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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Review for Pharmacovigilance Planning - August 27, 2009 - Gammaplex

Final Memorandum 

OBE/DE Review for Pharmacovigilance Planning

BLA 125329 

Gammaplex, Immune Globulin Intravenous (Human)

Bio Products Laboratory 

From:Ann Reed Gaines, PhD
Adverse Event Reviewer 
Through:Robert P. Wise, MD, MPH
Branch Chief, OBE/DE/TBSB Rickey Wilson, MD, MS, JD
Division Director, OBE/DE

Executive Summary

OBE/DE/TBSB has completed a review of BLA STN 125329 for Gammaplex, Immune Globulin Intravenous (Human) (IGIV), which is manufactured by Bio Products Laboratory (BPL).  For this review, Modules 1, 2, and 5 and the Risk Management Plan (Amendment # 8) were examined.  The purpose of this review was to identify potential safety issues that may need to be addressed through postmarketing safety monitoring, studies, or other pharmacovigilance activities, should the product be licensed.

Clinical trials of Gammaplex were conducted in primary immunodeficiency (PI) disease patients, consistent with the population of patients specified in the indications for use section of the professional package insert.  No serious adverse events were reported in the Phase I/pharmacokinetics study, and no subject withdrew from that study. 

The efficacy, safety, and pharmacokinetics of Gammaplex were evaluated in 50 PI subjects in an open, non-comparative study.  Subjects were treated for 12 months, and 45 subjects completed the study.  One subject withdrew because of non-serious adverse events.  No subject withdrew because of lack of effect.  Of the adverse events experienced, only two of the serious adverse events were considered product-related.  BPL concluded that both the primary efficacy criterion (i.e., number of serious, acute bacterial infections) and the primary endpoint for assessment of adverse events (i.e., number of infusions temporally associated with adverse events) were met.

Gammaplex has not yet been approved elsewhere; thus, there is no Gammaplex postmarketing data available.  BPL intends to conduct all postmarketing surveillance by means of routine pharmacovigilance through expedited reporting and addressing the known IGIV class effects in Periodic Safety Update Reports (PSURs).  We have no specific recommendations for additional Gammaplex postmarketing surveillance at this time.


Gammaplex is a sterile 5% solution of Immune Globulin Intravenous (Human) that contains 5 g of immunoglobulin G (IgG) stabilized with D-sorbitol. BPL developed Gammaplex from its currently manufactured and distributed IGIV product, Vigam Liquid, which was approved in the UK in 1997 and licensed in other countries but not in the U.S. When compared to Vigam Liquid, Gammaplex has ---------------------(b)(4)---------------------------, contains sorbitol as a stabilizer (instead of sucrose, which, in predecessor IGIVs, has been associated with renal insufficiency, and albumin, which, in other IGIVs, has been associated with “protein loading” and potential infectious disease transmission risk), and can be stored at room temperature (instead of at 2-8 oC).

Indication for Use

Gammaplex is indicated as replacement therapy in PI diseases such as congenital agammaglobulinemia and hypogammaglobulinemia, common variable immunodeficiency, severe combined immunodeficiency, and Wiskott Aldrich syndrome. (An ongoing open, noncomparative study with Gammaplex [BPL study code: GMX02] for idiopathic thrombocytopenic purpura is in progress but was not included in the present submission.)

Product Marketing History

Gammaplex has not yet been licensed by any regulatory authority.

Clinical Trials Summary

Phase I study (BPL study code GMX03).

The pharmacokinetics of Gammaplex were evaluated in a Phase I study. A single IV dose of 400 mg/kg was administered to 36 healthy subjects to evaluate the pharmacokinetics of Gammaplex compared to Vigam Liquid. Subjects were randomized to one of 3 treatment groups: Group 1 received Vigam Liquid infused at an initial rate of 0.01 to 0.02 mL/kg/min increasing to a maximum of 3 mL/min; Group 2 received Gammaplex infused at an initial rate of 0.01 to 0.02 mL/kg/min increasing to a maximum of 3 mL/min; and Group 3 received Gammaplex infused at an initial rate of 0.01 to 0.02 mL/kg/min increasing to a maximum of 6 mL/min. The follow-up period for all subjects was 84 days.

No serious adverse events were reported. No subject withdrew from the study. The most commonly reported treatment-related adverse event, as assessed by investigators, was headache (reported by 11 subjects). There was a trend towards a higher fraction (50%) of subjects with treatment-related headaches in Group 3, the group with the faster infusion rate.

Pivotal Phase III study (BPL study code: GMX01).

The efficacy, safety, and pharmacokinetics of Gammaplex were evaluated in 50 PI subjects in an open, non-comparative study. Study subjects met specified inclusion (e.g., age, gender, previous regular IGIV treatment) and exclusion criteria (e.g., IgA deficiency, increased serum creatinine beyond 2 times normal). Subjects were treated for 12 months, and 45 subjects completed the study. Three subjects withdrew because of adverse events that were not classified as serious, another withdrew for an unspecified but non-adverse-event-related reason, and the last withdrew because of pregnancy. No subject withdrew because of lack of effect.

