Health Industry Washington Watch : Washington DC Healthcare Industry Law Firm : Reed Smith : Health Industry Washington Watch : Regulations, Medicare/Medicaid, Governmental Organizations

This post was written by Jennifer Pike.

In recent weeks, the Food and Drug Administration (FDA) has issued a number of new draft and final guidance documents on a range of issues, including financial disclosure by clinical investigators, medical device recalls, prescription drug labeling, and medical devices for pediatric uses. Highlights include the following:

• Financial Disclosure by Clinical Investigators. This final guidance assists in interpreting and complying with regulations governing financial disclosure by clinical investigators. It provides FDA’s responses to the most frequently-asked questions regarding financial disclosure by clinical investigators.
• Distinguishing Medical Device Recalls from Product Enhancements: Reporting Requirements. This draft guidance clarifies when a potential change to a device is a medical device recall, distinguishes those instances from product enhancements, and identifies the reporting requirements for both recalls and product enhancements.
• Labeling for Human Prescription Drug and Biological Products: Implementing the PLR Content and Format Requirements. This final guidance is intended to assist applicants in complying with the content and format requirements of labeling for human prescription drug and biological products under the Physician Labeling Rule (PLR). It provides recommendations for applicants developing labeling for new prescription drugs and revising labeling for already approved prescription drugs.  
• Providing Information about Pediatric Uses of Medical Devices under Section 515A of the Federal Food, Drug, and Cosmetic Act (FFDCA). This draft guidance describes how to compile and submit the readily-available pediatric use information required under the FFDCA.

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This post was written by Jennifer Pike.

The FDA released draft guidance on January 3, 2013 entitled Providing Regulatory Submissions in Electronic Format – Certain Human Pharmaceutical Product Applications and Related Submissions Using eCTD Specifications. The guidance is being issued in accordance with the Food and Drug Administration Safety and Innovation Act, which amended to Federal Food, Drug, and Cosmetic Act to require that certain regulatory submissions be submitted in electronic format. The guidance describes how FDA plans to implement this requirement. According to the guidance, requirements for electronic submission will be phased in on the following schedule: (1) 24 months after publication of the final version of this draft guidance, the requirements will apply to new drug application (NDA), abbreviated new drug application (ANDA), and biologics license application (BLA) submissions, and (2) 36 months after publication of the final guidance, the requirements will apply to investigational new drug application (IND) submissions. Comments will be accepted until March 4, 2013. A second draft guidance document, Providing Submissions in Electronic Format – Summary Level Clinical Site Data for CDER’s Inspection Planning, is intended to assist applicants in the voluntary submission of a clinical dataset that describes and summarizes the characteristics and outcomes of clinical investigations at the individual study site level. Such datasets facilitate the use of a risk-based approach to timely identification of clinical investigator sites for onsite inspection by FDA during the review of marketing applications. The guidance describes a recommended electronic format for the datasets to be submitted voluntarily in NDA, BLA, and NDA and BLA supplemental applications submitted to CDER. Comments may be submitted to www.regulations.gov by February 19, 2013.

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This post was written by Jennifer Pike.

The FDA is seeking comments on draft guidance related to clinical trial enrichment: Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products. The document is designed to provide guidance to industry on enrichment strategies that can be used in clinical trials intended so support effectiveness and safety claims in NDAs and BLAs. According to FDA, enrichment could lead to smaller studies, lower development costs, and help develop more personalized medicine. The guidance defines and discusses three types of enrichment strategies: decreasing heterogeneity, predictive enrichment, and prognostic enrichment. The guidance also discusses general clinical trial design considerations, provides examples of various potential clinical trial designs, and discusses potential regulatory considerations when using enrichment strategies in clinical trials. Comments may be submitted at www.regulations.gov until February 15, 2013.

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This post was written by Jennifer Pike.

The FDA has released two final guidance documents intended to help sponsors and investigators comply with safety reporting requirements for IND applications and bioavailability (BA) and bioequivalence (BE) studies: Safety Reporting Requirements for INDs and BA/BE Studies, and Safety Reporting Requirements for INDs and BA/BE Studies – Small Entity Compliance Guide. Comments regarding both guidance documents may be submitted at any time.

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This post was written by Jennifer Pike.

