In March 2001, Fred Hutchinson Cancer Research Center (Hutchinson Center or FHCRC) in Seattle undertook a review of its present policies and practices in four areas, in order to assure the community of patient protection in clinical research trials conducted by the Hutchinson Center.
A Committee for Patient Protection in Research Trials (the CPPRT or the Committee) was established by the Center's Board of Trustees to conduct the review.
In conducting the review, the 12-member Committee invited four outside experts to focus on areas which were deemed critical in the area of patient protection: the Patient Informed Consent Process; Institutional Review Boards; Protocol Safety and Data Monitoring; and Conflict of Interest.
The experts, all of whom have national credentials in their area of expertise, studied documentation relative to their subject areas; reviewed files; interviewed staff; met with the Committee; and gave the Committee both oral and written reports.
In their reports, the experts expressed their judgment that the Hutchinson Center is in compliance with government regulations for human subjects research, and that the Center's practices are in conformity with those of other major cancer research centers in the United States. Each of the reports from the experts also identified areas in which either the policies or the practices of the Hutchinson Center could be improved.
In its report to the Hutchinson Center's Board of Trustees, dated September 6, 2001, the Committee for Patient Protection in Research Trials made seven general recommendations and nine specific recommendations.
One major recommendation is that the FHCRC strengthen its Conflict of Interest policy for individuals conducting human subjects trials so as to mandate an outright prohibition of any financial interest in for-profit corporations which may benefit from the results of such trials. In its report, the Committee stated that "a policy of outright prohibition of such interest is an important element in maintaining and enhancing public trust in future clinical trials at the Hutchinson Center."
Among the Committee's general recommendations are that the Hutchinson Center be certain that bio-ethical expertise is available to the Center, and that additional financial resources be allocated to implement several of the recommendations.
The Committee recommends that the Hutchinson Center Board of Trustees and the management actively participate in ongoing national discussions around the topics addressed in the report, and that the Hutchinson Center be in the forefront in implementing the policy changes which may emerge from them.
This section describes the reasons for the Committee's establishment; its purpose, membership and activities; and the general considerations under which it conducted its work.
The conduct of clinical trials has been under scrutiny by regulatory agencies and the media. Research centers across the nation are re-examining their policies and practices in response to evolving requirements with the goal of maintaining the safety of study participants and the integrity of clinical research. The Hutchinson Center sought to undertake a review of its practices in order to assure the community of patient safety in clinical research trials. The Board of Trustees designated a committee of local citizens to oversee a review of the Hutchinson Center's current practices related to patient participation in clinical studies pursuant to the following resolution:
"Whereas, the Executive Committee of the Board of Trustees believes that it is in the best interests of the Center and the community that it serves to ensure that the current practices of the Center regarding the protection of patients involved in research trials conducted at the Center adequately protect the Center's patients in a manner consistent with applicable legal and ethical principles."
"Whereas it is resolved: The Executive Committee hereby authorizes the formation of a Committee for Patient Protection in Research Trials. The Committee is charged with reviewing current practices of the Center relating to the Institutional Review Board, informed consent, monitoring of patient safety during trials, and conflict of interest and financial disclosure. The Committee is authorized and directed to retain such independent experts as they deem appropriate to review and audit the Center's practices and provide legal, scientific and other professional advice to the Committee." (Executive Committee Resolution, March 23, 2001)
The Committee was asked to evaluate reports of independent experts engaged to review the policies and procedures of the Hutchinson Center in regard to these areas: Institutional Review Board (IRB); Informed Consent Process; Protocol Safety and Data Monitoring; and Conflict of Interest and Financial Disclosure. Upon assessment of the reports from the independent experts, the Committee was asked to report on the status of current practices and make recommendations to the Hutchinson Center's Board of Trustees.
Committee MembershipThe Reverend William J. Sullivan, S.J., former President and current Chancellor of Seattle University, was selected to chair the Committee. The Committee Chair in consultation with the Chairman of the Board of Trustees selected members of the Committee on Patient Protection in Research Trials. The Committee is comprised of members of the community, some of whom have had personal experiences with cancer. As patients on Hutchinson Center clinical research protocols receive care at the Seattle Cancer Care Alliance (SCCA), University of Washington Medical Center (UWMC), and Children's Hospital and Regional Medical Center (CHRMC), six of the twelve members of the Committee are board members of one or more of the four organizations.
