Dealing With Risk Management Issues at the Clinical Trial Site
There have been a number of stories in the popular press and on television in recent months, detailing serious lapses in the way research institutions and physicians are running clinical trials. There is no doubt that conducting clinical studies presents some unique risk management challenges for research personnel at the site level, especially in light of increased scrutiny of the drug development process and changes in health care delivery that have taken place in recent years. This article lists some of the risk management challenges you face today.

Managed Review Playing an Important Role in CBER's Strategic Vision
The Center for Biologics Evaluation and Research (CBER) has embarked on an initiative to facilitate the review and approval of biologic products and their availability to the consumer. This new initiative is the enhancement and expansion of CBER's Managed Review Process (MRP). The current process is a system that was put into place to meet the performance measures and backlog goals mandated in the Prescription Drug User Fee Act of 1992 (PDUFA). CBER's success in meeting these goals impressed upon senior management the need to expand the principles of managed review - a process that is efficient, consistent, seamless and streamlined - to CBER's entire regulatory process. To this end, the goal of "a managed and integrated regulatory process, which is continuous from discovery through postmarketing," was incorporated into CBER's strategic vision for the year 2004.

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.

Pre-approval Promotion: Conforming to FDA Regulation
The development of new products based on the miracles of biotechnology has increased exponentially in recent years. However, it is a fact of life for many biotechnology companies and their investors that their one breakthrough product currently under development must become revenue-producing as soon as possible. A company with a new product in the works naturally wants to disseminate as much information as possible about that product, to gain an edge on the competition and maximize market share as soon as FDA approval is obtained. A month, a week or even a day of lost sales can have an impact on a company's bottom line.

Planning for Promotional Review
The FDA has an abiding interest in making sure that prescription drug advertising complies with regulations and does not compromise patient safety. In recent years, FDA surveillance of advertising and promotional materials has heightened. From a risk management perspective, this climate makes it imperative that companies develop and follow an effective process for producing materials that comply with FDA regulations while maintaining a competitive position in the marketplace.

FDA to Regulate Promotion by Pharmacy Benefit Management Companies
On January 5, 1998, the FDA issued for comment a draft guidance document on medical product promotion by healthcare organizations or pharmacy benefit management companies (PBMs).1

Under the guidance, the FDA will hold medical product sponsors responsible for the promotional activities of PBMs or health care organizations that the sponsor owns. The FDA will also hold medical product sponsors responsible if the sponsor has ties to or influences the content and distribution of promotional materials by a PBM or healthcare organization.

From a risk management perspective product sponsors will have more exposure, since they will have more responsibility for the promotional activities of PBMs or healthcare organizations with which they have ties. This article will discuss the draft guidance and some actions sponsors can take to help manage this potential new exposure.

A Reminder About Compliance
The FDA believes corporate compliance programs are important to ensure that the medical products a company sells or distributes are safe and effective for their intended use. The FDA looks for proof in the quality of a company's compliance program that the consumer will consistently receive acceptable products.

FDA Modernization Act of 1997
This commentary provides an overview of the events leading up to the signing of the FDA Modernization Act of 1997. It also discusses the rationale for the legislation, and summarizes the major provisions.

"Approved" With the Stroke of a Pen - Commentary on the FDA Modernization Act of 1997
Marketing folks like to say that their products are "approved", because they believe it enhances the credibility (and hence the value) of their products. It's a little like having a "Good Housekeeping" seal.

However, prior to 1997, the Food, Drug and Cosmetic Act prohibited drug companies from saying their drugs were approved. Section 301 (l) stated that "The using, on the labeling of any drug or device or in any advertising relating to such drug or device, of any representation...that approval of an (FDA)application...is in effect..." is prohibited.

FDA Background Information

A History of Informed Consent
In today's medical environment, a health practitioner or clinical trial sponsor would (or at least should) never consider performing a surgical or diagnostic procedure on a patient, or putting that individual in a clinical trial, without first obtaining informed consent. This is not only important from a risk management perspective, but is basic to the proper practice of medicine.

What follows is an overview of some of the milestones that have been reached in the still developing field of medical ethics and consent. Looking at how the concept of obtaining consent has developed over the years provides a rationale for current practice that in most cases requires investigators to obtain consent from clinical trial participants. As new therapies are discovered and are the subject of research, issues unique to future testing methodologies will emerge and need to be addressed. Risk managers must keep in mind that there is no place within an ethical management scheme for research that is done or contemplated without considering how best to protect the interests of the research subject.

The Basic Requirements of Informed Consent
Once a product has gone through the early stages of development, it is tested for efficacy and safety on humans in controlled clinical trials. However, before a subject can be enrolled in a clinical trial, that subject must agree to participate. The agreement to participate is known as informed consent.

Obtaining informed consent before enrolling subjects in clinical trials is an extremely important risk management consideration, as well as a key element of a well run clinical trial. A study subject who has been thoroughly informed of the risks and expectations of participating is less likely to bring legal action if adverse events occur than one who has not.

