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MEDICAL RESEARCH:A CONSUMER’S GUIDE FOR PARTICIPATION

H e a l t h L a w y e r s ’ P u b l i c I n f o r m a t i o n S e r i e s

Copyright 2009 byAmerican Health Lawyers Association

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TABLE OF CONTENTS

Medical Research: A Consumer’s Guide for Participation

I. Introduction........................................................3

II. The Basics of Medical Research ..................4

A. Translational vs. Clinical Research ........4

� 1. Translational Research........................4

� 2. Clinical Research ................................4

B. Regulation of Medical Research ............5

C. How Are Clinical Trials Conducted? ......6

� 1. Basics of Clinical Research Design ..6

� 2. Controlling Outside Factors................7

� 3. Randomized Trials ..............................7

� 4. The Phases of a Clinical Trial ............7

� 5. Where Are Clinical Trials Conducted? ........................................8

� 6. How Can I Find Out About a Clinical Trial? ......................................8

III. Protecting Research Volunteers ....................9

A. What Is an Institutional Review Board?........................................9

B. What Is a Data Safety Monitoring Board?..................................9

C. How Do I Make Sure My Decision Is Voluntary? ........................10

D. What Is Informed Consent? ................10

E. How Are Vulnerable PopulationsProtected in Medical Research? ..........11

IV. Rights and Responsibilities of Research Volunteers ......................................13

A. What Documents Must I Sign? ............13

B. How Is My Information Used?..............13

C. What Are My Privacy Rights? ..............14

D. Who Can I Contact if I Have Complaints or Concerns? ....................14

E. What Are My Responsibilities as aResearch Volunteer? ............................15

V. Payment for Research Treatments ..............16

A. Who Will Pay for My Care While I Am a Research Volunteer? ................16

B. Will My Insurance Plan Pay for My Care? ..............................................16

C. How Do Health Plans Define“Research”?..........................................16

D. Are the Costs Associated with ClinicalTrial Participation Covered?..................16

E. Can Coverage Continue After the Clinical Trial Has Ended?......................16

F. Can Research Volunteers Be Paid forParticipating in a Clinical Trial? ............17

G. What Will Insurance Plans Cover? ......17

H. What Is Medicare’s Payment Policy ....17

I. What Payment Rules Apply if theResearch Involves a Device?................18

J. What About Off-Label Uses of Drugs or Devices? ................................18

K. What Other Government Programs Help Pay for the Costs of Care? ..........19

L. Which States Require Coverage ofCertain Costs Incurred During a Clinical Trial? ........................................19

M. What Questions Should I Ask toDetermine Whether Coverage Will Be Provided? ................................19

VI. Conclusion ......................................................20

Appendix A: Glossary ............................................21

Appendix B: States Mandating InsuranceCoverage of Clinical Trials ....................................24

Appendix C: Online Resources ............................31

Author Profiles ........................................................32

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I. Introduction

Research is the process of going up alleys to see if they are blind.

— Marston Bates

People take part in medical research for manyreasons. Some want to learn more about a specificmedical condition and treatment options. Otherswant access to the newest drugs or devices that may beavailable only through a research study. Still, othersmay believe the quality of care in a research study isbetter than what is otherwise offered.

Sometimes people agree to take part in researchhoping to help others. Research can further science,attract more attention to a medical condition, or leadto new treatments for a specific condition. This maynot benefit the participant directly but it may be theparticipant’s hope that the experience will benefitfuture patients.

The goal of Medical Research: A Consumer’s Guide toParticipation (Guide) is to help you consider the issuesrelated to participating in research. The Guidedescribes many of the different kinds of research andhow research can expand options for healthcare. Itexplains why some research does not offer any benefitdirectly to participants and explains the legal protec-tions available to research volunteers. It discusses theresponsibilities of the researcher and the participantand addresses insurance and payment issues.

Most importantly, this Guide will help identify ques-tions to ask and factors to consider before and duringthe research study. There can be risks, as well as bene-fits, associated with volunteering for medical research.If you or a family member is thinking about takingpart in a research study, a good understanding ofthese risks and benefits is vital.

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INTRODUCTION

Medical Research: A Consumer’s Guide to Participation

Reesa Benkoff, Esquire Dawn R. Crumel, Esquire

Edward B. Goldman, EsquireJan L. Hewett, Esquire Laura E. Loeb, Esquire

Melissa L. Markey, EsquireRachel Nosowsky, Esquire

Lois Snyder, Esquire

Medical Research: A Consumer’s Guide For Participation

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II. The Basics of MedicalResearch

A. Translational vs. Clinical Research

Volunteers can take part in two types of medicalresearch: translational and clinical. The participationof volunteers is critical to the success of both types ofresearch.

1. Translational Research

Translational research is often referred to as “benchto bedside” research because it tries to take the discov-eries that were made in the laboratory and applythem to humans (clinical application). Translationalresearch uses tissues and body fluids from volunteersso that scientific discoveries can be applied to medicalconditions. For example, a newly discovered receptor(the part of a cell that binds to certain types of mole-cules) in skin or saliva may play a role in cancer. Bystudying tissue and body fluids that do or do notcontain that receptor or substance, the researcher canbegin to discover whether or not there is a link withcancer.

Scientists study both healthy and diseased tissue, oftenusing tissue that is left over after a medical procedure.Studying healthy tissue helps scientists understandhow normal cells work and what effect substances likedrugs and chemicals may have. Studying a removedtumor helps researchers understand the properties ofcancer cells and improve treatments. Tissue researchalso reveals new ways to diagnose health problemsthrough biomarkers which are molecules in the bloodthat indicate health or illness. For most translationalresearch, there is no direct risk to research volunteers.

Tissue research in the area of genetics—the study ofproteins or genes that affect cell development—is crit-ical. It helps scientists learn how certain proteins orgenes affect detection, diagnosis, or response to treat-ment. It also sheds light on the development ofdiseases that are passed from parents to children.Some doctors and scientists believe that many diseaseshave a genetic basis. If this is true, it might explainwhy medicines work well in some patients but do notwork in others. Improved understanding of the roleof genetics in health and illness may someday lead tomedicines that are tailored to match the patient’sgenetic code.

Removed tissue may be studied immediately or befrozen or preserved for later use. Frozen tissue isstored in a tissue bank, also known as a biorepository.

The stored tissue is identified by a number or code,not by the research volunteer’s name. However, someclinical or medical information about the volunteermay be included to help researchers understandexperiment results. This information can includegeneral health and past or current medical treat-ments. Sometimes, additional information about thevolunteer’s health is collected for years after thevolunteer has donated her tissue for research.Scientists study this information to better understandchanges related to the aging process, health statusand treatments the person has undergone.

Researchers collect tissue for research according to adocument called a protocol. The protocol describesin detail the research design and how the study willproceed. For tissue research, the protocol describeshow donations will occur, the type of tissue that willbe collected, how the tissue will be preserved, and theresearch that will be performed. In most cases,informed consent will be required. Informed consentrefers to the agreement of a person to take part inresearch after being told about its risks, potentialbenefits, and alternatives. In other words, theresearcher asks permission to collect and study aperson’s tissue or bodily fluids. A form is used torecord this information, which describes the type ofresearch that will be performed and explains a partici-pant’s right to revoke consent and end her participa-tion. A volunteer always has the right to revokeconsent. In some cases, the volunteer’s tissue may beremoved from the research study but in others,because of the way the tissue is stored, the tissueremains in the study but no more information aboutthe volunteer is collected.

A protocol is also usually developed so that tissuefrom a tissue bank can be used. The protocol willdescribe the plan for research using the tissue. Often,the informed consent that is used to collect tissueallows the tissue to be used for any kind of research.Sometimes, however, the informed consent will limitthe kind of research that can be done. Researchersrespect these limitations. To protect research volun-teers, a group of people called an institutional reviewboard (IRB)at the research institution conducting theresearch will review and approve the protocol.

2. Clinical Research

In clinical research, doctors and scientists test new ideasabout ways to prevent, diagnose and treat diseases.Another name for clinical research is clinical trial. Inclinical trials, a drug, medical device, biologic (e.g.,vaccine), blood product, gene therapy or surgicalprocedure is tested to answer the following questions:

• Is it effective and safe for use in humans?

• Should it be approved for wider use?

• If it works well for one condition, does it alsowork for another condition?

• Is there a common or existing treatment that isbetter?

• How does it compare to standard care or againsta placebo?

• Can a standard treatment that has already beenapproved be used differently to make it moreeffective, easier to use, and/or to decrease sideeffects?

• Can an existing treatment be used in a new way,or on different groups of people such as childrenor the elderly?

• Is there a better way to prevent a disease in thosewho never had it or to keep a disease fromreturning?

• How can comfort and quality of life for those witha chronic condition be improved?

• How do genetic characteristics change diagnosis or treatment of a disease?

There are different kinds of clinical trials based onthe purpose of the research. A treatment trial studiesnew treatments or combinations of existing treat-ments. A prevention trial studies how a disease can beprevented through medicine, exercise, diet, or otherchanges. Diagnostic and screening trials look forbetter ways to diagnose diseases or those at risk fordisease. Quality of life trials focus on how to improvecomfort and quality of life for those suffering fromchronic or untreatable conditions.

B. Regulation of Medical Research

Regulation of medical research in the United States isa patchwork of federal and state laws. There is nofederal law that applies to all clinical research. Federallaws and regulations only apply to research that isfunded or supported by the United States govern-ment or research that involves certain drugs ordevices.

Most, but not all, medical research performed in theUnited States is regulated by agencies of the U.S.Department of Health and Human Services (HHS).

These agencies include the Food and DrugAdministration (FDA) and the National Institutes ofHealth (NIH). Several years ago, HHS developedregulations for research supported by HHS agencies.Many other government agencies now use this regula-tion, called the “Common Rule,” to protect researchvolunteers.

The Common Rule codifies three basic ethicalrequirements for conducting human research:

• Respect for Persons – People have the right to begiven information about the risks and benefits ofresearch. People also have the right to make theirown decisions about participating in research.The agreement to take part in research should bevoluntary and free of coercion. There are somegroups of people, such as children, who areconsidered vulnerable or especially at risk ofbeing coerced or unfairly convinced to take partin a research study. Special protections apply forthese situations.

• Beneficence – Researchers must keep risks assmall as possible and make benefits as likely aspossible. This is accomplished through carefulresearch design, careful review of data, and stop-ping studies if they unexpectedly seem to bedoing more harm than good.

• Justice – The benefits and burdens of researchmust be shared fairly. Those most likely to benefitshould also shoulder the greatest burden. Certaingroups should not be selected to participatesimply because they are more convenient or easilyconvinced. If public funds are used to supportresearch on new therapies, those therapiesshould be made available even to those whocannot afford them.

For research supported by the United States PublicHealth Service (which comprises all agency divisionsof the HHS, including the NIH, the Centers forDisease Control & Prevention (CDC), and the Agencyfor Healthcare Research and Quality (AHRQ)), theCommon Rule is enforced by the Office for HumanResearch Protections (OHRP).

It is important to remember that a great deal ofresearch conducted in the United States is notsupported by federal agencies and, therefore, is notcovered by the Common Rule. Such research sponsorsmay include commercial drug and device manufac-turers, non-profit foundations, and research institu-tions. Many of them, but not all, voluntarily complywith the Common Rule requirements.

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THE BASICS OF MEDICAL RESEARCH

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Research involving drugs and devices is usually regu-lated by the FDA no matter who is funding theresearch. In addition, some research institutions areaccredited by a non-profit organization called theAssociation for the Advancement of Human ResearchProtection Programs (AAHRPP). AAHRPP sets stan-dards for the conduct of clinical trials and otherresearch and requires participating institutions toapply equal protections to all research volunteersregardless of how particular projects are funded.

