|
and the risks of the exercise stress. If the investigational protocol requires withholding of patient medication, this too should be listed as a risk.
The subject should be made aware of any benefits to the subject or to others that might reasonably be expected from the research. The description of benefits to the subject should not be overstated, and if no direct benefit is anticipated, this should be noted. Both direct benefits and indirect benefits should be listed. Examples of indirect benefits include more complete medical attention, additional monitoring, or tests or drugs at no charge. Sponsors and investigators must be aware, however, that benefits listed in the consent form may create binding contractual obligations. If the subject will be paid, the consent form should specify the amount and terms of compensation. Payment of research subjects for time and inconvenience, although not for pain or risk, is permissible so long as the amount of payment and the terms are not coercive.
Informed consent requires that any appropriate alternative procedures or forms of treatment that might be advantageous to the subject be made known to the subject. Although not every risk and benefit of every alternative treatment need be listed in the written consent documents, the person obtaining consent should be able to discuss alternatives and answer questions about them. Where either the patient’s condition or the study design does not involve alternative treatment, including the alternative not to participate in the study is appropriate.
Study subjects should be informed of the extent, if any, to which confidentiality of records identifying subjects will be maintained. They should be informed that the FDA is entitled to inspect study records including medical charts of study participants. If the sponsor or others have access to study records, this should be stated. At the option of the IRB, the consent document may state that subject names are not routinely required to be divulged to the FDA. When the FDA does require subject names, the agency will treat the information as confidential, but on rare occasions disclosure to third parties may be required under court order or on request of a congressional committee. Thus absolute protection of confidentiality cannot be promised or implied. Under the new HIPAA medical privacy laws in the United States, written volunteer approval for all foreseeable uses of their medical data has become even more important.
If the research involves more than minimal risk, the subject should be informed whether any compensation or medical treatment will be provided in case of injury. FDA regulations do not require compensation for research injury; it is left to sponsors, institutions, and investigators to decide what, if any, compensation to offer. They need to be aware that this portion of the consent form may create significant contractual obligations. The type and extent of compensation and conditions for eligibility should therefore be stated with care. If no compensation is available, this should be stated.
In the United States informed consent documents frequently provide for free medical treatment for injury incurred as a result of a subject’s participation in a sponsored clinical trial. Many sponsors specifically choose to ask volunteers to waive claims for additional financial compensation for lost wages, disability, or discomfort (“pain and suffering”) that may occur as a result of their participation in a study. The legality of such waivers, freely consented to in a properly documented process of informed consent, has been generally upheld.
The consent form must contain the names, addresses, and telephone numbers of contacts for questions about the research, questions about research subject rights, and questions about research-related injury. Note that these are three separate requirements. Frequently the principal investigator or research coordinator will serve as the contact for questions about the research or in the event of research injury, but it is best if someone not associated with the research serves as the contact for questions about research subject rights. The form should also include the name of the IRB that approved the research and the consent form.
The consent form must include a statement that participation in the research is voluntary, that refusal to participate will involve no penalty or loss of benefit to which the subject is otherwise entitled, and that the subject may discontinue participation at any time. Language limiting a subject’s right to withdraw from a study is not permitted, although the subject may be warned of particular risks of withdrawal. Excessive payment for study completion is not allowed.
Several additional elements of informed consent should be included when appropriate. If the study includes unforeseen risks to the subject or to the fetus or embryo, this should be stated. If measures to prevent pregnancy should be taken while subjects are in the study, the need for contraception or sexual abstinence should be explained. These requirements have assumed greater relevance since the issuance of FDA guidance on the inclusion of women in childbearing years in clinical trials.42
Anticipated circumstances under which the subject’s participation may be terminated by the investigator without regard to the subject’s consent should be explained. Any additional costs to the subject that may result from participation in the research should be listed. When withdrawal from the research study may have deleterious effects on the subject’s health or welfare, procedures for orderly termination of participation should be described. If it is anticipated that significant new findings that would be pertinent to a subject’s continued participation in the study are likely to emerge during the course of a study, the consent should include a statement that such findings will be made known to the subject. Where the number of subjects in the study is material to the subject’s decision to participate, the approximate number of subjects in the study should be disclosed.
