Advancing Clinical Research with Pregnant and Lactating Populations Overcoming Real and Perceived Liability Risks (2024) / Chapter Skim
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3 Strategies to Reduce Harm Through Clinical Research
3 Strategies to Reduce Harm Through Clinical Research
Pages 81-122
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From page 81... ...
Not only does the regulatory system and ethics oversight aim to reduce the risk of harm to research participants, but it also ensures that the risk of harm is reasonable in relation to the anticipated benefits of participating in clinical research. In clinical research involving pregnant and lactating women, reduc ing harm to the fetus and child is of paramount concern to research par ticipants, sponsors, investigators, and institutional review boards (IRBs)
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From page 82... ...
The first section, a review of the medical product development pathway, is meant to pro vide a necessary and important background for the current system of development, including the studies required to move along this pathway. The second section, reducing harm through FDA guidance and regula tions, provides an overview of the current rules and guidance documents applicable to conducting research with pregnant and lactating women and offers suggestions for potential improvements to current FDA guid ance and regulations.
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From page 83... ...
medical development pathway, which is a critical precursor to understanding how to improve current systems to safely include pregnant and lactating women in critical research studies. Preclinical Development Studies The goal of preclinical development studies is to serve as a bridge between initial laboratory findings that hold promise for a therapeutic target and use of the experimental product in a clinical setting.
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From page 84... ...
Studies DART studies identify the experimental product's adverse effects seen in animal species that may portend the types of toxicities that could occur in humans, including evaluation for teratogenicity. The results of these preclinical studies aid in selecting an initial starting dose and a potential dose titration schedule, and the results aid in estimating the probable highest safe dose for human clinical trials, while also ini tially characterizing potential adverse effects that might occur in humans (ICH, n.d.)
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From page 85... ...
This section provides a descrip tion of the phases of drug development and in following sections specifies the FDA guidance and special considerations for research with pregnant and lactating populations. PREPUBLICATION COPY -- Uncorrected Proofs A02260_Advancing_Clinical_Research_CH03.indd 85 3/28/24 6:16 AM
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From page 86... ...
. Usually, these studies begin by dosing three to five volunteers, at a dose anticipated to have no observable effect, determined during preclinical studies.
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From page 87... ...
Evaluated Safety Safety and Safety and Safety, efficacy in outcomes efficacy efficacy new populations and new indications, pharmacoeconomics, quality of life Study design PK/PD Usually Randomized, May be study randomized, blinded, interventional or placebo- placebo- observational controlled trial controlled trial NOTES: This applies to clinical trials broadly, but there are notable exceptions, particu larly for healthy volunteer participation in Phase I trials in some trials such as oncol ogy or HIV trials. The number of participants in each phase is largely determined by the condition being studied and the size of the patient population.
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From page 88... ...
Labeling for prescription medicines is required for all FDA-approved prescription drugs and biological products and contains a summary of the essential scientific information needed for the safe and effective use of the medicine.3 When a prescription product is approved for use in adults, the prod uct is also approved for use in pregnant and lactating women by default unless there is a clear contraindication or warnings against the product's use during pregnancy or lactation, which must then be included on the product label. This is because pregnant and lactating women are con sidered a subpopulation of the adult population and, therefore, absent a contraindication or warnings against the product's use during pregnancy or lactation, they are not excluded from the approved population when a drug or biological product is approved for use in adults.
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From page 89... ...
. This section discusses different types of FDA regulatory information relevant to pregnant, potentially pregnant, and lactating women and offers sug gestions for how this guidance might be improved to reduce harm for pregnant and lactating women, and their fetuses and children.
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From page 90... ...
Further, earlier completion of DART studies would allow for earlier detection of potential harmful pharmaceutical and biopharmaceutical products for pregnant and lactating women and their offspring. Timely conduct of DART studies could also enable women who become pregnant over the course of a clinical trial to remain in the trial once pregnant, which would provide critical information about the use of the product in early pregnancy.
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From page 91... ...
BOX 3-1 Data Safety Monitoring Boards DSMBs, also known as data monitoring committees, are a group of indepen dent experts without a vested interest in the clinical trial and who review evidence of adverse events and the outcomes of the trial to recommend whether a trial should be continued, altered, or terminated. DSMBs are generally unblinded to trial safety data, allowing them to make decisions about the scientific integrity of the clinical trial so sponsors and study investigators can remain blinded to trial results (Evans, 2022)
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From page 92... ...
