Clinical Research and the Law The legal implications of conducting clinical research and trials are becoming more complex. Everyone involved in clinical research increasingly needs to be aware of not only the ethical issues at stake but also how the law affects medical practice and research. Much of clinical research and trial law and litigation is comparatively recent and researchers need to ensure current compliance on a wide range of issues including: * standards and duty of care * conflicts of interest * establishing clinical trials * informed consent * research contracts * the disclosure and withholding of clinical trial results Clinical Research and the Law comprehensively discusses these topics and provides the answers to the legal questions and potential pitfalls encountered in medical research. It is an up-to-date, practical guide for clinical investigators and their institutional administrators, particularly risk managers and research administrators, as well as healthcare administrators and members of institutional review boards. This book is also a key resource for medical students, postgraduate research students, practicing attorneys and counselors for teaching hospitals and institutions undertaking clinical research and contract research organizations.
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Table of Contents
Chapter 1 Research malpractice and negligence
1.2 Drugs: brief description of definitions
1.3 Brief overview: conduct of clinical trials
1.4 Medical devices
1.5 Research malpractice: the basics
1.6 Negligence actions and research: interesting aspects of medical research negligence cases
Appendix to Chapter 1 Relevant portions of the code of federal regulations
Protection of human subjects
Investigational new drug application
Overview: FDA regulation of medical devices
Chapter 2 Duty of care: understanding the legal differences between medical treatment and medical research
2.1 Establishing duty of care
2.2 Do sponsors have a legal duty?
Chapter 3 Establishing standard of care and violation of standard of care
3.1 Research malpractice and using expert testimony to establish the standard of care
3.2 Lessons learned from surgical innovation cases
3.3 Standard of care and informed consent cases
Chapter 4 Informed consent in clinical research
4.1 Basics on informed consent in the clinical treatment setting: background
4.2 Informed consent as applied to the research setting
4.3 Informed consent and federal regulations
4.4 Case law and federal regulations
4.5 Clinical trials and pediatric patients
Appendix to Chapter 4 Title 45 of the code of federal regulations
46.116 General requirements for informed consent.
§46.117 Documentation of informed consent.
Chapter 5 Liability issues for institutional review boards (IRBs) and data safety monitoring boards (DSMBs)
5.1 Liability for negligence
5.2 Standard of care
5.3 Proximate cause and damages
5.5 Practical considerations: the need for indemnification
5.6 Special considerations for DSMBs
Chapter 6 Legal aspects of financial conflicts of interest in clinical trials
6.2 Legislative background: road to creating financial conflicts of interest
6.3 Financial conflicts of interest: evidence that financial conflicts of interest are problematic
6.5 Litigation involving financial conflicts of interest in clinical trials
6.6 Applying novel legal theories to financial conflicts of interest cases
6.7 Other clinical trial cases involving financial conflicts of interest claiming constitutional violations
Chapter 7 Disclosure of clinical trial information: legal ramifications of withholding study results
7.2 Vioxx and Merck
7.3 Government and other clinical trial disclosure requirements
7.4 Medical journal editors and disclosure of clinical trial information
Appendix to Chapter 7 Clinical trial registration: a statement from the International Committee of Medical Journal Editors
Chapter 8 Clinical trials and insider trading
8.1 Purpose of insider trading laws
8.2 Proving insider trading
8.4 Insider trading cases and clinical trials
8.5 Beware: investigators and relationships with the investment industry—a risk of recent vintage
8.6 Setting the stage
Chapter 9 Clinical trials and criminal law
9.1 How clinical trial investigators have been implicated in criminal acts
9.2 False Claims Act cases and health-care fraud
9.3 Clinical trial False Claims Act cases
9.4 Enforcement of the False Claims Act against institutions
9.5 Anti-kickback law
9.6 Health-care fraud
9.7 Mail and wire fraud/making false statements to government officials
9.8 Proposed new FDA rule
Chapter 10 Clinical trial contracts
10.1 Key terms/scope of study
10.4 Intellectual property
10.7 Various sundry provisions
Appendix A: Glossary of common terms used in connection with clinical trials
Appendix B: Research involving human subjects
VI. Decision Tree for Participation of Children in Research
VII. Additional Requirements for Research that Includes Children
Appendix C: Best pharmaceuticals for Children Act
SECTION 1. SHORT TITLE.
