66440 Federal Register / Vol. 70, No. 211 / Wednesday, November 2, 2005 / Notices 

Dated: October 25, 2005. 

Carolyn M. Clancy, 

Director. 

[FR Doc. 05–21866 Filed 11–1–05; 8:45 am] 

BILLING CODE 4160–90–M 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Administration on Aging 

2005 White House Conference on 

Aging 

AGENCY: Administration on Aging, HHS. 

ACTION: Notice of conference call. 

SUMMARY: Pursuant to section 10(a) of 

the Federal Advisory Committee Act as 

amended (5 U.S.C. Appendix 2), notice 

is hereby given that the Policy 

Committee of the 2005 White House 

Conference on Aging will vote on the 

Annotated Agenda for the WHCoA and 

may discuss other items related to 

finalizing the 2005 WHCoA during a 

conference call. The conference call will 

be open to the public to listen, with callins limited to the number of telephone 

lines available. Individuals who plan to 

call in and need special assistance, such 

as TTY, should inform the contact 

person listed below in advance of the 

conference call. This Notice is being 

published less than 15 days prior to the 

conference call due to scheduling 

problems. 

DATES: The conference call will be held 

on Thursday, November 3, 2005, at 5 

p.m., eastern standard time. 

ADDRESSES: The conference call may be 

accessed by dialing, U.S. toll-free, 1–

800–857–0419, passcode: 6045175, on 

the date and time indicated above. 

FOR FURTHER INFORMATION CONTACT: Kim 

Butcher, (301) 443–2887, or e-mail at 

Kim.Butcher@whcoa.gov. Registration is 

not required. Call in is on a first come, 

first-served basis. 

SUPPLEMENTARY INFORMATION: Pursuant 

to the Older Americans Act 

Amendments of 2000 (Pub. L. 106–501, 

November 2000), the Policy Committee 

will hold a meeting by conference call 

to vote on the Annotated Agenda for the 

2005 White House Conference on Aging. 

The public is invited to listen by dialing 

the telephone number and using the 

passcode listed above under the 

Address section. 

Dated: October 28, 2005. 

Edwin L. Walker, 

Deputy Assistant Secretary for Policy and 

Programs. 

[FR Doc. 05–21823 Filed 11–1–05; 8:45 am] 

BILLING CODE 4154–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. 2003N–0502] 

Agency Information Collection 

Activities; Submission for Office of 

Management and Budget Review; 

Comment Request; Study to Measure 

the Compliance of Prescribers With the 

Contraindication of the Use of Triptans 

in Migraine Headache Patients With 

Vascular Disease 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Notice. 

SUMMARY: The Food and Drug 

Administration (FDA) is announcing 

that a proposed collection of 

information has been submitted to the 

Office of Management and Budget 

(OMB) for review and clearance under 

the Paperwork Reduction Act of 1995. 

DATES: Fax written comments on the 

collection of information by December 

2, 2005. 

ADDRESSES: OMB is still experiencing 

significant delays in the regular mail, 

including first class and express mail, 

and messenger deliveries are not being 

accepted. To ensure that comments on 

the information collection are received, 

OMB recommends that written 

comments be faxed to the Office of 

Information and Regulatory Affairs, 

OMB, Attn: Fumie Yokota, Desk Officer 

for FDA, FAX: 202–395–6974. 

FOR FURTHER INFORMATION CONTACT: 

Karen L. Nelson, Office of Management 

Programs (HFA–250), Food and Drug 

Administration, 5600 Fishers Lane, 

Rockville, MD 20857, 301–827–1482. 

SUPPLEMENTARY INFORMATION: In 

compliance with 44 U.S.C. 3507, FDA 

has submitted the following proposed 

collection of information to OMB for 

review and clearance. 

Study to Measure the Compliance of 

Prescribers With the Contraindication 

of the Use of Triptans in Migraine 

Headache Patients With Vascular 

Disease 

Migraine headache affects about 20 

million Americans. Over the last 

decade, numerous drugs in a category 

referred to as ‘‘triptans’’ have been 

shown to be efficacious in treating 

migraine headache and have been 

approved for this condition. Triptan 

drugs have been prescribed to millions 

of patients. However, triptans are 

routinely contraindicated in patients 

with vascular diseases due to associated 

rare occurrence of myocardial 

infarction, stroke, and other ischemic 

events. In view of the wide use of this 

class of drugs and the potential impact 

on public health as a result of this 

contraindication, FDA believes it would 

be significantly helpful to better 

understand the prescribing practices for 

these drugs. 

FDA plans to examine the feasibility 

of using the Internet to recruit triptanuser migraine headache patients to 

determine whether prescribers follow 

the labeling recommendation by not 

prescribing this class of drugs to 

patients with pre-existing 

cardiovascular, cerebrovascular, or 

peripheral vascular syndromes or with 

cardiac risk factors. 