The Committee members are:
Brief biographical sketches of Committee members can be found in Attachment A.
Committee ActivitiesThe Committee met seven times during the months of April through August. Committee members determined the scope of their work and the organization of their activities during the months of April and May. During this time, members read articles from publications, as well as policies, and regulatory standards for the areas of review. In May, the Committee selected independent experts to conduct a review of the Hutchinson Center's policies and practices. In addition to attending regular committee meetings, members conferred with independent reviewers in six sessions during site visits in the months of May and June. During the months of July and August, the Committee discussed the findings of the reviewers, studied additional documents, and formulated their recommendations to the Hutchinson Center's Board of Trustees.
These points express the perspectives that guided the Committee in its work.
1. The charge from the FHCRC Board of Trustees to the Committee makes clear that the focus of the work of the Committee is on the present policies and procedures which govern research trials on human subjects at the Hutchinson Center. The establishment of the CPPRT and its charge are expressions of the priority that the Hutchinson Center Board gives to the protection of patients involved in its clinical trials now and in the future. The goal of the Committee is to ensure that the Hutchinson Center's leadership in cancer research and in clinical trials will be matched by leadership in the protection of patients.
2. The Committee recognizes that the FHCRC is essentially a scientific research center doing its work over a wide range of disciplines: basic sciences, public health sciences, clinical research, and the interdisciplinary studies of human biology. But the particular focus from which the Committee studied the Center is that of the protection of patients in clinical trials. While clinical trials are only a part of the overall work of the Hutchinson Center, the protection of patients in these trials is of the highest concern to the FHCRC Board and the essential concern of the Committee.
3. The culture of patient protection is at the heart of the four topics which we have studied. The issue of patient protection is, at its very root, an ethical question -- not simply a legal or scientific question. It is the key priority for the Committee and for the Hutchinson Center.
4. The credibility of this study and of its recommendations is enhanced by the nationally-recognized expertise of the outside reviewers whom the Committee selected. The credentials of these experts and the method by which they were chosen are described in Section II of this report.
5. From the beginning, the Committee recognized the critical importance of its independence from the administration of the Hutchinson Center. The Committee's independence was guaranteed by the Hutchinson Center Board and was exercised by the Committee. This applied to the selection of the Committee members; the selection of outside experts to perform the reviews in the selected areas; the work plans of the reviewers; and the composition and contents of this report.
6. At the present time there is an active national discussion about policies and practices relating to human subject research. There are indications of possible changes in government regulations relative to such research. The Hutchinson Center, like every cancer research institution, must be prepared for such changes.
7. The Committee is grateful for the wholehearted support of the Hutchinson Center Board of Trustees for its efforts and the unqualified cooperation of the administration and staff of the Center. It is our hope that this report will aid the FHCRC in its ongoing effort to improve its service in the fight against cancer, and ensure maximum patient protection in all of the work being done at the FHCRC.
This section describes the selection of independent experts to review the Hutchinson Center policies and procedures; the reviewers' activities; and the reviewers' reports, conclusions and recommendations in the four areas deemed critical in the area of patient protection: Institutional Review Boards; the Patient Informed Consent Process; Protocol Safety and Data Monitoring; and Conflict of Interest and Financial Disclosure.
The Committee was charged with overseeing the work of the independent reviewers of Hutchinson Center policies and practices. The Committee selected the independent experts to conduct the reviews. As part of the selection process, the Committee evaluated the curriculum vitae of prospective reviewers for relevant expertise and work experience. The Committee had references checked, and verified that no consultant had a conflict of interest in participating in a review of the Hutchinson Center. In its selection process, the Committee reviewed proposed work plans and time lines submitted by the prospective reviewers.
The Committee selected an outside expert or expert team for each area of evaluation. Each reviewer was asked to examine the present status of policies and procedures at the Hutchinson Center in their area of expertise.
