U.S. patent application number 12/376697 was filed with the patent office on 2011-07-28 for method for distribution of a drug.
Invention is credited to Carmen Bozic, Jeffrey K. Francer, Erika M. Gill, Anissa Kalinowski.
Application Number | 20110184747 12/376697 |
Document ID | / |
Family ID | 39082959 |
Filed Date | 2011-07-28 |
United States Patent
Application |
20110184747 |
Kind Code |
A1 |
Bozic; Carmen ; et
al. |
July 28, 2011 |
METHOD FOR DISTRIBUTION OF A DRUG
Abstract
A method of providing an anti-VLA-4 antibody to a patient.
Inventors: |
Bozic; Carmen; (Newton,
MA) ; Gill; Erika M.; (Arlington, MA) ;
Kalinowski; Anissa; (San Francisco, CA) ; Francer;
Jeffrey K.; (Washington, DC) |
Family ID: |
39082959 |
Appl. No.: |
12/376697 |
Filed: |
August 9, 2007 |
PCT Filed: |
August 9, 2007 |
PCT NO: |
PCT/US07/75577 |
371 Date: |
March 17, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60836530 |
Aug 9, 2006 |
|
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Current U.S.
Class: |
705/2 |
Current CPC
Class: |
Y02A 90/10 20180101;
G16H 10/20 20180101; G16H 20/10 20180101; G06Q 10/083 20130101 |
Class at
Publication: |
705/2 |
International
Class: |
G06Q 50/00 20060101
G06Q050/00; G06Q 10/00 20060101 G06Q010/00 |
Claims
1. A method of providing an anti-VLA-4 antibody to a patient having
relapsing MS comprising: (1) collecting patient and prescriber
information; (2) reviewing said information or enrollment form,
entering information into a record system, and generating an
authorization; (3) communicating the authorization generated in (2)
to a treatment site; and (4) conducting a treatment site review of
a patient including i. determining if the treatment site has a
current authorization for treatment of the patient; ii. confirming
that the treatment site does not have notice that the patient is no
longer authorized iii. providing the patient with information about
the drug; iv. asking the patient if symptoms have worsened; v.
asking the patient if he/she has a contraindicated medical
condition; and vi. asking the patient if he/she has taken a
contraindicated medication; wherein an answer of no to iv, v, and
vi allows administration of the drug to the patient and an answer
of yes to one of iv, v, or vi requires prescriber override to
administer the drug.
2. The method of claim 1, further comprising: (5) upon expiration
of an authorization, obtaining reauthorization for subsequent
treatment prior to subsequent treatment, wherein reauthorization
requires certification by the prescriber that (a) the patient still
under his/her care; (b) the patient is alive; (c) the patient has
had no unwanted side effect of the drug, no contraindicated
condition, or no contraindicated treatment that the prescriber has
not already reported to the central administrator, provided that if
the prescriber reauthorizes the patient must still undergo the
review in step (4) prior to receiving the drug.
3. The method of claim 1, wherein prior to each shipment of the
drug, a distributor of the drug obtains a shipment authorization
from the central administrator.
4. The method of claim 1, wherein said drug is shipped only to and
administered only at authorized treatment sites.
5. The method of claim 1, wherein central pharmacies that dispense
the drug to authorized treatment sites are enrolled in a tracking
system.
6. The method of claim 1, wherein the central administrator
systematically follows and actively solicits information on every
patient that receives the drug regarding any adverse events.
7. The method of claim 1, further comprising administering said
anti-VLA4 antibody.
8. The method of claim 1, wherein said anti-VLA4 antibody is
natalizumab.
9. The method of claim 1, wherein the method is applied to at least
500 patients.
10. A system configured to allow the practice of the method of
claim 1 comprising: instructions for carrying out the method of
claim 1; a user interface for inputting a query; and a processor
for generating a query result.
11. The system of claim 10, wherein the method carried out by the
system further comprises the following step: (5) upon expiration of
an authorization obtaining reauthorization for subsequent treatment
prior to subsequent treatment, wherein reauthorization requires
certification by the prescriber that (a) the patient still under
his/her care; (b) the patient is alive; (c) the patient has had no
unwanted side effect of the drug, no contraindicated condition, or
no contraindicated treatment that the prescriber has not already
reported to the central administrator, provided that if the
prescriber reauthorizes the patient must still undergo the review
in step (4) prior to receiving the drug.
12. The system of claim 10, wherein the method carried out by the
system further requires that prior to each shipment of the drug, a
distributor of the drug obtains a shipment authorization from the
central administrator.
13. The system of claim 10, wherein the method carried out by the
system further requires that said drug is shipped only to and
administered only at authorized treatment sites.
14. The system of claim 10, wherein the method carried out by the
system further requires that central pharmacies that dispense the
drug to authorized treatment sites are enrolled in a tracking
system.
15. The system of claim 10, wherein the method carried out by the
system further requires that the central administrator
systematically follows and actively solicits information on every
patient that receives the drug regarding any adverse events.
16. The system of claim 10, wherein said anti-VLA4 antibody is
natalizumab.
17. The system of claim 10, wherein said method is applied to at
least 500 patients.
18. A computer program product tangibly embodied in an information
carrier and comprising instructions that when executed by a
processor provide for performance of the method of claim 1.
19. A database which includes a record all of the forms and
information referred to in the method of claim 1 for a patient.
20. The database of claim 19, having records for at least 100
patients.
Description
[0001] The application claims priority to U.S. Provisional
Application No. 60/836,530, filed Aug. 9, 2006, which is hereby
incorporated by reference.
BACKGROUND
[0002] The invention relates generally to methods and systems for
drug distribution.
SUMMARY
[0003] The invention features methods and systems for distributing
or providing a therapy, e.g., a drug. The drug can be a VLA-4
blocking agent, e.g., an anti-VLA-4 antibody, e.g., TYSABRI.RTM.
(natalizumab) or an equivalent or similar antibody. Methods and
systems of the invention are particularly useful for drugs which
may weaken the immune system. The drug can be administered to treat
a patient for a disorder mediated by VLA-4. The drug can be used to
treat a patient having multiple sclerosis (MS), Crohn's disease, or
a fibrotic condition. In a preferred embodiment the patient has
relapsing MS. Methods and systems can include one or more of the
steps or elements described herein.
[0004] Accordingly, in one aspect, the invention features, a method
or system for providing a drug, e.g., an anti-VLA-4 antibody, to a
patient, e.g., an MS patient. The system or method includes:
[0005] (1) collecting patient and prescriber information, e.g., by
providing an enrollment form which includes patient and prescriber
information to a central administrator;
[0006] (2) reviewing the information, e.g., reviewing an enrollment
form which includes the information, entering the information into
a system (e.g., a computerized system of one or more computers
which can store data, allow data to be retrieved, generate
reminders, transmit information and the like), and generating an
authorization for treatment of the patient;
[0007] (3) communicating the authorization to a treatment site;
[0008] (4) conducting (or instructing or authorizing a party to
conduct) a treatment site review of a patient which includes
gathering medical information about the patient which information
is needed to allow administration of the drug, wherein said review
can include one or more of: [0009] i. determining if the treatment
site has a current authorization for treatment of the patient;
[0010] ii. confirming that the treatment site does not have notice
that the patient is no longer authorized [0011] iii. providing the
patient with information about the drug; [0012] iv. asking the
patient if symptoms have worsened; [0013] v. asking the patient if
he/she has a contraindicated medical condition; [0014] vi. asking
the patient if he/she has taken a contraindicated medication;
wherein an answer of no to iv, v, and vi (or a preselected subset
thereof) allows administration of the drug to the patient and an
answer of yes to one or more of iv, v, or vi requires the
prescriber (or the prescriber's designee) override in order for the
drug to be administered; and optionally
[0015] (5) upon expiration of an authorization obtaining
reauthorization for subsequent treatment prior to subsequent
treatment, wherein reauthorization can require certification by a
prescriber that the subject is qualified to be in the program,
e.g., by updating some or all of the information gathered in step
1, or by a prescriber certifying one or more of the following:
[0016] (a) the patient still under his/her care; [0017] (b) the
patient is alive; [0018] (c) the patient has had no unwanted side
effect of the drug, no contraindicated condition, or no
contraindicated treatment that the prescriber has not already
reported to the central administrator,
[0019] provided that if the prescriber reauthorizes the patient
must still undergo the review in step (4) prior to receiving the
drug.
[0020] In a preferred embodiment authorization is necessary but not
sufficient for allowing administration of the drug. In a preferred
embodiment authorization and satisfaction of treatment site review
are sufficient for administration. In a preferred embodiment
authorization and satisfaction of treatment site review are
necessary but not sufficient for administration.
[0021] In a preferred embodiment each shipment of the drug requires
that a distributor of the drug obtains a shipment authorization
from the central administrator.
[0022] In a preferred embodiment the drug is shipped only to and
administered only at authorized treatment sites.
[0023] In a preferred embodiment central pharmacies that dispense
the drug to authorized treatment sites are enrolled in a tracking
system.
[0024] In a preferred embodiment the central administrator
systematically follows and actively solicits information on every
patient that receives the drug regarding any adverse events.
[0025] In a preferred embodiment a system described herein
includes: a user interface for inputting a query; and a processor
for generating a query result.
[0026] In a preferred embodiment the method or system is applied to
at least 50, 100, 500, 1,000, or 10,000 patients.
[0027] The invention includes computers, databases, and
communication modules configured to implement the methods described
herein.
[0028] In another aspect, the invention features a method or system
for providing a drug, e.g., an anti-VLA-4 antibody to a patient,
e.g., an MS patient. The method or system includes one or more of
the following steps or elements:
[0029] (1) Enrollment of the patient and, optionally, the
prescriber in the system. In a preferred embodiment, once the
decision to prescribe is made, the prescriber and the patient
complete and, optionally, sign or acknowledge, an enrollment form
(forms, checklists and other documents referred to herein can
individually or collectively be any of electronic, digital, or
tangible, e.g., paper). The completed enrollment form is sent to
the central administrator.
[0030] (2) Review of the enrollment information. The central
administrator reviews the completed enrollment form, enters the
information from the form into the system (e.g., into a
computerized data base and generates an "authorization." The
authorization or approval can be, e.g., an electronic or paper
"form", e.g., an authorization form.
[0031] (3) Communicate information to the treatment center. The
authorization, and optionally other information, e.g., from the
authorization form generated in (2), is communicated to the
treatment site, e.g., an infusion site (as described herein) and to
the prescriber, e.g., by sending the authorization form to both by,
e.g., facsimile.
[0032] (4) Treatment site processing. When the patient arrives at
the treatment site, e.g., infusion site, a review is conducted.
Indication of the authorization, e.g., an authorization form
generated in (2), is necessary but not sufficient to allow
treatment. In addition to confirming possession of a current
authorization, the treatment site carries out a specific or
preselected procedure, in which the patient is screened for
eligibility to receive the drug. Thus, in addition to having a
current authorization for treatment, a number of issues are
resolved before the treatment site can treat the patient. An
exemplary treatment site review is as follows:
[0033] Before the treatment site can administer the drug, it must
check to see if the patient is currently authorized to receive the
drug. This can be done by the treatment site referring to the
patient's medical record and completing one or more, and preferably
all of, the following steps:
[0034] (a) If the patient did not receive his or her previous
infusion, and physician clearance was required, the treatment site
must confirm authorization from the prescriber before providing the
current treatment;
[0035] (b) Confirm that the treatment site has a current
"authorization" on file (if the information, e.g., an authorization
form, has been lost, the treatment site can contact the central
administer for a replacement form);
[0036] (c) Confirm that the treatment site does not have a notice
that the patient is no longer authorized, e.g., a Notice of
Discontinuation (described herein) or similar form, on file;
[0037] (d) Provide the patient with information about the drug,
e.g., provide a copy of a Patient Medication Guide (described
herein) or a similar guide or information;
[0038] (e) An investigation of one or more predetermined matters
must be made before treatment. These can include one or more of the
following inquiries: [0039] (i) Has the patient had worsening
symptoms? [0040] (ii) Does the patient have a contraindicated
medical condition, e.g., one that can weaken the immune system?
Examples are HIV infection or AIDS, leukemia or lymphoma, or an
organ transplant. [0041] (iii) Has the patient taken a
contraindicated medication? If the patient answers "no" to a
predetermined set of these inquiries, e.g., "no" to all of them,
treatment can proceed. If the patient answers "yes" (or does not
know the answer) to a preselected set, e.g., any one of these
inquiries, the patient cannot be treated without override by the
prescriber (or the prescriber's designee). In this case, the
prescriber must be contacted for further instructions. After the
treatment site discusses the findings with the patient's
prescriber, the prescriber can override and verbally instruct the
treatment site to treat the patient.
[0042] In a preferred embodiment, the treatment site is required to
send the central administrator notice that the procedure was
complied with. E.g., any authorization by the prescriber must be
documented.
[0043] In a preferred embodiment, step (4) includes substeps (b)
and (e).
[0044] (5) Reauthorization for treatment. The authorization lasts
for a maximum of a preselected period. At preselected intervals,
the central administrator will send the prescriber a status form,
e.g., a Patient Status Report and Reauthorization Questionnaire
described herein, or a similar form. This form must be completed
and entered into the system for further treatment to occur.
Exemplary questions on the status form can include, e.g., one or
more of: [0045] (a) Is the patient still under your care? [0046]
(b) Is the patient alive? [0047] (c) Does the patient have an
unwanted side effect of the drug, a contraindicated condition, or a
contraindicated treatment that you have not already reported to the
central administrator? The prescriber must provide answers to these
questions and recommend reauthorization for the treatment to
continue. If reauthorization is given, the patient would then show
up at the treatment site for his/her next treatment and be put
through the Treatment Site Processing described in step (4)
above.
[0048] (6) Controlled distribution system of the drug. Prior to
each shipment of the drug, a distributor obtains a shipment
authorization from the central administrator. The drug is shipped
only to authorized treatment sites, e.g., infusion sites,
designated by the central administrator.
[0049] (7) Training of treatment sites. The drug is shipped only to
and administered only at authorized treatment sites, e.g., infusion
sites. Authorized treatment sites are sites that have been trained
by the central administrator, e.g., employees of the central
administrator, on the known risks, potential benefits and
appropriate use of the drug, using educational materials. The
treatment sites must agree to comply with, e.g., one or more other
requirements described herein. For example, before treatment, the
treatment site will complete a checklist, e.g., a pre-treatment
checklist described herein, and return the completed checklist to
the central administrator, e.g., by mail, facsimile or computer.
The central administrator then enters information from the
checklist into the system.
[0050] (8) Enrollment of central pharmacy. Central pharmacies that
dispense the drug to authorized treatment sites are enrolled in a
tracking system described herein. Central pharmacies complete an
enrollment form, which is returned to the central administrator.
The central administrator enters information from the enrollment
form into the system, which generates an authorization for the
central pharmacy, which includes, e.g., an authorization number and
affiliated authorized treatment sites.
[0051] (9) Tracking system. The central administrator
systematically follows and actively solicits information on every
patient that receives the drug regarding any adverse events, e.g.,
any adverse event described herein. In some embodiments, the
central administrator will send a status form to every prescriber
for every patient regularly, e.g., every 2, 4, 6, 8, 10 or 12
months. The central administrator will use the status forms to
ascertain the vital status of the patient and the occurrence of
adverse events and for the prescriber to reauthorize the patient to
continue to receive the drug, e.g., for the next 6 months. The
central administrator will enter the data from the status forms
into the database whenever the central administrator receives a
status form.
[0052] In a preferred embodiment a system described herein
includes: a user interface for inputting a query; and a processor
for generating a query result.
[0053] In a preferred embodiment the method or system is applied to
at least 50, 100, 500, 1,000, or 10,000 patients.
[0054] In another aspect, the invention features, a database useful
in a method of system described herein, e.g., a database containing
one or more of the forms or elements of information described
herein, for each of a plurality of patients.
[0055] In a preferred embodiment the database is: disposed on
tangible medium; disposed on a single unit of tangible medium,
e.g., on a single computer, or in a single paper document; provided
on more than one unit of tangible medium, e.g., on more than one
computer, in more than a single paper document, partly on a paper
document and partly on computer readable medium; disposed on
computer readable medium; disposed on traditional medium, e.g.,
paper, which is readable by a human without the use of a computer,
e.g., a printed document, chart, table or card catalogue.
[0056] All patents, patent applications, and references are hereby
incorporated by reference in their entireties. In the case of
conflict, the present application controls.
[0057] The details of one or more embodiments of the invention are
set forth in the accompanying drawings and the description below.
Other features, objects, and advantages of the invention will be
apparent from the description and drawings, and from the
claims.
DESCRIPTION OF DRAWINGS
[0058] FIG. 1 is a schematic of a TYSABRI.RTM. drug distribution
process.
[0059] FIG. 2 is a schematic of a shipping authorization
process.
[0060] FIG. 3 is a schematic of an enrollment process for
prescribers and patients.
[0061] FIG. 4 is a schematic of an infusion site enrollment
process.
[0062] FIG. 5 is a schematic of a collection and tracking process
for Pre-infusion Patient Checklist data.
[0063] FIG. 6 is a schematic of a central pharmacy enrollment
process.
[0064] FIG. 7 is a schematic of a TYSABRI.RTM. Patient Status
Report and Reauthorization Questionnaire data collection
process.
[0065] FIG. 8 is a schematic of data collection in TOUCH
Prescribing Program.
[0066] FIG. 9 is a block diagram of computing devices and
systems.
DETAILED DESCRIPTION
[0067] Enrollment
[0068] In a preferred embodiment, the method includes enrollment of
the patient and, optionally, the prescriber, in the system
(referred to above as step (1)).
[0069] This process can begin with the patient and/or prescriber
providing information, e.g., by filling out a form, e.g., a paper
or computerized form, e.g., a patient and prescriber form, e.g.,
the Prescriber/Patient Enrollment Form described herein. Examples
of the information collected and of forms that can be used to
collect the information are provided herein.
[0070] The patient and prescriber form can be supplied by the
central administrator and is transmitted, e.g., by mail or computer
network, to the prescriber. Both the prescriber and the patient
review the form and optionally indicate assent or agreement by
signing it (signing can be by traditional indication or
electronically). Once the decision to prescribe is made, the
prescriber and patient will complete and sign the form. After
execution by the patient and the prescriber, the completed form is
returned to the central administrator, e.g., by facsimile, computer
or mail. Submission of the completed form to the central
administrator registers the patient and the prescriber in the
system.
[0071] In a preferred embodiment, the patient, e.g., an MS patient,
attests to one or more conditions set out herein. For example, the
patient attests to one or more of the following: [0072] that he/she
understands that the drug, e.g., an anti-VLA-4 antibody, e.g.,
TYSABRI.RTM., is approved for, or only for, a specific condition,
e.g., relapsing forms of multiple sclerosis (MS); [0073] that
he/she has read a document that provides preselected information on
the drug, e.g., the anti-VLA-4 antibody, e.g., TYSABRI.RTM. (an
example is the Patient Medication Guide for TYSABRI.RTM. described
herein); [0074] that he/she is aware that the drug, e.g., the
anti-VLA-4 antibody, e.g., TYSABRI.RTM., is associated with a
preselected risk, e.g., an increased risk of progressive multifocal
leukoencephalopathy (PML), which results in an undesirable outcome,
e.g., that usually causes disability and/or death and that is
untreatable; [0075] that he/she has discussed the risks and
benefits of the drug, e.g., the anti-VLA-4 antibody, e.g.,
TYSABRI.RTM., with his/her physician; [0076] that he/she
understands that he/she should call his/her physician promptly to
report any continuously worsening symptoms, e.g., those lasting
over several days; [0077] that he/she understands that in order to
receive the drug, e.g., the anti-VLA-4 antibody, e.g.,
TYSABRI.RTM., he/she will automatically be enrolled in a registry;
[0078] that he/she understands that the patient information
described herein may be provided treatment sites, e.g., infusion
sites, other administration sites, or pharmacies involved in
his/her treatment; [0079] that he/she understands that if he/she
does not complete or sign this form, he/she will not be able to
receive the drug, e.g., the anti-VLA-4 antibody, e.g.,
TYSABRI.RTM.; and [0080] that he/she agrees to bring to each
treatment, e.g., TYSABRI.RTM. treatment, a list of all medications
he/she has taken during the last month.
