• Decrease font size
  • Return font size to normal
  • Increase font size
U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

  • Print
  • Share
  • E-mail

Pediatric Plan - July 30, 2009

Pediatric Plan

Product Name & Active Ingredient/Dosage Form:GAMMAPLEX®

Applicant:  Bio Products Laboratory (BPL), 
Dagger Lane, 
Elstree,
Hertfordshire, WD6 3BX
United Kingdom
Proposed Indication: Primary immunodeficiency diseases
BLA #:125329
Date Submitted:14 November 2008

This Pediatric Plan proposes conducting a clinical study in pediatric subjects with primary immunodeficiency in accordance with the requirements of the Pediatric Research Equity Act (PREA) December 3, 2003.

The following information is included in this Pediatric Plan:

  1. Proposed Clinical Study Design
  2. Timeline for the completion of the Pediatric Study
  3. Development of an Age-appropriate Formulation
  4. Request for Deferral for Conducting the Pediatric Clinical Study
  5. Request for Waiver for Conducting the Pediatric Clinical Study in Specific Age Groups

A.      Proposed Clinical Study Design

The proposed clinical study has been submitted for review by FDA.  Prior to moving forward with this study, BPL would like feedback and advice from FDA as to whether this study will adequately address FDA requirements for IGIV investigation in pediatric subjects. 

1. Drug information:

  • Route of administration: Intravenous Infusion
  • Formulation:  Immune Globulin (Human), 5%
  • Dosage: 300–800 mg/kg/infusion
  • Regimen: every 21 or 28 days
  • Duration of treatment: 12 months

2. Types of Studies/Study Design:

A Phase III, Multicentre, Open-Label Study to Evaluate the Efficacy and Safety of GAMMAPLEX® in Primary Immunodeficiency Diseases in Children and Adolescents

3. Age Group and Population in which the Study will be Performed:

Children aged 2 to 11 (inclusive)

Adolescents aged 12 to 16 (inclusive)

4. Number of Patients to be Studied or Power of Study to be Achieved:

Plan to provide data on a total of 12 evaluable subjects in two treatment groups, i.e. six children aged, on recruitment to the study, 2 to 11 years and six adolescents aged 12 years to 16 years.