Reviewers: Institutional Review Board and Informed Consent ProcessErnest Prentice, Ph.D. Associate Vice Chancellor for Academic Affairs and Regulatory Compliance, University of Nebraska Medical Center, Omaha, Nebraska
Gwenn Oki, M.P.H. Director, Research Subjects Protection, City of Hope National Medical Center and Beckman Research Institute, Duarte, California
Reviewer: Protocol Safety and Data MonitoringJames Boyett, Ph.D. Chair, Biostatistics, St. Jude's Children's Research Hospital, Memphis, Tennessee
Reviewer: Conflict of Interest and Financial DisclosureMargaret Dale, J.D. Director of the Office for Research Issues, Harvard Medical School, Boston, Massachusetts
Reviewer ActivitiesEach reviewer or team of reviewers was asked to respond to several specific questions posed by the Committee.
Each reviewer or reviewer team conducted a detailed evaluation of Hutchinson Center policies and procedures, files, and data. The reviewers defined the materials for their evaluations, based on work plans approved by the Committee. The reviewers were provided free access to information and staff of the Hutchinson Center.
In addition to evaluating written materials, each reviewer team conducted a site visit. During the two-day or three-day session, the independent reviewers inspected additional documents and interviewed a number of Hutchinson Center staff.
Site visits included meetings with reviewers and members of the Committee. Reviewers conducted informal de-briefings at the end of the site visits, and followed up with written reports for the Committee.
The reviewer reports are included in the Committee report. They are attached as follows:
Scientific research has produced substantial social benefits. It has also posed some troubling ethical questions. At the conclusion of World War II, during the Nuremburg War Crime Trials, the Nuremburg code was drafted as a set of standards for judging those involved in reported abuses of human subjects in biomedical experiments. This code became the prototype of later codes designed to ensure the protection of human subjects in research. On July 12, 1974, the National Research Act established the existence of Institutional Review Boards to review biomedical and behavioral research involving human subjects. In March of 1983, the current federal regulations detailing the basic Health and Human Services Policy for the protection of human research subjects were adopted; they were updated August 19, 1991. These regulations, known as Title 45, Public Welfare, Part 46, detail more comprehensively the duties and responsibilities of Institutional Review Boards (IRB).
The Hutchinson Center has two IRB committees that review all research activities, or protocols, involving human subjects that are proposed by staff for use at the Center. The IRB is also responsible for review of amendments and/or revisions to on-going, approved activities.
IRB review of research activities involving human subjects ensures that ethical standards for the care and protection of human subjects have been established, and that research activities are in compliance with all pertinent regulations (federal, state and local) and with Hutchinson Center policies. The term "human subjects" may include patients, outpatients, donors of organs, tissues and services, informants and normal volunteers, including students, who are placed at risk during training.
The IRB approves research based on the determination that the following requirements have been satisfied:
The report from the independent reviewers, Dr. Ernest Prentice and Ms. Gwenn Oki, includes the following topics:
Dr. Prentice and Ms. Oki conclude that the research currently being conducted at the Hutchinson Center is in compliance with Health and Human Services (HHS) and Food and Drug Administration (FDA) regulations for the protection of human subjects, as well as with applicable state regulations. In comparison with standards at other cancer research centers in the United States, the operation and management of the FHCRC IRB is in conformity.
"… we would like to offer the following conclusions based on our site visit and reflected in the contents of this review letter: (1) Research conducted at FHCRC is in compliance with HHS and FDA regulations for the protection of human subjects and applicable state regulations. (2) The operation and management of FHCRC's IRBs conform to the standards of practice at other cancer research centers in the U.S." (Attachment B, Page 16)
The consultants also said:
"In our opinion, the FHCRC has the awareness and commitment to respond to any new regulatory requirements or emerging practice standards involving human subject protection." (Attachment B, Page 16)
Expert RecommendationsWhile clear in their judgment that the Hutchinson Center is in compliance with government regulations and in conformity with policies and practices of other major cancer research centers, Dr. Prentice and Ms. Oki offer a number of recommendations to improve the protection of research subjects, set forth in Attachment B.
