NEW YORK – The International Society for Cell and Gene Therapy (ISCT) wants stakeholders in the field to consider concerns about scientific integrity, ethics, and equity in giving patients compassionate-use access to promising investigational treatments as more enter clinical trials.
The US Food and Drug Administration's expanded access pathway began as a proposal by Anthony Fauci, former director of the National Institute of Allergy and Infectious Diseases, at a meeting in San Francisco in 1989 to make investigational drugs available to HIV-infected patients who were not able to participate in standard clinical trials and who had no approved therapy options. Today, the program allows patients with a serious or immediately life-threatening disease, who don't have standard treatment options and can't partake in clinical trials, access to drugs that the FDA hasn't approved for their condition. For patients to access investigational therapies through this pathway, the FDA, drugmakers, and patients' doctors must determine that the potential benefit of the treatment justifies its risks, and that giving patients the unapproved drug will not interfere with market authorization-enabling clinical trials underway.
More recently, the Right to Try Act became US federal law in 2018, adding another pathway for patients to access investigational drugs outside of clinical trials. However, the federal law and various state-level right-to-try laws have been criticized for not providing enough protections for patients and drugmakers.
At the same time, in the US, there has been increasing demand among patients for expanded access to cell and gene therapy products. But unlike small molecule drugs, cell and gene therapies have novel mechanisms and modes of action, and their effects are largely irreversible.
If a patient has a serious adverse event on a small molecule drug obtained through expanded access, those effects can generally be mitigated or fully reversed by discontinuing the therapy, which eliminates it from the body. Conversely, cell and gene therapies impose longer lasting or even permanent changes on the body that are not reversed by stopping treatment. Thus, the stakes for patients trying to access these advanced therapies through expanded access programs are higher.
In a report published in Cytotherapy last month, the ISCT highlighted areas of concern where future policy solutions are needed to protect patients and the overall integrity of the drug development process.
"Non-trial access to investigational products is nothing new," said Patricia Zettler, the report's author, an associate professor of law at Ohio State University and a former attorney at the FDA. "There have been non-trial access programs for decades, but because the cell and gene therapy field is maturing and patient interest is increasing, it's a good time to start thinking about what are the issues that might be particularly salient for the field."
Several CAR T-cell cancer therapies are currently, or were at one point, available through expanded access programs, including Gilead's Yescarta (axicabtagene ciloleucel), Novartis' Kymriah (tisagenlecleucel), Janssen's Carvykti (ciltacabtagene autoleucel), and Bristol Myers Squibb's Breyanzi (lisocabtagene maraleucel).
While expanded access programs like these, on the one hand, provide a way for patients to receive a potentially beneficial drug, the downside is that they're taking a risk on an unproven therapy. "By definition, there's a risk that you're getting something that's ineffective or maybe even unsafe," Zettler said.
There are risks for drugmakers as well. Studies show that drug trials are difficult to enroll, particularly in the era of precision medicines designed for small, biomarker-defined subsets of patients. By one estimate from 2018, around 20 percent of cancer clinical trials fail due to investigators' inability to enroll patients.
If patients are accessing unapproved therapies outside of a clinical trial, this may place additional pressure on drugmakers' ability to enroll ongoing drug trials. "If we don't protect clinical trials and the ability to develop rigorous evidence on safety and effectiveness, we may never know which products actually work and which products don't," Zettler said. "There is a need to balance non-trial access against the need to ensure that we can actually get the safety and effectiveness evidence that healthcare professionals and patients need in order to make decisions about their care."
Another emerging hazard is that these expanded access programs could become the primary route for commercializing drugs. Currently, FDA regulations limit sponsors from charging for investigational products. However, there are other ways to profit from expanded access programs.
"The regulatory requirements specify that [drug] developers cannot profit off the sale of the product itself. But there are concerns that others within the expanded access world can commercialize the services that come along with providing the products," such as nursing care, equipment, clinical procedures, and pharmacy services, Zettler said, adding that these approaches might occur "in ways that might undermine incentives to continue to study a product."
While the FDA limits drugmakers from profiting from unapproved drugs in the US, expanded access programs are structured differently in other countries. As such, a pharmaceutical company may garner approval for a product in the US and begin offering it to patients in other countries through an expanded access program while the drug undergoes regulatory and reimbursement review. Sometimes, the regulations in a particular country may even allow the sponsor to charge the health system for a drug offered through an expanded access program. For example, Alison Bateman-House, an assistant professor in New York University School of Medicine department of population health, said Australia's regulations allow its health system to pay for drugs not yet approved in the country. "In other countries, it might be the hospital or the patient [who pays]. There's no globally uniform policy," she said.
"I'm spending a lot of mental energy right now thinking about expanded access outside of the US," Bateman-House, who is also a member of NYU's working group on compassionate use and preapproval access, added. She said even when approval is granted quickly by regulatory bodies such as the European Commission, countries with single-payor systems in the EU often have price-setting negotiations with drugmakers before a treatment can be offered to patients in that market. These negotiations can sometimes take up to three years.
"As you can imagine, there's nothing more stressful for someone with a serious disease to know than that a drug has been approved, but you just can't get it in your country because no one's been able to agree upon a price for it yet," said Bateman-House.
That creates a strong demand for expanded access programs run by drugmakers in the interim. Typically, pharma companies provide expanded access treatments for free, but not always. "There's no rhyme or reason," Bateman-House said. "Sometimes, they charge what they would charge in the US, even though when they eventually come to market, they're going to be significantly cheaper."
The UK's Cancer Drugs Fund (CDF) is one pathway for providing earlier access to therapies for which regulators are still gathering evidence of effectiveness, and the National Institute for Health and Care Excellence is still determining cost effectiveness.
For example, in April, NICE recommended Gilead's Yescarta and Tecartus (brexucabtagene autoleucel) for inclusion in the CDF, which made Yescarta available to patients with diffuse large B-cell lymphoma as a second-line treatment and Tecartus to patients with relapsed or refractory B-cell acute lymphoblastic leukemia. The drugs will be available to patients through the NHS at a discount through a managed access agreement with Gilead while NICE collects additional data to address uncertainties about their long-term efficacies. The additional cost-effectiveness data will then inform the institute's final recommendation about whether these treatments should be available to NHS patients routinely.
Bateman-House felt that drugmakers' ability to charge for treatments provided within expanded access programs is something that policymakers needed to address. "Obviously, the price charged impacts the number of people who can get access," she said.
In its report, ISCT also addressed the need to promote equity and ensure that not just patients who have the resources to navigate the expanded access process are gaining access to unapproved cell and gene therapies. "Is it people gaining access who have the best social media presence or are the most compelling or most sophisticated in terms of their knowledge about how to work the system?" Zettler said, noting that these equity issues aren't unique to cell and gene therapies and have been raised about non-trial expanded access programs for investigational drugs broadly.
However, because cell and gene therapies comprise a still burgeoning field, it may be more vulnerable to inadvertent clinical trial delays due to expanded access to investigational drugs. This, in turn, can delay regulatory review and market entry of these products.
Zettler and her coauthors are planning to provide more prescriptive policy recommendations on expanded access for cell and gene therapies in a future publication. The current report, she said, "is meant to explain the history of non-trial access, and why this is a good time for the cell and gene therapy field to focus on these questions."