In response to the article published October 9, 2019, Richard Klein, director of expanded access programs and policy for the GE2P2 Global Foundation, submitted the following counterpoint:
Patients with serious and life-threatening diseases and conditions have been accessing investigational drugs for decades through the Food and Drug Administration (FDA) expanded access process. The FDA regulations provide a pathway for drug manufacturers to make their investigational drugs available to patients, outside of a clinical trial, who have exhausted or have no other treatment options, and might benefit.
Right to Try (RtT) was passed, first in states, and then on the federal level, providing an alternate pathway to accomplish exactly the same thing, but without FDA involvement. But Right to Try is actually less, not more flexible than expanded access on three counts.
First, because it only applies to life-threatening diseases[1] - a tighter restriction than FDA’s “serious or life-threatening” standard[2]. Second, because it limits access to only drugs that have completed phase 1 testing and are actively under development.[3] (FDA’s regulations allow treatment access at any point during the development process, and can even apply to approved drugs, or those no longer being actively developed under appropriate circumstances.)[4] And third, because RtT applies only to drugs and biologics,[5] while FDA regulations can afford patients access to medical devices as well.
One more difference is that expanded access allows for treatment of cohorts of patients, where RtT only applies to individual patients. So, even from a data collection standpoint, expanded access would provide more consistent and useful information about safety across a larger number of patients.
The FDA regulations include patient protections that RtT does not, assuring that the practitioner has the expertise to treat the patient with the investigational product, and requiring that an institutional review board, or IRB, ensure that the informed consent is adequate so that the patient is aware of the investigational nature of the treatment, and the attendant risks associated with such products.[6]
Because the commercial sponsor vets the request prior to FDA, the turnaround at FDA is quick, and there are no fees involved in FDA’s review. FDA allows more than 99% of requests to go forward.[7] The very few that do not are due to serious safety issues associated with the product.
Garr claims in the article that RtT was opposed by many because it was misunderstood. The fact is that it was opposed because it was unnecessary, owing to the fact that a working process for expanded access was already in place, and that RtT significantly reduced patient protections related to the use of treatments that were not fully tested or proven.[8]
RtT creates no additional incentives for companies, since the cost recovery rules are exactly the same as FDA’s.[9] And companies that use RtT lose the benefit of FDA review by professionals who have a broader view of potential risks and safeguards through experience with hundreds of types of drugs.
But the central claim being made in the article seems to center around the collection of real world evidence (RWE). The article suggests data collected outside of a trial under RtT will provide substantial evidence about the drug, leading to a faster approval. But the reason for inclusion and exclusion criteria for trials is to make the data more interpretable, while subjecting fewer patients to potentially harmful, or futile therapies. The fact remains that only about 10- 12% of drugs in development reach the market – either because they are too toxic, or provide little to no meaningful benefit.[10]
By studying the drug in patients with very advanced disease, or those who are taking other medications, or suffer from concomitant illnesses adds noise to the study data, making it harder to determine exactly the effect, or the safety profile of the drug. Data out of context is not necessarily better data.
Garr gives an example of patients using CBD products. Those patients are likely disqualified from the trial because teasing out the effect of the CBD will cloud the effect of the test drug, and make it nearly impossible to determine which, if either, is having a positive, or for that matter, negative impact on the patient.
The purpose of expanded access it to provide treatment for patients who have no other options - not to collect data. Placing data collection burdens on the physician is likely to disincentivize access, rather than improve it.
Physicians are already tasked with treating and tracking many patients. Adding the kind of data collection likely to be of value to regulators adds another layer of responsibility, for which the physician is not being compensated.
Once the quality of the data becomes diluted by unknowns, it’s less likely that the outcomes can really offer much toward marketing approval.
AND, those patients who might receive drug under RtT could as easily and quickly receive it under FDA’s expanded access rules. Most requests are turned around within 8 days, and emergency requests are generally turned around on the same day.[11]
Further adding to safety, the adverse event reporting under FDA’s expanded access rules happen in real time. If a serious and unexpected event occurs that poses threats to other patients receiving expanded access or enrolled in the trial, that information could save injury, or lives of other patients by alerting authorities to the potential danger.
The annual reporting cycle under RtT leaves those serious, possibly deadly reactions unknown for up to 12 months.[12]
As hard as it might be to believe, there are unscrupulous players in the drug development game. And they might prefer to hide adverse reactions rather than risk bad press and loss of investors.
FDA looked back over 10 years and thousands of drugs in development. It found a total of 2 instances when a clinical hold was placed on clinical trials because of adverse events reported under expanded access. Both involved unexpected deaths, and in both cases, studies were resumed by the sponsor. [13]
If the objective is to get promising drug therapies still under development to patients who might benefit, have exhausted other alternatives, and cannot participate in clinical trials, expanded access allows for that.
Richard Klein is currently the director of expanded access programs and policy for the GE2P2 Global Foundation, after a more than 41-year career with the US Food and Drug Administration (FDA).
Klein helped develop the revised expanded access regulations and guidelines, led the creation of the FDA expanded access website and played a role in the development of the streamlined application for individual patient access, and the Reagan-Udall Foundation Expanded Access Navigator. He also served as director of the FDA’s Patient Liaison Program in the agency’s Office of Health and Constituent Affairs.
Before taking on that role, he created the FDA’s HIV/AIDS program, working with AIDS activists and advocates to coordinate their input and participation in regulatory policy and decision-making related to HIV/AIDS.
References:
[7] 2017 GAO Report (page 17)
[8] The Hill, 40 patient advocacy groups oppose 'right to try' drug bill
[10] Health Care, Tufts study: it takes eight drugs in clinical trials to get one approval
[11] Expanded Access Program Report (page 15)
[13] Expanded Access of Investigational Drugs: The Experience of the Center of Drug Evaluation and Research Over a 10-Year Period