SUPPLEMENTARY INFORMATION:

Under the PRA (44 U.S.C. 3501-3521), Federal Agencies must obtain approval from the Office of Management and Budget ( printed page 57353) (OMB) for each collection of information they conduct or sponsor. “Collection of information” is defined in 44 U.S.C. 3502(3) and 5 CFR 1320.3(c) and includes Agency requests or requirements that members of the public submit reports, keep records, or provide information to a third party. Section 3506(c)(2)(A) of the PRA (44 U.S.C. 3506(c)(2)(A)) requires Federal Agencies to provide a 60-day notice in the Federal Register concerning each proposed collection of information before submitting the collection to OMB for approval. To comply with this requirement, in the Federal Register of April 26, 2024 (89 FR 32447), FDA published a 60-day notice requesting public comment on the proposed collection of information. In response to a request by OMB, FDA is republishing notice of the proposed collection of information set forth in this document.

With respect to the following collection of information, FDA invites comments on these topics: (1) whether the proposed collection of information is necessary for the proper performance of FDA's functions, including whether the information will have practical utility; (2) the accuracy of FDA's estimate of the burden of the proposed collection of information, including the validity of the methodology and assumptions used; (3) ways to enhance the quality, utility, and clarity of the information to be collected; and (4) ways to minimize the burden of the collection of information on respondents, including through the use of automated collection techniques, when appropriate, and other forms of information technology.

Pregnancy Exposure Registry Enrollment Project: A Survey of Healthcare Providers To Advance Pregnancy Safety Data Collection and Improve Health Communications

(OMB Control Number 0910—NEW)

I. Background

FDA has a need for data on pregnancy exposure registries (registries). The goal of the proposed Pregnancy Exposure Registry Enrollment Project survey is to determine healthcare providers' (HCPs) perceived barriers to sufficient patient enrollment in pregnancy exposure registries. FDA's authority to conduct research related to drugs and other FDA regulated products is set forth in the Federal Food, Drug, and Cosmetic Act (FD&C Act), (21 U.S.C. 393(d)(2)(C) and (D)).

To ensure that pregnancy information in product labeling is accurately communicated to HCPs so that they can make informed decisions about treatment options for their patients, human pregnancy safety data are collected postapproval. Registries are an important tool for pregnancy safety data collection in the postmarketing setting. Their prospective design and ability to collect detailed patient information are critical to obtain human data to inform pregnancy labeling in a timely manner.

The pharmaceutical industry typically sponsors registries often as a result of a postmarketing requirement (PMR) or commitment (PMC) FDA issues at the time of drug approval under section 505(o)(3) of the FD&C Act (21 U.S.C. 355(o)(3)). Under a PMR or PMC, pharmaceutical industry sponsors often work with private companies, nonprofits, and/or academic health centers to operate registries. Other times, private companies, nonprofits, Federal agencies other than FDA, or academic health centers may develop registries without FDA involvement to facilitate pregnancy-related research with other scientific goals. When developing registry protocols, sponsors and those who operate registries must comply with 45 CFR part 46 and meet the Criteria for IRB approval of research under 45 CFR 46.111, which provides protection of human research subjects, subjects' privacy, and the confidentiality of subjects' data.

Although registries are crucial to understanding the safety and potential toxicity of prescription products in the perinatal population, many registries fail to adequately enroll pregnant women. HCPs are a trusted source of information about health, and they serve as gatekeepers for recruiting pregnant individuals to enroll in clinical studies such as registries. Thus, HCPs are integral to the registry enrollment process. Publications suggest that low enrollment in registries may be related to HCPs' lack of awareness, time, incentives, and comfort with discussing clinical research with patients. Despite this speculation about the barriers that HCPs face, however, researchers have not surveyed HCPs to understand their challenges. FDA reviewed existing literature and engaged with other Offices and Centers within FDA and external experts and determined that this data collection is not duplicative.

During this voluntary, FDA-funded, qualitative survey, we will recruit through an existing panel of HCPs currently licensed to practice in clinical settings in the United States who routinely care for or counsel pregnant patients. We will engage three groups of HCPs: (1) primary HCPs (obstetrician/gynecologists, family practice physicians, certified nurse-midwives, physician assistants); (2) consulting HCPs (neurologists, infectious disease specialists, psychiatrists, rheumatologists, cardiologists, pulmonologists, dermatologists), and (3) pharmacists. To be eligible for the study, primary HCPs must routinely care for or counsel five or more pregnant patients per month, and consulting HCPs and pharmacists must routinely care for or counsel three or more pregnant patients per month. All eligible HCPs must have either a degree as a Doctor of Medicine, a Doctor of Osteopathic Medicine, or a Doctor of Pharmacy. Although we will recruit with representativeness in mind, we will weigh the data to ensure a nationally representative sample of HCPs. Generated tables will compare the weighted distributions of the variables used for weighting against their corresponding benchmarks.

A contracted research firm will collect data through internet administration. One hundred percent (100%) of participants will self-administer the internet survey via a computer, which will record responses and provide appropriate probes when needed. We will use automated technology in data collection, data reduction, and analyses. To identify eligible HCPs, we will send a recruitment email that links to a prequalifying screener on the internet. The screener will include questions about the HCP's specialty, number of years in practice, number of pregnant patients counseled per month, and demographics (age, race/ethnicity, and sex) and will confirm that the respondent does not work for FDA or a pharmaceutical company. We will invite all respondents who meet eligibility requirements to participate in the survey within 24 hours of completing the screener and obtain informed consent from all survey participants. The survey will assess experienced HCPs' knowledge of registries, their attitudes toward them, the barriers they face to recruiting patients, and their ideas about improving registry enrollment. Results from this project will advance pregnancy safety data collection from registries and ultimately improve health communications through inclusion of human safety data in pregnancy labeling. The survey is available on request at pedsdrugs@fda.hhs.gov.

