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Coordinator: Mr. Eric Ormsby, Therapeutic Products Directorate (613)
957-1058
Alternate: Ms. Marilyn Davis, Therapeutic Products Directorate (613) 957-6260
EXPERT ADVISORY COMMITTEE ON BIOAVAILABILITY
AND BIOEQUIVALENCE
November 15 & 16, 2001
RECORD of PROCEEDINGS
Committee Members Present: Dr. J. Thiessen (Chair), Dr. J.G. Besner,
Dr. A. Donner, Dr. R. Herman, Dr. F. Jamali, Dr. M. Kara, Dr. J.N. McMullen,
Dr. E. Palylyk-Colwell, Dr. K. Renton, Dr. D. Sitar
Health Canada (HC) Expert Advisory Committee Working Group Members:
E. Ormsby (EAC Coordinator, BPC*), L. Cockell (DBE*), G. Condran(BPA*),
D. Hoffman (BGTD*), C. Pereira (DBE), N. Pound (BPA), P. Roufail (BPA),
D. Vu (BLPA*), M. Davis (EAC Scientific Support, BPC)
HC Observers: L-N Cui (DBE), J. Gordon (DBE), A. Hassen (BPA),
C. Lourenco (DBE), S. Rau (DBE), C Simon (DBE), P. Wielowieski (DBE)
*Abbreviations for Health Canada Bureaux/Divisions:
BGTD = Biologics and Genetic Therapies Directorate
BLPA = Bureau of Licensed Product Assessment
BPA = Bureau of Pharmaceutical Assessment
BPC = Bureau of Policy and Coordination
DBE = Division of Biopharmaceutics Evaluation (BPA)
An information package was sent out to all members on October 29, 2001.
It contained an agenda and information on 11 agenda items. The numbering
of the items in this record of proceedings refers to the order in which
they were discussed, based on the revised agenda now posted on the HC
web site, to accommodate for member schedules. Dr. Donner was present
for discussions on November 15 only, and Dr. Herman had to depart around
lunch time on November 16 for an early flight. Any mention of TAB # refers
to the section of the information binder sent out to the members before
the meeting.
Ø ITEMS 1 & 2 - Opening Remarks, Review of Agenda
The Committee Coordinator opened the meeting by welcoming the members
and dealing with administrative items. He passed along regrets from the
Director General (DG) who was out of the country. Information inserts
for agenda items 4 and 9 were updated.
The meeting was turned over to the Chair who greeted the members and
outlined the format for this meeting. He suggested that a brief presentation
would be made by a HC representative for each topic, followed by debate
by the committee members, ending with a commitment to formalize an outcome.
The Chair indicated his intention to run this session as a meeting of
the collective group, giving HC individuals an opportunity to contribute.
The Chair polled the committee members as to whether any of them had
received feedback as a result of being on this Expert Advisory Committee
(EAC). One member mentioned an involvement in an issue with a generic
company and the member now had a better appreciation for the nuances of
drug regulations. The Coordinator stated that several requests to attend
this meeting were received from stakeholders and industry, and that this
issue should be addressed for future meetings. It was suggested that these
representatives may be allowed input, but not complete access to the meetings;
perhaps it would be appropriate to give an opportunity to present to the
EAC followed by a question/answer period as has been done with prior working
groups and committees. The Chair handed out correspondence to the TPD
from Drs. Small (McGill) and Keith (McMaster) which outlined the necessity
for caution when establishing bioequivalence criteria for nasal products.
This information was to be reviewed and included in the discussion of
nasal products (Items 16 and 17 on the revised agenda).
The agenda was reviewed and it was agreed that Item 9 on Levothyroxine
should be discussed in conjunction with Item 7 Critical Drugs.
Ø ITEM 3 - Orally Administered Products with Topical Action
A presentation was made by P. Roufail, thanking the members for their
input and giving an update on this item since it was discussed at the
last EAC meeting in March 2001. The guidance obtained has helped in dealing
with some products, misoprostol in particular, since it was proposed that
only bioequivalence was required in that case.
Feedback was also received from the innovator on 5-ASA.
