Q & A with
Jerry Siegel, PharmD, FASHP

Pharmacy Purchasing & Products: When is it appropriate to treat a biologic product as a commodity?
Jerry Siegel: From a purchasing perspective, any product can be considered a commodity if all products in that biologic class are interchangeable. For biologics, there is only one product—human albumin—whose brands do not have any advantages over each other, thus qualifying it as a commodity. Albumin is made by a variety of manufacturers, but from a strictly clinical standpoint, there is no need to consistently use the same brand. Outside of the concentration—5% versus 25%—the only other important consideration when purchasing albumin is availability. However, this is where problems can arise. A common issue is that a facility may be flush with 25% solution, but in need of 5% solution and it is not available from their manufacturer. Because albumin is often a high-volume use product, running out can lead to numerous challenges in plasmapheresis units, as well as during certain surgical procedures.

PP&P: What strategies can you suggest for managing commodity purchasing?
Siegel: First, look at the history of the product line for each supplier. Due to the relative frequency of shortages, be wary of initiating purchasing contracts that require the acquisition of one specific brand throughout. For example, such restrictions are common in contract bundles where the albumin product could be tied to, say, the hyperimmune globulin product. In this case, you might receive a very good price for albumin, but the product itself might not always be available. Going off contract to then get albumin from another supplier can result in significant cost increases, defeating the purpose of the bundle in the first place, which is cost savings. So, if you are in a bundled contract make sure your supply of albumin, as well as your supply of the other bundled products, is consistently adequate. Having to regularly buy off contract can be very costly.

PP&P: If the 5% albumin product is unavailable, is it acceptable to dilute a 25% albumin product?
Siegel: A 25% albumin product can be diluted but there are strict factors that need to be taken into account when doing so. Simply diluting a 25% product four-to-one with sterile water creates a hypotonic solution that can cause significant hemolysis. The electrolytes that are physiologic in 25% solutions would also be diluted, so the best substance to dilute an albumin product with is normal saline, as the risk of resultant hypotonic solutions and hyponatremia are reduced.

PP&P: What are the best approaches to conserving the use of albumin?
Siegel: As with any pharmaceutical, albumin should only be used when it is specifically required. Albumin is most commonly used as a blood volume expander, but in many cases, basic saline works just as well in this capacity. Given this, having a practice-use guideline in place to determine when and how much albumin should be used can be very valuable. This guideline should be reviewed at least quarterly to determine whether past albumin use has been appropriate. This review should involve the P&T committee, pharmacists, and physicians so that everyone is aware of the guidelines for proper use. Albumin should only be used for appropriate indications and other plasma expanders, or even saline, can be sufficient in many cases. Simply put, the easiest way to conserve albumin is to limit its use.

PP&P: Should IVIG products be treated as commodities?
Siegel: I do not consider them to be commodities, though most GPO organizations would love for them to be considered as such from a purchasing perspective, because once all products are considered equal then price becomes the only differentiating factor. In the case of IVIG products, it is the pharmaceutical differences between the products that prevents them from being considered commodities. At this point, there is no evidence in the literature that supports one product being clinically more effective than another, but as far as pharmaceutical commodities, they are not interchangeable because of differences in manufacturing methods, stabilizers used, antiviral methodology, etc. While all these products contain IgG and are all highly purified and considered safe, they are not all the same and so reasons differ as to why one product may be better for a particular patient population over another.

PP&P: Given the differences among them, how many IVIG products should a facility have on its formulary?
Siegel: Unfortunately, it is not as simple as choosing one product and assuming it will be acceptable for all patients. One compromise is to identify a workhorse product that is acceptable for the majority of your patients, as well as a secondary product for high-risk patients. Now, perhaps you consider most of your patients to be high-risk, but one way to help identify true high-risk patients is to review the biologic products’ package inserts and black box warnings for specific indications. The factors listed there tend to be indicative of high-risk patients, including those with renal insufficiency or risk for renal insufficiency and those at risk for problems with hemolysis or any kind of thromboembolic complications. Age should be a factor too, so if most of your patients are over 65 they should be designated as high-risk.