We have the following specific research questions:

1. What proportion of HCPs know about pregnancy exposure registries?

2. What proportion of HCPs have referred patients to pregnancy exposure registries? ( printed page 57354)

3. What proportion of HCPs have provided information from patient medical records to pregnancy exposure registries?

4. What barriers to patient enrollment in pregnancy exposure registries are identified by HCPs?

5. What ideas do HCPs have to improve enrollment in pregnancy exposure registries?

The target sample size for this study is 400 completed surveys. The sample will include an equal number of primary HCPs, consulting HCPs, and pharmacists. Such a design will help to ensure assessment of not only HCPs' perceptions generally, but also potential variations between different types of HCPs. HCPs are a difficult group to recruit, so several strategies will be put into place to achieve a high response rate. These strategies include tailoring contact materials, disclosing FDA sponsorship on survey materials, and providing a cash incentive.

To obtain 400 completed surveys, we estimate that 2,000 experienced HCPs will need to be screened. We estimate that participation in the study will take 17 minutes.

FDA estimates the burden of this collection of information as follows:

Prior to the main analysis, an outlier analysis will be performed for the time spent on any screen visited and total time to complete the survey. Extreme survey time will be identified and appropriate adjustments will be made prior to the final data analysis. The extent of any missing information will also be assessed to determine the data quality. Descriptive statistics will afford a look at the frequency of responses. Assessment of potential differences between primary HCPs, consulting HCPs, and pharmacists can be accomplished with pairwise comparisons between groups. We will also produce national-level estimates about attitudes toward pregnancy exposure registries and other key questions.

An analysis of item nonresponse will be made in the screener, if needed, and in the main survey. Item nonresponse rates will be tabulated for the questionnaire items, allowing for skip patterns. An analysis will be made of any questionnaire items that register unusually high item nonresponse rates. Multivariate item nonresponse relationships will be evaluated, including monotonicity patterns such as breakoffs (all items dropped after a particular item), and other types of “blocks” of multivariate item nonresponse. High levels of item nonresponse in particular items will have their correlations with other questionnaire item results in both the screener and main survey analyzed (tabulating how much the item nonresponse is concentrating in a particular subgroup of health providers).

The FDA anticipates disseminating the results of the study after final analyses of the data are completed, reviewed, and cleared. The information gathered on this topic will be used to inform regulatory guidance to sponsors and investigators designing pregnancy exposure registry protocols.

As noted, FDA published a 60-day notice requesting public comment on the proposed collection of information on April 26, 2024 (89 FR 32447). FDA is republishing the 60-day notice in order to satisfy PRA requirements in response to a request by OMB to republish the Federal Register Notice. No changes have been made to the information collection.

II. References

The following references are on display at the Dockets Management Staff (see ADDRESSES ) and are available for viewing by interested persons between 9 a.m. and 4 p.m., Monday through Friday; they are also available electronically at https://www.regulations.gov. Although FDA verified the website addresses in this document, please note that websites are subject to change over time.

1. Gelperin, K., H. Hammad, K. Leishear, et al., “A Systematic Review of Pregnancy Exposure Registries: Examination of Protocol-Specified Pregnancy Outcomes, Target Sample Size, and Comparator Selection,” Pharmacoepidemiology and Drug Safety, 2017 Feb;26(2):208-214. doi: 10.1002/pds.4150. Epub 2016 Dec 27. PMID: 28028914.

2. FDA, “Postapproval Pregnancy Safety Studies (May 2019).” Available at: https://www.fda.gov/​media/​124746/​download.

3. National Institutes of Health, Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC). Available at: https://www.nichd.nih.gov/​about/​advisory/​PRGLAC.

4. FDA, “Study Approaches and Methods to Evaluate the Safety of Drugs and Biological Products During Pregnancy in the Post-Approval Setting,” May 28-29, 2014. Available at: https://www.fda.gov/​media/​88387/​download.

5. Daniels, J.L., D.A. Savitz, C. Bradley, et al., “Attitudes Toward Participation in a Pregnancy and Child Cohort Study,” Paediatric and Perinatal Epidemiology, 2006 May;20(3):260-266. doi: 10.1111/j.1365-3016.2006.00720.x. PMID: 16629701.

6. Hartman, R.I. and A.B. Kimball, “Performing Research in Pregnancy: Challenges and Perspectives,” Clinics in Dermatology, 2016 May-Jun;34(3):410- 415. doi: 10.1016/j.clindermatol.2016.02.014. Epub 2016 Feb 11. PMID: 27265080.

7. Krueger, W.S., M.S. Anthony, C.W. Saltus, et al., “Evaluating the Safety of Medication Exposures During Pregnancy: A Case Study of Study Designs and Data Sources in Multiple Sclerosis,” Drugs Real World Outcomes, 2017 Sep;4(3):139-149. doi: 10.1007/s40801-017-0114-9. PMID: 28756575; PMCID: PMC5567459.

8. Sarker A., P. Chandrashekar, A. Magge, et al., “Discovering Cohorts of Pregnant Women From Social Media for Safety Surveillance and Analysis,” Journal of Medical internet Research, 2017 Oct 30;19(10):e361. doi: 10.2196/jmir.8164. PMID: 29084707; PMCID: PMC5684515.

9. Sinclair S., M. Cunnington, J. Messenheimer, et al., “Advantages and Problems With Pregnancy Registries: Observations and Surprises Throughout the Life of the International Lamotrigine Pregnancy Registry,” Pharmacoepidemiology and Drug Safety, 2014 Aug;23(8):779-786. doi: 10.1002/pds.3659. Epub 2014 Jun 27. ( printed page 57355) PMID:24974947; PMCID: PMC4406353.