FDA intends to solicit patients over 

the Internet to identify a group of triptan 

users. FDA will then ask these patients 

to complete a questionnaire about their 

medical history with a focus on vascular 

diseases. Following that, FDA will 

request medical records from a sample 

of the patients and review the submitted 

records to verify the medical history and 

the presence, if any, of cardiovascular, 

cerebrovascular, or peripheral vascular 

ischemic diseases. FDA will also collect 

information about patients’

demographics, route of administration 

(oral, injection, intranasal), and duration 

of exposure to triptans. 

In the Federal Register of November 

17, 2003 (68 FR 64902), FDA published 

a notice requesting comment on this 

information collection. Three comments 

were received in response to the notice, 

each raising several issues, as follows: 

(1) One comment contended that the 

agency has not put forth an adequate 

foundation for conducting the study. 

The comment said that no data or other 

information has been described to 

justify the expenditure of government 

resources and the imposition of 

information collection burdens on the 

industry. The comment said that the 

only rationale consists of speculation 

that ‘‘it would be of great use to better 

understand the prescribing practices as 

a result of this contraindication [use of 

triptans in patients with vascular 

diseases].’’ The comment contended 

that this is an insufficient predicate for 

conducting publicly-funded research 

that casts a cloud of suspicion over a 

class of currently marketed drug 

products that provide great clinical 

benefit to patients who suffer from 

migraine headaches. The comment said 

that the Federal Register notice 

provides no information about FDA’s 

view of the relative role of data derived 

from the survey in relation to data from 

controlled clinical studies, 

epidemiology studies, and spontaneous 

medical event reports. 

Federal Register / Vol. 70, No. 211 / Wednesday, November 2, 2005 / Notices 66441 

The comment also stated that 

although many marketed drugs carry 

contraindications and/or serious 

warnings, FDA has not explained how 

or why the triptan class of drugs was 

targeted for special attention. The 

comment said that the cumulative risk 

of population exposure to certain older 

drugs for migraine is substantially 

greater than the risk of exposure to the 

triptan class of medicines which are the 

newest drugs in the inventory of 

migraine drugs and collectively make 

up only about 40 percent of the market 

volume for acute migraine treatments. 

The comment said that one consequence 

of the sole focus on triptan drugs could 

be to shift patient use to the older drugs 

that could be assumed to be relatively 

free of safety risks. The comment said 

that FDA implies a current problem 

with triptans and prejudges the outcome 

of the study when it says in the Federal 

Register notice ‘‘* * * further action on 

the sponsor’s part to improve risk 

management * * * [to] include further 

study of the problem, a labeling change, 

educational programs performed by the 

sponsor, or increased restrictions on 

prescribing.’’ The comment said that 

FDA has already worked with sponsors 

to assure that the potential risks of use 

of all of these drugs are well 

characterized and accurately described 

in labeling. The comment said that to its 

knowledge, there are no new signals 

from the triptan-class of drugs. 

Response: The proposed Internetbased study is a way to explore new 

methods to assess appropriate 

prescribing of drugs. Currently used 

methods, such as surveys of population 

subsets such as HMOs (Health 

Maintenance Organizations), are costly 

and difficult. The Internet may offer a 

convenient and efficient approach to 

examine prescribing practices for drugs. 

The proposed study is a pilot 

methodology study, and a first step in 

determining the feasibility of this 

approach and in determining whether 

FDA can detect any instances of 

prescribing of triptans in patients with 

contraindications. If Internet-based 

studies are in fact feasible, then FDA 

will design further investigations to 

determine their validity. The feasibility 

endpoints of the proposed study are 

demographic characteristics of 

respondents, case confirmation rates, 

and ability to document participant 

assertions in their medical records. 

Because it is a feasibility study, FDA 

will not make inferences from the 

results regarding the appropriateness of 

prescribing habits. The cost of this study 

is relatively small. Furthermore, there is 

no burden to industry since members of 

the public and physicians’ offices will 

be the participants. 

Triptan-use is common, as is the 

prevalence of ischemic heart disease. A 

recent review of these factors in adverse 

event reports by FDA’s Office of Drug 

Safety showed that the great proportion 

of myocardial infarctions reported in 

association with triptans occurred in 

patients who had pre-existing 

contraindicated conditions. These 

factors make this class of drugs 

convenient for a feasibility test of our 

proposed Internet-based approach. 

(2) The comment also said that the 

proposed method of investigation is not 

valid and is inferior to well-accepted 

methodological alternatives for 

conducting exploratory analyses of this 

kind. The comment noted FDA’s 

statement that ‘‘* * * a signal of 

substantial prescribing to patients with 

vascular contraindications in this 

selected population may warrant further 

action on the sponsor’s part to improve 

risk management.’’ The comment 

contended that FDA provides neither 

specific details regarding how it intends 

to implement the study nor what it will 

judge to be a signal that will require 

action on the part of sponsors. The 

comment said that the absence of any 

definition of a signal and a sampling 

basis are critical flaws in the study. 

