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Michael A. Swit, Esq. Vice President, Life Sciences INFORMED CONSENT: Pledge, Promise, Contract or Platitude? Key Aspects of Informed Consent for the Regulatory.

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Presentation on theme: "Michael A. Swit, Esq. Vice President, Life Sciences INFORMED CONSENT: Pledge, Promise, Contract or Platitude? Key Aspects of Informed Consent for the Regulatory."— Presentation transcript:

1 Michael A. Swit, Esq. Vice President, Life Sciences INFORMED CONSENT: Pledge, Promise, Contract or Platitude? Key Aspects of Informed Consent for the Regulatory Professional RAPS Annual Conference Baltimore October 18, 2006 Christine K. Pierre, RN President

2 2 Our Agenda I -- Historical Background (Swit) II -- The Law of Informed Consent – Contract, Fiduciary Duty, Promise, Pledge or Platitude? (Swit) III – Informed Consent -- The Document and the Process (Pierre) IV -- Practical Issues in consenting (Pierre) V- FDA Observations – when it goes wrong (Swit) VI -- Difficult Issues in Consent (Swit) VII – Conclusion (Swit) VIII -- Q &A (Pierre & Swit)

3 3 I -- Historical Background (Swit)

4 4 The Nuremberg Code (1947) First modern ethical code requiring – Voluntary consent – Benefits outweigh risks – Ability of the subject to terminate participation

5 5 Declaration of Helsinki (1964) Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects Adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964; revised in Tokyo, 1975; Venice, 1983; Hong Kong, 1989; South Africa, 1996;Edinburgh 2000; Note of clarification on paragraph 29; Washington 2002

6 6 Helsinki Declaration … “Concern for the interests of the subject must always prevail over the interests of science and society”

7 7 Beecher Article (1966) “Ethics and clinical research” — Henry K. Beecher, New England Journal of Medicine 274 (1966): –22 published medical studies presenting risk to subjects without their knowledge or approval –Published in some of the most prestigious journals and conducted at some of the most acclaimed institutions by some of the most highly regarded researchers

8 8 Where the Burden Lies “The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment.” –Principle 1, The Nuremberg Code “When obtaining informed consent for a research project, the doctor should be particularly cautious if the subject is in a dependent relationship to him or her, or under duress.” –The Declaration of Helsinki

9 9 Where the Burden Lies … “In that case, the informed consent should be obtained by a doctor who is not engaged in the investigation and who is completely independent of this relationship.”

10 10 Beecher’s Paradox The voluntary consent of the human subject is absolutely essential. –Nuremberg True informed consent is probably an unattainable goal. –Beecher

11 11 The Belmont Report 1974 – The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979 – Commission Report – “Belmont” –Validates IRB role as a key aspect of subject protection 1981 – Federal Regulations Revised –“Common Rule” – basically across whole fed. govt. –FDA – some exceptions, minor in nature

12 12 Where the Regulations Lie HHS – if supported by federal funding – 45 CFR 116. FDA – 21 CFR Part 50 Differences –FDA, but not HHS, provides for an exception from the informed consent requirements in emergency situations. The provision is based on the Medical Device Amendments of 1976, but may be used in investigations involving drugs, devices, and other FDA regulated products in situations described in ß

13 13 Differences – FDA vs. HHS HHS provides for waiving or altering elements of informed consent under certain conditions. FDA has no such provision because the types of studies which would qualify for such waivers are either not regulated by FDA or are covered by the emergency treatment provisions (§ 50.23) FDA explicitly requires that subjects be informed that FDA may inspect the records of the study because FDA may occasionally examine a subject's medical records when they pertain to the study. While HHS has the right to inspect records of studies it funds, it does not impose that same informed consent requirement.

14 14 Differences – FDA v. HHS … FDA explicitly requires that consent forms be dated as well as signed by the subject or the subject's legally authorized representative. The HHS regulations do not explicitly require consent forms to be dated.

