New Challenges in Interactions among Sponsors, Clinical Trial Sites, and Study Subjects
In trials of promising therapeutic interventions, sponsors seek rapid study enrollment in order to complete trials, make regulatory applications, and maximize the time in which they may exclusively market a product. Increasingly, industry and academic focus has been drawn to the development of treatments for rare diseases and pediatric conditions, in part due to the incentives that manufacturers have under the U.S. Orphan Drug Act and the Best Pharmaceuticals for Children Act, such as market exclusivity. The small number of patients diagnosed with rare diseases, including in pediatric populations, creates a challenge for study sponsors and investigators to locate and recruit participants into clinical trials. In this environment, patient advocacy organizations provide a valuable means by which study sponsors can engage with patients diagnosed with specific diseases, educate physicians and communities about potential treatments and innovations, and stimulate recruitment into clinical trials. These relationships can assist greatly in identifying patients who may be eligible for studies and who are eager to enroll in them, which in turn can facilitate the testing and ultimate approval of significant new therapies. Yet the growing interaction between sponsors and patient populations has begun to blur significantly the traditional division of roles between sponsors and investigators, giving rise to complex ethical issues that, as of this writing, exist in a relative vacuum of guidance on how to navigate industry’s increasing involvement in activities traditionally reserved for investigators and site study teams, leading to practices that vary widely across sponsors. This document examines a few situations wherein interactions between clinical trial sites and study sponsors have created legal and ethical issues, after which several approaches and recommendations are suggested to address these challenges. These case studies are not meant to suggest that study sponsors should never be involved in patient engagement activities; instead, they illustrate the current divergence in approaches that results from the lack of adequate guidance in this area. Moreover, legal counsel, Institutional Review Board (“IRB”) administrators, and compliance staff for study sponsors (including academic institutions acting as study sponsors) often struggle to advise in this area, given the lack of “on point” guidance.
The division of roles, and the need to respect the roles, of sponsor and investigator are not trivial or merely academic concerns. The roles and duties are set by both regulation and by custom, and reflect differing professional and corporate obligations. The investigator, for example, is also often a treating physician for subjects, and even if not the regular treating physician, nevertheless in his or her role as an investigator, is effectively providing medically necessary care to subjects, if only as an adjunct to trial procedures. Unless sponsors are willing to act as health care providers and to assume providers’ concomitant professional obligations and liabilities, they must not act as investigators and should not be in the business of making promises directly to subjects that they cannot effectively honor. Further, sponsors, as the entities that file data to support regulatory submissions seeking marketing authorization, have primary duties to ensure data integrity in trials, and engaging in activities that may compromise that integrity would be inconsistent with these obligations. Physician-investigators, at the same time, should not compromise their duties as physicians, which encompass duties of care to patients/subjects as well as regulatory and professional obligations to maintain privacy of medical information. In other words, understanding who is doing what in a trial, and where primary duties lie, is essential to fulfilling the related ethical and legal obligations, including the obligation not to make promises or representations to subjects and prospective subjects that cannot be honored. It is for this reason that those in the clinical trial enterprise must act with caution when they act in ways that could confuse or compromise these roles.
- Case Examples
There are numerous ways in which the ambiguity of a sponsor’s and investigator’s role in a study can lead to troublesome results that could, for example, compromise the integrity of study data or implicate data privacy concerns. One of the most prevalent situations arising from this ambiguity is when the investigator/research site is not only the investigator, but is also the sponsor in a regulatory sense, which would occur in many investigator-initiated studies.
The following anonymized cases, while not representative of all sponsors’ practices, are anecdotal examples of complex legal and ethical issues that resulted in problematic outcomes, underscoring the need for additional guidance on these issues.
- An academic medical center (“AMC”) is the site of an investigator-initiated Phase I study of a unique gene therapy agent. The AMC also employs the investigator, holds the Investigational New Drug (“IND”), and owns the intellectual property being tested in the trial. The first subject enrolled makes a spectacular recovery from the condition being studied. While the study is ongoing, and before the first subject has completed their study participation, the AMC and the investigator approach the first subject and ask for cooperation to make a film about the subject’s trial participation and the success of the trial in that case, to be shown to the subject’s disease community as a study recruitment tool. The AMC’s public affairs office is involved in this effort and also seeks to use the completed film to show to donors to promote philanthropy.