The Committee advises that the recommendations in the Prentice/Oki report be given full consideration by the Hutchinson Center for implementation, but with special emphasis, in terms of prioritization, on the following:
1. Increase the Institutional Research Office staffing levels by 2.0 FTE's to achieve 100 - 200 protocols per FTE. This will allow more extensive pre-review of protocols before an IRB meeting. Such pre-review will enhance efficiency during meeting time; increase coordination of training time and support for investigators and IRB members; and accelerate the incorporation of regulatory changes. (Attachment B, Pages 7 and 8)
2. Appoint a senior IRB administrator to the IRB as a voting member in order that he or she have signatory authority, thus reducing the workload of the IRB chairmen. (Attachment B, Page 7)
3. Recognize and support IRB member service in the best interest of the institution and the patients it serves. (Attachment B, Pages 6 and 7)
4. Develop criteria for referral of internal and external adverse events for full IRB review. In addition, develop a mechanism that coordinates an institutional review of internal adverse events between the IRB, the Protocol and Data Monitoring Committee (PDMC) and the Data Safety Monitoring Boards (DSMB). (Attachment B, Pages 10 and 11)
5. Ensure and document that a protocol reviewed by the expedited method clearly meets the criteria for minimal risk and the eligibility category specified in the Federal Register. (Attachment B, Page 9)
6. Develop and document criteria for referring protocol amendments to the IRB for full review. (Attachment B, Page 10)
7. Develop and document criteria for determining appropriate frequency of continuing review, since certain protocols may require more frequent than annual review. (Attachment B, Page 9)
Note: The Committee calls attention to its disagreement with item # 23 of the Prentice/Oki report (Attachment B, Page 15). This is discussed below in the Committee's Specific Recommendations (Page 28, item d).
The Hutchinson Center's informed consent process is an interactive process that provides patients with ongoing explanations and supports patients in making educated decisions about their participation in a clinical research trial. Thus, the process of informed consent involves multiple conferences between Hutchinson Center physicians and prospective participants in a trial. During a series of meetings, the information discussed includes the purpose of the trial, description of the procedures of the study, risks and potential benefits to the patient, treatment options, and a review of the rights of patients as study participants. In addition, the physician provides patients with continuing updates on new information about trials. The updates are focused on information that could affect the participants' health, welfare, or willingness to remain in a study.
Informed consent is a process that uses documents that serve as information resources for patients as they go through the course of treatment. The informed consent documents are reviewed and approved by the IRB as part of its review of clinical research activities. Prior to treatment based on a trial, patients must sign consent forms. In many cases, patients are enrolled on various research studies in addition to their primary treatment protocol. A signed consent form is required for each clinical trial.
The steps in the informed consent process are as follows:
1. Consultation between the patient and a physician with specialization in the relevant disease process or anticipated treatment procedures. The consultation may include review and discussion of the following:
2. Arrival conference between the patient, family and the attending physician. A history is taken and a physical examination is performed. The patient and physician discuss:
3. A multidisciplinary evaluation of the patient is conducted over the next ten days. This evaluation includes:
4. Each patient's case is presented to a weekly clinical team meeting. A team reviews each patient's eligibility for enrollment in the recommended treatment trial.
5. A data review conference is held between the patient, family, primary nurse and attending physician. During this conference, the following is presented and reviewed:
Dr. Prentice and Ms. Oki reviewed the process and documents related to the Patient Informed Consent Process at the Hutchinson Center. The team evaluated IRB committee minutes, the files and records of the Institutional Review Office and of principal investigators, and informed consent forms. In addition, Dr. Prentice and Ms. Oki based their evaluation of the Informed Consent Process on interviews with staff, investigators, physicians, patients and their family members who participated in the process of informed consent.
