IG Indications

Immune globulin (IG) is used to treat a wide range of disorders. While the most common use of IG therapy is in treating primary immune deficiencies, its efficacy in numerous other disorders is well-documented. It is estimated that for every FDA-approved indication, there are more than 10 non-FDA-approved indications. In certain neurological and dermatological disorders, IG is considered a first-line agent. In other areas, such as renal transplant and cardiology, it has established itself as an integral part of the patient’s therapy. In the future, IG may be a potentially effective treatment for diseases and conditions for which there is no cure.

However, the expansion of use of IG therapy into many newly discovered areas is complicated. The two main issues are the recurrent short supply of plasma to make IG and continual reimbursement challenges. While costs to manufacture IG continue to rise, reimbursement in many cases is below the clinician’s acquisition cost of the product. And efforts to convince government and private insurance payers that higher reimbursement is necessary have been, for the most part, unsuccessful.

Production and Distribution

Five manufacturers supply IG to the U.S.: Talecris Biotherapeutics, CSL Behring, Baxter BioScience, Grifols USA and Octapharma USA. These manufacturers’ products come in both liquid and powder form. Manufacturers report that they are operating near or at full capacity, which means IG availability depends upon IG sales to the rest of the world, adoption of high-yield fractionation technologies and capacity enhancements.¹ In addition, since IG is manufactured from human plasma by fractionation — a lengthy, arduous process — plasma availability is a bottleneck to increase supply levels. The fractionation process takes approximately nine months from when an individual donates plasma to when the medication is ready for use.

On- and Off-Label Indications, and Standard of Care

Marketing for IG is currently approved for five indications: primary humoral immunodeficiency; immune thrombocytopenia; chronic demyelinating polyneuropathy (CIDP); B-cell lymphocytic leukemia; and Kawasaki syndrome. While all IG products carry an indication for primary immunodeficiency, no one product carries an indication for all five.

The number of off-label uses for IG far exceeds that of labeled indications. Although IG has been proven useful for many disease states, the likelihood of manufacturers pursuing FDA approval for already treated indications is remote given the high cost of conducting trials without the benefit of increased marketing advantages. The sometimes tenuous and limited supply of IG, combined with the high costs of treatment, require best practice standards be used when deciding to treat with IG. Some diseases commonly treated off label with IG are Guillain-Barré syndrome, polymyositis, dermatomyositis, multifocal motor neuropathy, stiff person syndrome, relapsingremitting multiple sclerosis and pemphigus.¹

Although there have been no controlled studies comparing one brand of IG to another, anecdotally, some patients report having fewer side effects with one product over another. IG does not come in a generic form and, therefore, brands of IG are not interchangeable. Any change in product should be monitored by a physician.⁴

All IG products have a risk of inducing an anaphylactic reaction to IgA. While it is not known what level of IgA induces the reaction, it has been shown that IG preparations depleted of IgA (0.4 to 2.9 µg/mL) were better tolerated by a limited number of patients who reacted to preparations with higher IgA concentrations. Currently, Gammagard S/D is the only IG product available that has a low IgA level. Gammagard S/D is available in two strengths — less than 2.2 µg/mL and less than 1 µg/mL — and is typically reserved for those patients who have documented IgA deficiency and, therefore, may be at a higher risk for anaphylaxis reactions or are unable to tolerate other products.

For patients with poor venous access or for those having difficulty tolerating the side effects of intravenous immune globulin (IVIG), subcutaneous immune globulin (SCIG) may be an option. As a matter of convenience, SCIG provides patients with an infusion option that can be given independently at home. Because SCIG is administered in smaller, more frequent doses, usually once a week, patients experience more consistent trough levels rather than the peaks and valleys that come with IVIG. Vivaglobin, manufactured by CSL Behring, is currently the only FDA-approved product for subcutaneous administration.

Indications Under Current Research

Many studies are currently being conducted to look at the efficacy of IG in non-FDA-approved indications. Two specific areas that are being explored, for which IG is not used as a standard of care, include Alzheimer’s and secondary recurrent miscarriage.

Alzheimer’s. While IVIG use in Alzheimer’s is in the early stages of investigation, it appears to have promising effects for both reducing the risk of developing Alzheimer’s, as well as improving the cognitive ability of those suffering from it. Results of a study presented at the International Alzheimer’s Symposium in 2008 showed that the risk of developing Alzheimer’s disease and related disorders (ADRD) may be reduced by about 40 percent in patients previously treated with IVIG. In the study, a total of 847 cases treated with IVIG were compared to 84,700 untreated controls matched by age, gender and other risk factors. The proportion of patients diagnosed with dementia was 2 percent for treated cases and 4.2 percent for untreated controls. The relative risk of developing ADRD over time was 0.577 for treated patients versus controls, indicating a 42 percent lower incidence rate of dementia in patients treated with IVIG.⁵