15 15 II -- The Law of Informed Consent – Contract, Fiduciary Duty, Promise, Pledge or Platitude? (Swit)

16 16 Treatment vs. Research – Key Distinction Law of Informed Consent – must remember that what governs medical treatment is not always same as what governs research Treatment –Doctor – arguably -- is a fiduciary – owes duty to protect patient –Traditional view – unconsented treatment = battery –Causation – Not disclosed Injured Reasonable Patient would want to know Reasonable Patient would have refused the treatment – HARD PART

17 17 How Research Differs from Treatment Goals – treatment vs. developing generalizable knowledge How Overseen: –Treatment – doctor supplies expertise –Research – highly regulated by sources other than the doctor – protocol and government regulation e.g., if sponsor concludes treatment is ineffective, must stop research Law – state (treatment) vs. federal (research) – some exceptions

18 18 Battery Problem – any failure could be alleged to be a battery, which is an intentional tort (technically); due to this, courts do not favor it as a remedy Will occur: –Complete lack of consent –Procedure given differed from that consented –“Ghost Surgery” – undisclosed replacement surgeon

19 19 Is the I.C. a Contract Legally Enforceable by the Subject? Basic contract law –Parties in privity – i.e., two make a deal –Legal subject –Offer –Acceptance –Consideration Problem – lack of privity – sponsor may provide the form, but it is obtained by P.I. from the subject – no privity

20 20 But, People (Alan Milstein) Still Argue Contracts Suthers & Abney Cases –GNDF trials – discontinued by Amgen as showing no benefit – thus, required under IND rules –Plaintiffs – you owe us the drug under normal contracts theory and the doctrine of “promissory estoppel” – also a contracts theory Clear promise Detrimental reliance by promisee Damages by promisee

21 21 Suthers and Abney Decisions No contract –Amgen not a party to I.C., nor was the P.I. an agent of Amgen that could bind Amgen via the I.C.; rather they were “independent contractors” Look at control over the P.I.’s work –Here the protocol drafted by the P.I. No promissory estoppel –Unable to show Amgen promised continued access

22 22 Fiduciary? Suthers & Abney – also asserted that the Amgen was a fiduciary; not found by court –Amgen did not set up the clinical initially; no unique duty owed to subjects or proof that Amgen’s role was done for the benefit on the patients Note: court suggested that the parties to be bound by contract via the I.C. were the P.I. and the universities where P.I. worked

23 23 Problems with Fiduciary Theory Goal of research – generalizable knowledge Subject is not the prime beneficiary of research – rather it is the public at large P.I. and sponsor both have less control over the way research is done

24 24 III – Informed Consent -- the Document and the Process (Pierre)

25 25 Informed Consent An ongoing process not just a document. An agreement not a contract?

26 26 What is informed consent related to clinical research?  Process of sharing and delivering comprehensible and relevant information  An individual’s ability to make a decision for voluntary participation  The listing of all regulatory requirements  Obtained with respect for person

27 27 The Belmont Report (1979) The National Commission  1974: Identify the basic ethical principles that underlie the conduct of human research  Develop guidelines to assure that human research is conducted in accordance with those principles Thanks to Jeff Cooper, MD

28 28 Belmont Report - What’s missing? Recognition of the litigious society we live in today

29 29 21CFR, Common Rule, SOPs, State Laws?  You can’t know them all (easily)  State-by-State Clinical Trial Requirements Reference Guide, Sept. 2004, Serio, et al., Editors, Barnett Educational Services  Focus on key states  Work with your IRB – they are required to know local conditions under federal law – thus, protocols and consents should be tailored by them to meet local rules

30 30 How have we evolved? Relationship based Fear based

31 31 “Less is More” Typical ICD was 3-5 pages long Typical ICD is pages long Not a concept we have embraced!

32 32 Informed Consent Document (ICD)  Who develops them?  Principal Investigator  Sponsor  How are they developed?  Templates  IRB provided checklist  Level of risk determines type of ICD  How are they executed?  How is the process documented?

