Potential Risk Exposures for IRBs, CROs, SMOs, and CSOs

There are certain exposures unique to institutional review boards (IRBs), contract research organizations (CROs), site management organizations (SMOs), and contract sales organizations (CSOs). Following is a discussion of some of the exposures with which these organizations may be confronted, along with some suggestions for managing the risks associated with these exposures.

 
IRBs

Most of the research done in the United States, including the clinical trials done by pharmaceutical, biotech and device companies, must be reviewed by an IRB. The purpose of this review is to assure that the proper steps are being taken to protect the rights and welfare of study participants. IRBs, through a group process, ensure that risks to study subjects are minimized and are reasonable, subjects are selected equitably, informed consent is properly obtained, and there is adequate provision for monitoring safety concerns and assuring confidentiality of data. IRBs must also make sure that there are appropriate safeguards in place to protect vulnerable populations such as children and prisoners.

IRBs have a very difficult but vital job to do; through the review process performed by IRBs, human subjects involved in research are much less likely to suffer abuse today than in the past. However, a number of emerging events both at the government and the local level are threatening the degree of vigilance that IRBs are able to bring to the task.

The workload that IRBs have is increasing exponentially, along with the complexity of the research protocols being reviewed. Members of these committees may have competing demands on their time, and their institutions may not give the review process the importance it deserves. These factors make it difficult for IRBs to perform the risk-benefit analysis that is an integral part of assessing the acceptability of a research protocol for human subjects' participation.

IRBs gain feedback on their effectiveness through federal monitoring activities that include on-site inspections and review of study documentation, IRB operations and alleged misconduct. Although this is the ideal, and the IRBs inspected learn from the feedback they receive from these inspections, federal monitoring activities are hampered by a lack of funds. Companies that send their protocols to IRBs for review may be lulled into a false sense of security that their studies have been given a thorough review, that the consent forms are comprehensible, and the studies have been found by the IRB to pose no unreasonable risk to study subjects.

Because of lack of time, inexperience in dealing with complex protocols, and infrequency of inspection by federal agencies, IRBs may in fact not be giving protocols appropriate review. Sponsors, not always objective about their own research projects, may erroneously believe that the IRB has adequately addressed patient safety and ethical issues. If consent forms have not been thoroughly reviewed and are not written in understandable language, subjects could participate in research projects with faulty knowledge. Sponsors could be exposed to liability if subjects who have not been properly informed suffer harm by participating in a study that poses unnecessary risks that have been overlooked. IRBs must make sure they have a complete package of information about the study, including the Clinical Investigators' Brochure, the drug monograph, and any other information needed to do a proper review.

Another area of exposure for IRBs is during the conduct of the study. IRBs are required to periodically review previously approved research, to decide whether or not the potential for harm to study subjects has changed. Investigators must report adverse events experienced by study subjects, so the IRB can assess whether the participants should be exposed to the risks posed by continuing participation in the study. Some IRBs are viewed by their institutions as a low-level administrative hurdle. Consequently, conduct of ongoing review can be superficial and is sometimes performed by overworked administrative staff without the scientific expertise needed to assess the significance of safety information received by the IRB.

 
CROs

CROs are organizations that partner with medical product sponsors to conduct clinical research, with the goal of producing the data needed to file applications to federal agencies for product approvals. CROs are typically involved in the design of clinical study protocols and case report forms, and gathering and managing clinical data by monitoring and auditing clinical studies. They may also provide statistical support for the sponsor by performing such functions as analyzing study data, developing databases, writing reports, preparing regulatory documents for filing, and representing the sponsor to federal agencies. Some CROs provide full study monitoring support, and some provide additional support for the sponsors' own monitors. A number of CROs are also involved in selecting investigators and recruiting study subjects, but these functions are increasingly being performed by SMOs.

The type of contract research services a company uses will depend on the size of the clinical and regulatory groups and expertise that the company has. If a company is just getting started, has many projects going on at the same time, or needs expertise in a particular area, these issues will drive what kind of CRO the company selects; either a comprehensive provider or a specialist. Some CROs provide a variety of services covering all phases of drug development, and some restrict their work to one or a few facets of the process. In some cases, the relationship between a CRO and a sponsor may be so close that the CRO really acts as an extension of the sponsor.

CROs have the same exposures that a medical product sponsor doing its own clinical trials may encounter. If the CRO is involved in study design, the risks and benefits of participating in the study must be balanced, to avoid unnecessary exposure for study subjects and potential liability. If the arrangement the CRO has with the sponsor gives the CRO responsibility for obtaining IRB approval, the CRO must be sure the IRB has all the necessary information to make a proper determination about the appropriateness of the study.

