Right-to-Try Bills Push the Needle on Risk

Diana Zuckerman, PhD

Congressional “right-to-try” legislation could make investigational drugs available to desperately ill patients sooner in the trials process, but there are substantial risks, said a panel of experts at the Patient-Centered Oncology Conference, held November 16-17 in Philadelphia, Pennsylvania.

Earlier in the clinical trials process, less is known about the drugs, which may be highly toxic and may have no efficacy. Furthermore, the House of Representatives’ version of the bill would allow companies to charge any amount for access to their investigational drugs. That is a scary proposition due to the potential for cost exploitation, members of the panel said.

“Any of those drugs can be made available to patients who are desperate and who might be encouraged to [try them] by an unscrupulous person or company that is selling the product for perhaps thousands of dollars,” said panelist Diana Zuckerman, PhD, who is president of the National Center for Health Research in Washington, DC.

Currently, for the purposes of expanded access, companies can charge only for the cost to produce the drug, or they can charge nothing at all. This removes the profit motive. “A lot of times, the companies say no, and a lot of times they say no for good reasons. They know that this isn’t something that is likely to work,” she said.

Whereas now patients may apply for access to investigational drugs that have passed phase II and phase III trials, the proposed legislation would make drugs available that have successful phase I trial results and remain under investigation. The current standards were meant to ensure that at least some evidence existed for a belief that a drug could help a patient. The right-to-try legislation would weaken that standard—perhaps too much, members of the panel said.

Even if a phase I trial has been successful, it most likely involved healthy volunteers, or patients who were substantially healthier than the typical patient who would seek expanded access as a last resort, having exhausted all approved treatment options. For this reason, the evidence may mislead a determination whether an investigational drug would have any value for an applicant through an expanded access program, panelists said. One of the problems, they said, is that legislators are under intense pressure to make these drugs more available to patients. A case in point is the Josh Hardy fight of several years ago over an antiviral agent being investigated by Chimerix of Durham, North Carolina. The company was demonized in the press until it relented and made the agent available to the young boy, whose family wanted the drug to manage a virus that resulted from immunosuppression treatment. The boy’s condition did improve following use of the drug, but Hardy eventually succumbed to his illness.

The right-to-try legislation, a version of which has already been approved in the Senate, would virtually remove the FDA from playing an oversight role in access to these investigational drugs. Currently, patients who want access must obtain sponsorship from their physician, must obtain permission from the biopharmaceutical company making or testing the drug, must obtain approval from the FDA, and also must obtain approval from a medical institution’s institutional review board (IRB).

These steps all take precious time away from the patient who may have only weeks to live, which is one of the objections to current policy. But the panelists noted that each of these stages represents an important safeguard and it is important keep protections in place while streamlining the process to ensure that drugs are available to patients who could truly benefit from them.

The FDA has made enormous strides in recent years to speed up the drug approvals process and to simplify the application process for expanded access to investigational drugs. The FDA announced in October that consent would now be needed from only 1 IRB member as opposed to the full panel.

The FDA’s track record on approving investigational drugs for expanded access is at 99% and this demonstrates the agency’s commitment to this program, the panelists noted, but they said the FDA is still much too soft on insisting on documentation compliance. Once these patients gain access, their doctors are not submitting reports on adverse events and outcomes as often as they should.

“Compliance, as I understand from the FDA, is as low as 60% in providing reports,” said panelist Marjorie A. Speers, PhD, executive director of the WCG Foundation, of Atlanta, Georgia, which advocates for patients with expanded access needs. “One thing we need to do is educate physicians who decide they want to use an investigational drug through expanded access. They need to know what their roles and regulatory responsibilities are.”

Zuckerman said that she believed the reporting compliance rate was as low as 30%. These comments baffled an audience member who recalled the struggle decades ago to make investigational drugs available to patients with HIV/AIDS. There was little hope for these patients and the disease was so widespread that pressure on companies and regulators to broaden access was intense. Even then, there was strong emphasis on collecting information about the effects these drugs were having on these nontrial users. “If you didn’t fill out the paperwork, you didn’t get next month’s supply of drug, so I’m a little surprised about these comments,” the clinician said.

One thing that should not go unrecognized is that as many as 85% of investigational drugs fail during human trials, the panelists said. This increases the odds against a patient deriving any benefit from a drug that has been tested only at the phase I level.

Panelist W. Kevin Kelly, DO, said patients often have an exaggerated belief that investigational drugs can help them. There is an educational step that has to come first, and it takes time to undo the damage that hype and misplaced expectations have caused. “I have patients coming to me all the time asking about investigational drugs,” said Kelly, who is a professor of medical oncology and urology and the director of the Division of Solid Tumor Oncology at the Sidney Kimmel Medical College, Thomas Jefferson University, in Philadelphia.

The drugs may or may not be appropriate, the patient’s disease state may not be a match, and there may still be FDA-approved drugs that are worth considering, Kelly said. “What is the disease, what is the treatment, and what is the reality?” Kelly said.

Even for agents that have advanced through the trials process and are in widespread use, substantial knowledge is still lacking that is essential for deciding how and when to use them. “The biggest example is checkpoint inhibitors,” Kelly said. “We’re just starting to understand the immunologic toxicities in the later stages [of disease].”

This makes it hard to believe that physicians in remote areas who are not as well equipped with staff, equipment, and up-to-date training can do an adequate job of vetting investigational drugs. “It’s all about safety. If you have a physician who’s never seen a drug and is in the middle of nowhere trying to get it to the patient, there are safety issues there,” Kelly said.

Speers said that not enough is done to ensure that physicians have exhausted all available options before applying for an investigational drug. She said teaching institutions and clinical research centers should make their services available to help with this process of identifying needs and solutions.

The panelists agreed that much more should be done to improve the reporting of adverse events and completion of documentation. It’s not just about a single patient who needs a drug. It’s about collecting information of vital importance to larger populations, they said.

“There is something that can be learned from these individual patient uses by reporting serious adverse events, and—more important—by providing the summary report to the FDA at the end of the treatment, because it tells us about the treatment use and what the outcome was for that particular patient,” Zuckerman said. Another goal should be to tailor the access process so that it’s easier and simpler but maintains a sufficient level of protection for the patient, members of the panel said.

Speers said a decision should be made whether the goal is to make more drugs available to more patients or simply to improve the way the program functions so patients who could actually benefit from investigational drugs can get them quickly. “We don’t want expanded access to become a substitute for clinical trials—for the drug approval process. We already have a drug approval process—it just could be more effi- cient,” Speers said.

“In the ideal situation, I would want to improve the clinical trial process so we don’t have to use expanded access,” she said.