Regulatory Guidance Documents on Adaptive Designs: An Industry Perspective

Abuse-deterrent formulations are one strategy for mitigating the epidemic of prescription opioid abuse. Regulatory guidance documents describe the requirements for developing abuse-deterrent formulations of novel drugs and formulations; however, they do not address “abuse-deterrence equivalence” for generic formulations. As generics may be produced with different excipients and formulations compared to reference drugs, differences in their properties may impact their abuse-deterrent features. Currently, it is unclear what specific studies are needed to support generic abuse-deterrence claims. This commentary outlines several recommendations on the in vitro and in vivo testing required, including the conditions for conducting a human abuse potential study.

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Adaptive designs: The Swiss Army knife among clinical trial designs?

Clinical Trials ◽

10.1177/1740774517699406 ◽

2017 ◽

Vol 14 (5) ◽

pp. 417-424 ◽

Cited By ~ 6

Author(s):

Frank Bretz ◽

Paul Gallo ◽

Willi Maurer

Keyword(s):

Clinical Trial ◽

Adaptive Design ◽

Clinical Trial Data ◽

Parameter Estimate ◽

Information Value ◽

Adaptive Designs ◽

Success Rates ◽

Linear Regression Models ◽

Regulatory Guidance ◽

Trace Back

There has been considerable progress in the development and implementation of adaptive designs over the past 30 years. A major driver for this class of novel designs is the possibility to increase the information value of clinical trial data to enable better decisions, leading to more efficient drug development processes and improved late-stage success rates. In the first part of this article, we review the development of adaptive designs from different perspectives. We trace back key historical papers, report on landmark adaptive design clinical trials, review major cross-industry collaborations, and highlight key regulatory guidance documents. In the second, more technical part of this article, we address the question of whether it is possible to define factors which guide the choice between a fixed or an adaptive design for a given trial. We show that in non-linear regression models with a moderate variance of the responses, the first-stage sample size of an adaptive design should be chosen sufficiently large in order to address variability in the interim parameter estimate. In conclusion, the choice between an adaptive and a fixed design depends in a sensitive manner on the specific statistical problem under investigation.

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Compilation of International Standards and Regulatory Guidance Documents for Evaluation of Biomaterials, Medical Devices, and 3-D Printed and Regenerative Medicine Products

Toxicologic Pathology ◽

10.1177/0192623318804121 ◽

2018 ◽

Vol 47 (3) ◽

pp. 344-357 ◽

Cited By ~ 8

Author(s):

JoAnn C. L. Schuh ◽

Kathleen A. Funk

Keyword(s):

Regenerative Medicine ◽

Medical Device ◽

International Standards ◽

International Organization ◽

Medical Products ◽

Regulatory Guidance ◽

Good Laboratory ◽

Standards And Guidelines ◽

Guidance Documents ◽

Country Specific

The development of biomaterials, medical device components, finished medical products, and 3-D printed and regenerative medicine products is governed by a variety of international and country-specific standards and guidelines. Of greatest importance to planning, executing, and reporting biocompatibility, safety and efficacy studies for most biomaterials and medical components or products are the International Organization for Standardization guidelines, U.S. Pharmacopeial Convention, ASTM International, and Conformité Européenne (European Conformity) marking. The International Medical Device Regulators Forum publishes harmonized standards similar to the International Council for Harmonization. Good Laboratory Practices are applicable and guidance documents for the development of drugs and biologics can also be relevant to biomaterials, medical device components, and medical products and more recently to products produced by 3-D printing or additive manufacturing. Regenerative products may have medical device–based scaffolding and may be treated as biologics, reflecting the cell and tissue components. This compilation of international standards and guidelines provides toxicologic pathologists, toxicologists, bioengineers, and allied professionals with an overview of and source for important regulatory documents that may apply to the nonclinical development of their products.

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Analysis of regulatory guidance on antidrug antibody testing for therapeutic protein products

Bioanalysis ◽

10.4155/bio-2019-0241 ◽

2019 ◽

Vol 11 (24) ◽

pp. 2283-2296 ◽

Cited By ~ 1

Author(s):

Nazneen Bano ◽

Troy McKelvey ◽

Nathan Spear ◽

Tong-Yuan Yang ◽

Gopi Shankar ◽

...

Keyword(s):

Immune Responses ◽

Antibody Testing ◽

Regulatory Guidance ◽

Antidrug Antibody ◽

Antibody Assays ◽

Guidance Documents ◽

Potential Impact ◽

Us Fda ◽

Key Aspects ◽

Development And Validation

Therapeutic proteins have the potential to induce unwanted immune responses. The potential impact of immunogenicity on pharmacokinetics, pharmacodynamics, safety and efficacy are well established. Here, we analyze key aspects of current US FDA and EMA guidelines on the development and validation of antidrug antibody assays. Although FDA and EMA guidance documents are in harmony on most points, EMA allows greater leeway for scientific judgement, while FDA recommends specific approaches that may not be appropriate in some situations. Many white papers suggest approaches different from the guidance documents, however, these can conflict with each other and are themselves only scientifically valid in certain situations. Here, we indicate when alternatives to guidance may be needed and what those approaches might be.

