Clinical trials conducted outside of the United States are booming. Most FDA and EMA approvals involve at least one foreign clinical study, and many rely exclusively on foreign data. Trials conducted overseas and particularly in markets with notoriously low levels of transparency carry with them additional risks of bribery that can taint studies both legally and ethically. There are steps that companies can take to reduce these risks, while bolstering their compliance structure and improving their reputation.
While this article discusses challenges for both sponsors and CROs, it is important to note that the risk and incentives are not the same for both communities. For example, the CRO is paid for the process, regardless of the outcome. The sponsor, by comparison, has a strong interest in a favorable outcome and so may have greater incentive to intervene inappropriately. While the goals of these two communities should be aligned, competition over qualified investigators, different commercial pressures and unequal negotiating power often obscures this. Both communities would benefit from a standardized approach that puts the integrity of the process above these differences.
Corruption Flashpoint: Permit Application
In the preparatory stages for a clinical trial, the sponsor or CRO seeks permission from the national authorities to import the drug or device to be used in the trial. Bribes may be demanded in exchange for expediting drug applications and product registration certificates — a great temptation in countries like China with long and cumbersome approval processes requiring multiple submissions to authorities, or in India where the Drugs Controller General employs just three pharmacists to sift through the huge number of applications. In each jurisdiction, companies should work to establish their reputation as an organization committed to the highest standards of compliance. Written guidelines should be available to employees in relevant languages describing the company’s policies clearly, and providing a contact within the company for questions or concerns. Companies should ensure that consultants are fully vetted and selected solely on the basis of qualifications. Success fees should be prohibited. Companies should communicate clear conflict of interest rules and decline to work with conflicted parties at any stage of the trial process.
Corruption Flashpoint: Engaging an Investigator
The selection and employment of a local physician as investigator for the clinical trial presents unique challenges.In many jurisdictions, physicians are employees of the government, public health service, or public hospital, rendering them “foreign officials” within the meaning of the US law criminalizing foreign bribery – the Foreign Corrupt Practices Act (FCPA). Pharmaceutical or medical device companies and CROs must satisfy themselves that the investigator meets industry standards for education and experience. (Prior to this, of course, the companies should have satisfied themselves that the CRO is itself a fully vetted, qualified and reputable partner.) The law allows for fair market compensation to be given to the investigator and his team, but a number of factors interfere with this analysis for qualified doctors. In many Latin American countries, ethical standards for pharmaceutical industry practices have been widely-published, yet doctors are frequently offered bribes. In India, the doctors’ privileged position, combined with a climate of corruption, create problems for companies trying to assess the professional capabilities and trustworthiness of physicians. In Cambodia, it is common for individuals to pay large sums in order to obtain government employment. The sums paid for health service positions are wildly disproportionate to official salaries. Having made a substantial investment in obtaining his employment, the employee has expectations that the employment will place him in a position to realize a handsome return on his investment. Due diligence at this stage is critical. Companies must be able to reach a high level of confidence that their investigator is qualified and reputable. Checking qualifications, screening media reports and conferring with experts in the industry is a good place to start. Thereafter, benchmarking appropriate compensation and tailoring it to a clearly delineated scope of work is an important next step.
Companies should ensure that the investigator has read and understood every clause in his contract. The contract must speak clearly to compensation, expenses, and objectives, and no extraterritorial payments should be permitted. All local laws should be observed, including tax provisions. Where feasible, the company should extend anti-bribery training to the investigator and explain the company’s position on conflicts of interest and any prohibitions on gifts and hospitality. Sponsors should support CROs in their efforts to reduce the likelihood that investigators will shop around to find trials with lower standards, representing less work and less oversight for them. When these steps are not practicable because of the limited role of the investigator, investigator meetings should nevertheless follow local and international standards regarding location, accommodation and related travel details. Extravagant arrangements should be prohibited. These steps can be managed sensitively and, if necessary, at arm’s length through the use of a third party adviser.
When the contract is with the facility and not with the investigator directly, contract language should be incorporated to ensure visibility into the selection and compensation of the investigator. While payment directly to the facility rather than the investigator may provide additional compliance comfort, this can be undermined if there is no insight into the details of the facility’s relationship with the investigator.
Corruption Flashpoint: Selecting a Medical Facility
The clinical trial facility is, in many countries, a public hospital. The director of this facility, also a public employee, has a stake in the trial, and a keen interest in enhancing the facility by obtaining equipment. In some countries — China most prominently — the government requires that the sponsor or CRO enter into a joint venture agreement with the government/hospital administration, encumbering the process and opening the door to facilitation payments and inappropriate supplier and subcontractor arrangements. Problems multiply with the scope of the trial; Phase II and Phase III trials typically involve multiple sites, multiple investigators, numerous levels of local and regional authorities and hundreds or even thousands of patients. In response, companies should endeavor to manage the process to the maximum extent possible, including robust conflict of interest provisions and contractual language requiring the disclosure and prior vetting and approval of third parties. Here again, the role of employee training programs can be key. Periodic training updates may help to keep the parties focused on the inherent challenges, and live training updates enable employees to discuss specific challenges and share best practices.
