Contains Nonbinding Recommendations
Draft Guidance on Lidocaine
This draft guidance, once finalized, will reprent the Food and Drug Administration's (FDA's)
current thinking on this topic. It does not create or confer any rights for or on any person and does
not operate to bind FDA or the public. You can u an alternative approach if the approach satisfies
the requirements of the applicable statutes and regulations. If you want to discuss an alternative
approach, contact the Office of Generic Drugs.
Active ingredient: Lidocaine
Form/Route: Patch/Topical
Recommended studies: 2 studies
1.Type of study: Fasting
Design: Single-do, in-vivo, using three topical patches
Strength: 5%; 700 mg/ patch
Subjects: Normal healthy males and females, general population.
Additional Comments:
•Apply three topical patches (2100 mg total do) simultaneously over a 12-hour period.
•You may u a smaller number of patches provided the plasma concentrations of lidocaine are measurable to adequately characterize the pharmacokinetic profile of lidocaine for bioequivalence
asssment bad on the 90% confidence interval criteria.
•Plea include a 24-hour post-do sampling time in the bioequivalence study.
•In addition to pharmacokinetic data, plea report the "apparent do" delivered. The apparent do can be determined by subtracting the remaining amount of lidocaine in each patch (ud patch) from
the manufactured amount. The amount of adhesive residue from each patch left on the skin should be
analyzed and included in the calculation.
Analytes to measure: Lidocaine in plasma.
Plea utilize a validated analytical method such as LC-MS/MS to reliably measure plasma lidocaine
concentrations. A lower limit of quantitation (LLOQ) of 0.20 ng/ mL is recommended to adequately
characterize the pharmacokinetics at the 2100 mg study do.
Bioequivalence bad on (90% CI): Lidocaine
_____________________________________________________________________________
2.Type of study: Skin irritation/nsitization study
Design: Single-do, in-vivo (preceded by an induction pha and a rest period)
Strength: 5%; 700 mg/ patch
Subjects: Normal healthy males and females, general population.
Additional comments: Specific recommendations are provided below for the skin
irritation/nsitization/adhesion study
______________________________________________________________________________
General comments:
•Plea note that the name of RLD is designated as lidocaine topical patch, 5%. This designation is bad on the concentration of lidocaine in the adhesive, which is 5%. Plea formulate your product to contain 5% of lidocaine in the adhesive, to have the same surface area and the same total amount of lidocaine in the patch as the RLD.
•You may submit a full bioequivalence study protocol for review prior to initiating the study.
Waiver request of in-vivo testing: Not Applicable
Dissolution test method and sampling times:
Plea note that a Dissolution Methods Databa is available to the public at the OGD website at
v/cder/ogd/index.htm. Plea find the dissolution information for this product at this website. Plea conduct comparative dissolution testing on 12 dosage units each of all strengths of the test and reference products. Specifications will be determined upon review of the application.
General recommendations regarding skin irritation/nsitization/adhesion evaluation of a generic lidocaine topical patch:
1.This product is intended to provide local pain relief of post-herpetic neuralgia at the application site. The
RLD labeling directs that the patch should be cut to the appropriate size for the intended skin area to be treated. Therefore, your patch design must allow for the patch to be safely cut to a smaller size. In
addition the active surface area of your patch should be comparable to that of the RLD.
2.Conduct the skin irritation and nsitization studies in healthy volunteers. Continuous same-site
exposure is necessary to provide the maximal provocative exposure that is intended in the skin irritation and nsitization studies.
3.The clinical review team recommends that irritation and nsitization be evaluated in the same study.
However, they should be evaluated with parate analys. Primary endpoint(s) for each of the analys need to be clearly defined prior to the start of the study. The two primary endpoints should be considered as co-primary endpoints, e.g., for each of them, the study must demonstrate that the test patches are no
wor than the reference listed drug (RLD). In addition, the corresponding primary analysis for each
primary endpoint needs to be specified in your protocol. Secondary endpoint(s) (if any) should also be clearly defined prior to the start of the study.
4.The OGD recommends that your patch have a design that can be cut to a smaller size as described in the
labeling of the RLD. One-fourth of a test patch and one-fourth of the reference patch should be appli
ed to the same individuals simultaneously for 21 days during the induction pha of the study. The patches should be applied continuously to the same sites and replaced with a new one-fourth patch 3 times
weekly. The 21-day induction pha is to be followed by a 2-week rest period and then a single 48- hour challenge application of each one-fourth test system to a naïve site.
5.No make-up, creams, lotions, powders or other topical products should be applied to the skin area where
the patch will be placed, as this could affect adhesive performance or induction of irritation.