Another comment said FDA should 

deduce what proportion of patients with 

pre-existing cardiovascular, 

cerebrovascular, or peripheral vascular 

disease would constitute a ‘‘signal’’ in 

the study protocol, and specify what 

level of ‘‘improvement of risk 

management’’ (for example, further 

study of the problem, a labeling change, 

educational programs, increased 

restrictions on prescribing) will be 

required in response to the observed 

signal. This predetermined signal 

should also be the basis for the sample 

size calculation. 

Response: This is a pilot study with 

an objective of evaluating the feasibility 

of the Internet-based approach and 

determining whether FDA can detect 

any instances of prescribing of triptans 

in patients with contraindications. The 

sample size for the study was selected 

based on a consideration of practicality 

and cost. The practical objectives of the 

study include, but are not limited to, 

determining whether enough patients 

can be recruited in a reasonable amount 

of time, whether patient questionnaires 

will be filled out completely, and 

whether FDA can document participant 

assertions in their medical records. FDA 

notes that, as with all study designs, the 

Internet-based approach is subject to 

some methodological weaknesses, but 

FDA intends to explore whether the use 

of the Internet can be an efficient means 

of conducting this type of study. Despite 

these limitations, FDA believes this 

approach has greater internal validity 

than a system of spontaneous reporting 

because of the inherent underreporting 

and potential bias involved with the 

latter method. If the findings of the pilot 

study suggest the need for further study 

in a larger setting, such as a managed 

care database, FDA anticipates that the 

results would be used to help plan for 

such future studies. FDA does not 

anticipate taking regulatory action based 

on the conclusions of the proposed 

study, nor will we extrapolate the 

frequency of apparent mis-prescribing to 

the general patient population. 

Therefore, it would be premature to 

define at this stage what would 

constitute an appropriate signal. If the 

survey indicates prescribing problems 

with triptans in migraine headache 

patients with vascular disease, then 

FDA can define what would constitute 

such a signal for future studies. 

(3) Another comment said it is 

unclear how patients will be invited to 

take part in the survey. An open 

invitation would result in a significantly 

biased sample, particularly if the goal of 

the survey is being mentioned, and this 

bias would not be resolved by the 

subsequent checking of medical records. 

The comment said that other sources of 

error inherent in the study include 

coverage, nonresponse, and 

measurement and sampling error. 

Measurement error is introduced due to 

the survey medium or due to poorly 

written questions/scales. Sampling error 

is the error associated with taking a 

sample of respondents and not a census, 

and it is impractical to conduct a 

random sample among online 

respondents. The comment said a small, 

voluntary survey will provide results 

that essentially represent testimonial 

evidence that can only support the 

hypothesis being evaluated. 

Response: FDA plans to use search 

engine web-pages as the primary 

recruitment platform for all cases. 

Participants will only be eligible for the 

study if they have been prescribed 

triptans or ergot alkaloids, and they will 

not be recruited into the study based on 

contraindicated comorbidities. 

Therefore, self selection bias (in relation 

to ischemic heart disease) is not likely. 

Participants will be recruited into the 

study by an advertisement linked to the 

keywords for migraine (for example, 

migraine, chronic headache, and so 

forth) and not for vascular disorders. 

Therefore, anyone searching for 

information on migraine headache can 

apply to participate in the study. 

66442 Federal Register / Vol. 70, No. 211 / Wednesday, November 2, 2005 / Notices 

FDA agrees that the study is not 

constructed as a population-based 

survey, nor could its results be used to 

compute rates in the general population. 

However, the demonstration of its 

feasibility, together with a description of 

the characteristics of participants, will 

provide insights into its likely utility. 

For example, it could form the basis for 

comparative studies or other innovative 

methodologies for determining 

characteristics of patients being 

prescribed pharmaceuticals. 

There is support for the value of 

online random surveys. By August 2003, 

surveys on Internet usage by the Bureau 

of International Information Programs, 

U.S. Department of State, indicated that 

the U.S. online population had reached 

approximately 126 million (Ref. 1). 

These data suggest that over two-thirds 

of adults in the United States now 

regularly access the Internet. The 

Internet is rapidly becoming part of the 

population’s daily activities. 

Information gathered by the Pew 

Internet & American Life Project 

through telephone interviews in 2004 

shows that ‘‘the vast majority of 

Americans say the Internet plays a role 

in their daily routines and that the 

rhythm of their everyday lives would be 

affected if they could no longer go 

online.’’ Nielson NetRatings has 

performed monthly surveys of Internet 

users to compile demographic reports. 

Their results are based on individuals 

responding to solicitations and are 

likely to be applicable to individuals 

responding to advertisements to 

participate in Internet-based studies. In 

their February 2004 survey, the modal 

age range was 35 to 49 years, 

representing 33 percent of Web users. 

Seventeen percent were aged >55 years, 

representing about 21 million 

individuals. Overall, 47 percent of users 

were women, a significant rise from 

1998. 