Patient/Family Session on Informed Consent
Dr. Prentice and Ms. Oki met with ten patients and family members in a group session in which the focus of discussion was on the process of consent. The patients and family members were invited to participate in this group by the social workers of the Seattle Cancer Care Alliance, the clinic where patients on Hutchinson Center studies receive their outpatient care. The social workers were non-selective about which individuals were approached, attempting only to include both adults and parents of pediatric patients, local as well as non-local patients, and to create a group of five to ten individuals with personal experience in the informed consent process. The identities of the participants were to remain confidential in order to maintain their privacy and to create a group environment in which the participants could speak freely with the reviewers.
The reviewers were particularly impressed with their interaction with ten individuals who were representative of FHCRC research participants. Their summary statement of this meeting was:
"All of the individuals who participated in the focus group appeared to be well educated and knowledgeable about the cancer treatments. Every individual enthusiastically complimented FHCRC physicians and staff for their caring attitude and responsiveness to any problems, questions or concerns which arose." (Attachment B, Page 14)
Conclusions of the Expert ReportThe reviewers' judgment is that the Informed Consent Process is in compliance with Health and Human Services regulations. They state:
"Indeed, investigators at FHCRC go to great lengths to ensure a valid informed consent process that often involves multiple conferences with the prospective subject and family members. The aforementioned finding was further verified during our meeting with the Patient/Family Focus Group which is discussed in section 21 of this report." (Attachment B, Page 12)
Dr. Prentice's and Ms. Oki's general conclusion to their reviews of the IRB and Patient Informed Consent Processes was quoted above (Page 11). It is cited again here:
"… we would like to offer the following conclusions based on our site visit and reflected in the contents of this review letter: (1) Research conducted at FHCRC is in compliance with HHS and FDA regulations for the protection of human subjects and applicable state regulations. (2) The operation and management of FHCRC's IRBs conform to the standards of practice at other cancer research centers in the U.S. In our opinion, FHCRC has the awareness and commitment to respond to any new regulatory requirements or emerging practice standards involving human subjects protection." (Attachment B, Page 16)
Expert Recommendations1. The reviewers recommend proper recognition for those involved in the complicated Patient Informed Consent Process as a means of signifying the importance of that work. (Attachment B, page 6)
2. The Consultants strongly recommend a simplification of the Informed Consent documentation and also recommend several record-keeping adjustments. (Attachment B, Pages 12, 13, and 14)
The Hutchinson Center, as a National Cancer Institute (NCI) Comprehensive Cancer Center, has in place a protocol review and monitoring system. The key components are the Clinical Investigator's Meeting, which provides an open forum for presentation and discussion of proposed clinical protocols; the Scientific Review Committee, which formulates formal internal review of all protocols and general scientific oversight of clinical research; and the Protocol Data Monitoring Committee, which monitors the progress of ongoing research protocols. Data and safety monitoring are carried out under the umbrella of these committees in cooperation with the Institutional Review Board (IRB).
All Hutchinson Center protocols must incorporate a safety monitoring plan in their design that is consistent with the potential risks and scale of the trial. Depending on the type of trial, the plan might include: dose-limiting toxicities, criteria for stopping the trial, stopping rules for prospectively defined undesirable events, creation of an independent Data Safety and Monitoring Board to review safety and other data. All protocols must include a section that specifies the procedures and conditions for the reporting of adverse events to the IRB.
Every protocol goes through multiple levels of review, as outlined below.
Dr. James Boyett submitted his report in the form of a nine-page letter to the Committee (Attachment C). The first three pages summarize his findings and the rest of the letter provides more detail on his specific recommendations for improvement. Dr. Boyett spent two days in the offices of the Hutchinson Center on May 30 and 31, 2001. He conducted extensive interviews with various members of the staff of the facility; held an exit briefing with the Committee and staff; and held an executive session with the Committee only. His specific itinerary is attached to his report.
All clinical trials require monitoring and this monitoring should be commensurate with the risks involved. Dr. Boyett was engaged to review the protocols at the FHCRC used to monitor data and safety in its clinical trials. The National Institute of Health provides the guidance for the protocols.