33 33 ICH Requirements  International Conference on Harmonization (ICH) guidelines require the same basic elements as FDA  ICH also requires that the consent form should be signed/dated by subject (or subject’s legally authorized representative, if applicable) and by the person conducting the informed consent discussion

34 34 Informed Consent – 21 CFR Part 50  Subpart B – Informed Consent of Human Subjects  General requirements for informed consent  Exception from general requirements  Exception from informed consent requirements for emergency research  Elements of informed consent  Documentation of informed consent

35 35 21 CFR Part 50 - Elements  Informed consent must contain eight required elements and, when applicable, six additional elements  Investigator’s responsibility to ensure the eight elements are provided to subject

36 36 21 CFR Basic Elements (1) Statement study involves research; purpose and expected duration of the subject’s participation; and description of procedures (2) Description of any reasonable foreseeable risks or discomforts (3) Description of any benefits to the subject or to others (4) Disclosure of appropriate alternative procedures (5) Statement describing extent confidentiality of records will be maintained (6) For research involving more than minimal risk, an explanation whether any compensation and/or medical treatments are available if injury occurs (7) Explanation of whom to contact for answers pertinent to questions about research and research subjects’ rights (8) Statement that participation is voluntary and that subject may discontinue participation at any time without penalty or loss of benefits

37 37 21 CFR Additional Elements (when appropriate) (1) Statement that particular treatment or procedure may involve risks to the subject (or to embryo or fetus if the subject may become pregnant) (2) Anticipated circumstances under which the subject’s participation may be terminated by the investigator without regard to the subject’s consent (3) Any additional costs to the subject that may result from participation in the research (4) The consequences of a subjects’ decision to withdraw from the research and procedures for orderly termination of participation by the subject (5) A statement that significant new findings developed during the course of the research which may relate to the subject’s willingness to continue participation will be provided to the subject and (6) The approximate number of subjects involved in the study

38 38 Investigator’s role in assuring respect for person  Fiduciary disclosure – if necessary  Ensures that subject who agree to participate understand all aspects of their volunteer agreement  Privacy and confidentiality

39 39 IV -- Practical Issues in Consenting (Pierre)

40 40 Preparing ICDs  Consider the reading level of the potential participants  Use simple language – 8 th grade  If you need to use scientific terms, define them  Avoid using abbreviations or acronyms unless they are spelled out first  Consider the age of the volunteer and the font size  Version control & number pages

41 41 ICD Development  Be concise  Use the pronoun “you” consistently throughout to refer to the subject/participant  Number the pages if the ICD is more than one page  Spell everything correctly and use correct grammar. The most common error is the spelling of principal investigator: it is principal not principle

42 42 When to revise the ICD  When risk/benefit ratio changes  New information becomes available  The Investigator decides, but needs ok from sponsor

43 43 Why re-consenting doesn’t go smoothly  Staff unsure of who needs to be re-consented  Unsure of what to do when revised IC is at the IRB and the subject has a visit and then the next one is not for months  Wrong consents are signed  Lack version control  Lack numbering of pages  Lack of review on on-going basis by sponsor  Site unaware that a revision is needed – educate!

44 44 How, What, When & Where of obtaining informed consent  Investigator’s involvement  Signatures & initial lines & dates  Witnesses  Documentation  Setting  Enrollment goals  Training on human subject protection

45 45 What is a Legally Authorized Representative?  FDA regulation 21 CFR § states that; “no investigator may involve a human being as a subject in research covered by these regulations unless the investigator has obtained the legally effective informed consent of the subject or the subject’s legally authorized representative.”

46 46 The Informed Consent Process  Those obtaining informed consent from subjects must be trained in the areas of human subject protection [Note: Ultimately it is the regulatory responsibility of the Investigator to ensure IC has been obtained and all regulations, laws, SOP’s followed]  Exchange of information between clinical investigators/study coordinators and subject  Reading and signing the ICD  Providing a copy to the subject  Ongoing process of informed consent

47 47 The Informed Consent – Process  During the IC discussion, the SC will measure the subject’s comprehension and understanding by asking study specific questions  Have Investigator review with subject any questions they may have in regards to the study  If subject is willing to participate, ask subject to sign/date ICD; if requested on form, person obtaining IC should sign/date form  Have witness sign/date ICD (if applicable)  Provide subject copy of the consent form