The 2018 draft guidance also includes information on the timing of enrollment for involving pregnant women in clinical trials. According to the draft guidance, Phase I and Phase II clinical trials in nonpregnant women, including potentially pregnant women, should be completed before enrolling pregnant women into later phases.
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From page 93... ...
These studies pose a different set of considerations from products to treat general conditions and warrant a specific discussion in guidance documents, especially for study design. FDA Guidance on Conducting Clinical Studies with Pregnant Women PK/PD Studies FDA's 2004 final guidance, "Pharmacokinetics in Pregnancy, Study Design, Data Analysis, and Impact on Dosing and Labeling," provides specific recommendations for designing and conducting PK/PD studies in pregnant women and lays out a framework to stimulate further study and research to assist in rational therapeutics for pregnant patients.
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From page 94... ...
Therefore, although current FDA guidance recommends PK studies be conducted if the product is going to be used by pregnant women, more concrete time lines for conducting PK/PD studies and additional guidelines on complet ing studies throughout stages of pregnancy may encourage sponsors to complete more of these studies. Data Collection When pregnant women are enrolled in a clinical trial, FDA's draft guidance, "Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials," provides that data collection elements should PREPUBLICATION COPY -- Uncorrected Proofs A02260_Advancing_Clinical_Research_CH03.indd 94 3/28/24 6:16 AM
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From page 95... ...
FDA Guidance Addressing Lactating Women in Clinical Research Drug exposure and risks during the lactation period are generally lower than pregnancy and depend on whether the child is breastfeeding, the transfer of the drug into human milk, and the absorption, metabo lism, and elimination of the drug by the breastfed child (Newton and Hale, 2015)
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From page 96... ...
Lactating women (milk only) study: Human milk is collected, and drug concentrations determined.
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From page 97... ...
For studies of new investigational products, FDA guidance on lacta tion dissuades lactating women from continuing to breastfeed, which could have detrimental health effects on the children receiving human milk, could affect their milk supply, maternal–infant bonding, and could be considered a harm in and of itself. While the mother may express milk to maintain her milk supply, particularly for a short-term study, the discontinuation of breastfeeding presents a major barrier for stud ies of medications to treat conditions not specific to breastfeeding as well as breastfeeding conditions, such as mastitis, low milk supply, or breastfeeding-associated pain.
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From page 98... ...
For human prescription drug and biological products approved on or after June 30, 2001, the PLLR required that the labeling be revised to include 1. a summary of the risks of using a drug during pregnancy (Section 8.1 of the labeling)
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From page 99... ...
. Postmarketing requirements, however, are preclinical studies or clinical trials that a sponsor is required to conduct in order to comply with certain laws and/or regulations, or to assess a known serious risk related to the use of the drug, assess signals of serious risk related to the use of a drug, or identify an unexpected serious risk when available data indicate the potential for a serious risk (FDA, 2016)
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From page 100... ...
. However, if human pregnancy or lactation data has not been collected at the time of FDA approval, FDA may not have the information required to determine whether there are potential risks to pregnant and lactating women to evaluate through postmarketing studies.
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From page 101... ...
. Pharmacovigi lance takes place throughout the life cycle of the pharmaceutical prod uct, including the entire drug development pathway and postmarketing surveillance.
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From page 102... ...
Therefore, FDA guidance recommends using additional sources to evaluate product safety, such as observational studies. Pregnancy Registries Pregnancy registries are a common study design that may be used to collect safety data in the postapproval setting and can help inform deci sion making among health care providers and their patients (FDA, 2023e)
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From page 103... ...
, there appear to be no existing lactation-specific registries. Complementary Database Studies FDA guidance on postmarketing studies also discusses complemen tary studies that may be conducted alongside pregnancy registries to address the "specific effects" of a drug or biological product during preg nancy (FDA, 2019b)
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From page 104... ...
In 1991, it was revised and codified by 15 federal departments and agencies, and became known as the "Common Rule." Research funded or conducted by HHS is subject to additional regula tory protections, including provisions specific to the conduct of research involving pregnant women. HHS regulations for the protection of the rights and welfare of human participants in research are codified in title 45 of the Code of Federal Regulations, part 46, including Subparts A through E
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From page 105... ...