SEC. 2. PEDIATRIC STUDIES OF ALREADY-MARKETED DRUGS.
SEC. 3. RESEARCH FUND FOR THE STUDY OF DRUGS.
SEC. 4. WRITTEN REQUEST TO HOLDERS OF APPROVED APPLICATIONS FOR DRUGS THAT HAVE MARKET EXCLUSIVITY.
SEC. 5. TIMELY LABELING CHANGES FOR DRUGS GRANTED EXCLUSIVITY; DRUG FEES.
SEC. 6. OFFICE OF PEDIATRIC THERAPEUTICS.
SEC. 7. NEONATES.
SEC. 8. SUNSET.
SEC. 9. DISSEMINATION OF PEDIATRIC INFORMATION.
SEC. 10. CLARIFICATION OF INTERACTION OF PEDIATRIC EXCLUSIVITY UNDER SECTION 505A OF THE FEDERAL FOOD, DRUG, AND COSMETIC ACT AND 180-DAY EXCLUSIVITY AWARDED TO AN APPLICANT FOR APPROVAL OF A DRUG UNDER SECTION 505(J) OF THAT ACT.
SEC. 11. PROMPT APPROVAL OF DRUGS UNDER SECTION 505(J) WHEN PEDIATRIC INFORMATION IS ADDED TO LABELING.
SEC. 12. STUDY CONCERNING RESEARCH INVOLVING CHILDREN.
SEC. 13. FOUNDATION FOR THE NATIONAL INSTITUTES OF HEALTH.
SEC. 14. PEDIATRIC PHARMACOLOGY ADVISORY COMMITTEE.
SEC. 15. PEDIATRIC SUBCOMMITTEE OF THE ONCOLOGIC DRUGS ADVISORY COMMITTEE.
SEC. 16. REPORT ON PEDIATRIC EXCLUSIVITY PROGRAM.
SEC. 17. ADVERSE-EVENT REPORTING.
SEC. 18. MINORITY CHILDREN AND PEDIATRIC-EXCLUSIVITY PROGRAM.
SEC. 19. TECHNICAL AND CONFORMING AMENDMENTS.
Appendix D: Pediatric research Equity Act of 2003
SECTION 1. SHORT TITLE.
SEC. 2. RESEARCH INTO PEDIATRIC USES FOR DRUGS AND BIOLOGICAL PRODUCTS.
SEC. 3. TECHNICAL AND CONFORMING AMENDMENTS.
SEC. 4. EFFECTIVE DATE.
Appendix E: Title 21–food and drugs: additional safeguards for children in clinical investigations
Sec. 50.50 IRB duties.
Sec. 50.51 Clinical investigations not involving greater than minimal risk.
Sec. 50.52 Clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects.
Sec. 50.53 Clinical investigations involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subjects’ disorder or condition.
Sec. 50.54 Clinical investigations not otherwise approvable that present an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children.
Sec. 50.55 Requirements for permission by parents or guardians and for assent by children.
Sec. 50.56 Wards.
Appendix F: Proposed standardized/ harmonized clauses for clinical trial agreements
PART I: PROPOSED STANDARDIZED/ HARMONIZED CLAUSES FOR COMPANY-SPONSORED CLINICAL TRIAL AGREEMENTS
PART II: PROPOSED STANDARDIZED/ HARMONIZED CLAUSES FOR INVESTIGATOR INITIATED CLINICAL TRIAL AGREEMENTS
Appendix G: Responsibility of applicants for promoting objectivity in research for which public health service funding is sought and responsible prospective contractors
TITLE 42—PUBLIC HEALTH
TITLE 45—PUBLIC WELFARE
This edition first published 2012, © 2012 Patricia M. Tereskerz.
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Library of Congress Cataloging-in-Publication Data
Tereskerz, Patricia M.
Clinical research and the law / Patricia M. Tereskerz ; consulting clinical editors, Robert Edelman, Ross McKinney, Jr.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-4051-9567-6 (paper)
[DNLM: 1. Biomedical Research–legislation & jurisprudence–United States. 2. Biomedical Research–standards–United States. 3. Clinical Trials as Topic–legislation & jurisprudence–United States. 4. Clinical Trials as Topic–standards–United States. 5. Human Experimentation–legislation & jurisprudence–United States. 6. Human Experimentation–standards–United States. W 33 AA1]
A catalogue record for this book is available from the British Library.
Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.
Until relatively recently, research institutions and investigators had not been named as defendants in lawsuits involving clinical trials. However, the death of Jesse Gelsinger in a clinical trial,1 which took place now more than a decade ago, proved to be a defining moment for the clinical research enterprise and opened the floodgates to litigation as well as to new legislation and regulations governing clinical research.2
Yet, many of the resources needed to support clinical research in the midst of these changes are missing. This is certainly the case with health professionals’ and administrators’ need for readily available information about clinical trial law. The literature on American law and clinical trials is severely limited for most topical areas and completely absent for others. Experts acknowledge the need to understand how the law affects medical practice and research, yet there is no current, comprehensive source for those associated with clinical trials to consult concerning the various legal aspects and potential pitfalls these trials embrace. Because clinical trial litigation is of such recent vintage, it is particularly difficult for the non-lawyer to find and interpret the relevant information, further underscoring the need for such a resource.
This book is intended to begin to fill this gap as a resource containing information and reference material to help identify and understand the legal issues, many of which are quite complex, that are associated with clinical trials. This book is limited to American law, and it is beyond its scope to discuss the legal aspects of international clinical trials, which is a topic deserving of a book unto itself.3
On many occasions the author of this book has needed to consult a comprehensive review of clinical trial law but could find only one book that came close—Clinical Research Law and Compliance Handbook.4 It provides an excellent and practical overview of regulatory and compliance requirements in structuring a clinical trial, but does not deal with clinical issues raised during the conduct of such trials to the extent this book does. The current book, on the other hand, provides an overview of relevant regulatory schemes and emphasizes and integrates into the reading cases involving the clinical aspects of trials. As such, the work will be a resource/ research aid handbook designed more for clinical investigators, their institution administrators, and counsel.
When reading the cases discussed in this book, it is important to remember that because a court has ruled one way in one jurisdiction it does not necessarily mean that courts in other jurisdictions will rule the same. After all, only the US Supreme Court renders decisions that become the law of the land. However, given the limited number of published court opinions in this area of the law, it is likely that courts from different jurisdictions will consider how other courts have ruled and may give some weight to these earlier decisions.
Finally, a word about what this book is not. It is not intended to be an academic or philosophical treatise on the law. It is meant to be an easy to read, practical resource for, primarily, non-lawyers who need this information but who do not want to undertake in-depth reading on the policy and analysis behind the law in each area, as would be expected of a legal resource for law students or attorneys. In addition, the references provided in each chapter are intended to offer health professionals a comprehensive resource of materials that they may consult for further reading on each topical area covered.
Patricia M. Tereskerz
1 Dembner A. Lawsuits target medical research. Boston Globe, 8/12/02. Quoting Janet Richardson, a Los Angeles lawyer who defends drug and medical device manufacturers.
2 Morreim EH. Clinical trials litigation: practical realities as seen from the trenches. Account Res. 2005; 12: 47–67.
3 Brunler DR, Nahler G. International Clinical Trials: A Guidebook and Compendium of National Drug Laws. CRC Press, 1999. Rozovsky FA, Adams RK. Clinical Trials and Human Research: A Practical Guide to Regulator Compliance. International Research, Chapter 18. John Wiley & Sons, 2003: 535–542.
4 Steiner JE, ed. Clinical Research Law And Compliance Handbook. Jones and Bartlett Publishers, 2005.
Research Malpractice and Negligence
As clinical trials continually undergo increased examination, commentators note that law suits involving these trials will likely continue to increase in the face of relatively recent high-profile litigation, which has garnered considerable media attention.1,2 Before moving on to a discussion of the specific legal aspects of clinical trials and research malpractice, it is first important to establish baseline definitions and gain an understanding of what is being discussed. The first part of this chapter is dedicated to explaining what is meant by terms frequently used throughout the book and to providing a brief overview and history of the research enterprise. Terms used throughout will follow the federal definitions as set out in the Code of Federal Regulations. This is followed by a discussion of the basic elements required to prove negligence.