48 48 The Informed Consent – Process  Retain original consent in separate study binder or regulatory binder  Put copy of signed consent form in subject’s source documents  Note in source documentation that consent was administered PRIOR to initiation of study procedures  Remember IC is an ongoing process  Document at follow-up visits patients desire to remain on study

49 49 Documentation Informed Consent Obtained Sample Date/Time Informed Consent was obtained for participation in the XXXX study. After explanation of the study the subject was given time to review the consent form and ask questions. The subject’s wife was present during the consent process. All study related procedures were performed after consent was obtained. A copy of the signed consent form along with contact numbers was given to the subject. The original consent form is filed in the informed consent binder and a copy if filed with the subject’s source documentation. Signature of person who obtained consent

50 50 Ongoing documentation of continued Informed Consent Date Asked subject today during study visit if they had any additional questions pertaining to the study, and subject said no. Subject expressed desire to continue in study and next visit was scheduled. Signature of person who spoke with and wrote the note

51 51 Verbal Clues & Numerical Clues Main reason for nonparticipation in clinical trials Reasons not to participate Verbal only formatCombined format Fear of side effects General safety/fear of trial Uncertainty about drug effectiveness Lack of adequate information Unwilling to commit time Source - Verbal labels can triple perceived risk in clinical trials: Dianne Barry, BSc, DPhil & March Hochhauser, PhD

52 52 Verbal Clues & Numerical Clues Main reason for participation in clinical trial Reasons to Participate Verbal only format Combined format Long-term relief/possible cure Last-resort relief/possible cure Altruism Condition being severe enough Being convinced of drug effectiveness Source - Verbal labels can triple perceived risk in clinical trials: Dianne Barry, BSc, DPhil & March Hochhauser, PhD

53 53 Literacy skills of US adults by ethnic background EthnicityBelow BasicBasicIntermediateProficient White7%25%51%17% Black24%43%31%2% Hispanic44%30%23% Asian/Pacific Islander 14%32%42%12% All adults14%29%44%13% Adults 65+23%38%34%4% Simple & concrete Simple - everyday skill Moderately challenging Complex & challenging Source: Culturally competent consent concepts Mark Hockhauser, PhD

54 54 Conflicts between informed consent values vs. multicultural values Informed Consent Values 1.Emphasis on verbal and written communication 2.Centered on the individual patient 3.Focused on the nuclear family 4.Requires verbal openness 5.Ask questions 6.Task oriented 7.Physical factors in health 8.Independence 9.Rely on data 10.Emphasis on rationality Multicultural Values 1.Emphasis on nonverbal communication 2.Centered on group identity 3.Focused on the extended family, often relying on the father 4.Silence as respect 5.Respect authority; questions may be seen as insulting to an authority, such as an MD or PhD 6.Trust oriented 7.Spiritually factors in health/illness 8.Conformity 9.Rely on relationships 10.Inclusion of emotion

55 55 The Ideal Informed Consent Process  Investigator discusses with his/her potential participant the nature of the study  If subject appears to meet eligibility requirements and shows interest in participating in the study, the patient can be referred to the study coordinator (SC)  The SC reviews the ICD with the subject and addresses any questions within his/her scope of knowledge  The SC provides the subject with the ICD and time to read the ICD

56 56 How long does it take to obtain IC for a “routine clinical study”? minutes – Source: Christine K. Pierre, personal observation in clinical research setting

57 57 Failure to comply…  Legal  FDA/OHRP; Battery; Negligence; Breach of fiduciary responsibility; Breach of contract; Wrongful death  Reputation  Lack of trust with patients, volunteers & public; Inability to achieve medical advances

58 58 V- FDA Observations – When Consent Goes Wrong (Swit)

59 59 Consent Over the Phone? “No subjects enrolled in the study had signed legally effective informed consent forms. –All subjects had notations in the informed consent indicating that the consent document had been read to them over the telephone. –The informed consent forms were signed by the investigator and/or witnesses rather than by the subject or the subject’s legally authorized representative as required. –None of the subjects were provided a copy of the informed consent.”