[0081] In a preferred embodiment, the prescriber attests to one or
more conditions set out herein. For example, the prescriber attests
to one or more of the following: [0082] that he/she will provide
the patient, e.g., an MS patient, with information about the drug,
e.g., the Patient Medication Guide for TYSABRI.RTM. (described
herein), will require the patient to read it and will discuss the
known risks and potential benefits of the drug, e.g., the
anti-VLA-4 antibody, e.g., TYSABRI.RTM., with the patient; [0083]
that he/she has read the full prescribing information for the drug,
e.g., the anti-VLA-4 antibody, e.g., TYSABRI.RTM.; [0084] that
he/she is aware that the drug, e.g., the anti-VLA-4 antibody, e.g.,
TYSABRI.RTM., increases the risk of a preselected disorder, e.g.,
in the case of TYSABRI.RTM., that TYSABRI.RTM. increases the risk
of PML, which usually causes disability and/or death and that is
untreatable; [0085] that he/she understands that the drug, e.g.,
the anti-VLA-4 antibody, e.g., TYSABRI.RTM., is indicated for a
preselected purpose, e.g., in the case of TYSABRI.RTM., it is
indicated as a monotherapy for relapsing forms of MS; [0086] that
he/she will promptly report any case of the preselected disorder to
the central administrator, e.g., in the case of TYSABRI.RTM.
treatment, will report any case of PML to the central
administrator; [0087] that he/she has discussed the risks and
benefits of the drug, e.g., the anti-VLA-4 antibody, e.g.,
TYSABRI.RTM., and has discussed other therapies, with the patient;
[0088] that he/she has confirmed that the patient has the disorder,
e.g. a relapsing form of MS, using preselected criteria, e.g.,
clinical and radiological criteria; [0089] that he/she confirms
that the patient has no known contraindications to the drug, e.g.,
the anti-VLA-4 antibody, e.g., TYSABRI.RTM.; [0090] that he/she is
not TYSABRI.RTM., is not prescribing any antineoplastic,
immunosuppressant, or immunotherapies (other than short courses of
corticosteroids) concurrently with TYSABRI.RTM.; [0091] that he/she
has instructed the patient to promptly report to his/her prescriber
any continuously worsening symptoms that persist over several days;
[0092] that he/she agrees to provide any information relating to
this patient that may be necessary to assess the incidence of risk
factors for the preselected disorder (PML in the case of
TYSABRI.RTM.) and other adverse affects that may be associated with
the treatment; [0093] that he/she is able to diagnose and manage
the preselected disorder (opportunistic infections and PML in the
case of TYSABRI.RTM.), or is prepared to refer patients to
specialists with these abilities; [0094] that he/she agrees that
this patient should be seen and evaluated at a preselected time
after the first administration, periodically thereafter for as long
as the patient receives the drug, and for at least a preselected
number of months after the drug has been discontinued, e.g., in the
case of TYSABRI.RTM., agrees that this patient should be seen and
evaluated 3 months after the first treatment, 6 months after the
first treatment, at least 6 months thereafter for as long as the
patient receives TYSABRI.RTM., and for at least 6 months after
TYSABRI.RTM. has been discontinued; [0095] that he/she will
determine at a preselected interval whether this patient should
continue on the drug and, if so, authorize treatment for a
preselected period, e.g., in the case of TYSABRI.RTM. treatment,
will determine every 6 months whether this patient should continue
on TYSABRI.RTM. and if so, authorize treatment every 6 months; and
[0096] that he/she understands that the patient and the prescriber
will be automatically enrolled in the registry.
[0097] The form can include a prescription for the drug. E.g., in
the case of TYSABRI.RTM., the form can include a preprinted
TYSABRI.RTM. prescription (1 vial; 12 refills; dose 300 mg;
directions: IV infusion per Prescribing Information every 4 weeks).
The prescriber has the option of reducing the number of refills
and/or the frequency of dosing on the form. It is the TYSABRI.RTM.
Status Report and Reauthorization Process (described herein) that
controls on-going patient re-authorizations, not the number of
refills on the prescription.
[0098] The patient and prescriber form can also include one or more
of the following: baseline demographic information such as the
patient's name, contact information, age, gender, and social
security number; the prescriber's name; a diagnosis, e.g., in the
case of TYSABRI.RTM., a diagnosis of relapsing MS diagnosis; an
indication of the most recent prior therapy, e.g., in the case of
TYSABRI.RTM., the most recent prior MS therapy; and a summary of
prior exposure to the drug, e.g., TYSABRI.RTM..
[0099] Review of Enrollment
[0100] In a preferred embodiment, the method includes a review of
the patient and prescriber form and its entry into the system. This
also includes the generation of an "approval" (referred to as step
(2) above). E.g., upon receipt at the central administrator, the
patient and prescriber form is reviewed, information from it is
entered into a computer, and an "authorization form" and unique
patient identifier are generated. This is described in the section
below.
[0101] Upon receipt of the patient and prescriber form, the central
administrator assigns a case manager to the patient, e.g., an MS
patient. The central administrator confirms that the patient and
the prescriber have properly executed the patient and prescriber
form (and thereby attested to the items described above). After
such confirmation, a data entry person enters information from
specific fields on the patient and prescriber form into
corresponding fields in a record in the computer. Entry of the
correct response into a field is required--if such entry does not
occur, the computer will not allow passage to the next field or
phase of completion. The case manager may assist the data entry
person in this phase. The case manager also matches the patient to
a treatment site, e.g., an infusion site (this assignment is based
on patient preference and insurance considerations but is not based
on any medical consideration or judgment) and confirms that the
treatment site is authorized. The computer generates a unique
patient enrollment number for the patient. This number remains the
same for the patient, even if the patient de-enrolls and
subsequently re-enrolls into the program.
[0102] A computer record is started for every patient and
prescriber form received by the central administrator, even though
some patient and prescriber forms may be defective in some way and
will not serve to make the patient eligible to receive drug and
will not result in the generation of an authorization form, e.g., a
Notice of Patient Authorization Form described herein.
[0103] The patient and prescriber form may be defective because it
lacks a relevant entry, e.g., the signature by the prescriber or
patient, or because it includes additional information not
requested by the queries on the patient and prescriber form.
[0104] The computer generates an authorization, e.g., the
authorization form, e.g., the Notice of Patient Authorization Form,
if, and only if, all fields on the patient and prescriber form are
correctly completed (thus for each field on the patient and
prescriber form, the relevant information must be entered into the
corresponding "field" in the computer). As discussed above, if a
field is not correctly filled out in the computer, the computer
will not generate an authorization form, e.g., a Notice of Patient
Authorization Form. In this event, the central administrator will
notify the prescriber and request a completed patient and
prescriber form. The new patient and prescriber form will serve to
reinitiate the procedure from the beginning.
[0105] The data entry person will follow a
standard-operating-procedure for dealing with patient and
prescriber forms that include information other than that called
for by the patient and prescriber form (e.g., the form includes
handwritten or other attached information), referred to herein as
"annotated patient and prescriber forms." No approval will be
generated for an annotated patient and prescriber form; rather, the
prescriber will be contacted and asked that a new properly
completed patient and prescriber form be filled out and sent to the
central administrator. The new patient and prescriber form will
serve to reinitiate the procedure from the beginning.
[0106] When all data fields are entered successfully, the computer
generates an authorization, e.g., a Notice of Patient Authorization
Form. The authorization form can include a computer-generated
patient enrollment number.
[0107] The computer will include records that correspond to: [0108]
(a) completed patient and prescriber forms; [0109] (b) completed
patient and prescriber forms where the patient has decided not to
go forward with treatment; and [0110] (c) incomplete, annotated or
incorrectly answered patient and prescriber forms.
[0111] Records in category (c) will not result in the generation of
an authorization form, e.g., a Notice of Patient Authorization
Form.
[0112] In the event that the patient changes prescribers, the
patient and new prescriber will be required to complete a new
patient and prescriber form. The central administrator will inform
the treatment site of the change in prescriber. If the patient does
not inform the central administrator of such a change, this will be
detected in a status form, e.g., the TYSABRI.RTM. Patient Status
Report and Reauthorization Questionnaire described herein.
[0113] In the event that the patient changes treatment sites, the
central administrator will send an, authorization form to the new
treatment site and a discontinuation notice, e.g., a Notice of
Discontinuation Form described herein, to the old treatment site.
If the patient does not inform the central administrator of such a
change, this will be detected by the central administrator when the
new treatment site contacts, e.g., by telephone, the central
administrator for approval, e.g., an authorization form, e.g., a
Notice of Patient Authorization. The central administrator will
update the treatment site data for the patient in the database and
will provide an authorization form to the new treatment site.
[0114] If a prescriber indicates that a patient is lost to follow
up, the central administrator will attempt to contact the patient.
If contact is successful and the patient wishes to continue
treatment, the patient and the new prescriber must complete a new
patient and prescriber form. Otherwise, the central administrator
will communicate to the prescriber and to the treatment site that
the patient is de-enrolled.
[0115] If a patient re-enrolls, the patient and prescriber must
submit a new patient and prescriber form.
[0116] The Treatment Site
[0117] Treatment site processing (referred to as step (4) above) is
a critical step in many embodiments of the invention. As will be
clear from the following discussion, the patient enrollment number
found on the authorization form is necessary but not sufficient to
allow treatment. In addition to confirming possession of a current
authorization form and a patient enrollment number, the treatment
site must carry out a specific procedure, in which a number of
issues must be resolved before the treatment site can treat, e.g.,
treat the patient for MS. These steps are described below. One or
more of the following steps can be performed. [0118] The treatment
site must confirm enrollment
[0119] Before the treatment site can administer the drug, it must
check to see if the patient is currently authorized to receive the
drug, e.g., the anti-VLA-4 antibody, e.g., TYSABRI.RTM.. This is
performed by the treatment site's referring to the patient's
medical record and completing the following steps: [0120] (a) If
the patient did not receive his/her previous treatment, and
prescriber clearance was required, the treatment site must confirm
authorization from the prescriber before providing the current
treatment; [0121] (b) Confirm that it has a current authorization
for the patient on file (in the case of TYSABRI.RTM., this is a
form which states that the authorization period is 6 months from
the first confirmed treatment). If the authorization form has been
lost, the treatment site can contact, e.g., by telephone, the
central administrator for a replacement authorization form); and
[0122] (c) Confirm that it does not have a discontinuation notice
on file. (If the central administrator learns that a patient is
de-enrolled from a status form, e.g., the TYSABRI.RTM. Patient
Status Report and Reauthorization Questionnaire described herein,
or otherwise from the patient, the central administrator sends,
e.g., by facsimile, a discontinuation notice to the treatment site.
The same information is also telephoned by the central
administrator to the treatment site). [0123] The treatment site
must provide information about the drug
[0124] The treatment site must provide the patient with information
about the drug, e.g., written information, e.g., the Patient
Medication Guide for TYSABRI.RTM. described herein. [0125] The
treatment site must conduct predetermined investigations prior to
treatment, e.g., the investigations specified on a checklist, e.g.,
the Pre-infusion Checklist described herein. The checklist requires
the treatment site ask the following questions of the patient:
[0126] i. Over the past month, have you had any new or worsening
medical problems (such as a new or sudden change in your thinking,
eyesight, balance, strength or other problems) that have persisted
over several days? [0127] ii. Do you have a medical condition that
can weaken your immune system, such as HIV infection or AIDS,
leukemia or lymphoma, or an organ transplant, that may suggest that
you body is not able to fight infections well? [0128] iii. In the
past month, have you taken medicines to treat cancer or MS or any
other medicines that weaken you immune system? (A list on the
reverse side of the checklist is reviewed with the patient.) [0129]
iv. In the past month, other than the treatment of a recent
relapse, have you taken any of the following medicines:
Solu-Medrol.RTM., methylprednisolone, Decadron.RTM., desamethasone,
Depo-Medrol.RTM., prednisone, or other steroid medicines?
[0130] The patient must answer "Yes" or "No" to each of these
questions. Based on the answers there are three possible outcomes:
treatment, no treatment or treatment by prescriber "override".
[0131] Treatment proceeds [0132] If the patent answers "No" to
questions 1, 2, 3 and 4 the patient can be treated. [0133] No
treatment or treatment by prescriber "override" [0134] If the
patent answers "Yes" (or does not know the answer) to any of 1, 2,
3, or 4 the patient cannot be treated without override by the
prescriber (or the prescriber's designee). If the answer to any of
these questions is "Yes", the prescriber must be contacted for
further instructions. After the treatment site discusses the
findings with the patient's prescriber, the prescriber can override
and verbally instruct the treatment site to infuse.
[0135] The treatment site is required to send the central
administrator a copy of the completed checklist, e.g., the
Pre-infusion Checklist described herein. Any authorization by the
prescriber must be documented. This will let the central
administrator know if the patient was treated. The checklist will
go into the database and be part of the patient's record in the
database. In some embodiments, the checklist can be computerized,
e.g., web-based, for electronic transmission to or electronic
access by the central administrator.
[0136] If a treatment site does not comply with these requirements,
the central administrator will send a warning letter to the
treatment site. In the event of continuing non-compliance, the
central administrator will de-list the treatment site and move the
patients elsewhere.
[0137] Reauthorization
[0138] In a preferred embodiment, the method includes
reauthorization for continued treatment, e.g., treatment of MS. For
example, the approval provided by the authorization form can last
for a maximum of six months. At six month intervals, the central
administrator will send, e.g., by facsimile, the prescriber a
status form, e.g., the TYSABRI.RTM. Patient Status Report and
Reauthorization Questionnaire described herein.
[0139] The prescriber is expected to complete the status form and
to return it to the central administrator, e.g., by mail or
facsimile. The information from the completed status form will be
entered into the computer. In some embodiments, the status form can
be computerized, e.g., web-based, for electronic transmission to or
electronic access by the central administrator. If the prescriber
does not make a timely reply, the central administrator will send
two facsimiles and make multiple telephone calls to the treatment
site.
[0140] The status form, e.g., the TYSABRI.RTM. Patient Status
Report and Reauthorization Questionnaire, will ask the following:
[0141] A. Is the patient still under your care? [0142] B. Is the
patient alive? [0143] C. Does the patient have a preselected
disorder, e.g., PML, that you have not already reported to the
central administrator? [0144] D. Has the patient been hospitalized
for a contraindicated condition, e.g., an opportunistic infection
that you have not already reported to the central administrator?
[0145] E. Is the patient currently receiving or has the patient
received contraindicated treatment, e.g., intermittent steroids for
the treatment of MS relapse within the last 6 months? (If "Yes",
how many steroid treatments?) [0146] F. Is the patient currently
receiving or has the patient received any immunomodulatory or
immunosuppressant products in the previous 6 months? (If "Yes",
indicate the specific drug and the number of uses.) [0147] G. Do
you reauthorize treatment for the next 6 months?
[0148] If the answer to Question A is "No", the central
administrator will send a new patient and prescriber form or will
initiate the steps to discontinue the patient from treatment.
[0149] If the answer to Question C or D is "Yes" or "Under
investigation", the central administrator will contact the
prescriber to obtain information
[0150] If the answer to Question G is "No", the central
administrator will contact, e.g., by telephone, the treatment site,
the patient, and the prescriber and make sure they know the patient
is de-enrolled. The central administrator will also send a
discontinuation notice, e.g., a Discontinuation Notification Form
described herein, to the treatment site, the patient and the
prescriber.
[0151] If the answer to Question G is "Yes", and the answers to
Questions C and D are "No", the central administrator will send a
new authorization form to the patient, the prescriber and treatment
site. The patient would then show up at the treatment site for
his/her next treatment and be put through the treatment site
process described in step (4) above.
[0152] Controlled Distribution System
[0153] In a preferred embodiment, the method includes a controlled
distribution system for the drug, e.g., TYSABRI.RTM. (referred to
as step (6) above) to treat MS. Under the controlled distribution
system, distributors and pharmacies (e.g., specialty and central
pharmacies described herein) will each be associated with
authorized treatment sites. The distributors will sell the drug,
e.g., the anti-VLA-4 antibody, e.g., TYSABRI.RTM., to customers,
but will ship the drug only to authorized pharmacies (e.g.,
specialty and central pharmacies) or treatment sites. The
distributors or specialty pharmacies will ship the drug, e.g., the
anti-VLA-4 antibody, e.g., TYSABRI.RTM., only to authorized
treatment sites or their affiliated central pharmacy designated by
the central administrator. The distributors or specialty pharmacies
must obtain shipment authorization, e.g., a shipment authorization
code, from the central administrator prior to each shipment.
[0154] In a preferred embodiment, the method includes only a single
distributor.
[0155] In a preferred embodiment, the treatment site receives drug
from one the following:
[0156] 1. Directly from a distributor, which first obtains a
shipment authorization from the central administrator, which then
delivers the drug from its warehouse to the treatment site;
[0157] 2. From a central pharmacy (described herein), which would
obtain the drug from a distributor. The distributor first obtains a
shipment authorization from the central administrator and then
delivers the drug from its warehouse to the central pharmacy. The
central pharmacy then dispenses the drug directly to the authorized
treatment site; or
[0158] 3. From a specialty pharmacy (described herein), which would
obtain the drug from a distributor. The distributor first obtains a
shipment authorization from the central administrator and then
delivers the drug from its warehouse to the specialty pharmacy. The
specialty pharmacy would then obtain a shipment authorization from
the central administrator to dispense the drug to the treatment
site.
[0159] Treatment Site Training
[0160] In a preferred embodiment, the method includes training of
the treatment site, e.g., by the central administrator, relevant to
the treatment of MS with the drug. Prior to treatment site
authorization, the central administrator will provide training,
e.g., on the known risks, potential benefits, and appropriate use
of the drug, e.g., the anti-VLA-4 antibody, e.g., TYSABRI.RTM.. The
central administrator can use training materials, e.g., educational
materials on the drug and/or its administration. The central
administrator will instruct the treatment sites to report adverse
events to the central administrator. In preferred embodiments, the
treatment sites will be required to distribute information about
the drug, e.g., the TYSABRI.RTM. Medication Guide described herein,
and to conduct one or more of a predetermined set of queries prior
to treatment, e.g., to complete a pre-treatment checklist, e.g., a
Pre-infusion Patient Checklist described herein. The treatment site
will then send, e.g., by mail, facsimile, or computer, the
completed pre-treatment checklist to the central administrator,
e.g., within 4, 8, 12, 24, 48, or 72 hours of the patient's visit,
regardless of whether the drug was administered.
[0161] In some embodiments, the central administrator enters into
the computer database information from the checklist, and the
information will be linked to the patient, treatment site and
prescriber data in the database. The central administrator will
contact the treatment site, e.g., by telephone, to follow-up on
incomplete or illegible checklists. If a treatment site does not
comply with these requirements, the central administrator will send
a warning letter to the treatment site. In the event of continuing
non-compliance, the central administrator will de-list the
treatment site and move the patients elsewhere, e.g., to another
treatment site.
[0162] Central Pharmacies
[0163] In some embodiments, the method includes enrollment of
central pharmacies (referred to as step (8) above). As described
herein, central pharmacies are located within, e.g., a hospital,
group practice or treatment site, and are affiliated with a
treatment site. Central pharmacies store drug inventory and release
it to a treatment site locally.
[0164] The central administrator will provide training to central
pharmacies by providing educational materials, e.g., on the
distribution system and inventory. The central pharmacy will
complete an enrollment form, e.g., the Central Pharmacy Enrollment
Form described herein, and return it to the central administrator.
The central administrator will enter the information from the
enrollment form into the computer database, at which time an
authorization number, e.g., a site authorization number described
herein, is assigned to the central pharmacy. The central
administrator will send, e.g., by facsimile or computer, an
authorization, e.g., a site authorization form, e.g., a Site
Authorization Confirmation described herein, to the central
pharmacy. The site authorization form includes an authorization
number and a list of affiliated authorized treatment sites.