Federal regulations concerning clinical trials can trace their origins to international guidelines or codes. In particular, the Nuremberg Code3 was adopted after World War II, following the horrendous Nazi medical experiments. The Code, which requires voluntary consent of human subjects, sets forth the following ten ethical principles for research involving human subjects.4
The Nuremberg code was followed by the Declaration of Helsinki,5 which provides international guidance for biomedical research undertaken by physicians. This Declaration was first adopted in 1964 and has been amended six times since, most recently in October 2008, and replaces all previous versions.
The United States Congress enacted the National Research Act of 1974, following several highly visible American research abuses which occurred in the mid-1970s, including the notorious Tuskegee syphilis experiments in which African-American men with syphilis were left untreated for many years so that researchers could study the clinical progression of syphilis.6
In 1979, the Belmont Report, which was written by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, was codified.7 The Department of Health, Education and Welfare, now the Department of Health and Human Services (DHHS), adopted the principles described in the Belmont report—respect for persons, beneficence, and justice—to assure a uniform system of human subject protection throughout relevant federal agencies and departments.8 These regulations are referred to as “The Common Rule” which provides the basic elements of informed consent. The Common Rule will be discussed in more detail in Chapter 4 on informed consent.
The Office for Protection of Research Risk (later named the Office of Human Research Protections (OHRP)) was established to oversee development and implementation of policies and procedures to protect research participants participating in DHHS-sponsored research,9 and is under the purview of the DHHS. The National Human Research Protections Advisory Committee (now called the Secretary’s Advisory Committee on Human Research Protections) was also put into place to provide broad scientific and ethical guidance to OHRP. While OHRP is charged with oversight, management, and guidance for clinical trials and other research studies in humans, the Food and Drug Administration (FDA) is responsible specifically for approving clinical trials to test a new drug, biological product, or medical device.10
The appendix to this chapter includes selected reprinted portions of relevant definition sections of the Code of Federal Regulations. Briefly, for the testing of new drugs, federal regulations state a “clinical investigation means any experiment that involves a test article and one or more human subjects.”11 Everyone participating in a clinical investigation is a subject, which is defined as a “human who participates in an investigation, either as a recipient of the investigational new drug or as a control. A subject may be a healthy human or a patient with a disease.”12
Institutional Review Boards (IRB) protect the rights and welfare of human subjects and are the groups formally designated to review, approve, and conduct periodic review of research involving human subjects.13
The sponsor is the person or organization “who takes responsibility for and initiates a clinical investigation.” “[A] sponsor may be an individual or pharmaceutical company, government agency, academic institution, private organization, or other organization.”14 A sponsor may retain a “contract research organization” which “assumes as an independent contractor with the sponsor, one or more obligations of a sponsor, e.g., design of a protocol, selection or monitoring of investigations, evaluation of reports, and preparation of materials to be submitted to the Food and Drug Administration.”15
Human clinical trials are undertaken in four phases, known as Phases I to IV. The Office of Human Protections describes the objectives of the four phases as follows:16
Phase I Drug Trial. Phase I trials include the initial introduction of an investigational new drug into humans. These studies are typically conducted with healthy volunteers; sometimes, where the drug is intended for use in patients with a particular disease, however, such patients may participate as subjects. Phase I trials are designed to determine the metabolic and pharmacological actions of the drug in humans, the side effects associated with increasing doses (to establish a safe dose range), and, if possible, to gain early evidence of effectiveness; they are typically closely monitored. The ultimate goal of Phase I trials is to obtain sufficient information about the drug’s pharmacokinetics and pharmacological effects to permit the design of well-controlled, sufficiently valid Phase II studies. Other examples of Phase I studies include studies of drug metabolism, structure–activity relationships, and mechanisms of actions in humans, as well as studies in which investigational drugs are used as research tools to explore biological phenomena or disease processes. The total number of subjects involved in Phase I investigations is generally in the range of 20 to 80.
Phase II Drug Trial.17 Phase II drug trials include controlled clinical studies conducted to evaluate the drug’s effectiveness for a particular indication in patients with the disease or condition under study, and to determine the common short-term side effects and risks associated with the drug. These studies are typically well-controlled, closely monitored, and conducted with a relatively small number of patients, usually involving no more than several hundred subjects.