- The industry sponsor of a study seeks to increase recruitment by contracting with an external vendor that can identify potential subjects and direct them to the sponsor’s hotline for evaluation of study eligibility. Subsequently, the sponsor steers the potential subject to a study site and follows up with the site to make sure that the potential subject made it to the site. The sponsor, for its initial eligibility assessment, interacts directly with the potential subjects and their regular health care providers to obtain background medical records and sends those records to the site that will consider enrolling the potential subject and perform final eligibility determination. In this process, the sponsor “screens out” some potential subjects and does not forward their contact and medical information to study sites, based on the sponsor’s assessment that the inquiring person would not be eligible for the study.
- In a large Phase III study, study sites experience problems with prompt uploading of data. The sponsor therefore contracts with an external data company, with that company detailing its own staff (either in person on site, or remotely) to assist the sites in uploading study data. In this way, the external data company is performing the same functions as the site’s own data staff.
- The Chief Medical Officer (“CMO”) of a biotech company develops close relationships with patients from her speaking engagements with a rare disease community. She becomes friends with patients and their parents and siblings, and as soon as she becomes aware that a Phase II study is about to commence for which a patient friend of hers may be eligible, she intervenes with the site to ensure that the patient is the first to be evaluated for eligibility. After the patient is enrolled, the CMO interacts repeatedly with the patient’s family members to listen to their accounts of the possible success of the experimental agent and to assist the family in determining whether there is an adverse reaction that should be reported to the site investigator.
- In a rare disease study, subjects must be recruited world-wide, and many of the few eligible subjects live in very resource-deprived settings, with some subjects’ daily family incomes being the equivalent of only a few USD. The sites for the interventional study are located at a couple of academic medical centers in the U.S., neither of which has infrastructure to support a world-wide recruitment effort, or to assist subjects and their families to undergo initial screening in their home countries and to bring them to the U.S. site for extended periods for trial procedures. The sponsor, which has the commercial incentive to complete enrollment quickly to speed study results, undertakes the international recruitment effort and becomes the liaison between the subjects’ families, local hospitals and labs, the U.S. site, and travel and logistics contractors, whose services have been secured and paid for by the sponsor. The result is that very indigent families are re-located for sustained periods to the U.S. for trial participation, and their primary support and contact during travel and U.S. visiting period is the sponsor’s designated staff and agents, not the investigator and research team. In this circumstance, the sponsor looms larger than the investigator in the daily lives of the subjects and their families.
There have been two reported federal court decisions about a specific study in which the court emphasized the importance of the separation between sponsors and investigators in the context of clinical trials. These two decisions provide useful context about the difficulties in separating roles and responsibilities in clinical trials. One such case involves a pharmaceutical company that supported open-label trials of a treatment for patients diagnosed with Parkinson’s disease. Subsequent to the open-label trials, the company sponsored a Phase II study to test the safety and efficacy of delivering the treatment through infusion. As the study progressed, results showed less than expected efficacy, but study participants attested to physical, cognitive, and emotional improvement. During the trial, however, study participants began developing antibodies that would neutralize the effects of the substance upon which the treatment was based, as well as naturally occurring instances of the substance; further, primates in a long-term toxicology study of the treatment developed brain lesions. In response, the sponsor announced that the study would be terminated on the basis of safety risk findings. The study participants sought legal recourse against the sponsor in order to continue receiving the treatment, by arguing that the sponsor had promised to continue providing the treatment and that the participants relied on that promise. The case made its way to the U.S. Court of Appeals for the Sixth Circuit, which found that the sponsor had no obligation to continue providing the treatment to the participants. The court’s reasoning was based upon the fact that the study participants asserted their right to continue receiving the treatment based on promises made by the principal investigators of the study, but in the eyes of the court, the investigators were not agents of the sponsor and therefore lacked the authority to bind the sponsor.
The U.S. District Court for the Southern District of New York presided over a case with nearly identical facts in April 2006, during which the court found that the study sponsor did not have a fiduciary relationship with the study participants and therefore did not have an obligation to continue providing an intervention after the study was terminated. The court’s reasoning was based, in part, on the traditional framework of clinical trials contemplated in the Common Rule, under which sponsors are detached from study participants and therefore are not positioned to act as the participants’ fiduciary. The court further opined that “importation of an ill-defined fiduciary duty into the field of clinical drug trials . . . would likely undermine the reliability of research results, which, in turn, could undermine drug safety. . . . [T]he requirement of informed consent is the principal protection provided to the participant.”