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Representation of published core outcome sets for research in regulatory guidance: protocol

HRB Open Research ◽

10.12688/hrbopenres.13139.1 ◽

2021 ◽

Vol 4 ◽

pp. 45

Author(s):

Susanna Dodd ◽

Rebecca Fish ◽

Sarah Gorst ◽

Deborah Hall ◽

Pamela Jacobsen ◽

...

Keyword(s):

Patient Involvement ◽

European Medicines Agency ◽

Core Outcome ◽

Core Outcome Sets ◽

Regulatory Guidance ◽

The Core ◽

Key Stakeholders ◽

Regulatory Guidelines ◽

Core Outcomes ◽

Guidance Documents

Background: The COMET Initiative promotes the development and use of ‘core outcome sets’ (COS), agreed standardised sets of outcomes that should be measured and reported in all studies in a particular clinical condition. COS are determined by consensus amongst key stakeholders, including health professionals, policymakers and patients, ensuring that the priorities and expertise of these representatives inform the choice of the most important outcomes to measure for a given condition. There is increased recognition of the need to integrate COS across the healthcare system and with existing regulatory apparatus, to ensure that outcomes being recorded are those of key relevance to important stakeholders. The aim of this study is to assess the degree of concordance between outcomes recommended in COS for research and in guidance provided by two key regulators: US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Methods: COS for research published during 2015-2019 with patient involvement and covering drug or device interventions will be compared against relevant regulatory guidelines, matched by condition. Guidance documents which match in scope (relating to intervention and population) to a COS for research will be scrutinised to identify all suggested outcomes for comparison against the core outcomes in the corresponding COS. Discussion: This study will identify variation between outcomes suggested in EMA and FDA regulatory guidance relative to outcomes included in published COS for research, thus demonstrating the degree of representation of COS in regulatory guidance and vice versa. If the findings of this study reveal a lack of concordance between COS and regulatory guidance overall or for particular disease areas, we will invite feedback from FDA and EMA and will seek to highlight where findings support the recommendations towards using well-developed COS or will make recommendations to COS developers on outcomes of importance to these key regulators.

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Compilation of International Regulatory Guidance Documents for Neuropathology Assessment During Nonclinical General Toxicity and Specialized Neurotoxicity Studies

Toxicologic Pathology ◽

10.1177/0192623310385145 ◽

2010 ◽

Vol 39 (1) ◽

pp. 92-96 ◽

Cited By ~ 19

Author(s):

Brad Bolon ◽

Alys Bradley ◽

Mark Butt ◽

Karl Jensen ◽

Georg Krinke ◽

...

Keyword(s):

Regulatory Guidance ◽

General Toxicity ◽

Guidance Documents

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Nonclinical Immunotoxicity Testing in the Pharmaceutical World: The Past, Present, and Future

Therapeutic Innovation & Regulatory Science ◽

10.1177/2168479019864555 ◽

2019 ◽

pp. 216847901986455

Author(s):

Paul Baldrick

Keyword(s):

Small Molecule ◽

Clinical Pathology ◽

Main Tool ◽

New Drugs ◽

Regulatory Guidance ◽

The Past ◽

Toxicology Study ◽

Stem Cell Product ◽

Guidance Documents

An examination for potential direct or indirect adverse effects on the immune system (immunotoxicity) is an established component of nonclinical testing to support safe use of new drugs. Testing recommendations occur in various regulatory guidance documents, especially ICH S8, and these will be presented. Key evaluation usually occurs in toxicology studies with further investigative work a consideration if a positive signal is seen. Expectations around whether findings may occur are related to the type of compound being developed, including a chemically synthesized small molecule, a small molecule oncology drug, a biopharmaceutical, an oligonucleotide, a gene therapy/stem cell product, a vaccine, or reformulation of drugs in liposomes or depots. Examples of immunotoxicity/immunogenicity findings will be discussed for all of these types of compound. Overall, it can be concluded that our main tool for evaluation of potential immunotoxicity/immunogenicity for a new drug still remains standard toxicology study testing with key assessment for effects on clinical pathology and lymphoid organs/tissues (weights and cellularity). Additional evaluation from studies using a T cell–dependent antibody response (TDAR) and lymphocyte phenotyping is also valuable, if needed. Thus, using the tools from the past, it is the role of toxicologists to work with clinical teams now and in the future, to interpret findings from nonclinical testing to possible adverse findings in humans.

