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, 66440-66445 [05-21807]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 70, Number 211 (Wednesday, November 2, 2005)]
[Notices]
[Pages 66440-66445]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 05-21807]


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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.

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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 triptan-user 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.

[[Page 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 Internet-based 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.

[[Page 66442]]

    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 Internet-based, 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 
Internet-based 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 
Internet-based 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 
Internet-based 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,

[[Page 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 case-control study was also able to recruit a control group that 
resembled Internet-users 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 Internet-
based 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 patient-
physician 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:

[[Page 66444]]

    (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 de-identified 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 triptan-
associated 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

[[Page 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 
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    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 Burden\1\
----------------------------------------------------------------------------------------------------------------
                            Annual Frequency        Total Annual
   No. of Respondents         per Response            Responses        Hours per  Response       Total Hours
----------------------------------------------------------------------------------------------------------------
500                                          1                   500                     2                1,000
----------------------------------------------------------------------------------------------------------------
\1\ There 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