Programs of Internet-based 

epidemiologic and clinical studies are 

already well underway among a number 

of research groups. One of the first was 

the Epidemiologic Cyberspace Cohort 

Study (Refs. 2 and 3). This study 

solicited participation over the Internet 

and used electronic registration as a 

surrogate for a signed consent. Data 

were collected by questionnaire 

modules and were encrypted during 

submission. Lenert and colleagues 

tested the feasibility and validity of 

online quality-of-life studies among 

individuals with ulcerative colitis (Refs. 

4 and 5). The same team also explored 

the feasibility of longitudinal outcomes 

studies of Internet users who have 

ulcerative colitis (Refs. 4 and 5). The 

Internet has also been used to 

administer interventions such as 

smoking cessation programs and the 

Arthritis Self-Management course (Refs. 

6 and 7). It has been explored as a way 

to research migraine headaches (Refs. 8 

and 9), and to measure self-reported 

disease activity in rheumatoid arthritis 

(Ref. 10). A methodologically successful 

Internet-based clinical trial of 

glucosamine was conducted and its 

results are described in publications in 

the British Medical Journal and the 

American Journal of Medicine (Refs. 11 

and 12). 

(4) A comment said that an Internetbased, patient directed survey would be 

inherently biased and would provide 

inaccurate information. The comment 

explained that spontaneously obtained 

adverse event data is sensitive to many 

external factors, and that reports 

solicited via an Internet survey will 

share some of the same shortcomings of 

selection/reporting bias as spontaneous 

reports. The comment said that because 

the premise for the study has now been 

publicly described, a balanced response 

is questionable and FDA will be unable 

to quantitatively correlate the number of 

cases identified with the actual rate of 

occurrence of inappropriate prescribing 

among users of triptans. The comment 

also contended that Internet-based 

studies have significant potential to 

attract patients that disproportionately 

fit the profile of interest and are not 

representative of the population of 

triptan users at large, and would 

provide biased information regarding 

the true rate or strength of the signal. 

The comment said it would be more 

productive to explore the possibility of 

inappropriate prescribing by using drug 

utilization databases and 

complementary epidemiological 

research. The comment noted that FDA 

acknowledged that the study population 

obtained through the study would most 

likely not reflect the population of users 

of triptan drugs at large, and asked how 

this statement is reconciled with the 

goal of estimating the rate of 

inappropriate prescribing. 

Another comment suggested an 

alternative strategy for the survey. The 

comment said that information bias or 

recall bias (for example, concomitant 

medications and medical history) can be 

avoided by using medical claims and 

pharmacy databases. By utilizing a large 

managed care database, the comment 

said it would be possible to identify 

triptan users through pharmacy data, 

and then to determine the rate of 

vascular disease and risk factors by 

reviewing the linked medical records. 

Response: FDA agrees that the study 

population obtained through Internetbased recruitment may not reflect the 

general population of triptan users. 

Therefore, FDA is placing the following 

restriction on the definition of the 

source population: Individuals who use 

search engines with which the study 

Web site is registered. As reported in 

other studies, it is likely that this 

sample will resemble Internet users in 

general because the sample is drawn 

from among such users. Furthermore, it 

might allow the agency to define a 

source population that would represent 

an epidemiologically valid sampling 

frame for future studies. FDA does not 

intend to generalize to the general 

patient population the findings of this 

pilot study regarding the use of triptans 

in patients with contraindications. That 

is, FDA will not quantitatively correlate 

the number of cases identified with the 

actual rate of occurrence of 

inappropriate prescribing among users 

of triptans. Rather, this pilot study 

represents a first attempt to examine the 

feasibility of this approach and to 

determine whether FDA can detect any 

instances of prescribing of triptans in 

patients with contraindications. The 

goal of testing the Internet as a study 

platform is to avoid the prohibitive 

burden and expense of other types of 

studies. If the findings of the pilot study 

suggest the need for further study in a 

larger setting, such as a managed care 

database, FDA anticipates that the 

results would be used to help plan for 

such future studies. 

(5) Several comments said that 

information obtained from the proposed 

Internet-based study will have limited 

validity for a number of reasons, and 

that there are several potential 

shortcomings with an Internet-based 

survey that may result in selection and/ 

or information bias and may make it 

difficult to draw the following valid and 

meaningful conclusions: 

(a) The target audience will not 

accurately reflect the population of 

triptan users because comparisons of 

telephone/mail surveys and Internetbased surveys indicate there are 

significant differences in response 

propensity by several demographic, 

health, and treatment characteristics, 

including education, sex, age, race, 

socioeconomic status, computer 

literacy/access to the Internet, and 

patient satisfaction/dissatisfaction with 

their physician/treatment. 