5. Entry Criteria:

Inclusion criteria:  1. The subject is between 2 to 16 years of age, of either sex, belonging to any ethnic group, and above a minimum weight of 10 kg.  This weight is based on the amount of blood required for testing.  2. The subject has a primary immunodeficiency disease, which has as a significant component of hypogammaglobulinemia and/or antibody deficiency (e.g., common variable immunodeficiency, X-linked and autosomal forms of agammaglobulinemia, hyper-IgM syndrome, Wiskott-Aldrich Syndrome).  Isolated deficiency of a single IgG subclass, or of specific antibodies without hypogammaglobulinemia per se, does not qualify for inclusion.  3. The subject has been receiving licensed or investigational (Phase III or IIIb) IGIV replacement therapy at a dose that has not changed by + 50% of the mean dose for at least 3 months before study entry and has maintained a trough level at least 300 mg/dL above baseline serum IgG levels (defined as before initiation of any gamma globulin treatment for that subject).  4. The subject has documented trough levels of IgG, dose of IGIV, and treatment intervals for the last 2 consecutive routine IGIV treatments (licensed or investigational product) must be documented for each subject before the first infusion in this study can be administered.  5. If a subject is a female of child-bearing potential, she must have a negative result on an HCG-based pregnancy test.  6. If a subject is a female who is or becomes sexually active, she must practice contraception by using a method of proven reliability for the duration of the study.  7. The subject is willing to comply with all aspects of the protocol, including blood sampling, for the duration of the study.  8. The subject, if old enough (generally 6 to 16 years) has signed a Child Assent form and the subject’s parent or legal guardian has signed the informed consent form, both approved by the Institutional Review Board (IRB). Exclusion Criteria:  1. The subject has a history of any severe anaphylactic reaction to blood or any blood-derived product.  2. The subject is known to be intolerant to any component of GAMMAPLEX®, such as sorbitol (i.e., intolerance to fructose).  3. The subject has selective IgA deficiency, history of reaction to products containing IgA, or has a history of antibodies to IgA.  4. Subjects who have completed the study and subjects who have withdrawn cannot participate in the study for a second time.  5. The subject is currently receiving, or has received, any investigational agent, other than an immune serum globulin (ISG) preparation that is being evaluated in a Phase III or IIIb study, within the prior 3 months.  6. The subject has been exposed to blood or any blood product or derivative within the last 6 months, other than a commercially available IGIV or other forms of commercially available and licensed ISG or an ISG product that is in Phase III or IIIb studies.  7. The subject is pregnant or is nursing  8. The subject, at screening, has levels greater than 2.5 times the upper limit of normal as defined at the central laboratory of any of the following:  (Alanine transaminase (ALT); Aspartate transaminase (AST) Lactate dehydrogenase (LDH)). 9. The subject has a severe renal impairment (defined as serum creatinine greater than 2 times the upper limit of normal or BUN greater than 2.5 times the upper limit of normal for the range of the laboratory doing the analysis); the subject is on dialysis; the subject has a history of acute renal failure.  10. The subject is known to abuse alcohol, opiates, psychotropic agents, or other chemicals or drugs, or has done so within the past 12 months.  11. The subject has a history of DVT, or thrombotic complications of IGIV therapy.  12. The subject suffers from any acute or chronic medical condition (e.g., renal disease or predisposing conditions for renal disease, coronary artery disease, or protein losing state) that, in the opinion of the investigator, may interfere with the conduct of the study.  13. The subject has an acquired medical condition, such as chronic or recurrent neutropenia (ANC < 1000 x 109/L) or AIDS known to cause secondary immune deficiency, or is post hematopoetic stem cell transplantation.  14. The subject is receiving the following medication:  immunosuppressive drugs, immunomodulatory drugs, long-term oral corticosteroids > 1 mg of prednisone, equivalent /kg/day (note that topical, intranasal and inhalational for asthma, burst or intermittent corticosteroids are not excluded).  15. The subject has anemia (hemoglobin < 10 g/dL) at screening. 

6. Clinical Endpoints:

Study variables and criteria for evaluation:

Primary Efficacy Variable

The primary variable is the number of serious, acute, bacterial infections per subject year, and will be based on the total of all of the following events as defined by the FDA:  bacterial pneumonia, bacteremia or sepsis, osteomyelitis/septic arthritis, visceral abscess, bacterial meningitis.

Secondary Efficacy Variables:

Secondary efficacy will be determined by using the following variables:

  • number of days of school missed because of infection per subject year;
  • number and days of hospitalizations because of infection per subject year;
  • number of visits to physicians for acute problems and/or number of visits to hospital emergency rooms per subject year;
  • other infections documented by fever or a positive result on a radiograph and/or culture per subject year;
  • number of infectious episodes per subject per year;
  • number of days on therapeutic and prophylactic antibiotics.

Safety Variables

The variables used to assess safety will be the following: number and percent of adverse events (AEs); vital signs; clinical laboratory tests and Direct Coombs’ Test; transmission of viruses; physical examination.

7. Timing of Assessments:

  • Daily assessments via diary cards to record data to allow quantification of primary and secondary variables
  • Measurement of trough total IgG levels before each infusion.
  • Analysis of adverse events up to 72 hours after the end of an infusion.

8. Statistical Information (Statistical Analyses of the Data to be Performed):

Summary statistics will be provided for categorical variables. 

Inferential and summary statistics will be used to evaluate primary efficacy variables.

Descriptive statistics will be used to analyse secondary efficacy data

Safety data will be analysed using descriptive statistics.

9. Timeframe for Submitting Reports of the Studies:

2013

B.      Timeline for the Completion of the Pediatric Study

The suggested date for submission of the pediatric study results would be April 2013.  Note, this date is contingent upon FDA’s agreement with the study protocol and also contingent upon enrolment of sufficient patients as outlined and agreed to in the protocol.