Phase III Drug Trial. Phase III trials involve the administration of a new drug to a larger number of patients in different clinical settings to determine its safety, effectiveness, and appropriate dosage. They are performed after preliminary evidence of effectiveness has been obtained, and are intended to gather necessary additional information about effectiveness and safety for evaluating the overall benefit–risk relationship of the drug, and to provide an adequate basis for physician labeling. In Phase III studies, the drug is used the way it would be administered when marketed. When these studies are completed and the sponsor believes that the drug is safe and effective under specific conditions, the sponsor applies to FDA for approval to market the drug. Phase III trials usually involve several hundred to several thousand patient-subjects.
Phase IV Drug Trial. Concurrent with marketing approval, FDA may seek agreement from the sponsor to conduct certain postmarketing (Phase IV) studies to delineate additional information about the drug’s risks, benefits, and optimal use. These studies could include, but would not be limited to, studying different doses or schedules of administration than were used in Phase II studies, use of the drug in other patient populations or other stages of the disease, or use of the drug over a longer period of time.18
Medical devices entering the market must also comply with the Food and Drug Cosmetic Act. However, the approval process for medical devices is less arduous than that for drugs and often does not require “true” clinical trials for safety and efficacy.19 However, beginning in 1990, the FDA has required more rigorous device evaluations concerning their risks and benefits. Nevertheless, few new device evaluations involve randomized controlled clinical trials.20
Given that there are so many different types of devices ranging from those that present little to no risk to other much more complicated devices such as implants, the Medical Device Amendment Act of 1976 acknowledges this variation and classifies devices into three categories based on the level of risk. An explanation of how devices are classified is available on the FDA website and is included in the appendix to this chapter.
Most lawsuits dealing with research malpractice are grounded in the legal theory of negligence. To prove negligence, a plaintiff must prove each of the following elements: (1) the existence of a duty, recognized by law, to adhere to a standard to protect others against unreasonable risks; (2) a breach of this duty; (3) a causal connection, often referred to as “proximate cause,” between this breach; and (4) a resulting injury—damages.21 If a breach in duty does not result in any injury, then negligence cannot be established. Duty of care and standard of care are the two elements that have been treated somewhat differently within the research malpractice setting as opposed to medical malpractice. Therefore, Chapters 2 and 3 of this text will discuss the application of these elements in great detail with an eye as to how courts have treated these when it comes to clinical research.
To preface this discussion, it is important to distinguish medical research from medical practice and to consider some basic concepts of each. One noted scholar has emphasized the need for a well-founded approach to research-related injuries by the courts because it is necessary to consider what research is and how it is different from medical treatment.22
Morreim notes that the primary difference between research and ordinary medical practice are the goals of each. The goal of research is to “advance generalizable knowledge and thereby to benefit broader populations.”23 Research may use techniques such as randomization, double-blinding, and inclusion of placebos as controls, which means a research participant’s personal interests may be secondary to the goal of the research. Further, Morreim points out that while those participating in clinical research may receive benefits from the study, it is not the goal of the research to benefit the individual research participant. In research, participants may be exposed to unanticipated risks of experimental treatments or receive only a placebo. This stands in contrast to medical practice, where the goal is to benefit the patient and, as embraced by the Hippocratic Oath, to “do no harm” to the patient.24 Although the risks are less known in research, investigators must still minimize known and unknown risks to the extent possible.
Despite these differences, courts have relied on the medical malpractice framework to guide their judgment in considering research malpractice cases. In some of the early court cases, courts were not willing to allow practices in research that were not consistent with accepted medical practice,25 and in fact it was not until the 1930s that courts accepted clinical research as a necessary enterprise where a court acknowledged that “[w]e recognize the fact that, if the general practice of medicine and surgery is to progress, there must be a certain amount of experimentation. …”26
One of the interesting aspects of negligence cases involving medical research is how a wide net has been cast in naming defendants in these cases and how traditional legal theories are being expanded to reach research malpractice lawsuits, illustrating how this is a relatively new and evolving area of the law. For example, defendants have been named in law suits involving clinical research who heretofore would not have been considered targets, including bioethicists and members of boards such as IRBs. The Gelsinger27 case, which will be discussed in detail later in this book, was one of the first instances in which the plaintiff’s attorney named defendants who had previously never been targets of malpractice claims, including a clinical ethicist and members of the IRB. In addition, lawsuits involving clinical trials have also attempted to apply novel legal theories, which will also be discussed in greater detail later in this book.
