Study on the Effectiveness Judgment of Approving the Application for New Drugs and It’s Related Issues in U S

Abstract

Doctoral Dissertation Title Study on the Effectiveness Judgment of Approving the Application for New Drugs and It’s Related Issues in U S Author’s Name：Hsien-Teng Su Advisor’s Name：Ing-Ling Hou Dr jur Department & College：Department of Law National Cheng Kung University SUMMARY The theme of this dissertation is to discuss the effectiveness Judgment of approving a new drug application and it’s related issues in U S First from the industry perspective to explore the sponsor how to design and conduct adequate and well-controlled investigations and the applicant how to determines the effectiveness claim of a drug and its conditions of use level and scope Second from the normative side to discuss how to prove the applicant's effectiveness claim of the drug and the indications and conditions of use contained in the labeling with substantial evidence and it’s quantity Then from the scientific viewpoint to investigate how to prove the effectiveness of the drug with the designs of investigation and why it is necessary to be statistically significant and clinically significant as an important connotation of drug effectiveness Secondly from the perspective of administrative regulation and judicial supervision after the listing of a new drug the issues related to the approved on-labeling and the unapproved off-labeling are discussed especially the relationships between the drug manufacturer ’s off-labeling use and the misbranded provision in FDCA and the complex issues of the off-labeling promotion and commercial freedom of speech protected by the First Amendment Finally to discuss the question of whether the drug manufacturer's off-labeling use should bear the responsibility of False Claim Act and the product liability of the tort Key words: claim of effectiveness substantial evidence statistical significance clinical significance off-labeling use False Claim Act INTRODUCTION This dissertation mainly discusses the effectiveness judgment and related issues of approving a application of new drug (NDA) in the United States It is divided into six chapters the first chapter: the introduction; the second chapter: the U S approved new drug listing legal system and its connotation; the third chapter: the effectiveness judgment of approving a application of new drug (NDA) in U S ; Chapter 4: How to regulate the effectiveness of a new drug in the United States after the approval of the listing ; Chapter 5: The judicial regulatory system for the effectiveness of new drugs approved for listing in the United States: Chapter VI: Conclusions The main contribution of this dissertation is to firstly put forward the "the theory of the claim/purport of effectiveness for drug " in the third chapter to clarify that the scope of the objectively possible therapeutic efficacy of a drug is different from the content level and effectiveness of the applicant's decision to apply for listing approval The applicant's requirements for the efficacy content and scope of the drug's claims should be demonstrated in the form of "substantive evidence" The term “substantial evidence” means evidence consisting of adequate and well-controlled investigations including clinical investigations by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed recommended or suggested in the labeling or proposed labeling thereof Its relevant details this paper will make a fairly precise discussion from the U S law and have invoked the normative basis in a detailed and correct manner This article also explains how to prove the effectiveness of a drug including the significance test the equivalence test the superiority test and the non-inferiority test And from the FDA review and court judgment practice and then draw two important core connotations of drug effectiveness: statistical significance and clinical significance this paper also makes a meaningful discussion and contributes the study of the drug law The fourth chapter of this dissertation puts forward the "the theory of claim of effectiveness for drug" "drug premarket approval or clearance theory" and " the theory of drugs labeling should based on approved content " from the perspective of administrative regulation as the boundaries of administrative regulation of the effectiveness for a drug after it is approved for listing and as the basis of inference and analysis of "on- labeling use" and "off-labeling use" (commonly known to as "off-label use") "Off-labeling use" is a approved drug for unapproved use In the legislative policy a physician's "off-labeling prescription" is recognized as part of medical practice and the FDA should not intervene or limit it But a physician's "off-labeling use" (such as sales advertising promotion) other than prescriptions is not part of the medical practice and is still regulated by the "misbranded" provisions of the Food Drug and Cosmetic Act (FDCA) The drug manufacturer's "off-labeling use" is subject to the FDCA's "misbranded" provision which is prohibited by the FDCA（21 U S C §§331 333） but the drug manufacturer's off-labeling use in addition to direct sales promotion of drugs there are also in indirect ways to distribute a scientific journal or textbook reprint (i e “enduring material”) to sponsor the continuing medical education (CME) or the activity of medical seminars or forums and to disseminate the enduring materials or to present or highlight intentionally the issue of the off-labeling use of it's drug at meetings For this circumstance “is this a true and useful scientific information?”or“Is it illegal to off-labeling promotion? Whether it should be protected by the freedom of speech (commercial speech) of the First Amendment has caused and raised many lawsuits and academic disputes in the United States What is the essence of "off-labeling use"? What is the reason for the theory of "the pros and cons of off-labeling use" ? Although the United States District Court in the W L F v Friedman case (1998) and the Federal Court of Appeal in the United States v Caronia case (2009) it had declared respectively that the guidelines issued by the FDA and the FDCA's misbranded provisions are unconstitutional and found that the manufacturer's “off-labeling promotion” is a true non-misleading and legal speech but this dissertation holds the opinion of opposition from various viewpoints and think that the drug manufacturer’s “off-labeling promotion” of it’s drug is a false misleading and illegal speech Furthermore in the fifth chapter this dissertation explores the liability of the "The False Claim Act(FCA)" and the strict liability of Tort in common law from the perspective of judicial supervision and the "off-labeling promotion" for pharmaceutical manufacturers to induce the physician and the pharmacist to present the false claim of the U S Medicare or Medicaid reimbursement for the off-labeling prescription /dispense Should there be a civil liability for the false claim? In addition this dissertation also introduces FDA or the Ministry of Justice's enforcement policy and its results in the U S At last the off-labeling