Opened 3 years ago

Last modified 3 years ago

#197 assigned question

Request a new unit of measure (SQ-HDM) to UCUM for use in SPL

Reported by: Bill Gray Owned by: Gunther Schadow
Priority: critical Milestone:
Component: unit definitions Keywords: Needed to submit SPL label
Cc: Dr., Gunther, Schadow

Description

ODACTRA was approved by the U.S. FDA on March 1, 2017. The unit of measure for the product is “SQ-HDM”. Additional information is provided below and the U.S. package insert is attached for your information.

The U.S. FDA SPL staff recommended that we ask you for assistance to add SQ-HDM to UCUM to allow SPLs to be created (FDA requirement). Can you please assist us in adding the unit of measure “HQ-SDM” to UCUM so we can use this for SPL? Since approval has been received, the SPL will need to be submitted to eLIST soon, so if this will take some time, will a manual override be needed in the interim? Please let us know if you need additional information for this request.

Product: ODACTRA™ Generic or Proper name: House Dust Mite (Dermatophagoides farinae and Dermatophagoides pteronyssinus) Allergen Extract Tablet, 12 SQ-HDM

ODACTRA is available as a tablet of 12 SQ-HDM [6 SQ-HDM D. farinae and 6 SQ-HDM D. pteronyssinus]. Each tablet contains a 1:1:1:1 potency ratio of D. farinae group 1 allergen, D. farinae group 2 allergen, D. pteronyssinus group 1 allergen, and D. pteronyssinus group 2 allergen.

SQ-HDM: SQ is a method of standardization of biological potency, major allergen content and complexity of the allergen extract. HDM is an abbreviation for house dust mite.

Background: When Merck filed the BLA for ODACTRA, we requested approval for the new unit of measure and addition of the unit of measure to UCUM. We received approval to use the new unit of measure in labeling, but were directed to contact you (SPL e-mail) or Regenstrief Institute directly, after approval, to confirm if SQ-HDM would be added to UCUM and used in SPL.

Change History (10)

comment:1 Changed 3 years ago by Gunther Schadow

Owner: set to Gunther Schadow
Status: newassigned

This is a difficult one.

From what I can find in the literature in common use is a "standardized quality unit" often written as "SQ-U", or "[SQ-U]". This form [SQ-U] matches the UCUM style and we could add that, as there is comparable use as for [AU] and [BAU].

https://www.researchgate.net/publication/5531276_European_allergen_extract_units_and_potency_Review_of_available_information

A notation that reflects the substance in the unit is something we would consider rather strange. It would be akin to writing the name of every substance after the unit mg. We write "Metformin 500 mg tablets contain 500 mg of Metformin" not "500 mg-MTF of Metformin". So why must the name of your allergen be written into the unit?

I could not find evidence for such use in the general literature.

In the above referenced article, we find an clarifying definition on the relationship between [BAU] and [SQ-U]:

"Definition. Standardized quality units (SQ-U) and STU are applied to subcutaneous products and are based on clinical efficacy trials not on skin prick tests. As a result of these trials, the optimal dose for maintenance treatment is defined as 100,000 SQ-U or 1,000 STU. The older units, HEP and BU, however, were based on skin prick tests (Table 1). Their relationship to the newer clinically defined units varies per individual allergen. As an example, the STU/BU relation for house dust mite (100 STU ⫽ 1 BU) varies from that for Lolium (40 STU ⫽ 1 BU)."

This definition hints at why one might have been compelled to reflect the substance, here the "house dust mite allergen", in the unit, because once you know that, you might be able to make an empirical conversion to [BAU].

However, this is no different than the conversion between amount of substance (mol) and mass (gram) that depends on the substance. Again, we would not write mol-MTF to indicate amount of substance of metformin only to fix the conversion to mg.

The NCI Thesaurus mentions the standard quality unit and writes it as {SQ}, also not including the substance into the name of the unit. https://nciterms.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI%20Thesaurus&version=16.11d&ns=NCI_Thesaurus&code=C116234

I propose to add "[SQU]" as a unit to UCUM and leave it at that. One can use curly-brace annotations to put anything like "HDM" as a suffix. So someone could write "[SQU]{HDM}" as a unit if they wish, but it would not be semantically different from just [SQU].

comment:2 Changed 3 years ago by Gunther Schadow

Adding reference to the approved label: https://www.fda.gov/downloads/biologicsbloodvaccines/allergenics/ucm544382.pdf

Even though the approved label contains "SQ-HDM" I do not consider that binding for UCUM. The SPL strength unit could very well be [SQU].