From: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=50. 04/01/2010.
As used in this part:
[45 FR 36390, May 30, 1980, as amended at 46 FR 8950, Jan. 27, 1981; 54 FR 9038, Mar. 3, 1989; 56 FR 28028, June 18, 1991; 61 FR 51528, Oct. 2, 1996; 62 FR 39440, July 23, 1997; 64 FR 399, Jan. 5, 1999; 64 FR 56448, Oct. 20, 1999; 66 FR 20597, Apr. 24, 2001]
From: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312. 04/01/2010.
[52 FR 8831, Mar. 19, 1987, as amended at 64 FR 401, Jan. 5, 1999; 64 FR 56449, Oct. 20, 1999; 73 FR 22815, Apr. 28, 2008]
From: http://www.qrasupport.com/FDA_MED_DEVICE.html. 05/06/2003.
Many of the regulations enforced by the Food and Drug Administration (FDA) with regard to medical devices can be found in Title 21 Code of Federal Regulations (CFR) Part 800 to Part 1299. This reference is abbreviated to 21 CFR 800 to 1299.
A medical device is defined within the Food Drug & Cosmetic Act as “… an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is: recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them, intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of it’s primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.”
Medical devices distributed in the United Sates are subject to General Controls, pre-marketing and post marketing regulatory controls, as outlined below.
General Controls include:
Pre-marketing controls are device and device classification specific. Pre-marketing controls for a medical device may include: clearance to market by 510(k) or approval to market by Pre-Market Approval (PMA). Post marketing controls include Device Listing, Medical Device Reporting (MDR), Establishment Registration and Quality System Compliance Inspection.
There are 3 FDA regulatory classifications of medical devices: Class I, Class II and Class III. The classifications are assigned by the risk the medical device presents to the patient and the level of regulatory control the FDA determines is needed to legally market the device. As the classification level increases, the risk to the patient and FDA regulatory control increase. Accessories to medical devices, devices used with a medical device to support use of the device, are considered the same classification as the medical device.
The FDA classification of medical devices is based upon classifications for devices currently legally marketed in the United States. The FDA determines the device classification by the device intended use and risk the device presents to the patient. New medical devices are compared to legally marketed medical device classifications with the same intended use and technological characteristics to determine the device classification.
Class I medical devices have the least amount of regulatory control. Class I devices present minimal potential harm to the user. Class I devices are typically simple in design, manufacture and have a history of safe use. Examples of Class I devices include tongue depressors, arm slings, and hand-held surgical instruments. Most Class I devices are exempt from the premarket notification and may be exempt from compliance with the good manufacturing practices regulation.
Class II medical devices are devices where General Controls are not sufficient to assure safety and effectiveness and existing methods/ standards/ guidance documents are available to provide assurances of safety and effectiveness. In addition to compliance with General Controls, Class II devices are required to comply with Special Controls. Special Controls include:
Special labeling requirements,
Mandatory performance standards, both International and United States
FDA medical device specific guidance
Class II devices typically require pre-market notification by submission and FDA review of a 510(k) clearance to market submission. A few Class II devices are exempt from the premarket notification. Information on Class II exempt devices is located within the device regulation, 21 CFR 862 through 892. Examples of Class II devices include physiologic monitors, x-ray systems, gas analyzers, pumps, and surgical drapes.
Class III medical devices have the most stringent regulatory controls. For Class III medical devices, sufficient information is not available to assure safety and effectiveness through the application of General Controls and Special Controls. Class III devices usually support or sustain human life, are of substantial importance in preventing impairment of human health, or present a potential unreasonable risk of illness or injury to the patient. Typically a Pre-Market Approval (PMA) submission to the FDA is required to allow marketing of a Class III medical device. A few Class III medical devices are required to only have a 510(k) cleared by the FDA to be marketed. Examples of Class III devices that require a PMA are: replacement heart valves, silicone gel-filled breast implants, and implanted cerebella stimulators.
The majority of Class II medical devices are cleared to market by submission and FDA review of a 510(k) Pre-Market Notification submission. The 510(k) submission identifies characteristics of the new or modified medical device as compared to a medical device with similar intended use, currently legally marketed in the United States. The currently legally marketed device is referred to as the “predicate” device.