To do so, FDA will review published literature, hold a public workshop, and publish a workshop report describing the framework. The second step of FDA's commit ment to improving pregnancy safety involves conducting demonstration projects to address gaps in knowledge about different study designs.
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From page 106... ...
HHS regulations for human subject protections do not specifically address considerations for lactating women, nor do they clarify whether Subpart D, additional protections for children, apply when a child is exposed to the milk of a lactating woman participating in clinical research. Despite this regulatory ambiguity, the Secretary's Advisory Commit tee on Human Research Protections (SACHRP)
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From page 107... ...
. Additionally, FDA released a proposed rule in 2022 that would harmonize certain sections of FDA's regulations on the protection of human subjects and IRBs with HHS regulations.12 FDA's regulations for human subject protections and IRBs do not have specific considerations for pregnancy, other than to note that IRBs are to implement additional safeguards for clinical studies that include pregnant women, and that IRBs might consider including among its membership individuals with relevant expertise if they regu larly review protocols that include pregnant women.
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From page 108... ...
. OHRP guid ance applicable to the inclusion of pregnant and lactating women in clini cal research could help IRBs provide feedback to protocols and ultimately approve more protocols for human subject research involving pregnant and lactating women.
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From page 109... ...
It also ensures that informed consent is adequate and that there is equitable selection of research participants. REDUCING HARM THROUGH RESEARCH DESIGN Postmarket observational studies are informative, but they delay the generation of safety data for pregnant and lactating women until the product is already being broadly used by the public, thus amplifying the potential for harm.
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From page 110... ...
. While it unquestionably represents an example of the successful conduct of clinical trials in pregnant and lactating women, it also offers significant lessons for research involving pregnant and lactating women going forward.
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From page 111... ...
Importantly, the committee emphasizes that it is possible to include pregnant and lactating women in clinical research without expanding the risk of harm from delayed product approval, but careful consideration for which staging approach fits the research needs of the project being conducted is important. Nothing in current FDA regulations or the committee's recommendations would require clinical studies in pregnant and lactating women to be complete before product approval for the general adult population.
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From page 112... ...
Because pregnant and lactating women would be enrolled in Phase II or Phase III trials, researchers would be able to collect data relevant to these phases of research simul taneously with the basic safety data being collected (Baylis and Halperin, 2012)
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From page 113... ...
Regardless, an opportunistic approach to enrollment can be an effective strategy for collecting data on the use of the product in early stages of pregnancy. Pragmatic Study Designs A pragmatic study design, specifically when focusing on pregnant and lactating women as the study population, is pivotal in advancing the understanding of medical products within real-world clinical settings (Eke et al., 2019)
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From page 114... ...
By integrating seamlessly into clinical practice, pragmatic trials can gather data in a nonintrusive manner that respects the demands of health care delivery. Opportunistic Studies Nonrandomized opportunistic studies, a subset of observational research, provide a unique way to study pregnant and lactating women already using specific medical products or interventions (Sheffield et al., 2014)
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From page 115... ...
In Vivo Exposure Assessment Methods The use of methods that minimize exposure to the medical product being studied, specifically microdosing and short-course (targeted) PK study approaches that have been increasingly employed, could generate early data for pregnant and lactating women (van Nuland et al., 2019)
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From page 116... ...
This is because pregnant and lactating women are often excluded from clinical research, which leaves them and their health care providers with insufficient safety and efficacy data to make informed decisions about using medical products. Conclusion 3-2: Current FDA guidance on clinical studies with pregnant and lactating women describes limited aspects of study design, research time lines, safeguards, and product-specific monitoring.
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From page 117... ...
2016. Microdosing and other phase 0 clinical trials: Facilitating translation in drug development.
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2020. Innovative approaches for pharmacology studies in pregnant and lactating women: A viewpoint and lessons from HIV.
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2024b. Use of data monitoring committees in clinical trials guidance for industry.
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2023. Inclusion of pregnant and lactating persons in clinical trials: Proceedings of a workshop.
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From page 121... ...
In Clinical research involving pregnant women, edited by F Baylis and A
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2018. Factors influencing the recruitment of lactating women in a clinical trial involving direct oral anticoagulants: A qualitative study.
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