The Common Rule, FDA regulations, and AAHRPPstandards establish similar requirements including:

• Oversight of the research by an ethics committeeor institutional review board (IRB). IRBs have atleast 5 members with different skills and back-grounds. For example, IRBs include at least onelayperson and at least one individual who has norelationship with the research institution.

• IRB policies that govern review, approval, andongoing oversight of human research.

• Research designs that minimize risks andenhance possible benefits of the research.Research should include only risks that arereasonable compared to the possible benefits.

• Fair recruitment and selection of potentialresearch participants and, absent a waiverapproved by the IRB, voluntary, informed consentof those who have agreed to participate.

• Privacy protection.

• Special protections for children and, under theCommon Rule and AAHRPP standards, pregnantwomen, neonates, and prisoners.

When requirements for human research are discussedthroughout this Guide, we are referring to these stan-dards. If you are asked to participate in a researchstudy, you should know who is funding the researchand whether the research involves a drug or device.You may also want to ask whether the organizationconducting the research is accredited (accreditationgenerally means that the organization or institutionperforming the research has been recognized andapproved as having conformed with certain standards).The answers to these questions can help you under-stand your research volunteer protections.

C. How Are Clinical Trials Conducted?

Most medical researchers are dedicated scientists andhealthcare providers who want to improve health andfind good ways to prevent and treat illness. Theresearcher in charge of a study is called the principalinvestigator. In clinical trials, the principal investigatoris often a doctor but in other studies, she may beanother type of healthcare professional such as anurse, psychologist, audiologist, or physical therapist.The skills needed to be a principal investigator aredetermined by the study details.

The principal investigator leads a research team.Usually, each member of the research team hasreceived special training in research activities. Researchteams often include research nurses, research coordi-nators and assistants. Some teams include researchpharmacists who have special skills related tocombining drugs and working with new drugs.

Sometimes clinical trials are developed and funded bycompanies that make the product being tested. Thesecompanies are called sponsors. Sponsors have dutiesto help make sure the clinical trial is conducted as thelaw requires. Sometimes, sponsors can also be individ-uals, government agencies, doctors, and non-profitfoundations.

1. Basics of Clinical Research Design

Clinical trials are conducted according to the researchplan described in the protocol. When developing aresearch plan, the researchers pose questions thatthey hope the research will answer. Research design isimportant. A well-designed research plan protectsresearch volunteers and also improves the chance thatthe data from the research will answer importantquestions.

One way to make sure the research answers importantquestions is to control variables. A variable is an eventor factor that changes, manipulates, or influencesresearch outcomes. A common saying in science isthat “correlation is not causation.” In other words, thefact that two things are seen together does not meanthat one causes the other. When there are too manyvariables, it is hard to tell which variable was mostimportant.

2. Controlling Outside Factors

All research studies try to control outside factors thatmight affect the results. One outside factor is thehope of research volunteers and researchers that theproduct being studied will work. Science shows that ifresearch volunteers or researchers strongly believe,hope, or expect that the item being studied will orwill not work, their belief will influence their analysisof the data and more likely turn their belief or expec-tation into a reality. This effect is called bias. One ofthe ways researchers avoid bias is by using a single ordouble blinded study design.

In single blind studies, a duplicate or placebo of thestudy product is used. A placebo looks exactly like thestudy product but has no effect or therapeutic value.The use of placebos prevents bias from affectingresearch results. In a single blind study, the researchvolunteer does not know if she is receiving the studyproduct or the placebo. In a double blind study, thedetails of whether the research volunteer is receivingthe study product or a placebo is hidden from boththe research volunteer and the research team.

Sometimes, it is not possible to conduct a blind astudy. An open-label study is when both the patientand the research team knows that the actual studyproduct is being used. For example, most studiesthat involve surgery are open label. Also, manymedical device studies are open-label because it isdifficult to create a placebo of the medical device(e.g., a prosthetic for the leg).

3. Randomized Trials

Some clinical trials are randomized. Randomizing isanother way that researchers try to limit the impact ofoutside factors. In a randomized trial, participants arearbitrarily assigned to the control group or the experi-mental group. The control group receives no treat-ment or receives a placebo. The experimental groupreceives the treatment or product being studied.

Randomized trials can provide more objective results.Like double blind studies, randomized trials areconsidered more reliable and scientifically valid.There is no tendency to place certain individuals inthe control group or experimental group based onhow they will react to treatment. There can be riskswith randomized or double blind studies because aresearch volunteer may be placed in the controlgroup that receives no treatment or the group thatreceive the placebo. For serious illnesses like cancer, itcan be risky to use a placebo if an effective treatmentis available. To decrease this risk, research studies for

serious diseases often provide some standard therapyin addition to the product being tested.

4. The Phases of a Clinical Trial

Most clinical trials are conducted in several differentphases. First, the drug or device is usually tested onanimals. Once the scientists know how the drug ordevice affects animals, human research is allowed tobegin. When a device or drug is tested, many ques-tions are answered in the laboratory bench phase andthrough animal testing which occur through proof ofconcept or feasibility studies, and pilot or pivotal trials(trials regarding a new device). Screening, preven-tion, diagnostic, and quality-of-life studies do notalways follow this approach.

Phase I of clinical trials is the first step in testing a newdrug or device on humans. Phase I testing helps scien-tists determine whether the new product is safe forhumans. Researchers watch closely for harmful sideeffects. Different doses are tested to identify whatdosage is safest and most effective. The dosage of thenew drug is gradually increased as the scientists gainknowledge about the product. The goal is to identifythe highest dosage amount for further testing. Theways in which a new drug or product is administeredare also tested. Some different ways of administeringdrugs are by mouth (oral) or through shots (underthe skin or into muscle). Phase I trials usually includea relatively small number (10-100) of participants andthey often use healthy participants because the goal atthis phase is to evaluate safety rather than determinewhether the product is effective.

Phase II trials evaluate the safety and effectiveness ofthe new treatment or product. Phase II is the stagewhere scientists start to measure whether the productworks in humans. The drug is tested on about 100 to500 participants. Because this phase of testing looks atwhether the drug is effective, Phase II participantsoften have the medical condition the product isintended to treat. Phase II may also include a controlgroup of individuals who do not have the disease.

Phase III trials are the next step. Phase III studiesgather more information about how effective thedrug is. The research is designed to see whether, andhow well, the drug improves the targeted medicalcondition. Researchers also continue to watch care-fully for side effects and safety concerns.

Because Phase III trials focus on how well the drugworks, participants usually have the disease the drug isintended to treat. Sometimes Phase III trials willcompare the new drug to the current standard

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THE BASICS OF MEDICAL RESEARCH

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therapy to assess safety and effectiveness. Other PhaseIII trials look at existing treatments to see if they areeffective for a different condition. Phase III trials mayalso look at whether changing the dose or the way thedrug is provided changes how well the treatmentworks.

In some Phase III trials, all participants receive thedrug being tested. In others, participants arerandomly assigned to different groups, usually bycomputer. This protects against bias and helps toensure that human choices and outside factors do notinfluence the study’s results. One group (Group A)receives the product being tested, and the othergroup (Group B) may receive standard therapy or aplacebo. In a blinded study, neither the participantnor the research team knows if the participant isreceiving the product being tested. In some trials,Group A and Group B switch places halfway throughthe trials so that each group receives the studyproduct for one-half of the trial. This is called a cross-over design.

Studies generally move into Phase III only after theproduct has shown promise in Phases I and II. PhaseIII trials often involve large numbers of people (1,000to 5,000) and are often conducted in several locations.Some Phase III trials take place in multiple countries.On average, it takes about seven years to completePhases I, II, and III testing of a new treatment.

Phase IV trials evaluate the long term safety and effec-tiveness of a drug. Phase IV usually occurs after thedrug has been approved for use by the FDA. Severalthousands of individuals may participate in a Phase IVstudy. This level of participation is less common inPhase I, II or III. Phase IV studies are increasinglybeing required by regulators to assure long termsafety and effectiveness after initial approval.

Medical devices are studied in a similar way. After adevice is developed, an initial study called a feasibilitystudy is conducted. Feasibility studies focus on evalu-ating whether the device is useful. A feasibility study isalso called a pilot study. Wider testing of the device

occurs in a pivotal study. Pivotal studies are similar toPhase II and Phase III studies in drugs. Even after adevice is approved for use by the FDA, long termstudies may be conducted.

5. Where Are Clinical Trials Conducted?

Clinical trials may be conducted at hospitals, in clinics,or through physician offices. Research can also beconducted at nursing homes, community cancerprograms, and special research institutes. The choiceabout where to hold a clinical trial is partly based onthe kinds of research activities required. Some proce-dures, for example, need to be done in a hospital,while others can be safely done in a clinic or physi-cian’s office. The location of the trial can also be basedon the risks associated with the trial. In some cases, it isimportant to hold the study in a location that canhandle surgical emergencies. Other studies mayrequire that special medication be available. Whenplanning a clinical trial, sponsors look for physicianswho are experienced principal investigators, whounderstand the special requirements of clinical trials,and who have access to well-trained research supportteams. Many academic medical centers and teachinghospitals have research as part of their mission, as domany community hospitals.

6. How Can I Find Out About a Clinical Trial?

Physicians often have information about clinical trials.Hospital websites also list research options. Clinicaltrials can be found in newspapers or through radioand television ads. There are several differentresources on the internet. For example, the federalwebsite www.clinicaltrials.gov lists many different kindsof clinical trials. Individuals can search for trials basedon a certain disease or where the research is beingconducted. In addition, patient support groups oftenhave information on where clinical trials are beingconducted for specific diseases.

III. Protecting ResearchVolunteers

Research participants are volunteers. Special rulesoften exist to protect research volunteers. These rulesmay be based on:

• The policies of the hospital or research centerwhere the research will occur.

• The fact that the research is supported by thefederal government.

• The fact that the sponsor wants to use data fromthe research to be allowed to sell a new drug ordevice.

One very common way to provide this special protec-tion is through an institutional review board (IRB).An IRB is a special ethics committee that overseeshuman research studies.

A. What Is an Institutional Review Board?

The main purpose of the IRB is to protect clinicaltrial participants. When reviewing research, the IRBconsiders:

• Risk to research volunteers, compared to potential benefits.

• Activities that are only for research purposes andthose that would occur anyway.

• Ways that researchers plan to keep risk as low aspossible.

• Ways that researchers plan to protect the privacyof research volunteers.

• Information that researchers will give potentialvolunteers about the trial.

• Methods the researchers will use to get theinformed consent of research volunteers.

• Whether the research answers an important question.

Once the IRB approves the research, it continues tooversee the study. It will require reports from theresearchers about how the clinical trial is going. Ifthere are harmful or adverse events, those must alsobe reported to the IRB. If the IRB thinks the risks aregreater than the benefits, the IRB can order theresearch to stop.

Many research institutions have their own IRBs. Someinstitutions or principal investigators will arrange foran outside IRB to approve and review their researchstudy.

IRB members are selected for their skills. Differentskills and backgrounds help ensure that the IRB isable to protect the rights and welfare of researchvolunteers. An IRB usually has at least five members.These individuals possess different but necessary skillsand interests. This helps balance the IRB’s review.Members usually include scientists, non-scientists, andindividuals with no relationship to the research insti-tution or research.

When the IRB approves a research plan, it decideshow often the IRB will review the progress or resultsof the study. Generally, research studies are reviewedonce a year. Sometimes, the IRB will decide that thestudy should be reviewed more often. This canhappen if a study involves several different risks. It canalso happen if some of the risks are very serious.

