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Coordinator: Mr. Eric Ormsby, Therapeutic Products Programme
(613) 941-3694
Alternate: Ms. Marilyn Davis, Therapeutic Products Programme
(613) 957-6260
EXPERT ADVISORY COMMITTEE ON
BIOAVAILABILITY AND BIOEQUIVALENCE
March 22 - 23, 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. E. Palylyk-Colwell,
Dr. K. Renton, Dr. D. Sitar
Regrets: Dr. J.N. McMullen
Health Canada (HC) Representatives Present: R. Peterson (DG*,
Executive Secretary),
E. Ormsby (EAC Coordinator, BPC*), M. Davis (EAC Scientific Support, BPC)
HC Expert Advisory Committee Working Group Members and Presenters:
L. Begin (BPC), J. Gordon (DBE*), D. Hoffman (BBR*), K. Kourad (BBR),
S. Mishkin (BPA*), E.J. Northey (Justice Canada), C. Pereira (DBE), N.
Pound (DBE),
B. Rotter (BPA), C. Simon (DBE), D. Vu (BLPA*)
HC Observers: I. Aldeen (DBE), A. Chow (BPA), L. Cockell (DBE),
K. Fitchett (BPA),
M. Harczy (BPA), A. Hassen (BPA), T. Mueller (BPA), S. Qureshi (BPC),
P. Wielowieyski (DBE), G. Zaror-Behrens (BPA)
Ø Director General's Opening Remarks
The Director General (DG) opened the meeting by welcoming the committee
members and thanking them for agreeing to participate in this Expert Advisory
Committee (EAC). He outlined the importance of their participation in
providing advice to Health Canada (HC).
The DG spoke of the existence of several guidelines on bioavailability
and bioequivalence (BB) which now exist in draft form. His hopes are that
this EAC will facilitate the move of the drafts forward to a formal status.
He stressed the need to settle controversial issues in a definitive manner.
The EAC members were informed that the proceedings of these meetings will
be posted to the HC web-site as there is a great deal of interest in this
area. The DG described the need for a clear record of decision from the
Chair of the committee. He mentioned that the members must remember to
exercise caution with regard to confidential documents and issues, and
to ensure that they do not represent any comments they might make outside
of the committee as anything but their own opinion, and not the view of
the committee. Any inquiries from stakeholders, including the press, to
the committee members on issues discussed by the committee should be referred
to the Chair of the EAC.
The DG briefly addressed the Food and Drugs Act, which is the legislation
that governs many of the processes developed by HC and the Therapeutic
Products Programme (TPP). Guidelines developed pursuant to this legislation
by HC, with the help of EAC members, must be accurate and represent the
way in which business is conducted at present. However, once written,
they can be updated occasionally to reflect current interpretations of
scientific principles and data.
The DG concluded by turning the meeting over to the Chair for introduction
of members and a brief outline of their expertise and interest in BB.
Ø Roundtable Introductions/Chair's Vision of BB-EAC
After the members introduced themselves, the Chair gave a brief outline
of the Mandate of the EAC and of his personal goals for the operation
and results expected. He stated that the EAC should function based on
a forum of open dialogue, and he encouraged views from varying perspectives
in an effort to form a consensus with authoritative recommendations as
an outcome. He commented that members may experience added pressure in
accomplishing this task due to the transparency under which this committee
must operate.
The Chair likened the impact of bioavailability and bioequivalence to
an image of three overlapping circles which represent the chief faces
of BB: 1) the elements of science and statistics, 2) the clinical and
practical issues influencing product selection and product interchangeability,
and 3) the commercial interests which encompass the marketing of competitive
products. There might not always be total agreement (overlap) among these
three spheres.
In concluding his remarks, he welcomed the challenge of participating
in this committee.
Ø Review Agenda
The agenda was reviewed and accepted.
Ø Overview of Legislation and Regulation
L. Begin (BPC) delivered a presentation intended to give EAC members
a basic understanding of the authority and responsibility to regulate
therapeutic products under the Food and Drug Act and Regulations. Definitions
of terms were given and the Decision-Making and Policy Processes were
addressed. Members found the presentation informative and requested a
copy of the electronic version of the presentation.
Action: HC to send electronic version of presentation to members.
Terms of Reference (TOR)
Ø Terms of Reference (Tor)
The Chair reviewed the elements of the TOR with the members and discussed
preferences for distribution to committee members of materials and minutes
generated from meetings.
The Terms of Reference were accepted as is and the members support their
use as a guide for the EAC's activities.
Ø Identification of Inadequate Subject Profiles in a Bioequivalence
Study
A presentation of the issue was made by J. Gordon (DBE) and the following
question was posed to the committee for deliberation:
What criteria should be used to define an adequately characterized
concentration-time profile, and when can subjects with inadequate profiles
be removed from the statistical analyses of the study data without negating
the validity of the study?