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Development of social and hygienic monitoring at the regional level

Hygiene and Sanitation ◽

10.18821/0016-9900-2016-95-11-1033-1036 ◽

2019 ◽

Vol 95 (11) ◽

pp. 1033-1036 ◽

Cited By ~ 3

Author(s):

S. I. Savelyev ◽

Galina M. Trukhina ◽

V. A. Bondarev ◽

N. V. Nakhichevanskaya

Keyword(s):

Public Health ◽

The State ◽

Annual Reports ◽

Managerial Decision ◽

Good Tool ◽

Demographic Situation ◽

Regulatory Guidance ◽

Environment And Health ◽

Guidance Documents

The system of the environment and health monitoring system has been introduced into the work of the State Sanitary and Epidemiological Service of the Lipetsk region in 1995. During this period, there was created a database for the collection of regional information on the quality and safety of the environment and public health. Methodology of the analysis is based on an assessment of the habitat on the total rank sanitary and hygiene index of the risk assessment to public health. The established relationships between adverse impacts of environmental factors on health are supported by statistical methods and are visualized in the form of cartograms. The results of multivariate analysis of the environment and the state of public health are summarized in the annual reports and 4 atlases “Sanitary-epidemiological situation in the Lipetsk region” being a good tool for the coordination of managerial decision-making basis for the development of legislative, administrative and regulatory guidance documents on public health. In recent years, in the region there are noted stable trends in the improvement of the quality of the environment, the health of the population and the demographic situation.

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Illuminating Regulatory Guidance

Michigan Journal of Environmental & Administrative Law ◽

10.36640/mjeal.9.2.illuminating ◽

2020 ◽

pp. 243

Author(s):

Cary Coglianese

Keyword(s):

Best Practices ◽

Federal Government ◽

Basic Problem ◽

Administrative State ◽

Legal Requirements ◽

The Public ◽

Regulatory Guidance ◽

Disclosure Requirements ◽

Guidance Documents ◽

Technological Fix

Administrative agencies issue many guidance documents each year in an effort to provide clarity and direction to the public about important programs, policies, and rules. But these guidance documents are only helpful to the public if they can be readily found by those who they will benefit. Unfortunately, too many agency guidance documents are inaccessible, reaching the point where some observers even worry that guidance has become a form of regulatory “dark matter.” This article identifies a series of measures for agencies to take to bring their guidance documents better into the light. It begins by explaining why, unlike the disclosure requirements for binding agency rules, existing legal requirements have failed to make guidance documents more accessible. The basic problem is that the law on guidance disclosure is not self-enforcing. As a result, guidance availability is ultimately a managerial challenge for agencies—dependent on the adoption of internal disclosure practices—as much as it is a problem with a legal or technological fix. To aid agency leaders in meeting their managerial challenge, this article reviews best practices in guidance disclosure across the federal government. It considers these practices in light of four key criteria for assessing guidance management—comprehensiveness, currency, accessibility, and comprehensibility—and provides a series of practical steps that agencies can take to illuminate their guidance. Given the important role that guidance plays in the modern administrative state, meaningful governmental transparency today dictates that agencies take seriously their responsibility to manage the production and release of their guidance documents in a manner that makes them consistently and readily available to the public.

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Representation of published core outcome sets for research in regulatory guidance: protocol

HRB Open Research ◽

10.12688/hrbopenres.13139.2 ◽

2021 ◽

Vol 4 ◽

pp. 45

Author(s):

Susanna Dodd ◽

Rebecca Fish ◽

Sarah Gorst ◽

Deborah Hall ◽

Pamela Jacobsen ◽

...

Keyword(s):

Patient Involvement ◽

European Medicines Agency ◽

Core Outcome ◽

Core Outcome Sets ◽

Regulatory Guidance ◽

The Core ◽

Key Stakeholders ◽

Regulatory Guidelines ◽

Core Outcomes ◽

Guidance Documents

Background: The COMET Initiative promotes the development and use of ‘core outcome sets’ (COS), agreed standardised sets of outcomes that should be measured and reported in all studies in a particular clinical condition. COS are determined by consensus amongst key stakeholders, including health professionals, policymakers and patients, ensuring that the priorities and expertise of these representatives inform the choice of the most important outcomes to measure for a given condition. There is increased recognition of the need to integrate COS across the healthcare system and with existing regulatory apparatus, to ensure that outcomes being recorded are those of key relevance to important stakeholders. The aim of this study is to assess the degree of concordance between outcomes recommended in COS for research and in guidance provided by two key regulators: US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Methods: COS for research published during 2015-2019 with patient involvement and covering drug or device interventions will be compared against relevant regulatory guidelines, matched by condition. Guidance documents matching in scope (relating to intervention and population) to a COS for research will be scrutinised to identify all suggested outcomes for comparison against the core outcomes in the corresponding COS. Discussion: This study will identify variation between outcomes suggested in FDA and EMA regulatory guidance relative to outcomes included in published COS for research, thus demonstrating the degree of representation of COS in regulatory guidance and vice versa. We will share the study findings (in particular, highlighting any lack of concordance between COS and regulatory guidance overall or for particular disease areas) and will invite feedback from FDA and EMA; we will seek to highlight where findings support the recommendations towards using well-developed COS or will make recommendations to COS developers on outcomes of importance to these key regulators.

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