[0165] Tracking
[0166] In some embodiments, the method provides for systematic
tracking of all drug-treated patients. The central administrator
will systematically follow and actively solicit information
regarding the occurrence of any adverse event (e.g., PML and other
serious opportunistic infections in the case of TYSABRI.RTM.)
through a variety of mechanisms on every drug-treated patient in
the US. For example: [0167] Through periodic collection, e.g.,
weekly, monthly, or semi-annually, of pre-treatment checklists
described herein, the central administrator will track drug dosing
on an up-to-date, individual patient basis. [0168] On the mandatory
patient and prescriber form described herein, prescribers must
attest to report to the central administrator any case of an
adverse event (in the case of TYSABRI.RTM., PML, other serious OI,
or death). [0169] On the mandatory patient and prescriber form,
patients must attest that they will report to their prescriber any
new or worsening symptoms that last several days, especially
nervous symptoms. The drug information, e.g., the TYSABRI.RTM.
Medication Guide, also provides these instructions to the patient.
If the prescriber determines that the symptoms are related to PML
(in the case of TYSABRI.RTM.), then the prescriber is obligated to
report the case to the central administrator. [0170] For additional
diligence, the central administrator will actively query
prescribers, e.g., every 1 month, e.g., every 2, 3, 4, 5, 6, 8, 10
or 12 months, on each of their patients regarding the occurrence of
an adverse event (in the case of TYSABRI.RTM., PML, other serious
OI, or death) using a status form, e.g., the TYSABRI.RTM. Patient
Status Report and Reauthorization Questionnaire described herein.
If a patient discontinues treatment, the central administrator will
actively follow-up on the status of such a patient.
[0171] In some embodiments, the central administrator will send a
status form, e.g., a TYSABRI.RTM. Patient Status Report and
Reauthorization Questionnaire, to every prescriber for every
patient regularly, e.g., every 2, 4, 6, 8, 10 or 12 months. The
central administrator will use the status forms to ascertain the
vital status of the patient and the occurrence of adverse events
(e.g., PML or other serious OI in the case of TYSABRI.RTM.), and
for the prescriber to reauthorize the patient to continue to
receive the drug, e.g., for the next 6 months. For example,
prescribers will be asked whether the patient is still under their
care, whether the patient is alive, whether the patient has a
diagnosis of PML or has been hospitalized for an opportunistic
infection. In addition, the status form will ask whether the
patient is receiving or has received within, e.g., the last 6
months any immunomodulatory or immunosuppressant therapies, whether
the patient is currently or has received within, e.g., the last 6
months any systemic steroids, whether the patient has received
intermittent steroids within, e.g., the last 6 months, and whether
the prescriber is authorizing the continuation of drug treatment in
this patient, e.g., for the next 6 months. The central
administrator will send the status form to the prescriber, e.g.,
via facsimile, mail or computer, who will be expected to complete
and return it to the central administrator, e.g., by facsimile,
mail or computer. The central administrator will enter the data
from the status forms into the database whenever the central
administrator receives a status form.
[0172] The prescriber must reauthorize drug treatment for the
patient, e.g., every 6 months using the status form, e.g., the
TYSABRI.RTM. Patient Status Report and Reauthorization
Questionnaire. All data fields on the status form must be completed
and the answers appropriate. In addition, the prescriber must
authorize the continuation of the drug in order for the patient to
continue to receive drug treatment.
[0173] An appropriately completed status form is a requirement for
the patient to continue to receive drug treatment. In order for the
prescriber to be able to complete this status form, the central
administrator expects that the prescriber will have recently
examined the patient. By requiring reauthorization for drug use
through the use of this status form, the central administrator
helps to facilitate close clinical follow-up of the patient by
his/her prescriber, including patient-prescriber visits, e.g.,
every 6 months. Upon reauthorization, an authorization form, e.g.,
a Notice of Patient Authorization described herein, will be sent to
the prescriber and the treatment site with the new patient
authorization period. Treatment site personnel will confirm that
the patient is currently authorized prior to every treatment.
[0174] In a preferred embodiment, the central administrator will
follow steps to determine whether a patient may have discontinued
drug treatment. These include: [0175] A prescriber may complete
send to the central administrator, e.g., by facsimile or computer,
a form to discontinue the patient. [0176] Through monthly
collection of pre-treatment checklists, e.g., Pre-Infusion Patient
Checklists, the central administrator will track drug dosing on an
individual patient basis. By diligently following-up on any missing
pre-treatment checklists, the central administrator will identify
any patient who has discontinued drug treatment. [0177] The central
administrator will identify patient discontinuations through the
status form, e.g., the TYSABRI.RTM. Patient Status Report and
Reauthorization Questionnaire (e.g., if the prescriber does not
authorize the continuation of drug treatment). [0178] The central
administrator may also confirm patient discontinuations through
spontaneous reporting by the patient, prescriber, or treatment
site.
EXAMPLES
Example 1
Controlled Distribution of TYSABRI.RTM. for Relapsing MS
[0179] The following example describes a plan for the controlled
distribution of TYSABRI.RTM. by Biogen Idec. Although the plan
refers to Biogen Idec as the central administrator, it is
applicable to any central administrator. Although the plan refers
to TYSABRI.RTM., the plan can be adapted to other drugs. Although
the following plan includes many features, a plan may include all
or a subset of these features as needed for a particular
application.
1. Risk Management Plan Background
1.1 Overview
[0180] Biogen Idec (the Sponsor) has developed a comprehensive risk
management plan (RiskMAP), consisting of both risk assessment and a
risk minimization features. This document outlines the goals,
objectives, and processes of the revised TYSABRI.RTM. RiskMAP based
on discussions with the Agency and the recommendations of the
Peripheral and Central Nervous System Drugs Advisory Committee
(Advisory Committee). The TYSABRI.RTM. RiskMAP is designed to
promote informed risk-benefit decisions between prescribers and
patients regarding the use of TYSABRI.RTM. in relapsing multiple
sclerosis (MS), to minimize morbidity and mortality due to
progressive multifocal leukoencephalopathy (PML) through early
detection with clinical vigilance, and to minimize the risk of PML
by treating patients who are not immunocompromised and, consistent
with the Prescribing Information (PI), warning against concurrent
use with antineoplastics, immunosuppressants or immunomodulators,
such as beta-interferons or glatiramer acetate. In addition, the
plan seeks to determine the incidence and risk factors for PML and
other serious opportunistic infections (OI) in patients treated
with TYSABRI.RTM., as well as the overall safety of TYSABRI.RTM. in
the clinical practice setting.
[0181] This plan has been developed in collaboration with the FDA,
in consideration of FDA's Guidance Document on this topic, and in
consideration of the deliberations of the Advisory Committee. In
addition, the Sponsor sought extensive feedback from neurologists
to obtain their recommendations on how best to minimize the risk of
PML, and surveyed many neurologists, MS patients, infusion nurses,
infusion sites, and central pharmacies regarding the feasibility of
the plan. Biogen Idec has also developed a companion Quality Plan
that outlines the monitoring of systems and compliance data
generated by the RiskMAP.
[0182] The TOUCH (TYSABRI.RTM. Outreach: Unified Commitment to
Health) Prescribing Program (Table 1) features, among other things:
[0183] Mandatory enrollment of all prescribers and patients into
the TOUCH Prescribing Program, a registry that provides diligent
safety surveillance and systematic tracking of all patients [0184]
Mandatory training and enrollment of all infusion sites, and all
central pharmacies affiliated with authorized infusion sites, into
the TOUCH Prescribing Program. [0185] Controlled distribution
system for TYSABRI.RTM. so that TYSABRI.RTM. is delivered to and
administered only in authorized infusion sites [0186] Mandatory
completion of the Pre-Infusion Patient Checklist and distribution
of the Medication Guide to each patient prior to each monthly
TYSABRI.RTM. dose [0187] Real-time submission of Pre-Infusion
Patient Checklists to Biogen Idec to monitor infusion site
compliance and to track TYSABRI.RTM. dosing on a patient-specific
basis [0188] Mandatory prescriber re-authorization of TYSABRI.RTM.
dosing for each patient every 6 months [0189] At the heart of the
TOUCH Prescribing Program is an integrated, computerized, validated
database that captures enrollment, patient tracking, and drug
distribution data.
TABLE-US-00001 [0189] TABLE 1 TOUCH Program Elements ENROLLMENT
TRACKING Patients Pre-Infusion Patient Checklists Physicians
Patient Status Report and Infusion Sites Reauthorization
Questionnaires Central Pharmacies Patient Discontinuation
Questionnaires Single Distributor Follow-Up of Checklists and
.ltoreq.12 Specialty Pharmacies Questionnaires
[0190] The RiskMAP primarily seeks to minimize the risk of PML, a
rare, but serious, adverse event without creating unintended
consequences that may obstruct appropriate patient access to the
potential significant benefits of TYSABRI.RTM.. Once implemented,
Biogen Idec will continue to assess the effectiveness of the
RiskMAP and the information that it generates through a
multi-disciplinary TYSABRI.RTM. Risk Management Review Committee,
report the outcomes to FDA, and act promptly to revise and improve
the plan, as necessary, in order to achieve its goals.
1.2 Risk Management Goals
[0191] In consideration of FDA's risk management guidance document,
the TYSABRI.RTM. RiskMAP incorporates both risk minimization and
risk assessment goals. The goals of risk minimization are: [0192]
To promote informed risk-benefit decisions regarding TYSABRI.RTM.
use in MS patients. Prescribers and their patients should know that
TYSABRI.RTM. is associated with an increased risk of PML, which
usually causes death or severe disability. Prescribers should also
know that TYSABRI.RTM. is indicated only for the treatment of
relapsing MS. [0193] To minimize the risk of PML. To the extent
possible, based on currently available data, patients who are
already at risk of developing PML should not receive TYSABRI.RTM.
treatment. Patients who are immunocompromised are at increased risk
of developing PML and, consistent with the PI, generally should not
receive TYSABRI.RTM. treatment. In addition, based on limited data,
use of TYSABRI.RTM. in combination with antineoplastic,
immunosuppressant or immunomodulatory agents may further increase
the risk of PML compared to TYSABRI.RTM. monotherapy. Thus,
prescribers should know that TYSABRI.RTM. should not be used
concurrently with antineoplastics, immunosuppressants or
immunomodulators. [0194] To minimize death and disability due to
PML. Although the data are limited, it is prudent to encourage
early detection and immune-reconstitution in any patient who
develops PML in order to potentially improve patient outcome. Thus,
it is important that prescribers know how to diagnose PML and know
to withhold TYSABRI.RTM. dosing immediately at the first signs or
symptoms suggestive of PML. Patients should know to promptly report
to their prescriber any continuously worsening nervous system
symptoms lasting over several days.
[0195] The goals of risk assessment are: [0196] To determine the
incidence and risk factors for PML and other serious opportunistic
infections with TYSABRI.RTM. treatment. Safety data from the TOUCH
Prescribing Program will support this goal, as will data from a
long-term observational study (TYSABRI.RTM. Global Observational
Program in Safety [TYGRIS]). [0197] To assess further the overall
safety profile of TYSABRI.RTM.. Biogen Idec will continue to study
the safety profile of TYSABRI.RTM. beyond 2 years of dosing and in
the clinical practice setting, the nature and incidence of rare
unanticipated adverse events, and the effect of TYSABRI.RTM. on
humoral and cell-mediated immunity. Safety data from the TOUCH
Prescribing Program, TYGRIS, and TYSABRI.RTM. clinical trials will
support this goal.
1.3 Important Features of Medical Management of MS Patients
[0198] There are several important aspects about the medical
management of patients with MS and the administration of
TYSABRI.RTM. that allow for successful implementation of the Risk
Minimization Action plan (RiskMAP).
1. TYSABRI.RTM. is Prescribed by Prescribers Who Specialize in the
Care of Patients with MS.
[0199] In the United States, patients with MS receive medical
treatment by a relatively small group of physicians, primarily
neurologists. Approximately 6,000 physicians treat 90% of patients
with MS. This is in contrast to 170,000 family practitioners that
treat primary care diseases in the US. Biogen Idec has a dedicated
force of physicians and sales representatives that interact with
neurologists and other healthcare professionals who care for
patients with MS. Consequently, Biogen Idec can readily reach
nearly all prescribers who are expected to prescribe
TYSABRI.RTM..
[0200] Because PML is a disease of the central nervous system, the
targeted prescribers of TYSABRI.RTM. are also the best-qualified
physicians to diagnose and manage PML. Neurologists have the
expertise to monitor subjects for signs and symptoms indicative of
PML and select appropriate diagnostic tests to diagnose a patient
with PML.
2. Patients with Ms are Knowledgeable about their Treatment
Options.
[0201] Patients with MS are generally a young, highly motivated
patient population. In a recent survey, 94% to 99% of patients with
MS were aware of their treatment options, including
beta-interferons and glatiramer acetate (GA) (Biogen Idec, data on
file). During the period when TYSABRI.RTM. was available
commercially, Biogen Idec found that 79% of patients with MS were
aware of the introduction of TYSABRI.RTM.. Also, Biogen Idec has
sought feedback from patients with MS and found that the potential
risk of PML with TYSABRI.RTM. has been broadly disseminated in the
MS community. Based on Biogen Idec's market research, patients with
MS want to learn more about the risks of PML with TYSABRI.RTM..
3. Discussion of Risks and Benefits Associated with Ms Treatment is
the Standard of Care in Neurology Practice.
[0202] Prescribing a disease-modifying treatment for a serious,
disabling disease such as MS is a carefully considered and
deliberate decision. Based upon feedback from to neurologists and
MS patients, this decision usually involves a detailed discussion
between the prescriber and patient about the risks and benefits of
available therapies. Some neurologists already use an
informed-consent form prior to initiating therapy with an
immunomodulatory agent such as interferon-beta or glatiramer
acetate. The TYSABRI.RTM. risk minimization strategy builds upon
this existing decision-making process.
4. TYSABRI.RTM. is Administered Monthly by Healthcare Professionals
in Infusion Sites.
[0203] In contrast to therapies that are self-administered in the
patient's home, TYSABRI.RTM. is administered intravenously every
month at an infusion site under the care and management of infusion
nurses. This regulated, procedure-oriented dispensing environment
allows for monthly monitoring of patients for potential symptoms
suggestive of PML and for effective dissemination of information on
TYSABRI.RTM. that reinforces appropriate use.
[0204] The TOUCH Prescribing Program is designed to inform
prescribers, infusion nurses, and MS patients about the risk of PML
and how to minimize that risk. A RiskMAP system of mandatory
enrollment of all prescribers and patients, controlled distribution
of TYSABRI.RTM., and administration of TYSABRI.RTM. only in trained
and authorized infusion sites was developed to build upon the
unique aspects of the medical management of MS patients and the
administration of TYSABRI.RTM..
2. Controlled Distribution System for TYSABRI.RTM.
[0205] Biogen Idec and Elan have designed a controlled distribution
system to deliver TYSABRI.RTM. only to infusion sites (or, if
appropriate, their affiliated central pharmacies) that have been
trained by Biogen Idec or Elan personnel on the known risks and
appropriate use of TYSABRI.RTM., using education tools 1, and have
attested that they will follow the RiskMAP requirements (See
Section 4.2 and 4.3). The controlled distribution of TYSABRI.RTM.
will allow Biogen Idec and Elan to track TYSABRI.RTM. shipments,
i.e., the location and number of vials shipped to infusion sites
and central pharmacies.
2.1 Distribution System Description
[0206] Under the controlled distribution plan, a single
distributor, specialty pharmacies, and central pharmacies will each
be associated with authorized infusion sites. Elan has contracted
with a single distributor and will contract with a limited number
of specialty pharmacies (.ltoreq.12) to distribute TYSABRI.RTM.
only to authorized infusion sites. The single distributor will sell
TYSABRI.RTM. to its customers, but only ship product to authorized
specialty pharmacies, central pharmacies or infusion sites.
[0207] The single distributor and participating specialty
pharmacies will be contractually obligated to follow RiskMAP
requirements in order to purchase and distribute TYSABRI.RTM.. The
contracts will specify, among other requirements, that: [0208]
TYSABRI.RTM. will be shipped only to authorized infusion sites (or
their authorized affiliated central pharmacy) designated by Biogen
Idec and Elan, either directly from the single distributor or
through one of the specialty pharmacies. [0209] A shipment
authorization code must be obtained from Biogen Idec and Elan for
each shipment prior to each shipment.
[0210] Specialty pharmacy providers are organizations that dispense
specialty products, including injectable and infusible therapies.
Product is labeled with the patient's name, and is typically
dispensed directly to an authorized infusion site (e.g.,
physician's office or other infusion site).
[0211] Central pharmacies are distinct from specialty pharmacies. A
central pharmacy is located within a hospital, group practice or
infusion site, and is affiliated with an infusion site. The central
pharmacy is responsible for purchasing, storing, and dispensing
product to its affiliated infusion site. Biogen Idec will provide
each authorized central pharmacy with a list of the authorized
infusion sites to which it may release product. The central
pharmacy may only dispense product to these authorized sites and
must maintain a TOUCH Central Pharmacy Inventory Tracking Log. This
log is meant to document each instance TYSABRI.RTM. is released by
the central pharmacy, including the number of vials released and
the infusion site (including its unique Site Authorization Number)
that received the product. The Central Pharmacy should retain its
Inventory Tracking Logs for 5 years. As requested by the FDA, prior
to distributing education materials relating to the RiskMAP, the
Sponsor shall submit them for FDA review.
2.2 Distribution System Process The TYSABRI.RTM. shipment and
authorization process is illustrated in FIG. 1. There are three
ways in which an infusion site can receive product. A shipment
authorization is required prior to shipment in each of these
cases.
[0212] 1. Infusion site obtains product directly from the single
distributor. The single distributor would obtain a shipment
authorization from Biogen Idec and Elan, and deliver TYSABRI.RTM.
directly from the single distributor warehouse to the infusion
site.
[0213] 2. Infusion site utilizes an affiliated central pharmacy.
The central pharmacy would obtain TYSABRI.RTM. from the single
distributor. The single distributor would obtain a shipment
authorization from Biogen Idec and Elan, and deliver TYSABRI.RTM.
directly from the single distributor warehouse to the central
pharmacy. The central pharmacy will then dispense TYSABRI.RTM.
directly to the authorized infusion site.
[0214] 3. Infusion site obtains TYSABRI.RTM. from a specialty
pharmacy. The specialty pharmacy would obtain TYSABRI.RTM. from the
single distributor. The single distributor would obtain a shipment
authorization from Biogen Idec and Elan, and deliver TYSABRI.RTM.
directly from the single distributor warehouse to the specialty
pharmacy. The specialty pharmacy would then obtain a shipment
authorization from Biogen Idec and Elan to dispense TYSABRI.RTM. to
the infusion site.
2.3 Shipment Authorization
[0215] Biogen Idec and Elan will permit TYSABRI.RTM. delivery only
to authorized infusion sites and only in quantities justified by
the number of authorized patients at the site. Biogen Idec will
maintain the list of authorized sites (authorized infusion sites
and authorized central pharmacies) in the TOUCH database as
described in Sections 4.4 and 5.2. An acceptable order quantity
will be established on a site-by-site basis taking into account the
amount of drug previously shipped to the site relative to the
confirmed and expected demand from enrolled patients at the
site.
[0216] As described in FIG. 2, when the single distributor receives
an order from an infusion site, the single distributor would first
confirm that the order quantity is less than the maximum acceptable
order for that site. Then, the single distributor will access the
TYSABRIdirect.com web site and enter the infusion site or central
pharmacy address that TYSABRI.RTM. will be shipped to. The web site
will access the TOUCH database and if the "ship to" address that
the single distributor entered matches an authorized infusion site
(or affiliated authorized central pharmacy), a shipment
authorization code will be provided to the central distributor and
will be captured in the TOUCH database. Specialty pharmacies follow
the same process of authorization based on the "ship to" address,
but are not required to confirm order quantity because they only
dispense on a per patient basis. The single distributor and SPPs
must not ship TYSABRI.RTM. without a shipment authorization
code.
