside of the academic medical center community. So those who have not handled gene therapy products previously, who need to be educated and then disseminate that information through those healthcare provider networks. So this is a very busy slide and there’s a lot of criteria on here. I do want to touch on the bio-safety level one and bio-safety level two on terms of what’s specific for those. So the assessment of that bio-safety levels, as I mentioned before, is based on the risk assessment of the agent with that information provided by the pharmaceutical sponsor to the pharmacy and nursing staff and to the clinicians.

So these bio-safety levels then are composite of the construction of the facilities, those facilities’ equipment, the practices and operational procedures all the way down to the disinfectant. We go into extreme detail because these are the kinds of questions that nurses and doctors and pharmacists come up with as they’re handling these drugs for the first time. So the lowest bio-safety level, bio-safety level one, is used for work with those microbes and organisms and viruses that are not known to cause disease in healthy human adults. Very typically you’ll find standard laboratory ecoli, adeno associated viruses handled and or approved by institutions at a bio-safety level one category. Now there’s a lot more criteria that goes with that, but that’s the overall standard.

And then at bio-safety level two, many institutions classify the drawing of human blood for it’s an unknown nature of the types of diseases that might be inherent in the blood of blood draws to be a bio-safety level two. So that’s suitable for work involving microbes that possess a moderate risk to workers in the environment. We’ve seen frequently that a adeno associated virus, while it’s risk might be risk group one, overall the institution through either it’s IBC in a clinical trial or in it’s FDA approved drug status will handle the drug overall as bio-safety level two, not because of the agent but because of the blood from the patients that are being pulled as part of the overall assessment of the drugs efficacy. And then I put the increasing criteria, BSL three, bio-safety level three and bio-safety level four in here only to show that for nearly 99.9% of clinical trials and FDA approved drugs, you would not be handling these in these types of environments. So as we go into a little bit more detail on bio-safety level one, these are things like washing hands after working with the agent, operating in a clinical or laboratory or pharmaceutical environment that you’re handling most specifically the biggest issue that we find are needle sticks in pharmacies, especially with live viruses. So if you are using a needle or have to use a needle or the sponsor hasn’t done testing on a closed system transfer device, which would eliminate a needle hazard, that the folks have safety-engineered sharps devices in order to close off the needle after it’s pulled out of the vial septum, drawing up this product. As well as the using inappropriate disinfectant of the work surfaces after the completion of work.

So when working in a BSL one, bio-safety level one laboratory, there are no primary barriers that are required from a hazard standpoint, usually, typically it’s personal protective equipment of a lab coat and gloves. There may be other reasons to utilize facilities, like a biological safety cabinet that are in the pharmacy, for product sterility, but from a hazard standpoint, it’s not required solely if you’re looking at the basis of hazard. So the other items that when you’re looking at from a bio-safety level one perspective, and this is typical for pharmacies that are operating under USB 797900 is that there’s controlled access, not anyone can walk off the street and handle these drugs. Benches are able to be able to support the loads and use and are easy to clean and that people can wash their hands after handling these agents. All rudimentary, but just to provide a backbone of what is expected when handling these biologics.

Because typically when we get into bio-safety level two, this is apply when those agents are moderate risk. So if you’re handling a product that could be herpes simplex virus or a lentivirus based product, typically in the clinical trials that’s bio-safety level two and when you see that get into a FDA approved product, many of those practices and procedures will be carried forward by the sponsor as part of their FDA approval. so as mentioned earlier, the procedures and facilities required for BSL two build upon those for BSL one and include limited access to the laboratory when work is being conducted, a clear indication of biohazard warning signs or a communication of what’s required to handle the specific agents that are present in that pharmacy and in the clinic when they’re dosing the patient, that staff are working with protective equipment that could go beyond a lab coat and gloves. It could even include eye protection or a face mask of some type to minimize potential aerosols or splashes so that the pharmacist or nurse handling the product does not have a potential for exposure to these live biologics.

In addition, the facility itself should have self-closing doors, sinks for washing hands, access to an eyewash station if there was an exposure and some mechanism for disinfecting and inactivation of biohazardous waste.

In a recent paper in summer of 2019, folks from Cleveland Clinic and nationwide and industry have published a article for the healthcare pharmacist. So in the Journal of Pharmacy Practice, in the back of an article on the considerations for healthcare pharmacists, there’s a decision tree for considering and handling of gene therapy products given there is not a lot of guidance out there once the post-FDA approval status has been obtained for a sponsor, for a drug. So as a pharmacist and as a clinical manager and as a clinician who wishes to dose with these products and you’ve never handled them or have to operate in facilities that might be at an academic medical center but are different than your clinical research areas, we wanted to utilize this to focus on, is the product a genetically viable biologic? Can it replicate? And if it can replicate, and I’m showing the bottom part of the decision tree that’s on the slides right now. If it is replication competent, can it replicate? And then what type of gene does it carry.