When an IRB conducts its later reviews, it considersmany of the same things as it does in its initial review.It also considers:

• What progress has been made in the research;

• How many volunteers are participating in thetrial; and

• Any problems or adverse events that may haveoccurred.

If the study is going well and there are not manyadverse events or other problems, the IRB usuallyallows the study to continue. The IRB may also decideto revise, suspend, or terminate the project.Suspension or termination may occur if certain rulesare not being followed or if the research is causingunexpected harm to the volunteers. Sometimes theclinical trial may show early proof that the treatmentor product being researched is safe and effective. Inthat case, the sponsor may try to end the study so thatthe treatment or product can be offered to morepeople.

B. What is a Data Safety Monitoring Board?

Regular review of the research data is necessary tohelp protect research volunteers. By frequentlyreviewing the data, any new risks can be quickly iden-tified. The frequency of data review is based on howmuch risk the research poses. Studies that poseserious risks to volunteers or studies that have many

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different risks are subject to frequent and extensivedata review. Studies that target serious diseases alsohave frequent data review.

The IRB reviews certain safety data based on reportsof problems and the annual review report. In somecases, however, a data safety monitoring board(DSMB) is used. The DSMB is a special committeethat monitors the safety of volunteers involved in aclinical trial. The DSMB includes experts on thedisease that is being studied as well as experts onsafety, ethics and statistics. DSMBs are usually usedwhen there are many different sites or locationsinvolved in the study.

There are several differences between an IRB and aDSMB:

• An IRB often only looks closely at the data fromone site. A DSMB collects and reviews data fromall of the sites where the study is beingconducted.

• Safety data is often reported more frequently andin more detail when a DSMB is reviewing it.

• Conflicts of interest can occur in some cases if theIRB is influenced by the researchers. A DSMB canminimize any conflicts of interest because it isindependent of the research sites.

• In some cases, the DSMB may include or be ableto consult with experts that are less accessible to alocal IRB or research institution.

C. How Do I Make Sure My Decision isVoluntary?

A person’s decision to take part in a research study isstrictly voluntary. To help make sure the choice isreally informed, ask the following questions:

• Do I understand the risks and possible benefits ofthe study?

• Do I understand exactly what I must do to be inthe study?

• Do I understand which procedures are onlyneeded because of the research and which procedures I would have anyway?

• How often do I need to be seen by my doctorduring the study?

• What happens if I miss a follow-up visit?

• What are my options if I don’t want to be part ofthe study?

• If my regular doctor is conducting the study, willour usual relationship change during the study orif I decide to stop participating?

• Have I had a chance to ask questions and have allmy questions been answered?

• Have I had time and the opportunity to thinkabout my decision?

• Do I feel like I am being pressured to take part inthe study?

You are not required to volunteer for research to getor keep insurance coverage or to receive other bene-fits to which you are entitled. A choice not to volun-teer will have no impact on your regular medical care.If any researcher ever suggests otherwise, you shouldtalk to the IRB that is overseeing the research.Contact information for the IRB should be includedin the informed consent form.

D. What Is Informed Consent?

In most studies, a researcher must obtain informedconsent before allowing a volunteer to take part inthe study. Informed consent occurs when an indi-vidual makes a voluntary choice to enroll. Informedconsent is not just about signing a document. Theprocess of informed consent includes receiving verbaland sometimes written, videotaped or electronic infor-mation about the study. This includes informationabout the risks, potential benefits, and alternatives tothe research. The consent process continues as longas the research continues. As changes are made to theprotocol, you may be given more information aboutrisks and benefits and you may be asked to sign a newconsent form.

Researchers usually use an informed consent docu-ment to show that a volunteer has agreed to take partin a study. This document must be approved by theIRB. The informed consent document may varyamong researchers and institutions, but it usuallyincludes:

• A statement confirming the study is for researchpurposes.

• The purpose of the study.

• The length of time the study is expected tocontinue.

• A description of the procedure or treatmentbeing studied.

• An explanation of any part of the study that isexperimental.

• A description of any reasonably foreseeable risksor discomforts.

• A description of any possible benefits to theparticipant or others.

• Alternative procedures, treatments, or productsthat might be helpful to the participant.

• A statement describing how researchers willprotect the confidentiality of research volunteer information.

• Information on whom to contact with questions and concerns.

• A statement that participation is voluntary andthat the volunteer can leave the study at any timewithout penalty.

Some informed consent documents will include addi-tional information. Sometimes, the IRB may waivesome statements or elements. However, there arecertain statements that cannot be included in theinformed consent document. For example, the docu-ment cannot require the volunteer to waive or appearto waive legal rights, like the right to sue for malprac-tice that might occur during the study.

Informed consent forms should be easy to under-stand. For studies recruiting people who do not speakEnglish or are blind, the forms should be translatedto languages they can read and understand. Theresearch team should explain the information in theinformed consent form and answer any questions.After questions have been answered, the volunteercan decide whether to sign the form. It is importantto remember that the informed consent document isnot a contract. The volunteer is free to withdraw fromthe study at any time.

If the research volunteer is able to make medical deci-sions, the volunteer signs the informed consent form;however, some research involves individuals whocannot make medical decisions. In this case, the IRBusually requires the consent of a legally authorizedrepresentative. For children, this is usually a parent orguardian. Sometimes, adults cannot make medicaldecisions, so the legally authorized representativemight be another adult or an organization, such as a

court, permitted under state law to make decisions. Alegal representative’s authority to grant permission isbased on state law. The requirements may vary amongstates.

Informed consent, or use of consent forms, may bewaived or excused by the IRB. IRBs waive informedconsent only after careful consideration. A waiverusually will be approved only when the study posesvery little or no risk to the volunteer. A waiver won’tbe granted just because it is hard to get informedconsent. A waiver may be approved if there is noreasonable way to get informed consent. This canoccur when the researcher is only using informationcollected beforehand (e.g. through another study) –called a retrospective study. Another reason an IRBmight approve the waiver is when simply knowing thatone is participating in the study could change theresults. For example, when the study only involvesobservation of the participant, knowledge of participa-tion may change the outcome. Sometimes,researchers will tell participants about the researchafter the data collection is completed.

Some studies will involve information that is especiallyprivate or sensitive in nature. If the informed consentform is the only thing that would link a researchvolunteer to the research, the IRB may permit waiverof the documentation. In this case, information aboutthe research will be given to the participant but thedocument does not have to be signed by the volun-teer. This avoids making a connection between thevolunteer and the results. The volunteer always hasthe right to ask for a copy of the consent formwhether or not it needs to be signed.

Another way that confidentiality can be protected inresearch is through a Certificate of Confidentiality.These certificates are issued by the National Institutesof Health and they help protect against disclosure ofsensitive information, even if a court orders disclo-sure. More information about the Certificate ofConfidentiality program can be found atwww.grants.nih.gov/grants/policy/coc/.

E. How Are Vulnerable Populations Protected inMedical Research?

Federal regulations (the Common Rule) treat preg-nant women, fetuses, prisoners, and children asvulnerable to possible coercion or to special risks ofparticipation in research not encountered by others.Some institutions may consider other groups asvulnerable. For example, the elderly may be viewed asa vulnerable population. Special rules apply to thesegroups. For example, there are special informed

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consent rules. The IRB may also have special duties tominimize risk and protect these volunteers. There aresome kinds of research in which vulnerable popula-tions cannot usually participate. These special rulesare intended to provide extra protection to vulner-able individuals.

It is important to understand the definitions of eachvulnerable population. Under the federal rules, awoman is considered “pregnant” from the timeconception is confirmed until the child has beendelivered. A “fetus” is the product of conception fromimplantation until delivery (from HHS regulations onthe protection of human subjects). A “prisoner” issomeone who has been confined or detained againsther will in a penal institution or a similar facility. Aprisoner can also be someone who is being held whileawaiting arraignment, trial, or sentencing. A “child” isa person who is not yet old enough to legally consent

– generally under the age of 18. In some states,teenagers are allowed to consent for certain kinds ofmedical care. Whether that confers the right toconsent to research is a question of state law. If a childis a “ward” of the state, extra protections are provided.A ward is a child who is placed in the legal custody ofthe State, a child welfare agency, or an institution.

Other “at-risk” volunteers may include people who:

• Have limited ability to understand complex ideas.

• Have impaired ability to make decisions.

• Are at risk for suicidal behaviors.

There are no specific regulations to protect these at-risk populations but some researchers will offerspecial protections to these individuals.

IV. Rights and Responsibilities ofResearch Volunteers

A. What Documents Must I Sign?

Your medical information is confidential. This meansthat it can only be used or disclosed in certain cases.Rules about the use of confidential information areestablished by laws and by ethical standards. A federallaw called the Health Insurance Portability andAccountability Act (HIPAA) created federal rules toprotect the privacy of certain medical information.Many states also have additional rules about healthinformation privacy.

Under HIPAA, your health information can be usedfor some things, like treatment and payment, withoutyour written permission. Other uses of your healthinformation are only allowed if certain requirementsare met. Use of your health information for researchusually requires your permission. If you decide tobecome a research volunteer, you may be asked tosign a special form called a privacy authorization. Theprivacy authorization explains exactly how your infor-mation can be used for the study. Sometimes theprivacy authorization is part of the informed consentform. Sometimes the privacy authorization is a sepa-rate form.

The IRB may also serve as the Privacy Board of aresearch institution. A Privacy Board is a group ofpeople that helps ensure compliance with privacy andconfidentiality rules under HIPAA. Because the IRB isskilled at protecting the rights of research volunteers,the IRB is often also responsible for protecting privacyrights in research studies. This guidebook will use theterm “IRB” even when it is referring to its role as aPrivacy Board.

Sometimes, the IRB will decide that health informa-tion can be used for research without written permis-sion. This is called a waiver of authorization. Thereare special rules for when the IRB can approve thisapproach. To approve a waiver of authorization, theresearcher must show that:

• Identifiable information is needed for theresearch.

• The use or disclosure involves no more thanminimal risk to privacy.

• The research could not realistically be donewithout the waiver

Under HIPAA, researchers can also use your privateinformation without your written permission forreviews preparatory to research. This rule allowsresearchers to look at private information while theresearch project is being planned. For example,researchers may look at medical records to see if theresearch idea makes sense or if there are enoughpeople who might be interested in the research tomake it worthwhile.

Under HIPAA, your medical information remainsprivate even after you die but there is a special rulethat allows researchers to use the medical informationof decedents without written permission. Theresearcher must get the approval of the IRB for thisuse. Researchers may decide to ask family membersfor permission to use the information. Usually oneperson is responsible for taking care of the affairs ofthe patient after death. That person can agree to theuse of the patient’s private information after death.

B. How Is My Information Used?

Private information is often collected during aresearch study. This private information may includeinformation about the volunteer’s health, disease orcondition, treatment, and life style. A good researchstudy will limit its information collection to facts thatwill help researchers answer the research question.Research volunteers should understand what informa-tion is being collected and why.

The research information collected is called data. Thedata will be reviewed regularly. These reviews considerhow the study is progressing, how the treatment orproduct is working, and whether the new treatmentor product is safe and effective. Data is reviewed bythe research team and the IRB. In some cases, datawill also be reviewed by the DSMB as discussed earlierin this guidebook. The DSMB is a group of individ-uals who review research data to determine if the risksinvolved in the study are acceptable. The DSMBfocuses on the safety of the study, while the IRBreviews each study to ensure that the rights of theresearch volunteers are protected.