A total of 581 adverse events occurred, regardless of causality (or product-relatedness). All subjects had at least one adverse event, most of which were mild (94.0%) or moderate (70.0%) in severity. Forty subjects (80.0%) had at least one infection or adverse event of possible infectious etiology (e.g., diarrhea) during the study.

There were 186 product-related adverse events. Approximately half of the subjects (48.0%) had at least one such event. Only two of the serious adverse events were considered product-related. The most common product-related events were headache (36.0%), fatigue (12.0%), nausea (12.0%), pyrexia (12.0%), hypertension (6%), myalgia (6%), pain (6%), and vomiting (6%). More subjects on the 21-day infusion cycle had at least one product-related adverse event (63.6%) than in the 28-day cycle (35.7%).

The two serious and severe adverse events that were assessed as possibly product-related occurred in a 30-year-old female and consisted of thrombosis and chest pain. The thrombotic event was a deep vein thrombosis of the left internal jugular, basilica, and cephalic veins that occurred within 24 hr of infusion, resulted in hospitalization, and resolved with heparin treatment. The chest pain occurred 2 months later, also within 24 hr of infusion. At that time, an EKG and a CT scan were negative. A coronary angiogram showed no evidence of significant coronary artery disease, and a cardiac catheterization indicated normal findings. However, a nuclear stress test (nucleotide imaging) was abnormal and suggestive of anterior wall myocardial ischemia. The patient was discharged on anticoagulation therapy. The patient experienced no other complication or sequela. She later withdrew from the study, however, because of syncope that occurred 1 month after a subsequent infusion and because of a subsequent diagnosis of antiphospholipid syndrome (which BPL noted as a possible underlying thrombosis/thromboembolic risk factor).

The primary efficacy endpoint was the number of serious, acute bacterial infection. As defined by CBER in the “Guidance for Industry: Safety, Efficacy, and Pharmacokinetic Studies to Support Marketing of Immune Globulin Intravenous (Human) as Replacement Therapy for Primary Humoral Immunodeficiency,” dated June 2008 (http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation
), those include bacterial pneumonia, bacteremia or sepsis, osteomyelitis or septic arthritis, visceral abscess, and/or bacterial meningitis. The primary endpoint is defined as no more than 1 infection/patient/yr. No serious, acute bacterial infection occurred in any subject during the study. The mean event rate of serious, acute, bacterial infections/patient/yr was zero. This is in contrast to the 6 subjects (12.0%) who had at least 1 serious, acute, bacterial infection in the 6 months before enrollment into the study.

During the 12-month study, 40 of 50 subjects (80.0%) experienced other (i.e., non-efficacy-endpoint) infection(s), with a mean of 3.28 infections/patient/yr. In comparison, in the 6 months prior to the study, 27 of 50 subjects (54.0%) reported a total of 33 documented infections, with a mean of 1.32 infections/patient/yr. However, BPL noted that the pre-study infection data were obtained from retrospective diary cards while the study infection data were obtained from hospital records. BPL interprets the infection data from the Gammaplex study as consistent with other IGIV infection data that has been published for Gammagard Liquid and Flebogamma DIF. BPL concludes that the incidence of infections in the Gammaplex study does not raise concern about a possible lack of efficacy.

Of the 703 infusions administered, a total of 59 (8.4%) infusions were temporally associated with at least one product-related adverse event within 48 hr of infusion, and 64 (9.1%) infusions were temporally associated with product-related adverse events within 72 hr of infusion. Overall, regardless of causality, 149 (21.2%) infusions were temporally associated with an adverse event within 72 hours of infusion. According to the guidance, not more than 40% of infusions, irrespective of product-relatedness, should be temporally related. BPL concludes that this endpoint criterion was met.

Postmarketing (Non-study) Experience

There has been no postmarketing experience for Gammaplex. However, Gammaplex was developed from another BPL IGIV (Vigam Liquid), which was developed from Vigam-S, a predecessor of Vigam Liquid. As requested by FDA, BPL submitted the most recent Summary Safety Report for those IGIVs, which covered the reporting period of June 1, 2005 through June 30, 2008, as part of this BLA. Of the 69 case reports included, 25 involved dermatologic (e.g., itchy skin rash/pruritus) and urticaria (e.g., urticaria/hives, facial/lip/tongue swelling) adverse events that occurred primarily, but not exclusively, with Vigam Liquid. However, following changes in manufacturing (e.g., replacement of a faulty valve seal), these events returned to baseline frequency. No specific cause was ever identified. No other serious, unexpected, or increased frequency adverse events were identified.