And then that can help decide or influence your overall organization’s handling of bio-safety level one or two or special considerations for these products, because you’re looking at can it integrate candidate, can it carry a gene that could cause other issues if there was an exposure. And so that’s the idea behind providing some guidance for pharmacist in this post-FDA approved world that we’re starting to enter.

So that gives a overview of the risk assessment and overview of the biological considerations. So now I want to talk a little bit about preparation for institutions specifically with AAV based gene therapies. As I mentioned earlier, there are a couple of products that have been approved by the FDA. There is what I loved in this recent conference I went to from the FDA is they used the image of a tidal wave to indicate the number of drugs and products that are coming that are AAV and cell and gene therapy that are imminent over the next five to 10 years. So the field that has been discussed for so long is now starting to see the fruits of a lot of work from some incredible academic research and clinical organizations and pharmaceutical companies that have moved this field forward.

But when we talk about AAV, the reason why I want to highlight this is because there are a number of products and more institutions are having to grapple with how to make these types of risk assessments, and AAV is becoming a very common virus that is being utilized for FDA approved drugs. So AAVs are part of the parvovirus family. That’s a single-stranded small DNA virus. They are intrinsically replication incompetent. That means they need a helper virus, such as another virus, like an adeno-virus or herpes simplex virus just to be able to grow more of themselves. That is a really nice safety feature from a hazard standpoint.

In addition, these AAVs have several different serotypes, meaning different kinds of AAVs that impact their tropism, or the types of cells that they infect. And none of these serotypes have been shown to be pathogenic in healthy adults, which is also a great reason for their utilization and research into these vectors. So AAV based vectors are generally non-integrating and they persist in the cell nucleus predominantly as what’s called an extra-chromosomal episome. So they’re not integrating usually into the DNA of the cells of the patient that they’re going into. They are efficient at infecting both dividing and non-dividing cells. So that makes them a great candidate for all types of disease states and types of cells to go into. The types of routes from a risk assessment standpoint that AAVs are transmitted include both respiratory and gastrointestinal GI routes.

So some of the safety features of AAV adeno-associated virus vectors is that their safety profile is really well known. It’s been well-characterized in preclinical and clinical studies. They’re one of the smallest viruses. I like to think of them as like a Ford Pinto, in that the size of their non-envelope capsid can carry a small amount of DNA as part of their pale or for their transgene. although they have a high sero prevalence in the human population as you age, the virus itself has not been associated with human illness and it hence is considered to be a risk group one.

They are naturally replication-deficient and need co-infection with that helper virus. So when there is no helper virus, the AAVs can insert their DNA into that home chromosome stably and remain latent. So we see that with the approved AAV products that are there. AAVs do not contain potentially harmful transgenes normally. So it’s then up to the pharmaceutical company and research groups if they are going to put a certain type of maybe proto-oncogene agent in there for the assessment of the healthcare providers. But so far, to date, the type of genes that are being introduced into the AAV to be carried into a patient are usually a rare disease, up regulation of a gene that’s malfunctioning or is not being expressed correctly. But if it did carry a transgene that could cause issues, that’s where you would assess the bio-safety level at a different, possibly upping the bio-safety

-level. In addition, AAV vectors are also great to use in the sense that they’re susceptible to antimicrobial products that have been approved for work with blood materials. So using 10% bleach or PDI Sani cloth wipes that are [inaudible 00:28:15] ammonium-based, which many hospitals and clinics already use, would be part of the process, standard operating procedures for your pharmacy to wipe down your biological safety cabinet, as well as in your clinic when you’re dosing these patients and you’re cleaning the materials afterwards that have been utilizing the product, that you can utilize materials that have already been approved through infection control for an activation.

In addition, the AAV vectors being biologically active have been shown to be very efficient in both preclinical and clinical studies. They may be transmitted by aerosol droplet exposure, as well as ingestion and injection. So we do want to take care when handling these, not because of disease or illness, but because they can raise the risk of potential serial conversion of an antibody-negative individual exposed to an AAV vector. So I want to pause in that moment because the most common question that we get from new institutions, typically a new pharmacy or a nursing group, is that they want to know that if they are exposed to this virus, does that preclude them from being potentially eligible for future vaccine, or future treatments with this type of virus in the future? And the answer is complicated.