The Food and Drug Administration (FDA) recently issued two draft guidance documents related to the conduct of clinical trials. The first draft guidance, Draft Guidance for IRBs, Clinical Investigators and Sponsors: IRB Responsibilities for Reviewing the Qualifications of Investigators, Adequacy of Research Sites, and the Determination of Whether an IND/IDE Is Needed is intended to assist institutional review boards (IRBs), clinical investigators, and sponsors involved in clinical investigations of FDA-regulated products in determining whether the proposed research satisfies the criteria for IRB approval. Specifically, the guidance addresses the IRB’s role in reviewing: (1) the qualifications of investigators; (2) the adequacy of research sites; and (3) the determination of whether an investigational new drug (IND) application or investigational device exemption (IDE) is needed. Many of the recommendations in the guidance have appeared in other FDA guidance documents or have been communicated to IRBs who have contacted the agency directly about these issues, but FDA has compiled the information here to ensure that all IRBs are aware of and have access to it. When finalized, this guidance will supersede Question 56 in FDA’s January 1998 guidance Institutional Review Board Frequently Asked Questions – Information Sheet Guidance for Institutional Review Boards and Clinical Investigators.

The second draft guidance, Draft Guidance for Industry: Electronic Source Data in Clinical Investigations, provides guidance to sponsors, contract research organizations (CROs), data management centers, clinical investigators, and others involved in capturing, reviewing, and archiving electronic source data in FDA-regulated clinical investigations. This guidance revises and updates the draft guidance Electronic Source Documentation in Clinical Investigations. The draft guidance addresses source data (from clinical investigations) used to fill the predefined fields in an electronic case report form (eCRF), according to protocol , and discusses the following topics related to electronic source data: (1) identifying and specifying authorized source data originators; (2) creating data element identifiers to facilitate sponsors, FDA, and other authorized parties in examining the audit trail of data; (3) capturing source data into the eCRF using either manual or electronic capture methods; and (4) investigator responsibilities with respect to reviewing and retaining electronic data. Comments on both guidance documents will be accepted at www.regulations.gov until January 22, 2013.

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This post was written by Erin Janssen.

The FDA has published a notice announcing the availability of draft guidance on "Considerations When Transferring Clinical Investigation Oversight to Another IRB." This guidance discusses the regulatory responsibilities of institutional review boards (IRBs), clinical investigators, and sponsors when oversight of a previously approved clinical investigation under FDA’s jurisdiction is transferred from one IRB to another IRB. This guidance also addresses questions previously raised concerning procedures and processes that are required and/or recommended by FDA when such oversight is transferred. Comments are due by August 13, 2012.

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FDA recently published a final rule that expands the scope of clinical investigator disqualification. Under the rule, when the FDA determines that an investigator is ineligible to receive one kind of test article (drugs, devices, or new animal drugs), the investigator also will be ineligible to conduct any clinical investigation that supports an application for a research or marketing permit for other kinds of products regulated by FDA. The rule is effective May 30, 2012.

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This post was written by Erin Janssen.

FDA will conduct a 2-day public hearing on April 23 and 24, 2012 to obtain input from interested persons on FDA’s scope and direction in modernizing the regulations, policies, and practices that apply to the conduct of clinical trials of FDA-regulated products. Individuals who wish to attend or present at the public hearing must register by April 2, 2012.

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This post was written by Erin A. Janssen.

FDA has issued guidance in the form of a Small Entity Compliance Guide entitled “Questions and Answers on Informed Consent Elements, 21 CFR § 50.25(c).” This guidance is intended to help sponsors, investigators and Institutional Review Boards better understand new informed consent requirements. In the Federal Register of January 4, 2012 (76 Fed. Reg. 256), FDA published a final regulation amending the current informed consent regulations to require that informed consent documents and processes for applicable drug (including biological products) and device clinical trials include a specific statement that clinical trial information will be entered into a databank. The new guidance document provides detailed questions and answers related to the new requirements.

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This post was written by Erin Janssen.

The FDA recently issued draft guidance entitled “Evaluation of Sex Differences in Medical Device Clinical Studies,” which indicates FDA's current view of the study and evaluation of sex-specific differences in medical device clinical trials to support marketing submissions and post-approval study. In particular, the focus is on addressing potential differences in study design, conduct, outcomes, and interpretation that should be considered to ensure sex-specific issues are adequately addressed. The intent of the guidance is to improve the quality and consistency of available data regarding the performance of medical devices in both sexes, to encourage proportional enrollment of women representative of disease demographics and provide guidance on reporting of sex-specific information. Although comments can be submitted at any time, FDA is requesting that interested parties submit their comments by March 19, 2012.

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CMS is seeking comments on its Medicare coverage with evidence development (CED) policy, under which CMS provides conditional Medicare coverage for an item while collecting clinical data. CMS is looking for feedback on the use of CED in national coverage determinations and its impact on Medicare and its beneficiaries. The input will be used to "to develop a guidance document that better aligns CED with the rapidly evolving changes in our healthcare system," and to help the CED process serve "as a mechanism that simultaneously reduces barriers for innovation and enables CMS to make better informed decisions that improve health outcomes for Medicare beneficiaries." Comments will be accepted until January 6, 2012.

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This post was written by Erin Janssen and Areta Kupchyk.