60 60 Timely Consents? Failure to obtain signed and dated study informed consent documents from all study subjects. (21 CFR , 50.20, and 50.27) –Several study subjects had not signed the study informed consent document at the time of the [FDA] inspection.

61 61 Subject Get a Copy? In addition, you failed to provide study subjects with a copy of their signed informed consent document. 21 CFR requires that a copy of the signed and dated informed consent document be given to the person signing the form. –At the time of the [FDA] inspection, no study subject had been provided a copy of the signed informed consent document.

62 62 When Was That Consent Really Signed? You did not obtain informed consent from all subjects participating in the clinical study. There is no documentation to determine when all subjects consented. Not all consent Forms were signed and dated by the subjects in the study. For example, someone other than subjects [redacted], [redacted], [redacted], [redacted] and [redacted] entered the date next to the subject’s signature. In addition, there is no consent for subject [redacted].

63 63 Kitchen Sink of Problems You did not obtain informed consent for the prescreening phase and prior to the initiation of the washout period when the subjects’ routine therapy was discontinued for seven subjects. The informed consent did not describe the wash out period or its duration as well as the risks associated with the discontinuation of Outdated consent forms were used for subjects 004 and 008. Informed consents signed at the time of the prescreening phase were discarded. The informed consent for the open label phase did not indicate that a Sustacal load would be performed.

64 64 Exculpatory Language Patients signed a "Release and Covenant Not to Sue." This document included statements that the patient and spouse "covenant and agree not to institute or pursue legal proceedings or any other claim or action challenging the use of this new technology in my treatment." They also were asked to "forever waive all claims and complaints as a condition for being permitted to undergo treatment with this new technology." These statements contain exculpatory language and are prohibited under 21 CFR

65 65 Signing Wrong Consent The inspection revealed that a five (5) subjects signed the initial informed consent document approved by [redacted] IRB after the [redacted] IRB had approved the study and revised the informed consent document. Informed consent must be documented by use of the written consent form approved by the IRB.

66 66 All the I.C.’s Were Bad? A review of all 10 patient records at your study site revealed the following: –You failed to obtain written informed consent prior to surgery for one patient. The patient signed the informed consent form after the surgery date. –You failed to provide 5 out of the 10 patients enrolled in the study with an IRB approved informed consent form. –You signed two of the informed consent forms approximately one month after the patients signed them.

67 67 VI – Difficult Issues in Consent (Swit)

68 68 Emergency Research Challenge – diminished or non-existent capacity (e.g., knocked out) Why Hot – Northfield Labs – Blood Substitute where FDA authorized informed consent exemption Public Reaction – highly critical FDA Response – Draft Guidance

69 69 Draft Guidance -- Basics “Studies involving an exception from the informed consent requirements may proceed only after a sponsor has received prior written authorization from the FDA, and the IRB has found and documented that specific conditions have been met,” Regulations for emergency research contain specific human subject protection requirements including – the need for consultation with representatives of the communities being used in the research; –public disclosure of information before the start of the study and following its completion, –a commitment by the investigator to make efforts to contact a family member to determine whether the family member objects to the subject's participation, –and establishment of an independent data monitoring committee (DMC). “These additional requirements are necessary because the emergency research permitted under 21 CFR involves a particularly vulnerable population,” said the FDA.

70 70 Blood/Tissue Sampling Consent for tissue storage/sampling should be separate from clinical research consent Subjects must be told that that tissue storage presents different issues than the clinical research Consent should address confidentiality and assure that de-identification will occur Must have choices as to type of research to be done in future on samples Must be told sponsor might profit from future use of samples

71 71 Financial Disclosure in I.C. Moore v. Regents of State of California – even a financial interest must be disclosed if it reasonably could be concluded that it might impact physician’s decision –Caveat – not a research case –However – facts are easily applicable to research Gelsinger – P.I.’s link to technology not disclosed Future – personal view (Swit’s) is that Moore & Gelsinger will dictate the result nationwide

72 72 “Therapeutic Misconception” Premise – no matter how good the consent is, the subject so inherently hopes that the treatment will be effective and overstate the benefits and understate the risks of the clinical study Challenge – effective communication is hampered by all the factors already discussed

73 73 VII – Conclusion (Swit)

74 74 Conclusion  Since the 1960s, there has been ethical review of research involving humans. Ethics review applies to medical, social and behavioral research.  Clinical research is conducted in accordance with ethical guidelines, good clinical practice (GCP) and in most cases in accordance with legislation.  You must consider not only ethical principles but practical methods of educating and communicating with the patient in order to truly obtain informed consent.  Do we have to continue to practice defensive clinical research?