Research involving children and adolescents presents special concerns.43 In the case of older children able to understand the research, many ethicists believe that the assent of the child and the consent of the parent or guardian should be required. The DHSS version of the Common Rule includes specific additional protections for children involved as subjects in research.44 FDA regulations do not specifically address this issue, but the agency has expressed an opinion that IRBs should consider whether to require the assent of older children before their enrollment in a research study. This can be accomplished either by developing a second, simplified consent form understandable by the child or by including a section for the child’s assent in the standard consent form.
The clinical investigator is responsible for ensuring that informed consent is obtained from each research subject before the subject participates in the research study. Although an investigator may discuss a study with a prospective subject without first obtaining consent, informed consent must be obtained before any screening procedure that is performed solely for the purpose of determining study eligibility is initiated. In some cases the IRB may find it appropriate to limit the scope of the screening consent to a description of the screening tests and a brief summary description of the research study.
The FDA does not require the investigator to personally obtain the informed consent, but the investigator remains ultimately responsible that it is properly obtained. The subject or the subject’s legal representative must sign and date the consent, with the dated signature permitting verification that consent was obtained prospectively. A subject’s consent obtained after a procedure, legally termed ratification, may protect a physician from malpractice liability for failure to obtain consent but does not fulfill regulatory requirements.45 A copy of the consent document must be provided to the subject, and the investigator should retain the signed consent document in the study records.
FDA REPORTING
Investigators are required by FDA regulation to report all adverse experiences with drugs or devices occurring during the course of a study to the sponsor. For serious and unexpected adverse experiences for drugs, investigators must report these promptly to the sponsor and to the reviewing IRB. Device investigators must report any unanticipated adverse device effects to their sponsor and IRB as soon as possible but not later than 10 working days after the investigator first learned of them. A serious adverse experience is any experience that is fatal or life-threatening, is permanently disabling, requires inpatient hospitalization, or is a congenital anomaly, cancer, or overdose. An unexpected adverse experience is any adverse experience that is not identified in nature, severity, or frequency in the current investigator brochure. An unanticipated adverse device effect is one that is serious or life-threatening and not previously identified in the investigational plan. Generally, sponsors request that investigators report all adverse experiences to them even if, in the judgment of the investigator, the experience is unrelated to the study drug or device.
LOCAL LAWS
The federal Common Rule and FDA regulations do not preclude state and local laws governing the conduct of human subject research that are stricter or provide additional protection for subjects. Thus malpractice law applies to the subject and investigator who share a doctor-patient relationship. In addition, the investigator-subject relationship creates a fiduciary duty flowing from the investigator to the subject. This relationship is governed by principles of tort law and by applicable statutes. One consequence of this relationship is a duty on the part of the investigator to be responsible for or bring to the subject’s attention medical information about the subject such as incidentally discovered laboratory abnormalities discovered in the course of research. An example of the seriousness of the investigator-subject relationship is a California law that creates civil and criminal liability including imprisonment for an investigator who willfully fails to obtain consent of a subject who is thereby exposed to a known substantial risk of serious injury.46
Based on these concerns the prudent investigator will review his or her malpractice insurance for coverage of incidents arising as a result of research, whether brought on a theory of medical malpractice or violation of investigator duties. The investigator should also carefully review and negotiate any indemnification provisions in agreements with research sponsors and be aware that unauthorized protocol changes may void indemnification provisions, subjecting the investigator to great personal liability.
PROTECTION OF RESEARCH DATA INTEGRITY
Protection of data integrity is a key component of the principal of “regard for the truth.” The topic of research data integrity encompasses a variety of regulations and procedures designed to ensure the scientific value, accuracy, authenticity, and credibility of research data. It encompasses study design, execution, monitoring, and oversight. The study sponsor, monitor, clinical investigators, IRB, research institution, and regulatory oversight agencies all play important roles. Of these, the clinical investigator, defined as an individual who actually conducts a clinical investigation, is central. Investigators can and often do delegate some of the work involved; such delegation does not relieve the investigator of ultimate responsibility for the study.
Investigators are required to maintain adequate accurate case histories for all subjects including control groups. These primary records, whether first recorded on paper or electronically, are referred to as source documents. The investigator must maintain these source documents even if the sponsor retains the same records. Data should be attributable, original, accurate, contemporaneous, and legible. If hospital records are used, the prudent investigator will keep copies of pertinent sections. Any individual entering information in source documents should sign and date all entries. Proposed regulations relating to electronic data entry would require password-protected access and time stamping of source data forms.47
The investigator must account for study articles. This includes a requirement to maintain records indicating the receipt, dispensing, and final disposition of study drugs and devices. Study articles should not be transferred from one investigative site to another unless authorized by the sponsor and must not be used outside the study setting.
