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Unapproved Drug for Babies? Ethics Experts Weigh In

— You voted, now see the results and expert discussion

MedpageToday
A baby in a crib in a hospital receiving intravenous fluids

Welcome to Ethics Consult -- an opportunity to discuss, debate (respectfully), and learn together. We select an ethical dilemma in patient care, you vote, and then we present an expert's judgment.

Last week, you voted on if it was OK to give babies an investigational drug outside of a clinical trial. Here are the results from more than 300 votes:

1. Is it worthwhile to attempt to get non-trial [MOU1] access to investigational drugs with limited evidence to support their use?

Yes: 298

No: 37

2. Who should make the final decision as to whether the twins should get access?

Parents/guardians: 147

Medical team: 71

Pharmaceutical company: 6

Ethics committee/institutional review board: 88

FDA: 24

3. Is it permissible for physicians to participate in social media campaigns to pressure pharmaceutical companies to give patients access to investigational drugs?

Yes: 175

No: 159

And now bioethical experts Alyssa Burgart, MD, MA, and Alison Bateman-House, MPH, PhD, weigh in:

Desperately ill patients and families with unmet medical needs may request access to experimental, non-FDA approved medications or devices outside clinical trials.

In this case, the parent requesting access to experimental therapy has especially relevant experiences that lead to the request. A previous child has already died from the same condition affecting her twin sons, and that child was enrolled in a clinical trial testing the requested experimental therapy. That trial is now closed and not available to her infant sons.

This tragic story calls on our desire to rescue patients, whenever possible, even when the chance of success or unintended harm is unclear. Requests for unapproved treatments create ethical concerns around safety, efficacy, therapeutic misconception, informed consent, fairness, cost, and unrealistic hope.

This family's familiarity with both the untreated disease and the experimental product allows them a level of knowledge that is fairly atypical in such cases, and which increases the likelihood of truly informed choice by the parents on behalf of the children.

Seeking access to investigational medical products outside of clinical trials -- not for research but in the hopes of deriving therapeutic benefit for a patient -- has traditionally been called "compassionate use," although this term is more recently being replaced by "preapproval access." The FDA's to access such potential treatments is called "expanded access" (EA).

EA, as a regulatory pathway, evolved out of the AIDS crisis, when patients were dying faster than treatments could be studied and approved, and when only small numbers of patients were able to enroll in clinical trials for possibly effective treatments. In the EA process, the patient must be terminally or seriously ill, have no approved medicines left to try, and be unable to participate in any trial ongoing for the desired investigational product.

A libertarian organization led a campaign encouraging states to enact "right to try" (RTT) laws attempting to bypass the FDA, claiming the process was too burdensome to be effective. These laws were irrelevant, as states do not have authority over investigational medicines (a federal issue, adjudicated by the FDA). However, the momentum led to a federal Right to Try law (signed into law in 2018) creating a regulatory pathway parallel to the existing EA pathway.

The two share many commonalities, but diverge in terms of oversight: the RTT process excludes the FDA, which otherwise provides valuable guidance to enhance patient protection. The federal Right To Try Act is more restrictive than EA, requiring eligible patients to be terminally ill and unable to participate in any trial ongoing for the desired investigational product, applying to only certain types of investigational drugs, and accommodating only single patients (while EA can accommodate requests from groups of similar patients).

At present, less than 10 patients have accessed products via the federal RTT law, while most patients who receive non-trial preapproval access do so via EA. Patient requests for non-trial access to investigational, unapproved drugs must come through physicians, so clinicians have an active role to play in these decisions, whether it's via EA or RTT.

While the RTT law wasn't a good solution, it made apparent the frustration of those who want to try experimental medical products but can't get access. For the most part, this is due to companies being unwilling to grant access to their products in development. Companies may decline access for a variety of reasons, such as concerns about dangerous side effects leading to patient harm, legal costs, and bad press.

There can be other negative financial impacts if investors perceive that the experimental drug is too risky. With the power to decline access, companies essentially have the final say on whether a patient will get to try therapy. Right to Try did not effectively address this issue, as it was primarily intended to remove oversight by the FDA and institutional oversight boards. Right to Try advocates claimed that the FDA was too slow and often declined to permit patients to try investigational products outside of clinical trials -- claims that are not supported by the data.

Indeed, the FDA has worked to relieve barriers to access and made the process far easier for clinicians to navigate. At this time, the agency approves , although the FDA may make changes to the proposed treatment plan.

Regardless of whether the EA or RTT pathways are used, multiple steps must be taken to get access to experimental therapies outside of a clinical trial, and numerous stakeholders must agree to move forward.

First, the clinician and patient must agree that an experimental drug is worth trying. Navigating the informed consent process may be particularly difficult when we're unsure about potential benefits and harms. Patients need to understand that most drugs in development never make it to market, due to safety and efficacy problems. Plus, there's no guarantee an experimental drug will work for the patient. Some drugs might be lifesavers, but others may contribute to suffering or even an earlier death.

We know from social psychology studies that people tend to believe that spending more money is a proxy for "better," so clinicians need to make sure patients understand that an expensive experimental therapy isn't necessarily any better than a cheap one or even no therapy at all. Some patients fear abandonment if they stop curative treatment, so we need to make sure we communicate that patients will be cared for regardless of their decision to receive an experimental intervention (or not).

Additionally, clinicians need to disclose if they have relevant conflicts of interest influencing their decision to recommend an investigational product. We also need a mechanism for mandatory reporting on patient outcomes from EA and RTT cases. These cases can help us learn how to continuously improve the informed consent process and further contribute to the research landscape.

In terms of steps to get access, the physician caring for the patient must reach out to the drug manufacturer and request access; the hospital's Institutional Review Board must approve non-emergency interventions (mandatory in EA, possible in RTT); and in EA, the FDA is asked to review the treatment plan.

Patients, families, and clinicians may not realize that most insurance companies will not pay for investigational medicines outside of clinical trials. Some will pay for associated costs (staff, room and board, tests), but others won't. Clinicians should discover what costs will be reimbursed and how their institutions will react to unpaid expenses.

In the United States, where there is differential access to even basic medical care, access to non-trial preapproval drugs is at risk for great inequity (as with who gets to participate in clinical trials in the first place).

Whether clinicians should participate in social media advocacy campaigns is not an area where there is clear guidance. The American Medical Association on a number of pressing healthcare issues, and from that standpoint, there is no prohibition on advocacy for access to experimental drugs and devices. If a clinician feels very strongly, based on available evidence and knowledge of the case, that access to therapy outside of a trial is justified, the clinician may understandably see advocacy as a professional responsibility to the patient.

The driven commitment of the medical team is a vital component to access, and public-facing pleas from healthcare providers may be useful in swaying companies to grant it. However, such advocacy is not obligatory. In that sense, we see this as permissible, and up to the individual clinician.

For further reading on this topic, Bateman-House's work includes:

, is assistant professor of anesthesia at Stanford University School of Medicine and core faculty in the . She is a bioethicist at Stanford Healthcare and Lucile Packard Children's Hospital.

is assistant professor in the Division of Medical Ethics at NYU Langone Health's Grossman School of Medicine. She is co-chair of NYU Langone's Working Group on Compassionate Use and Preapproval Access (CUPA).

Also check out some of our past Ethics Consult cases:

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'Freeze' Little Girl in 6-Year-Old Body?

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