Sponsors who fund studies may send a trainedmonitor to the research site. This individual willensure that the collected data is accurate andcomplete and that private information is kept confi-dential. The monitor will compare the research dataagainst the volunteer’s medical record. This helpsensure there are no errors in the data and that theresults can be reliably used to make decisions aboutproduct approval or future treatment standards.Often, research is done on new drugs or devices to

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determine whether the product is safe and effective.In this case, the sponsor may submit the data to theFDA to obtain permission to market the product. Ifthe sponsor wants to market the product in othercountries, government agencies of those countriesmay review the data. The data may also be reviewedby other U.S. regulatory agencies like the Office ofHuman Research and Protections (OHRP) of theU.S. Department of Health and Human Services.OHRP is responsible for overseeing research volun-teer protection for federally-supported research.Other agencies may review data for other purposes,such as an audit. An audit is a review of the researchprogram’s operations to ensure that research is beingconducted safely and in compliance with the law.Research data may be published in a professionalmagazine or journal. This allows physicians, scientists,and other interested people to learn the results of theresearch. However, these publications will not includeyour name or other identifying information unlessyou give your permission.

C. What Are My Privacy Rights?

Research often requires the use of very private infor-mation. State laws and HIPAA protect this personalhealth information. In some cases, other documentswill be needed.

There are research methods that help protect theprivacy of research volunteers. For example, theresearcher may assign a unique number to identifyeach research volunteer. This allows the researchteam to record and analyze data based on theassigned number rather than by name. This preservesanonymity since only the number is released for datareviews, not the individual’s name. The list of volun-teers and their assigned numbers is kept by researchstaff in case a volunteer needs to be informed ofcertain information regarding her care.

Not everyone is required to protect a volunteer’spersonal information. Only “covered entities” areregulated by HIPAA. Physicians, hospitals, and healthinsurance plans are “covered entities” but otherresearchers and sponsors are not “covered entitiesand, therefore, not covered by HIPAA. Also, stateprivacy laws usually only apply to certain people andcompanies. Studies that are not conducted at acovered entity and which are not subject to theCommon Rule or FDA oversight may have differentduties regarding confidentiality. It is important forvolunteers to understand who might see their infor-mation and whether that person or company isrequired to protect the volunteer’s privacy. Private

information can lose protection when it is disclosed tosomeone who is not subject to the privacy laws.

In assessing privacy risks, volunteers may want to askthe following questions:

• Do I understand the authorization form?

• Who will be allowed to see, use and share mypersonal health information? Are all of themsubject to privacy laws?

• How long will the information be used or shared?

• What heath information is needed and why?

• Do I have the right to cancel my authorization?How do I cancel?

• What happens if I decide to not sign the authori-zation form?

• What happens to my private information after thestudy is completed?

• Have I had the opportunity to ask questionsabout the authorization and have they beenanswered?

D. Who Can I Contact if I Have Complaints orConcerns?

The informed consent and authorization formsshould provide information on whom to contact withconcerns, questions, or complaints about the study.The contact person will usually be a member of theresearch team. This person could be the study coordi-nator or the principal investigator. Other points ofcontact include:

• The hospital or institution in which the researchis taking or took place, the IRB that reviewed andapproved the research plan, and the company orsponsor that made the treatment or product thatis being tested;

• The FDA or the OHRP if federal money was usedto support the study; or

• The state licensing board if the research volun-teer wishes to file a complaint about a specifichealthcare provider or researcher.

If a volunteer has questions or concerns, it is impor-tant to talk to someone. This brings the issue to the

research team’s attention and may improve theresearch study going forward.

If a research volunteer believes her privacy wasviolated, she should inform the research team, prin-cipal investigator, and/or the hospital conducting theresearch. The volunteer can also contact the Officefor Civil Rights at the U.S. Department of Health andHuman Services.

E. What Are My Responsibilities as a ResearchVolunteer?

The volunteer is responsible for carefully consideringthe informed consent information. If the informationis not easy to understand, the individual should askquestions until she understands all of the parts of theresearch study.

It is important for the participant to follow all of theprincipal investigator’s instructions. Even a minorchange can impact the study. Participants shouldpromptly report changes in her condition. This isespecially true of any side effects, also called “adverseevents.“ These events should be reported even if theydo not seem related to the study.

A person may participate in a study while receivingtreatment for an unrelated medical condition.Changes in therapy or treatment for that conditionmay have an impact on the study. Therefore, changesto a volunteer’s medical treatment should be reportedimmediately to the research staff. If a volunteer isbeing treated by several doctors, she should inform allof them about her participation in the study. Regularphysicians may want to discuss the details of the studywith the principal investigator to ensure the patient’ssafety.

Many research studies will present risk. A risk is thepossibility that something will go wrong or that thevolunteer might be injured. Research involves riskbecause there are many unknowns in a study, espe-cially during the earlier phases. Some risks in researchare the same as the risks in normal medical care. Forexample, the risk of bruising that may occur whendrawing a blood sample would be the same whetherconducted for normal medical care or for researchpurposes. However, other risks are unique to the

research study. For example, if the study involves theadministration of a new treatment or product inwhich the side effects are not yet known, those sideeffects are a risk unique to the research.

Not all risks from a research study are physical. Whenprivate or sensitive information is collected, privacyrisks exist if the data is misused. When genetic infor-mation is collected, there are risks linked withlearning about the individual’s genetic make-up. Forexample, the volunteer could learn that he is at riskfor a genetically-based disease. Information aboutracial and ethnic heritage can also be revealed. Whenconsidering participation in such studies, the volun-teer should ask questions about privacy protectionand whether genetic information will be shared.

The volunteer should evaluate whether the researchrisk is acceptable as compared to the potential bene-fits. Three factors help with this decision: 1) the risksand potential benefits themselves, 2) the likelihood ofthe risk, and 3) how serious the risk would be if itoccurred. In the blood drawing example, mildbruising that disappears in a day or two may be anacceptable risk. But, bruising is a more serious risk ifthe participant suffers from a bleeding disorder ortakes medicine that affects clotting. Deciding on theacceptability of risk is a personal decision that must bemade by the volunteer.

Potential volunteers should consider the benefits of astudy. It is important to remember that the participantmay not receive any direct benefit. The treatment orproduct being tested may not work. The participantmay be assigned to the control group and receive notreatment or the standard medical therapy may bemore effective in treating the participant’s condition.Even so, the individual may feel that she benefited bycontributing to the advancement of medicine andscience. Enrolling in a study may provide a volunteerwith access to treatments that may not be available tothe public. Being a volunteer may also provide aheightened level of medical attention. The researcherand research team strive to understand how the studyis affecting the human body, so medical care is para-mount. Being a volunteer may also give an individualmore control over her medical care. As with risks,identifying the benefits is a personal decision.

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V. Payment for ResearchTreatments

Health insurance coverage for some research may bedifficult to obtain. When talking about insurancecoverage for research, two different kinds of caremust be considered. The first is care that is onlyprovided because of the research study, sometimescalled research-only care. This includes, for example,the product being studied and tests that are requiredonly because of the research. The other is care thatwould have been provided for the volunteer even ifthe volunteer was not taking part in the researchstudy. This is often called routine care.

A. Who Will Pay for My Care While I Am aResearch Volunteer?

Responsibility to pay for costs of care during researchcan vary. In translational research, there are usuallyno costs to the volunteer. The tissue and fluids arecollected as part of the volunteer’s medical care, andthe volunteer is not required to have additional tests.In most clinical studies, some of the treatmentprovided will be experimental or investigational(provided only because of the research), and somewill be routine care. Routine care is generally coveredby insurance. Often, investigational and experimentalcare is not covered. In this case, research-only caremay be paid for by the sponsor. There are some caseswhere even the routine medical care is covered orpaid for by a sponsor. There are also some caseswhere the experimental care is covered by insurance.This is most common in cancer research and variesfrom state to state. Volunteers should discuss costswith the research team or principal investigatorduring the informed consent process.

Insurers often require therapeutic intent before evenroutine care is covered. Therapeutic intent is researchthat not only gathers data about a product’s effective-ness but also tries to treat the disease or condition.The research will not be covered if it is merely todetermine safety and proper dosage. This require-ment can make obtaining insurance coverage forPhase I trials especially difficult but there are somecases where even Phase I trials meet this standard. Forexample, Phase I oncology trials usually have thepotential for therapeutic benefit for active cancerpatients enrolled in the study.

B. Will My Insurance Plan Pay for My Care?

This is a complicated question that does not have aneasy answer. A good place to start is the volunteer’shealth plan contract. Health plan contracts may

provide a general outline as to what the insuranceplan will cover during a research study.Understanding Medicare and the individual’s stateregulations for coverage will help in understandingthe individual’s health plan coverage.

C. How Do Health Plans Define “Research”?

An individual’s health plan contract will usually havedefinitions for “research,” “investigational,” and/or“experimental” care. Experimental care is usually notcovered by insurance plans. Research or investiga-tional care and/or routine care provided during astudy may be covered, particularly under Medicare.There are no standard definitions for these terms. It isimportant to understand the individual health plan’sdefinition for each. For example, some studies willinvolve research or investigation on a treatment thathas not yet been approved by the FDA. In other cases,the research or investigation might involve a new usefor a product that has been approved by the FDA foranother purpose. Other studies could compare twotreatments already approved by the FDA. Each ofthese can be treated differently by different healthplans.

D. Are the Costs Associated with Clinical TrialParticipation Covered?

Clinical trials can be sponsored. Sponsors can be apharmaceutical or device company, a federal agencylike the NIH or U.S. Department of Veterans Affairs,or individuals such as a physician. The sponsor usuallypays for certain costs associated with the research.These costs could include data collection andmanagement, research team time, research tests, andthe experimental treatment or product.

E. Can Coverage Continue After the Clinical TrialHas Ended?

Some sponsors continue to provide the research treat-ment or product at no charge for a limited periodafter the trial. This occurs through a patient assistanceprogram (PAP). PAPs are operated by the sponsors orthrough an independent organization. The clinicalsite hosting the clinical trial may also assist and coverthe new treatment or product for a limited time.Volunteers should ask about the existence of suchprograms from the sponsor or clinical site if the treat-ment proves beneficial.

F. Can Research Volunteers Be Paid forParticipating in a Clinical Trial?

Volunteers are sometimes paid by sponsors for theirparticipation in trials. This is especially true in theearly phases of investigational drug, biologic, ordevice development. Payment for participation is arecruitment incentive. These financial incentives areused most often when health benefits to the volunteerare minimal or nonexistent. They may also be offeredif the research requires many visits to the clinical site.Volunteers may be offered compensation for theirtime and any discomfort experienced during the trial.The amount of compensation is determined by thesponsor.

G. What Will Insurance Plans Cover?

Sponsors generally do not subsidize all patient carecosts linked with the clinical trial. Trial sponsors relyon insurers to pay for usual and routine patient care.This can include doctor visits, hospital stays, labora-tory tests, and x-rays. These are generally costs relatedto treatment the patient would have received even ifhe had not volunteered for the study. But healthinsurance and managed care providers often do notcover what they consider to be extra care costs relatedto volunteering for research. Coverage varies byhealth plan and study. Some health plans may notcover clinical trials if the treatment or product beingstudied is considered experimental or investigational.If enough data indicates that the treatment orproduct is safe and effective, a health plan mayconsider it “established” and cover some or all of thecosts. Whether an insurer will pay for medical careconnected with research can have a significant impacton whether a patient volunteers for the research.

A health plan contract may have rules that a trial mustsatisfy to be covered. For example, the trial may haveto be sponsored by a specific organization or beconsidered “medically necessary.” A plan may requirethat the treatment not be significantly more expensivethan other available treatments. Some plans onlycover studies for diseases that have no standard oreffective treatment. The facility and medical staff mayhave to meet the plan’s standards to conduct certainprocedures.