We don’t entirely know what the rate of serial conversion is for these drugs as they’re entering in the pharmacy. But I can say is that many of these institutions, especially for women of childbearing age, which can comprise a large number of nursing capabilities as well as pharmacy groups, that some institutions have taken the care to have a certain subset of those pharmacists and nursing groups actually draw up the product, or handle the drug, just as part of safety precautions for their own institutional policy. So that is an item that comes up. It’s probably the most common question we get from institutions, is the risk of serial conversion and what that means for them as a nurse, or them as a pharmacist. So I did want to touch on that.

In addition, a couple other items that have come up is the shedding. So in terms of determining the bio-distribution and shedding profile of the AAV vector, that’s being studied and it’s essential for identifying the safety of proposed early phase clinical trials. So we’ve gotten to the point now where we have a couple of FDA approved drugs, but continuously we are moving forward with other research into AAV serotypes and vectors that are being administered at Vivo. And so we do know they can be shed by a number of different routes. So when I say they, I mean these AAV serotype vectors, including tears, stool, saliva, urine, and semen for a few days or weeks post-treatment. But again, the shed AAV based vectors are not expected to be infectious. And because of that possibility of vector shedding, the AAV vectors must be handled with the special considerations for that individual virus. And so that’s where, again, we recommend that the personnel involved in these studies need to be informed and educated.

The second biggest challenge we find is, now that this becomes an FDA approved drug, it becomes on a formulary or able to be prescribed at the hospital, is identifying the chain inside of the institution of the pharmacist or the pharmacy team that’s going to receive the drugs. Who’s going to draw it up? Who are they going to hand it to from the treatment side, what’s the chain of custody? Because these are not insignificantly priced products, so we need to handle them with care, but also for safety for the individuals and handling those agents. So the handling procedures for each AAV vector are based on the bio-distribution and shedding data of that vector stereotype product.

So as I mentioned previously, there’s guidance on handling gene therapies, but you have to pull it from different sources. So currently in North America, there is no NIH or FDA or CDC specific guidance on handling procedures for gene therapies that minimize potential exposure risk to healthcare personnel. It just doesn’t exist. So that means you have to institutionally, or at your institution, you have to set up a risk assessment for each drug. And if your experience with the institutional biosafety committee model, I highly suggest that type of model or similar model for handling FDA post approved drugs. So hospital institutions and pharmacy departments have had to develop these individually, and sometimes with not a lot of guidance from the regulatory authorities, and from there have to reach out to other colleague institutions on how they’re handling these drugs with limited published data. While developing those procedures, I really recommend that you evaluate these products individually, taken into consideration as we mentioned before, the risk group and bio-safety level, because that’ll determine that risk for the encoding transgene.

There are some other resources out there. So I do want to highlight that there is a resource that has been published by the University of Kentucky and others in the paper I discussed earlier. And we really are, the field as a whole in the pharmacy sector and nursing sector is really trying to raise that awareness through a webinar like this for healthcare providers as these drugs become more mainstream. That’s to help with all the steps in the process of receipt, preparation, dispensing, administration, and waste disposal of gene therapies.

So I do want to talk a little bit and go through each of those steps in a little bit more granular detail. Some bio-safety considerations for pharmacy staff. So let’s talk about storage. So in USP 797 or 800 type pharmacies, these products are expected to be classified by the NIOSH standards in 2020 as a hazardous material. But right now they’re just silent on that topic. So it’s generally recommended that they’re handled in their ACEP to conditions during storage, handling, preparation, dispensing. During the pulling out of the product or receiving the product, it’s recommended that staff wear, whether it’s a technician or receiving, wear a lab coat and gloves. In terms of receiving the product, identifying if it’s usually at a negative 80 or on dry ice when it’s received, that they handle with the appropriate personal protective equipment.

So then we highly recommend that the gene therapy products are put into a designated isolated storage area, separate from other drugs, as is typically we find from the FDA approved drugs, is what is also recommended. And in addition, that the areas should be for storage are appropriately labeled, ie. with the biohazard symbol if needed, to alert employees of the risk group and possible hazard, as well as the shipping container that’s received, and might also be used as storage if it’s like a doer or contains the material, is also labeled and inspected by the pharmacist to ensure that it had safe transit in delivery. Because again, mentioned that while there’s little to no hazard from these AAV based products, there is a substantial financial impact for pharmacies. And you want to make sure that you have SOPs for handling these types of products.