For lower-risk patients—those that do not display factors listed on black box warnings—look for a product that is readily available, easy to use, and carries the lowest cost. Generally, having two IVIG products on formulary will suffice. However, there are times you may require a patient-specific product. For example, if a patient is admitted who has been treated with numerous IVIG products and can only  tolerate one, it is advisable to keep that patient on that one product due to the risk of reintroducing adverse events or intolerances the patient has already dealt with in the past.

PP&P:   What factors should be considered in determining which IVIG products to include on formulary?
Siegel: One important consideration would be the vial sizes available for particular products. If you have a large pediatric population and the manufacturer’s smallest vial size is 5 g, that may be much higher than what is needed per patient. Thus, look for products that have 1 or 2.5 g
vial sizes to satisfy that patient population. It is common practice to round off the final dose to the lowest vial size, but for pediatrics, that may result in a 50% difference in the total volume ultimately needed as compared to vial size, and that would be outside a reasonable range.

Another consideration should be products that contain sucrose. These products have been associated with a higher risk of renal insufficiency due to higher osmolar loads and should only be used in patients with low risk factors according to the black box warning. If the patient is low risk, then these products will be well tolerated. However, with a close evaluation of your patient population, you may find you do not have many low-risk patients. In this case, moving to products that are 10% IVIG yet remain in an isotonic range (amino acid stabilized) can be very helpful for higher-risk populations.

PP&P:  How often should you review the formulary status of your IVIG products?
Siegel: Assuming the facility has guidelines in place indicating which patients should receive which products, it makes sense to review those guidelines at least quarterly to ensure their integrity. A review of your product selection criteria and your process for matching patient to product is a prudent thing to do and will improve overall safety with IVIG. It is also important to have a real-time review at the time of order to assure the correct product is being selected for the patient based on risk factors.

Another suggestion is to regularly review the indications for the products and make sure the patients are receiving IVIG for indications that are FDA, compendium, and/or literature supported. As IVIG often is used as a last-ditch effort based on fairly obscure indications, it is essential to be certain that usage does not stray beyond reasonable use parameters. Lastly, take into account whether doses are consistently out of range, either by too much or too little. There are a variety of dose ranges in use today, so you need to confirm that the total amount given to a patient in one day is not unreasonable. Therefore, it is best to perform formulary review on an ongoing basis. Even though such reviews are rarely done as frequently as suggested, keeping records of IVIG utilization is very important and using data collection sheets that track a patient’s dose, indication, and tolerance facilitates a far easier review than having to pull individual IVIG patient charts.

PP&P: What are the product selection issues for facilities with large pediatric populations?
Siegel: In addition to resolving vial size issues as previously mentioned, you also should consider pH levels for IVIG solutions given to pediatric populations. The pH levels of liquid IVIG products can range from about 4.2 to 5.5. In adult populations these lower pH levels are of little concern because adult blood volume is significant enough to buffer the solution and few adverse effects have been seen in adults due to pH levels. However, among neonatal populations, a lower pH may be cause for concern due to an insufficient blood volume to dilute and buffer the pH. Cases such as these may be more theoretical, but it warrants consideration, especially when IVIG is administered to premature neonates. By assuring a slow rate of infusion these concerns can be alleviated.

An additional level of caution is required among pediatric populations for line access. If you are administering IVIG through a large line or a catheter there is little concern for phlebitis at the site of infusion with solutions that have a low pH. However, if you are administering IVIG through a small peripheral vein, then extra caution must be taken at the site to ensure phlebitis is not a result of using the low pH product.