The next step will be to develop a directive or guidance to give direction
to industry. It was discussed that each drug of this type must be considered
on its own merit, based on the amount of drug absorbed systemically and
sites of absorption, etc. It was stated that under the regulations, bioequivalence
could be assessed based on comparative bioavailability data, pharmacodynamic
data or clinical data, depending on the individual drug characteristics.
The presentation concluded with a reminder that comments would be welcome
from committee members, both now and in the future. The committee was
directed to the Issue Analysis Summary (IAS) entitled "Orally administered
drugs intended for topical/local action- data requirements for subsequent
entry products" found in TAB 2 of the information package. A potential
typo on page 5 of IAS 20 mcg (IV column) was identified.
A discussion ensued with regards to clinical data being used to establish
product bioequivalence and the following comments were made:
Ø The design of a study must be approved. Clinical studies
to establish equivalence require clinical parameters that are capable
of discerning significant differences between formulations. These parameters
must be clinically important or meaningful, as the choice of measurement
will influence what the significant clinical difference is. This may not
necessarily be the 20% difference used for bioavailabilty data.
Ø If drug levels can be measured, they should be as they
may be related to toxicity or adverse drug reactions(ADR), even if the
concentration in plasma is not therapeutically important.
Ø Whenever possible, pharmacokinetic (pk) studies should
be completed and the customary bioequivalence metrics and criteria used;
clinical studies could be conducted to support efficacy and safety.
Ø Individual guidances are supported for individual drugs
due to complex differences in topically acting drugs (i.e. consideration
must be given to whether the drug effect is mediated systemically or locally,
or if the release of the drug is site-specific.)
Ø A case by case analysis or guideline is needed.
Ø Sponsors might look for loopholes if the guidances are
too general, they must be specific to each drug.
Ø There is an inherent problem in defining clinical outcomes
vs. pk studies; clinical response is not always as discriminating as pk
evidence.
Recommendation: TPD to develop drug specific recommendations
on a case by case basis.
Ø ITEM 4 - Inadequately Characterized Concentration-Time Profiles
A presentation was made by N. Pound. This issue of defining adequately
characterized concentration-time profiles and determining when subjects
with inadequate profiles can be removed from the statistical analyses
was discussed at the March 2001 meeting. The guidance document entitled
"Bioavailability Requirements: Inadequately Characterized Concentration-time
Profiles" (TAB 3) was introduced and had been revised to reflect the comments
of the EAC. HC now seeks confirmation from the members that this guidance
accurately reflects the recommendations made in March.
A discussion ensued, with the following points of interest arising:
Ø A comment was made that the distribution of inadequate
profiles should be similar for the comparative products.
Ø The section on exclusion from analysis (lines 16 - 19,
TAB 3) needs to be more rigid on the issue of potential outliers.
Ø Non-compliance is not a valid reason to remove a subject.
Ø Inadequate profiles are rarely an issue for conventional
products; they arise predominantly in trials of non-conventional dosage
forms (e.g. enteric coated formulations.)
Ø Again, it was identified that there is a need to better
differentiate between outliers and inadequately characterized profiles,
(better definition) i.e.: Outlier = observed values are
aberrant Missing data/inadequate profiles = do not have
adequate data to calculate a value
Ø Missing data likely arise most often due to problems
in the blood sampling schedule.
Ø Removing outliers is discouraged because the observation
may be due to a defective dosage unit or a subject by formulation interaction.
Ø The criteria for removal of inadequate profiles (lines
85 - 91, TAB 3) need more clarification.
Ø An a priori criteria statement is needed to justify
removal.
Recommendation: TPD to re-draft guidance and send out for stakeholder
comment. This would include the EAC.
Ø ITEM 6 - Exclusion of Data from Bioequivalence Studies
A presentation was given by N. Pound asking the EAC to address the issue
of defining criteria for the identification and exclusion of outliers
from comparative bioavailability studies for the purpose of establishing
bioequivalence. An Issue Analysis Summary was contained in the Information
package (TAB 4).
A discussion ensued, with the following points of interest arising:
Ø The committee questioned the recommendation (line 93,
TAB 4) stating that "subjects (observations) to be removed are to be identified
before the statistical analysis is undertaken." Ideally they should be
identified prior to any analysis (i.e. analytical or statistical) being
undertaken.