Then as we get into the handling and preparation, again what you wear in your USP 797 or 800 pharmacy in terms of lab coat, gloves, possible mask, eye protection, hair bonnet, shoe covers, must be determined through that risk assessment as well as through your own standards. All preparations, typically for many of these types of drugs, we find that the sponsors are recommending or requiring some sort of pharmaceutical-grade isolator or class two biosafety cabinet, and ideally a class two B2 cabinet because that way if there is a drug mix of a biologic and chemotherapy compounds, you can work with biologic and chemicals in the same hood, that are compliant with the standard from the National Science Foundation called NSF 49. And so a lot of pharmacies will do those certifications even beyond the one year, but also at six-month intervals, to ensure that those cabinets or hoods that provide a curtain of air that’s protecting the pharmacist or pharmacy tech, the product itself in front or the environment, that those are operating. And just as a side note, that airflow, if you’re on a treadmill, is typically around one mile per hour. So think of how slow one mile per hour is, and that’s the curtain of air that’s separating the product and keeping it sterile when handling these inside of a B2 cabinet or A2 cabinet.

In addition, these cabinets before and after, especially if they’re a B2 cabinet, these pharmacies, especially healthcare pharmacies that are inpatient, these are operating 24/7 and so it can be a real challenge to disinfect, decontaminate a cabinet, bring it up for a biologic, like an AAV product, draw that up, then decontaminate and turn it back over to a chemotherapy. That’s probably the third largest issue we find is integrating these types of biological products into the workflow of your standard pharmacy, in inpatient or outpatient pharmacy for the drawing these up. And so we always recommend then afterwards of drawing the product up, that’s decontaminated with the disinfectants we’ve talked about before, and we’ve found that many pharmacies are also utilizing double gloves where they take off a layer of the glove after handling the product inside of the cabinet, and then taking off the second glove when they exit the facility proper from the pharmacy.

And now when we go into the dispensing, we again mentioned, I mentioned before, so now the products inside were usually inside of a class two hood. There’s been a lot of chatter and movement in USP 897 and USP 800 of having dedicated airflow, biological safety cabinets, exhausting air out of the buildings. A lot of institutions you’ll find are in the process of installing a class two B2, which are 100% exhausted cabinets, so that they can handle both chemotherapy compounds as well as these biological agents.

So again, the personal protective equipment when handling those drugs should be for the followed per their USP 797 or 800. The products should be triple checked in terms of, a lot of these are weight-based or come as a kit where you have to drop a certain amount, and there is a very minimal overfill in a lot of these types of vials. So you have to really, as a pharmacist, or pharmacy tech, really track how you’re drawing these products out down to the one to two decimal points for an appropriate dose. You have to document that and ensure that’s checked before releasing the product outside of the pharmacy.

So then the issue that comes up, or the questions that come up is around an accidental exposure. In terms of the pharmacy preparation, this is where you need to have some sort of spill kit or emergency guidelines where we highly encourage contacting your local infection control group who has standards for what to do in the case of a spill, or spill kit, or your Roekel environmental health and safety group. And many of you who may not know these individuals, but there’s a group of professionals called biosafety officers at or nearby in your institutions or academic medical centers that advise on the handling of these types of agents every day in the preclinical and clinical trial arena.

The spill kits would contain hard shell, leak-proof containers, paper towels, sponges, the PDI Sani cloth wipe type disinfectants with bleach, eye protection and masks, as well as a process for notifying your environmental health or infection control. That’s another item that comes up and really stumps a lot of pharmacies and a lot of clinical groups when preparing these types of products.

Then after you’ve drawn up the product and the pharmacy, comes the question of disposing of the materials and the personal protective equipment. So how does that material get into biohazard waste containers or sharps containers? Are you choosing, as a pharmacy, to only use what are called closed system transfer devices? For those of you unfamiliar with those, those are devices that you can puncture through the septum of a vial. And in that, it removes the needle that has to be pulled out, and removes a potential needle stick. And so for accidental exposure, that’s the number one area that research has shown for exposure to biological hazards. We want to minimize that and CSTD, or closed system transfer devices, are a really good tool for doing that. Problem is that a lot of these vials may not be large enough, because of their volume contents, to be able to utilize that device. In addition, a lot of the sponsors and and institutions may not have done testing on all the different types of plastics and materials that these CSTD are composed of. There may be a compatibility issue to using one that has not been tested. As a pharmacist or as a pharmacy tech, you would definitely want to clear the use of a CSTD with the sponsor who’s providing the gene therapy to ensure that it can be used.