75 75 VIII -- Q &A (Pierre & Swit)

76 76 About the speakers Christine K. Pierre, RN, is President and CEO for RxTrials, RxTi and ForeSite Publications. Ms. Pierre is founder of RxTrials, a network of clinical research sites, RxTi a training organization providing public and customized clinical research site management, marketing and business development courses, and ForeWard Newsletter, the first customized newsletter designed to help the public learn about clinical research directly from the investigator. She has been the co-principal investigator of a multi-center study and various single-center studies. Ms. Pierre frequently lectures, moderates, and conducts workshops at national and international conferences, and is on the Editorial Board of Clinical Trials Advisor. She co-authored the book, Responsible Research: A Coordinators Guide. Ms. Pierre is the Vice Chair of ACRP and will assume the role of Chair in In 2003, she was nominated one of the top female business professionals in Maryland.

77 77 About the speakers … Michael A. Swit, Esq., who is Vice President, Life Sciences at THE WEINBERG GROUP INC., has extensive experience in all aspects of FDA regulation with a particular emphasis on drugs and medical device regulation. In addition to his private legal and consulting experience, Mr. Swit also served for three and a half years as vice president and general counsel of Pharmaceutical Resources, Inc. (PRI) a prominent generic drug company and, thus, brings an industry and commercial perspective to his representation of FDA-regulated companies. While at PRI from 1990 to late 1993, Mr. Swit spearheaded the company’s defense of multiple grand jury investigations, other federal and state proceedings, and securities litigation stemming from the acts of prior management. Mr. Swit then served from 1994 to 1998 as CEO of Washington Business Information, Inc. (WBII) a premier publisher of FDA regulatory newsletters and other specialty information products for the FDA publishing company. Before joining THE WEINBERG GROUP, he served in the FDA Regulatory Law Practices at both Heller Ehrman and McKenna & Cuneo, first in that firm’s D.C. office and then in its San Diego office. He first practiced FDA regulatory law with the D.C. office of Burditt & Radzius from 1984 to Mr. Swit has taught and written on a wide variety of subjects relating to FDA law including, since 1989, co- directing a three-day intensive course on the generic drug approval process, serving on the Editorial Board of the Food & Drug Law Journal, and editing a guide to the generic drug approval process, Getting Your Generic Drug Approved, published by WBII. Mr. Swit holds an A.B., magna cum laude, with high honors in history, in 1979, from Bowdoin College, and earned his law degree from Emory University in He is a member of the California, Virginia and District of Columbia bars.

78 78 Call, , fax or write: Christine Pierre, RN President RxTrials, Inc 2838 Leaf Shade Drive Suite B Ellicott City MD phone fax Questions?

79 79 Call, , fax or write: Michael A. Swit, Esq. Vice President, Life Sciences THE WEINBERG GROUP INC. 336 North Coast Hwy. 101 Suite C Encinitas, CA Phone Fax Cell D.C. Office Questions?

80 80 RxTrials, Inc. is a multi-specialty clinical research organization that conducts clinical trials in the Washington DC, Maryland, and Virginia medical community. Our Areas of Clinical Research Specialization (Inpatient & Outpatient) Cardiology Cardiothoracic Surgery Critical Care Endocrinology and Metabolism Gastroenterology Internal Medicine Infectious Disease Pulmonology Rheumatology Urology RxTrials, Inc.

81 81 For more than twenty years, leading companies have depended on THE WEINBERG GROUP when their products are at risk. Our technical, scientific and regulatory experts deliver the crucial results that get products to market and keep them there. Washington, D.C. ♦ San Francisco ♦ Brussels


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