Appendix CPopulation, Intervention, Comparators, Outcomes and Dosage Specification

Publication Details

1. POPULATION

Patients with allergic rhinoconjunctivitis and/or allergic asthma due to airborne allergies.

Includes:

  • Children (no age group distinction)
  • Adults (no gender distinction)
  • Elderly
  • Pregnant women
  • Minorities (we will include all the races and ethnicities found in the literature)
  • Inner-city and rural residents
  • Patients with severe asthma
  • Monosensitized individuals

Allergic rhinoconjunctivitis must be confirmed by skin tests or RAST (radioallergosorbent test)

Asthma must be confirmed by pulmonary lung function (FEV; metacholine challenge). Asthma diagnosis needs to be objective; response to bronchodilator needs to be assessed.

2. INTERVENTION AND COMPARATORS

Table of comparators and definitions.

Table

Table of comparators and definitions.

Treatments to be included in the review;

SCIT:

U.S. FDA-approved aqueous extracts for subcutaneous injection (SCIT)

SLIT: Aqueous sublingual extracts - available in U.S. as off-label products from U.S. manufacturers, and the comparable aqueous extracts from European manufacturers (off-label in U.S.; approved in EU)

Non-SIT: Placebo; pharmacotherapy; usual care; environmental control; homeopathy

Treatments to be excluded from the review

SLIT-Tablet: sublingual dissolvable tablet products [not available in U.S.; approved in Europe (eg: Grassax; Oralair)]

Modified Allergens: tyrosine-absorbed extracts; allergoids; polymerized allergens [not available in U.S.; approved in Europe]

Adjuvants: CpG-oligonucleotides; MPL; alum-precipitated extracts; pyridine-extracted alum extracts [not available in U.S. except in clinical trials; some approved in Europe]

Peptides: treatment with specific allergen epitope sequences [not available in U.S. or Europe except in cx trials]

Recombinant Allergens: alteration of the allergen molecule by substitution of an amino acid [not available in U.S. or Europe except in clinical trials]

Combination Products: European products in which several of the above are coupled (ex: Timothy Quattro: aqueous Timothy grass extract prepared as an allergoid modification + Tyrosine absorption + incorporation of an MPL adjuvant onto the molecule)

Other: lymphatic injection of allergen; local nasal IT; bronchial inhaled IT; epicutaneous IT; etc [not available in U.S. or Europe except in clinical trials]

3. SPECIFIC OUTCOMES FOR RHINOCONJUNCTIVITIS OR ASTHMA STUDIES

A. Rhinitis/Rhinoconjunctivitis Studies

Primary Outcomes

  1. Symptom diary score (Nasal Symptom Score, Ocular Symptom Scores, Combined Symptom Score)
  2. Medication score (Rhinitis-Rhinoconjunctivitis medication use)
  3. Combined symptom-medication scores

Additional Secondary Endpoints

  1. Individual symptoms (sneezing/nasal congestion/rhinorrhea/itchy nose/ocular symptoms/etc)
  2. QOL
  3. symptom-free days
  4. Days with no use of rescue medicine (e.g.: antihistamine; decongestant)
  5. Visual analog score
  6. Asthma symptoms (asthma may develop in a patient for the first time during the study)
  7. Adverse events
  8. Safety blood indices

B. Asthma Studies

Primary Outcomes

  1. Symptom diary score (Total Asthma Symptom Score)
  2. Asthma medication score
  3. Combined asthma symptom-medication scores
  4. QOL

Secondary Endpoints

  1. Pulmonary function tests (FEV1/FVC/ratio)
  2. PEFR (peak expiratory flow readings; done at home)
  3. Challenge function tests
  4. Adherence
  5. Convenience and compliance
  6. Long term outcomes
  7. Adverse events

4. ALLERGEN UNITAGE SPECIFICATIONS, CHARACTERIZATION, AND STANDARDIZATION

UNITAGE SPECIFICATIONS

BIOEQUIVALENT ALLERGY UNITS/ML (BAU/ML)- biological potency unit assigned to standardized grass pollen and cat allergenic extracts, following in-vitro comparison of the test extract to a FDA CBER reference standard. The FDA CBER reference standard is assigned a specific BAU unitage based on quantitative skin testing.

ALLERGY UNITS/ML (AU/ML) - biological potency unit assigned to standardized mite and short ragweed pollen allergenic extracts, following in-vitro comparison of the test extract to a FDA CBER reference standard. The FDA CBER reference mite standard is assigned a specific AU unitage based on quantitative skin testing. For the short ragweed pollen allergen extract FDA CBER reference mite standard is assigned a specific AU unitage based on specific ragweed allergen content.

MAJOR PROTEIN UNITS (μg Ag/ML) – micrograms of the major protein moiety(s) of the specific allergen (e.g. ragweed, Amb a 1; cat, Fel d 1)

PROTEIN NITROGEN UNIT (PNU) - potency unit based on the micro-Kjeldahl measurement of protein nitrogen in an acid precipitated extract. Compared with other protein determination methods, 1 mg of protein nitrogen typically equals 100,000 PNU.

WEIGHT TO VOLUME (W/V) - potency unit expressed as a ratio of the weight of allergen source material extracted to the volume of diluting fluid, and adjusted based on subsequent dilutions.

HISTAMINE EQUIVALENT PRICK (HEP) – histamine equivalent prick unitage for standardization of an allergen.

BIOLOGIC UNITS/ML (BU/ML) – biological unitage assigned to define allergen potency.

STANDARDISED QUALITY-UNIT (SQ-U) - biological potency unit assigned to certain allergen extracts by a manufacturer.

OTHER – we will include other allergen characterization unitage were noted in a paper.

