Bioethics committee weighs in on continued drug use
Bioethics committee weighs in on continued drug use
Flow chart helps PIs steer ethical course
Whether investigators are conducting pharmaceutical research domestically or overseas, there always is a question about what will happen to subjects when the study ends. There are a variety of ethical questions regarding whether it’s better to continue to provide access to a study drug or whether it’s best to let the access end with the trial.
Eli Lilly & Co. in Indianapolis has tackled this question through guidance developed by a bioethics committee that has been in place since the late 1990s, says Mark Lange, JD, an associate general counsel for global regulatory and a member of the bioethics committee.
"We have fairly senior people who serve on the committee, and it focuses on ethical questions in the clinical research phase," Lange says. "One role we play is to look at topics within the industry that we think we need internal guidance on."
So one of the topics analyzed by the bioethics committee was the issue of what is an ethical obligation of a pharmaceutical company for patients who participate in clinical trials when the study ends, Lange explains.
The committee developed a risk-benefit analysis that takes into account what is known about the drug and the patient’s response to it, but which also recognizes that the drug’s use is part of research and not treatment, Lange says.
"So we don’t know definitively that it’s safe and efficacious," Lange notes.
The risk-benefit analysis is reflected in a flow chart that considers these questions regarding the study drug:
— severity of disease: Does study involve treatment of a serious or life-threatening disease? If no, then it is not recommended to provide continuing access to the study drug;
— market availability of Lilly drug: Is Lilly product on market in country of study and can it be lawfully prescribed for the disease? If yes, then it is not recommended to provide continuing access to the study drug;
— phase of development of Lilly drug: In what phase of development is the drug? If it’s a phase I study, then it is not recommended to provide continuing access to the study drug;
— individual patient response to Lilly drug and other therapy options: In a phase II study, has the individual patient received the Lilly drug in the study and shown benefit? If not, then continuing access is not recommended. In a phase III study, has the individual patient received the Lilly drug in the study and shown benefit? If yes, then the Lilly drug is offered to the patient, based on best clinical judgment of study investigator and as part of a roll-over/extension study until the Lilly drug is commercially available in study country or development of drug/indication is discontinued;
— length of time and method of supply of Lilly drug: Have all available therapies marketed in study country failed to benefit the individual patient? If no, then it is not recommended to continue access to study drug; if yes, then continued access is offered.
The decision tree is for the drug study team to consider when writing the protocol, Lange says.
"You’re working with a company and saying, What should I do? What should I say in the protocol?’ and the algorithm gives you a guide for thinking it through," Lange says. "We leave the decision up to the individual drug development team, but the decision tree gives them guidance."
The bioethics committee also has made it clear that the protocol will spell out for investigators and IRBs what will be done with regard to continuing access of the study drug, and it will discuss the rationale for the decision, Lange says.
"You always say in the protocol for the IRB’s benefit what you’re going to do, even if you’re not going to do anything, and put in the rationale for why you are doing it," Lange adds.
Lange explains how the bioethics committee developed the guidance about continuing access to study drug at the end of a clinical trial:
• Global ethical standards set the stage: The bioethics committee considered Article 30 of the Declaration of Helsinki, which states, "At the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic, and therapeutic methods identified by the study."
Also, a 2004 clarification includes this language: "reaffirms its position that it is necessary during the study planning process to identify post-trial access" and "post-trial access arrangements or other care must be described in the study protocol so the ethical review committee may consider such arrangements during its review."
Committee members discussed what is meant by the terms "access" and "best proven therapy," Lange says.
For instance, does access mean that the person is provided the drug for free, or does it simply mean that the drug is provided before it has been approved by regulatory agencies and is available on the marketplace, Lange says.
The bioethics committee decided that access referred to regulatory access and not financial access because how could anyone make a decision about financial affordability for each patient, he says.
"How do you decide whether they are wealthy enough or not to afford this drug, and when does your obligation continue?" Lange says. "Is it a lifetime obligation? Where do you draw the line?"
Also, if continuing access meant lifetime access, then it would become fiscally challenging for pharmaceutical companies, particularly with large studies and post-market research, Lange says. So the decision tree ends the continuing access to the drug when the drug is readily available on the market and patients could be prescribed it by physicians, he says.
• Severity of illness is a major consideration: "The more serious the illness, the more likely we should consider providing the drug to the patient, even if it hasn’t been approved," Lange says.
"Conversely, for a less serious illness we’ll shy away from continuing to provide the drug because you’re still taking some risk with that patient population," Lange adds.
One issue that arises with subjects who have severe illness is whether providing continuing access to a study drug is too great of an incentive for joining a clinical trial, and whether subjects should be told up front that they will be offered continuing access to the drug at the trial’s completion, Lange says.
"Are you withholding the whole picture, or are you making too much incentive?" Lange asks. "We’re still working through that one."
• The study phase matters: Oncology trials are not included in the algorithm because they are unique, but with other types of studies, the decision tree recommends that continuing access to a drug not be provided for phase I studies, Lange says.
"We don’t know if we’d have enough information to provide that drug at a phase I study," Lange says. "At a phase II or III study, we’re seeing the patient’s response to it, so if there are no other drugs on the market, then we can provide them the drug." The decision is tiered by the study’s phase, the individual subject’s response, and whether there are alternative treatments available, Lange says.
Whether investigators are conducting pharmaceutical research domestically or overseas, there always is a question about what will happen to subjects when the study ends. There are a variety of ethical questions regarding whether its better to continue to provide access to a study drug or whether its best to let the access end with the trial.Subscribe Now for Access
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