Last edited 3 years ago by Gunther Schadow (previous) (diff)

comment:3 Changed 3 years ago by Gunther Schadow

Here is the European label (SmPC) of this product in the EU market: https://mri.cts-mrp.eu/download/DE_H_1947_001_FinalSPC.pdf

German SmPC https://portal.dimdi.de/amispb/doc/pei/Web/2613318-spcde-20150901.pdf

Here is the Australian Label https://s0.whitepages.com.au/80ca5256-021a-494c-b9ab-28c3fa715804/csl-limited-document.pdf

None of these labels give any information how the unit is actually defined and how it can be compared with any other allergenic product

Here is a house dust mite allergenic extract with a description defining its strength explicitly. http://www.greerlabs.com/files/AM-C-10A-Mite-Dfar-Dpter-Feb-2013.pdf

I am still not convinced that the "HDM" suffix really needs to be in the unit.

To move forward with the SQU unit we have to clarify what the magnitude even means.

"As a result of these trials, the optimal dose for maintenance treatment is defined as 100,000 SQ-U or 1,000 STU."

this is in very different magnitude than those "12 SQ-HDM" as per label of the product here. What does the number "12" mean? How can anyone interpret that number? What does it compare to?

comment:4 Changed 3 years ago by Gunther Schadow

In short, the principal questions are:

  1. How is your unit "SQ-HDM" defined? -- Note the description that SQ is a method of standardization and HDM and abbreviation for the house dust mite is not a definition. Somebody should have an idea what 12 means?
  1. What does 6 SQ-HDM of D. farinae mean? And how is it that these strengths of 2 antigens are additive? Let's say you had a product of 6 International Units [IU] of ingredient A and 6 [IU] of ingredient B, how does it make sense to say that the product therefore has strength 12 [IU]?
  1. How is the HDM relevant to be put into the unit? As an analogy, even through 1 mg is a well defined unit, the amount of substance and the biological effect of 1 mg of NaCl? is very different from 1 mg of metoprolol tartrate, and yet we do not put abbreviations of the substance into the unit notation. This question may become moot if question 2 has been answered.

I believe that the best answer to all of this should be found in your approval dossier, perhaps under eCTD 3.2.S.5 Reference Standards or Materials. If you could send that document or,. even better, a publication which contains these full definitions so that other people could understand what 12 SQ-HDM means (e.g. could actually measure that strength somehow), then we would have what we need.

Last edited 3 years ago by Gunther Schadow (previous) (diff)

comment:5 Changed 3 years ago by william.hess

Gunther,

Has the firm responded to your principal questions?

Thanks, Bill

comment:6 Changed 3 years ago by Gunther Schadow

Actually, I found reply in email. I am abbreviating the information down to delete unnecessary details which might be confidential.

Rationale

The SQ standardization method for the ... drug substances complies with the standardization principles for allergen extracts described in the European Pharmacopeia (Ph. Eur.) 1063 and the EMA guideline on Allergen Products, Production and Quality Issues.

The SQ standardization for the ... drug substances comprises analysis of several quality attributes defined by the Ph. Eur. including

  • measurement of the major allergen content and
  • total allergenic activity,
  • assessment of the allergen and
  • protein profiles and
  • a value assignment (potency or strength) of the specific batch.

Many of the quality attributes are determined relative to an In-House Reference (IHR). The IHRs have been characterized in vivo in humans to fulfill the requirement for biological potency determination by in vivo techniques such as skin testing, as outlined in the Ph. Eur. monograph Allergen Products (1063). All of the attributes must conform to predefined specifications.

To calculate the strength of a commercial batch drug substance,

  • the content of group 1 and group 2 major allergens and
  • the total allergenic activity

are measured relative to the IHR.

The measured values of these attributes must

  1. first conform to predefined specification limits;
  2. secondly the measured values are included with equal weight when formulating the drug substances (SQ-HDM units).

Details of the methods, their validations, justification for the specification and standardization will be provided in Module 3.2.S.4 Control of Drug Substance.

Standardization is performed to produce extracts that are consistent in composition. All aspects of manufacturing including the manufacture of source materials, extraction, purification, and stabilization of the drug substances impact batch quality. The manufacturing process and controls, ... ensure the robustness of standardization.

The standardization procedure is very important for patient treatment as demonstrated in extensive clinical trials, by confirming that in addition to total allergenic activity, the group 1 and group 2 major allergens are present and within established specifications.