2.4 Shipping Data Provided by Single Distributor and Specialty
Pharmacies
[0217] The single distributor and specialty pharmacies will be
required to provide shipment authorization codes as well as other
information critical to monitoring shipments to authorized infusion
sites and inventory levels on a weekly basis to Biogen Idec and
Elan, including: [0218] Central Distributor information: unique
identifier, name, invoice number, location shipped from [0219] SPP
information: unique identifier, name, location shipped from [0220]
Shipment information: quantity shipped, quantity returned, date
[0221] Ship-to information: identifier, name, address, class of
trade [0222] Shipment authorization code: as obtained from TOUCH
database for each shipment
2.5 Reconciliation of Shipping Addresses and Quantities
[0223] Biogen Idec and Elan will reconcile the shipping addresses
that have received TYSABRI.RTM. shipments against the list of
authorized sites on an on-going basis. Biogen Idec will reconcile,
at least monthly, the amount of drug shipped to each site compared
to the expected volume of infusions for that site. These site
reconciliations will be conducted by analyzing beginning inventory
balances, product shipped during the reconciliation period, product
returns, and the number of confirmed patient infusions. Any
discrepancies identified by this reconciliation would be flagged
for further investigation. Such investigations could include
for-cause audits of physical inventory on an as-needed basis to
confirm that the calculated inventory level at a site is consistent
with the actual inventory level. This combination of ongoing
reconciliation and follow-up investigations is intended to enable
management of low inventory levels across the distribution
system.
[0224] Reconciliations will also be performed with central pharmacy
data. Product shipped into the Central Pharmacy will be reconciled
against confirmed infusions of authorized patients at the
affiliated authorized infusion sites, at least monthly. In
addition, Biogen Idec will examine a sample of inventory tracking
logs and reconcile them with shipping data to measure central
pharmacy compliance.
3 Mandatory Enrollment of Prescribers and Patients
[0225] A key feature of the RiskMAP is mandatory enrollment of all
prescribers and patients into the TOUCH Prescribing Program as a
prerequisite to prescribing or receiving TYSABRI.RTM.
treatment.
3.1 Prescriber/Patient Enrollment Form
[0226] Prescribers and patients must complete and sign a mandatory
Prescriber/Patient Enrollment Form and send it to Biogen Idec prior
to initiating TYSABRI.RTM. treatment.
[0227] The purpose of the Prescriber/Patient Enrollment Form is to
help assure that (1) both the prescriber and patient are informed
of the known risks of TYSABRI.RTM., including the risk of PML, (2)
TYSABRI.RTM. is prescribed only for appropriate patients, and (3)
that patients will be tracked longitudinally for safety
outcomes.
[0228] The Prescriber/Patient Enrollment Form will be used to
collect baseline demographic information including the prescriber's
name and contact information, patient's name, contact information,
age, gender, social security number, relapsing MS diagnosis, most
recent prior MS therapy; prior TYSABRI.RTM. exposure; a
TYSABRI.RTM. prescription; and a Patient-Prescriber
Acknowledgement.
[0229] The TYSABRI.RTM. prescription is pre-printed as a 300 mg
dose to be administered by IV infusion every 4 weeks, with 12
refills/doses. The prescriber has the option of reducing the number
of refills and/or the frequency of dosing on the Enrollment form.
Prescribers are able to de-enroll patients at any time,
notwithstanding the number of refills indicated on this
prescription. It is the TYSABRI.RTM. Status Report and
Reauthorization process (described in Section 6.3 and 6.4) that
controls on-going patient re-authorizations, not the number of
refills on the prescription.
[0230] Biogen Idec will require that, prior to starting
TYSABRI.RTM. treatment, the prescriber will provide the patient
with the TYSABRI.RTM. Medication Guide, will require the patient to
read it, and will discuss the known risks and potential benefits of
TYSABRI.RTM. with the patient. Once the decision to prescribe
TYSABRI.RTM. is made, the prescriber and patient will complete and
sign the Prescriber/Patient Enrollment Form. The completed and
signed Enrollment Form must be faxed to Biogen Idec before the
prescriber may prescribe TYSABRI.RTM. and the patient may receive
an infusion. Biogen Idec will have mail and fax options to send and
receive forms. By signing the Enrollment Form, the patient and the
prescriber acknowledge the following:
[0231] Patient Acknowledgement
[0232] I acknowledge that:
[0233] TYSABRI.RTM. is a medicine approved only to treat patients
with relapsing forms of multiple sclerosis (MS). [0234]
TYSABRI.RTM. is generally recommended for patients who have not
been helped enough by, or cannot tolerate other treatments for MS
[0235] I have talked to my doctor and understand the benefits and
risks of TYSABRI.RTM. treatment
[0236] TYSABRI.RTM. increases your chance of getting a rare brain
infection that usually causes death or severe disability. [0237]
This infection is called progressive multifocal leukoencephalopathy
(PML). PML usually happens in people with weakened immune systems
[0238] No one can predict who will get PML. There is no known
treatment, prevention, or cure for PML [0239] My chance for getting
PML may be higher if I am also being treated with other medicines
that can weaken my immune system, including other MS treatments.
[0240] Even if I use TYSABRI.RTM. alone to treat my MS, it is not
known if my chance for getting PML will be lower. It is also not
known if treatment for a long period of time with TYSABRI.RTM. can
increase my chance for PML [0241] I should call my doctor right
away if I get any new or worsening symptoms that last several days,
especially nervous system symptoms. Some of these symptoms include
a new or sudden change in my thinking, eyesight, balance, or
strength, but I should also report other new or worsening
symptoms
[0242] To receive TYSABRI.RTM., all patients must be authorized in
a special program called the TOUCH Prescribing Program. [0243] The
TOUCH Prescribing Program is run by the company that makes
TYSABRI.RTM.. The company will collect information about my health
at regular time periods. I cannot receive TYSABRI.RTM. if I do not
agree to follow the requirements of the TOUCH Prescribing Program
[0244] I must notify the TOUCH Prescribing Program if I switch
prescribers or infusion sites [0245] I have received, read, and
understand the Patient Medication Guide [0246] I will bring to each
TYSABRI.RTM. infusion a list of all medicines and treatments that I
have taken during the last month
[0247] Prescriber Acknowledgement
[0248] I acknowledge that: [0249] I have read and understand the
full Prescribing Information for TYSABRI.RTM. [0250] TYSABRI.RTM.
is indicated as monotherapy for relapsing forms of MS [0251] This
patient has a relapsing form of MS based on clinical and
radiological evidence [0252] TYSABRI.RTM. increases the risk of
progressive multifocal leukoencephalopathy (PML), an opportunistic
viral infection of the brain that usually leads to death or severe
disability. Although the cases of PML were limited to patients with
recent or concomitant exposure to immunomodulators or
immunosuppressants, there were too few cases to rule out the
possibility that PML may occur with TYSABRI.RTM. monotherapy [0253]
I am able to diagnose and manage opportunistic infections and PML,
or am prepared to refer patients to specialists with these
abilities [0254] Because TYSABRI.RTM. increases the risk of PML, it
is generally recommended for patients who have had an inadequate
response to, or are unable to tolerate, alternate MS therapies. I
have discussed other MS treatments with this patient [0255]
TYSABRI.RTM. is not ordinarily recommended for patients who are
receiving chronic immunosuppressant or immunomodulatory therapy, or
who are significantly immunocompromised from any other cause [0256]
This patient has no known contraindications to TYSABRI.RTM.
treatment, including PML [0257] I have instructed the patient to
promptly report to me any continuously worsening symptoms that
persist over several days [0258] This patient should be seen and
evaluated 3 months after the first infusion, 6 months after the
first infusion, at least every 6 months thereafter for as long as
the patient receives TYSABRI.RTM., and for at least 6 months after
TYSABRI.RTM. has been discontinued [0259] I will determine every 6
months whether this patient should continue on TYSABRI.RTM. and if
so, authorize treatment every 6 months [0260] I should report, as
soon as possible, any case of PML, any hospitalization due to
opportunistic infection, and any death to Biogen Idec [0261] Data
concerning this patient and me will be entered into the mandatory
TOUCH Prescribing Program. Biogen Idec requires my cooperation with
periodic data collection. Failure to provide the requested
information or otherwise comply with the requirements of the TOUCH
Prescribing Program may result in discontinuation of TYSABRI.RTM.
treatment for this patient and forfeiture of my authorization to
prescribe TYSABRI.RTM. [0262] I have received educational materials
regarding the benefits and risks of TYSABRI.RTM. treatment [0263] I
have, or another healthcare provider under my direction has,
educated this patient on the benefits and risks of treatment with
TYSABRI.RTM., provided him or her with the Patient Medication Guide
and Enrollment Form, instructed him or her to read these materials,
and encouraged him or her to ask questions when considering
TYSABRI.RTM.
3.2 Enrollment Process for Prescribers and Patients
[0264] Biogen Idec will maintain the complete list of prescribers
and patients authorized in the TOUCH Prescribing Program in the
TOUCH database.
[0265] As described in FIG. 3, Biogen Idec will review the
submitted Prescriber/Patient Enrollment Form for completeness and
accuracy, and verify that both the prescriber and the patient have
signed the form. The prescriber and patient information will be
entered into the TOUCH database. Biogen Idec will confirm the
patient name, social security number (if provided) and date of
birth against all current and previous patients in the database in
order to avoid duplicate entries. At that time, a unique Patient
Enrollment Number will be assigned to the patient in the TOUCH
database, which should remain the same for that patient, even if
the patient de-enrolls and subsequently re-enrolls into the
program. Biogen Idec will assign a case manager to the patient.
Then Biogen Idec will match the patient to an authorized infusion
site, or confirm that the infusion site to which the prescriber has
referred the patient is authorized in the TOUCH Prescribing
Program.
[0266] Biogen Idec will communicate initial patient enrollment to
both the infusion site and prescriber by means of a Notice of
Patient Authorization fax. The infusion site will use this Notice
of Patient Authorization to verify patient enrollment in the TOUCH
Prescribing Program before administering the first dose of
TYSABRI.RTM. to the patient. After the infusion site notifies
Biogen Idec that the first dose has been administered (see Section
4.6), Biogen Idec will communicate current patient enrollment
status to both the infusion site and the prescriber by means of a
second Notice of Patient Authorization fax. The patient
authorization period stated on this second fax is 6 months from the
first confirmed infusion. Both the start and stop date of the
authorization period are noted on the fax. If an infusion site
misplaces the Notice of Patient Authorization fax, they may call
Biogen Idec at 1-800-456-2255 and request a replacement Notice of
Patient Authorization fax.
[0267] The prescriber must complete and sign a new
Prescriber/Patient Enrollment Form for every patient of his or hers
that enrolls into the TOUCH Prescribing Program. In addition, after
a patient has authorized, the prescriber must reauthorize
TYSABRI.RTM. use for that patient every 6 months, as described in
Section 6.5.
3.3 Process for Patients Who Change Prescribers
[0268] Patients attest on the Prescriber/Patient Enrollment Form
that they will inform Biogen Idec when and if they change
prescribers. The patient will be required to complete a new
Prescriber/Patient Enrollment Form with the new prescriber to
ensure that the new prescriber is authorized in the TOUCH
Prescribing Program, and that the patient and new prescriber have
discussed the known risks and potential benefits of TYSABRI.RTM.
treatment. Biogen Idec will then inform the infusion site of the
change in prescriber. If a patient does not inform Biogen Idec when
he/she changes prescribers, Biogen Idec will obtain this
information during the TYSABRI.RTM. Patient Status Report and
Reauthorization Questionnaire process (see Section 6.3).
3.4 Process for Patients Who Change Infusion Sites
[0269] Patients attest on the Prescriber/Patient Enrollment Form
that they will inform Biogen Idec if they change infusion sites. If
a patient changes infusion sites, Biogen Idec will verify that the
new infusion site is authorized in the TOUCH Prescribing Program
and then Biogen Idec will send a Notice of Patient Authorization
fax with the patient's enrollment number and authorization period
to the new infusion site and the prescriber. Biogen Idec will send
Notice of Discontinuation to the previous infusion site stating
that the patient is no longer eligible to receive treatment at that
site. In the event that the patient changes infusion sites and does
not inform Biogen Idec, Biogen Idec will identify this information
when the new infusion site contacts Biogen Idec to obtain the
Notice of Patient Authorization. Upon notice of the new infusion
site, Biogen Idec will update the infusion site data linked to the
patient in the TOUCH database and provide the new infusion site
with the Notice of Patient Authorization Fax.
3.5 Process for Patients Who are Hospitalized
[0270] If a patient is hospitalized and due for his or her next
infusion, the patient may receive TYSABRI.RTM. at an authorized
infusion site within the hospital if medically appropriate. The
patient must be physically moved to the authorized infusion site to
receive TYSABRI.RTM. under the care of the trained personnel who
will administer the infusion. The authorized infusion site will
contact Biogen Idec to obtain the Notice of Patient Authorization
for that patient. If the hospital does not have an authorized
infusion site, the infusion should be deferred until the patient is
discharged and able to return to his or her usual authorized
infusion site.
3.6 Prescriber De-Enrollment from the TOUCH Prescribing Program
[0271] By signing the Prescriber/Patient Enrollment Form,
prescribers will acknowledge that a significant pattern of
non-compliance with the requirements of the RiskMAP may result in
his or her de-enrollment from the TOUCH Prescribing Program and
forfeiture of authorization to prescribe TYSABRI.RTM.. Affected
patients will be directed to other authorized prescribers in the
area; if this is not possible, then the affected patients could
potentially be de-authorized as well (see Section 10.3.2)
3.7 Patient Discontinuation from the TOUCH Prescribing Program
[0272] If a patient discontinues TYSABRI.RTM. treatment as
indicated on the TYSABRI.RTM. Patient Status Report and
Reauthorization Questionnaire (described in Section 6.4), or by
notifying Biogen Idec, Biogen Idec will call the infusion site,
communicate the patient's discontinuation, confirm the patient is
not scheduled for future TYSABRI.RTM. infusions and send a Notice
of Discontinuation to the prescriber, patient and infusion site
stating that the patient is no longer authorized in the TOUCH
Prescribing Program, and is not authorized to continue TYSABRI.RTM.
treatment. Biogen Idec will document these calls to the infusion
site.
[0273] If a prescriber indicates that a patient is lost to
follow-up, Biogen Idec will attempt to contact that patient. If the
patient plans to continue TYSABRI.RTM.-treatment, he/she will be
instructed to contact his or her new prescriber to complete a new
Prescriber/Patient Enrollment form. If this new Prescriber/Patient
Enrollment form is not completed, Biogen Idec will communicate to
the prescriber, patient and infusion site that the patient is no
longer authorized in the TOUCH Prescribing Program, and is not
authorized to continue TYSABRI.RTM. treatment. If Biogen Idec is
unable to contact the patient, we will communicate to the
prescriber and infusion site that the patient is no longer
authorized to receive TYSABRI.RTM. treatment (see Section
10.3.2).
[0274] Prescribers will be required to complete a Patient
Discontinuation Questionnaire when a patient discontinues
TYSABRI.RTM. and 6 months after the patient discontinues
TYSABRI.RTM., as outlined in Section 6.8.
3.8 Re-Enrollment into the TOUCH Prescribing Program
[0275] A patient who is interested in re-starting TYSABRI.RTM.
treatment is required to complete a new Prescriber/Patient
Enrollment Form with his or her prescriber. Biogen Idec will follow
the same enrollment processes to assist the patient in starting
therapy. The patient will have the same unique Patient Enrollment
Number as before, so that Biogen Idec can measure each patient's
exposure to TYSABRI.RTM. over time. Therefore, the patient's new
enrollment is linked to his or her prior enrollment, and Biogen
Idec will be able to measure a patient's TYSABRI.RTM. exposure over
time, or during a particular enrollment period.
4 Mandatory Training and Enrollment of Infusion Sites
[0276] TYSABRI.RTM. will be shipped only to and administered only
at infusion sites authorized in the TOUCH Prescribing Program.
Authorized infusion sites are sites that have been trained by
Biogen Idec and Elan on the known risks, potential benefits and
appropriate use of TYSABRI.RTM., using educational materials. The
infusion sites must also agree to comply with the RiskMAP
requirements.
4.1 Criteria for Selection of Infusion Sites
[0277] Biogen Idec estimates that, after completion of the infusion
site training, approximately 2,000 infusion sites will become
authorized to administer TYSABRI.RTM.. An infusion site can be
located in a hospital, a stand-alone clinic, or a physician's
office. Infusion sites will be selected based on capability to
execute the required RiskMAP activities, as well as patient need
and geography. Biogen Idec and Elan will try to assure that each
geographic region has an adequate number of authorized infusion
sites to provide appropriate patients access to TYSABRI.RTM.
therapy.
4.2 Training of Infusion Sites
[0278] Biogen Idec and Elan representatives will visit infusion
sites, prior to their authorization, and provide training on the
known risks, potential benefits, and appropriate use of
TYSABRI.RTM. using the various TOUCH documents, including TOUCH
Education Slide Set, Pre-infusion Patient Checklist, and Medication
Guide. Infusion sites will be instructed that healthcare providers
should promptly report serious adverse events to Biogen Idec.
Infusion sites will be required to distribute the TYSABRI.RTM.
Medication Guide and complete a Pre-infusion Patient Checklist for
each patient prior to each monthly infusion and forward the
Pre-infusion Patient Checklist including the date of infusion to
Biogen Idec.
4.3 Infusion Site Enrollment Form
[0279] To enroll in the TOUCH Prescribing Program, the infusion
site completes and signs the Infusion Site Enrollment Form. The
infusion site will designate a person with appropriate authority to
sign the Infusion Site Enrollment Form on behalf of the infusion
site. The infusion site must acknowledge the following:
[0280] Infusion Site Acknowledgement [0281] A representative of
Biogen Idec or Elan Pharmaceuticals, Inc. has provided training and
education materials on the TOUCH Prescribing Program [0282]
TYSABRI.RTM. will be administered only to patients who are enrolled
in the TOUCH Prescribing Program [0283] Only currently authorized
patients will receive TYSABRI.RTM.. Authorization is confirmed by
ensuring that there is a current Notice of Patient Authorization on
file and that the site has not received a Notice of Patient
Discontinuation. [0284] Each patient will receive a copy of the
TYSABRI.RTM. Patient Medication Guide prior to each infusion
[0285] A TYSABRI.RTM. Pre-infusion Patient Checklist must be
completed for every patient scheduled to receive TYSABRI.RTM.. The
Pre-infusion Patient Checklist must be faxed to Biogen Idec within
1 business day of patient visit, and a copy placed in the patient's
medical record [0286] I understand that, per the requirements of
the TOUCH Prescribing Program, this infusion site may be audited by
the Food and Drug Administration (FDA), Biogen Idec, Elan
Pharmaceuticals, Inc., and/or a third party designated by the FDA,
Biogen Idec, or Elan Pharmaceuticals, Inc. [0287] Noncompliance
with the requirements of the TOUCH Prescribing Program will result
in de-enrollment of the infusion site and forfeiture of the
authorization to infuse TYSABRI.RTM.
[0288] After completing and signing the Infusion Site Enrollment
Form, the infusion site faxes it to Biogen Idec.
4.4 Infusion Site Enrollment Process
[0289] Biogen Idec will maintain the complete list of authorized
infusion sites in the TOUCH database.
[0290] As described in FIG. 4, when Biogen Idec receives the
Infusion Site Enrollment Form, Biogen Idec will verify that the
form is complete, accurate and signed. Then Biogen Idec will enter
the infusion site information into the TOUCH database, thus
initiating enrollment and authorization of the infusion site in the
TOUCH Prescribing Program. At that time, a unique Site
Authorization Number will be assigned to the infusion site in the
TOUCH database and Biogen Idec will fax a Site Authorization
Confirmation. The infusion site will be instructed to use the Site
Authorization Number when ordering TYSABRI.RTM.. If an infusion
site misplaces the Site Authorization Confirmation fax, the site
may call Biogen Idec at 1-800-456-2255 to request a copy.
4.5 Pre-Infusion Patient Checklists
[0291] Prior to each infusion, an authorized infusion site must
verify the patient is currently authorized to receive TYSABRI.RTM.
treatment from the medical record. In order to do this, the site
must refer to the patient's medical record and complete the
following steps prior to every infusion. [0292] 1. If the patient
did not receive his or her previous infusion, and physician
clearance was required, the site must confirm authorization from
the prescriber before providing the current infusion. [0293] 2.
Confirm that there is a current Notice of Patient Authorization on
file and verify the infusion is within the current authorization
period. [0294] 3. Confirm there is not a Notice of Discontinuation
on file. As stated previously in Section 3.7, if the patient
discontinues TYSABRI.RTM., Biogen Idec will call the infusion site,
communicate discontinuation, confirm the patient is not scheduled
for future TYSABRI.RTM. infusions and send a Notice of
Discontinuation to the prescriber, patient and infusion site
stating that the patient is no longer authorized in the TOUCH
Prescribing Program, and is not authorized to continue TYSABRI.RTM.
treatment. Biogen Idec will document these calls to the infusion
site.