promotion is not a "adequate use instructions" or "full unsafe use warning" for the labeling of drugs Should it be held liable for infringement of tort ? This dissertation also makes a detailed analysis and discussion In particular this dissertation thinks that the “falsity” of off-label promotion of drugs in the field of FDCA does not allow Medicare or Medicaid or other insurance plans to include the “off-labeling use ” of drugs in reimbursement items (such as “covered outpatient drugs ”) with a few exceptions The drug manufacturer's off-labeling promotion of its drug inducing the physician to make an off-labeling prescription and causing the government or Medicare or Medicaid system to pay through a certain compliance record of the prescription constituting medical health care fraud the drug manufacturer should be responsible for FCA From this point of view the "falsity" of the off-labeling promotion of drugs in the FDCA field and the "falsity" of the FCA field for the claim of government's reimbursement are related but not the same and the violation of FDCA does not necessarily violate the FCA Whether the defendant should bear the responsibility of the FCA should rely on whether the reimbursement claim to the U S government itself has "falsity" to judge The final conclusion of this dissertation summarizes the essentials of this paper and compares it with the relevant laws of Pharmacy Law of R O C (TAIWAN)and makes some recommendations This dissertation is limited to the paper length the scope of discussion is only limited to "drug" and does not include medical device MATERIALS AND METHODS The literature collection of this dissertation mainly uses the "data collection method" First to find out the laws and their subsidiary regulations related to the effectiveness of drugs in the U S including the FDCA of 1938/1962 the FDAMA and the PHSA and its subsidiary regulations including“Investigational New Drug Application” (21 CFR Part 312) “Applications For FDA Approval To Market A New Drug” (21 CFR Part 314) “Labeling” (21 CFR Part 201) and “Prescription Drug Advertising” (21 CFR Part 202) and so on Second to collect relevant guidance documents issued by the FDA such as “Guidance for Industry- Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products (1998)” “Non-Inferiority Clinical Trials to Establish Effectiveness Guidance for Industry(2016)” etc and Relevant guidelines issued by ICH such as "E9: Statistical Principles for Clinical Trials (1998)" " E10: Choice of Control Group and Related Issues in Clinical Trials(2000) "etc Again for specific research subtopics (such as off-label use false requests etc ) browse the official websites such as FDA NCBI SSRN or N Eng J Med databases of scientific journals and law reviews of law schools or universities in the U S and then the outdated regulations or FDA Notices through the Federal Register or the Library of Congress website Finally the jurisprudence of the Federal Courts is available on the Find Law or through Google search Then the various information and materials collected will be studied or read The research subtopics of this dissertation will be analyzed through the "inductive method" to understand the research connotation and direction of each subtopics of the professional science statistics and law Furthermore from the process of translate and read the federal court's decisions learn how the American society operates the court how the specific disputes attack and defend the perspective of thinking and the court's explanation of precedents and legal reasoning methods all of which help to think about the breadth and depth of the problem And then use the "deductive method" to analyze the various aspects of the problems involved in the subtopics areas and their possible solutions RESULTS AND DISCUSSION The results of this dissertation is to to put forward three theories of "the theory of the claim/purport of effectiveness for drug " "drug premarket approval or clearance theory" and " the theory of drugs labeling should based on approved content " as the basic structure of this dissertation First based on the ""the theory of the claim/purport of effectiveness for drug " the scope of the "objective efficacy" of a drug and the "subjective efficacy " claimed by the applicant are distinguished The applicant should propose the substantial evidence to demonstrate the scope of the "subjective efficacy " claimed together with the corresponding conformity labeling (including label inner/outer package and package insert) is submitted to the FDA for approval and listing and after being reviewed and evaluated by the FDA to confirm its safety and effectiveness in use it will be approved for listing Based on the ""drug premarket approval or clearance theory" the applicants should market their drugs only with approved the scope of the "claims of effectiveness " and labeling of their drugs Once the drug has been approved for marketing the applicant (mainly the drug manufacturer) has an obligation to comply with the “the theory of drugs labeling should based on approved content ” if it exceeds the range described or not described in the labeling will constitute " off-labeling" The "off-labeling use" of the drug is essentially a test that proves to be ineffective and proves to be effective with inadequate trial or not tested at all and has a high risk of safety and efficacy in use In the regulatory policy FDA will also prohibit the “off-labeling use”to implement the integrity and consistency of the drug regulatory system and to ensure the safety and effectiveness of the drug FDCA stipulates that if a labeling relates to “false or misleading" or "the lack of adequate instructions for use or adequate safety warnings" should be considered as "misbranded" The "off-labeling use" not only violates the FDCA's misbranded provisions and constitutes a criminal offence but also the "off- labeling " promotion dissemination and distribution should be considered as a " false misleading and illegal " commercial speech unprotected by the First Amendment and even the "off-labeling use" of drugs have caused to submit a false claims to the government or health care plans resulting in a unnecessary or improper reimbursement and also causing problems with FCA liability If therefore caused the patient's injury the drug manufacturer will bear a product liability of tort in common law CONCLUSION 1 The safety and effectiveness of the drug is the FDCA's core When the applicant Submits s NDA to FDA he should present the “substantial evidence” together with the corresponding conformity labeling to demonstrate the safety and effectiveness of the drug 2 The "off- labeling " promotion dissemination and distribution should be considered as a " false misleading and illegal " commercial speech unprotected by the First Amendment 3 The "off-labeling use" of drugs have caused to submit a false claims to the government or health care plans for reimbursement and the drug manufacturer would or might be liable for a FCA liability and even bear the product liability of tort in common law

Date of Award	2019
Original language	English
Supervisor	Ing-Ling Hou (Supervisor)