Response: FDA agrees that the study 

population obtained through Internetbased recruitment may not entirely 

reflect the general population of triptan 

users. However, this approach might 

allow FDA to define a source population 

that would represent an 

epidemiologically valid sampling frame 

for future studies. As explained above, 

Federal Register / Vol. 70, No. 211 / Wednesday, November 2, 2005 / Notices 66443 

FDA does not intend to generalize the 

findings of this pilot study regarding the 

use of triptans in patients with 

contraindications to the general patient 

population. Also, this sample will likely 

resemble that of Internet users in 

general. It is of note that Internet use in 

the population has risen progressively 

during the last few years and continues 

to increase (Ref. 1). Current estimates 

indicate that 128 million Americans use 

the Internet regularly. Furthermore, 

recent Internet-based studies do not 

show major biases. For example, the 

Online Glucosamine Trial recruited a 

sample that was similar to those 

observed in traditional trials and 

included many women, elderly 

individuals, and individuals with low 

incomes (Ref. 12). An online lupus casecontrol study was also able to recruit a 

control group that resembled Internetusers as a whole, including a similar 

proportion of African American 

participants (Ref. 13). Thus, the pilot 

study represents a first attempt to 

examine the feasibility of this Internetbased approach and determine whether 

FDA can detect any instances of 

prescribing of triptans in patients with 

contraindications. 

(b) The study will involve selection 

bias because the respondents will be 

self-selected, have little incentive to 

complete an Internet questionnaire, and 

are therefore more likely to have 

suffered adverse events from the use of 

triptans. In the absence of a true 

denominator, the comment said it 

would not be possible to calculate with 

accuracy the prevalence of vascular 

disorders which contraindicate the use 

of triptans. The comments stated that 

respondents to an Internet survey are 

unlikely to be representative of triptan 

users on the very characteristic that is 

being studied. Respondents may be 

more likely to have adverse events with 

triptans and medical histories that are 

positive for pre-existing cardiovascular, 

cerebrovascular, or peripheral vascular 

disease. Thus, the comment concluded 

that the prevalence of pre-existing 

vascular disease among triptan users 

may be dramatically overestimated. 

Response: Participants will only be 

eligible for the study if they have been 

prescribed triptans or ergot alkaloids, 

and they will not be recruited into the 

study based on contraindicated 

comorbidities. Participants will be 

recruited into the study by an 

advertisement linked to the keywords 

for migraine (for example, migraine, 

chronic headache, and so forth) and not 

for vascular disorders. Therefore, 

anyone searching for information on 

migraine headache can apply to 

participate in the study and selection 

bias is not likely. The information that 

the FDA is collecting is related to 

patients experiencing a contraindication 

before exposure to triptans and not 

adverse events from the use of triptans. 

(c) The study may select against a 

large group of migraine sufferers 

because migraine is a disorder more 

common in individuals with low 

education and low socioeconomic status 

(SES), and Internet users have a higher 

SES. This design would permit a 

demonstration that some migraine 

sufferers receive triptans despite 

cardiovascular-relative 

contraindications, but will not permit 

an estimate of the prevalence or 

incidence of inappropriate prescribing. 

Response: FDA agrees that 

participants might have a higher SES. 

However, this factor is expected to 

influence the generalizability of the 

study results but not the internal 

validity of the work. In addition, this 

factor might bias the results towards the 

null and would not likely flag a problem 

that does not exist. As mentioned 

earlier, FDA does not intend to 

generalize the study findings to all 

migraine patients or estimate a 

prevalence or incidence of 

inappropriate prescribing. 

(d) The lack of accuracy of patient 

self-reporting of medical diagnoses and 

the timing of adverse events could also 

lead to significant information and 

recall bias. In addition, the significance 

of a reported adverse vascular outcome 

in a respondent who has used a triptan 

in the past may be unclear. With a lack 

of veracity in assuring the accuracy of 

the medical information reported, it will 

be difficult and inadvisable to draw 

meaningful conclusions from the study. 

The dynamic environment, process of 

informed consent, and clinical 

decisionmaking which takes place in 

the context of a private patientphysician encounter, cannot be reliably 

reproduced even with accurate 

completion of the questionnaire and 

ascertainment of the medical record. 

Response: Participants in the 

proposed study will be thoroughly 

authenticated through the process of 

obtaining informed consent, approved 

by both FDA and the data contractor’s 

institutional review board, and by 

reviewing copies of their medical 

records. Consent forms will authorize 

the FDA investigator and data contractor 

to obtain further information about the 

patient’s disorder by means of a 

checklist sent to their physician and 

copies of their medical records. The 

consent form will ask the patients for 

permission to write to their physician 

and/or hospital to request 

documentation of their migraine or 

other medical disorders. It will ask 

respondents to confirm their identity 

and will emphasize the legal nature of 

the document. 

(6) Several comments suggested 

certain areas for inclusion in the final 

protocol for the proposed study and said 

that the proposed study must be explicit 

and address the following points: 

(a) A strategy for identifying a 

representative sample of migraine 

sufferers treated with triptans and a 

method by which this population is 

contacted and the description of the 

rationale and purpose of the study used 

to convince patients to complete the 

questionnaire (the method must be free 

of bias and coercion); another comment 

asked for a description of the means by 

which patients will be obtained for 

participation (e.g., mail, e-mail, Web 

sites, doctor offices, pharmacies, and so 

forth); 

Response: FDA will use search engine 

Web pages as the primary recruitment 

platform for all cases. FDA will place 

advertisements on the search engine 

sites, and will register the study site 

with each of the search engines, using 

a set of key terms (for example, 

migraine, chronic headache, and so 

forth). 