Health plans are less likely to have review processes inplace for prevention and screening trials, so researchparticipants may have difficulty obtaining coverage forthose trial costs. In many cases, it is important to havesomeone from the clinical research team discuss thedetails of coverage with the health plan.

Many states have passed legislation or developed poli-cies requiring health plans to cover the costs ofcertain clinical trials (see Appendix B).

H. What is Medicare’s Payment Policy forClinical Trial Participation?

On June 7, 2000, President William J. Clinton issuedan executive memorandum relating to Medicarepayments during clinical trials. The memorandumdirected the U.S. Department of Health and HumanServices Secretary to “explicitly authorize [Medicare]payment for routine patient care costs… and costsdue to medical complications associated with partici-pation in clinical trials.” Since then, regulationsgoverning Medicare payment policy for clinical trialparticipation have evolved. This evolution has createdconfusion among Medicare beneficiaries and thecontractors who manage the Medicare program.

After July 9, 2007, Medicare covers routine costs ofqualifying clinical trials and “reasonable and neces-sary” items and services used to diagnose and treatclinical trial complications. Routine costs of a clinicaltrial include all items and services that are otherwisegenerally available to Medicare beneficiaries. Theseitems and services can be provided in either theexperimental or control arms of the clinical trial. Theitems and services must fall into a Medicare benefitcategory, not be statutorily excluded, and they mustnot be the subject of a national non-coverage deci-sion. However, there are a few things that are notcovered:

• The investigational item or service itself unless itis covered outside of the clinical trial;

• Items and services provided solely to satisfy datacollection and analysis needs, or items and serv-ices that are not used in the direct clinicalmanagement of the patient (e.g., monthly CTscans for a condition that usually requires only asingle scan); and

• Items and services customarily provided by theresearch sponsors free of charge for any enrolleein the trial.

Medicare defines routine clinical trial costs as:

• Items or services that are typically providedabsent a clinical trial (e.g., conventional care);

• Items or services required solely for the provisionof the investigational item or service (e.g., admin-istration of a non-covered chemotherapeutic

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agent), the clinically appropriate monitoring ofthe effects of the item or service, or the preven-tion of complications; and

• Items or services needed for reasonable andnecessary care, particularly arising from the provi-sion of an investigational item or service for thediagnosis or treatment of complications.

This policy does not withdraw Medicare coverage foritems and services that may be covered by localmedical review policies (LMRPs) or the regulationson category B investigational device exemptions(IDE), described further below.

Medicare generally covers only the treatment ofcomplications arising from the delivery of non-covered items or services and unrelated reasonableand necessary care. This even includes complicationsfrom items and services that may be statutorily prohib-ited. As long as the item or service is not subject to anational non-coverage policy, Medicare will coverroutine costs of qualifying clinical trials. However, thenon-covered item or service iteself will not becovered.

Medicare regulations require Medicare Advantage(MA) organizations to follow Medicare’s nationalcoverage decisions (NCDs). MAs are Medicare’smanaged care plans. The October 17, 2007 NCDconfirmed Medicare coverage of routine care costsconnected with clinical trials and the investigationalitem itself if covered outside the trial. This requiressome modification of most MA organizations’ rulesgoverning provision of in and out-of-network itemsand services. MA organizations must now cover serv-ices provided in clinical trials regardless of whetherthey are available through in-network providers. MAorganizations may also have reporting requirementsto track and coordinate care of clinical trial partici-pants, but MA organizations cannot require priorauthorization or approval.

I. What Payment Rules Apply if the ResearchInvolves a Device?

There are special Medicare coverage rules aboutdevice use in an investigational device exemption(IDE). An IDE allows investigational devices to be usedin clinical studies to determine safety and effectiveness.This data is required to support a Premarket Approval(PMA) application or a Premarket Notification(510(k)) for the FDA. Clinical studies are most oftenconducted to support a PMA. Only a small percentageof 510(k)s require clinical data to support the applica-tion. This exemption includes clinical evaluation of

modifications made to a current standard device ornew uses of legally marketed devices.

The FDA categorizes devices with IDEs as eitherCategory A or Category B devices. Category A devicesare considered experimental. Medicare and commer-cial insurance rarely cover Category A devices in clin-ical trials. Category B devices are considered “nextgeneration” versions of approved devices. Medicareand commercial insurance plans will frequently coverthese devices.

An individual should ask her physician if the clinicaltrial device is under an IDE. If so, the individualshould further question if the device falls intoCategory A or B. This will make a difference as towhether the device is covered by a health plan or not.

J. What About Off-Label Uses of Drugs orDevices?

Many clinical trials study off-label uses of drugs. “Off-label” means a drug or device is used for a purpose forwhich the FDA has not approved. One example of anoff-label use is prescribing a drug that has been FDA-approved to treat cancer to treat migraines instead.Even though physicians have discretion to prescribe adrug or device for off-label use, the physician shouldinform her patient when a prescribed drug or device isbeing used off-label. Some health plans will not coveroff-label use, and patients should be aware of off-labeluse before agreeing to treatment. This is especiallytrue with cancer and psychiatric disorders since thesedrugs are often prescribed off-label.

Medicare may cover anti-cancer infused drugs for off-label use. Off-label use may also be covered:

• If the proposed use is noted in one of severalapproved compendia that track evidence of effi-cacy for off-label uses; or

• If a Medicare contractor believes there is suffi-cient evidence of efficacy in peer-reviewed litera-ture.

Many commercial insurers follow Medicare’s lead inthis area. A health plan might deny coverage of atreatment or product because it was used off-label. Ifthe use is noted in a drug compendia or peer-reviewliterature, the volunteer or patient should considerappealing the coverage denial and ask the physicianto assist in the appeal. The physician should be willingand able to share with the patient’s health planevidence that was used to make the decision toprescribe the drug or treatment off-label.

K. What Other Government Programs Help Payfor the Costs of Care?

Beneficiaries of TRICARE, the U.S. Department ofDefense’s health program, have coverage for medicalcosts related to some clinical trials. These trialsinclude participation in National Cancer Institute(NCI) sponsored Phase II and Phase III cancerprevention and treatment trials. This includesscreening and early detection for cancer patients. TheU.S. Department of Veterans Affairs allows eligibleveterans to participate in NCI sponsored prevention,diagnosis, and treatment studies. All phases and typesof NCI sponsored trials are included.

Medicaid patients may have to pay for certain costsregarding care in clinical trials, but these policies varyby state. Medicaid is the federal government’s state-administered health program for individuals andfamilies of low incomes.

L. Which States Require Coverage of CertainCosts Incurred During a Clinical Trial?

A growing number of states have passed legislation orinstituted special agreements requiring health plansto pay the cost of routine medical care during a clin-ical trial. As with Medicare policy, these laws andagreements do not cover the research costs associatedwith the trial that includes research tests. In mostcases, the research costs would be paid for by thesponsor, such as the NCI or a pharmaceutical ordevice company. States that mandate clinical trialcoverage are listed in Appendix B.

M. What Questions Should I Ask to DetermineWhether Coverage Will Be Provided?

• Who is sponsoring the research: the physician orprincipal investigator, the hospital or academicmedical center, a pharmaceutical or medicaldevice company, or a federal agency such as theNational Cancer Institute?

• In what phase of the research will I be partici-pating?

• Will the research involve off-label use of analready approved drug or device, or will it involveuse of an unapproved drug or device?

• Will the treatment that is being provided as partof the research protocol be covered by my insur-ance plan? If not, why not? What are my appealrights regarding a non-coverage decision? Ifcovered, specifically which services will be coveredand not covered? What will my co-payment be forcovered services?

• What are my options for continued coverage afterthe clinical trial is over?

• If I am a Medicare beneficiary, does the researchinvolve off-label use of an anti-cancer drug or adevice that falls under an investigational deviceexemption?

• Does my state law require that health insuranceplans cover certain costs of clinical trials and off-label uses? What costs are covered?

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VI. ConclusionThrough medical research, scientists and cliniciansimprove prevention, diagnosis and treatment ofdisease, and improve the quality of life of thosesuffering from disease. The decision to volunteer toparticipate in a medical research program is animportant decision. We hope this guidebook hasprovided you with information that will help youmake that decision. We encourage you to ask ques-tions, be informed, and be active in your healthcare.

GLOSSARYThere are many special words that are used todescribe and talk about research. To help you betterunderstand issues related to medical research, a glos-sary of commonly used terms is provided below. Whilenot all of the words in this glossary appear in thisGuidebook, they are helpful to know as you decidewhether or not to participate in a clinical trial.

Assent: The process of obtaining one’s agreement toparticipate in research.

Bench Research: General scientific research thatoccurs in a laboratory.

Bias: Permitting expectations or hopes to influencedecisions or analysis of data.

Biologic: A substance made from a living organismthat is used to prevent, diagnose or treat a disease,such as a vaccine.

Biomarker: A protein occurring in the blood thatindicates health or the presence of an illness.

Biorepository: A facility that collects and stores tissueand body fluids for research, also referred to as atissue bank.

Blinded: A study design used to decrease bias. In asingle-blinded study, the research volunteer does notknow if she is receiving the study product. In adouble-blinded study, neither the research volunteernor the principal investigator knows who is receivingthe study product.

Case Reports: A research and teaching approach thatuses a detailed discussion of the clinical progress ofone person or several people (case series) and followsthe progress of the person’s disease or treatment.Researchers hope to learn more about the diseaseand its treatment by examining how the diseaseprogresses and what effect a given treatment has.

Case-Control Study: A research approach thatcompares detailed information about two very similargroups of people (one that has a disease and one thatdoesn’t). Researchers use this technique to try toidentify what causes one group to be sick and theother to be healthy.

Case Report Form (CRF): The form used to collectand submit information and data about a researchstudy.

Cells: The basic functional units of the body. Groupsof cells that perform common functions create tissues.

Clinical Trial: Research into how a new medicalapproach works in people. Clinical trials can studyprevention, diagnosis, and treatment options. Alsoreferred to as clinical research.

Cohort Study: A cohort is a group of people who havecommon characteristics. A cohort study looks atoutcomes and compares groups of people who arealike in many ways but have some differences.

Common Rule: The term used for the regulationsthat were developed to guide research that issupported by the federal government and involveshuman volunteers as participants.

Compassionate Use Trial: A clinical trial that permitsuse of a new, possibly helpful treatment by peoplewho have a serious disease but do not qualify to beincluded in a clinical trial exploring the treatment.

Control Group (also control arm): The group ofpeople in a clinical trial that do not have the diseaseor do not receive the experimental product. Controlgroup participants may receive a placebo, an alternatetreatment, or no treatment.

Controlled Clinical Trial (also controlled study): Aclinical trial that uses a control group as comparisonto the experimental product.

Cross-Over: A study design where the experimentaland control groups switch halfway through the trial sothat each group receives the study product for one-half of the trial.

Data and Safety Monitoring Board (DSMB): A groupof people who review data during a clinical trial todetermine whether the risk/benefit ratio remainsacceptable.

Device: A product that is used to prevent, diagnose ortreat disease, but which does not work by a chemicalreaction or metabolism. A device is often an item thatis implanted or applied to the body.

Diagnostic Trial (also screening trial): A clinical trialthat looks for better diagnostic tests for diseases.

Dose: The amount of drug or biologic given at onetime.

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APPENDIX A

22

Dose-Limiting: The dose at which side effects are sosignificant that no higher dose should be given.