C.      Development of an Age-appropriate Formulation

BPL does not intend to produce an age-appropriate formulation for Gammaplex®

There is no requirement for a different strength formulation for children with this type of product, as is evident by the fact that no other manufacturers of IGIV products currently produce a “pediatric strength” formulation.  The dose is based on body weight and with a liquid infusion can be adjusted to the child’s weight easily.  BPL does produce a smaller 2.5 g bottle size, as well as the normal 5 g and 10 g bottle sizes.  This smaller bottle is more conducive in providing a more precise dose; and thus helping to prevent unnecessary wastage of product

D.      Request for Deferral for Conducting the Pediatric Clinical Study

BPL has provided a request for deferral for conducting the pediatric study after BLA approval.  BPL plan to conduct a study in children and adolescents only.

Indication:                   Primary Immunodeficiency Diseases

  1. BPL request a deferral for the following pediatric age groups:
  • Child: 2 to 11 years
  • Adolescent: 12 years to 16 years

The following reasons are cited for requesting a deferral for each age group, now that BPL has completed the pivotal study on Gammaplex® which is ready for approval:

  1. Child

a)   Adult studies completed and ready for approval.

e)   Difficulty in enrolling pediatric patients (children with primary immunodeficiency diseases).

  • The pivotal study GMX01 (mentioned above) had an entry criterion of >3 years of age but only 2 child subjects were enrolled (ages 9 and 10 years) out of a total population of 50 subjects of all ages
  • These are rare conditions.  The Primary Immune Deficiency Foundation undertook the first national survey in 1995 to provide an estimate of the magnitude of primary immune deficiency in the American population.  The survey suggested approximately 50,000 persons in the US have been diagnosed with one of these conditions.  Half of these persons are not diagnosed until they are adolescents or older. Children aged 6 years and under make up approximately 10% of these cases (i.e., 5,000) and a further 20% are aged 6 to 12 years (i.e., 10,000 cases).
  • The onset for the more common forms, such as common variable immunodeficiency (incidence is about one case per 10,000 to 50,000 persons) is generally after 2 years of age.  On average diagnosis for this form of immunodeficiency is in the mid to late twenties (Ballow, 2002).  Therefore finding children with a more common form of PID or a diagnosis for one of the rarer forms is more difficult than identifying adults with the same underlying conditions.

Adolescent

a) Adult studies completed and ready for approval.

e) Difficulty in enrolling pediatric patients (adolescents with primary immunodeficiency diseases).

  • The pivotal study GMX01 (mentioned above) had an entry criterion of >3 years of age but only 2 adolescent subjects (≤16 years) were enrolled (ages 12 and 12) out of a total population of 50 subjects of all ages (there were two subjects both aged 16 years at enrolment)
  • These are rare conditions.  The Primary Immune Deficiency Foundation undertook the first national survey in 1995 to provide an estimate of the magnitude of primary immune deficiency in the American population.  The survey suggested approximately 50,000 persons in the US have been diagnosed with one of these rare conditions.  Half of these persons are not diagnosed until they are adolescents or olderAdolescents aged 13 to 17 years make up approximately 10% of these cases (i.e., 5,000).
  • The onset for the more common forms, such as common variable immunodeficiency (incidence is about one case per 10,000 to 50,000 persons) is generally after 2 years of age.  On average diagnosis for this form of immunodeficiency is in the mid to late twenties (Ballow, 2002).  Therefore finding adolescents with a more common form of PID or a diagnosis for one of the rarer forms is more difficult than identifying adults with the same underlying conditions.
  1. The following age groups are not included in this deferral request:

Neonates

Infants

  1. Reasons for not including the following pediatric age groups listed in 3 in the deferral request include:

Neonates

c) Requesting a waiver

Infants

c) Requesting a waiver

  1. BPL included an initial draft of a study synopsis for pediatric patients’ ages 2 to 16 years with the BLA submission #125329.  The projected time frame for submitting a more comprehensive pediatric plan would be no later than 60 days post approval of the GammaplexÒ BLA for the Primary Immunodeficiency Disease indication.  However, BPL requests an opportunity to discuss these plans with FDA prior to submission of the more comprehensive plan.
  1. The suggested date for submission of the pediatric study results would be April of 2013.  Note, this date is contingent upon FDA’s agreement with the study protocol and also contingent upon enrolment of sufficient patients as outlined and agreed to in the protocol.
  1. Applicant Certification 

BPL requests a deferral of the requirements for ages 2 to 16 years of age as outlined in 21CFR314.55(a) (Section 505B(a)(3) of the Act).  BPL certifies that adequate justification for this deferral is provided, as included in this request based on 21CFR314.55(b)(2).