PP&P: What are the product selection issues for facilities with large geriatric populations?
Siegel: For geriatric populations, the greatest area of concern should be the overall volume of IVIG given to the patient in a day. Generally, administering a more concentrated product is desirable due to the restriction on overall volume, but this is only true if the osmolar load is about 300 milliosmoles per liter within isotonic range. So, for example, by diluting certain lyophilized products down to, say, 10% concentration, this could push the osmolar load to greater than 1,200 milliosmoles per liter. In this case, such a high osmolar load would increase the risk for hyperviscosity and thromboembolism, especially in a geriatric population.

The process of doubly concentrating a product to 10% originally was done to decrease the overall volume given to a patient, but it disregarded the potential for adverse effects associated with infusing a hyperosmolar solution.

PP&P: What is the best way to manage a new patient who is being treated with a non-formulary IVIG product?
Siegel: In the case of a new patient being admitted to the hospital, it is important to determine what brand of IVIG the patient is being treated with, the duration of treatment, the presence of any adverse events associated with the product, and whether it is the only brand he or she has been treated with. If it is the only product, it may be reasonable to try converting to your formulary product. However, if the patient has had a history of adverse events and has changed products or has a history of intolerance to the product you carry, then it is probably worthwhile to order the specific product the patient has been successfully using. If there is a supply issue with this product, then finding the most similar product would be the secondary course of action. For example, if the patient is on a 10% liquid product not available in your facility, finding another 10% liquid product with similar characteristics would be the best alternative.

PP&P: In the event of a supply disruption for specific IVIG products, what steps should be taken to switch to a new product?
Siegel: Unfortunately, supply disruptions are relatively common for IVIG. In particular, the withdrawal of a product from the market can create short supplies for all the remaining products. Regardless of the reason, the proper steps depend, in part, on what product you are switching to. If the switch is from a lyophilized product to a 10% liquid product, then it is critical to make sure the rates and concentrations are correct for the patient. In all cases where a switch must be made, the affected patients should be treated as if they never had IVIG before. That is, the escalation scale will need to revert to that of a new IVIG patient because changing brands requires additional monitoring until tolerance and maximum infusion rates can be determined. It is advisable to avoid administering pre-medications initially, as only about 30% of patients require pre-medications such as diphenhydramine or acetaminophen. Until you know how the patient tolerates the IVIG, it is best to limit the use of pre-medications. Remember that patient reactions or intolerabilities to new products will never be identical, so in the event of a necessary product switch, you should treat them all as new IVIG patients. This can be a tedious process, but it is necessary to ensure patient safety.

PP&P: What are the general causes of IVIG shortages, and are they expected to continue into the future?
Siegel: Concern over shortages is fairly consistent for three main reasons. First, if a problem arises with a manufacturing plant requiring a withdrawal of IVIG product from the market, even for a short term, that usually has a detrimental effect on the overall IVIG supply. The second reason would be a disruption to the human blood supply, which is the only source material for IVIG production. Such a disruption may be due to decreased blood donations, an increased risk within the blood population, or even involvement in war requiring increased demand, which can divert blood supplies. Something as simple as extended snowstorms and bad weather can decrease routine blood donations, affecting the supply of whole blood and all fractionated blood derivatives. The third reason can be contributed to new FDA indications. The most concerning among these at present is evidence indicating IVIG may be beneficial in the treatment of Alzheimer’s disease. Since the population with Alzheimer’s is exceedingly large compared to the orphan disease populations treated with IVIG, there is significant concern that the current production of IVIG would be compromised if a large percentage of it were shifted to that new indication.

From a purchasing perspective, there is an overabundance of IVIG available today, but that balance can shift rather quickly. Given this, it is prudent to maintain an ample supply for your current patient populations’ routine needs. The best way to qualify available supply is to follow the track records of the different manufacturers and monitor their backorder status over the past year. Note whether backordering has affected their entire line, part of the line, or not at all, and review your own contracts for binding obligations to a singular product such that a shortage of that product could make it very difficult to acquire an additional or different product.