Data from source documents are transferred to case report forms that are submitted to and retained by the study sponsor. Case report forms should include the study identification, sponsor name, date of each visit by each subject, and a record of procedures and tests ordered or completed at each visit including results. In addition, any concomitant medications used by the subject, any adverse experience, a notation that the study article was dispensed, and information regarding any protocol-directed procedures and work done or omitted should be included.
In addition to source documents and inventory accounting records, investigators should retain consent forms, copies of all correspondence related to the study, and a copy of the study protocol. FDA regulations require that clinical investigators retain records for at least 2 years after either final FDA action on the marketing applications supported by the study or discontinuation of the study by the sponsor and notification of the FDA that an application will not be submitted. Note that this 2-year period begins based on action by the FDA and/or the sponsor and is not based on withdrawal of the particular investigator from the study. Investigators should therefore insist that their clinical investigation agreement include a provision requiring the sponsor to notify the investigator of these events.
Even if a hospital or clinic keeps the records, the investigator must still ensure that the records are retained for the required time. Investigators and sponsors may transfer custody of records to any other person who will accept responsibility for them including the requirement of making them available to the FDA. Whenever records are transferred, the FDA must be notified within 10 working days.48
FDA regulations require that clinical investigators in drug studies provide sponsors with progress reports on ongoing studies, safety reports after any adverse effects that the investigator thinks might be associated with the drug being tested, and a final report submitted shortly after completion of each study. In addition, investigators must report to their IRB any changes in research activity and all unanticipated problems in the study that could present a risk to subjects. Device investigators are bound by similar, although not identical, requirements to submit specified reports to sponsors, monitors, IRBs, and the FDA.49
To help ensure the integrity of primary laboratory data, the FDA requires that biologic samples be tested only in an accredited laboratory. The investigator must retain a copy of the accreditation of laboratories used in the study. The accreditation must be current for the length of the study and should be checked periodically.
FDA regulations require that a sponsor monitor the progress of a clinical investigation. The monitoring function may be performed by the sponsor’s own employees or may be delegated to a contract research organization.50 Monitoring should be carried out by appropriately trained and qualified individuals using established written procedures. Proper monitoring is necessary to ensure adequate protection of the rights of human subjects, the safety of subjects, and the quality and integrity of the resulting data.
In contrast to the high-level oversight function provided by the IRB, the monitor performs a detailed on-site training and auditing function. Typically this is carried out during preinvestigation visits, study initiation visits, periodic visits, and final closeout visits. During the preinvestigation visit the monitor should ascertain that each investigator clearly understands and accepts the obligations incurred in undertaking the clinical investigation and has adequate resources and time to devote to it.
A study initiation visit is typically carried out after all preliminary approvals are obtained and study material has been received at the investigative site. Frequently, the monitor arranges to be present during the initial patient study. During this visit the monitor will check that applicable regulations have been followed, necessary approvals have been obtained, and the investigator and the investigator’s staff understand and will follow the research protocol.
Periodic visits are designed to assure the sponsor that the facilities used by the investigator continue to be acceptable, that the study protocol or investigational plan is being followed, that accurate, complete, and current records are being maintained, and that accurate, complete, and timely reports are being made to the sponsor and the IRB. During these periodic visits the monitor will usually carry out a detailed audit of some or all subject records to ensure that they are complete, accurate, and legible. The monitor or sponsor should maintain a record of the findings, conclusions, and actions taken as a result of these site visits.
During the final closeout visit the monitor will ascertain that all study articles have been properly accounted for, that final reports have been or will be prepared and submitted to the sponsor and IRB, and that the investigator understands the record retention requirements.
Clinical investigators of FDA-regulated products are subject to FDA inspection under the bioresearch monitoring program. The purpose of this program is to ensure the integrity of scientific testing and the reliability of test data submitted to the FDA to permit sound judgments regarding the safety and efficacy of regulated articles and to determine that the rights of research subjects are adequately protected.51
Under the bioresearch monitoring program the FDA conducts routine or surveillance inspections and directed or “for cause” inspections. Generally, inspections are carried out by appointment. The more common routine inspections usually last 2 or 3 days. Directed inspections are usually longer and more intense. The clinical investigator and his or her staff should understand that an FDA inspector is a law enforcement officer. The function of the FDA inspector is to ascertain compliance with FDA regulations and to detect violations of law and regulations. The inspector is not visiting the site to educate or consult with the investigator and his or her staff. Thus an appropriate response to an FDA inspection should be similar to the response to a traffic stop or tax audit. The investigator and the staff should treat the inspector with courtesy and respect and should have records of the study organized and easily accessible but should ordinarily not volunteer information.