In addition, waste containers that are either inside the biological safety cabinet, like the little sharps containers with the biohazard symbol that are hard shell, or a vials container, those should be labeled and treated and displayed with the biohazard symbol.

We’ve talked about a lot of different areas and topics as part of handling these drugs. The field is just now getting to the point where

They’re exiting clinical trials. They’re getting into FDA approved status. We know there’s a bunch of coming and so I really want to focus on and leave with the take home messages of, if you are a clinical operation or a healthcare provider, seek out some of this guidance from the CDC and NIH that defines these biosafety levels and risk groups. Get educated, spend a little time around what biosafety level one and two would mean for your pharmacy and for your clinic. That is some great resource.

We expect NIOSH and upcoming USP guidance through USP 800 to provide further clarity there. Though that’s not fully defined yet we do expect to hear some additional information in that arena. As a reminder on AAV’s particular which we think is going to be the really increasing vector that’s going to be utilized, the biological risks from working with AAV vectors again are considered very low. That risk group one we talked about.

And so most of these can be handled from a hazard standpoint of biosafety level one. But that would mean that your other pharmacy practices, utilizing a biological safety cabinet, transferring the materials in sealed containers, we’d want to ensure that that chain of custody for these agents is followed. As I mentioned earlier, the biggest challenge has been getting institutional readiness. So formal enabling the quick and safe uptake of these gene therapies.

So what happens is a doctor, a neuromuscular physician, he has found has a patient, they want to dose them right away. And the institution has been talking about it for a while, but they’re just not ready. And so that can be a real problem, because especially if there’s a timing issue and weight issue on the type of patients being treated is we should start having these conversations now. And so having that staff training, having the sponsor common educate, educating the pharmacists, the nurses, the clinicians on the biology behind these drugs and their hazards will go a long way in smoothing the road towards successful uptake by these clinics and institutions.

And so those are the five points I want to leave you with. At this particular time, we’ve been taking some questions throughout the webinar and we’re going to take a brief audience Q&A. Before I go into that, just want to thank you for your time and going through the main part of the webinar. And now I’ll address some of the questions that have come through as we’ve address the issues throughout here. So one question’s come in, where do most centers administer these infusions? Is it inpatient, is it clinics, or is it negative pressure rooms? How do you decide?

That’s a good question. So the location depends really on that type of agent. So if it’s an adeno-associated virus, or herpes simplex virus, it really depends on that virus, or the treatment that’s being given. It depends on the manufacturer’s guidance, depends on your own facilities. It depends on the type of drug and it goes back to that risk assessment of the agent itself and where it fits in with risk. So typically, for the majority of the FDA approved IV delivered products, this can take place at an infusion center with a dedicated room. So I hope that that answers that question.

Our next question, what facility designs and equipment should hospital pharmacies start incorporating to handle new gene therapies in the pipeline? That’s a good question and we’re seeing a lot of construction right now in pharmacies getting ready for, or updating their IV rooms from USP 797 to USP 800. Until NIOSH updates are available, my recommendation is that each institution develop its own procedures and evaluate the gene therapy products individually. Again, taking into that consideration of the risk group, a biosafety level that’s determined for each viral vector.

So one example, I’m just thinking through one center I’ve worked with, it’s where a biological safety cabinet was always utilized. Because I just didn’t want to take any chances on the product sterility and the pharmacy tech, or pharmacist handling the drug. And because of the way those are handled or utilized, these biological safety cabinets with their curtain of air protecting the individual as well as the product itself with sterility. And we’re seeing a lot of pharmacies move towards utilizing what’s called a Class II, B2 cabinet. Which is 100% filtered air through a HEPA filter, that’s 100% exhausted out of the building completely. Which would allow that cabinet in that pharmacy to switch between being used as a bios for handling biologics. And then after being an activator decontaminated to being used for chemotherapy.

So what we don’t want to use, and I just want to highlight this point, we don’t want to use a clean bench. A clean bench blows air to protect product that’s been filtered, but with a biologic, the last thing we want to do is dose the pharmacy, or technician or the pharmacist with the agent that’s being prepared, because it’s just protecting product. It’s not protecting the individual. And you still see those in a lot of pharmacies around. That was a good question.