Because of differences between Gammaplex and both Vigam Liquid and Vigam-S, postmarketing experience with “Vigam” cannot serve as a surrogate for Gammaplex. For context, however, FDA approved Flebogamma, which is also a sorbitol-containing IGIV, manufactured by Instituto Grifols, in December 2004. No sorbitol-related issue has arisen with Flebogamma since licensure.

Pharmacovigilance Planning

Routine Pharmacovigilance Plan

BPL intends to conduct routine pharmacovigilance for Gammaplex as follows:

  • Maintain systems and processes that ensure that information about all suspected adverse event reactions is collected and collated in an accessible manner.
  • Prepare Expedited adverse drug reactions reports and PSURs for regulatory authorities.

Summary of Safety Concerns and Pharmacovigilance Actions

BPL maintains that there is no specific safety concern for Gammaplex. Thus, BPL intends to conduct all postmarketing surveillance by means of routine pharmacovigilance with expedited reporting and specifically addressing the issues identified below in PSURs.

Because BPL maintains that the safety profile of Gammaplex is consistent with that of other FDA-licensed IGIVs, the sponsor intends to review and report the following known IGIV class effects either as expedited reports or in PSURs.

  • Infusion-related reactions
  • Hypersensitivity reactions, anaphylactic or anaphylactoid reactions
  • Aseptic meningitis
  • Hemolytic anemia/hemolysis
  • Thrombotic events
  • Acute renal failure or increase in serum creatinine
  • Transmission of infective agents
  • Impairment of efficacy of live attenuated virus vaccines
  • Infusion-related reactions
  • Hypersensitivity reactions, anaphylactic or anaphylactoid reactions
  • Aseptic meningitis
  • Interference with serological testing

In addition, the following product-related adverse events were observed in the PI study (GMX01) and will be reviewed and reported as either expedited reports or in PSURs. (Some, but not all of these adverse events, were observed in the healthy subjects [GMX03] study.)

  • Cardiac disorders (e.g., tachycardia)
  • Ear and labyrinth disorders (e.g., vertigo)
  • Gastrointestinal disorders (e.g., nausea)
  • General disorders and administration site conditions (e.g., chills)
  • Metabolism and nutrition disorders (e.g., decreased appetite)
  • Musculoskeletal and connective tissue disorders (e.g., arthralgia)
  • Nervous system disorders (e.g., headache)
  • Psychiatric disorders (e.g., insomnia)
  • Respiratory, thoracic and mediastinal disorders (e.g., bronchospasm)
  • Vascular disorders (e.g., hypertension)

BPL also intends to specifically discuss and address any spontaneous adverse events reported for the following issues in PSURs.

  • Incidence of headache and possible hypertension reported at the 0.08 mL/kg/min infusion rate in the PI study.
  • Safety profile following administration to patients with hepatic impairment and children < 10 yr of age, neither of which has been established. (Patients with hepatic impairment are specified because D-sorbitol is metabolized by the liver and excreted intact by the kidneys. The rate of clearance is dependent upon the hepatic blood flow rate, which may be halved in subjects with cirrhosis. However, even if Gammaplex is used for unlabeled indications, it is unlikely to be administered at doses that would risk significant D-sorbitol accumulation in patients with hepatic impairment.)

Risk Minimization Activities

For both the IGIV class effect adverse events and those specific to Gammaplex, BPL maintains that the safety profile of Gammaplex is consistent with other human IGIV products. BPL notes that routine risk management activities, including routine pharmacovigilance reporting and product labeling, adequately address these concerns.


During the labeling review/revision meeting, BLA committee members discussed that the wording in the adverse events section needed revision. The OBRR/DH/CRB medical reviewer requested a consult from OBE/DE/TBSB for AERS adverse event frequencies and requested suggested language for specified adverse event reactions (e.g., hemolysis). The information requested was provided and incorporated in numerous instances.


Gammaplex is an Immune Globulin Intravenous (Human) that is indicated for treatment of PI disease. Gammaplex has not been approved by any regulatory authority and is not yet commercially available in any market.

On the basis of the clinical trial data:

  • The total number of exposed subjects in the clinical trials, although consistent with CBER guidelines for IGIV clinical trials in PI patients, was limited (36 subjects in GMX03 and 50 patients in GMX01). Uncommon adverse events that could be reported after licensure may not have been detected in this small population.
  • Clinical trial data do not demonstrate a discrete safety signal or other serious risk associated with administration of this product.
  • Adverse events observed in clinical studies with Gammaplex were almost all mild or moderate in severity, with one severe event and consistent with adverse events observed during postmarketing surveillance with other FDA-licensed IGIVs.
  • The proposed pharmacovigilance plan includes routine monitoring and reporting of the adverse events and patient populations as outlined (above). Based on the adverse events observed in the clinical studies, the proposed pharmacovigilance activities seem to be adequate at this time.


We have no specific recommendations for Gammaplex postmarketing surveillance at this time.

Letter-ready Comments

We have no additional recommendations for Gammaplex postmarketing surveillance.