How Right to Try Bypasses the FDA

Right to Try, law — Before Right to Try became law, patients with life-threatening diseases, through their doctors, have been able to request investigational protocols via the FDA's expanded access pathway (also known as compassionate use) for more than 30 years. sturti/Getty Images

On May 30, 2018, President Donald J. Trump signed S.204: the "Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try Act of 2017" (whew) into law. The Right to Try (RtT) legislation gives terminally ill patients who've exhausted all approved treatment options and aren't able to participate in a clinical trial, the right to work directly with drug companies for access to investigational new drugs (IND) that haven't secured approval by the U.S. Food and Drug Administration (FDA).

The law's intent is to make the process of obtaining potentially life-saving drugs (completely untested by the FDA) easier on the whole by avoiding the FDA altogether. In response to previous statements by FDA Commissioner Scott Gottlieb, M.D., regarding how the agency intends to implement the law — especially as it relates to new regulations that oversee patient safety and protection under Right to Try — the main proponent of the bill, Senator Ron Johnson (R-WI), wrote in a letter to Gottlieb that the goal of Right to Try is to "diminish the FDA's power over people's lives, not increase it."

Critics, including physician's and ethicists, worry that the lack of oversight may make vulnerable, end-of-life patients more susceptible to purveyors of false hope and opportunistic companies who could take advantage of them financially. Supporters contend that it will provide a pathway to new treatment options for dying patients who have exhausted all the alternatives. But the bottom line is that the pharmaceutical company gets the final say about whether to provide a drug or not.

"Right to Try does not give any 'new' rights or privileges to patients," Richard Klein, former director of the FDA's Patient Liaison Program, says in an email. "It exempts investigational drug use from certain protections — namely criteria for informed consent under FDA, HHS (Health and Human Services) regulations and from IRB (investigational review board) review. The latter reviews informed consent to assure it adequately informs the patient of what they're getting into: What are the potential benefits, what are the potential dangers, as there may be serious toxicities associated with investigational agents, especially. It is the patient, the doctor and the company that have to consider when it's appropriate to try an investigational agent. There are a lot of variables that need to be considered and it is the company that holds the cards in deciding whether they are able and willing to provide the product."

Who Pays for Experimental Treatment?

The Right to Try bill doesn't require insurance companies to cover the experimental treatments. So who pays for the investigational drugs under Right to Try?

According to a May 2018 report, medical bills are the leading cause of bankruptcy in the U.S. While Right to Try may be a "great name" (drag video timeline to the 8:00 minute mark) for a bill, it may not be a great idea for already financially fraught terminally ill patients and their families who could wind up paying hundreds of thousands of dollars out of pocket for drugs with no proven efficacy and unknown side-effects that may further shorten their lives. Bearing that in mind, what, if any, alternative funding is available for patients who can't afford the potentially astronomical cost of Right to Try therapies?

Klein notes that there are FDA regulations that determine cost recovery for expanded access (EA) and prohibit companies from "commercializing" an unapproved drug for profit.

"So, cost recovery is limited to the cost of manufacturing the product. If you look at (d)(ii) of the regulation, you'll see that other costs of developing the drug aren't allowed in the calculation," he says. "Companies usually don't want to reveal that it cost them $6 to make a drug that will ultimately sell for $200. So almost no one ever applies for cost recovery."

The Right to Try legislation exempts manufacturers from a lot of FDA regulations, but not from charging for investigational drugs under an IND.

"There is a LOT of confusion about this," says Klein. "While the FDA regulations require that sponsors justify the cost and submit a CPA's audit of the calculation, the Right to Try stops short by just saying you can't charge more than the cost of producing the drug.

"If there is no requirement to submit the cost calculations to anyone, or to prove the cost, how are costs actually calculated? There is also no enforcement authority that I can see," says Klein. "So, no one seems responsible for checking the calculation, or enforcing the justified cost. You can see this wasn't a well-thought-out piece of legislation. Or maybe it was and that's what they were trying to do. Who knows? It has yet to be tested."

Prior to the enactment of the Right to Try law, patients with serious and life-threatening diseases, through their doctors, have been able to request investigational drugs, vaccines, devices and biologics via the FDA's expanded access pathway (also known as compassionate use) for more than 30 years.

Expanded access is an FDA regulatory process that allows companies to provide unapproved therapies to a patient if the company decides to do so. There are numerous reasons a company might say no, but the FDA allows more than 99 percent of requests to go forward. The small percentage of scenarios where the FDA denies expanded access involves cases where there is a known risk that outweighs the benefit to the patient.

Alison Bateman-House, Ph.D., MPH, MA, medical ethicist and co-chair of Working Group on Compassionate Use and Pre-Approval Access (CUPA) at NYU Langone Health, says in an email, "I see no reason for a company to provide its investigational products under Right to Try instead of under expanded access, which I find to be far preferable, with an appropriate balancing of patient autonomy and reasonable prudence to prevent foreseeable harm or exploitation."

The Upside for Patients?

Exactly what the Right to Try legislation will mean for patients and patient groups, health care providers and institutions, drug companies and other sponsors is unclear.

Asked in an email what he thinks the new federal Right to Try law will mean to his practice and to his patients, R. Donald Harvey, director, Phase 1 Clinical Trials Section, Winship Cancer Institute of Emory University, says, "Candidly, very little. We already have a robust system in place for expanded access and single patient IND processes that partner with industry and the FDA. Our patients have been, and will continue to be, well served by this approach."

Harvey is concerned that patients may not understand how access to investigational agents is obtained — specifically, that the primary gatekeeper is the entity that holds the IND — and that the gatekeeper is the industry sponsor. He stresses that patients will still need a clinician/physician champion as well as industry (IND holder) approval: "If they don't allow us to access the drug(s), it's the end of the story, regardless of the path of right to try or expanded access. Right to Try takes away FDA oversight, which most clinicians, professional organizations and industry representatives view as a negative," he says.

Does he have concerns that unregulated phase 1 drugs may further shorten lives?

"Not particularly, as access to these agents still has to go through industry, and I don't see most companies allowing access at the first-in-human stage of drug development. Also, the rate of direct, fatal harm to selected patients in phase 1 trials has been less than 1 percent," says Harvey.

Physician Knowledge Replaces FDA Approval

Asked if doctors will know and understand the dosage and potential side-effects of the drugs they are expected to administer under Right to Try, Harvey says, "Certainly, there may be gaps in knowledge based on where a drug is in development (phase I, II or III). One would hope that dose and schedule have been defined prior to any approval to use outside of a clinical trial and that a general knowledge of safety would be available. Generally, I don't see most companies releasing agents prior to the phase III trial initiation, at the earliest."

What we know for certain is that Right to Try and expanded access now co-exist as pathways to pre-approval of investigational drugs, making it easier for terminally ill patients to seek experimental treatments outside of clinical trials. Companies may choose to grant access via Right to Try, expanded access, both, or neither one.

Harvey's general impression?

"Right to try seems to me to be a political rather than policy approach to drug access. To me, it falls into the 'if it's not broken, don't fix it' category."