References

Ballow M. Primary Immunodeficiency disorders: antibody deficiency.  J. Allergy Clin Immunol, 2002; 109: 581-91.

Primary Immune Deficiency Diseases in America – The first national survey of patients and specialists.  Accessed September 23 2008, at: http://www.primaryimmune.org/pid/patient_survey_publication.pdf.

E.      Request for Waiver for Conducting the Pediatric Study in Specific Age Groups

  1. BPL request a waiver for the following pediatric age groups:
  • Neonate: birth to 1 month
  • Infant: 1 month to 2 years
  1. With reference to applicable statutory authority, the following reasons cited for requesting a waiver for each age group:

Neonates 

Option A

Studies are impossible or highly impractical (because, for example, the number of pediatric patients is so small or geographically dispersed). 

  • Acknowledged by FDA that it is difficult to study subjects of less than 2 years as they may well not be diagnosed at that age. (as per meeting between Michael Wiack (FDA), --------(b)(6)---------- and BPL in August of 2005); therefore, it is unlikely that GammaplexÒ would be prescribed in a substantial number (typically 50,000 or more) of pediatric patients.
  • It is BPL’s understanding that FDA requires patients in clinical studies for the Primary Immunodeficiency Disease indication to be evaluated for serious bacterial infections over a one year period.  As the neonate patient population is defined as birth to 1 month, efficacy, as defined by FDA, would not be achievable. 
  • Neonates have poorly developed immune systems which are supplemented by maternal antibodies transplacentally and by breast feeding.  IGIV has generally been used in this population to treat specific sepsis and in some studies as prophylaxis, but results are inconclusive, so use is rare.  Therefore it is difficult to ascertain whether neonates have primary immunodeficiency (Review by Ramamurthy 1997).
  • Maternal antibodies found in this patient population may confound assessment, as during the first 6 months of age, the maternal antibodies are still in operation. (Ballow, 2002).

Infants

Option A

Studies are impossible or highly impractical (because, for example, the number of pediatric patients is so small or geographically dispersed). 

  • Acknowledged by FDA that it is difficult to study subjects of less than 2 years as they may well not be diagnosed at that age. (as per meeting between Michael Wiack (FDA), --------(b)(6)---------- and BPL in August of 2005); therefore, it is unlikely that GammaplexÒ would be prescribed in a substantial number (typically 50,000 or more) of pediatric patients.
  • Finding infants with a clinical diagnosis of PID under the age of 2 years is very difficult.  The usual forms of PID diagnosed under 2 years are for the rarer disorders e.g. SCID which is diagnosed in male infants, less than 6 months of age, as 1 case per 100,000 to 500,000. (Cooper et al, 2003)   Such cases are generally treated by bone marrow transplant.
  • The onset for the more common forms, such as common variable immunodeficiency is generally after 2 years of age. On average, diagnosis for this form of immunodeficiency is in the mid to late twenties (Ballow, 2002)
  • A study in infants would be difficult to monitor for safety since sufficient quantities of blood could not be drawn.  The current estimate for blood volume required for this study, based on the number of blood draws from the GMX01 study in subjects with PID, is approximately 500 mL over the course of the study.
  1. Evidence that the statutory reasons for waiver of pediatric studies for both neonates and infants is not required as category 2(a) has been checked.
  1. Applicant certification

BPL requests a partial waiver of the requirements for the age ranges: neonates and infants.  BPL certifies that adequate justification for the partial waiver is provided, as included in this request based on 21CFR314.55(c)(2)(ii) (section 505B(a)(4)(B)(i) of the Act).

References

Ballow M. Primary Immunodeficiency disorders: antibody deficiency.  J. Allergy Clin Immunol, 2002; 109: 581-91.

Cooper MA, Pommering TL, Koranyi K. Primary immunodeficiencies. American Family Physician, 2003; 68(10): 2001-2008.

Ramamurthy RS.  Intravenous immunoglobulin use in the newborn infant: treatment and prevention of infection. Intravenous Immunoglobulins in Clincal Practice.  Marcel Dekker, Inc.; 1997