Corruption Flashpoint: Ethical Review
Prior to commencement of the clinical trial, an Internal Review Board (IRB) reviews the proposed clinical trial for ethical, safety and medical merits. IRBs have come under criticism in recent years, and there are clear compliance weak spots in which the CRO or sponsor can exercise undue influence on the review committee. Unlike IRBs in the U.S., the composition of these review boards, or of the local ethical committees (EC) which serve hospitals abroad, is generally not subject to disclosure requirements. Bribes may flow in both directions – from the investigator or CRO to members of the review committee, and vice versa when, for example, a review board member has an acquaintance or relative who does not meet the study parameters, but for whom an exception is made. Not only might this lead to payments under the table, it also violates the study protocol and compromises the data collected. In order to ensure independence and professionalism within the review board or ethical committee, disclosure may be mandated in the sponsor’s or the CRO’s contract with the facility. Periodic reviews of the qualifications and connections of committee members may also be required.
Corruption Flashpoint: Informed Consent
Informed consent has been a sensitive issue in clinical trials conducted abroad for decades. Recent cases have highlighted the need to enunciate the purpose of the study as well as the risks involved. Per-patient payments, offered to physicians as a financial incentivefor recruiting and retaining patients for clinical studies, make fertile ground for violations of the law. In Russia, where a physician may earn three hundred dollars per month, each patient in a clinical trial can bring twenty times his monthly salary. Doctors in Argentina received $350 per participant in a clinical trial where it was later claimed that informed consent had not been obtained. In order to protect themselves from the pitfalls abundant in the recruiting and informed consent process, companies must ensure that the trial protocol has been properly reviewed and approved by qualified, independent professionals and that the investigator has a thorough understanding of all of its provisions. Oversight is key. Even the most explicit protocol may not be implemented correctly at every site. In India, investigators routinely tell patients that participation in a clinical trial is required as part of their treatment. Financial incentives sway patients as well as physicians and, for some, access to reliable medical care is sufficient incentive to participate. Because consent may be obtained in the course of a personal exchange between parties with very different levels of medical sophistication, providing participants with recourse to a confidential hotline for additional questions might help ensure that the process is working. The consent process should be documented, with evidence that adequate time has been accorded to explaining the study and that explanations have been made in a language understood by the patient. Identification and verification programs like TRAC can be used to ensure that the participant is who he claims to be and is not participating in conflicting trials.
Corruption Flashpoint: Confusing Clinical Trials with Sales Initiatives
As the clinical trial comes to a conclusion, additional risks arise in connection with publication and use of the results. Pressure may be exerted to stop a trial, suppress adverse data, or even to extend the trial for the benefit of the facility or the investigator. Phase IV carries its own corruption risks. Companies have used follow-up studies for marketing purposes, (“seeding studies”), in which the trial itself, and not the results of the trial, is the objective of the sponsor. This has become a greater temptation as pharmaceutical companies have expanded their sales markets within emerging economies. Companies are conducting more clinical trials in these countries, not only for cost savings and ease of access to patient populations, but also to gain a foothold for subsequent sales in these expanding markets. Seeding studies are not illegal, but they may open the door to marketing methods that run afoul of the FCPA and similar laws. In order to safeguard against abuses, no consideration should be granted for the ultimate value of business resulting from a trial. Compensation to the investigator and his staff should not be linked to the value of medical devices or products the consultants may later use for their own practice. If the sponsor’s equipment is to be left on-site following the clinical trial, the agreement with the facility should provide expressly for market value compensation for equipment designated to stay behind.
Whose Responsibility is it?
A final and only tangentially related issue should be addressed. On whom should the burden of anti-bribery compliance fall: the CRO or thepharmaceutical company? Of course, the risk and responsibility are shared and both parties benefit from a trial conducted with integrity. Nevertheless, a tension often develops, as CROs may be asked to implement the sponsor’s own compliance programs, including duplicative training, and to manage parallel sets of documentation. If best practices could be documented with reliability and CROs and sponsors could agree upon a standardized set of best practices, overall compliance could be enhanced, and costs to both parties reduced. This has been done in other fields and seems overdue in the clinical trials arena.
Markets for conducting clinical trials have grown exponentially in the last decade, and companies have fallen prey to problems while working in uncharted waters. On the other hand, there is always a risk of duplicative efforts that provide little additional benefit. Today, with increasing understanding of reasonable and cost-effective compliance strategies, companies should be able to compete and to grow, while implementing robust controls and protecting themselves from future liability.
TRACE is celebrating its tenth year as an anti-bribery compliance organization offering practical tools and services. TRACE offers an extensive library of benchmarking tools and four levels of due diligence as well as TRAC, our new, free identification and verification tool. TRACE also provides on-line training for commercial intermediaries at no cost, free workshops around the world, an on-line database summarizing local anti-bribery laws in 130 countries, a comprehensive dashboard solution to help member companies manage their third party due diligence and complementary Gifts & Hospitality Tracking Software.
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