Ø The design of a protocol should include filters to include
or exclude subjects on the basis of baseline characteristics, and not
on the basis of what occurred during the study.
Ø Conditions for exclusion should be set before a study
begins (a priori), e.g. if a women gets pregnant after the onset
of the study, it is not a violation of the protocol; these conditions
must be practical. When unforseen or unanticipated conditions arise, they
could offer a logical and reasonable reason for removal of outliers providing
this is not an abuse of the intent to treat principle.
Ø There is a need for logical and scientifically defensible
reasons for exclusion.
Ø It was pointed out that the standards are based on a
parametric analysis and statistical tests are related to normality assumptions.
Ø A study should not be allowed to pass based on: -bogus
conclusions -"mining for data" -non-legitimate reasons
Ø The sponsor must be able to prove if it is a formulation
effect, or a physical event on a given day.
Ø Retesting can only be done on the basis of factors other
than "bad observable results."
Ø Retesting could be done to remove potential "Subject
by Formulation" interaction only.
The committee members summarized the above debate with these criteria
for exclusion:
Removal of Subjects
1. Justification to exclude subjects on a statistical basis alone
is not acceptable.
2. Subject exclusion may be permitted if a protocol violation has
occurred (that was stated a priori), provided the reason(s) for
removal are medically and/or scientifically justified, and no more than
5% of subjects in total are excluded.
3. An unanticipated event such as an inadequately characterized profile
(as defined elsewhere) or a serious medical event has occurred.
Requirement - To exclude any subject on the basis of the above, the
decision to do so would have been made prior to any analysis (i.e. analytical
or statistical) being undertaken. The likely underlying causes (medical
and/or scientifically justified) must be given, and no more than 5% of
subjects can be excluded in total.
The debate resumed, with further issues discussed:
Ø A sponsor could include extra subjects to compensate
for those that had to be excluded. These individuals would have been subjected
to similar conditions and time frames as the original set to be observed,
but the sponsor's data will have to be scrutinized before decision to
replace them is allowed.
Ø If subjects do not complete the study and the samples
are not analyzed, then they could be removed, as long as it is deemed
to be "pre-analysis" removal. These pre-analysis exclusions could be excluded
from the 5% maximum exclusion limit. Once the analysis occurs, then all
subjects must be included and the 5% maximum exclusion limit would apply.
Ø Some acceptable reasons to exclude subjects could be:
-pre-screening (pre-dose) blood samples demonstrating a concentration
of the drug;
-analytical interference, i.e. concomitant substance;
-disease state that can impact absorption, (e.g. GI cancer that progresses,
or migraines, which could impair absorption, that occur during the 2nd
arm of the trial;
-subject vomits.
Ø In principle, recall and retesting of subjects is considered
to be unacceptable. Such a practice raises questions regarding the statistical
analysis of such data and does not address potential observations caused
by defective dosage units. This is not to be confused with the practice
of re-analyzing samples during the analysis portion of a study.
Recommendation: The EAC members want to revisit the issue of
recalling and retesting subjects at the next meeting, with additional
information from USA or European thinking on the subject.
Ø ITEM 7 - Critical Dose Drugs
A presentation was given by N. Pound. This issue was previously addressed
at the March 2001 meeting under the title of Narrow Therapeutic Range
(NTR) Drugs. HC would like the EAC's recommendations regarding the addition
of highly toxic drugs into this category and renaming the group with a
designation of Critical Dose Drugs, and would also like feedback on the
new draft guidance (TAB 5) for this issue. The EAC members would also
be invited to assist in revising and updating the current list of NTR
drugs to include toxic drugs.
Recommendation: The EAC members unanimously agreed to combine
NTR and toxic drugs into one category called Critical Dose Drugs.
The first filter for critical drugs is "dose and concentration causing
marked effects." The following list was formulated from committee discussion:
Factors to consider when including drugs in a list of Critical Dose
Drugs: (1)
-serious dose-dependent adverse effects exist
close to the dosing range
-Narrow Therapeutic Range (NTR) or narrow tolerance range
-requirement for blood level monitoring to control and individualize
treatment; this is the standard of care or normal condition of use
-dosing based on body weight or other highly individualized dosing
requirements
-serious clinical consequences of overdosing (toxicity) or under-dosing
(lack of effect)
-steep dose response relationship for efficacy and/or toxicity, or
both
The Chair presented an example (Disopyramide) to illustrate
the evidence and process needed to define whether a drug falls into the
"Critical Dose Drugs" category.