As implied by the courts’ reasoning in these two cases, a sponsor’s detachment from a study is not only a typical aspect of an industry-sponsored study but also may ensure accurate perceptions by subjects of the sponsor’s and investigator’s respective roles. It is important that expectations of all parties in a clinical trial be accurate, especially the subjects, who may misunderstand and conflate the sponsor’s and investigator’s roles, even though as a legal matter, those roles may nonetheless be considered distinct in the eyes of the law. It is critical for these reasons that the scope of sponsors’ and investigators’ roles and duties be kept clear—not only to convey to subjects accurate representations about the roles and responsibilities of sites, investigators, and sponsors and to protect study subjects from incorrect expectations, but also to reduce any uncertainty that a sponsor and investigator currently face when assessing their respective liabilities and risk exposures. Implementation of appropriate internal policies and procedures by the sponsor would avoid misleading communications being made to study participants. Similarly, internal policies at research sites and within research institutions can ensure that investigator and research team representations to participants are clear regarding sponsor and research site/investigator roles and responsibilities. Such policies can also help to avoid participant misperceptions that the investigator is an agent or extension of the sponsor. Most importantly, as a matter of ethics, regulatory compliance, and operational effectiveness, the complexities of these new forms of interaction between sponsors, investigators, and participants need to be recognized explicitly, and behavioral rules and expectations established.
- Key Issues
The above examples illustrate complexities that can arise when the traditional distinction between the sponsor and investigator become blurred. In recent years, the blurring of this distinction has appeared in several areas. Three of the most prevalent include: (1) interactions between clinical trial sponsors and potential study subjects for clinical trial recruitment purposes; (2) programs through which clinical trial sponsors engage study subjects in ongoing clinical trials or subjects who have recently completed the trial to produce testimonials for the company’s own use; and (3) engagement of vendors by sponsors to perform services on behalf of study sites.
- Interactions between Clinical Trial Sponsors and Potential Study Subjects
Increasingly, sponsors seek to play an active role in recruitment of study subjects, often most intensely in rare disease and in pediatric trials. Such involvement may be needed to accelerate testing and subsequent marketing approvals for rare disease treatments. Recruitment for these trials is often difficult and costly, sometimes with only one or two patients enrolled per study site. Given the significant resources required to develop rare disease treatments, study sponsors are well-positioned to ensure sufficient recruitment for the study and to assist sites with recruitment of subjects. However, there is a dearth of guidance on the ways in which sponsors may appropriately use their resources to support patient recruitment activities while preserving their independence from investigators and sites. The U.S. Food and Drug Administration (“FDA”) guidance regarding clinical trial subject recruitment was issued over 20 years ago, in January 1998, and is directed to IRBs and clinical investigators, not contemplating a role for sponsors in the clinical trial recruitment ecosystem. The Office for Human Research Protections (“OHRP”) guidance is slightly newer, published in 2005, and identifies sponsors as a “target audience” for the guidance. Like the FDA guidance, however, the OHRP guidance does not discuss the role for sponsors in the clinical trial recruitment process.
Several questions arise when the sponsor becomes involved in clinical trial recruitment activities. These include the following:
- To what extent are the activities of the research sponsor in recruitment subject to IRB oversight?
- To what extent can the sponsor conduct initial screening of a subject to refer potential subjects to clinical trial sites without actually making an eligibility determination with respect to a specific subject?
- To what extent should clinical personnel of the sponsor, such as the medical director or chief medical officer become involved in discussions with potential subjects (and their families), and what should be limits within these interactions?
The U.S. Department of Health and Human Services Secretary’s Advisory Committee on Human Research Protections (“SACHRP”) believes that the research community would benefit from clearer guidance that acknowledges the increasingly active role that sponsors play in the research recruitment space and clarifies that several principles applicable to sponsor study subject recruitment activities are the same as those that apply when those activities are performed by investigators and study sites. Such guidance is necessary, particularly because of the conflict of interest that sponsors have in steering recruitment to clinical trials of a product that ultimately will inure in a commercial sense to the benefit of the sponsor. Because both FDA and OHRP recognize study subject recruitment as the beginning of the informed consent process, trial-specific recruitment activities performed by sponsors should be subject to these same requirements for IRB oversight as those performed by investigators and study sites. When the sponsor will be involved in subject-directed recruitment activities, these activities should be described in the recruitment section of the clinical trial protocol so that they are made transparent to the cognizant IRB. Subject-directed recruitment materials produced by the sponsor should be reviewed by the cognizant IRB, including any scripts or template emails that sponsor staff use to screen subjects. In addition, clearer guidance on the roles of sponsors and investigators would empower institutions to develop policies governing clinical trial and patient recruitment activities. Such institutional policies could complement IRB oversight by signaling to sponsors and investigators whether certain contemplated activities are permissible at an institutional level even before IRB review, thereby alleviating some of the burden on IRBs and facilitating more efficient oversight of clinical trials.