[0295] Only if the patient is authorized to receive TYSABRI.RTM.,
the site next provides the patient with the TYSABRI.RTM. Medication
Guide, gives the patient time to read the Medication Guide, and
completes the Pre-Infusion Patient Checklist.
[0296] Infusion nurses will be instructed to complete the
Pre-infusion Patient Checklist for each patient prior to each
TYSABRI.RTM. infusion.
[0297] In order to assure that patient care is not jeopardized due
to late communication of reauthorization, infusion sites will be
allowed to provide one infusion past the authorization date. If a
patient presents outside of the authorized period, the infusion
site is required to call Biogen Idec. Biogen Idec will record all
infusions that take place during this period.
[0298] The Pre-infusion Patient Checklist is designed to minimize
inappropriate use of TYSABRI.RTM. and to facilitate early detection
of worsening neurological symptoms that might be indicative of PML
through regular, monthly assessments by infusion nurses at infusion
sites. Using the Pre-Infusion Checklist, the infusion nurse is
instructed to ask the following questions to the patient:
[0299] Pre-Infusion Patient Checklist Questions: [0300] 1. Over the
past month, have you had any new or worsening medical problems
(such as a new or sudden change in your thinking, eyesight,
balance, strength, or other problems) that have persisted over
several days? [0301] 2. Do you have a medical condition that can
weaken your immune system, such as HIV infection or AIDS, leukemia
or lymphoma, or an organ transplant, that may suggest that your
body is not able to fight infections well? [0302] 3. In the past
month, have you taken medicines to treat cancer or MS or any other
medicines that weaken your immune system? (Review the list on the
reverse side with the patient.) [0303] 4. In the past month, other
than for the treatment of a recent relapse, have you taken any of
the following medicines: Solu-Medrol.RTM., methylprednisolone,
Decadron.RTM., dexamethasone, Depo-Medrol.RTM., prednisone, or
other steroid medicines?
[0304] If the patient answers NO to questions 1, 2, 3, and 4, the
patient may be infused. If the patient answers YES (or the patient
does not know the answer) to any of questions 1, 2, 3, or 4, then
the patient should not be infused at that time, and the prescriber
should be contacted for further instructions. After the infusion
nurse discusses the findings with the patient's prescriber, the
prescriber may give authorization to proceed with the infusion.
Otherwise, the infusion must not be given and the patient must be
promptly referred to their prescriber for further evaluation. The
infusion nurse must document if authorization was given, and for
all patients, the infusion nurse will document whether or not the
patient was infused. The Pre-Infusion Patient Checklist must be
faxed to Biogen Idec regardless of whether or not the patient
received the infusion.
[0305] Thus, the Pre-Infusion Patient Checklist is designed to
trigger a neurologist's consultation if the patient reports any
worsening neurological symptoms lasting several days, if the
patient reports any medical condition that may lead to an
immunocompromised state (e.g., HIV infection), or if the patient
reports receiving any concurrent immunomodulatory or
immunosuppressant therapies, or steroid use.
4.6 Real-Time Centralized Collection and Tracking of Pre-Infusion
Patient Checklists
[0306] So that the Sponsor may monitor infusion site compliance
with completion of the Pre-Infusion Patient Checklist and track
infusions on a real-time, patient-specific basis, the infusion site
must fax the Pre-Infusion Patient Checklist to Biogen Idec within 1
business day after the patient's infusion visit, whether the
patient received the TYSABRI.RTM. infusion or not.
[0307] As described in FIG. 5, the Pre-Infusion Patient Checklist
data will be entered into the TOUCH database whenever Biogen Idec
receives a Pre-Infusion Patient Checklist. The Pre-Infusion Patient
Checklist data will be linked to the patient, infusion site and
prescriber data in the TOUCH database. A history of Pre-Infusion
Patient Checklist data will be tracked for each patient, each
infusion site and each prescriber.
[0308] In a later phase of the program, infusion sites may be able
to use a web-based system to directly enter the Pre-Infusion
Patient Checklist data into the TOUCH database, or continue to fax
to Biogen Idec. This web-based system may simplify monitoring of
compliance with the TOUCH Prescribing Program and tracking of
individual patient dosing.
4.7 Diligence with Follow-Up of Missing Pre-Infusion Patient
Checklists
[0309] Biogen Idec will make diligent efforts to obtain a completed
Pre-Infusion Patient Checklist from every infusion site on every
patient every month.
[0310] The Pre-Infusion Patient Checklist asks for the next
scheduled infusion date, which will assist Biogen Idec in targeting
when the next infusion will be given. If a date of next infusion is
provided, Biogen Idec will follow-up on a missing Pre-Infusion
Patient Checklist 3 days after that date.
[0311] If this next scheduled infusion date field is left blank,
Biogen Idec will follow-up with the infusion site 45 days after the
previous infusion, based on the following assumptions. The
TYSABRI.RTM. approved PI will indicate that infusions are
administered every 4 weeks. Assuming a 14-day window to allow for
patient scheduling variation and an additional 3 days for
variability surrounding the infusion site submission of the
completed Pre-Infusion Patient Checklist, Biogen Idec expects to
receive almost all completed Pre-Infusion Patient Checklists within
45 days after the previous infusion. If the Pre-Infusion Patient
Checklist has not been submitted within this timeframe, Biogen Idec
will telephone the infusion site in order to determine whether:
[0312] 1. The patient has received a TYSABRI.RTM. infusion but the
infusion site has not yet submitted the Pre-Infusion Patient
Checklist, OR [0313] 2. The infusion appointment is scheduled to
occur shortly, OR [0314] 3. The patient did not come to his or her
scheduled infusion appointment
[0315] In the case of (1), Biogen Idec will request that the
infusion site send in the completed checklist and will remind the
infusion site that a checklist must be completed on every patient
before every dose and promptly submitted to Biogen Idec.
Significant non-compliance on the part of the infusion site may
result in de-enrollment of the infusion site and forfeiture of the
authorization to administer TYSABRI.RTM. (see Section 10.3.2 for
De-Enrollment Process).
[0316] In the case of (3), Biogen Idec will contact the prescriber
to determine whether the patient is alive, whether the patient is
receiving TYSABRI.RTM., and whether the patient has developed PML
or other serious OI. If attempts to obtain information from the
prescriber are unsuccessful, then Biogen Idec will attempt to
contact the patient directly in order to determine if the patient
is alive, whether the patient is on TYSABRI.RTM. treatment, whether
the patient has been hospitalized, and to remind the patient to
contact his or her prescriber. If the patient has died, has PML, or
other serious OI, or has been hospitalized, the Biogen Idec Drug
Safety will diligently investigate the case and report to the FDA
as appropriate.
[0317] If after these attempts, Biogen Idec is unable to reach the
patient, then Biogen Idec will follow the Patient Discontinuation
process outlined in Section 3.7. Significant non-compliance with
these requirements on the part of the prescriber may result in
de-enrollment of the prescriber and forfeiture of the authorization
to prescribe TYSABRI.RTM., after review by the TYSABRI.RTM.
Compliance Review Committee (See Section 10.3.2). Affected patients
will be directed to other authorized prescribers in the area; if
this is not possible, then the affected patients could potentially
be de-authorized as well. Similarly, a persistent pattern of
non-compliance on the part of the infusion site may result in
de-enrollment of the infusion site and forfeiture of the
authorization to administer TYSABRI.RTM., after review by the
Compliance Review Committee (described in Section 10.1 and
10.3.2).
[0318] If the patient has discontinued TYSABRI.RTM., Biogen Idec
will follow the Patient Discontinuation process outlined in Section
3.7. Biogen Idec will then contact the prescriber 6 months later to
complete a TYSABRI.RTM. Discontinuation Questionnaire to obtain the
final safety follow-up on the patient (described in Section
6.8).
[0319] Consistent with the PI, the Sponsor recommends that
TYSABRI.RTM. be administered every 4 weeks (28 days). TYSABRI.RTM.
clinical trials permitted dosing within +/-5 days of the 28-day
dosing interval.
4.8 Follow-Up of Pre-Infusion Patient Checklist Findings
[0320] Biogen Idec intends to follow-up on certain findings on the
Pre-Infusion Patient Checklists. When Biogen Idec receives a
completed Pre-Infusion Patient Checklist, Biogen Idec will review
the data on the Checklist. Biogen Idec will call the infusion site
to follow-up on incomplete or illegible forms. The Sponsor will
follow-up within two business days to obtain this information.
[0321] If Biogen Idec receives a checklist in which the infusion
site did not provide the Medication Guide, and/or confirm the
patient's enrollment status, and the patient was infused, Biogen
Idec will send a fax to the infusion site instructing the site of
these requirements prior to every infusion. In addition, in other
cases of infusion site non-compliance (e.g., the answer to Question
1, 2, 3, or 4 was YES, the patient was infused but the prescriber
did not approve the infusion), Biogen Idec will contact the site to
re-enforce its TOUCH Prescribing Program obligations with respect
to the Pre-Infusion Patient Checklist.
[0322] As discussed during the Advisory Committee meeting, Biogen
Idec expects that a high proportion of submitted Pre-Infusion
Patient Checklists will contain reports of "worsening symptoms"
that are in fact, MS-related symptoms, including relapses. The
Pre-Infusion Patient Checklist is designed to trigger prescriber
consultation in the event that the patient reports such symptoms
and in turn, prescribers are required to report any case of PML to
Biogen Idec promptly. Therefore, Biogen Idec will notify the
prescriber in the event that the answer to Questions 1, 2, 3, or 4
is YES and the form indicates that the infusion site did not notify
the prescriber. Under these circumstances, Biogen Idec will contact
the prescriber and inform him/her of the findings and recommend
further evaluation, if justified (see Section 10.2.5). In addition,
the checklist prompts infusion personnel to refer to the previous
checklist prior to an infusion. If the previous checklist notes
that follow-up with the prescriber was required, infusion site
personnel must confirm authorization from the prescriber was
obtained prior to providing the current infusion.
[0323] Because PML is a rare event and because neurological
symptoms are common in MS patients, it is likely that the
Pre-Infusion Patient Checklist will have a low "signal to noise"
ratio with respect to worsening neurological symptoms indicative of
PML. In light of this, Biogen Idec is proposing an aggressive
approach to follow-up on a single missing Pre-Infusion Patient
Checklist, as a missing checklist may be more likely to be
indicative of a prolonged dose suspension in the setting of PML or
another serious adverse event (see Section 4.7).
5 Mandatory Enrollment of Central Pharmacies
[0324] Central pharmacies that dispense TYSABRI.RTM. to authorized
infusion sites must also enroll in the TOUCH Prescribing Program.
Note that central pharmacies are distinct from specialty pharmacies
described in Section 2. Central pharmacies are located within a
hospital, group practice, or infusion site, and are affiliated with
an infusion site (i.e., the central pharmacy stores product
inventory and releases it to an infusion site locally). Retail
pharmacies and wholesalers are excluded from holding and dispensing
TYSABRI.RTM..
5.1 Central Pharmacy Enrollment Form
[0325] Biogen Idec or Elan will provide training to central
pharmacies by providing the various TOUCH Prescribing Program
educational materials, including the TOUCH Prescribing Program
Slide Set and Inventory Log. The central pharmacy will designate a
person with appropriate authority to sign the Central Pharmacy
Enrollment Form on behalf of the central pharmacy. By signing the
form, central pharmacies acknowledge the following:
[0326] Central Pharmacy Acknowledgement
[0327] The central pharmacy acknowledges that: [0328] A
representative of Biogen Idec or Elan Pharmaceuticals, Inc. has
provided training and educational materials on the TOUCH
Prescribing Program [0329] Central pharmacies may dispense
TYSABRI.RTM. only to authorized infusion sites [0330] The
TYSABRI.RTM. Inventory Tracking Log must be completed for every
dose of TYSABRI.RTM. dispensed to authorized infusion sites.
Inventory Tracking logs must be kept for at least 5 years from the
date of the final log entry. [0331] I understand that, per the
requirements of the TOUCH Prescribing Program, this central
pharmacy may be audited by the Food and Drug Administration (FDA),
Biogen Idec, Elan Pharmaceuticals, Inc., and/or a third party
designated by the FDA, Biogen Idec, or Elan Pharmaceuticals, Inc.
[0332] Noncompliance with the requirements of the TOUCH Prescribing
Program may result in de-enrollment of the central pharmacy and
forfeiture of the authorization to dispense TYSABRI.RTM.
[0333] The completed and signed form must be faxed to Biogen
Idec.
5.2 Central Pharmacy Enrollment Process
[0334] Biogen Idec will maintain the complete list of authorized
central pharmacies in the TOUCH database. As described in FIG. 6,
these pharmacies will be entered into the TOUCH database when
Biogen Idec receives a properly completed Central Pharmacy
Enrollment Form. At that time, a unique Site Authorization Number
will be assigned to the central pharmacy in the TOUCH database.
Biogen Idec will fax the Central Pharmacy a Site Authorization
Confirmation, which includes an Site Authorization Number, and a
list of affiliated authorized infusion sites. This Site
Authorization Number will be used by the central pharmacy to order
TYSABRI.RTM.. If a Central Pharmacy misplaces the Site
Authorization Confirmation, they may call Biogen Idec at
1-800-456-2255 and request a copy.
6. Systematic Tracking of All TYSABRI.RTM.-Treated Patients
6.1 TOUCH Prescribing Program Safety Surveillance Goals
[0335] The TOUCH Prescribing Program is designed to assess the
incidence and risk factors for PML and other serious OI with
TYSABRI.RTM. treatment. In contrast to the typical post-marketing
surveillance model that relies on spontaneous reporting of adverse
events to the manufacturer, Biogen Idec through the TOUCH
Prescribing Program, will systematically follow and actively
solicit information regarding the occurrence of PML and other
serious opportunistic infections through a variety of mechanisms on
every TYSABRI.RTM.-treated patient in the US. The TOUCH Prescribing
Program will seek to provide a complete denominator of
TYSABRI.RTM.-treated patients (including person-years of exposure)
and a complete numerator of any PML or other serious OI that may
occur. In addition, careful analysis of any case of PML or other
serious OI may provide insights into potential risk factors for
such events.
[0336] Thus, Biogen Idec will closely monitor the incidence, rate,
and morbidity and mortality of PML and other serious OI over time
after the re-introduction of TYSABRI.RTM. into the US market. Any
clinically significant change in the estimated risk of PML or other
serious OI will trigger a prompt discussion with the FDA and
appropriate action.
6.2 Multimodality Safety Tracking for PML and Other Serious OI
[0337] The TOUCH Prescribing Program is intended to provide
diligent safety surveillance and systematic tracking of all
patients treated with TYSABRI.RTM. for the occurrence of PML and
other serious OI. Biogen Idec will actively solicit information
regarding the occurrence of PML and other serious OI through
multiple methodologies. [0338] Through monthly, real-time
collection of Pre-Infusion Patient Checklists, Biogen Idec will
track TYSABRI.RTM. dosing on an up-to-date, individual patient
basis. Biogen Idec has proposed an intensive diligence process to
follow-up on missing Pre-infusion Patient Checklists or on
Pre-Infusion Patient Checklists with findings (Section 4.7 and
4.8). [0339] On the mandatory Prescriber/Patient Enrollment Form,
prescribers must attest to report to Biogen Idec any case of PML,
other serious OI, or death (Section 3.1). [0340] On the mandatory
Prescriber/Patient Enrollment Form, patients must attest that they
will report to their prescriber any new or worsening symptoms that
last several days, especially nervous symptoms (Section 3.1). The
Medication Guide also provides these instructions to the patient.
If the prescriber determines that the symptoms are related to PML
then the prescriber is obligated to report the case to Biogen Idec.
[0341] The TOUCH Prescribing Program Overview will be disseminated
to healthcare professionals involved in TYSABRI.RTM. treatment and
will instruct them to report serious adverse events to Biogen Idec
at 1-800-456-2255. [0342] For additional diligence, Biogen Idec
will actively query prescribers every 6 months on each of their
patients regarding the occurrence of PML, other serious OI, or
death using a TYSABRI.RTM. Patient Status Report and
Reauthorization Questionnaire, described in Section 6.3. If a
patient discontinues TYSABRI.RTM. treatment, Biogen Idec will
actively follow-up on the status of such a patient as described in
Section 3.7 and 6.8, respectively.
[0343] Thus, Biogen Idec has multiple mechanisms, in addition to
spontaneous reporting, to help assure that if PML or other serious
OI occurs, Biogen Idec will be informed about it as soon as
possible.
6.3 Description of TYSABRI.RTM. Patient Status Report and
Reauthorization Questionnaire
[0344] The TYSABRI.RTM. Patient Status Report and Reauthorization
Questionnaire will be sent to every prescriber for every patient
every 6 months.
[0345] The purpose of this questionnaire is to ascertain the vital
status of the patient and the occurrence of PML or other serious
OI, and for the prescriber to reauthorize the patient to continue
to receive TYSABRI.RTM. for the next 6 months. Specifically,
prescribers will be asked whether the patient is still under their
care, whether the patient is alive, whether the patient has a
diagnosis of PML or has been hospitalized for an opportunistic
infection. In addition, the Questionnaire will ask whether the
patient is receiving or has received within the last 6 months any
immunomodulatory or immunosuppressant therapies, whether the
patient is currently or has received within the last 6 months any
systemic steroids, whether the patient has received intermittent
steroids within the last 6 months, and whether the prescriber is
authorizing the continuation of TYSABRI.RTM. treatment in this
patient for the next 6 months. Biogen Idec will fax the
questionnaire to the prescriber who will be expected to complete
and return it to Biogen Idec by fax or mail.
6.4 TYSABRI.RTM. Patient Status Report and Reauthorization
Questionnaire Process
[0346] Biogen Idec will maintain the data from each TYSABRI.RTM.
Patient Status Report and Reauthorization Questionnaire in the
TOUCH database. As described in FIG. 7, these data will be entered
into the TOUCH database whenever Biogen Idec receives a
TYSABRI.RTM. Patient Status Report and Reauthorization
Questionnaire. Biogen Idec will verify that the data are complete
and accurate. If there is missing information on the questionnaire,
Biogen Idec will contact the prescriber to provide the missing
information. If Biogen Idec does not receive the questionnaire in a
timely fashion from the prescriber, Biogen Idec has a diligence
process to obtain a completed questionnaire (described in Section
6.7). If a prescriber reports a case of PML, other serious OI, or
death on the questionnaire, Biogen Idec Drug Safety will rapidly
contact the prescriber and diligently obtain more information on
the case (described in Section 7). Biogen Idec will report to FDA
in an expedited basis (within 15 calendar days) all confirmed PML
cases, as well as cases of serious OI or death (described in
Section 10.2.1).
[0347] The TYSABRI.RTM. Patient Status Report and Reauthorization
Questionnaire data will be linked to the patient, infusion site and
prescriber data in the TOUCH database. A history of the
TYSABRI.RTM. Patient Status Report and Reauthorization
Questionnaire data will be tracked for each patient and each
prescriber. In a later phase of the program, prescribers may have
the option of using a web-based system to directly enter the
Questionnaire data into the TOUCH database. This web-based
capability may simplify monitoring of compliance with the TOUCH
Prescribing Program.
6.5 Reauthorization Process for Every Patient Every 6 Months
[0348] The prescriber must reauthorize TYSABRI.RTM. use for the
patient every 6 months using the TYSABRI.RTM. Patient Status Report
and Reauthorization Questionnaire. Note that all data fields on the
questionnaire must be completed and the answers appropriate (i.e.,
the prescriber has answered Questions A, B, C, and D as YES, YES,
NO, and NO, respectively, as described in Section 6.6). In
addition, the prescriber must authorize the continuation of
TYSABRI.RTM. in order for the patient to continue to receive
TYSABRI.RTM. treatment.
[0349] An appropriately completed questionnaire is a requirement
for the patient to continue to receive TYSABRI.RTM. treatment. In
order for the prescriber to be able to complete this questionnaire,
the Sponsor expects that the prescriber will have recently examined
the patient. By requiring reauthorization for TYSABRI.RTM. use
through the use of this questionnaire, Biogen Idec helps to
facilitate close clinical follow-up of the patient by their
prescriber, including patient-prescriber visits every 6 months.