Recommendations: Members agreed on the following revised definition
for critical drugs (lines 6-8, TAB 5) outlined in the new draft guidance
document:
"Critical dose drugs are defined as those drugs where comparatively
small differences in dose or concentration lead to dose- and concentration-dependant,
serious therapeutic failures and/or adverse drug reactions which may be
persistent, irreversible, slowly reversible, or life threatening events."
(The Chair asked committee members how they would like to proceed for
revising the current list? The members agreed that they will help, but
the format for their contribution was not decided. It was suggested to
modify the title of the list to "Examples of Critical Dose Drugs.")
Ø ITEM 9 - Bioequivalence Criteria for Levothyroxine Tablets
A presentation was made by N. Pound requesting the EAC to comment on
the bioequivalence criteria required for Levothyroxine sodium solid oral
dosage forms. In addition, G. Condran provided background on the history
of stability and reproducibility of levothyroxine sodium tablets marketed
in Canada in contrast to concerns that had arisen over these issues for
products marketed in the USA.
HC had a specific list of questions on this issue which the committee
responded to :
1. What would be an appropriate Canadian Reference Product: Eltroxin
and/or Synthroid, or an oral solution?
Eltroxin and Synthroid have been determined to be interchangeable
in some provinces. The committee members agreed that for practicality,
comparisons should be made to one of the solid (tablet) forms rather than
the solution form. This is particularly important if the bioequivalence
studies are to be used as a basis for provincial interchangeability decisions.
2. Is Levothyroxine an NTR drug? If so, presumably it follows that criteria
for "Critical Drugs" will apply?
With the absence of compelling evidence, the committee does not consider
it to be a NTR.
3. Should these criteria also be applied to the metabolite, T3?
No. T4 can be considered a pro-drug with slow metabolism
to T3. T4 is also the absorbed moiety (as opposed
to T3) and can be measured in plasma. Therefore it makes no
sense to measure the metabolite.
4. Is it appropriate to approve eleven pharmaceutically proportional
strengths based on studies conducted on only one strength (preferably
the highest?)
Yes, if evidence is provided that all strengths are proportionally
formulated.
5. The FDA recommends a 600 µg dose, presumably to suppress, and
thereby reduce the interference from endogenous T4/T3. Is this appropriate?
A 600 µg dose has been deemed to be appropriate.
6. Current TPD requirements call for sampling to 72 hours (FDA states
48 hrs). Can one assume that the suppression of endogenous levels is sufficient
to permit meaningful data up to (only?) 48 hrs? 72 hrs?
72 hours is consistent with current TPD practice for drugs with long
half-lives; however, 48 hours is considered adequate. This issue will
be revisited when long half-life drugs are discussed in the future.
Ø ITEM 11 - Drugs Exhibiting Non-linear Pharmacokinetics
A presentation was given by N. Pound asking the EAC members to comment
on the minimum number and type of comparative bioavailability studies
required, and the standards to be met to establish bioequivalence for
drugs that exhibit non-linear pharmacokinetics (NLPK.) A draft Guidance
was contained in TAB 6.
Again, a question and answer format was used for this issue: 1. Do NLPK
drugs require more stringent bioequivalence requirements than "uncomplicated"
drugs?
No, the same standards as required for uncomplicated drugs apply.
2. Are both fasting and fed single dose studies necessary?
A fed study would be required when the non-linearity is related to
a capacity-limited process such as absorption and/or pre-systemic metabolism.
Food may affect the rate of disintegration/dissolution of the drug, which
in turn would affect the rate of availability of the drug to the capacity-limited
absorption or pre-systemic metabolic site, thus influencing the observed
concentrations.
3. Should bioequivalence criteria be the same for fasted and fed conditions?
Yes.
4. How should drugs with NLPK be defined/identified? (What degree of
non-linearity is considered significant?)
Dose normalized AUC values giving a 25% or greater deviation (increase
or decrease) should be considered non-linear. This criterion applies over
the practical clinically recommended single dosage range.