The EAC members agreed on this final answer to the question posed by
HC:
A concentration versus time profile is ideally characterized when
the absorption and elimination phases are adequately captured and AUCt
is 80% of the AUCi. This usually requires 12-18 points, as stated in Guideline
A. Placement of sampling times will depend on inter-subject variability
and also upon the drug, formulation and study conditions. The onus is
on the sponsor of a study to collect samples at appropriate times that
will adequately characterize all potential subject profiles. It is acknowledged
that, from time to time, the occasional individual subject data derived
from a bioequivalence study may be less than ideal. The theoretical number
of points needed to define the three metrics, Cmax, AUCt and AUCi legitimately
must be at least two, where the second point must be of a lower concentration.
Therefore profiles with zero, one, two points (where the second measured
point is of a higher concentration that the first) are not considered
to be adequate. It follows that such profiles may legitimately be removed
from the statistical analysis when a sound scientific rationale to do
so is stated in advance in the study protocol (a priori criteria). If
the inadequate profiles cannot justifiably be removed then the study itself
is invalid and not amenable to further analysis. Likewise, exclusion of
adequate profiles is also only justified with a sound scientific rationale.
The committee reinforced the statement in Guidelines A and B which states,
"It is rarely acceptable to exclude more than 5% of the subjects
or more than 10% of the data for a single subject-formulation combination."
Ø Orally Administered Products with Topical Action
Two of the EAC members declared possible Conflict of Interest (COI) for
this issue. A roundtable poll of the remaining members showed a unanimous
acceptance and belief that the two individuals could operate free of bias
on this topic, and agreed to allow the two members to continue participation
in the deliberation.
A presentation of the issue was made by B. Rotter (BPA) and the following
questions were posed to the committee for deliberation:
-
For orally administered products with topical/local action (e.g.
5-ASA, Misoprostol) is a properly designed comparative bioavailability
study sufficient to establish bioequivalence and hence the safety
and efficacy of a second-entry product?
-
If not, what specific circumstances would necessitate clinical
studies for orally administered products with topical/local action
(e.g. 5-ASA, Misoprostol)?
- Is there a validated surrogate marker that can be utilized either
for 5-ASA or Misoprostol to conduct a pharmacodynamic study (PD)? Should
the PD study be carried out in patients or healthy volunteers?
S. Mishkin, (Gastroenterology, Hematology and Oncology Division, BPA)
joined the EAC members by teleconference for the discussion of this issue.
The EAC members concluded that each of the two drugs cited in the questions
posed by HC (and in general, drugs in this category) should be addressed
individually for the following reasons:
the sites of release and absorption of the drug in the GI tract may
be therapeutically important,
the degree of systemic absorption of the drugs differ,
the formulations of the drugs differ (i.e. immediate versus modified release).
MISOPROSTOL
For Misoprostol, a properly designed comparative bioavailability
study is sufficient to establish bioequivalence and hence the safety and
efficacy for immediate release products.
If a drug (e.g. Misoprostol) is systemically absorbed comparatively
rapidly and completely, then regardless of its site of action, the effect
is evident during the systemic absorption phase and continues after the
formulation is absorbed. Hence, as long as the two formulations demonstrate
comparable rate and extent of absorption, they should be considered bioequivalent.
5-ASA
Aminosalicylate formulations for subsequent marketed Modified Release
(MR) products should be considered in the context of Group III drug products
as described in Report B "Oral Modified Release Formulations".
The subsequent entry product has to show that the site of release
is comparable to the reference product. It is unknown if absorption and
action are at the same site. Drugs can have the same absorption profile
but different action profiles.
The committee could not reach a consensus on these issues at this
time. However, it was stated that concentration/time data is not sufficient
to determine bioequivalence. A need for clinical study was identified.
Action Item: EAC members to investigate the feasibility (sensitivity,
specificity) of a surrogate pharmacodynamic marker(s) to accurately measure
the site of GIT absorption for orally administered, topically acting drugs
(eg. 51Cr EDTA, mannitol, etc.)
Ø Conflict of Interest and Indemnification with respect to
Expert Advisory Committees
A brief presentation was made by J. Northey, Counsel from Department
of Justice Canada to ensure that the members have a common understanding
of legal issues associated with Health Canada Expert Advisory Committees
(EAC). The presentation touched on Indemnification, Conflict of Interest
and Access to Information Policy.
Discussion during and after the presentation centered around "care
and control" of confidential documents and member's personal notes.
The members requested more information on this subject.
Action: HC to research this issue and send the members an information
package on the matter.
Ø Adjournment of Day 1
The Chair discussed the schedule for tomorrow and set mutually agreeable
times for certain issues which were not completed in the time frame allowed
to be revisited on Day 2.