CROs must also make sure their procedures for data collection promote accuracy and timeliness of these functions. If data is not handled properly, study progress can be slowed significantly with attendant delays in filing regulatory submissions. This exposes the sponsor to delays in going to market and potential loss of revenue. Another area of exposure for CROs is concerned with use of electronic data collection, retrieval and transmission systems. These must be validated and subject to some kind of quality check, to ensure the integrity of the data being transmitted to the sponsor. With the increasing use of technology, the potential for exposure if data is not handled properly will also increase.

CROs monitor clinical studies to make sure that investigators are conducting the studies according to good clinical practice (GCP) standards. It is important that monitors have the proper level of expertise in the clinical area of study and in the regulations to be able to assess whether or not the investigator is in compliance. Some CROs may claim expertise in managing all facets of development for drugs, devices and biologics, when they may not have capability in all these areas and make mistakes, creating liability exposure for the sponsor.

CROs involved in writing reports and producing regulatory documents for sponsors must make sure that they have not hired any personnel involved in compilation of data who have been disbarred by the FDA. The FDA will reject any application that contains data provided by disbarred individuals.

 
SMOs

SMOs are service companies that organize and manage clinical investigations at one study site or at multiple sites. This is done either through contractual relationships with the sites or ownership of the sites. The goal of these organizations is to add efficiencies to the areas of clinical trial management that typically end up as bottlenecks: data collection and coordination, study initiation and logistics, and patient enrollment.

These organizations generally manage the sites at which clinical trials are conducted, concentrating in the areas of investigator identification, site initiation, and enrollment of qualified study subjects. One result of the emergence of SMOs has been the consolidation of the fragmented clinical investigator market. The chief goal of SMOs is to move pharmaceuticals quickly through the clinical trial process for the medical product sponsor or the CRO for which the SMO is working.

There is some overlap in the kinds of services provided by CROs and SMOs, especially in the area of selecting study subjects and investigators. In general, however, SMOs concentrate more on recruitment and study initiation, and CROs on monitoring functions and data management.

SMOs face a number of exposures if they do not manage their activities properly, starting with subject recruitment. There is a potential for SMOs to recruit improper study subjects who do not meet the study criteria, if a commitment has been made to complete enrollment quickly. This results in a situation where the data gathered on that subject is not evaluable, slowing up the progress of the study and potentially invalidating study results. Another area of exposure for the SMO and the sponsor is in executing the informed consent. Study coordinators may not do an adequate job of obtaining informed consent from potential study subjects by overemphasizing the benefits to be gained from participating, by downplaying side effects that the subject could experience, or by not explaining the study thoroughly. A study subject who experiences adverse events is more likely to bring suit against the SMO if that subject was not adequately informed of the risks of participating.

SMOs may be responsible for the management of the clinical drug supplies for a study, which must be inventoried and stored properly. If the study drug is not dispensed properly, study subjects' safety could be jeopardized and the study compromised.

SMOs must also exercise care in selecting competent investigators for a particular study, who have experience in the therapeutic area being studied. The SMO must also be sure that the investigators selected have not been disqualified from clinical trial work by the FDA, as this could also jeopardize the application.

 
CSOs

CSOs are contact sales organizations that undertake to sell one or more medical products for a sponsor. A sponsoring company can use a contract sales force as its primary selling arm, or as an adjunct to its regular sales force, if more personnel are needed on a temporary basis (such as for a product launch or to sell new drugs acquired in a company merger). A medical product sponsor may contract directly with a CSO, or through another organization. More and more CROs are developing their own CSOs, and the line between the two is becoming less distinct. CROs may be developing sales organizations with the idea that this will help them sustain a continuing relationship with a sponsor for which they have done clinical and analytical work.

Sales representatives are in a unique position to provide health care providers with technical and marketing information about their company and its products, and can represent the company in a very effective way through personal contact with these providers. However, this situation, while presenting sales opportunities, can create some significant exposure for the product sponsor. Because sales representatives work out in the field, usually from their homes, it is difficult for a company to supervise their activities on a daily basis. This may be especially true for sales representatives whose first loyalty is to their contract organization and not the hiring medical products company.

Companies that have their own sales force usually educate this group about the organizational structure of the company, record keeping, what representatives can say about the company's products, policies for responding to physician questions, and what the regulatory and legal implications of their actions out in the field may be. This helps to minimize the exposure that could result from overpromotion of the company's products.

It is generally the responsibility of the sponsoring company to give contract representatives training on the specific characteristics of the drug or product being promoted, just as the company provides for its in-house staff. However, the sponsor may not always provide the outside representatives with training in the legal and regulatory issues impacting promotion of that product. Because meeting market share objectives is a big motivator for a contract sales force, there may be a tendency to overpromote the product. This can expose the sponsor to potential liability if inappropriate claims are made for the product. Sponsors can minimize this exposure by making sure that the CSO contract spells out who is responsible for training the representatives in regulatory issues, and for supervising their activities out in the field.

Madeleine M. Jester, RN, JD