PP&P: How is a biologics recall different from a regular drug recall?
Siegel: A biologics recall can be caused by a variety of reasons, but mostly they are the result of reports of increased adverse events attributed to a particular brand or lot. The challenge herein is that IVIG products have different lot numbers for each vial size and when a dose is ordered, often numerous vials are used to make the final product, so the actual IVIG dose the patient receives may consist of several different lots. Thus, keeping track of all individual lot numbers, while tedious, is very important.

In the event of a recall due to the detection of an infectious agent, such as occurred in the mid-1990s when hepatitis C was transmitted through some of the older products, the inability to track lots directly to the patients makes it very difficult to identify which patients to warn about the potential for infection. In that case many more patients had to be warned and tested than were actually at risk. Even now, lot numbers of common drugs administered in hospitals are rarely tracked to specific patients, but biologics, especially, should be.

PP&P: What steps must be taken in response to an IVIG product recall?
Siegel: The most obvious step is to quarantine the products in your inventory that are within the recall. This can be tricky, however, as there may be a delay in the distribution of recall information and in that intermediate period it is likely that patients will have received the recalled lots. It is common sense—and a medically ethical requirement—to immediately discontinue treating patients with recalled lots once that information has been received from the FDA’s Center for Biologics Evaluation & Research (CBER), but until recall information is known, treatment using recalled lots sometimes continues. Upon learning of a recall, the hospital should move quickly to cease administration, and inform any patients that may have received recalled lots. These patients then should be closely monitored for any problems. This is why it is vital to track lot numbers for biologic products such as IVIG. Remember, at the same time those recalled lots are being quarantined, you will likely need to acquire a different brand or unaffected lots of the same brand, to avoid a total disruption to the medication supply.

PP&P: Can you share some tips for planning an annual purchasing budget for biologics?
Siegel: Understanding the cost of biologics is key, because some products, such as hemophilic factors, may be the single most expensive line items in your formulary. As such, I have found it easier to carve biologics out as a separate budget item rather than mix them into the general pharmaceutical budget. Biologics require strict monitoring, as shifting costs often depend upon such capricious episodes as a patient with particularly excessive bleeding. Treating one significant episode of bleeding for a patient with hemophilia can result in several million dollars of drug liability. Obviously, these events are difficult to forecast, hence, it may prove easier to segregate hemophilic factors, and other biologics, from the general budget so they are clearly encapsulated and readily discernible.

Other aspects of planning ahead include following trends of new or updated indications, such as the Alzheimer’s indication, which would result in a tremendous increase in your budget should it be FDA approved. Every attempt should be made to secure comprehensive contracts and supply lines, thereby limiting the need to buy off contract or from third party suppliers. This was a big issue during shortages, wherein certain third party suppliers, sometimes referred to as gray market suppliers, would purchase as much product as they could when it was available only to resell it under their own rules, often at great markup. Having a solid, well thought out contract is the best way to ensure a reliable, safe, and cost-effective supply of biologics.
 

PP&P: Do you have any final words for us?
Siegel: Try to avoid putting all your eggs in one basket. With influenza vaccines, for example, consider contracting your vaccine supply from at least two different manufacturers, so in the event of a shortage from one manufacturer, hopefully the other manufacturer(s) would be unaffected. Finally, when it comes to biologics, remember that while cost is certainly an important concern, the main issue is always going to be supply. Achieving a balance between having too much of a certain product, or not enough, requires thorough and consistent review.

Jerry Siegel, PharmD, FASHP, is the former senior director for pharmaceutical services at The Ohio State University Medical Center, where he worked for over 35 years. He graduated from The Ohio State University College of Pharmacy with both his BS and PharmD. Jerry also served as assistant dean of medical center affairs at The Ohio State University College of Pharmacy. He remains clinical associate professor at the College of Pharmacy there. Prior to this, Jerry worked as a clinical microbiologist and as a clinical pharmacist in transplantation and hematology/oncology before focusing on administration. He has lectured extensively on immunology, infectious disease, and pharmacoeconomics, and is a fellow of the American Society of Health-System Pharmacists (FASHP).