Upon reauthorization, a Notice of Patient Authorization will be
sent to the prescriber and infusion site with the new patient
authorization period. Infusion site personnel will be prompted to
confirm that the patient is currently authorized prior to every
infusion via directions on the Pre-Infusion Patient Checklist.
[0350] If the prescriber does not reauthorize the continuation of
TYSABRI.RTM. treatment, then Biogen Idec will follow the patient
discontinuation process outlined in Section 3.7 Biogen Idec will
then send the prescriber a final follow-up TYSABRI.RTM. Patient
Discontinuation Questionnaire on this patient 6 months later, as
described in Section 6.7.
6.6 Follow-Up of Findings on the TYSABRI.RTM. Patient Status Report
and Reauthorization Questionnaires
[0351] Question A: Is this patient still under your care?
[0352] If the answer to this question is NO and the prescriber does
not know the name of the new prescriber caring for the patient,
then Biogen Idec will contact the patient to determine whether the
patient is still receiving TYSABRI.RTM. treatment and to obtain the
name and contact information of the patient's new prescriber.
[0353] If the patient is still receiving TYSABRI.RTM. treatment but
has changed prescribers, then Biogen Idec will remind the patient
of his or her obligation to notify Biogen Idec upon changing
prescribers, and will send a Prescriber/Patient Enrollment Form to
the new prescriber to request completion and return to Biogen Idec.
Then Biogen Idec will send the new prescriber a TYSABRI.RTM.
Patient Status Report and Reauthorization Questionnaire to complete
on this patient.
[0354] If the patient is no longer receiving TYSABRI.RTM.
treatment, Biogen Idec will follow the Patient Discontinuation
process outlined in Section 3.7. Biogen Idec will contact the
patient's current prescriber 6 months later to complete a
TYSABRI.RTM. Patient Discontinuation Questionnaire on this
patient.
[0355] Question B: Is the patient alive?
[0356] If the answer is NO, Biogen Idec Drug Safety will rapidly
contact the prescriber and will diligently obtain detailed
information on the case. The follow-up of death is described in
Section 7.
[0357] Question C and D: Does the patient have a diagnosis of PML
that you have not already reported to Biogen Idec? Has the patient
been hospitalized for an opportunistic infection that you have not
already reported to Biogen Idec?
[0358] If the answer to either of these questions is YES or UNDER
INVESTIGATION, Biogen Idec Drug Safety will rapidly contact the
prescriber and will diligently obtain detailed information on the
case. The follow-up of suspected PML and other serious OI is
described in Section 7.
[0359] Question E: Is the patient currently or has the patient
received intermittent courses of steroids for the treatment of MS
relapse in the previous 6 months? If YES, please indicate the
number of courses received.
[0360] These data can be used to characterize the pattern of
intermittent use of steroids in the TOUCH prescribing program
population.
[0361] Question F: Is the patient currently or has the patient
received any immunomodulatory or immunosuppressant therapies in the
previous 6 months? If YES, please indicate the type of therapy
(AVONEX, Betaseron, Copaxone, Rebif, Novantrone, Azathioprine,
Methotrexate, Mycophenolate, Cyclophosmamide, Chronic Systemic
Steroids or Other immunomodulatory or immunosuppressive therapy)
and number of months of use.
[0362] If the answer to this question is YES, Biogen Idec will send
the prescribing physician a letter warning them that TYSABRI.RTM.
is indicated for use as a monotherapy and warning against the use
of TYSABRI.RTM. in combination with other immunosuppressants or
immunomodulators.
[0363] Question G: If the patient is still under your care, do you
authorize the continuation of TYSABRI.RTM. treatment for the next 6
months for this patient?
[0364] For the patient to continue to receive TYSABRI.RTM., the
answer to question G must be YES. (Of course, the patient must not
have or be under investigation for PML or serious OI to continue
TYSABRI.RTM. treatment).
[0365] If the Answer to G is NO, then Biogen Idec will follow the
Patient Discontinuation process outlined in Section 3.7. Biogen
Idec will then send the prescriber a TYSABRI.RTM. Patient
Discontinuation Questionnaire 6 months later to ascertain the
status of the patient.
6.7 Diligence with Follow-Up of Missing TYSABRI.RTM. Patient Status
Report and Reauthorization Questionnaires
[0366] Biogen Idec will make diligent efforts to obtain a completed
TYSABRI.RTM. Patient Status Report and Reauthorization
Questionnaire from the prescriber on each authorized patient every
6 months.
[0367] For every patient every 6 months, Biogen Idec will send the
prescriber the questionnaire approximately 5 months after the first
dose or 5 months after the most recent previous TYSABRI.RTM.
Patient Status Report and Reauthorization Questionnaire (which ever
is later). If there is no response, then Biogen Idec will send the
prescriber a second copy of the questionnaire. If after these
attempts the prescriber does not provide this information, Biogen
Idec will contact the prescriber by telephone up to 3 times. If the
prescriber has still not completed the questionnaire, then Biogen
Idec will make up to 2 telephone contacts directly to the patient.
The purpose of these patient contacts is to determine the vital
status of the patient, whether the patient is on TYSABRI.RTM.
treatment, whether the patient has been hospitalized, and remind
the patient to contact their prescriber. If the patient has died or
has been hospitalized, the Biogen Idec Drug Safety will rapidly and
diligently investigate the case.
[0368] If Biogen Idec cannot reach the patient despite these
attempts, Biogen Idec will follow the Patient Discontinuation
process outlined in Section 3.7. A significant pattern of
non-compliance with these requirements on the part of the
prescriber may result in de-enrollment of the prescriber and
forfeiture to prescribe TYSABRI.RTM., upon review by the Compliance
Review Committee. Affected patients will be directed to other
authorized prescribers in the area (see Section 10.3.2).
[0369] If the patient has changed prescribers, then Biogen Idec
will contact the new prescriber to request completion and
submission of a new Prescriber/Patient Enrollment Form to Biogen
Idec. Then, Biogen Idec will send the new prescriber a TYSABRI.RTM.
Patient Status Report and Reauthorization Questionnaire to complete
on the patient and send back to Biogen Idec.
6.8 TYSABRI.RTM. Patient Discontinuation Questionnaire: Follow-Up
For Patients Who Discontinue TYSABRI.RTM. Treatment
[0370] Biogen Idec has designed several mechanisms to determine
whether a patient may have discontinued TYSABRI.RTM. treatment.
These include: [0371] A prescriber may complete, and fax in a
Patient Discontinuation Notification Form. This form will be
provided to prescribers in the Enrollment Kit. [0372] Through
monthly collection of Pre-Infusion Patient Checklists, Biogen Idec
will track TYSABRI.RTM. dosing on an individual patient basis. By
diligently following-up on any missing Pre-infusion Patient
Checklists, Biogen will identify any patient who has discontinued
TYSABRI.RTM. treatment (Section 4.7 and 4.8). [0373] Biogen Idec
will identify patient discontinuations through the TYSABRI.RTM.
Patient Status Report and Reauthorization Questionnaire (e.g., if
the prescriber does not authorize the continuation of TYSABRI.RTM.
dosing in the patient). [0374] Biogen Idec may also confirm patient
discontinuations through spontaneous reporting by the patient,
prescriber, or infusion site.
[0375] If a patient discontinues TYSABRI.RTM. treatment, Biogen
Idec will follow the Patient Discontinuation process outlined in
Section 3.7. Physicians will be expected to complete a TYSABRI.RTM.
Patient Discontinuation Questionnaire both at the time that the
patient discontinues TYSABRI.RTM. as well as 6 months after their
last dose. At both these timepoints, the prescriber will be sent a
TYSABRI.RTM. Patient Discontinuation Questionnaire to complete and
send back to Biogen Idec. This questionnaire queries the prescriber
regarding the vital status of the patient, and the occurrence of
PML or other serious OI.
[0376] The same diligence process described in Section 6.7 will be
applied to facilitate the receipt of the completed TYSABRI.RTM.
Patient Discontinuation Questionnaire. In addition, as described in
Section 6.6, if there is a report of patient death, PML, or other
serious OI on the questionnaire, then Biogen Idec Drug Safety will
rapidly contact the prescriber and will diligently obtain detailed
information on the case.
6.9 TOUCH Prescribing Program: Summary of Patient Data
Collection
[0377] At the heart of the TOUCH Prescribing Program is an
integrated, computerized, validated database that captures
enrollment, patient tracking, and drug distribution data, as
presented in FIG. 8.
[0378] Biogen Idec will collect the following data in the TOUCH
Prescribing Program:
[0379] Prescriber/Patient Enrollment Form
[0380] The Prescriber/Patient Enrollment Form will be used to
collect the following data on each patient: [0381] patient's name,
contact information, and social security number [0382] date of
birth [0383] gender [0384] signed prescriber acknowledgement [0385]
signed patient acknowledgement [0386] name of the most recent MS
therapy [0387] duration of most recent MS therapy [0388] any prior
TYSABRI.RTM. treatment [0389] infusion site information [0390]
TYSABRI.RTM. prescription
[0391] Monthly Pre-infusion Patient Checklist
[0392] The following data will be collected on each Pre-Infusion
Patient Checklist: [0393] Dosing information, i.e., whether dose
was administered, date of dosing [0394] Patient receipt of
Medication Guide [0395] Patient report of worsening neurological
symptoms lasting several days [0396] Patient report of new medical
conditions that could compromise immune function [0397] Patient
report of concomitant use of antineoplastic, immunosuppressant or
immunomodulatory agents [0398] Patient report of concomitant
steroid use [0399] Prescriber consultation in event of findings on
checklist; documentation of authorization to infuse TYSABRI.RTM.
was received [0400] Next scheduled infusion date (if known)
[0401] TYSABRI.RTM. Patient Status Report and Reauthorization and
Patient Discontinuation Questionnaires
[0402] The following data will be collected on these
questionnaires: [0403] Treating prescriber [0404] Vital Status
[0405] Occurrence of PML [0406] Occurrence of hospitalization for
an opportunistic infection [0407] Prescriber authorization to
continue TYSABRI.RTM. (Patient Reauthorization Questionnaire only)
[0408] Treatment with any concurrent immunomodulatory or
immunosuppressant therapies or chronic systemic corticosteroids
including number of months received
(Patient Reauthorization Questionnaire Only)
[0408] [0409] Treatment with intermittent corticosteroids,
including number of courses received (Patient Reauthorization
Questionnaire only)
[0410] TYSABRI.RTM. Distribution Data: [0411] Central Distributor
information: unique identifier, name, invoice number, location
shipped from [0412] SPP information: unique identifier, name,
location shipped from [0413] Shipment information: quantity
shipped, quantity returned, date [0414] Ship-to information:
identifier, name, address, class of trade [0415] Shipment
Authorization code: as obtained from TOUCH database for each
shipment
[0416] In addition to data above, Biogen Idec will collect the date
of patient discontinuation from TYSABRI.RTM. treatment (see Section
6.8), as well as data collected through the course of diligence
efforts (e.g., missing Pre-Infusion Patient Checklists, see Section
4.7). Note that diligence efforts in response to Pre-Infusion
Patient Checklists will be coordinated with diligence efforts in
response to Patient Status and Reauthorization and Discontinuation
Questionnaires.
[0417] Finally, Biogen Idec will collect adverse events reported
through the TOUCH Prescribing Program. These adverse events,
whether reported by a patient, prescriber, or other person, will be
entered and tracked in Biogen Idec's Drug Safety's Global Database
(Oracle AERS). Reporting of pre-infusion patient checklist data
will be handled consistently with section 10.2.5.
7 Special Assessments for PML, Other Serious OI, and Death
[0418] Biogen Idec Drug Safety will rapidly, diligently, and
actively seek, and follow up on, all relevant details and source
information of each case of PML, serious OL or death, both those
reported spontaneously and those reported through the Patient
Status and Reauthorization and Discontinuation Questionnaires, to
enable adequate assessment of the diagnosis, the course of the
event, and potential predisposing factors. Biogen Idec Drug Safety
will promptly contact the prescriber to request complete clinical
details on each case, as well as submission of relevant source
documentation (e.g., pathology results, microbiology results),
potential predisposing factors (e.g., prior and concurrent
therapies, underlying co-morbidities), clinical course and
outcome.
[0419] Specifically, any report of PML will be evaluated in the
following manner: [0420] Biogen Idec will rapidly attempt to
contact the prescriber to obtain detailed information about the
patient, using a PML-specific questionnaire. Biogen Idec will
request full clinical details as well as submission of source
documentation (such as clinical findings, MRI, and CSF JC viral DNA
results). [0421] A case of PML will be considered confirmed based
on pre-defined criteria that have been developed in collaboration
with external independent experts. Specifically, a case will be
considered confirmed by the presence of JC viral DNA in either the
cerebrospinal fluid (CSF) or brain biopsy, in the appropriate
clinical and MRI setting. [0422] If the diagnosis of PML is
indeterminate, the Biogen Idec will submit the source documentation
on the case to an external PML expert for an opinion of the
diagnosis. [0423] Finally, a qualitative analysis of the case will
be performed to identify any potential risk factors for PML
development (e.g., prior or concomitant therapies, underlying
co-morbidities, etc).
[0424] Similar diligence will be exercised in the investigation of
any report of serious opportunistic infection or death of any
cause. If a patient has died, the death certificate will be
obtained on the patient. If the patient was hospitalized, the
patient's hospital records will be requested. Finally, the National
Death Index will be queried to ascertain the vital status of any
patient lost to follow-up (see Section 10.2.6).
[0425] For the purpose of expedited reporting, a serious OI is
defined as an infection due to an organism that generally does not
cause disease, or causes only mild or self-limited disease, in
people with normally functioning immune systems, but causes more
significant disease in people with impaired immunity. These
infections are frequently severe, prolonged or disseminated.
Examples include esophageal candidiasis, systemic fungal
infections, pneumocystis carinii pneumonia, mycobacterial
infections (including both pulmonary and extra-pulmonary
tuberculosis), chronic intestinal cryptosporidiosis, and
disseminated viral infections (such as disseminated herpes or
cytomegalovirus infections).
[0426] For any adverse event of special interest such as PML, other
serious OI, or death, Biogen Idec Drug Safety will obtain the
patient's exposure to TYSABRI.RTM. from the TOUCH database: In
addition, Biogen Idec Drug Safety will request that the reporter
provide the patient's exposure history to TYSABRI.RTM. (if any)
prior to the patient's enrollment into the TOUCH Prescribing
Program, including any prior commercial or clinical trial exposure,
the number of doses, and the approximate dates. If such a patient
had been previously exposed to TYSABRI.RTM. in a clinical trial,
Biogen Idec Drug Safety would obtain that patient's TYSABRI.RTM.
exposure from the clinical trial database (assuming that the
reporter is able to provide the patient's name, date of birth, and
the name of the investigator who previously authorized that patient
into a TYSABRI.RTM. clinical trial or the location of the
investigational site). Thus, Biogen Idec will attempt to ascertain
the patient's total exposure to TYSABRI.RTM., both within the TOUCH
Prescribing Program and any previous exposure in clinical trials or
commercially. This will facilitate analysis of the relationship, if
any, between adverse events of interest and duration of
TYSABRI.RTM. exposure. These adverse events will be entered and
tracked in Biogen Idec Drug Safety's Global Safety Database (Oracle
AERS).
[0427] Although occurrence of PML would be considered an "expected"
event based on 21 C.F.R. 600.80 and the proposed revised Package
Insert, Biogen Idec will nevertheless report all cases with a
confirmed diagnosis of PML to the FDA on an expedited basis, i.e.,
within 15 calendar days of receipt of the case. In addition, other
serious OI or death of any cause will be reported to the FDA on an
expedited basis.
[0428] More details on the proposed reporting plan for PML, other
serious OI, and death are provided in Section 10.2.1.
8 Risk Minimization Tools
8.1 Tools for Prescribers, Patients, Infusion Sites, and Central
Pharmacies
[0429] Biogen Idec sought feedback from neurologists, infusion
sites, infusion nurses, central pharmacies and MS patients to
develop materials that would be useful, effective, and practical
for managing the risk of PML. Based upon this feedback, Biogen Idec
has developed a number of tools that will educate healthcare
providers, and thus their patients, about the potential risk for,
and consequences of, PML with TYSABRI.RTM. treatment. Biogen Idec
will use these materials, all subject to FDA review and approval,
in educating healthcare providers, and thus patients, of the known
risks and potential benefits of TYSABRI.RTM. treatment. These tools
will be distributed directly to the infusion sites and prescribers
with subsequent dissemination to patients. Patients and healthcare
providers can also access up-to-date information at Biogen Idec's
website, TYSABRI.com, and through a toll-free phone-line to Biogen
Idec's call center. Distribution of enrollment forms will be
controlled and available only from Biogen Idec and Elan directly.
Materials that are essential to implementation of the risk
management plan are listed in Table 2.
TABLE-US-00002 TABLE 2 RiskMAP Materials Material Brief Description
Patient Medication The Medication Guide describes the known risks
of Guide TYSABRI .RTM. in patient-oriented language. The Medication
Guide will accompany the package insert. In addition, the
Medication Guide will be shipped directly to infusion sites and
provided prior to every infusion to every patient. Large-Font
Large-font version of FDA-approved labeling, to facilitate Versions
of Patient readability and functionality of this information.
Medication Guide and Full Prescribing Information TOUCH PowerPoint
presentation to provide education necessary to Prescribing execute
TOUCH Prescribing Program Program Education Slide set TYSABRI .RTM.
and PowerPoint presentation that includes clinical data and an
TOUCH overview of the TOUCH Prescribing Program elements,
Prescribing intended for physicians and patients (2 sections)
Program Slide set TOUCH General description of the TYSABRI .RTM.
risk management Prescribing program outlining responsibilities for
prescribers, infusion Program Overview sites, central pharmacies,
and patients. Prescriber/Patient Form to be signed by all patients
and prescribers for Enrollment Form enrollment into the TOUCH
Prescribing Program. Infusion Site Form to be signed by infusion
sites for enrollment into the Enrollment Form TOUCH Prescribing
Program and to obtain designation as an authorized infusion site.
Only authorized infusion sites are eligible to receive TYSABRI
.RTM. shipments. Central Pharmacy Form to be signed by central
pharmacies for enrollment into Enrollment Form the TOUCH
Prescribing Program and to obtain designation as an authorized
central pharmacy. Only authorized central pharmacies are eligible
to receive TYSABRI .RTM. shipments and may dispense TYSABRI .RTM.
only to authorized infusion sites within their
organization/institution. TYSABRI .RTM. Tracking log required for
use by central pharmacies to Inventory Tracking document dispensing
of TYSABRI .RTM. to authorized infusion Log sites associated to a
central pharmacy Pre-infusion Pre-infusion Patient Checklist to be
used prior to each Patient Checklist infusion for every patient on
TYSABRI .RTM.. Checklist must be submitted to Biogen Idec upon
completion. Patient Status Form that must be filled out every 6
months to obtain patient Report and status and enable prescriber
reauthorization of the patient in Reauthorization the TOUCH Program
Questionnaire Patient A form that may be used by prescribers to
discontinue a Discontinuation patient and de-enroll them from the
TOUCH Prescribing Notification Form Program.. Patient This form
will be provided to prescribers when a patient Discontinuation
discontinues TYSABRI .RTM. treatment and 6 months after
Questionnaire discontinuation. TOUCH A folder provided to potential
prescribers that contains Enrollment Kit approved TOUCH Materials
(listed above) and outlines specific responsibilities of each of
the parties involved in the TOUCH Prescribing Program. Dear Doctor
Letter Communication to neurologists containing important safety
information regarding reintroduction of TYSABRI .RTM. Dear Patient
Letter Communication to patients who have expressed an interest in
receiving updates regarding TYSABRI .RTM., containing important
safety information regarding reintroduction of TYSABRI .RTM.
Patient Getting Brochure designed to assist patients considering
starting Started Brochure treatment with TYSABRI .RTM.. Contains
summary information on the known risks and potential benefits of
therapy, in addition to an overview of TOUCH Requirements.