Conclusions of the Expert ReportDr. Boyett's conclusions are, in part, as follows (Attachment C, Summary, Pages 1 and 2):
One of Dr. Boyett's charges was to give the Committee his views on areas of weakness or suggestions for improvement. He stated that his suggestions "… are offered in the context that the FHCRC is compliant with federal regulations and operates consistent with current industry standards for NCI funded cancer centers. These recommendations are made with the intent of improving the infrastructure supporting the staff in the conduct of clinical research." (Attachment C, Report, Page 1)
Dr. Boyett's suggestions are outlined in his report. The following recommendations for improvement are those the Committee considered of higher priority:
Management of conflicts of interest involving persons responsible for the design, conduct or reporting of research conducted at the Hutchinson Center is governed by the Conflict of Interest Policy and its Policy and Guidelines for Involvement with Outside Interests. These policies were originally adopted in 1983 and underwent substantial modifications in 1996 to make them consistent with NIH's Policy on Objectivity in Research.
1. Conflict of Interest Policy
The Conflict of Interest Policy applies to all Center representatives, including scientific staff, visiting investigators, employees, trainees, affiliates, officers and trustees. In general, this policy restricts Center representatives from participating in transactions involving Hutchinson Center if 1) the representative or a family member has or receives a significant economic interest; or 2) the transaction involves a business entity in which the representative or a family member has or receives a significant economic interest or a business entity of which the representative or a family member is a trustee, director or officer.
If there is a conflict, the transaction must first be reviewed and approved in accordance with applicable Hutchinson Center policies to ensure that the conflict is properly managed, reduced or eliminated. The definition of significant economic interest tracks the definition in the NIH Policy on Objectivity in Research and includes essentially anything of monetary value except the following: a) salary, royalties or other remuneration from FHCRC; b) income from seminars, lectures, or teaching engagements sponsored by public entities or nonprofit entities; c) income from service on advisory committees or review panels for public or nonprofit entities; d) an equity interest that when aggregated for the representative and the representative's family members, meets both of the following tests: (1) does not exceed $10,000 in value as determined through reference to public prices or other reasonable measures of fair market value, and (2) does not represent more than a five percent ownership interest in any single entity; or e) salary, royalties or other payments that when aggregated for the representative and the representative's spouse and family members over the next twelve months, are not expected to exceed $10,000.
2. Policy and Guidelines for Involvement with Outside Interests
The Policy and Guidelines for Involvement with Outside Interests contains more detailed procedures for managing the involvement with outside interests of FHCRC scientific staff and other employees who are responsible for the design, conduct or reporting of research. This policy requires management, reduction or elimination of any conflict of interest involving a significant economic interest of a person subject to the policy which reasonably appears to be directly and significantly affected by research being performed at FHCRC.
3. Division Policies
Persons in the Clinical Research Division who have a significant economic interest in an outside entity (1) may not be the principal investigator of a clinical trial sponsored by an outside entity or evaluating products of that entity, (2) may not consent patients for any such trial, (3) may not recruit patients to such a trial and (4) may not evaluate responses of patients treated on such a trial.
Reporting Requirements
Members of the scientific staff and others responsible for the design, conduct or reporting of research at the Center report at four different times concerning possible conflict situations:
Review Procedure
If at any point a significant economic interest is identified, the person with the interest meets with the director of the Division in which that person holds his or her primary appointment. After discussing the matter, the Division Director determines whether or not the interest could directly and significantly affect or be affected by any research that the person with the interest is involved in at the Center. If it is determined that there is a significant and direct effect, a written conflict management plan is developed with appropriate input and assistance from the General Counsel. The final conflict management plan is submitted to the Center Director for approval.
The conflict management plan may impose conditions or restrictions on the conduct of the research including a) public disclosure of significant economic interests; b) monitoring of research by independent reviewers; c) modification of the research plan; d) disqualification from participation in all or a portion of the research by that person; e) divestiture of the significant economic interest; or f) severance of the relationship that creates the conflict. Generally, conflict management plans have required either independent review by scientists without a conflict and/or a disclosure of the conflict in any publication concerning the study.
Overview of the Expert ReportMargaret Dale, J.D., Associate Dean for Faculty Affairs, Harvard Medical School, was selected because of her hands-on experience at a prestigious institution as Director of the Office for Research Issues.