Because the investigator remains responsible for determining study subject eligibility, sponsor staff discussing study enrollment with potential subjects should typically seek to limit such discussions to basic information about the study, such as information that could be found on publicly-available websites (e.g., clinicaltrials.gov), answering questions about eligibility criteria, and referring interested individuals to clinical study sites to undergo the screening process, which most often would be in person. Sponsor staff members’ exercising restraint in dealing with prospective subjects would seem important in this context, since a sponsor’s commercial interests are directly related to and dependent on rapid study enrollment and completion. Sponsor staff who are involved in the clinical trial recruitment function should be trained to adhere to the principles of subject recruitment found in FDA and OHRP guidance, including:
- Making clear when a product under study is investigational and has not been demonstrated to be safe or effective,
- Not promising free treatment when the only free treatment provided is the investigational product, and
- Not overemphasizing or touting the amount of payment to be made to study subjects.
Because sponsor staff do not control whether a subject is ultimately found eligible for trial participation by an investigator, sponsor staff must be trained not to promise that any particular subject will be found eligible (or ineligible) to enroll in the study – although sponsor staff should be able to convey obvious eligibility considerations, such as that a person who does not have diabetes would be ineligible for a diabetes study or that a person who is a minor would not meet age of majority protocol eligibility standards. When sSponsor staff with clinical credentials, such as a licensed physician, nurse, or pharmacist in the sponsor’s medical affairs or clinical operations functions, becomes involved in the recruitment process, such personnel may be tempted to engage in activities that cause them to be perceived by subjects or prospective subjects as a health care provider and/or investigator, which would, of course, be an inaccurate understanding of their role and their duties to subjects. Recruitment vendors engaged by sponsors should be required by contract to adhere to these same principles. While these principles may seem obvious, they in some cases have not been well-articulated with respect to recruitment activities performed by sponsors.
Often, investigators are affiliated with an institution, such as a university or an AMC. In institutions with a distinct research administration function, the institution’s research administration office could assist the IRB and investigator in evaluating particularly complex situations of sponsor-led or sponsor-involved recruitment and defining the limitations on recruitment activities that the sponsor can perform. Such policies would inform preliminary discussions between the investigator and sponsor, as well as the terms of negotiation of clinical trial agreements.
Interactions between sponsors and study subjects also raise data privacy considerations. More specifically, industry sponsors typically receive subject-level data from clinical trial sites in a coded or “pseudonymized” format through which the data lack direct identifiers that could be used to identify a particular study subject. Informed consent forms frequently promise study subjects that the industry sponsor will not learn their identity during the course of the study except in certain circumstances, such as a research misconduct inquiry, audits, or in the event a subject injury leads to the sponsor’s providing reimbursement to the subject for treatment of injuries. If the sponsor receives direct identifiers of subjects as part of the recruitment process, however, then identifiable information of subjects has already been received by sponsor staff and is presumably retained within sponsor records. Sponsors should take steps to segregate any identifiable information held by recruitment staff from the coded data received by the sponsor through other information conduits during the clinical trial, in order to avoid compromising the privacy of study subjects.