The HHS Office for Human Subject Protections (OHRP) and the Food and Drug Administration (FDA) are seeking comments on a joint draft document entitled “Guidance on Exculpatory Language in Informed Consent.” Among other things, the draft document:

• Provides guidance on the regulatory prohibition on the inclusion in informed consent of exculpatory language (that is, language which has the general effect of freeing or appearing to free an individual or an entity from malpractice, negligence, blame, fault, or guilt);
• Includes examples of language that OHRP and FDA consider acceptable as well as examples of language that the agencies would consider exculpatory; and
• Clarifies that OHRP and FDA have concluded that language in informed consent is not exculpatory if it informs subjects that, by agreeing to allow the use of their biospecimens for research purposes, they are giving up any legal right to be compensated for the use of the biospecimens. This represents a change from OHRP's November 15, 1996 guidance on point, "Exculpatory Language in Informed Consent," which identified as "exculpatory" certain informed consent statements in which subjects gave up any rights they might have in their biospecimens. OHRP and FDA now consider these statements to be acceptable for inclusion in informed consent, and they are restated as examples of acceptable language in the draft guidance. Thus, for example, it would now be acceptable to include language in a consent form such as "I give up any property rights I may have" in biospecimens, or "I voluntarily and freely donate" the biospecimens to a particular institution.

When finalized, the draft document will supersede OHRP's November 15, 1996 guidance entitled, "Exculpatory Language in Informed Consent" and question number 52 in FDA's January 1998 guidance entitled "Institutional Review Boards Frequently Asked Questions - Information Sheet Guidance for Institutional Review Boards and Clinical Investigators." FDA is accepting comments on the draft until November 7, 2011. A September 7, 2011 Federal Register notice of availability of the guidance, the joint draft guidance document, and instructions for submitting comments can be accessed on the OHRP website. 

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This post was written by Erin Janssen and Areta Kupchyk.

On September 23, 2011, FDA released guidance entitled “Reproductive and Developmental Toxicities--Integrating Study Results to Assess Concerns.” The guidance describes an approach to estimating possible human developmental or reproductive risks associated with drug or biological product exposure when a finding of toxicity has been identified, but definitive human data are unavailable. The guidance is intended for drug developers intending to submit NDAs and BLAs, and who are assessing nonclinical toxicity information. The recommendations included will also help to ensure a consistent review of reproductive and developmental toxicity data among Center for Drug Evaluation and Research review staff.

The guidance does not: (1) give detailed advice about labeling or placement of toxicity information in product labeling (for information on labeling, see 21 CFR 201.57); or (2) discuss clinical data, the integration of nonclinical and clinical data, or the clinical implications of these data. The approach presented in the guidance for assessing nonclinical reproductive and developmental toxicity data involves the integration and careful consideration of a variety of different types of nonclinical information: Reproductive toxicology; general toxicology; and toxicokinetic and pharmacokinetic information, including absorption, distribution, metabolism, and elimination findings. The approach is used when there is a toxicity finding and focuses on assessing the likelihood that a drug will increase the risk of adverse human developmental or reproductive outcomes. The approach includes noting when studies were not conducted or when they were not performed using relevant model systems or at appropriate dose ranges.

FDA released a prior draft of this guidance in 2001, however, one important change has been made. The description of a process that involved assignment of values of +1, -1 or 0 to the various factors was removed from the guidance. Comments on the guidance may be submitted at any time.

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This post was written by Erin Janssen.

On September 1, 2011, HHS published a notice extending the comment period for the advance notice of proposed rulemaking (ANPRM) on how current regulations for protecting human subjects might be modernized and revised to be more effective. That ANPRM, entitled "Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators," was published in the Federal Register on July 26, 2011, with a comment deadline of September 26, 2011. Since the ANPRM was published, HHS has received requests to extend the comment period to allow sufficient time for a full review of the ANPRM. In response to these requests, the comment period will be extended by 30 days to October 26, 2011.

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This post was written by Erin Janssen.

On August 29, 2011, the FDA released draft guidance entitled “Oversight of Clinical Investigations: A Risk-Based Approach to Monitoring.” FDA published the draft guidance to assist sponsors of clinical investigations in developing risk-based monitoring strategies and plans for clinical investigations of human drug and biological products, medical devices, and combinations thereof. The guidance is intended to make clear that sponsors can use a variety of approaches to meet their monitoring responsibilities during clinical investigations. The guidance describes a risk-based approach to monitoring that focuses on critical study parameters and relies on a combination of monitoring activities to effectively oversee a study. For example, the guidance encourages greater use of centralized monitoring methods where appropriate. The guidance also makes recommendations about how to develop monitoring plans and document monitoring activities. While interested parties may submit comments on the guidance at any time, the agency is requesting comments by November 28, 2011.