The information required in a 510(k) submission is defined 21 CFR 807.87. A 510(k) submission includes:
Device trade or proprietary name, common or usual name or classification, Class of the device (Class I, II, III)
Submitter’s name and address, Contact person, telephone number and fax number, Representative/ Consultant if applicable
Name and address of manufacturing/ packaging/ sterilization facilities, Registration number of each manufacturing facility
Action taken to comply with the requirements of the Special Controls.
Proposed labels, labeling, and advertisements to describe the device, its intended use, and the directions for its use.
510(k) summary or a 510(k) statement.
For Class III medical device, a Class III certification and a Class III summary.
Photographs of the device, Engineering drawings of the device.
Identification of the marketed device(s) to which equivalence is claimed including labeling and description of the medical device.
Statement of similarities and/or differences with marketed device(s)
Data to show consequences and effects of a modified device, performance Data (bench, animal, clinical)
Sterilization information (as applicable)
Software development, verification and validation information
Hardware design and development information
Information requested in specific guidance documents (as applicable)
Kit Certification Statement (for a 510(k) submission with kit components only)
Truthful and Accurate Statement
Depending on the complexity of the new or modified medical device, the FDA Review of a 510(k) submission takes between 20 and 90+ days. The more complex the changes or comparison required to support the safety and effectiveness of the new or modified medical device, the longer the FDA review process.
A PMA is required for FDA Approval of medical devices that present significant risk to the patient and/or require significant scientific review of the safety and effectiveness of the medical device prior to commercial introduction. Most Class III medical devices require a PMA. Section 515(c)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) specifies the required contents of a PMA. PMA application content includes:
full reports of all information, published or known to or which should reasonably be known to the applicant, concerning investigations which have been made to show whether or not such device is safe and effective;
a full statement of the components, ingredients, and properties and of the principle or principles of operation, of such device;
a full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and, when relevant, packing and installation of such device;
an identifying reference to any performance standard under Section 514 which would be applicable to any aspect of such device if it were a Class II device, and either adequate information to show that such aspect of such device fully meets such performance standard or adequate information to justify any deviation from such standards;
such samples of such device and of components thereof as the Secretary may reasonably require, except that where the submission of such samples is impracticable or unduly burdensome, the requirement of this subparagraph may be met by the submission of complete information concerning the location of one or more such devices readily available for examination and testing;
specimens of the labeling proposed to be used for such device; and
such other information relevant to the subject matter of the application as the Secretary, with the concurrence of the appropriate panel under Section 513, may require.
The FDA has a statutory 180-day review cycle for PMA applications. Often PMA applications require medical advisory board review prior to the FDA granting approval to market the medical device. A facility inspection verifying the manufacturing systems present to manufacture the medical device is usually performed prior to FDA PMA approval. FDA approval of a PMA often requires significantly more than 180 days.
The Good Manufacturing Practice (GMP) requirements are defined in 21 CFR 820. The GMP is also referred to as the Quality System (QS) Regulation. A quality system is required for the design, manufacture, packaging, labeling, storage, installation, and servicing of finished medical devices intended for commercial distribution in the United States. The QS Regulation is similar to ISO 9001:1994, with FDA particular requirements. The QS Regulation covers:
quality management and organization,
purchase and handling of components,
production and process controls,
packaging and labeling control,
The FDA may audit the manufacturing facility for GMP compliance every 2 years. FDA compliance inspections are based upon results of prior audits, device risks, recall of devices and FDA initiatives in regard to particular classifications of devices.
Establishments involved in the production and distribution of medical devices intended for marketing in the United States are required to register with the FDA. Establishment Registration requirements are defined in 21 CFR 807. Establishment Registrations are verified and updated annually.
Foreign establishments engaged in the manufacture, preparation, propagation, compounding, or processing of a device that is imported, or offered for import, into the United States must register their establishments and provide the FDA with the name of the United States agent representing their establishment. Foreign establishments must provide FDA with a list of the devices that they are exporting to the United States.
Most medical device establishments required to register with FDA must list the devices they have in commercial distribution. Medical device listing is completed by the classification name the FDA has assigned to the medical device, see 21 CFR Part 862 to 892.