- Contact of Enrolled Study Subjects by Clinical Trial Sponsors
Sponsors of clinical studies are increasingly interested in contacting subjects enrolled in ongoing studies to obtain information regarding such subjects’ experience with the disease or condition under investigation, as well as the subjects’ experience in the trial. The format for such contact is varied, with sponsors sometimes wanting to distribute questionnaires to the subjects and other times wanting to film “testimonials” with study subjects. The purpose for which such information is collected also varies. Frequently, sponsors wish to use the information collected to educate their internal staff about the burden of a particular disease for which the company manufactures an investigational product or to educate the sponsor’s personnel about the clinical trial process. In other cases, the sponsors wish to use the communications for external, promotional purposes, and in the case of sponsors that are universities or academic medical centers, they may wish to use the testimonials for philanthropic fund-raising purposes. In addition, sponsors’ and investigators’ increasing use of social media to connect with potential study subjects adds another layer of complexity that has yet to be clarified by the available guidance. The dearth of guidance on how to navigate the benefits that sponsors (including AMCs) derive from directly contacting study subjects has resulted in a spectrum of practices across sponsors. Additional clarity on the scope of acceptable interactions among sponsors, investigators, and study subjects could also allow institutions to develop more robust policies governing sponsor-subject interactions, which would establish a baseline of acceptable activities; doing so would complement IRB oversight and preempt some of the difficult ethical quandaries presented in the case examples above.
Contacting active study subjects by the sponsor can raise several concerns. First, contact with active study subjects for purposes of distributing a questionnaire or asking if the subjects would be willing to participate in a video testimonial would properly be considered a new intervention with the subjects that should be implemented through a protocol amendment approved by the IRB. To preserve the distinction between the role of the sponsor and the role of the investigator, any contact should typically be carried out through the investigator rather than by the sponsor directly. For example, the investigator could ask subjects if they are willing to participate in an optional questionnaire or video testimonial for the sponsor and leave it to the subject to contact the sponsor or the sponsor’s vendor, if the subject is interested in pursuing the opportunity. Second, contact of active study subjects risks introducing bias into the study with respect to the reporting of adverse events and any subject-reported outcomes. For example, subjects may believe that they were selected to participate in the program on the basis of their experience with the product (either good or bad), thus causing them potentially to over- or under-report adverse events or subject-reported outcomes. In considering whether to permit these types of activities, IRBs should consider the nature of the study at issue and whether it is likely to suffer from bias as a result of the sponsor’s initiating and maintaining direct contact with study subjects. IRB approvals for such contact ideally would contain specific limitations on the nature and duration of this contact. Concerns with contact of study subjects to participate in questionnaires or testimonials for the sponsor are lessened when the activities involve only study subjects who have already completed the study (or at least the intensive, interventional segment of a study that includes long-term data collection, such as gene transfer studies), because such situations represent decreased risk of data bias in the study and decreased risk of subject perception of undue pressure from the sponsor. Such subjects would no longer be participating in collection of the most essential subject-reported data or outcomes, such as improvement in symptoms, increased mobility, or decrease in acuity of pain. Ifsubjects have already completed study interventions, the sponsor’s contact of an interaction with such subjects would not be an intervention conducted as part of the research and thus arguably would not require IRB oversight. However, an IRB could also reasonably take the position that interactions with subjects in an ongoing study—even if the specific subjects in question have completed the study visits and procedures—would fall under its jurisdiction and require IRB approval, particularly if the subjects who are contacted regarding the testimonial are enrolled at a study site at which subjects continue to participate in the trial.
Further, the content of such communications should be considered carefully to avoid unintentional promotion of an investigational product. For this reason, the questionnaires or testimonials should focus on the subject’s experience with the disease under study or experience with the clinical trial. If questions are asked about the subject’s experience with the experimental agent, the questions should be phrased in a neutral manner that asks about both good and bad experiences. Any use of such testimonials by sales or marketing staff should be considered carefully to comply both with FDA promotional concerns and U.S. Securities and Exchange Commission requirements.
- HIPAA Complexities in handling Medical Information of Potential Study Subjects
The blurring of the traditional division of roles between sponsors and investigators has also given rise to questions about how collection of medical information for recruitment activities should be characterized under the Health Insurance Portability and Accountability Act of 1996 (“HIPAA”) Privacy Rule. Sponsors increasingly engage vendors to perform a wide variety of services on behalf of clinical trial sites, or even perform those services directly. This can include engaging vendors that perform clinical trial recruitment services on behalf of sites, travel services that arrange for subjects (and in some cases their family members) to travel to sites to complete enrollment activities, and attorneys who will complete immigration processes for study subjects who travel to the U.S. from abroad to enroll in a study. Performance of these services often requires the disclosure of the subject’s protected health information (“PHI”) from the study site (typically a HIPAA covered entity) to the vendor for the performance of such activities. If the subject is already enrolled at a study site, then the research team or investigator can ask the subject to sign an authorization permitting the site to disclose the PHI to the applicable vendor. In the case of clinical trial subject recruitment however, disclosure of PHI from a prospective subject’s health care provider often needs to take place to permit the recruitment vendor (or even the sponsor’s own staff) to discuss their specific eligibility issues with the prospective subject. In turn, for a sponsor or recruitment vendor to have this health information in hand to enable a meaningful eligibility discussion with a prospective subject, the sponsor or recruitment vendor must have obtained an authorization from any prospective subject directing that person’s health care providers to disclose relevant PHI to the sponsor or recruitment vendor.