History of the Naming Convention

In Europe, no official units are given in the Ph. Eur. or EMA guideline on Allergen Products, and traditionally each allergen manufacturer in Europe has labelled allergen products with company specific dose units using IHRs and company-specific standardization methods. This approach has been used for currently-authorized allergy immunotherapy (AIT) products including the SLIT tablets by both ALK-Abelló A/S (ALK) and Stallergenes. The US-approved ORALAIR® (300 IR) utilizes the unit IR (Index of Reactivity) to describe product dose. Other example products approved in Europe include GRAZAX® (75,000 SQ-T) and most recently ACARIZAX® (12 SQ-HDM).

The consistency of allergen extracts in Europe is confirmed primarily by the use of IHRs. In contrast, consistency of allergen extracts in the US is achieved by mandating detailed CBER release methods and reference standards for use by all manufacturers. Previously the Sponsor demonstrated that the CBER release method and reference standards could not be applied to the ... SLIT tablet ... In the absence of an applicable CBER reference for (the drug substance), the Allergy Unit (AU) cannot be assigned to the product dosage unit for labeling purposes. In addition, there are no HDM international references that are accepted worldwide. Therefore, the Sponsor proposes to use the EU principles for standardization and the unit SQ-HDM for the US market.

Use of the EU principles of standardization is advantageous in that it allows doctors to identify the methods used for different products through the unit, and allows manufacturers to implement new methods for evaluation of the extracts. Although using the EU principles does not allow for direct comparison of the potency of HDM allergen extracts from different manufacturers to the ... SLIT tablet, the extensive clinical trial documentation for ... SLIT tablet can be used to inform the prescriber regarding content and potency. More importantly ... is a fixed dose tablet taken once daily; therefore, there is no need for the prescriber to titrate like an allergen extract.

The designation SQ-HDM for the dosage unit signifies that ... is standardized using the specific SQ methodology for the HDM SLIT-tablet described above. The intended marketed dose of 12 SQ-HDM is the dose found to provide the most robust efficacy based on the phase II and III trials while maintaining a safety and tolerability profile acceptable for self-administration once the first dose is tolerated under medical supervision. 12 SQ-HDM is 12 times higher than the lowest dose in the first-in-man trial ..., where the lowest dose was defined as 1 Development Unit[1]. Clinical publications supporting the chosen dosage and using the unit of SQ-HDM are cited in Appendix I – references.

Conclusion

The scientific basis for the dosage strength and unit, 12 SQ-HDM, is the SQ standardization method for determining dose strength and composition. The SQ standardization is founded on well-defined manufacturing processes and controls, and quality control tests which evaluate the protein and allergen profile and quantify the allergenic activity and major allergen content using IHRs that are established using the same processes. Furthermore, the intended marketed dose of ..., 12 SQHDM, is based on extensive clinical trial documentation, and several literature references referring to the unit of SQ-HDM are available to prescribers to ensure there is sufficient understanding of the product before use (Appendix 1).

References Supporting the Dosage and Chosen Unit of SQ-HDM

[Ref. 3.3: 043PK6] Mosbech, H., Deckelmann, R., de Blay, F., Pastorello, E.A., Trebas-Pietras, E., Prieto Andres, L., Malcus, I., Ljørring, C., Canonica, G.W. “Standardized quality (SQ) house dust mite sublingual immunotherapy tablet (ALK) reduces inhaled corticosteroid use while maintaining asthma control: A randomized, double-blind, placebo-controlled trial.” J Allergy Clin Immunol. 2014.

[Ref. 3.3: 049QNL] de Blay, F. et al. “SQ HDM SLIT-tablet (ALK) in treatment of asthma – Post hoc results from a randomised trial.” Respiratory Medicine , Volume 108, 1430 - 1437

[Ref. 3.3: 049QNR] Demoly, Pascal, Waltraud Emminger, Dorte Rehm, Vibeke Backer, Lene

Tommerup, and Jörg Kleine-Tebbe. "Effective Treatment of House Dust Mite–induced Allergic Rhinitis with 2 Doses of the SQ HDM SLIT-tablet: Results from a Randomized Double-blind,

Placebo-controlled Phase III Trial." Journal of Allergy and Clinical Immunology (2015): n. pag. Web.