Dose-Dependent:When the action or effect of a drugor biologic varies based on the dose.

Drug: Any substance (other than a food) that is usedto prevent, diagnose or treat illness or symptoms of anillness; also, any substance that changes mood,thinking, or body function.

Efficacy: Effectiveness. How well a product works toprevent, diagnose or treat an illness.

Eligibility Criteria: The characteristics that must bepresent to be allowed to participate in a clinical trial.

Experimental (also investigational): A drug, device orbiologic that has passed animal testing and can betested in humans, but has not yet been recognized tobe safe or effective. Some insurance companies andother payors distinguish between experimental, whichcannot be covered, and investigational, which can becovered in some cases.

FDA: The U.S. Food and Drug Administration. Theagency charged with ensuring the safety of food andsafety and efficacy of drugs, devices and biologics.

Feasibility Study (also pilot trial): A preliminary studyto determine the chance of success, costs and benefitsof a research project.

Follow-Up: Continuing the monitoring of a person’scondition after a clinical trial is completed. Follow-upis used to gather information about long-term effectsof a study product.

Gene: The segment of DNA that passes on character-istics from parents to offspring based on how they arearranged.

Good Clinical Practice: The internationally-acceptedethical and scientific standards for conductingresearch involving human volunteers. GCPs areintended to assure that data is valid, reliable, ethicallyobtained, and volunteer participants are protected.

Informed Consent: The process that verifies a volun-teer’s willingness to participate in research after thevolunteer has received and considered informationabout that research. Information provided forinformed consent includes information about theresearch project; risks, benefits and alternatives; whocan participate and how to end participation; andwho to contact with questions. The informed consent

process is ongoing throughout the research andincludes updating the volunteer about newly discov-ered risks, benefits, and alternatives.

Institutional Review Board (IRB): A group of people,including physicians, scientists, and non-scientists, whoreview and oversee research that involves human volun-teers. The IRB is responsible for ensuring that humanresearch volunteers are protected and treated fairly.

Investigational (also experimental): A drug, device orbiologic that has completed animal testing and isbeing tested in humans. An approved drug, device orbiologic can be investigational if it is being studied fordifferent uses at different dosages or given in adifferent way.

Legally Authorized Representative: The person orentity legally authorized to make decisions aboutparticipating in research for a person who cannotmake those decisions for him/herself.

Open-Label: A study design where both the patientand the research team know that an actual studyproduct, and not a placebo, is being used. Open-labelstudies are conducted when it is difficult or notpossible to blind the study.

Phase I Study: The first human-based research projectto evaluate a possible new product. Primarily deter-mines absorption, distribution, dosing, toxicity andsafety. In some cases, there may be therapeutic intent,especially in cancer trials.

Phase II Study: After successful conclusion of a PhaseI study, this phase evaluates the safety of the productin a larger study group that typically has the disease orcondition the product is intended to treat.

Phase III Study: Studies the safety and efficacy of aproduct in a larger study population. The study popu-lation consists of those with the disease or conditionthe product is intended to treat. If successful, this istypically followed by an application to the FDA forpermission to market the product.

Phase IV Study: Studies the long-term safety and effec-tiveness of a drug or device. These studies usuallyinvolve thousands of individuals and occur after FDAapproval has been received.

Pilot Trial (also feasibility study): The preliminary trialof a drug or device using a small number of animals.The goal is to gather general information rather thanto obtain statistically significant results.

Pivotal Trial: The clinical trial of a new device.

Placebo: An inactive substance that is made toresemble the product being studied. Placebos areused when there is no effective treatment for thedisease or condition being studied. Placebo isintended to prevent bias from affecting researchresults.

Prevention Trial: A clinical trial to study how a diseasecan be prevented through medicine, exercise, diet, orother changes.

Principal Investigator: The scientist or healthcareprovider who is primarily responsible for the conductof a research project. The principal investigator isresponsible for making sure that the protocol isfollowed, only people who meet eligibility criteria areenrolled, and she oversees the safety of researchvolunteers. She works with the sponsor, the DSMB,and the IRB to make sure the research is safe, scientif-ically useful, and ethical.

Proof of Concept Study: A study intended to showthat a hypothesis or concept is valid.

Protocol: The document that describes the researchdesign for a given research project.

Quality of Life Trial: A clinical trial to study methodsto improve the quality of life for individuals sufferingfrom chronic conditions.

Randomized: A process where each volunteer in astudy has an equal chance of being placed in thetreatment arm or the control arm of the study.Randomization is intended to prevent bias fromaffecting the research results.

Research: A systematic study of an issue, intended tolead to generalizable results.

Research Design: The plan for conducting research ina way that makes it scientifically useful and ethical.The research design includes determining whetherthe study will be blinded, whether a control group willbe used, and whether volunteers will be assigned toan arm randomly. The research design is described inthe protocol.

Revoking Consent: The participant’s decision to endher participation in the clinical trial. A volunteeralways has the right to revoke consent.

Risk/Benefit Ratio: The comparison between therisks and the benefits of proposed research. Whether

the risk/benefit ratio is acceptable depends on howserious the disease being studied is and whetheranother effective treatment exists for that disease.

Screening Trial (also diagnostic trial): A clinical trialto identify better ways to diagnose diseases or individ-uals at risk for a disease.

Sponsor: The individual or organization funding theresearch study. A sponsor can be the company thatdeveloped the product being tested or governmentagencies, doctors, or non-profit foundations that havea research idea.

Standard Treatment (also standard therapy): Thetreatment or therapy thought to be effective andusually used for a given disease or condition.

Test Article: The product that is being evaluated in aresearch study.

Therapeutic Intent:When a research study isintended both to gather data about the effect of aproduct and to treat a disease or condition.

Tissue: A group of cells that have similar structureand work together to perform a specific function.

Tissue Bank (also biorepository): A facility thatcollects, stores, and distributes tissues and cells forresearch purposes.

Toxicity: The degree of damage that a product cancause to an organism by chemical action.

Translational Research: Research that takes discov-eries in the laboratory and applies them to humans.

Treatment Trial: A clinical trial to study new treat-ments or combinations of existing treatments.

Variable: A factor that can be changed or manipu-lated in an experiment to determine its effect on theresearch outcome.

Vulnerable Group: A group that is considered espe-cially at risk of being coerced into taking part in aresearch study. Pregnant women, neonates, childrenand prisoners are often considered vulnerable popu-lations. Special protections exist to protect thesegroups.

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APPENDIX A

24

STATES MANDATING INSURANCECOVERAGE OF CLINICAL TRIALS

ArizonaLegislation: Senate Bill 1213

Effective: January 2001

What clinical trials are covered? Phase I, II, III, and IVclinical trials for treatment, palliation (supportivecare) or prevention of cancer approved by one of thefollowing:

• National Institutes of Health (NIH)

• NIH cooperative group or center

• U.S. Food and Drug Administration (under anInvestigational New Drug application)

• U.S. Department of Defense

• U.S. Department of Veterans Affairs

• A qualified research entity that meets NIHcriteria for grant eligibility.

• A panel of qualified clinical research expertsfrom academic health institutions in the state.

Who is required to pay? Private insurers and managedcare plans.

Other key criteria:

• Trial must be reviewed and approved by anInstitutional Review Board of an institution inArizona.

• Health professional must agree to accept reim-bursement from the insurer as payment in full.

• There is no clearly superior, non-investigationaltreatment alternative.

• Excludes coverage for trials outside of Arizona.

CaliforniaLegislation: Senate Bill 37

Effective: August 2001

What clinical trials are covered? Phase I, II, III, and IVclinical trials with a therapeutic intent for patientswith cancer and recommended by a treating physi-cian. Trial must either involve a drug exempt from aNew Drug Application (NDA) under federal regula-tions or be approved by one of the following:

• National Institutes of Health (NIH)

• U.S. Food and Drug Administration

• U.S. Department of Defense

• U.S. Department of Veterans Affairs

Who is required to pay? All California insurers,including the state’s Medicaid program and othermedical assistance programs.

Other key criteria:

• Plan may restrict coverage to services inCalifornia unless protocol is not provided at aCalifornia hospital or by a California physician.

ConnecticutLegislation: Senate Bill 325

Effective: January 2002

What clinical trials are covered? Clinical trials fortreatment, palliation (supportive care), or preventionof cancer approved by one of the following:

• National Institutes of Health (NIH)

• National Cancer Institute cooperative group orcenter

• U.S. Food and Drug Administration

• U.S. Department of Defense

• U.S. Department of Veterans Affairs

Who is required to pay? Private insurers, includingindividual and group health plans.

Other key criteria:

• Prevention trials are covered only in Phase IIIand only if they involve therapeutic intervention.

• Insurer may require documentation of the likelihood of therapeutic benefit, informedconsent, protocol information and test results,and/or a summary of costs involved.

DelawareLegislation: Senate Bill 181

Effective: July 2001

What clinical trials are covered? Clinical trials fortreatment, palliation (supportive care), or preventionof cancer approved by one of the following:

• National Institutes of Health (NIH)

• NIH cooperative group or center

• U.S. Department of Defense

• U.S. Department of Veterans Affairs

• Institutional Review Board that has a MultipleProject Assurance (MPA) from the U.S.Department of Health and Human Services’Office for Human Research Protections.

� • A qualified research entity that meets thecriteria for NIH Center Support grant eligibility.

Who is required to pay? Every group or blanket policy.

Other key provisions:

• The trial must have therapeutic intent andenroll individuals diagnosed with the disease.

• The trial must not be designed exclusively totest toxicity or disease pathophysiology (thefunctional changes that accompany a partic-ular syndrome or disease).

GeorgiaAgreement: Georgia Cancer Coalition agreement(for separate legislation, see following section onLegislation).

Effective: 2002

What clinical trials are covered? Phase I, II, III or IVcancer clinical trials for patients with cancer and recom-mended by a treating physician. The trial must either(1) involve a drug that is currently exempt underfederal regulations from a new drug application or (2)be a trial that is approved by one of the following:

• National Institutes of Health (NIH)

• NIH-sponsored cooperative group or center

• U.S. Department of Defense

• U.S. Department of Veterans Affairs

• U.S. Food and Drug Administration

• An Institutional Review Board of any accred-ited school of medicine, nursing, or pharmacyin the state of Georgia

Who is required to pay?

• Kaiser

• BlueCross/BlueShield of Georgia

• United Health Care

• Aetna

• Humana

• Coventry

• OneHealth

• Cigna

• The Georgia Department of CommunityHealth (which administers the State HealthBenefit Plan, Medicaid, and PeachCare).

Other key provisions:

• The agreement also provides for the coverage ofcancer screens and examinations in accordancewith the most recently published guidelines and

recommendations established by any nationallyrecognized healthcare organization.

Legislation:

• The Georgia Cancer Coalition agreementcovers both adults and children. There is also alaw in effect for children only. The law (SenateBill 603) was passed in 1998 and requires allhealth plans in Georgia to reimburse the patientcare costs associated with a dependent child’sparticipation in a phase II or phase III cancerclinical trial that is testing prescription drugs.The child has to have been diagnosed withcancer prior to his or her nineteenth birthday,and the trial has to have been approved by theU.S. Food and Drug Administration or the U.S.National Cancer Institute.

LouisianaLegislation: Senate Bill 761

Effective: July 1999

What clinical trials are covered? Phase II, III, and IVclinical trials for the treatment, supportive care, earlydetection, and prevention of cancer. The trial must beapproved by one of the following:

• Cooperative group funded by a component ofthe National Institutes of Health

• U.S. Food and Drug Administration

• U.S. Department of Veterans Affairs

• U.S. Department of Defense

• Federally funded general clinical research center

• Coalition of National Cancer CooperativeGroups

Also, the clinical trial protocol must have beenreviewed and approved by a qualified InstitutionalReview Board operating within the state that has amultiple project assurance contract approved by theOffice of Protection from Research Risks, U.S.Department of Health and Human Services.