(b) The rationale and power 

calculations used to define the 500 

participants; 

Response: FDA selected the sample 

size based on a consideration of 

practicality and cost. This is a pilot 

study with an objective of evaluating the 

feasibility of the Internet-based 

approach and determining whether FDA 

can detect any instances of prescribing 

of triptans in patients with 

contraindications. Practical objectives 

include, but are not limited to, 

determining whether enough patients 

can be recruited in a reasonable amount 

of time, whether patient questionnaires 

will be filled out completely, and 

whether FDA can document participant 

assertions in their medical records. If 

the findings of the pilot study suggest 

the need for further study in a larger 

setting, such as a managed care 

database, FDA anticipates that the 

results will be used to help plan for 

such future studies. FDA will not 

extrapolate the frequency of apparent 

misprescribing to the general patient 

population. 

(c) Any proposed incentive for 

patients to participate in the study. 

Response: There are no incentives 

offered for patients to participate in the 

pilot study. 

(7) Another comment raised the 

following additional issues about the 

proposed Internet-based survey: 

66444 Federal Register / Vol. 70, No. 211 / Wednesday, November 2, 2005 / Notices 

(a) There is no specific question about 

whether a patient has ever been 

prescribed a triptan for treatment of his/ 

her migraine headaches; 

Response: The question about 

migraine medications states: ‘‘Please 

check the box for each medication that 

has ever been prescribed to you for 

migraine treatment.’’ Therefore, the 

information suggested by the comment 

will be captured. 

(b) Because some triptans have a 

variety of formulations and others do 

not, only the appropriate route(s) of 

administration for each triptan should 

be listed in the questionnaire to avoid 

invalid data; 

Response: Information on the exact 

formulation of triptans will be collected. 

(c) The questions regarding triptan 

prescribing and medical history are not 

constructed in a way that the 

compliance of prescribers can be 

evaluated appropriately, resulting in a 

false-positive response; 

Response: The questions about triptan 

prescribing request information about 

the dates of the prescription and how 

often it is used. In addition, the medical 

history questions also ask about the 

timing of the medical conditions. 

Therefore, such information will be 

sufficient to assess compliance of 

prescribers and concurrent use of other 

medications. 

(d) It is not clear whether FDA will 

use the data collected in the 

‘‘Medications’’ section to evaluate 

concurrent or contemporaneous 

medication use among triptan users—

this information would not be sufficient 

to assess whether other medications are 

taken concurrently or 

contemporaneously with triptans. 

Response: Data will be collected on 

other medications taken by patients. 

However, evaluating concurrent 

medication use among triptan users is 

not one of the primary goals of the 

study. 

(e) Because of the unrestricted access 

to the survey, there is the potential for 

fraudulent entry of information. 

Response: As mentioned earlier, 

participants in the proposed study will 

be thoroughly authenticated through the 

process of obtaining informed consent 

and reviewing copies of their medical 

records. 

(f) Relevant and complete medical 

records of all respondents must be 

reviewed. In addition, the method by 

which additional medical information 

will be acquired for incomplete cases 

must be addressed, or the criteria for 

discarding a case when the necessary 

medical data is incomplete must be 

explicit. 

Response: As mentioned earlier, the 

consent forms that patients will sign 

will authorize the FDA investigator and 

data contractor to obtain further 

information about the patient’s disorder 

by means of a checklist sent to their 

physician and copies of their medical 

records. If these records do not verify 

what the patient reported, the case will 

be discarded. 

(8) Two of the comments discussed 

the Health Insurance Portability and 

Accountability Act (HIPPA) and its 

regulations and how it may affect the 

proposed study. 

The comments requested that the 

study protocol address how the 

completion of an Internet-based 

questionnaire and the review and 

sampling of patient records would 

comply with the HIPPA regulations 

regarding medical privacy. A comment 

said that the method by which medical 

records and questionnaires will be deidentified may conflict with HIPPA 

regulations. The comment also asked for 

a description of the method and the 

appropriateness of obtaining a waiver 

from the new HIPPA regulations. 

Another comment said that the 

proposed study needs to address the 

method of review of medical records: 

For example, the proportion of patients’

medical records that will be reviewed, 

the means to obtain informed consent, 

strategies to be used to address 

constraints on record access due to 

HIPAA regulations, responsibility for 

medical chart review, medical record 

abstracting forms, and other ways of 

verifying medical history when medical 

records are not available or incomplete. 

Another comment said that the accuracy 

of self-reported vascular disease on the 

Internet is uncertain and that this 

limitation might be partially offset by a 

medical record review in a subset of 

respondents to confirm the accuracy of 

self-reporting. However, the comment 

said, a representative sampling of 

patient records may be restricted by the 

HIPAA regulations. 