Existing HHS regulatory preamble commentary on HIPAA considers research recruitment to be a research activity and not a “health care operation.” However, as SACHRP recognized in 2004, guidances issued by the National Institutes of Health (“NIH”) have suggested that certain research recruitment activities may be considered a “health care operation” under the HIPAA Privacy Rule. Accordingly, NIH and the HHS Office for Civil Rights (“OCR”) do not presently appear entirely aligned as to whether recruitment activities are properly characterized as research or as health care operations under the HIPAA Privacy Rule. This distinction matters because if recruitment activities are always considered to be research activities, they must take place pursuant to a research basis for use and disclosure of PHI under the Privacy Rule, such as a waiver of authorization issued by an IRB. In such a case, the external recruitment vendor would not be considered a business associate of the covered entity site. Within the HIPAA framework, a preparatory to research provision allows covered entities to use or disclose PHI for “purposes preparatory to research,” such as study recruitment, provided that no PHI is removed from the covered entity during the course of the review. HHS has clarified in FAQ guidance that “researchers” (without specifying whether the term extends to sponsor staff or vendors) who are external to covered entities may use the preparatory to research provision to review records to identify eligible subject but may not use the preparatory to research provision to contact prospective research subjects; instead, such “researchers” are instructed to obtain a partial waiver of individual authorization by an IRB or privacy board. By contrast, if recruitment activities are considered health care operations, the disclosure of PHI to the recruitment vendor could be made provided that the vendor enters into a business associate agreement (“BAA”) with the site.
In either alternative, it would appear inappropriate for a sponsor itself to rely on a waiver of authorization to “cold call” prospective subjects, most of whom would be surprised – and many of whom would be alarmed – to receive such a call. It is more common for sponsors to fund third-party entities to act as BAAs of research sites in making outreach to prospective subjects identified through researchers’ records reviews under a waiver of authorization. IRBs, however, typically prefer that outreach to patients of a facility to encourage trial enrollment be conducted by the facility’s own staff as more consistent with patient expectations, and such outreach is normally done either under an IRB-approved waiver of authorization or for the purpose of seeking authorization for clinical trial enrollment.
Given the ambiguity discussed above, there remains a question in the regulated community regarding the proper HIPAA framework that applies to these research recruitment scenarios, with some sites and recruitment vendors entering into BAAs and others relying on IRB waivers of authorization. This confusion can lead to protracted negotiations between sponsors, recruitment vendors and sites, delaying the start of research. SACHRP encourages NIH and OCR to work together to clarify this issue through issuing unified guidance indicating that for external sponsors, research recruitment is permissible with a BAA under the HIPAA Privacy Rule. At this time, SACHRP would prefer the use of BAAs over the use of a waiver of authorization for these purposes, because a BAA would permit access by non-covered entities (e.g., industry sponsors) to covered entities’ PHI with specific, required privacy and security protections. A waiver of authorization, on the other hand, has multiple additional complexities, such as the need for the HIPAA covered entity to account for these disclosures in patient records, the legal difficulties in “clawing back” PHI handed out to a non-covered entity under a waiver, and the risk that the non-covered entity recipient could re-use and even further distribute the PHI without accountability to the covered entity or HHS. To address these issues, some HIPAA covered entities that allow use of a waiver of authorization for this purpose, require that recipient of PHI under a waiver enter into an agreement with the covered entity committing the recipient to adhere to defined privacy and security protections. In such a case, however, the contractual provisions would be evocative of similar requirements in a BAA – leading one to ask why BAAs should not in fact be the preferred alternative. Even if OCR would allow a waiver of authorization for industry and other external sponsors to comb medical records and make direct contact with patients for recruitment, health care providers may choose not to honor any such waiver, due to professional ethics concerns and patient expectations of privacy. The issuance of guidance on this topic would appear timely given that NIH has indicated on its website that it is in the process of revising its long-standing guidance on the HIPAA Privacy Rule and research.