CHARACTERIZATION AND STANDARDIZATION

Many (some) of the allergens currently commercially available for use have been characterized by manufacturers or researchers based on major (and minor) proteins, but many others (most trees, molds, and pollens) have not. The FDA has characterized and standardized certain of the allergens that are currently commercially available (see below). The FDA feels that “biological” potency is a more robust and accurate methodology for assaying allergens as opposed to major protein, alone (ie: various other proteins in an allergen’s make-up may be important and would be overlooked by only assaying and defining a product based on 1 or 2 proteins). Hence, the FDA and the WHO are not in agreement on standardization, and the U.S. and European manufacturers “march to a different drum” (often their own internal standardization methods (SQ units/IR units/etc)].

FDA STANDARDIZED ALLERGENS

  1. Ragweed: FDA actually standardized this allergen based on Amb a 1 content prior to the development of BAU/AU (and because 95% of RW’s allergenicity is recognized as being due to Amb a 1, they never felt the need to rename it based on BAU) [a RW extract containing 350 +/− 20% μg Amb a 1 would be considered = to a 100,000 AU product];
    Background Information: “FDA would like to add the following unit of measure to UCUM: Amb a 1 Units/ML – an arbitrary unit for the measurement of Amb a 1, a 38 kD glycoprotein that is the major allergen in short ragweed pollen allergen extracts. The amount of Amb a 1 units are determined by an in-vitro comparison of a test short ragweed extract to a FDA CBER Amb a 1 reference standard.
    Antigen E and Amb a 1 are synonymous. Antigen E is the old term that was in the regulations for allergenics back in the 80s. The more up-to-date scientific name is Amb a 1. [However, you will still have manufacturers using the old term of Antigen E since that is in their license].
    In the old regulations (which have since been removed), the Radial Immuno Diffusion (RID) method for determining Antigen E potency was specified. The number of units/ml is simply that which is obtained by comparison of a test sample (lot for release) against the US reference standard that has a labeled content of Antigen E (also a US reference preparation of anti-antigen E serum is used in the test). The requirement is for the assayed value of the US reference for antigen E to be within +/− 25% of the labeled value.
    The general working theory is that a Unit/mL of Antigen E(Amb a 1) is equivalent to a microgram of AntigenE(Amb a 1)/mL but we are still looking for solid references discussing this fact - this was not an FDA mandated unit expression due to the incorporation of the old methods specified under the regulation into the firm’s BLAs under 52 FR 37605. FDA has not since initiated the legal process required under the 680s for a unit change (see below discussion on BAU/mL). The benefit of a unit change for allergenics always has to be balanced against the risk to patients on incorrect dosing that may occur despite all best education efforts when such a change is made”.
    1. Amb a 1 is the up-to-date term for the short ragweed pollen allergen that was originally described as Antigen E. They are synonyms. Although Antigen E is no longer used in the scientific literature, its meaning is unambiguous. The manufacturers are still licensed to use Antigen E as the designation.
    2. Amb a 1 U = AgE U
    3. The relationship between AgE U and BAU (350 AgE U/mL = 100,000 BAU/mL) was based on studies done decades ago, reportedly on 15 study subjects. CBER considered mandating a conversion to BAU/mL in the labeling of short ragweed pollen products, based on AgE content, but this was never implemented.
    4. CBER provides two US standard reagents to manufacturers for their determination of Amb a 1 content, a reference standard and a reference serum. The assay used is a radial immunodiffusion assay (RID).
    5. Solid references discussing the relationship between Antigen E U/mL/Amb a 1 U/mL and micrograms of Antigen E U/mL/Amb a 1/mL are being researched]”.
  2. Grasses: Bermuda grass (10,000 BAU/ml) and eight related Northern Pasture grasses [Timothy, Kentucky bluegrass, perennial rye grass, orchard grass, meadow fescue, red top, and sweet vernal] (expressed as 100,000 BAU/ml); these were initially standardized by quantitative skin testing in highly allergic subjects, and subsequently standardized to the standard extract by in vitro methods];
  3. House Dust Mites (Dermatophagoides pteronyssinus and farina): expressed as either 10,000 or 5,000 BAU/mL [initially standardized by quantitative skin testing in highly allergic subjects (identified by hx), and subsequently standardized to the standard extract by in vitro methods];
  4. Cat hair or pelt: The potency of Standardized Cat Hair Extract is based on the amount of Fel d 1 allergen in the extract. Extract containing 5–9.9 units per mL is assigned a potency of 5,000 Bioequivalent Allergy Units (BAU/mL). Extract containing 10–19.9 Fel d1 units is assigned a potency of 10,000 BAU/mL. [BAU/mL values are based on quantitative skin testing].

Background Information: “The primary allergen of Standardized Cat Hair Extract is Fel d1. Standardized Cat Pelt Extract contains Fel d1, as well as non-Fel d1 allergens. The latter are believed to be components of cat serum, such as albumin. Pelt extracts have a higher protein content than hair extracts, and the isoelectric focusing (IEF) pattern of the pelt extract reveals protein bands that are not present in cat hair extracts. The IEF pattern of cat hair extracts shows primarily Fel d1 allergen without serum components. The importance of Fel d1 as a means of standardizing the potency of cat extract is based on the following observations:

The intensity of skin reactions to cat extract correlates with the Fel d1 content of the extract in most cat sensitive patients1; the absorption of cat extract with monospecific antisera to Fel d1 causes a reduction in the allergenic activity of cat extract1; the precipitin arc of Fel d1 in cat extract binds most of the IgE antibody in sera obtained from cat-allergic individuals”].

WHO standardized extracts also include dog (based on Can 1), alternaria (based on Alt 1), and various grasses (based on Phl p 5; Lol p 1; etc), birch (based on Bet v 5).