Response: The proposed study, 

including the Internet-based 

questionnaire and review and sampling 

of patient records, does not violate the 

HIPAA regulations, 45 CFR parts 160 

and 164. The signed consent form, in 

accordance with the HIPAA regulations, 

authorizes the physician and/or hospital 

to provide documentation of the 

patient’s migraine or other medical 

disorders. The signed consent form also 

authorizes, in accordance with the 

HIPAA regulations, the study 

investigators to receive and use this 

medical record information. 

All information that allows direct 

identification of participants will be 

omitted from the study databases. These 

databases will only contain information 

of a nonsensitive nature. Safeguards will 

be imposed to prevent tampering or 

accessing of these data by nonstudy 

personnel. All hardcopy information, 

including copies of medical charts, will 

be stored in a locked filing cabinet in a 

locked office at the FDA data 

contractor’s site. The data will be used 

for study purposes only and will not be 

distributed to other parties without the 

participant’s permission. The identities 

of all individuals who participate as 

‘‘cases’’ of triptan users with vascular 

disease and at least 20 percent of the 

remainder of patients will be thoroughly 

authenticated through the process of 

obtaining informed consent and 

reviewing copies of their medical 

records. Consent forms will authorize 

the investigator to obtain further 

information about their disorder by 

means of a checklist sent to their 

physician and copies of their medical 

records. The consent form will ask them 

for permission to write to their 

physician and/or hospital to request 

documentation of their migraine or 

other medical disorders. It will ask 

respondents to confirm their identity 

and will emphasize the legal nature of 

the document. 

(9) A comment said that before 

conducting the study, FDA should 

consult with sponsors of marketed 

triptan drugs and other companies with 

research, development, and commercial 

marketing experience about optimal 

study design and assessment. The 

comment also said that prior to 

implementing the study, FDA should 

disclose specific details about the 

proposed collection (for example, how 

the purpose of the survey will be 

explained to patients, a prospective 

definition of a ‘‘signal,’’ and so forth), 

and offer an opportunity for public 

comment on these specifics. Another 

comment described the findings of a 

panel it convened to evaluate the 

scientific and clinical data on triptanassociated cardiovascular risk and to 

formulate consensus recommendations 

to guide health care providers in making 

informed prescribing decisions for 

patients with migraine. The comment 

also described other studies containing 

estimates of the rates of various vascular 

diseases and cardiac risk factors among 

patients using triptans. The comment 

contrasted these studies with the 

proposed FDA Internet-based study and 

said that the FDA proposed study has a 

number of methodological limitations 

that may produce misleading data and 

may lead to a renewed and unnecessary 

Federal Register / Vol. 70, No. 211 / Wednesday, November 2, 2005 / Notices 66445 

sense of alarm among patients and 

practitioners. 

Response: The purpose of the 

November 17, 2003, Federal Register 

notice was to describe the proposed 

study and offer an opportunity for 

comment by the sponsors of marketed 

triptans. The responses to the comments 

in this notice also provide additional 

explanation and another opportunity for 

all interested parties to participate 

through additional comments. In 

addition, FDA has responded in this 

document to those comments expressing 

concern with the study methods. 

References 

The following references have been 

placed on display in the Division of 

Dockets Management (HFA–305), Food 

and Drug Administration, 5630 Fishers 

Lane, rm. 1061, Rockville, MD 20857, 

and may be seen by interested persons 

between 9 a.m. and 4 p.m., Monday 

through Friday. (FDA has verified the 

Web site address, but FDA is not 

responsible for any subsequent changes 

to the Web site after this document 

publishes in the Federal Register.) 

1. Who Online: Pew Internet & American 

Life Project, February–March 2005 Tracking 

Survey, 2005. 

2. Dorgan, J.F., M.E. Reichman, J.T. Judd, 

C. Brown, C. Longcope, A. Schatzkin, et al., 

‘‘The relation of reported alcohol ingestion to 

plasma levels of estrogens and androgens in 

premenopausal women (Maryland, United 

States),’’ Cancer Causes Control, 5(1):53–60, 

1994. 

3. Kushi, L.H., J. Finnegan, B. Martinson, 

J. Rightmyer, C. Vachon, L. Yochum, 

‘‘Epidemiology and the Internet,’’ [letter; 

comment], Epidemiology 1997;8 (6):689–90, 

1997. 

4. Soetikno, R.M., R. Mrad, V. Pao, L.A. 

Lenert, ‘‘Quality-of-life research on the 

Internet: feasibility and potential biases in 

patients with ulcerative colitis,’’ Journal of 

the American Medical Informatics 

Association, 4(6):426–35, 1997. 

5. Soetikno, R.M., D. Provenzale, L.A. 

Lenert, ‘‘Studying ulcerative colitis over the 

World Wide Web, [see comments], American 

Journal of Gastroenterology, 92(3):457–60, 

1997. 

6. L. Lenert, R.F. Munoz, J. Stoddard, K. 

Delucchi, A. Bansod, S. Skoczen, et al., 

‘‘Design and pilot evaluation of an internet 

smoking cessation program,’’ Journal of the 

American Medical Informatics Association, 

10(1):16–20, 2003. 