Most importantly, however, it is essential that sponsors, vendors, sites and investigators (including all research team members) be mindful at all times of the distinctions in privacy-related obligations of the parties. Sites and investigators typically are HIPAA-covered entities, and cannot share PHI with research sponsors, sponsors’ vendors or others without either authorizations from subjects or applicable exceptions to the authorization requirement. Further, any sponsor contact directly with a study participant or former participant at a HIPAA covered entity trial site should only proceed under a compliant HIPAA authorization allowing the contact and citing the purpose of the contact. Such authorizations should be separate from the HIPAA research authorization, unless the contact would somehow be necessary for the conduct of the study itself and is clearly contemplated in the approved study protocol.
Site and investigator responsibilities to maintain the privacy of subjects’ medical information is also subject to promises made in the informed consent process about who will receive subjects’ research-related information, and for what purposes. Sponsors offering recruitment services as part of the clinical trial implementation may have first contact with prospective subjects, and often collaborate with patient advocacy organizations to reach individual prospective research participants without having to proceed through or with HIPAA covered entity health care providers. Although sponsors and their vendors are typically not health care providers or HIPAA covered entities, they nevertheless may have privacy obligations to subjects based on common law principles, state privacy laws, and/or promises made to prospective subjects in the course of interacting with those subjects. Moreover, as identified above, if a sponsor or its vendor seeks PHI from HIPAA-covered entities to assess possible trial eligibility, they may not lawfully obtain such PHI without either patient authorization or successful and accurate invocation of a HIPAA pathway, including a BAA. The increased frequency and intensity of sponsor and vendor involvement in recruiting subjects and assisting subjects during the course of a trial (for example, with travel arrangements) has made more pressing the need for all parties to understand, respect and plan for honoring their various privacy obligations.
As the interactions between sponsors, clinical trial sites, and study subjects continue to evolve and become increasingly complex, clarity on the acceptable scope of sponsors’ and investigators’ roles in the context of a clinical trial would mitigate some of the current confusion and uncertainty present in these areas that leads to delays in the start of research. As may be inferred from the discussion above, the following general principles (as well as other applicable standards and regulations, including those of FDA) should be respected in sponsor, investigator and site interactions with subjects:
- Sponsor or third-party vendor involvement in recruitment activities should not place sponsor or vendor staff in the role of final determination of trial eligibility. These personnel may share and discuss study eligibility information and answer questions from prospective subjects regarding eligibility criteria. Wth appropriate consents and authorization, these personnel may also collect relevant clinical information relating to prospective subjects, in order to share that information with site investigators, but should avoid acting in the role of the clinician-investigator who ultimately must make eligibility determinations based on their assessments of patients, their medical conditions and their verified medical records.
- Sponsor or vendor interactions with subjects during the course of studies (for example, continued assistance with lodging and transportation) should respect professional and ethical boundaries, and should avoid personal involvement that couldbias study results or give subjects and their families misimpressions of the sponsor’s obligations. Sponsors should seek to avoid that in the course of their trial support activities, sponsor personnel (or a vendor’s personnel) develop relationships with subjects and their families that exceed the sponsor support activities pre-approved by the IRB and pre-cleared with the investigator.
- All sponsor and sponsor’s vendors’ interactions with subjects or prospective subjects must be planned and executed to respect applicable privacy obligations of sponsors and vendors, as well as the privacy obligations of patients’ and subjects’ health care providers and of research sites and investigators. As a baseline sponsor obligation in these interactions, prospective subjects should be informed of how their personal information will be used and disclosed by the sponsor and/or the sponsor’s vendor performing recruitment services.
- When, in investigator-initiated studies, the sponsor is effectively the AMC or university employer of the investigator, the AMC or university should approach these issues with a respect for institutional and investigators’ responsibilities and duties regarding respect for and protection of human research participants and the integrity of the research process; these responsibilities and duties may be distinct from other institutional interests. For example, it would appear to be over-reaching for an AMC or university to pressure its investigator to persuade unwilling or hesitant subjects to undergo publicity interviews, or even to expect investigators in ongoing trials to become deeply involved in crafting positive trial-specific publicity messaging meant to enhance institutional profile. In regard to privacy issues, an AMC or university study sponsor should be mindful that subjects’ authorizations to allow use and disclosure of PHI for research does not extend to allow use of that PHI for other institutional purposes, such as media relations and fundraising.