Ms. Dale's pre-site visit preparation and scope of review are detailed in her report (Attachment D). It should be noted that prior to her visit, Ms. Dale also reviewed the policies of the Dana-Farber Cancer Institute, the Harvard Medical School, the Duke School of Medicine, the Fox Chase Cancer Center, the Johns Hopkins School of Medicine, the Memorial Sloan-Kettering Cancer Center, the M.D. Anderson Cancer Center, the Stanford University School of Medicine, and the University of Washington.
Ms. Dale notes that:
1. Only in the past few years have the topics of conflicts of interest and financial disclosure received proper attention; 2. There are a range of policies and practices in the area of conflict of interest and there is no consistent "industry standard."
Conclusions of the Expert ReportMs. Dale concludes that with regard to compliance with current federal regulations and with regard to peer institutions:
"… The Center's conflict of interest policies and procedures generally meet the requirements of the regulations." And "While there are improvements that might be made… the Center's policies are well within the range of policies…in peer cancer research centers and universities." [emphasis added] (Attachment D, Pages 1 and 2)
With regards to meeting peer standards of practice, Ms. Dale concludes that the Center falls within the range of practices and is consistent with the only federal guideline. Ms. Dale points out that the spectrum of practices within research institutions and universities ranges from the more proscriptive policies (allowing no conflicts) on one end to the more discretionary policies (allowing financial interests but emphasizing disclosure and management of the same) at the other end.
The Hutchinson Center's policies provide four primary areas of disclosure by the investigator. Ms. Dale points out that, under current guidance, adequate disclosure is made of financial interests of the investigators.
With regard to institutional conflicts and disclosure, there was little review. It was determined by the Committee that there was even less direction on a national level and little guidance from peer institutions. The Committee believes this to be an important area and Ms. Dale refers to this as an area to be watched.
Expert RecommendationsThe Dale report offers twelve recommendations for consideration. It must be noted that Dale's recommendations are set within the framework of a new policy of "Disclosure and Management." In light of the Committee's own recommendations for a new policy of "Outright Prohibition," these recommendations would be moot, if the FHCRC Board should adopt such a policy. For the record, Ms. Dale's major recommendations include the following:
This section lists the Committee's seven general recommendations and nine specific recommendations to the FHCRC Board of Trustees, and presents the Committee's conclusions.
a. The Committee recommends that the Hutchinson Center Board establish a Standing Committee of the Board to work with the Center administration in the review and the appropriate implementation of these recommendations. This Standing Committee would also oversee compliance with all policies relating to the protection of human subjects.
b. The Committee commends to the FHCRC Standing Committee and to the administration a careful study of all the recommendations included in the reports of the outside experts. It is to be noted that the Committee disagreed with one of the recommendations of the Prentice/Oki report (Attachment B, Page 15, item 23), as discussed in the Specific Recommendations outlined below (Page 28, item d). Also, the recommendations in the Dale report would be rendered moot if the Board opted to establish a new conflict of interest policy based on the approach of "outright prohibition" as recommended under Specific Recommendations of this report (Section III A, Page 28).
c. The Committee recommends that the Board allocate additional financial resources to the areas where such resources are necessary for the implementation of several of these recommendations, for example, additional staffing in support of the IRB process.
d. The Committee recommends that the Board arrange for a return visit to the Hutchinson Center, at an interval of one year, by those outside experts who contributed to this report. In doing so it would seek their evaluation of the progress that the Center has made relative to these recommendations for improvement.
e. The Committee recommends that careful attention be given to the availability of additional expertise in the area of bioethics. Any institution engaged in human subjects research should have experts to assist the IRB deliberations and to advise on other aspects of its clinical trials work.
f. The Committee recommends that the Board and the Center give careful attention to the ongoing national discussion around the four topics addressed in this report. Leadership at the Center should participate actively in these discussions; the Hutchinson Center should be in the forefront of implementing the policy changes which may emerge from them.
g. The Committee recommends and expects that the FHCRC Board publish this report and the reports of the outside experts.