Recommendation: The EAC proposed a wording change to the Guidance,
for pg. (v), section i) TAB 6 which now reads:
"For drugs with non-linear pharmacokinetics in the single unit dose range
of approved strengths resulting in greater than proportional increases
in AUC with increasing dose, the comparative bioavailability studies
must be conducted on at least the highest strength."
Proposal: change the wording "highest strength" to "highest
labeled (common) dose"
Ø ITEM 14 - Food Administration Requirements for Comparative
Bioavailability Studies
A presentation was made by N. Pound outlining the need to define appropriate
food administration protocols for comparative bioavailability studies
undertaken to demonstrate the bioequivalence of two oral dosage forms.
An IAS and a draft guidance were contained in TAB 7 of the information
package.
The questions for the EAC members were as follows: Should bioequivalence
studies always be conducted under fasted conditions, if at all possible?
If so, are there situations where waiver of the fasted study is appropriate?
The wording of Product Monographs is important to determine whether
fasted or fed studies are required. For uncomplicated products, fasted
studies are generally required. The wording of the guidance under section
5.1 (pg 2) TAB 7 (Immediate release products with uncomplicated pharmacokinetic
characteristics) was accepted:
"It is recognized that in some very rare instances, the conduct of
a comparative bioavailability study under fasted conditions may be precluded
due to the very poor, or highly variable absorption of an active ingredient
in the absence of food, or the development of serious gastric upset when
dosing occurs under fasted conditions. In such situations, when the accepted
Canadian labeling for the reference product indicates that the product
is to be taken only with food, it may be possible to provide a scientific
justification for conducting a comparative bioavailability study under
fed conditions in lieu of the standard fasted study."
Recommendation: Generally, every attempt should be made to
determine bioequivalence in the fasted state. In the event that a study
cannot be conducted in the fasted state due to gastro-intestinal disturbances,
a low-fat meal (defined elsewhere) could be an acceptable compromise.
If the label says "food must be given," then the committee felt that a
fed study is necessary, and a low-fat study could be an acceptable replacement
for a fasted study.
The EAC also felt that bioequivalence criteria should be the same
for studies conducted under fasted and fed conditions.
A 1997 draft Food and Drug Administration (FDA) guidance document on
food effect was cited. It suggested that other factors such as solubility
and permeability be reviewed if there is evidence that an excipient affects
absorption.
Ø ITEM 16 - Abbreviated New Drug Submissions for Subsequent
Market Entry, Topical Dermatologic, Ophthalmic, Otic and Nasal Drug Products
Two presentations were given on this topic. The first, by N. Pound outlined
the request to the EAC for guidance regarding data required to evaluate
bioequivalence of topical dermatological, ophthalmic, otic and nasal drug
products.
The second presentation by G. Condran put the following two proposals
to the committee regarding requirements for subsequent market entry topical
solutions: (numbering refers to the corresponding section in the guidance
document) TAB 9
2a) A quantitative and qualitative comparison of non-medicinal ingredients
in the subsequent market entry and Canadian reference product must be
provided.
Proposal: The amount/concentration of the inactive ingredients should
be essentially the same, (i.e. each within ± 5% of the Canadian
reference product.) {Exceptions: Penetration enhancers}
Recommendation: The committee agreed to a ± 5% tolerance
around the labeled content and stated that tighter tolerances are a likely
requirement for penetration enhancers; these must be clearly identified.
2c) Physicochemical properties might include, but are not limited to
pH, buffering capacity, tonicity, viscosity and surface tension.
Proposal: Should criteria for comparative physical/chemical properties:
e.g. viscosity, droplet size, be established? How much tolerance is
acceptable?
Recommendation: The committee members felt that reasonable
criteria and tolerance limits should be established for comparative physical/chemical
properties. In determining tolerance limits, consideration must be given
to the individual parameter (i.e. viscosity, surface tension, etc.), as
well as the manufacturing tolerances permitted. Furthermore, it was noted
that the container or delivery system can be very important (i.e. to ensure
comparable droplet size, etc.); therefore such aspects should be the same
as for the reference product.