6.Subjects should return for visits three times per week for irritation scoring and patch replacement during
the induction pha. Scoring of skin reactions should be performed by a trained and blinded obrver at each patch removal, using an appropriate scale. Dermal reactions should be scored on a scale that
describes the amount of erythema, edema, and other features indicative of irritation. An example of
an appropriate irritation scale is as follows:
DERMAL RESPONSE
0= no evidence of irritation
1 = minimal erythema, barely perceptible
2 = definite erythema, readily visible; minimal edema or minimal papular respon
3 = erythema and papules
4 = definite edema
5 = erythema, edema and papules
6 = vesicular eruption
7 = strong reaction spreading beyond application site
OTHER EFFECTS
0 = no other obrvations
1 = slight glazed appearance
2 = marked glazed appearance
3 = glazing with peeling and cracking
4 = glazing with fissures
5 = film of dried rous exudates covering all or part of the patch site
6 = small petechial erosions and/or scabs
7.If the degree of irritation for a given patch is such that a new patch cannot be applied to the same site,
then the product should be discontinued and the highest score obrved prior to patch discontinuation should be carried forward for all remaining obrvations in the irritation analysis. Subquent
applications of the product may be applied to a different skin site in order to complete the induction
pha for the skin nsitization evaluation.
8.To be valid for cumulative irritation analysis, the quential patch applications for the particular product
must not be detached from the skin for longer than 24 hours during the 21 day induction period (unless the patch was removed for an unacceptable degree of irritation).
9.Scoring of skin irritation should not be limited to reactions that appear to be related to only one
component of the generic system. Any skin reaction should be included in the irritation analysis,
regardless of the area of the patch associated with the reaction.
10.The cumulative irritation score, the total number of obrvations with a maximum irritation score for
each product, the number of patches that were removed due to an unacceptable degree of irritation,
and the number of days until sufficient irritation occurred to preclude patch application should be calculated for each test and reference product, and a statistical analysis of the comparative results should be
performed. In addition to the cumulative irritation scores, plea provide a frequency chart showing the number of applications of each product with each irritation score on each study day. To support
approval, the test product must be no more irritating than the reference product.
11.Subjects should be questioned about any itching, burning, pain or soreness at the application site.
The symptoms should be recorded and compared between products.
12.To be included in the nsitization analysis, patches should be evaluated by a trained and blinded
obrver at 30 minutes, and at 24, 48 and 72 hours after removal of the challenge patch. Dermal
reactions should be scored on a scale that describes the amount of erythema, edema, and other features indicative of nsitization.
13. A narrative description of each reaction in the challenge pha should be provided, together with the
opinion of the investigator as to whether such reactions are felt to be indicative of a contact nsitization.
Your protocol will need to include a clear objective definition of a nsitization reaction a priori. The test product should be no wor than the reference product with regard to the rate of nsitization.
14.If a patch completely detaches, it should be replaced within 24 hours and the subject should continue in
the study. If a patch cannot be replaced within 24 hours or a subject does not know when the patch fell off, the subject should be excluded from both the irritation and nsitization analys of that product.
The subject should note the date and time of detachment as soon as it occurs.
15.If you are not relying upon adhesion data from the skin irritation and nsitization study to establish
adequate adhesion performance of your product, then you may consider establishing criteria for using
tape to reinforce any patches that are lifting during the study. In addition, you should consider replacing any detached patches within 24 hours to ensure valid cumulative irritation and nsitization induction.
16.Adhesion data should be collected during the cour of the study to document that adhesion of the
products is adequate for the intended induction of skin irritation and nsitization, even if you are not
relying upon this study to establish adequate adhesive performance of your product.
17.Cutting patches to a smaller size is likely to change the shape as well as the size of the patch and may
change adhesive performance of the patch. Therefore, adhesion data from your skin irritation and
nsitization study may not be adequate to demonstrate that your to-be-marketed patch adheres at least as well as the RLD. Therefore, you should consider collecting adhesion data during your PK
bioequivalence study, using an acceptable 5-point (0 to 4) scale. Reinforcement of the patches should
therefore not be allowed in the PK study if it is also being ud to demonstrate adequate adhesion, and
you may need to increa the size of that study to allow for detached patches. Alternately, you may
conduct a parate paired single-application adhesion study to demonstrate that your product adheres at least as well as the RLD.