2. Specific Recommendationsa. A major recommendation of this Committee is that the Center strengthen its Conflict of Interest policy so as to mandate an outright prohibition on the part of individuals involved in human subject trials of any financial interest in for-profit corporations which may benefit from the result of such trials. The Committee believes that a policy of outright prohibition of such interest is an important element in maintaining and enhancing public trust in future clinical trials work at the Hutchinson Center. The Committee has not attempted to draft a revised Conflict of Interest policy in detail. This is the responsibility of the Board. This recommendation suggests the goal of an orderly transition to a new policy.
b. The issue of Conflict of Interest as it applies to the institution itself, i.e., the FHCRC, is a subject of ongoing national discussion. The Hutchinson Center must be actively involved in that discussion as it relates to clinical trials. Since the benefits of collaboration with the for-profit sector are recognized, guidelines for grants from the for-profit sector to the institution must be developed for the present and for the future.
c. In the Committee's judgment, a culture which supports such a Conflict of Interest policy is of great importance. All those involved in the work of the Hutchinson Center must understand and support the values which ground such a prohibition of personal financial interest.
d. The Committee recommends that as part of the Patient Informed Consent Process, there be full disclosure to a prospective participant in clinical trials of any financial interest, apparent financial interest, or the absence thereof on the part of the investigators, Center administrators or staff, or the Center itself. In making this recommendation, the Committee strongly disagrees with the recommendation in the Prentice/Oki report that financial conflict of interest information should not be given to a patient (Attachment B, Page 15, item 23).
e. The Committee recommends that those responsible for the Patient Informed Consent Process be sensitive to the cultural, racial and language differences which might impede the patient's understanding of the nature and the risk of the protocol. The Committee also recommends continued careful attention to the Hutchinson Center's practices of including children of an age of understanding, as well as their parents, in the Patient Informed Consent Process.
f. The Committee believes that protocol compliance and the integrity of the data developed in trials and reviews are of the utmost importance. These must regularly be tested for accuracy by auditors who are independent of the investigators and staff conducting the research and collecting the data. Adequate resources must be allocated for these purposes.
g. Because of the complexity and the continuing evolution of the various government and professional regulations regarding patient protection, the Committee recommends the establishment of a central office to monitor these regulations and compliance with them at the Center. This "Office of Regulatory Affairs" should report to the director of the Center and should give annual reports to the FHCRC Board.
h. The Committee recommends that the Hutchinson Center use appropriate means to encourage participation by all qualified employees in the work of the IRBs and in the Patient Informed Consent Process. Such work must receive proper recognition as a means of signifying the importance of this work.
i. The Committee recommends simplification of the Patient Informed Consent documents and continued efforts to improve the process. Efforts should be made to reduce the number of documents which a patient is required to sign.
The Committee was charged by the Board of Trustees with examining the Hutchinson Center's current policies and practices dealing with human subject research. The work of the Committee focused on four areas which are deemed critical in the area of patient protection:
With the submission of this report, the Committee completes its work on the charge given to it by the Board.
In pursuing its work, the Committee invited the participation of four outside experts. These individuals, who have national credentials in the areas they were asked to examine, studied documentation relative to their subjects; visited the Center personally; met with the Center staff and with the Committee; and gave the Committee both oral and written reports.
The Committee's work yielded three major results:
The Committee also recommends that the Hutchinson Center should lead by:
The conclusion that the Hutchinson Center is in compliance with regulatory requirements and in conformity with the standards of practice of its peer centers, and the suggestions for areas of improvement are equally important in the judgment of this Committee.
As the Committee submits this report to the Hutchinson Center Board of Trustees, the responsibility for the implementation of any of these recommendations lies with the Board of Trustees and with the management of the Center.
Attachment A. Committee Membership- Committee for Patient Protection in Research Trials
(PDF, 275K)
Attachment B. Reviewer Report on Institutional Review Board and Informed Consent Process
(PDF, 1220K)
Attachment C. Reviewer Report on Protocol Safety and Data Monitoring (PDF, 767K)
Attachment D. Reviewer Report on Conflict of Interest and Financial Disclosure (PDF, 1128K)
Reviewers' biographies
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