Upon arrival, FDA inspectors are required to issue a notice of inspection and present their credentials. Generally, inspectors will not identify a “for cause” inspection as such. The inspection will include observation of facilities and equipment and a detailed audit of source documents, case report forms, and material accountability records. At the close of the inspection inspectors will meet with the clinical investigator. If the inspectors discover deviations from regulations or from the study protocol, they may issue a so-called form FDA 483, list of inspectional observations. If there are only minor variations, the inspectors may discuss them with the investigator but not issue a form 483. If investigators disagree with an observation on form 483, they may carefully and politely communicate disagreements to the inspector.
A clinical investigator receiving a form FDA 483 should consult with the sponsor, a consultant, or a knowledgeable colleague. The investigator should prepare a written response to be transmitted to the FDA within 10 days. This response should address each observation and should explain what steps have already been taken or will be taken to address the problem. The tone should be professional, cooperative, and factual. If the noted deviations are extensive or serious, the investigator may need to consider retaining counsel.
After the inspection the FDA inspector prepares a report that is forwarded to FDA headquarters for final review. These inspection reports are available through the freedom of information office of FDA and will become part of the public record.
In a recent year, the FDA inspected 460 clinical sites and alleged deviations in more than 60% of them. Many deviations were minor, with little potential to affect study integrity, and called only for voluntary action by the investigator. Others were more serious, resulting in official action by the FDA. The most common deficiencies noted during routine inspections related to problems with the informed consent form. Other common problems included protocol nonadherence, inadequate drug accountability, and inadequate and inaccurate records.
The FDA choice of regulatory action depends on the seriousness of the violations uncovered and the willingness of the clinical investigator to take corrective action. Generally, the FDA works with investigators in an effort to obtain voluntary compliance. However, where fraud is suspected, the FDA has taken immediate regulatory action.
When a clinical investigator under an IND has repeatedly or deliberately violated FDA regulations or has deliberately submitted false information to the sponsor in a required report, the FDA may initiate a proceeding to disqualify the investigator. Although currently the disqualification provision covers drugs and biologics but not devices, the FDA has proposed extending these provisions to devices to establish consistent bioresearch monitoring for all products regulated by the FDA and improve the remedies available to deal with clinical investigator misconduct.52
When the FDA elects to disqualify an investigator, the investigator will be provided an opportunity for a hearing. The hearing is informal in the sense that the strict rules of evidence applicable in a courtroom do not apply. However, anything said by the investigator can be used against him or her in a subsequent prosecution. Under these circumstances the prudent investigator will obtain legal counsel. Most investigators choose to enter a consent agreement rather than submit to the expense and risks involved in a hearing. Depending on the violation involved, such agreements may provide for limitations or supervision of the investigator’s research, disqualification of the investigator for a limited time, or lifetime disqualification. Notice of the impending or contemplated action or consent agreement will be sent to those persons having a legitimate interest in knowing that the investigator may be disqualified. These include sponsors, the investigator’s institution and IRB, and state, federal, and local agencies. The investigator can expect this information to become widely publicized.
For research funded through DHSS the Office for Protection from Research Risks is responsible for compliance oversight. In the case of serious violations a debarment procedure analogous to the FDA disqualification procedure may be brought to prevent further federal funding of the investigator’s research.53
In the case of serious violations of FDA regulations or of the Food, Drug, and Cosmetic Act, the FDA may refer a case to the Justice Department for criminal prosecution. Prosecutions of clinical investigators, which are rare, have generally involved investigators who have knowingly or willingly submitted false information to a research sponsor. Under the Agency’s application integrity program, the FDA aggressively pursues those who alter, fabricate, or deliberately withhold data.54 Conviction of violations involving fraud carries substantial fines and lengthy prison terms.
|
|
Original Business Thinking for the Life Sciences |
|
Allan M. Green, MD, PhD, JD, LLC Attorney at Law |
|
FDA Regulations for Clinical Investigators: A Summary (Part 2) |
|
Allan M. Green, MD,PhD,JD Neil Steinmetz, MD, JD |
To contact us call:1-617-447-5999 |