18.For adhesion analysis, plea provide adhesion scores for a single application of the intended duration of
patch wear using a scale such as the following:
0 = ≥ 90% adhered (esntially no lift off of the skin)
≥ 75% to < 90% adhered (some edges only lifting off of the skin)
1
=
≥ 50% to < 75% adhered (less than half of the system lifting off of the skin)
2
=
3 = < 50% adhered by not detached (more than half the system lifting off of the skin without falling off)
4 = patch detached (patch completely off the skin)
For any patch that detaches, plea carry forward a score consistent with detachment for all remaining
obrvation periods.
19.The cumulative adhesion score and the time from application until patch detachment should be calculated
for each test and reference product, and a statistical analysis of the comparative results should be
performed. In addition to the mean cumulative adhesion scores, plea provide a frequency chart showing the number of patches in each group with each adhesion score at each obrvation. Plea also provide data regarding the number of patches that detached and duration of wear prior to detachment. To support product approval, the test product must adhere at least as well as the reference product.
20.Due to likely differences in appearance of the patches, blinding of the obrver/evaluator may not be
possible, especially for evaluation of patch adhesion, which requires direct obrvation of the patch itlf.
However, efforts should be made to blind the evaluation of irritation and nsitization.
21.The same investigator should perform all irritation evaluations and/or all patch adherence evaluations for
each individual subject. The sponsor should consider training all investigators and potential alternat
es
according to the protocol in order to ensure consistency in evaluations.
22.The study results should show that the propod product does not produce any greater degree of irritation
or nsitization than that produced by the RLD and that the adhesive performance over the intended
duration of wear is at least as good as that of the RLD.
23.The analysis populations should be defined parately for irritation and nsitization and should be
defined per product instead of per subject. Each property should have a parate test population and
reference population for each product.
24.The Population Definitions for the Per-Protocol (PP) evaluation for each parameter should include the
following:
•Irritation Analysis– a product needs to be worn for the entire 3 weeks to be valid for the cumulative irritation evaluation OR if a patch is removed due to excessive irritation, it should be included using
Last Obrvation Carried Forward (LOCF).
•Sensitization Analysis – all subjects that wear the product for the full 21 day induction pha and for
48 hours during the challenge pha and return for evaluation 24 hours after removal of the challenge
patch (OR if the product is removed prior to 48 hours due to a nsitization reaction that caud the
product to be removed) should be included using LOCF.
25.As the irritation and adhesive properties may be nsitive to climate changes, we prefer that the study be
conducted in multiple centers with varying climate conditions
26.Plea refer to 21 CFR 320.38 and 320.63 regarding retention of study drug samples. For more
information, plea refer to the Guidance for Industry: “Handling and Retention of BA and BE Testing Samples” (May 2004). Retention samples should be randomly lected from each drug shipment by each study site prior to dispensing the medication to subjects. Samples must be randomly lected at each investigational site where the medication is dispend and retained by the investigator or an independent third party not involved with packaging and labeling of the study products. Retention samples should not be returned to the sponsor at any time.
27.It is recommended that an independent party generates and holds the randomization code throughout the
study in order to decrea the chance of unblinding and to minimize bias. The sponsor may generate the randomization code if not involved in packaging and labeling of study drugs.
28. A aled copy of the randomization scheme should be retained at the study site and should be available to
FDA investigators at the time of site inspection to allow verification of the treatment identity for each subject.
29.The OGD generally does not provide sample size recommendations. It is your responsibility to include
sufficient patients in the study to demonstrate non-inferiority of skin irritation potential and adhesion
performance of your product compared to the reference listed drug (RLD).
30.When submitting results of skin irritation, nsitization and adhesion studies in an ANDA, study data
should be submitted in electronic format including the following information:
a. A list of file names included in the CD or diskette(s) with a simple description of the content of each
file. A document file containing a description of each datat and an explanation of the variables
included in each of the SAS datats. (See v/cder/guidance/2353fnl.pdf regarding
"define.pdf.")
All SAS transport files should u .xpt as the file extension and should not be compresd.
The SAS program to open the transport files and an explanation of the format for each SAS
variable should be included.
b.You should identify and provide the list of subjects that are included and excluded from each
population analysis parately for each product. The variable(s) derived for analysis should include
specific data such as treatment per patch, analysis populations (e.g., per protocol (PP) for each of the
three analys), irritation scores, days to patch detachment, days to patch removal, etc. You should
also provide the reason(s) for exclusion of subjects from each of the PP and other population(s) ud
for analysis. The variables could be included in a single SAS transport file.
c.SAS transport file(s) – covering all variables collected in the Ca Report Forms (CRFs) per subjec
t:
You should provide a summary datat to include such variables as demographics, baline
admission criteria, baline vital signs, adver events, reasons for discontinuation of treatment,
medical history, compliance and comments, etc.
