In 2012, Arturito Estopinan was diagnosed with thymidine kinase 2 deficiency (TK2d) at 17 months old. This extremely rare form of mitochondrial myopathy causes weakness in the limbs, as well as trouble breathing and swallowing.
At the time, there was no approved treatment for TK2d, but his parents, Olga and Art, learned of an investigational therapy being studied by Michio Hirano, MD, a neurologist at Columbia University Irving Medical Center in New York, an MDA Care Center. They reached out to Dr. Hirano, who agreed to see Arturito.
At this point, Arturito’s condition was declining rapidly. In just a few months, he had lost almost all movement and the ability to swallow, and he required breathing support.
The Estopinan family with Michio Hirano, MD (left)
“When TK2d progresses, unfortunately, it can lead to early and premature death,” Dr. Hirano says. He was involved in a clinical trial for a therapy that helps the body make more mitochondrial DNA, which is lacking in TK2d. “This therapy, in many cases, restores some motor functions to the patients, especially young patients.”
Dr. Hirano thought the therapy could help Arturito, but it was not yet approved by the US Food and Drug Administration (FDA), and Arturito could not join the clinical trial.
With Olga and Art’s support, Dr. Hirano requested that the investigational therapy be administered to Arturito outside of the clinical trial through a pathway called expanded access. After the pharmaceutical company developing the therapy agreed, the FDA reviewed the request and approved it within two weeks. When Arturito was 20 months old, he began receiving the therapy, which he continues to this day.
Now, at 14 years old, Arturito has gained back much of the movement he lost. He drives a power wheelchair and breathes independently at school. “Arturito is a very determined young man,” Art says of his son.
What is expanded access?
Expanded access, also called compassionate use, is when a pharmaceutical company provides an investigational, unapproved product to a patient outside of a clinical trial.
Expanded access may be granted in cases where an individual is not eligible to participate in a clinical trial and has a serious or life-threatening condition.
A physician must request expanded access on behalf of their patient. If the pharmaceutical company is willing to provide the drug outside of a clinical trial, the physician will seek approval from an Institutional Review Board (IRB) and the FDA. The FDA will consider many factors, including whether the potential benefits to the patient outweigh the risks and if providing the drug to the patient would interfere with the drug development program.
“All of these experts need to get together and decide that the benefits of taking this investigational product — for which we don’t have a full understanding of the effectiveness and safety because the FDA has not yet approved it — still outweigh the risks for the patient,” says Paul Melmeyer, MDA’s Executive Vice President of Policy and Advocacy. “That is not an easy bar for a prospective therapy to overcome, and consequently, at any given time, only a handful of therapies may be permissible to be obtained via expanded access.”
If a patient is in a life-threatening situation, the FDA may give immediate approval for expanded access. Typically, the review process takes about 30 days.
When expanded access is granted, the drug is provided free or at cost; the pharmaceutical company is not allowed to make a profit. However, families may be responsible for costs associated with administering the therapy — such as infusions and examinations by healthcare providers, or hospital stays — which may not be covered by health insurance.
Balancing risks and rewards
Investigational, unapproved therapies are still being studied, and researchers may not be aware of all the potential side effects. The earlier a therapy is in the drug development process, the less is known about its possible effects. Before requesting expanded access, individuals and families should carefully consider how potential risks compare to the potential benefits of an investigational treatment.
In Arturito’s case, Olga and Art understood that the therapy could cause side effects and was not guaranteed to help Arturito. However, there were no other treatments, and his TK2d had progressed to the point of causing frequent episodes of life-threatening respiratory distress. “This was the only saving answer that we had potentially for our son, and no one really knew what would happen,” Art says.
Arturito, now 14, has gained much of the movement he lost.
After Arturito started the therapy, his breathing improved, and he began regaining motor milestones he had lost. However, while the therapy was beneficial for him, that is not always the case. Sometimes, promising results in a clinical trial do not translate to other situations, such as when a disease is more advanced. There is also the risk that the investigational therapy could lead to reduced quality of life and even shortened life expectancy.
For these reasons, pharmaceutical companies and the FDA consider each request for expanded access on an individual basis. They also have other reasons to be cautious about granting expanded access.
Pharmaceutical companies must consider whether there is enough supply of the drug to make it available outside the clinical trial. Before a drug is approved and made commercially available, there may not be a way to manufacture extra doses. Companies may also be concerned about whether allowing the therapy to be used outside the closely controlled conditions of a clinical trial will affect the review and approval of the product.
In addition, the FDA must consider how granting expanded access could impact other clinical trials. Once a patient takes an investigational therapy, they may not be eligible for future clinical trials.
“The FDA is thinking about all those folks who might participate in a clinical trial. Is giving them expanded access now potentially compromising those future efforts?” Paul says. This is an especially important consideration for rare diseases because the patient population is small.
While expanded access gives individuals in need the opportunity to take investigational drugs, clinical trials have the potential to develop new therapies that will benefit a broader group of people.
“Clinical trials are still the most important and best way for our community to access therapies before FDA approval,” Paul says. “However, we know many folks are unable to participate in a clinical trial, and there isn’t an FDA-approved product that would comparably benefit their health, and consequently, an expanded access program may be their best option.”
MDA’s role in expanded access
Many neuromuscular diseases do not yet have effective treatments, and there is a robust drug development pipeline. MDA’s advocacy team engages with pharmaceutical companies and the FDA to encourage them to consider expanded access programs.
“We want to empower the FDA to have all the information and resources that they need to make an educated choice when it comes to expanded access,” Paul says.
In fact, Art has spoken with the FDA multiple times, serving as a parent advocate to help them understand the impact TK2d and expanded access have had on his family. The neuromuscular community plays a significant role in encouraging the FDA to consider patient and family experiences and the urgency of treating progressive diseases.
“For example, we think about the ALS community,” Paul says. “Some folks, after being diagnosed with ALS, may have as short as a handful of months. It’s such an urgent situation that if there’s an expanded access possibility, we strongly encourage everybody involved with that investigational product — the pharmaceutical company, clinical community, FDA, and IRB — to do everything possible to offer expanded access.”
MDA recognizes that expanded access to investigational drugs can be a lifeline in cases like Arturito’s. The ultimate goal is to balance current and future patient needs.
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