So next question. So I know we have a several more here to go. So any practical information for preparation in a hospital pharmacy clean room? So the standards still apply. USP 797, 800 once pharmacies have to follow, that provides the information on standards for preparing compound and sterile medications as well as going into the safe handling for hazardous drugs. In which we are told otherwise, that’s really where we expect gene therapy products to land from NIOSH. Those standards have not yet become official. And from the last we’ve heard that this is the list of NIOSH hazardous drugs expected to be updated in 2020. So as of right now, we’re still in a gray area without a lot of formal guidance from our regulators. And so that’s where that institutional risk assessments come in. Is a closed system transfer device recommended for preparation? So, we’ve run across this a lot. So a lot of institutions are making the debate of going from using a non-sharps needles to safety sharps needles where you can click over a unit that goes over the bore of the needle. And we’re seeing more and more institutions utilizing this closed system transfer device. And if you’re a pharmacist, or a pharmacy tech, I highly encourage you and investigate that type of system and multiple systems, because they really eliminate the big issue with these biologics, which is a needle stick. Which we don’t want to have at an accidental exposure.

And those will operate by, again, punching the septum with the unit, twisting on a syringe, or a unit that you’re pulling the product in, drawing it out and then being able to disattach the syringe without having to use a needle, really reduces the risk of exposure to that group. So I highly recommend if your pharmacy hasn’t thought about it so far to utilize those units. Good question.

So next question. For the pharmacy preparing the doses, what is required for deactivation and decontamination of the AAV vectors? So some viruses are a little heartier than others, but AAV’s, so you have to use more than soap and water on it obviously. So EPA has what they call their disinfecting list and most hospitals and clinics and academic medical centers will use anything from 10% bleach to 70% ethanol. And so you want to look at the virus, see what it’s susceptible to off of language from the sponsor, or the pathogen safety data sheets, or the NIH materials. You can’t go wrong with bleach, but it pits stainless steel. That’s a problem. And so a lot of institutions use the PDI Sani-Cloth wipes, that are quaternary ammonium-based, or bleach-base, and then follow that up with sterile water, so that it prevents the pitting to their stainless steel units. So, that would be my recommendation there.

So next question, what are the recommendations, or options for the waste stream with gene therapy products? That’s a good one. Okay. So what we found is that the waste stream really depends on the city, state, county of each institution. What we found is that a lot of biologics that are autoclaved out by their biowaste vendor such as Stericycle, and they’re treated as biohazards with red containers.

But what we find in a lot of pharmacies is that the biologics get autoclaved, which is heat pressurization, but agents like chemotherapy get incinerated. And so that’s a higher level of an activation. And so what a lot of pharmacies will do is actually merge the biologics and chemotherapy compounds together in a yellow container for their ease and space considerations. Because both the biologics and chemo will be compliant but incinerated at a higher level. So you do see that sometimes, but that’s the route for the waste stream.

Last question. This a good one. So how much do you anticipate that immune reactivity and caregivers and siblings will limit any future children in that family from receiving AAV-based gene therapy? That’s a good question. And that’s going to come from additional data and research because right now the risk of serial conversion from contact with patients dosed with any gene therapy product, or AAV-based product simply is not known. But generally speaking, the manufacturer’s guidance should be consulted to develop that product specific procedures with regards to vector shedding to minimize inadvertent exposure to the vector by family members. And so that risk of seroconversion with AAV, we do know there’s been a population studies over time that it increases, and that there is an increase of anti-AAV antibodies. But we find is that the younger you are the less of a likelihood that you already have those AAV antibodies, and so we’re trying to limit any potential exposure there.

And so I have seen in some clinical trials and some dosing where if there are two or three siblings to someone getting an AAV-based vector, that the family members will actually isolate the child receiving the agent by hotel room, or living separately for a period of time to prevent contact to their siblings and the event that they might need some type of treatment for a similar disease, or other future treatments in the future based off of these vectors. Really good questions. Thank you for bringing that one. That’s definitely one of the most common that we get. And so this is our last slide I want to say thank you. That’s all the time we have for our other questions at this moment.

I want to take a moment to thank the people from the Gene Therapy Network who sponsored this webinar. So it’s a free resource for healthcare providers and other individuals interested in learning more about gene therapy and with a great set of expertise and content that’s being updated every day. I highly recommend going to a genetherapynetwork.com to register and get access to hundreds of resources and becoming more fluent in this rapidly expanding FDA approved world of gene therapy products for healthcare providers like pharmacists, nurses, and docs who are entering into this world. So I’ll register there. Thank you for attending. Have a wonderful rest of your day. And I look forward to seeing this field expand beyond what we could imagine with the hope that’s always been promised. Thank you.

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