Healthcare Designed for use in the infusion-setting. Provides
practical Professional step-by-step considerations for appropriate
infusion of Infusion Guide TYSABRI .RTM. and reinforcement of TOUCH
requirements. TYSABRI.com Website designed to disseminate approved
labeling information for TYSABRI .RTM. and an overview of TOUCH
Program requirements. Guidance for Document provides guidance to
healthcare professionals when Evaluation of New undertaking the
assessment and management of new or Neurologic worsening neurologic
symptoms in multiple sclerosis (MS) Symptoms in patients treated
with TYSABRI .RTM.. Patients Receiving TYSABRI .RTM. (natalizumab)
Additional Biogen Idec will support various other initiatives to
provide Education educational materials about the PML risk and
appropriate-use conditions for TYSABRI .RTM., to neurologists and
infusion nurses for use with MS patients. All neurologists in
Biogen Idec's database, including prescribers who have completed
and submitted a Prescriber/Patient Enrollment Form, will receive
periodic educational mailings. Prescribers will be expected to
share this information with their patients. These documents will be
pre-cleared with DDMAC. A toll-free help-line will provide
prescribers and nurses access to health care professionals in
Biogen Idec's medical information department who can answer
questions related to TYSABRI .RTM.. Biogen Idec will support
educational initiatives through the National MS Society (NMSS)
Infusion Nurse Society (INS), International Organization for MS
Nurses (IOMSN) and will facilitate the generation and dissemination
of medical information on PML and TYSABRI .RTM. through media such
as review articles, seminars, and Continuing Medical Education
(CME) programs directed at neurologists and infusion nurses.
9 Additional Studies
9.1 TYSABRI.RTM. Global Observational Program in Safety
(TYGRIS)
[0430] Biogen Idec proposes that a large subset of patients in the
TOUCH Prescribing Program also enroll into a voluntary
observational study called the TYSABRI.RTM.Global Observational
Program in Safety (TYGRIS).
[0431] TYGRIS will enroll approximately 5,000 patients worldwide,
of which approximately 3,000 patients will be authorized in the US,
and these patients will be systematically followed for up to 5
years. Note that in the US, only prescribers and patients already
authorized in the mandatory TOUCH Prescribing Program will be
eligible to participate in the voluntary TYGRIS study. The
objectives of this observational study are to determine the
incidence and pattern of serious infections and malignancies, as
well as the overall safety profile of TYSABRI.RTM. in MS patients
with long-term use in clinical practice.
[0432] Whereas the TOUCH Prescribing Program is focused on
determining the incidence of PML and other serious OI, TYGRIS will
evaluate newly emerging risks, if any, with TYSABRI.RTM.
monotherapy treatment in MS patients. While the safety profile of
TYSABRI.RTM. in clinical trials has been well-characterized
regarding the incidence and nature of common serious adverse events
over a 2-year period, the incidence of rare events, the safety
profile beyond 2 years, and the safety profile in clinical practice
will be better characterized in this study. For example, while the
clinical trial data on malignancy is reassuring, it would be
important to evaluate the incidence of malignancy over the longer
term because malignancies can be long-latency events. In addition
to the very targeted data collection in the TOUCH Prescribing
Program, data collection in an observational study such as TYGRIS
allows Biogen Idec to evaluate a broader range of as yet unknown
issues as well unexpected safety findings with TYSABRI.RTM. use in
the clinical practice setting.
[0433] Baseline demographic data have been collected on all
patients on the Prescriber/Patient Enrollment Form for the TOUCH
Prescribing Program, as described in Section 6.9. For patients also
participating in TYGRIS, additional baseline demographics will be
collected, including past medical history (including history of
serious infections, malignancies, other serious adverse events, and
pregnancy status, if applicable), MS history (including past or
current treatments), prior use and duration of immunomodulatory,
antineoplastic, or immunosuppressive agents, and prior detailed use
of TYSABRI.RTM..
[0434] Thereafter, prescribers participating in TYGRIS are
instructed to report any serious adverse event to Biogen Idec
within 24 hours of the site becoming aware of the event.
Participating prescribers will also be contacted every 6 months and
will be asked to provide any serious adverse events that they have
not yet reported as well as the patients' exposure to any
concomitant antineoplastic, immunomodulatory or immunosuppressant
therapies, or systemic corticosteroids. The RiskMAP discourages
concurrent use of TYSABRI.RTM. with such therapies; therefore
Biogen Idec anticipates that there should be little or no use of
such therapies concurrently with TYSABRI.RTM.. It should also be
noted that participating prescribers in TYGRIS in the US, like all
prescribers authorized in the TOUCH Prescribing Program, must also
reauthorize TYSABRI.RTM. dosing on every patient every 6
months.
[0435] Biogen Idec intends to recruit a large number of prescribers
(approximately 250 in the US) from both private and hospital-based
practices. Prescribers who will employ a central Institutional
Review Board (IRB) for the study will be given preference for
participation. In this way, Biogen Idec will strive to enroll into
TYGRIS a patient population that is representative of patients
treated in a clinical practice setting.
[0436] A sample size of 5000 MS patients will be enrolled and
followed for 5 years whether continuing on TYSABRI.RTM. or not.
Assuming a 20% discontinuation rate from TYSABRI.RTM. at the
beginning of year 2 and a 10% annual discontinuation rate from
TYSABRI.RTM. thereafter, it is estimated that 18,700 patient-years
of TYSABRI.RTM. exposure will be completed in this study. Assuming
approximately 1000 patient-years lost to follow-up, a total of
24,000 patient-years of follow-up will accrue. This study design
will allow the detection of important rare serious adverse
reactions that occur with an incidence of 0.06% with a 95%
probability and an incidence of 0.05% with 92% probability.
9.2 Pregnancy Registry
[0437] Biogen Idec will establish a Pregnancy Registry in the US to
determine the safety of TYSABRI.RTM. in pregnant patients.
Approximately 300 TYSABRI.RTM.-exposed pregnant MS patients will be
authorized. The primary objective of this study will be to evaluate
any pattern or increase in birth defects in children of women with
multiple sclerosis who were exposed to TYSABRI.RTM. at any time
within 3 months prior to conception, or at any time during
pregnancy, where the outcome of the pregnancy is unknown at the
time of enrollment. The secondary objectives will be to
descriptively evaluate the following outcomes in pregnant women
exposed to natalizumab: live born infants, fetal loss (stillbirths,
elective/spontaneous abortions), and gestational age, body weight,
gender, head circumference, and length of child. Biogen Idec
committed to this study as part of the post-approval commitments
for the initial BLA.
9.3 Safety of Re-Exposure to TYSABRI.RTM.
[0438] In order to evaluate the safety of TYSABRI.RTM. with
re-exposure after an interval without treatment, Biogen Idec will
conduct two multi-national, open-label studies. Approximately 1,500
patients with MS who previously received TYSABRI.RTM. treatment
during their participation in clinical studies will be
authorized.
9.4 Effect of TYSABRI.RTM. on Immune Function
[0439] Biogen Idec will conduct a study in approximately 40 MS
patients to evaluate the effect of TYSABRI.RTM. on humoral and
cellular immunity to recall and neo-antigens. Both cellular (ex
vivo proliferation responses) and humoral (specific serum
immunoglobulin) immune responses to recall vaccine antigens (e.g.,
tetanus and pneumovax) and naive antigens (KLH) will be studied
with or without natalizumab treatment. Data from this study may
provide information into potential immunological risk factors for
PML with TYSABRI.RTM. treatment. Biogen Idec committed to this
study as part of the post-approval commitments to the initial
BLA.
9.5 Non-Clinical Studies
[0440] A direct animal model of JC virus associated PML has not
been described. Biogen Idec will initiate specific in vitro studies
to investigate the effects of natalizumab interaction with specific
cellular targets and functions with respect to JC virus infection
and replication. In addition, the effects of short-term alpha
4-integrin inhibition in rodent and guinea pig experimental
autoimmune encephalomyelitis will be evaluated, specifically with
respect to effects on immune function. These non-clinical studies,
while exploratory, may provide insights into potential
immunological risk factors for PML with TYSABRI.RTM. therapy.
10 Evaluation/Quality Plan
[0441] Biogen Idec and Elan are committed to evaluating the
effectiveness of the TYSABRI.RTM. RiskMAP and reporting the results
on a quarterly basis to the FDA. Each submission will include two
major datasets: (1) Health Outcomes Data (e.g., PML rate, overall
safety), and (2) Systems/Process Data, Quality and Compliance
Metrics. The specific type and frequency of data that the Sponsor
will submit to the FDA is outlined in detail in this Section. A
more detailed description of the systems and compliance data being
monitored and evaluated can be found in the Quality Plan.
[0442] A key feature of the Sponsor's RiskMAP evaluation process
will be internal senior management review of these data by a
multi-disciplinary TYSABRI.RTM. Risk Management Review
Committee.
[0443] The Evaluation/Quality Plan will allow Biogen Idec to assess
the effectiveness of the RiskMAP in an ongoing fashion and to
improve the plan, as necessary.
10.1 TYSABRI.RTM. Risk Management Review Committee
[0444] A multi-disciplinary TYSABRI.RTM. Risk Management Review
Committee composed of senior representatives from Biogen Idec and
Elan's Drug Safety, Clinical, Commercial, Regulatory, Legal, and
Quality Departments will be formed. This Committee will evaluate
the effectiveness of the risk management plan on a quarterly basis,
both from a health outcomes perspective (e.g., PML rate, overall
safety) as well from a systems/process perspective (e.g., Quality
Plan execution and systems/compliance metrics). This Committee will
also make decisions regarding any major corrective actions to the
RiskMAP, if needed. The decisions and outcomes of this Committee
will be included in the quarterly reports to the FDA.
10.1.1 TYSABRI.RTM. Safety Review Committee
[0445] Biogen Idec and Elan will create a joint TYSABRI.RTM. Safety
Review Committee chaired by Drug Safety and Risk Management of
Biogen Idec and composed of a cross-functional team from both
Biogen Idec and Elan. The Purpose of this Committee is to review
TYSABRI.RTM. safety data and to determine appropriate corrective
actions, if needed. The Committee will meet on a regular basis to
review the data discussed in Section 10.2 of this document.
10.1.2 TYSABRI.RTM. Compliance Review Committee
[0446] Biogen Idec and Elan will create a joint TYSABRI.RTM.
Compliance Review Committee chaired by Quality at Biogen Idec and
composed of a cross-functional team from both Biogen Idec and Elan.
The Purpose of this Committee is to facilitate RiskMAP compliance
and effective execution of the Quality Plan. The Committee will
meet on a monthly basis, and as needed, to review results from
monitoring of operational processes, distribution data, audit data
and any emerging trends or out of tolerance levels. In addition,
this committee will determine the appropriate corrective action to
be taken to address non-compliance and to ensure continuous
improvement for any of the RiskMAP activities.
10.2 Health Outcomes Evaluation
[0447] The following results will be provided to the FDA, according
to Table 3.
TABLE-US-00003 TABLE 3 Health Outcomes Evaluation: Metrics and
Methods. Expected date after re-introduction into Metric Evaluation
method US market Baseline Demographics in TOUCH TOUCH Quarterly for
the first Prescribing Program (i.e., summary Prescribing year,
biannually statistics on age, gender, relapsing MS Program: (every
6 months) for diagnosis, most recent MS therapy, any Enrollment
Form 2 years, then prior TYSABRI .RTM. exposure) annually
thereafter Proportion of patients who have TOUCH Quarterly for the
first received concurrent immunomodulatory Prescribing year,
biannually or immunosuppressant agents or Program: Patient (every 6
months) for chronic systemic corticosteroids and Status and 2
years, then months of exposure to such therapies** Reauthorization
annually thereafter Proportion of patients who have Form received
intermittent corticosteroids and number of courses received
Baseline Demographics in TYGRIS TYGRIS Study Quarterly for the
first (i.e., summary statistics as above, as year, biannually well
as past MS history, all prior (every 6 months) for immunomodulatory
and 2 years, then immunosuppressant therapies, past annually
thereafter medical history, past serious
infections/malignancies/other SAEs) Proportion of patients
concurrently TYGRIS Study Quarterly for the first treated with
immunomodulatory or year, biannually immunosuppressant agents**
(every 6 months) for 2 years, then annually thereafter Listings and
case narratives for all TOUCH Quarterly for the first confirmed and
suspected PML cases, Prescribing year, biannually other serious OI,
and deaths; Program (every 6 months) for Estimate of PML and other
serious OI 2 years, then incidence and rate (based on number of
annually thereafter confirmed cases per 1000 persons/person-years
of exposure); qualitative analysis of risk factors for PML and
other serious OI based on review of confirmed cases Listing,
incidence, and rate of patients TOUCH Quarterly for the first who
discontinued TYSABRI .RTM. Prescribing year, biannually Program
(every 6 months) for 2 years, then annually thereafter
Post-Marketing Safety Adverse Events PSUR* every 3 collected from
the months for first 2 TOUCH years, then semi- Prescribing Program
annually Incidence and pattern of serious TYGRIS Study Yearly
Interim infections and malignancies Clinical Study Reports Note
that related SAEs from TYGRIS will be provided in the PSUR*.
Results of National Death Index Search National Death Every 12
months Index Safety with Re-Treatment IND Annual Report Annually
(final for Re-Dosing Clinical Study Studies Report when studies
completed) Note that related SAEs from these studies will be
provided in the PSUR*. TYSABRI .RTM. impact on immune IND Annual
Report Annually (as well as function for Immune final Clinical
Study Function/Vaccine Report when studies Study completed) Note
that related SAEs from these studies will be provided in the PSUR*.
TYSABRI .RTM. impact on pregnancy Pregnancy Registry Analyses will
be outcomes provided in the PSUR*. *PSUR = Periodic Safety Update
Report, please see Section 10.2.4 **Consistent with the PI, TYSABRI
.RTM. is not ordinarily recommended in patients who are receiving
chronic immunosuppressant or immunomodulatory therapy; therefore
Biogen Idec anticipates little or no reported use of TYSABRI .RTM.
under these circumstances in the TOUCH Prescribing Program.
10.2.1 Expedited Reporting of Events of Interest (e.g., PML,
Serious OI, Death) in the TOUCH Prescribing Program
[0448] Following the commercial re-introduction of TYSABRI.RTM.
into the US market, the Sponsor is proposing the following paradigm
for the reporting of adverse events in the TOUCH Prescribing
Program.
[0449] All spontaneous and solicited adverse event reports from any
post-marketing source will be reported as per 21 CFR 600.80
(Post-marketing Reporting of Adverse Experiences).
[0450] In addition, the following describes the process for
expedited reporting for key safety events from any source in the
post-marketing space:
[0451] Progressive Multifocal Leukoencephalopathy:
[0452] The Sponsor will diligently follow-up on any report of
possible PML, and will expedite to FDA within 15 calendar days any
PML case considered confirmed by the presence of JC viral DNA in
the CSF or brain biopsy in the appropriate clinical and MRI
setting. All other possible cases, not confirmed by the presence of
JC viral DNA in the CSF or brain biopsy, will be reported quarterly
in the Periodic Report (Section 10.2.4).
[0453] Other Serious Opportunistic Infections and Deaths of Any
Cause:
[0454] The Sponsor will diligently follow-up on and provide
expedited reporting to FDA within 15 calendar days of receiving any
report of other serious opportunistic infections or deaths of any
cause. The definition for serious OI is provided in Section 7.
10.2.2 Expedited Reporting of Events of Interest from TYSABRI.RTM.
Studies and Clinical Trials
[0455] The Sponsor is proposing the following paradigm for the
reporting of adverse events in TYSABRI.RTM. studies and clinical
trials (i.e., TYGRIS and Re-Dosing Studies).
[0456] In TYSABRI.RTM. studies and clinical trials, all serious
unexpected and related events will be reported in an expedited
fashion to the Agency as per 21 CFR 312.32 (IND Safety
Reports).
[0457] In addition, the following describes the process for
expedited reporting for key safety events from any TYSABRI.RTM.
studies or clinical trials:
[0458] Progressive Multifocal Leukoencephalopathy:
[0459] The Sponsor will diligently follow-up on any report of
possible PML, and will expedite to FDA within 15 calendar days any
PML case considered confirmed by the presence of JC viral DNA in
the CSF or brain biopsy in the appropriate clinical and MRI
setting, regardless of the investigator causality assessment.
Other Serious Opportunistic Infections:
[0460] The Sponsor will diligently follow-up on and expedite to FDA
within 15 calendar days of receiving any report of other serious
opportunistic infections, regardless of the investigator causality
assessment. The definition for serious OI is provided in Section
7.
[0461] Deaths of Any Cause:
[0462] The Sponsor will diligently follow-up on any report of death
and expedite to FDA within 15 calendar days any report of death
that is unexpected and considered related according to the
investigator. However, if the death is due to a confirmed case of
PML or a serious OI, then the Sponsor will expedite within 15
calendar days regardless of the investigator causality
assessment.
10.2.3 PML and Other Serious OI Incidence, Rate and Risk
Factors
[0463] Biogen Idec will closely monitor the incidence, rate, and
morbidity and mortality of PML and other serious OI over time after
the re-introduction of TYSABRI.RTM. into the US market. Any
clinically significant change in the risk of PML or other serious
OI will trigger a prompt discussion with the FDA and appropriate
action.
[0464] In addition, cases of confirmed PML and other serious OI
will be tabulated every 3 months after re-introduction and provided
to the FDA expressed as: [0465] Number of cases per estimate of
total population exposed (cases/persons exposed) [0466] Number of
cases per estimate of person-years of TYSABRI.RTM. exposure
(cases/person-years exposure) [0467] A qualitative analysis of any
confirmed cases of PML and other serious OI will be made to
identify any potential risk factors (e.g., prior or concomitant
therapies, underlying co-morbidities, etc).
[0468] The person-years of exposure will be derived from the total
number of patients treated with TYSABRI.RTM. in the TOUCH
Prescribing Program and from the total number of TYSABRI.RTM.
infusion administered (the latter will be obtained from the
submitted Pre-Infusion Patient Checklist data).
10.2.4 Periodic Reports
[0469] Biogen Idec and Elan are proposing to substitute the
Periodic Adverse Event Report (PAER) (as per 21 CFR 600.80 (c)(2)),
with the international Periodic Safety Update Report (PSUR) (as per
the International Conference on Harmonization (ICH) guideline
designated as ICH-E2C and published in the Federal Register on 19
May 1997).
[0470] This PSUR will be submitted quarterly for the first 2 years
after re-introduction of TYSABRI.RTM., and semi-annually
thereafter.
10.2.5 Reporting of Pre-Infusion Patient Checklist Data
[0471] Biogen Idec will collect Pre-Infusion Patient Checklists to
monitor infusion site compliance with this important requirement
and to track the dosing of TYSABRI.RTM. on an individual patient
basis. As discussed at the Advisory Committee meeting, Biogen Idec
expects that these checklists, collectively, will contain an
extremely high prevalence of reports of "worsening symptoms" that
are, in fact, MS symptoms, including relapses. The Pre-Infusion
Checklist is designed to trigger further follow-up (i.e.,
neurological consultation) under theses circumstances, and
prescribers are required to report any cases of PML to Biogen Idec.
Thus, Biogen Idec does not intend to report all cases of
"continuously worsening symptoms" received in monthly Pre-Infusion
Patient Checklists as adverse drug experiences under 21 C.F.R.
600.80. Instead, Biogen Idec will report all confirmed cases of
PML, as well as serious opportunistic infections and deaths on an
expedited basis.
10.2.6 Results of National Death Index search
[0472] The National Death Index will be queried to ascertain the
vital status of any patient lost to follow-up. The National Death
Index provides a match with identifiers for a person who has died,
the State of death, and the death certificate number. Then Biogen
Idec will request the death certificates from the State Health
Department. Recognizing that there is a lag time of approximately
18 months between patient death and the updating of records in the
National Death Index, the results of these queries will be provided
to the FDA every 12 months after commercial re-introduction.
10.3 Systems/Process, Quality and Compliance Metrics
[0473] The following results will be provided to the FDA, according
to Table 4.