Ø ITEM 17 - Waiver of Comparative Bioavailability Studies for
Drug Solutions with Nasal Delivery for Systemic Therapeutic Actions
A presentation by N. Pound outlined the issue for the EAC. HC requests
guidance in defining conditions for and factors to be addressed in justifying
a waiver of comparative bioavailability/clinical studies for solutions
for nasal delivery with systemic therapeutic action.
Recommendation: The committee stressed that it is imperative
to clarify very precisely what the ingredients are in such products. They
agreed that a waiver is permissible for simple aqueous solutions (with
no thickening agents, surfactants, etc. as defined in group 1 uncomplicated
drugs.) This refers basically to the drug in an aqueous solution with
buffers only. The solutions must be essentially similar.
The committee felt that there may be cause to sharpen the definition
of a simple true solution, and therefore, the description of the drug
(solution).
Ø ITEM 18 - Review of Section C.08.001.1(b) of the Regulations
to the Food and Drugs Act: DESIGNATION OF A CANADIAN REFERENCE PRODUCT
A presentation was made by N. Pound explaining section C.08.001.1 of
the Regulations which defines a Canadian Reference Product (CRP).
HC wishes to recommend changes to paragraphs (b) and (c) to amend the
criteria to be used in designating a product for use under this section.
Concern was expressed over the need to ensure that subsequent-entry generics
are compared to the same single reference product in Canada (i.e. same
common denominator). There is a clear need to be consistent, from the
provincial perspective, because subsequent entry generics are generally
considered to be interchangeable with each other if they have been designated
bioequivalent with the same reference product. The CRP is usually the
innovator product. However, if the innovator product is no longer available,
the CRP could be the first-entry generic product, the market leader generic
product, or a cross-licensed product with the innovator.
Problems arise when the CRP is no longer available. In the absence of
the CRP, there is provision in the Regulations to allow selection of an
alternate reference product; however, it should be noted that the ability
to do so was precipitated by a court case. In practical terms, the use
of a non-Canadian reference product is problematic due to the difficulty
for the TPD to verify that a foreign reference product has been manufactured
to standards comparable to those required by Canada, or if the approval
of the foreign product was granted in a country with a regulatory system
that would be acceptable to Canada. It was also noted that from a post-marketing
perspective, the TPD would have data on the CRP throughout the product's
life-cycle; however, the TPD would not have similar data on a foreign
product.
The use of a reference product purchased in Canada is essential when
assessing the acceptability of a subsequent-entry product for a provincial
formulary.
The International Conference on Harmonization, with the development of
it's common technical document, is moving towards accepting foreign reviews,
but is not there just yet.
The committee came to the following conclusion:
Recommendation: The reference product should always be the
CRP (innovator), unless it is no longer available on the market in Canada.
The reference product could then default to a second entry product, purchased
in Canada, such as the first-entry generic, the market leader generic
product, or a cross-licensed product with the innovator. (Any product
used would be assumed to have a Notice of Compliance.) Any reference product
so designated shall thereafter be used consistently to ensure that
all subsequent-entry generic products are compared to a single reference
product.
Ø ITEM 21 - Bioanalytical Method Validation
A presentation was made by N. Pound requesting the EAC's opinion on the
removal of the current requirement that 15% of the clinical (incurred)
samples be randomly selected and re-assayed when single assays are performed.
Recommendation: The committee agreed unanimously to the proposal
to remove the requirement of 15% of clinical samples.
A short discussion of the issue of sample size (n) for resampling followed.
Ø ITEM 22 - Future Agenda Item Proposals/Administrative
Details/Closing remarks
Ø As issues from this meeting are finalized, documents
will be e-mailed to committee members for approval, and unless concerns
are expressed, no future debate will occur.
Ø Committee members must confirm agreement within 7 working
days of receipt of documents.
Ø If comments or concerns arise on these issues, the committee
members will be advised before the next meeting, and discussions can be
reopened.
Ø Teleconferences were proposed as a possible means of
finalizing some issues before the next meeting if debate is needed.
Ø ITEM 23 - Scheduling of next meeting and adjournment
Meeting adjourned. Next proposed meeting: April or May, 2002 Prepared
by: M. Davis
References
 1. Reference
to Am J Kidney Dis 1999 Feb;33(2):389-97 in formulation of list
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