- Sponsors planning contact and/or interactions with enrolled subjects during the course of a study must be transparent about such plans with investigators and with any cognizant IRB or ethics committees. In addition, sponsors should not contact or interact with subjects without the pre-approval of relevant activities by the site investigator and IRB/ethics committee. There may be necessary exceptions to this in order for sponsors to fulfill obligations to subjects as set forth in an approved or amended protocol, such as reimbursement for health care costs associated with an adverse event or continuation of experimental therapy after a trial has ended.
- Sponsors interacting with subjects during trials (as well as research institutions and investigators interacting with subjects for reasons other than regular medical care or fulfillment of trial protocol requirements) should do so in ways that are least intrusive to subjects and should be respectful of any reluctance of subjects or their families to engage in such interactions. In approaching subjects (which should be done through the site investigator initially), sponsors and investigators must be mindful of the possible perception of subjects and families that they may have little meaningful choice but to cooperate in these “extra” requests, and should calibrate approaches accordingly.
- Sponsor and investigator/site requests to subjects and families to engage in media and public relations activities should be confined to the period after the subject has completed his or trial participation. Optimally, such requests and activities would occur after the site has completed study visits for all enrolled subjects.
- Use of interviews with subjects or subject “testimonials” for ongoing trial recruitment or for recruitment for related studies should not tout investigative therapies as “treatment” and should not appear to offer curative interventions, but should accurately portray clinical studies as use of unproven, though promising, experimental agents or procedures.
Adhering to these principles will avoid the confusion of roles that is encountered with increasing frequency in the clinical research enterprise. Ensuring the appropriate division of responsibilities in a study will help to protect data integrity and sound research ethics, and will ensure that duties of sponsors, investigators, clinical trial sites, and vendors are fulfilled appropriately, with least risk to the welfare and comfort of subjects and their families.
 In 1998, FDA indicated that sponsor involvement in recruitment activities would require IRB review and approval. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/recruiting-study-subjects In 2019, FDA issued a guidance document, Live Case Presentations During IDE Clinical Trials, https://www.fda.gov/media/88454/download, regarding sponsor requests for “live case” presentations of surgical procedures involving devices in a clinical trial under an IDE. The issues addressed in that guidance – enhanced risk to subjects in such “live case” presentations, informed consent, IRB approval for this additional procedure within a study context, and FDA approval and oversight – echo many of the issues and concerns addressed in this document. The essential conclusions of that FDA guidance – including need for non-coercive approaches to subjects asked to participate in these “extra” procedures, privacy concerns, need for IRB pre-approval – appear fully consistent with the principles set forth in this document. It would be useful to the regulated community if FDA were to issue additional guidance addressing from its own regulatory perspective the various new and emerging concerns addressed herein.
 Abney v. Amgen, 443 F.3d 540, 543 (6th Cir. 2006).
 Id. at 543.
 Id. at 544.
 Id. at 544.
 Id. at 544.
 Id. at 545.
 Id. at 549.
 Id. at 549.
 Suthers v. Amgen, 441 F. Supp. 2d 478, 488 (S.D.N.Y. 2006).
 Id. at 488.
 When the university or AMC itself serves as the sponsor of a study, that entity must understand its own obligations to respect and protect the interests of research subjects, which would include respecting – and not interfering with – the distinct obligations of the investigator, and refraining from direct interactions with subjects, just as industry sponsors refrain from doing so, except under circumstances approved by the IRB and accepted by the investigator.
 67 FR 53182 at 53230 (Aug. 14, 2002) (“Research recruitment is neither a marketing nor a health care operations activity.”).
 45 C.F.R. § 164.512(i)(1)(ii).
 This is an unusual business associate arrangement, however—typically, the business associate is a vendor of the covered entity, whereas here, the business associate is a vendor of the sponsor
 https://privacyruleandresearch.nih.gov/ (noting that “[t]his website is currently in the process of being updated” and referring visitors to the website to the OCR website for further information about HIPAA and research). SACHRP would strongly encourage NIH to address in its revisions the issue of using a waiver of authorization to allow non-reseacher access to patient records for recruitment and contact activities, and SACHRP may choose to address this issue more fully in its own later advisory recommendations.