TABLE-US-00004 TABLE 4 Systems and Processes: Metrics and Methods
Metric Evaluation method Expected Date Prescriber knowledge and
behavior Prescriber survey Every 6 months regarding TYSABRI .RTM.
and PML Infusion nurse knowledge and behavior Infusion nurse survey
Every 6 months regarding TYSABRI .RTM. and PML Availability and use
of tools at infusion Prescriber survey and Every 6 months sites and
prescriber offices infusion nurse survey Percentage of vials
shipped to Distribution data Quarterly for authorized infusion
sites and central the first year, pharmacies biannually (every 6
months) for 2 years, then annually thereafter Number of authorized
patients, Enrollment Forms Quarterly for prescribers, infusion
sites, central pharmacies the first year, biannually (every 6
months) for 2 years, then annually thereafter Number of infusions
administered Pre-Infusion Patient Quarterly for Checklists and
Phone the first year, calls to Infusions Sites biannually (every 6
months) for 2 years, then annually thereafter Percent and Number of
Pre-Infusion Pre-Infusion Patient Quarterly for Checklists received
by Biogen Idec Checklists the first year, based on Confirmed
Infusions biannually (every 6 months) for 2 years, then annually
thereafter Number of Checklists with a "No" Pre-Infusion Patient
Quarterly for response to Questions 1-4, number Checklists the
first year, where infusion withheld, number where biannually
infusion was administered, number (every 6 where prescriber was
contacted, number months) for 2 where prescriber was unable to be
years, then contacted annually thereafter Percent and Number of
TYSABRI .RTM. TYSABRI .RTM. Patient Quarterly for Patient Status
and Re-Authorization Status Report and the first year,
Questionnaire completed compared to Reauthorization biannually
questionnaires sent Questionnaire data (every 6 months) for 2
years, then annually thereafter Number of TYSABRI .RTM. patients
dosed TYSABRI .RTM. Patient Annually outside of the
re-authorization period Status Report and Questionnaire data, and
Pre-Infusion Checklists Infusion Site compliance with Pre-infusion
Patient Quarterly for submission of completed Pre-infusion
Checklists the first year, Patient Checklists biannually (every 6
months) for 2 years, then annually thereafter
[0474] The utility and ongoing need for the TOUCH Prescribing
Program will be assessed 3 years after the re-introduction of
TYSABRI.RTM..
10.3.1 Audit Plan
[0475] Biogen Idec and Elan plan a detailed surveillance and audit
process to monitor TOUCH Prescribing Program compliance and the
control and dispensing of the drug. The ongoing monitoring will
include verification of the completed Pre-Infusion Patient
Checklists against data from the TOUCH Prescribing Program,
verification of all distribution data to ensure that TYSABRI.RTM.
is only shipped to authorized infusion sites and central
pharmacies, that patients are affiliated to authorized infusion
sites, and that pre-infusion checklists are collected from infusion
sites and in alignment with distribution data. In addition to
ongoing monitoring and reconciliation, Biogen Idec's Quality group
will conduct audits at a select number of central pharmacies and
infusion sites. Sites will be selected for audit based on a random
sampling, taking into account geographic region and infusion center
type. The auditors will perform a physical inventory and review
accountability of product at the site. The auditors will also
review certain TOUCH Prescribing Program related documentation. The
auditors will report on noted discrepancies, such as, discrepancies
in inventory levels or in TOUCH Prescribing Program forms.
Significant noncompliance will be included in established exception
reports and reviewed by the TYSABRI.RTM. Compliance Review
Committee.
[0476] Routine compliance audits will be conducted at the single
distributor and specialty pharmacies. As warranted, for cause
audits will be conducted at a given site authorized in the TOUCH
Prescribing Program.
[0477] Additional details of the monitoring and surveillance of the
TOUCH program is contained in the Quality Plan.
10.3.2 De-Enrollment Process for Prescribers, Patients, Infusion
Sites, Central Pharmacies, and Central Pharmacies for
Non-Compliance
[0478] The Compliance Review Committee will review drug
distribution, Pre-Infusion Patient Checklist, and TYSABRI.RTM.
Patient Status Report and Reauthorization Questionnaire compliance
data to ensure all parties are compliant. The committee will review
exceptions, monthly and on a case by case basis, and will make
determinations as to whether any parties should be de-authorized in
the TOUCH Prescribing Program due to significant
non-compliance.
[0479] The system to handle non-compliance will be modeled after
the Biogen Idec exception system used in the manufacturing, testing
and distribution of product. Quality approved procedures will
address identification, notification, investigation, impact
assessment, corrective and preventive action, escalation, tracking,
monitoring, trending and documentation for exceptions. An exception
will be classified as major or minor based upon potential for
significant impact on the objectives of the TOUCH Prescribing
Program. An exception classified as minor is not likely to impact
the objectives of the RiskMAP, however, recurring minor exceptions
may be classified as major and may be indicative of a system issue.
The Compliance Review Committee will promptly review major
exceptions. Quality will reside over the Committee and have
oversight in determination of corrective and preventive actions
taken to address the root cause of non-compliance. In addition,
exceptions will be reviewed monthly by the Compliance Review
Committee, and quarterly by the TYSABRI.RTM. Management Review
Committee, to assess suitability and effectiveness of procedures,
processes and systems to meet the objectives of the RiskMAP.
10.3.2.1 Prescriber De-Enrollment Process for Non-Compliance
[0480] Significant non-compliance with the requirements of the
TOUCH Prescribing Program may result in de-enrollment of the
prescriber and forfeiture of the authorization to prescribe
TYSABRI.RTM.. The Compliance Review Committee will consider such
cases on a case-by-case basis. Affected patients will be directed
to other authorized prescribers in the area; if this is not
possible, then the affected patients could potentially be
de-authorized as well.
10.3.2.2 Patient De-Enrollment Process for Non-Compliance
[0481] If a patient discontinues TYSABRI.RTM. as indicated on the
TYSABRI.RTM. Patient Status Report and Reauthorization
Questionnaire, or by notifying Biogen Idec, Biogen Idec will follow
the Patient Discontinuation process outlined in Section 3.7. If a
prescriber indicates that a patient is lost to follow-up, Biogen
Idec will contact that patient. If the patient plans to continue
TYSABRI.RTM.-treatment, he/she will be instructed to contact his or
her new prescriber to complete a new Prescriber/Patient Enrollment
form. If the form is not completed or Biogen Idec is unable to
reach the patient, Biogen Idec will follow the Patient
Discontinuation process outlined in Section 3.7.
10.3.2.3 Infusion Site Process for Non-Compliance
[0482] An authorized infusion site will be informed that
significant non-compliance with the requirements of the TOUCH
Prescribing Program may result in de-enrollment of the infusion
site and forfeiture of its authorization to administer
TYSABRI.RTM.. Actionable non-compliance may include actions such as
dosing a non-authorized TYSABRI.RTM. patient, and non-compliance
with the requirement to complete and submit the Pre-infusion
Patient Checklist. The Compliance Review Committee will consider
such cases on a case-by-case basis. In such cases, Biogen Idec will
provide patients and prescribers with information about other
authorized infusion sites in the area. Biogen Idec will notify
central pharmacies not to distributed TYSABRI.RTM. to de-authorized
infused sites.
10.3.2.4 Central Pharmacies Process for Non-Compliance
[0483] Significant noncompliance with the requirements of the TOUCH
Prescribing Program may result in de-enrollment of the central
pharmacy and forfeiture of the authorization to dispense
TYSABRI.RTM.. Actionable non-compliance may include dispensing
TYSABRI.RTM. to non-authorized infusion sites. The Compliance
Review Committee will consider such cases on a case-by-case basis.
Biogen Idec will notify infusion sites affiliated with central
pharmacies about the central pharmacy de-enrollment.
10.3.2.5 Specialty Pharmacies
[0484] Specialty Pharmacies are contractually obligated to comply
with the controlled distribution system requirements. Noncompliance
with the RiskMAP requirements may result in de-enrollment of the
Specialty Pharmacy and forfeiture of the authorization to dispense
TYSABRI.RTM.. Actionable non-compliance may include dispensing
TYSABRI.RTM. to non-authorized infusion sites or not providing
distribution data. The Compliance Review Committee will consider
such cases on a case-by-case basis.
10.3.3 Assessment of Knowledge and Behaviors
[0485] Knowledge, attitude and behavior (KAB) surveys will be
developed to survey, prescribers and infusion site nurses on their
knowledge of the key risk management messages of the TYSABRI.RTM.
Risk Management Program and the actions taken to minimize risk. The
surveys will be developed and tested prior to implementation using
standard psychometric methods for survey research (e.g., health
literacy, content validity). A more detailed description of the
surveys will be provided to the FDA after approval.
10.3.3.1 Prescriber Survey
[0486] A sample of prescribers identified from the group of
prescribers who have authorized into the TOUCH prescribing program
will be invited to participate in the prescriber survey. For
generalizability of results, a randomly selected statistical sample
of prescribers will be used. Prescriber samples will be mailed a
KAB survey and asked to return it in a postage paid envelope. If
the survey is not returned within 2 weeks, a follow-up reminder
post card will be mailed. Prescribers who do not respond within
another two weeks will be telephoned and surveyed by direct
interview. Each selected sample will be unique, i.e., prescribers
will be interviewed only once in any given one year period.
10.3.3.2 Infusion Nurse Survey
[0487] A randomly selected, statistical sample of infusion nurses
from the list of authorized infusion sites will be selected for the
infusion nurse survey. An attempt will be made to include nurses
who administer the Pre-Infusion Patient Checklist and infuse
TYSABRI.RTM.. The selected infusion nurse will be mailed a KAB
survey and asked to return it in a postage paid envelope. If the
survey is not returned within 2 weeks, a follow-up reminder post
card will be mailed. Infusion site nurses who do not respond within
another two weeks will be telephoned and surveyed by direct
interview.
Example 2
Exemplary Computer Implementation
[0488] In an exemplary computer implementation, FIG. 9 is a block
diagram of computing devices and systems 400, 450. Computing device
400 is intended to represent various forms of digital computers,
such as laptops, desktops, workstations, personal digital
assistants, servers, blade servers, mainframes, and other
appropriate computers. Computing device 450 is intended to
represent various forms of mobile devices, such as personal digital
assistants, cellular telephones, smartphones, and other similar
computing devices. The components shown here, their connections and
relationships, and their functions, are meant to be exemplary only,
and are not meant to limit implementations of the inventions
described and/or claimed in this document.
[0489] Computing device 400 includes a processor 402, memory 404, a
storage device 406, a high-speed interface 408 connecting to memory
404 and high-speed expansion ports 410, and a low speed interface
412 connecting to low speed bus 414 and storage device 406. Each of
the components 402, 404, 406, 408, 410, and 412, are interconnected
using various busses, and can be mounted on a common motherboard or
in other manners as appropriate. The processor 402 can process
instructions for execution within the computing device 400,
including instructions stored in the memory 404 or on the storage
device 406 to display graphical information for a GUI on an
external input/output device, such as display 416 coupled to high
speed interface 408. In other implementations, multiple processors
and/or multiple buses can be used, as appropriate, along with
multiple memories and types of memory. Also, multiple computing
devices 400 can be connected, with each device providing portions
of the necessary operations (e.g., as a server bank, a group of
blade servers, or a multi-processor system).
[0490] The memory 404 stores information within the computing
device 400. In one implementation, the memory 404 is a
computer-readable medium. In one implementation, the memory 404 is
a volatile memory unit or units. In another implementation, the
memory 404 is a non-volatile memory unit or units.
[0491] The storage device 406 is capable of providing mass storage
for the computing device 400. In one implementation, the storage
device 406 is a computer-readable medium. In various different
implementations, the storage device 406 can be a floppy disk
device, a hard disk device, an optical disk device, or a tape
device, a flash memory or other similar solid state memory device,
or an array of devices, including devices in a storage area network
or other configurations. In one implementation, a computer program
product is tangibly embodied in an information carrier. The
computer program product contains instructions that, when executed,
perform one or more methods, such as those described above. The
information carrier is a computer- or machine-readable medium, such
as the memory 404, the storage device 406, memory on processor 402,
or a propagated signal.
[0492] The high speed controller 408 manages bandwidth-intensive
operations for the computing device 400, while the low speed
controller 412 manages lower bandwidth-intensive operations. Such
allocation of duties is exemplary only. In one implementation, the
high-speed controller 408 is coupled to memory 404, display 416
(e.g., through a graphics processor or accelerator), and to
high-speed expansion ports 410, which can accept various expansion
cards (not shown). In the implementation, low-speed controller 412
is coupled to storage device 406 and low-speed expansion port 414.
The low-speed expansion port, which can include various
communication ports (e.g., USB, Bluetooth, Ethernet, wireless
Ethernet) can be coupled to one or more input/output devices, such
as a keyboard, a pointing device, a scanner, or a networking device
such as a switch or router, e.g., through a network adapter.
[0493] The computing device 400 can be implemented in a number of
different forms, as shown in the figure. For example, it can be
implemented as a standard server 420, or multiple times in a group
of such servers. It can also be implemented as part of a rack
server system 424. In addition, it can be implemented in a personal
computer such as a laptop computer 422. Alternatively, components
from computing device 400 can be combined with other components in
a mobile device (not shown), such as device 450. Each of such
devices can contain one or more of computing device 400, 450, and
an entire system can be made up of multiple computing devices 400,
450 communicating with each other.
[0494] Computing device 450 includes a processor 452, memory 464,
one or more input/output device such as a display 454, a
communication interface 466, and a transceiver 468, among other
components. The device 450 can also be provided with a storage
device, such as a microdrive or other device, to provide additional
storage. Each of the components 450, 452, 464, 454, 466, and 468,
are interconnected using various buses, and several of the
components can be mounted on a common motherboard or in other
manners as appropriate.
[0495] The processor 452 can process instructions for execution
within the computing device 450, including instructions stored in
the memory 464. The processor can also include separate analog and
digital processors. The processor can provide, for example, for
coordination of the other components of the device 450, such as
control of user interfaces, applications run by device 450, and
wireless communication by device 450.
[0496] Processor 452 can communicate with a user(s) through one or
more control interface 458 and display interface 456 coupled to a
display 454. The display 454 can be, for example, a TFT LCD display
or an OLED display, or other appropriate display technology. The
display interface 456 can comprise appropriate circuitry for
driving the display 454 to present graphical and other information
to a user. The control interface 458 can receive commands from a
user and convert them for submission to the processor 452. In
addition, an external interface 462 can be provide in communication
with processor 452, so as to enable near area communication of
device 450 with other devices. External interface 462 can provide,
for example, for wired communication (e.g., via a docking
procedure) or for wireless communication (e.g., via Bluetooth or
other such technologies).
[0497] The memory 464 stores information within the computing
device 450. In one implementation, the memory 464 is a
computer-readable medium. In one implementation, the memory 464 is
a volatile memory unit or units. In another implementation, the
memory 464 is a non-volatile memory unit or units. Expansion memory
474 can also be provided and connected to device 450 through
expansion interface 472, which can include, for example, a SIMM
card interface. Such expansion memory 474 can provide extra storage
space for device 450, or can also store applications or other
information for device 450. Specifically, expansion memory 474 can
include instructions to carry out or supplement the processes
described above, and can include secure information also. Thus, for
example, expansion memory 474 can be provide as a security module
for device 450, and can be programmed with instructions that permit
secure use of device 450. In addition, secure applications can be
provided via the SIMM cards, along with additional information,
such as placing identifying information on the SIMM card in a
non-hackable manner.
[0498] The memory can include for example, flash memory and/or MRAM
memory, as discussed below. In one implementation, a computer
program product is tangibly embodied in an information carrier. The
computer program product contains instructions that, when executed,
perform one or more methods, such as those described above. The
information carrier is a computer- or machine-readable medium, such
as the memory 464, expansion memory 474, memory on processor 452,
or a propagated signal.
[0499] Device 450 can communicate wirelessly through communication
interface 466, which can include digital signal processing
circuitry where necessary. Communication interface 466 can provide
for communications under various modes or protocols, such as GSM
voice calls, SMS, EMS, or MMS messaging, CDMA, TDMA, PDC, WCDMA,
CDMA2000, or GPRS, among others. Such communication can occur, for
example, through radio-frequency transceiver 468. In addition,
short-range communication can occur, such as using a Bluetooth,
WiFi, or other such transceiver (not shown). In addition, GPS
receiver module 470 can provide additional wireless data to device
450, which can be used as appropriate by applications running on
device 450.
[0500] Device 450 can also communication audibly using audio codec
460, which can receive spoken information from a user and convert
it to usable digital information. Audio codex 460 can likewise
generate audible sound for a user, such as through a speaker, e.g.,
in a handset of device 450. Such sound can include sound from voice
telephone calls, can include recorded sound (e.g., voice messages,
music files, etc.) and can also include sound generated by
applications operating on device 450.
[0501] The computing device 450 can be implemented in a number of
different forms, as shown in the figure. For example, it can be
implemented as a cellular telephone 480. It can also be implemented
as part of a smartphone 482, personal digital assistant, or other
similar mobile device.
[0502] Where appropriate, the systems and the functional operations
described in this specification can be implemented in digital
electronic circuitry, or in computer software, firmware, or
hardware, including the structural means disclosed in this
specification and structural equivalents thereof, or in
combinations of them. The techniques can be implemented as one or
more computer program products, i.e., one or more computer programs
tangibly embodied in an information carrier, e.g., in a machine
readable storage device or in a propagated signal, for execution
by, or to control the operation of, data processing apparatus,
e.g., a programmable processor, a computer, or multiple computers.
A computer program (also known as a program, software, software
application, or code) can be written in any form of programming
language, including compiled or interpreted languages, and it can
be deployed in any form, including as a stand alone program or as a
module, component, subroutine, or other unit suitable for use in a
computing environment. A computer program does not necessarily
correspond to a file. A program can be stored in a portion of a
file that holds other programs or data, in a single file dedicated
to the program in question, or in multiple coordinated files (e.g.,
files that store one or more modules, sub programs, or portions of
code). A computer program can be deployed to be executed on one
computer or on multiple computers at one site or distributed across
multiple sites and interconnected by a communication network.
[0503] The processes and logic flows described in this
specification can be performed by one or more programmable
processors executing one or more computer programs to perform the
described functions by operating on input data and generating
output. The processes and logic flows can also be performed by, and
apparatus can be implemented as, special purpose logic circuitry,
e.g., an FPGA (field programmable gate array) or an ASIC
(application specific integrated circuit).
[0504] Processors suitable for the execution of a computer program
include, by way of example, both general and special purpose
microprocessors, and any one or more processors of any kind of
digital computer. Generally, the processor will receive
instructions and data from a read only memory or a random access
memory or both. The essential elements of a computer are a
processor for executing instructions and one or more memory devices
for storing instructions and data. Generally, a computer will also
include, or be operatively coupled to receive data from or transfer
data to, or both, one or more mass storage devices for storing
data, e.g., magnetic, magneto optical disks, or optical disks.
Information carriers suitable for embodying computer program
instructions and data include all forms of non volatile memory,
including by way of example semiconductor memory devices, e.g.,
EPROM, EEPROM, and flash memory devices; magnetic disks, e.g.,
internal hard disks or removable disks; magneto optical disks; and
CD ROM and DVD-ROM disks. The processor and the memory can be
supplemented by, or incorporated in, special purpose logic
circuitry.
[0505] To provide for interaction with a user, aspects of the
described techniques can be implemented on a computer having a
display device, e.g., a CRT (cathode ray tube) or LCD (liquid
crystal display) monitor, for displaying information to the user
and a keyboard and a pointing device, e.g., a mouse or a trackball,
by which the user can provide input to the computer. Other kinds of
devices can be used to provide for interaction with a user as well;
for example, feedback provided to the user can be any form of
sensory feedback, e.g., visual feedback, auditory feedback, or
tactile feedback; and input from the user can be received in any
form, including acoustic, speech, or tactile input.
[0506] The techniques can be implemented in a computing system that
includes a back-end component, e.g., as a data server, or that
includes a middleware component, e.g., an application server, or
that includes a front-end component, e.g., a client computer having
a graphical user interface or a Web browser through which a user
can interact with an implementation, or any combination of such
back-end, middleware, or front-end components. The components of
the system can be interconnected by any form or medium of digital
data communication, e.g., a communication network. Examples of
communication networks include a local area network ("LAN") and a
wide area network ("WAN"), e.g., the Internet.
[0507] The computing system can include clients and servers. A
client and server are generally remote from each other and
typically interact through a communication network. The
relationship of client and server arises by virtue of computer
programs running on the respective computers and having a
client-server relationship to each other.
Example 3
Forms
[0508] A number of embodiments of the invention have been
described. Nevertheless, it will be understood that various
modifications may be made without departing from the spirit and
scope of the invention. Accordingly, other embodiments are within
the scope of the following claims.
* * * * *