[Ref. 3.3: 049QNY] Mosbech, Holger et al. “SQ house dust mite sublingually administered immunotherapy tablet (ALK) improves allergic rhinitis in patients with house dust mite allergic asthma and rhinitis symptoms.” Annals of Allergy, Asthma & Immunology , Volume 114, 134 140.e1

[Ref. 3.3: 049QP0] Jennifer Maloney; Bruce M. Prenner; David I. Bernstein; Susan Lu; Sandra Gawchik; Gary Berman; Amarjot Kaur; Ziliang Li; Hendrik Nolte. “Safety of house dust mite sublingual immunotherapy standardized quality tablet in children allergic to house dust mites.” Annals of Allergy, Asthma & Immunology, In press 2015

comment:7 Changed 3 years ago by Gunther Schadow

Here is my assessment of what I just read.

(1) The SQ HDM scale is a ratio scale:

  • 0 would mean nothing
  • 1 is the smallest amount that has been used in the human testing
  • 12 is 12 times that smallest amount.

This is good for understanding SQ.

I am still puzzled how 6 SQ'U from one allergen and 6 SQ'U from another allergen can be additive to make 12 SQ'U together. But I do remember that this was already a question with the IR unit we had added somewhere in 2013 or 14.

(2) There is precedence in related units AU and IR, AU being based on some reference standard maintained by the FDA, but for the HDM product there is no such reference standard nor any international reference standard. This justifies SQ as a unit, but still not really the HDM suffix. We know from AU, IR, IU, and SQ that you need to know the reference standard and the measurement procedure in detail in order to reproduce or interpret the measurement beyond a simple intra-scale comparison. So, we are still good with [SQ'U] only.

(3) It seems like the SQ standard is still basically an in-house reference standard (as it is apparently common use in the EU) and for all the insight into general methodology the rest of the text gives us, the only way for any laboratory to reproduce this quantity (i.e., to check whether 12 SQ'U tablets really do contain 12 SQ'U is to have insight into the detail of the CTD 3.2.S.4 Control of Drug Substance, ans likely others 3.2.S.5 Reference Standard, etc.

Because that is not realistic, we can simply treat SQ Units as an arbitrary unit, not comparable with anything else. And because that is so, SQ'U is enough as a symbol.

Recommendation

Barring an objection, the SQ'U unit should be defined. The sort of objection that would shake up this recommendation, would explain why it is that AU, IU, etc. are written as units without the suffix of the specific method and reference standard while SQ'U should have that HDM suffix. We know that the method and reference standard must be specific to the allergen. What we don't know is why that is any different from AU, IU, to justify dragging the identity of the allergen into the name of the unit.

comment:8 Changed 3 years ago by Gunther Schadow

To clarify, the proposal is to use "[SQU]" (no apostrophe).

comment:9 Changed 3 years ago by william.hess

Gunther,

We should point out that the unit of measure that is being proposed is for eListing purposes, and that SQ-HDM can still appear in the text of the content of labeling.

Bill

comment:10 Changed 3 years ago by Gunther Schadow

WilliamGray? again in email (which is why it was missed) has submitted the following contention:

"SQ-U is used as unit of measure in multiple countries for subcutaneous immunotherapy (SCIT) products. The manufacturing of the drug substances (DSs) and hence the corresponding in-house reference (IHR) preparations used for the calculation of the strength in SQ-HDM differ from the manufacturing process of the DSs and corresponding IHR preparations used for the calculation of the strength in SQ-U. As the DSs are complex biological mixtures characterized relative to specific IHRs, strengths expressed in SQ-HDM and SQ-U are not comparable. Using units that appear to be comparable, but in reality aren’t, poses a significant risk to patient safety."

I find this not very convincing. We all know that all these arbitrary units are not comparable because the reference standards differ. But this isn't even really a unit issue. Strengths of different substances are never comparable, even less so if the strengths are expressed in mass. Every substance has different molar mass and hence strength by mass ("weight", e.g., "milligram") is not comparable from one substance to the other.

What matters is if the principle of the unit is the same while the reference standard and specific measurement protocols may be different.

For example, if the issue is the subcutaneous use vs. the sublingual use, then should that be the distinguishing factor in the units? But why would that be? Are we measuring insulin units different depending on subcutaneous use vs. intravenous use? Or are we measuring the mass of clonazepam differently based on oral vs. sublingual use? And again, one cannot claim that 5 mg of clonazepam equal to 5 mg of diazepam, strength of two different substances are never comparable, which is why we never need to put the abbreviation of the substance into the unit of strength.

Note: See TracTickets for help on using tickets.