7. Lorig, K.R., D.D. Laurent, R.A. Deyo, 

M.E. Marnell, M.A. Minor, P.L. Ritter, ‘‘Can 

a Back Pain E-mail Discussion Group 

improve health status and lower health care 

costs?: A randomized study,’’ Archives of 

Internal Medicine, 162(7):792–6, 2002. 

8. Lenert, L.A., ‘‘Use of willingness to pay 

to study values for pharmacotherapies for 

migraine headache, Medical Care, 41(2):299–

308, 2003. 

9. Lenert, L.A., T. Looman, T. Agoncillo, 

M. Nguyen, A. Sturley, C.M. Jackson, 

‘‘Potential validity of conducting research on 

headache in internet populations,’’

Headache, 42(3):200–3, 2002. 

10. Athale, N., A. Sturley, S. Skoczen, A. 

Kavanaugh, L. Lenert, ‘‘A web-compatible 

instrument for measuring self-reported 

disease activity in arthritis,’’ Journal of 

Rheumatology, 31:223/8, 2004. 

11. McAlindon, T., M. Formica, M. 

LaValley, M. Lehmer, K. Kabbara, 

‘‘Effectiveness of glucosamine for symptoms 

of knee osteoarthritis: results from an 

internet-based randomized double-blind 

controlled trial,’’ American Journal of 

Medicine, 117(9):643–9, 2004. 

12. McAlindon, T., M. Formica, K. 

Kabbara, M. LaValley, M. Lehmer, 

‘‘Conducting clinical trials over the internet: 

feasibility study,’’ The British Medical 

Journal, 327(7413):484–7, 2003. 

13. McAlindon, T.E., M.K. Formica, C.E. 

Chaisson, R. Woods, J. Fletcher, ‘‘Feasibility 

Of An Internet-Based Case-Control Study Of 

Recent-Onset SLE,’’ Arthritis Rheum, 50(9 

(Suppl)):682, 2004. 

FDA estimates that approximately 500 

persons will voluntarily complete the 

questionnaire. The estimated time for 

completing each questionnaire is 

approximately 2 hours, resulting in a 

total burden of 1,000 hours per year. 

The burden of this collection of 

information is estimated as follows: 

TABLE 1.—ESTIMATED ONE-TIME REPORTING BURDEN1

No. of Respondents Annual Frequency 

per Response 

Total Annual 

Responses 

Hours per 

Response Total Hours 

500 1 500 2 1,000 

1There are no capital costs or operating and maintenance costs associated with this collection of information. 

Dated: October 26, 2005. 

Jeffrey Shuren, 

Assistant Commissioner for Policy. 

[FR Doc. 05–21807 Filed 11–1–05; 8:45 am] 

BILLING CODE 4160–01–S 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

National Institutes of Health 

Government-Owned Inventions; 

Availability for Licensing 

AGENCY: National Institutes of Health, 

Public Health Service, DHHS. 

ACTION: Notice. 

SUMMARY: The inventions listed below 

are owned by an agency of the U.S. 

Government and are available for 

licensing in the U.S. in accordance with 

35 U.S.C. 207 to achieve expeditious 

commercialization of results of 

federally-funded research and 

development. Foreign patent 

applications are filed on selected 

inventions to extend market coverage 

for companies and may also be available 

for licensing. 

ADDRESSES: Licensing information and 

copies of the U.S. patent applications 

listed below may be obtained by writing 

to the indicated licensing contact at the 

Office of Technology Transfer, National 

Institutes of Health, 6011 Executive 

Boulevard, Suite 325, Rockville, 

Maryland 20852–3804; telephone: 301/ 

496–7057; fax: 301/402–0220. A signed 

Confidential Disclosure Agreement will 

be required to receive copies of the 

patent applications. 

Antibodies Against Insulin-Like 

Growth Factor II and Uses Thereof 

Dimiter S. Dimitrov et al. (NCI). 

U.S. Provisional Application No. 60/ 

709,226 filed 17 Aug 2005 (HHS 

Reference No. E–217–2005/0–US–01). 

Licensing Contact: Michelle A. Booden; 

301/451–7337; 

boodenm@mail.nih.gov. 

The type 1 insulin-like growth factor 

(IGF) receptor (IGF1R) is over-expressed 

by many tumors and mediates 

proliferation, motility, and protection 

from apoptosis. Agents that inhibit 

IGF1R expression or function can 

potentially block tumor growth and 

metastasis. Its major ligand, IGF–II, is 

over-expressed by multiple tumor types. 

Previous studies indicate that inhibition 

of IGF–II binding to its cognizant 

receptor negatively modulates signal 

transduction through the IGF pathway 

and concomitant cell growth. 

The present invention relates to the 

identification of multiple, novel fully 

human monoclonal antibodies that are 

specific for IGF–II and do not cross-react 

with IGF–1 or insulin. The present 

invention also describes methods 

employing these novel antibodies to 

inhibit IGF–1R phosphorylation and