As of early 2009, several small clinical trials have shown promising results for treating Alzheimer’s with IVIG. Two studies examined the effects of IVIG in Alzheimer’s disease at a mild to moderate stage of the illness. In those studies, 13 patients were treated, and while the study group was too small a number to establish conclusively whether the treatment works, IVIG was well-tolerated by the patients, and the majority showed improved cognitive ability. In addition, the first clinical study conducted at the New York-Presbyterian Hospital/Weill Cornell Medical Center suggests that IVIG may stabilize or improve cognitive function when administered over a period of a year or more. These are significant findings since other drugs on the market only work to temporarily halt or slow deterioration. A larger and more thorough Phase III clinical study is currently being developed that will involve a higher number of patients and blind studies that incorporate placebo controls to determine the usefulness of IVIG for treating Alzheimer’s patients.⁶

Secondary Recurrent Miscarriage. Several clinical trials have been conducted to determine whether IVIG is an effective treatment for recurrent miscarriage. While clinical trials are still ongoing, one particular study consisted of a systematic review of randomized controlled trials, comparing all dosages of IVIG to a placebo or an active control. The study looked at eight trials involving 442 women that evaluated IVIG therapy used to treat recurrent miscarriage. The findings showed that, overall, IVIG did not significantly increase the odds ratio of live birth when compared with a placebo for treatment of recurrent miscarriage. However, there was a significant increase in live births following IVIG use in women with secondary recurrent miscarriage, while those with primary miscarriage did not experience the same benefit.⁷

Plasma Supply

Although plasma is not currently in short supply and IG medicines are not depleted, the United States has experienced shortages in the past. For instance, in 2007, the shortfall of supply relative to demand was about 14 percent, and this was probably underestimated because existing demand is often suppressed by hospital protocols and reimbursement problems.² In a survey of public hospitals, approximately 50 percent indicated they could not purchase enough IG to meet all patient needs. As a result, 56 percent reported they had implemented a protocol to prioritize and monitor use of IG in their facilities. In addition, a survey of 310 hospital pharmacy directors conducted by the Immune Deficiency Foundation found that 27 percent of hospitals had instituted criteria for prioritizing IG use.

A more serious shortage occurred in 1998 when scarcity forced doctors to cut dosages for some patients, postpone treatment for others or switch brands, which all affect patients differently.³ The shortage occurred due to a combination of events, including a recall of plasma products that carried a theoretical but unproven risk of transmitting a fatal, little-understood disease; the discovery of serious violations of manufacturing standards among makers of plasma products, which prompted a demand for improvements that slowed production; an increase by manufacturers in overseas shipments of the drug by about 2 percentage points, to almost 19 percent of the total available; and the discovery of uses for the drug for other illnesses, which significantly increased demand.

In 2007, manufacturers estimated annual IG demand growth between 6 percent and 8 percent, but healthcare providers predicted demand to fall between 10 percent and 15 percent annually.² Should the number of diseases approved by the FDA to be treated by IG continue to increase, and the number of plasma fractionation plants fail to keep up with that demand, another shortage could become a reality.

Medicare Reimbursement

Many patient groups and physicians have reported problems to the U.S. Department of Health and Human Services regarding access under current Medicare reimbursement levels. These problems include increased difficulty in acquiring IVIG, switching from administration in a physician’s office to a hospital outpatient facility, fewer treatments due to difficulty acquiring IVIG and switching among IVIG products.²

An anonymous survey conducted by the American Academy of Allergy, Asthma and Immunology (AAAAI) revealed that more than 95 percent of AAAAI’s member physicians feel that current reimbursement standards present a health risk to their patients with primary immunodeficiencies.4 In another survey by the Immune Deficiency Foundation, 26 percent of Medicare patients and 10 percent of other patients experienced adverse health outcomes due to problems with IVIG access.

Access problems are often attributed to the reduction in Medicare reimbursement rates for IG, a consequence of the average sales price (ASP) methodology, introduced in the Medicare Modernization Act of 2003 (MMA), for Part B covered drugs that are not paid on a cost or prospective payment basis. The ASP methodology is based on quarterly drug pricing data submitted to the Centers for Medicare and Medicaid Services (CMS) by drug manufacturers. The lag time inherent in this approach means that the payment rate in a quarter is based on the ASP from two quarters prior. In a rising price environment, some healthcare providers are paying more, sometimes substantially more, than the ASP plus 6 percent, and therefore, are not fully reimbursed.²

Conclusion

The future of IG does look promising for its ability to treat a host of disease states. However, for treatment to truly be effective for a growing number of patients, equal effort will need to be given to finding solutions to the supply and reimbursement issues as is given to the testing of the product to spread its reach.