If you or a loved one has a serious or life-threatening illness and have exhausted all the medical options at your disposal to no avail, you're likely, as the proverb about the drowning man goes, to grasp at straws – to grab hold of anything that might save or extend yours or your loved one's life. Hope, it seems, is hard-wired into the human condition: Surely the potential benefits of an investigational modality will prove the risk worthwhile? But when it comes to experimental drugs and therapies for untreatable conditions, it may be healthier to avoid false hope and approach potential outcomes with pragmatic optimism instead.
When President Donald J. Trump signed the Right to Try Act (which grants no real rights, but rather, grants permission for a patient to request an experimental drug from a pharmaceutical company) into effect on May 30, 2018, he stated that, "We will be saving....hundreds of thousands. We're going to be saving tremendous numbers of lives."
Is Right to Try Viable?
But many experts and professionals question whether the law will save even a single life, especially when juxtaposed with the lives it could potentially shorten.
Richard Klein, former director of the Food and Drug Administration's (FDA) Patient Liaison Program, says in an email that he has no use for the Right to Try (RtT) laws. "They were ideologically based and lacked an understanding of both the drug development process and what obstacles patients who would like to try an investigational drug outside of a clinical trial face."
Klein believes that there's no reason for a company to provide its investigational products under RtT because the FDA already has a program that does almost exactly the same thing and with an appropriate balancing of patient autonomy and reasonable prudence to prevent foreseeable harm or exploitation of the patient.
"In essence," says Klein, "patients and their doctors have had the 'right to try' investigational agents when all else fails and the company is willing to make the product available, for decades."
For more than 30 years, people with serious diseases have had access to investigational drugs, vaccines, devices and biologics via the FDA's expanded access pathway. Under the current program, which is also referred to as compassionate use, once a company agrees to provide an investigational product, the FDA and an institutional review board (IRB) must approve the product before it is administered to the patient. And the FDA retains the right to deny certain requests for drugs that it has not yet approved for safe use within the general population.
"Expanded access is really a 'pathway,' a regulatory process that permits companies to provide unapproved therapeutic agents to a patient if the company decides to do so. There are many reasons companies might say no. But the FDA allows more than 99 percent of requests to go forward. The small number of situations where the FDA doesn't allow the expanded access use of the drug to proceed involves situations where there is a known risk that outweighs the potential benefit for the patient," says Klein.
The expanded access program began in 1987 during the HIV/AIDS epidemic, when sick patients demanded that protocols be established for those not enrolled in a clinical trial who wanted to try potentially life-saving medications when nothing else was available.
"With the promising therapies for Aids being developed and the need to get these drugs to patients ineligible for trials," says Klein, "the agency created the investigational new drug (IND) treatment which codified compassionate use and created a formal pathway for access."
Emergency Use Provision
The FDA's only category of expanded access under which there is an emergency use provision is called emergency IND for single patients, with requests often being approved in real time on the phone via the FDA's 24/7 emergency call center. For most emergency access, the physician would call the appropriate review division during regular working hours for an application request – a process that was streamlined in 2016 so that it now takes only about 45 minutes to complete. In 2017, the Institutional Review Board (IRB) process was also streamlined to exempt a full review before granting expanded access, making the process faster.
Klein notes that emergency use is considered on a case-by-case basis and only applies to a single individual. Emergency IND is used when there is not sufficient time to prepare and submit the paperwork – for say, a heart attack patient who needs specific life-saving drugs administered within a couple of hours.
Klein offers this scenario of how it works: “Suppose a patient came into the hospital late at night and had a stroke and the doctor thought a particular investigational drug was an appropriate option for this particular patient. The physician could contact the emergency call center, which would contact the medical officer on duty. They would review the case, ask a few pointed questions as necessary and provide an IND number by email or possibly over the phone. The IND allows the investigational product to be administered.”
Emergency use is generally employed in situations where there aren't any other options, but it can also be used when approved options are ineffective, or if the patient has a known allergy that precludes an approved therapy. As well, expanded access under the FDA's regulatory pathway allows for treating serious or life-threatening illness or conditions. Again, decisions are made on a case-by-case basis, taking into account the benefit-to-risk ratio of the individual patient in terms of variation in disease, stage of disease, age, underlying health and organ function.
Both RtT and compassionate use allow access to pre-approval of medications for those with life-threatening conditions – making it easier for terminally ill patients to try drugs that have not yet completed their trials. Both only apply when the patient and doctor have exhausted all other alternative treatments. The key difference is that the RtT law gives access without the need for FDA approval.
Expanded Access Broader Than Right to Try
Klein is explicit that expanded access is broader than RtT, which only applies to life-threatening illness. Further, RtT is limited to investigational agents in active development, which have completed only a phase 1 trial.
According to Alison Bateman-House, Ph.D., MPH, MA, Division of Medical Ethics at NYU Langone Health, in an email: "Phase 1 is primarily used to determine what the largest dose of the investigational drug is that you can give to someone without causing them unacceptable side effects due to the dosing. But just because you don't have dosing problems doesn't mean the drug itself is safe. There is no guarantee of safety or efficacy post phase 1 – although in some exceptional drugs, you may see evidence of efficiency in phase 1 – but this is VERY uncommon: Phase 1 is not intended to be even looking for efficacy!"
Klein points out that serious adverse events may occur despite no evidence from the animal or phase 1 study: “Past experiences, such as that with fialuridine [in which a 1993 clinical trial for a new hepatitis B medication was abruptly terminated], demonstrate that serious adverse events may occur despite no evidence from the animal or phase 1 study.”
Bateman-House says that many of the drugs that make it through phase 1 get dropped later due either to concerns about safety or efficacy. "Same for many of the drugs that get through phase 2 – indeed, even drugs that get through phase 3 and FDA approval can have side effects – think about the side effect list of any medication you take – and drugs that have been approved by the FDA can be withdrawn because, once much larger numbers of patients use the products than used them during the trials, problems may appear. Vioxx is one example."
According to Klein, "The FDA will consider (and grants) expanded access to products at any stage of development, as well as products that may not be in active development, for example, an approved product that was withdrawn from market, or a promising product that may be impractical to study in trials because a disease is so rare that there are insufficient patients to study it adequately for marketing."
Bateman-House wonders about the net effect of RtT in relation to FDA expanded access:
"We now have two different pathways by which to seek access to investigational drugs outside of clinical trials. It is up to the company, the doctor and the institution to decide which if any of these pathways they will allow to be used – all, none, or just one. It is my prediction that most ethical and experienced stakeholders will continue to use expanded access. Despite being given a bad name by the proponents of right to try, expanded access has many backers in patient advocacy groups, the pharmaceutical industry and in medicine. As an ethicist, I would be immediately suspicious of a doctor, company, or institution that did not use expanded access but was willing to use right to try: I'd be concerned that they were using the far, far laxer standards of Right to Try to act in ways I would not condone."