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On August 25, 2011, HHS published a final rule on the Responsibility of Applicants for Promoting Objectivity in Research for which Public Health Service (PHS) Funding is Sought and Responsible Prospective Contractors. The final rule revises 1995 standards on this subject in order to “update enhance the objectivity and integrity of the research process” and provide “a framework for identifying, managing, and ultimately avoiding investigators’ financial conflicts of interest.“ Among other thing, the rule revises: the definition of significant financial interest (SFI); modifies the extent of investigator disclosure (including lowering the monetary threshold at which SFI requires disclosure, generally from $10,000 to $5,000, and requiring investigators to disclose to their institutions all of their significant financial interests related to their institutional responsibilities); changes the information reported to the PHS awarding component and made accessible to the public; and updates investigator training requirements. An institution applying for or receiving PHS funding covered by the rule must be in full compliance with the regulatory requirements no later than August 24, 2012; and immediately upon making its Institutional Financial Conflict of Interest policy publicly accessible, as described in the rule.  Additional information about the rule is available at the National Institutes of Health website.

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This post was written by Erin Janssen.

The Food and Drug Administration (FDA) issued draft guidance on August 15, 2011 to help researchers and manufacturers design better quality clinical studies in support of premarket approval applications for certain medical devices. Although the public can comment on the draft guidance at any time, FDA has requested that interested parties submit their comments by November 14, 2011. FDA has previously articulated policies related to design of studies intended to support specific device types, and a general policy of tailoring the evidentiary burden to the regulatory requirement, but the FDA has not previously attempted to describe the different clinical study designs that may be appropriate to support a device premarket submission, or to define how a sponsor should decide which pivotal clinical study design should be used to support a submission for a particular device. The draft guidance describes different study design principles relevant to the development of medical device clinical studies that can be used to fulfill premarket clinical data requirements. The guidance applies to therapeutic and aesthetic devices and diagnostic devices. While the guidance also includes principles that are applicable to device-specific issues for combination products defined under 21 CFR Part 3 (e.g., device-drug products; device-biologic products), drug-specific or biologic-specific issues that may also be relevant for a combination product are not described. In addition, the document is not intended to provide a comprehensive tutorial on the best clinical and statistical practices for investigational medical device studies. 

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This post was written by Erin Janssen.

The FDA has announced the opening of registration for its third annual FDA Clinical Investigator Training Course, co-sponsored by the FDA Office of Critical Path Programs and the Clinical Trials Transformation Initiative (CTTI). The course will be held on November 7-9, 2011 in Silver Spring, Maryland. Topics to be discussed include the design, conduct, and analysis of clinical trials; regulatory considerations essential for clinical research; the role of the Data and Safety Monitoring Board and Institutional Review Board in clinical studies; preclinical and pharmacological issues in clinical studies; safety assessment during clinical trials; inclusion of special populations such as pregnant women in clinical studies; and the role of personalized medicine in the future of medical product development. The course has been designed with the goal of enabling investigators to improve the quality of clinical trials and to enhance the safety of trial participants.

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The Government Accountability Office (GAO) has issued a report entitled "Pediatric Research: Products Studied under Two Related Laws, but Improved Tracking Needed by FDA." The report examines the extent to which the Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA) have impacted the conduct of pediatric studies since Congress reauthorized the laws in 2007. The GAO reports that at least 130 products (80 products under PREA and 50 under BPCA) have been studied for use in children since the 2007 reauthorization, all of which had labeling changes that included important pediatric information. The FDA’s data may be incomplete due to shortcomings in tracking practices. The GAO also found that stakeholders, including sponsors, pediatricians, and health advocacy organizations, described challenges that could limit the success of PREA and BPCA, including confusion about compliance requirement due to a lack of FDA guidance and a lack of economic incentives to study products with no remaining market exclusivity. The GAO recommends that FDA improve its information tracking and data maintenance processes.

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FDA has released for public comment a draft guidance document entitled “Financial Disclosures by Clinical Investigators.”   The guidance, which will supersede March 2001 guidance on this issue, seeks to respond to a January 2009 HHS Office of the Inspector General (OIG) report that concluded that clinical investigators may not be disclosing all financial interests (). It also addresses questions FDA has received from industry and the public. The draft guidance describes: (1) the sponsor’s responsibility to collect the financial disclosure information prior to an investigator participating in a study and ensure that all required forms and attachments are submitted in marketing applications; (2) what is meant by ‘‘due diligence’’ in obtaining financial disclosures from investigators; and (3) how FDA will review financial disclosure information. The guidance also solicits comment on the circumstances under which FDA should consider public release of financial disclosure information related to an approved marketing application. FDA is accepting comments on the draft guidance until July 25, 2011.

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