Meeting adjourned until March 23, 2001, 8:30 am. Welcome and review of
Agenda for Day 2
The timetable was adjusted to allow for the early departure of some members.
For continuity and ease of flow of information, all material discussed
on one agenda item will be reported under the one heading in these minutes,
even if the topic was discussed on both days.
Ø Narrow Therapeutic Range (NTR) Drugs
A presentation of the issue was made by C. Pereira (DBE) and the following
questions were posed to the committee for deliberation:
-
For regulatory purposes, is it necessary to have a NTR category
of drugs/products to which more stringent bioequivalence requirements
will apply? Or are current bioequivalence requirements for 'uncomplicated'
drugs (90% CI for AUCt and relative mean Cmax between 80 to 125%)
adequate for all drugs/products for which in vivo demonstration of
bioequivalence is required?
[The following questions assume that the recommendation on the above
question is that it is necessary to have a 'NTR' category of
drugs.]
-
What is the definition of 'NTR'? And should some other
drugs be included in this group such as some which may undergo therapeutic
drug monitoring (TDM) but which don't fit the definition of NTR drugs
in terms of defined effective and toxic concentrations?
-
What bioequivalence standards should be applied to NTR drugs?
At present, the standard applied is based on 95% CI for both AUCt
and Cmax between 80 to 125% potency-corrected and un-corrected, in
single-dose cross-over studies under both fasted and fed condition.
Various suggestions have been made, including narrowing the CI (e.g.
90 to 112%).
-
Should studies under both fasting and fed conditions be required,
or is one condition sufficient? At the present time, bioequivalence
standards must be met under both fasting and fed conditions for drugs
deemed to have a NTR. Also, should the same bioequivalence standards
be applied to studies under fed conditions as to studies under fasted
conditions?
- Under what (if any) conditions should studies under steady-state
conditions be required? If such studies are required, what bioequivalence
standards should be applied?
The EAC members formulated the following answers to the five questions
on this issue:
-
Conceptually, some drugs may be categorized as "critical
drugs"; such drugs require stringent bioequivalence requirements.
-
"Critical drugs" can generally be defined as those where:
Comparatively small differences in dose or concentration lead
to serious therapeutic failures and/or adverse drug reactions which
may be persistent, irreversible, slowly reversible, or life threatening
events.
-
For "critical drugs", goal-posts must be narrowed.
-
For "critical drugs", both fasting and fed studies are
necessary. Bioequivalence criteria need to be the same for fasted
and fed conditions:
Fasted
AUCt 90% CI within 90 to 112%
Cmax 90% CI within 80 to 125%
Fed
AUCt 90% CI within 90 to 112%
Cmax 90% CI within 80 to 125%
- Steady state studies are not required for "critical drugs"
unless warranted by exceptional circumstances.
Further consultation with the EAC may be necessary to refine the definition/description
of the "critical" category of drugs to which the more stringent
bioequivalence standards will apply. Further guidance will also be sought
with respect to compiling a list of drugs to which these standards will
apply.
Action Item: EAC Members to compile criteria and listings
of probable drugs to include in this category to be brought forward for
discussion at the next EAC meeting.
Ø Future Agenda Item Proposals
N. Pound (DBE) gave a short presentation outlining some issues that the
Therapeutic Products Programme (TPP) is currently addressing. Topics from
this list may serve as agenda items at upcoming EAC meetings.
Report C - drugs with complicated kinetics (7 categories)
NTR Drugs
- Non-linear kinetics
- Highly toxic
- Long half-life
- Multiple active ingredients
- Pharmacodynamic studies
- Critical time onset or rate of absorption
- Locally topically acting oral drugs
- Exclusion of inadequate profiles
- Topical products for Dermatological, Ophthalmic, Otic and Nasal use
- Nasal solutions for systemic action
- Fed and fasted studies
- International Committee on Harmonization (ICH) Common Technical Document
- Exclusion of "Extreme" values
- Bioanalytical method validation
- In vivo - In vitro / Correlation
- In vitro bioequivalence
- Canadian Reference Standard
Ø Scheduling of next meeting and adjournment of meeting
The Chair thanked all expert members, HC representatives from different
Bureaux, and the Coordinator and Secretariate for the Committee for their
time and participation. A tentative date of October, 2001 was proposed
for the next meeting, the exact date to be determined.
Meeting adjourned.
Next meeting: November 15 & 16, 2001
Prepared by: M. Davis
*Abbreviations for Health Canada Bureaux/Divisions:
BBR = Bureau of Biologics and Radiopharmaceuticals
BLPA = Bureau of Licensed Product Assessment
BPA = Bureau of Pharmaceutical Assessment
BPC = Bureau of Policy and Coordination
DBE = Division of Biopharmaceutics Evaluation (BPA)
DG = Director General
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