Who is required to pay?Health maintenance organi-zations, preferred provider organizations, the StateEmployee Benefits Group Program, other specifiedinsurers.

Other key provisions:

• There is no clearly superior, noninvestigationalapproach.

• The available clinical or preclinical data provide areasonable expectation that the treatment will beas effective as the noninvestigational alternative.

• The patient has signed an IRB-approvedinformed consent form.

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APPENDIX B

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MaineLegislation: 24-A: Maine Insurance Code

Effective: 1999

What clinical trials are covered? Clinical trialsenrolling individuals who have a life-threatening orserious illness for which no standard treatment iseffective. Trial must be approved and funded by anyone of the following:

• National Institutes of Health (NIH)

• NIH-sponsored cooperative group or center

• U.S. Department of Health and HumanServices

Who is required to pay?Managed care organizationsand private insurers.

Other key provisions:

• Participation must offer meaningful potentialfor significant clinical benefit to the enrollee.

• Referring physician must conclude that trialparticipation is appropriate.

MassachusettsLegislation:House Bill 4376 (Chapter 257)

Effective: January 2003

What clinical trials are covered? All phases of cancertreatment trials. Trial must be peer-reviewed andapproved by one of the following:

• National Institutes of Health (NIH)

• NIH-sponsored cooperative group or center

• U.S. Department of Defense

• U.S. Department of Veterans Affairs

• U.S. Food and Drug Administration

• A qualified non-government research entity

Who is required to pay? All health plans issued orrenewed after January 1, 2003.

Other key provisions:

• Insurers must provide payment for servicesthat are “consistent with the usual andcustomary standard of care” provided underthe trial’s protocol and that would be coveredif the patient did not participate in the trial.

MichiganAgreement:Michigan Consensus Agreement

Effective: February 2002

What clinical trials are covered? Phase II and IIIcancer clinical trials that are sponsored or approvedby any one of the following:

• National Institutes of Health (NIH)

• National Cancer Institute

• U.S. Food and Drug Administration

• U.S. Department of Defense

• U.S. Department of Veterans Affairs

• Centers for Medicare and Medicaid Services

• Centers for Disease Control and Prevention

• The agreement also would cover any sideeffects from the clinical trial treatment,including hospitalization costs.

Who is required to pay? Private insurance plans,HMOs and the Michigan Medicaid Program.

Other key provisions:

• Coverage for Phase I trials is under consideration.

MissouriLegislation: Senate Bill 1026; Senate Bills 567 & 792

Effective: August 28, 2002 (S.B. 1026); May 12, 2006(S.B. 567 & 792)

What clinical trials are covered? Phase II, III or IVclinical trials for the prevention, early detection, ortreatment of cancer as approved or funded by one ofthe following:

• National Institutes of Health (NIH)

• NIH Cooperative Group or Center

• U.S. Food and Drug Administration

• U.S. Department of Defense

• U.S. Department of Veterans Affairs

• An Institutional Review Board in Missouri thathas been approved by the U.S. Department ofHealth and Human Services

• A qualified research entity that meets thecriteria for NIH Center support grant eligibility

Who is required to pay? All health benefit plans oper-ating in the state.

Other key provisions:

• There must be identical or superior noninvesti-gational treatment alternatives available before

providing clinical trial treatment, and theremust be a reasonable expectation that the clin-ical trial treatment will be superior to thenoninvestigational alternatives.

• Requires coverage of FDA-approved drugs anddevices used in cancer clinical trials even ifthose drugs and devices have not beenapproved for use in treatment of the patient’sparticular condition.

• Health benefit plans may limit coverage ofroutine care costs of patients in phase II trialsto those facilities within the plans’ providernetwork.

• For individually underwritten health plans, thephase II provision is not mandatory but mustbe offered as an option.

New HampshireLegislation: Senate Bill 409

Effective: January 2001

What clinical trials are covered? Phase I, II, III, and IVtrials for cancer and other life-threatening conditions,with coverage for Phase I and II trials to be decidedon a case-by-case basis. Coverage is required for clin-ical trials that are approved by:

• National Institutes of Health (NIH)

• NIH cooperative group or center

• U.S. Food and Drug Administration

• U.S. Department of Veterans Affairs

• U.S. Department of Defense

• An Institutional Review Board of an institutionin New Hampshire with a Multiple ProjectAssurance (MPA) from the U.S. Department ofHealth and Human Services’ Office forHuman Research Protections

Coverage is also required for reasonable andmedically necessary services to administer the drug ordevice under evaluation in the clinical trial.

Who is required to pay? Private insurers and specifiedmanaged care plans.

Other key provisions:

� • Trials are covered when standard treatmenthas been or would be ineffective or does notexist, or when there is no clearly superiornoninvestigational alternative.

NevadaLegislation: Senate Bill 29

Effective: January 1, 2006 (extends legislation ineffect since January 2004 to include phase I cancerclinical trials)

What clinical trials are covered? Phase I clinical trialsfor the treatment of cancer, and phase II, III, and IVclinical trials for the treatment of cancer or chronicfatigue syndrome that are approved by one of thefollowing:

• National Institutes of Health (NIH)

• NIH cooperative group

• U.S. Food and Drug Administration (FDA)

• U.S. Department of Veterans Affairs

• U.S. Department of Defense

Who is required to pay? Private insurers and managedcare plans.

Other key provisions:

• There is no medical treatment available that isconsidered more appropriate treatment thanthe treatment provided in the clinical trial.

• Trial must be conducted in Nevada

New JerseyAgreement: New Jersey Consensus Agreement

Effective: December 1999

What clinical trials are covered? All phases of cancerclinical trials run by:

• National Institutes of Health (NIH)

• NIH cooperative group or center

• U.S. Food and Drug Administration

• U.S. Department of Defense

• U.S. Department of Veterans Affairs

Who is required to pay? All insurers in the state,including those affiliated with the New JerseyAssociation of Health Plans.

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APPENDIX B

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New MexicoLegislation: Senate Bill 240

Effective:March 14, 2001

What clinical trials are covered? Phase II, III, and IVclinical trials for the early detection, treatment, pallia-tion (supportive care), or prevention of recurrence ofcancer. Trials must be approved by one of the following:

• National Institutes of Health (NIH)

• NIH cooperative group or center

• U.S. Food and Drug Administration (under anInvestigational New Drug application)

• U.S. Department of Defense

• U.S. Department of Veterans Affairs

• Research entities meeting NIH grant standards.

Who is required to pay? Private insurers, specifiedmanaged care plans, Medicaid, and other statemedical assistance programs.

Other key provisions:

• Legislation is effective through July 1, 2009 (asper Senate Bill 73).

• Trial must have therapeutic intent.

• There must be a reasonable expectation thattreatment will be at least as effective as stan-dard or noninvestigational cancer treatment.

• Payment is limited to in-state or in-networkcosts, unless the plan covers standard out-of-state or out-of-network treatment.

North CarolinaLegislation: Senate Bill 199

Effective: January 2002

What clinical trials are covered? The law extendscoverage to all people diagnosed with a life-threat-ening condition who choose to enroll in a Phase II,III, or IV clinical trial. Includes clinical trials approvedand funded by any one of the following:

• National Institutes of Health (NIH)

• NIH cooperative group or center

• U.S. Food and Drug Administration

• Centers for Disease Control and Prevention

• Agency for Healthcare Research and Quality

• U.S. Department of Defense

• U.S. Department of Veterans Affairs

Who is required to pay? All health insurance plansand the teachers’ and state employees’ comprehen-sive major medical plan.

Other key provisions:

• Mandated coverage is effective for health plansthat are in effect or renewed on or after March1, 2002.

• Patients suffering from a life-threateningdisease or chronic condition may designate aspecialist who is capable of coordinating theirhealth care needs as their primary care physi-cian. The law also established an Office ofManaged Care Patient Assistance.

OhioAgreement:Ohio Med Plan

Effective:March 1999

What clinical trials are covered? National CancerInstitute-sponsored Phase II and III cancer treatmentclinical trials for Ohio state employees enrolled in theOhio Med Plan.

Who is required to pay? The state’s Ohio Med Plan.

Other key provisions:

� • Preauthorization is required for clinical trialparticipation.

Rhode IslandLegislation: Senate Bill 2623; Senate Bill 1, House Bill 5062

Effective: 1995 (SB 2623); 1998 (SB1, HB 5062)

What clinical trials are covered? Phase II, III, and IVcancer clinical trials approved by one of the following:

• National Institutes of Health (NIH)

• A community clinical oncology program

• U.S. Food and Drug Administration

• U.S. Department of Veterans Affairs

• A qualified nongovernmental research entity,as identified by an NIH support grant.

Who is required to pay? Private insurers and specifiedmanaged care plans.

TennesseeLegislation:House Bill 837

Effective: July 2005

What clinical trials are covered? Phase I, II, III, and IVclinical trials for the treatment of cancer approved byone of the following:

• National Institutes of Health (NIH)

• U.S. Food and Drug Administration (FDA)through an Investigational New Drug application

• U.S. Department of Defense

• U.S. Department of Veterans Affairs

Who is required to pay? Any health benefit planoffered by an employer; excludes individually under-written health insurance policies.

Other key criteria:

• The subject of the trial must evaluate a drug,medical device or service that falls within aMedicare benefit category.

• Limits coverage to those drugs, medicaldevices, and services that have been approvedby the FDA and that are used in the clinicalmanagement of the patient.

VermontLegislation:House Bill 6

Effective: February 24, 2005 (extends and modifieslegislation in effect since March 2002)

What clinical trials are covered? Approved cancer clinical trials conducted under the auspices of thefollowing cancer care providers:

• The Vermont Cancer Center at Fletcher AllenHealth Care

• The Norris Cotton Cancer Center atDartmouth-Hitchcock Medical Center

If no suitable trial is available at the above locations, thelaw covers approved cancer clinical trials being admin-istered by a hospital and its affiliated, qualified cancercare providers in or outside the state of Vermont.

Who is required to pay? All health insurance policiesand health benefit plans issued in Vermont, includingthe Vermont Medicaid program.

Other key provisions:

• Participants in cancer trials located outsideVermont must provide notice to the healthbenefit plan prior to their participation.

• Health insurers are permitted to require

patients participating in a trial outside theprovider network to receive routine follow-upcare within the plan’s network, unless thepatient’s cancer care provider determines thiswould not be in the best interest of the patient.

• Cancer care providers and the state’s fourlargest health insurers are required to partici-pate in a cost analysis to determine the impactof the program on health insurance premiums.

VirginiaLegislation: Senate Bill 1235, House Bill 871

Effective: July 1999

What clinical trials are covered? Phase II, III, and IVcancer treatment trials, with Phase I trials covered ona case-by-case basis. Trial must be approved by one ofthe following:

• National Cancer Institute (NCI)

• NCI cooperative group or center

• U.S. Food and Drug Administration

• U.S. Department of Defense

• U.S. Department of Veterans Affairs

• An Institutional Review Board of a Virginiainstitution with a Multiple Project Assurance(MPA) from the U.S. Department of Healthand Human Services’ Office for HumanResearch Protections.

Who is required to pay? Private insurers, specifiedmanaged care plans, and public employee health plans.

Other key provisions:

• There is no clearly superior, noninvestigationalalternative.

• Data provide a reasonable expectation that thetreatment will be at least as effective as thealternative.