There is a well-defined process required by the Food and Drug Administration (FDA) to obtain informed consent from research subjects who participate in clinical studies of drugs, medical devices and biological products regulated by that Agency (this includes most of the research done in the United States).

FDA regulations require certain elements to be included in informed consent documents. Aside from these requirements, there are a number of actions investigators can take to make sure potential study subjects receive enough information to make a truly informed decision to participate in a research study.

Some Exceptions to Informed Consent
Generally, no investigator may involve a human subject in research regulated by the federal government unless that subject or the subject's legal representative has given informed consent. The Food, Drug and Cosmetic Act requires that investigators obtain this consent except where it is not feasible, or in the investigator's judgement, contrary to the best interests of the study subject.

This article discusses three situations in which there has been a deviation from the normal procedures usually followed in obtaining informed consent to the use of investigational test articles. One is a wartime scenario, one involves patients who present for emergency treatment and are unable to give consent for themselves, and one involves enrolling children in clinical studies. In situations such as these narrow exceptions to the normal requirements, it is extremely important to be aware of the rights of potential study subjects to be protected from unnecessary risks.

IRBs - The Basics
The Department of Health and Human Services has developed a regulatory apparatus that oversees biomedical research in the United States, and is responsible for seeing that individual researchers and institutions comply with federal laws and regulations for protecting human subjects. This regulatory apparatus has been put into place to counter breakdowns in the protection of human subjects rights that have taken place in recent years in the United States.

The FDA is the government entity responsible for the oversight of the human protection system for the products it regulates. Most research done in the United States is subject to the regulations pertaining to human subject protection, and is reviewed by local committees called institutional review boards (IRBs).

These community-based committees make sure that the research conducted within that locality is consistent with community ethics, and that the rights of the research subjects involved in the study are protected. The efforts of local IRBs have helped to heighten the research community’s awareness of ethical conduct standards.

Balancing Benefit and Risk in Clinical Research
When an institutional review board (IRB) evaluates a research proposal, it must also consider if the risks to the research subjects are justified by the benefits to be gained. This risk analysis focus on the short-term effects of the research on the individual subject, and not the long-range benefits of the research to mankind.

The IRB must first determine if the premise of the research is valid, and look at the nature and magnitude of the risk to the participants. The IRB then decides if the estimates of the probability of harm or benefit to study subjects are reasonable. There will be a greater tolerance for higher risks in research on some types of products more than others, depending on such factors as the severity of the disease and the availability of other treatments.

It is very important to this process that sponsors provide as much data as possible to the IRBs making these risk-benefit determinations, and not minimize important information about side effects that could impact the assessment of the risk-benefit ratio.

IRBs-Are They Still Working?
There is no doubt that serious abuse of human research subjects is much less likely to occur today than in the past because of the institutional review board (IRB) oversight process. However, no oversight system can guarantee complete protection for each individual.

At the request of Congress, the Government Accounting Office (GAO) reviewed the existing systems for protecting human subjects, to assess how well IRBs are working to protect research subjects’ rights.The GAO found that due to time constraints and lack of expertise on the part of the FDA inspectors, IRBs were not being properly inspected in a timely manner. The report also noted that some IRBs themselves were not consistently in conformance with FDA regulations, and that protocol reviews could be compromised by such factors as lack of procedures and too heavy a workload.

The report demonstrated that more still needs to be done, to ensure that the rights of research subjects will continue to be protected in an increasingly complex research environment.

This article discusses the findings of the GAO investigation, and offers some suggestions for sponsors and IRBs to manage their exposures in this area.

Case Study About Informed Consent
This is a true story about a participant in a clinical trial who suffered a serious medical event while enrolled in the study. It makes a powerful point about how important it is from a risk management perspective to obtain proper informed consent from research subjects.

Information Technology Update

Problem: How to get value from IT acquisitions?
Solution: CNA's Diane Carco
When Diane Carco looked for a book or seminar to help her staff make smart information technology investments and understand the acquisition process, she came up empty. The CNA senior financial officer for the Information Technology Department found nothing out there.

Yet the problem is huge: 40 percent of all corporate investment is now in IT. Companies over and over again are paying too much for wrong information technology goods and services, and they are buying technology with restrictive terms. Further, corporate execs have become simply exasperated by the whole IT acquisition process and have difficulty finding the value received for the dollars spent.

Loss Control

Gene Therapy Research (cross-listed under Regulatory Issues)

Pharmaceutical Outsourcing Report - Risk Management
Insuring Materials in Transit: When $.60 a Pound Isn't Enough
Bio/pharmaceutical companies run the risk of catastrophic losses when their goods are in transit or stored at a contractor's location.

As a consequence of outsourcing, materials are frequently in transit via common carriers, and stored at vendor sites. Active drug substances are shipped from chemical and biological manufacturers to finished dose manufacturers, and from there to packagers, distributors and clinical test sites. With every transfer, the risk of loss, damage and delayed delivery--and the resultant financial loss--is heightened, even after preventive measures like shipping validation have been taken.