Device listing should be completed within 30 days of entering a device into commercial distribution in the United States. Device listing is updated when a new classification of device is entered into commercial distribution, the marketing of a device classification is discontinued, or marketing of a discontinued device is started again.
The Medical Device Reporting (MDR) regulation requires firms who have received complaints of device malfunctions, serious injuries or deaths associated with medical devices to notify FDA of the incident. The requirements for medical device reporting are defined in 21 CFR 803. The regulation requires:
A written MDR procedure,
MDR event files,
Individual adverse event reports,
5-day MDR reports of remedial action taken to prevent unreasonable risk of substantial harm to public health,
30-day MDR reports of deaths, serious injuries and malfunction attributed to the medical device,
Baseline reports for the medical device.
1 Jansson RL. Researcher liability for negligence in human subject research: informed consent and researcher malpractice actions. Wash Law Rev. 2003; 78: 229–262.
2 Lowe C. Clinical trial litigation. Med Mal Law Strategy. 2007; 24 (No.4): 1.
3 The Nuremberg Code (1949). http://ohsr.od.nih.gov/guidelines/nuremberg.html. Accessed Oct. 2011.
4 Reprinted from Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law, No. 10, Vol. 2, pp. 181–182. Washington, DC: US Government Printing Office, 1949.
5 World Medical Association. Declaration of Helsinki: Recommendations Guiding Medical Doctor in Biomedical Research Involving Human Subjects, 1964. http://www.wma.net/en/30publications/10policies/b3/. Accessed Oct. 2011.
6 Beecher HK. Ethics and clinical research. N Engl J Med. 1966; 274: 1354–60. See also Surgeon General, Public Health Service to the Heads of the Institutions Conducting Research with Public Health Service Grants, 8 February 1966. Clinical Research and Investigations Involving Human Beings. ACHRE No. HHS—090794-A.
7 Codified at 45 CFR Section 46 (1981).
8 Katz HS, McCarroll B. Clinical trials: Alternative revenue stream or just another potential lawsuit. Health Law. 2004; 16 (No.6): 1.
9 DHHS Fact Sheet Protecting Human Research Subjects, June 6, 2000. http://archive.hhs.gov/news/press/2000pres/20000606a.html. Accessed Oct. 2011.
10 21 CFR Section 2c107(e); 45 CFR Section 46.109(e).
11 21 CFR Section 312.3(b). See also CFR 56.102(c)—limited to planned FDA submissions—from the IRB regs, as opposed to the IND regs.
12 Id. [NOW 21 CFR Section 312.3(b)] Id.
13 21 CFR Section 56.201(g).
14 21 CFR Section 312.3 (b).
16 Office for Human Research Protections, US Department of Health and Human Services. IRB Guidebook. Chapter 5. http://www.hhs.gov/ohrp/archive/irb/irb_guidebook.htm. Accessed Oct. 2011.
17 Definitions of Phase II drug trials and Phase II vaccine trials are different. See: http://www.avac.org/ht/d/sp/i/323/pid/323 for definitions.
18 21 CFR 312.85.
19 Sweet BV, Schemm AK, Parsons DM. Review of the processes for FDA oversight of drugs, medical devices, and combination products. J Managed Care Pharm. 2011; 17: 40–50.
21 Strausberg GI, Getz RD. Health care workers with AIDS: Duties, rights, and potential tort liability. Univ Baltimore Law Rev. 1992; 21: 285–310.
22 Morreim EH. Litigation in clinical research: malpractice doctrines versus research realities. J Law Med Ethics. 2004; 32: 474–481.
24 Tyson P. The Hippocratic Oath Today, 03/27/01. http://www.pbs.org/wgbh/nova/doctors/oath_modern.html. Accessed Oct. 2011.
25 Carpenter v. Blake, 60 Barb NY 488, 523–24, rev’d 50 NY 696 (NY Gen Term 1871) (finding negligence in treatment deviating from standard practice.)
26 Jansson RL. Researcher liability for negligence in human subject research: Informed consent and researcher malpractice actions. Wash Law Rev. 2003; 78: 229–263, citing Forner v. Koch, 251 NW 762, 765 (Mich 1935).
27 Tereskerz P. A recent clinical trial involving financial conflicts of interest: Applying traditional legal theories. Chapter 6. In:
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