West VirginiaLegislation:House Bill 2675

Effective: June 2003

What clinical trials are covered? Phase II, III, or IVclinical trials for the prevention, early detection, ortreatment of cancer, or for the treatment of any otherlife-threatening condition.

The clinical trial must be approved by one of thefollowing:

• National Institutes of Health (NIH)

• NIH-sponsored cooperative group or center

• U.S. Food and Drug Administration (FDA)

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APPENDIX B

30

• U.S. Department of Veterans Affairs

• The Institutional Review Board (IRB) of aninstitution in West Virginia that has a MultipleProject Assurance contract approved by theNIH Office of Protection from Research Risks

Who is required to pay? Private insurers, managedcare plans, Medicaid or state medical assistance,public employee health plans.

Other key provisions:

• The treatment must have therapeutic intent.

• There is no clearly superior, noninvestigationalalternative.

• The available clinical or pre-clinical dataprovide a reasonable expectation that the treat-ment will be more effective than the noninves-tigational treatment alternative.

• Does not require reimbursement for clinicaltrials intended to:

– Extend the patent of any existing drug.

– Gain approval of or coverage for a metabo-lite of an existing drug.

– Gain approval or coverage relating to addi-tional clinical indications for an existingdrug.

– Keep a generic version of a drug fromcoming to market.

– Gain approval of or coverage for reformu-lated or repackaged version of an existingdrug.

WisconsinLegislation: Assembly Bill 617

Effective: Nov. 1, 2006

What clinical trials are covered? All phases of cancerclinical trials, as approved by one of the following:

• National Institutes of Health (NIH)

• NIH Cooperative Group or Center

• U.S. Food and Drug Administration

• U.S. Department of Defense

• U.S. Department of Veterans Affairs

Who is required to pay? All health benefit plans oper-ating in the state, including self-insured plans.

Other key provisions:

• The cancer trial must have therapeutic intent,not exclusively testing toxicity or disease patho-physiology.

ONLINE RESOURCES

Protecting the Research Volunteer and EnsuringVoluntary Decision-Making:

Monitoring the Safety of Clinical Trials www.cancer.gov/clinicaltrials/understanding/monitoring-safety-of-trials(Although this website is hosted by the NationalCancer Institute, the information it presents isextremely helpful and applies to non-cancer-relatedresearch as well as cancer-related research).

Informed Consent:

Informed Consent Checklist www.hhs.gov/ohrp/humansubjects/assurance/consentckls.htm

Informed Consent Tips www.hhs.gov/ohrp/humansubjects/guidance/ictips.htm

Informed Consent FAQ’s www.hhs.gov/ohrp/faq.html

Exculpatory Language in Informed ConsentDocuments www.hhs.gov/ohrp/humansubjects/guidance/exculp.htm

Volunteering for a Research Study? Talk to YourDoctor about What You Should Know www.acponline.org/running_practice/ethics

Guide to Understanding Informed Consent www.cancer.gov/clinicaltrials/conducting/informed-consent-guide(Although this website is hosted by the NationalCancer Institute, the information it presents isextremely helpful and applies to non-cancer-relatedresearch as well as cancer-related research).

Should I Enter a Clinical Trial? A Patient ReferenceGuide for Adults with a Serious or Life-ThreateningIllness www.ecri.org/Documents/Clinical_Trials_Patient_Reference_Guide.pdf

Vulnerable Populations:

Childrenwww.hhs.gov/ohrp/researchfaq.html

Prisonerswww.hhs.gov/ohrp/prisonerfaq.html

Pregnant Women and Fetuseswww.hhs.gov/ohrp/faq.html

More on Vulnerable Populationswww.grants.nih.gov/grants/policy/hs/populations.htm

Persons at High Risk for Suicidality www.nimh.nih.gov/health/topics/suicide-prevention/issues-to-consider-in-intervention-research-with-persons-at-high-risk-for-suicidality.shtml

Persons with Impaired Decision-making Abilitieswww.grants.nih.gov/grants/policy/questionablecapacity.htm

Informed Consent from Individuals with ImpairedDecision-making Abilities www.hhs.gov/ohrp/faq.html

Privacy Rights of the Research Volunteer:

Letting Your Personal Health Information be Usedand Shared for Research, NIH publication 05-5613 http://privacyruleandresearch.nih.gov/patients.asp

US Department of Health and Human ServicesOffice for Civil Rights www.hhs.gov/ocr/privacy/psa/complaint/

HIPAA Privacy Rule www.hhs.gov/ocr/hipaa

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APPENDIX C

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ABOUT THE AUTHORSReesa Benkoff, Esquire is an attorney with HallRender Killian Heath & Lyman, PC. Her areas ofpractice include business transactions and service, realestate and construction, and regulatory and compli-ance law. She graduated from the University ofMichigan in 2004 with a degree in BusinessAdministration and received her law degree from theBoston University School of Law, cum laude, in 2007.Ms. Benkoff is a member of the Michigan BarAssociation and the Oakland County Bar Association.

Dawn R. Crumel, Esquire is Senior AssociateCounsel at Children’s National Medical Center inWashington, DC where she provides legal advice onstrategic planning, healthcare regulations, transac-tions, medical research, real estate, contracts, biomed-ical ethics, immigration and general hospital opera-tional issues. Previously, she was in-house counsel inthe Medicaid managed care industry, working atUnitedHealth Group and Centene. In addition, shehas been in-house counsel for the University ofPennsylvania Health System and Howard UniversityMedical Center. She clerked for the New JerseySupreme Court and was a healthcare associate withthe law firm, Buchanan Ingersoll. Ms. Crumel is amember of the American Health Lawyers Associationand was recently appointed Vice Chair in theTeaching Hospital and Academic Medical CentersPractice Group of AHLA. She is former Vice Chair ofthe Health Steering Committee of the District ofColumbia Bar Association and has lectured onbiomedical ethics and medical jurisprudence tomedical, dentistry and nursing students as well asinterns, residents and physicians. Ms. Crumel holds aB.A. in Biomedical Ethics from Brown University anda J.D. from the University of Pennsylvania.

Edward B. Goldman, Esquire is the Associate VicePresident and Deputy General Counsel at theUniversity of Michigan. He also lectures on health lawas an Adjunct Professor at the University of MichiganMedical School and the University of MichiganSchool of Public Health. Mr. Goldman is a well-knownauthor on a number of healthcare topics, includingrefusing treatment, informed consent for treatment,laws for emergency care in neonatal emergencies,privacy issues, genetics, wrongful birth, fetal versusmaternal rights, and medical education. Mr. Goldmanworked on healthcare reform as a member of theWhite House legal audit task force in 1993 and asChair of the Michigan Governors Commission onGenetic Privacy and Progress in 1999. He wasappointed to the State of Michigan Certificate ofNeed Commission in 2001 and elected as Vice Chair

of the Commission in 2005. Mr. Goldman is amember of the Michigan State Bar and serves on theEditorial Board of the Journal of Critical Care. He hasbeen a speaker at the AHLA’s annual AcademicMedical Centers conference. Mr. Goldman graduatedfrom the University of Michigan in 1965 with a degreein Social Science. He is a 1968 graduate of theUniversity of Michigan law school.

Jan L. Hewett, Esquire is Director of the InstitutionalReview Board of the University of Michigan MedicalSchool. She has held various clinical research, grantsmanagement, nursing, and administrative positions atGeorgetown University, the Vincent T. LombardiCancer Center, the Research & TechnologyDevelopment Service, George Washington UniversityMedical Center, and the Henri Beufour Institute. Shealso serves as the Consumer Advocate on the Foodand Drug Administration’s Nonprescription DrugAdvisory Committee. Ms. Hewett holds an R.N.Certification from Royal Prince Alfred Hospital-SydneyUniversity and received her B.S. from GeorgetownUniversity. She received her law degree from theUniversity of Michigan Law School.

Laura E. Loeb, Esquire is a shareholder in King &Spalding LLP’s FDA/Healthcare Practice Group inWashington, D.C. Her main areas of practice areMedicare, Medicaid, and regulatory law. Her clientsinclude academic medical centers, medical devicemanufacturers, pharmaceutical companies, durablemedical equipment suppliers, physician and alliedhealthcare provider associations, and healthcareinsurance companies. During her career, Ms. Loebsuccessfully obtained the passage of groundbreakinglegislation to provide Medicare coverage for newbreast cancer diagnostic tests. She also obtained aletter from the U.S. Department of Health andHuman Services releasing many academic medicalcenters from the Physicians at General TeachingHospitals audits. Additionally, she is a well-knownhealth law writer and speaker. Ms. Loeb graduatedfrom the University of Illinois in 1981 and fromStanford University’s Law School in 1984.

Melissa L. Markey, Esquire is a shareholder withHall Render Killian Heath and Lyman, PC. She islicensed in Texas and Michigan. Ms. Markey leads theLife Sciences team at Hall Render and has a partic-ular interest in emergency preparedness, humansubject research, and technology law, including elec-tronic health records, health information exchange,software licensing, data rights management, and e-commerce issues, as well as patient care issues andcompliance. She is a member of the State Bar ofMichigan, the American Bar Association, and the

American Health Lawyers Association, for which sheis the Chair of the Teaching Hospitals and AcademicMedical Centers practice group. Ms. Markey haspresented and authored publications both withinMichigan and nationally, including articles on clinicalresearch and human subject protection researchmisconduct, emergency preparedness and responselaw, electronic medical records, HIPAA privacy andsecurity, and the clinical-technology interface. Ms.Markey graduated summa cum laude from St. LouisUniversity School of Law and is a Michigan licensedand Nationally Registered Emergency MedicalTechnician-Paramedic with many years of field experi-ence. She is also licensed in Texas.

Rachel Nosowsky, Esquire is Senior Counsel withMiller Canfield in Ann Arbor, MI. She practices in theareas of healthcare, and life sciences and biotech-nology. During her career she has represented hospi-tals, academic medical centers, physician groups, clin-ical laboratories, managed care plans and otherhealthcare providers and payers in a broad range ofhealth law and regulatory compliance matters, inparticular in the areas of corporate governance, ethicsand compliance; medical staff bylaws, credentialingand peer review; physician-hospital relations; andhuman research protection, biospecimen banking,and clinical trials and FDA regulation. She also haswritten and spoken extensively on human researchand health privacy issues and currently serves as Co-

Director of the National Cancer Institute’s caBIG®Data Sharing and Intellectual Capital KnowledgeCenter. Before joining Miller Canfield, Ms. Nosowskyserved as Assistant General Counsel at the Universityof Michigan. She is a graduate of the University ofCalifornia at Berkley Law School where she served asEditor-in-Chief of the Berkeley Journal of Employment andLabor Law.

Lois Snyder, Esquire is Director of the Center forEthics and Professionalism at the American College ofPhysicians, the national professional society of doctorsof internal medicine and the subspecialties of internalmedicine. She has also been Adjunct AssistantProfessor of Bioethics and Fellow of the University ofPennsylvania Center for Bioethics. Before joining theCollege, she was a healthcare consultant on medicalmalpractice, risk management and bioethics issues forhospitals. Ms. Snyder is a frequent writer and speakeron healthcare policy, bioethical and medical-legalissues. She has edited a number of books, includingComplementary and Alternative Medicine: Ethics, the Patient,and the Physician (Humana), The Physician’s Guide toEnd-of-Life Care (ACP Press) and Ethical Choices: CaseStudies for Medical Practice, volumes I and II (ACPPress). Ms. Snyder received her B.A. in health plan-ning and policy from the University of Pennsylvaniaand her law degree from Temple University School of Law.

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ABOUT THE AUTHORS

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