“There’s lots of things that she used to be able to do just fine,” said her mom, Londen Tabor, who lives with her daughter in Gillette, Wyoming. Autumn’s speech has become slurred and her cognitive skills slower. She needs help with many tasks, such as writing, showering and dressing, and while she can walk, her balance is off.

Autumn has been turned down for clinical trials because she is too young.

“It is so frustrating to me,” Tabor said. “I would sell my soul to try to get any type [of treatment] to help my daughter.”

For patients like Autumn with serious or immediately life-threatening conditions who do not qualify for clinical trials and have exhausted all treatment options, there may be another option: seeking approval from the Food and Drug Administration for , or compassionate use, of experimental therapies.

Definitive numbers are hard to find, but studies from researchers, actions by drugmakers and insights from experts suggest that getting expanded access to unproven therapies for rare diseases is more difficult than for more common illnesses, such as cancer.

Even with experimental treatments on the rise, patients with rare diseases frequently face an unwillingness by drug companies to provide them before clinical studies are completed. Developing drugs for these diseases is an especially fragile process because the patient populations are small and often diverse, having different genetics, symptoms and other characteristics, which makes studying the drugs’ effects difficult.

Drugmakers believe offering a drug before studies are finished could impair its development and jeopardize FDA approval.

Companies working on therapies for rare diseases, especially smaller ones, could feel those repercussions acutely, said Lisa Kearns, a researcher in the ethics division of New York University’s medical school and member of the division’s working group on compassionate use and preapproval access. “There’s not as much investment in rare diseases, so an [adverse] event could frighten the already limited number of potential investors.”

Drugs that were not made available for compassionate use last year until studies were completed include , ; Enspryng, for an ; and , .

A spokesperson for Roche, which makes Evrysdi and Enspryng and is working on a treatment for Huntington’s disease, said the decision was tied not to the type of disease but to company policy: Roche does not set up expanded access programs for any drugs until results are available from a phase 3 clinical trial. (Those phase 3 studies are typically the last testing done before the company seeks drug approval.)

Another company’s experimental drug for , an autoimmune disease that leads to skeletal muscle weakness, similarly was not available through until , and no programs have started for a therapy being studied in and , a fatal neurodegenerative disease often referred to as Lou Gehrig’s disease.

One slight, but notable, deviation: Drugmaker Biogen this year to allow certain ALS patients to receive an experimental drug , after the testing was to be completed but before the results are known.

Dr. Merit Cudkowicz, a neurologist at Massachusetts General Hospital in Boston, has helped patients get therapies through expanded access. Since September 2018, she and colleagues being developed by drug companies, but only about 120 patients have received therapies this way. More than 16,000 people in the United States in 2015 to have ALS and do not qualify for clinical trials because of the progression of their disease or very strict eligibility requirements.

These examples contrast with some drugs for more common problems. , for leukemia, was offered to thousands of patients through expanded access programs before the manufacturer completed the clinical studies that led to FDA approval. , for HIV/AIDS, and , for the most common type of lung cancer, were similarly offered to large numbers of patients even as clinical trials were ongoing.

Last year, Novartis gave more than 7,000 patients worldwide early access to cancer drugs.

Doctors also report that getting experimental drugs for cancer patients is relatively simple. More than 200 physicians around the country were surveyed, and among those who applied for access, said they had secured drugs still being investigated for patients who were not responding to approved therapies.

California researchers found similar trends in a of 23 social media campaigns launched by patients between 2005 and 2015 seeking a variety of experimental treatments. While seven of the 19 patients with cancer received early access to requested drugs, no access was allowed for three patients with rare diseases, although one of those patients was allowed to enroll in a clinical trial.

Companies base their decisions on whether to provide a therapy through expanded access on a number of factors, said Jess Rabourn, CEO of WideTrial, which helps pharmaceutical companies run compassionate use programs. In general, there should be evidence that patients can tolerate the treatment and an expectation that any benefit outweighs the risk, he said.

“This idea that you have to wait until the research is done is baloney,” he said. “We’re talking about patients who are going to die if they’re told to wait.”

But drugmakers often view it differently, even though evidence suggests that granting early access drug approval.

Kearns explained that companies often wait until phase 3, or after, because they can be “relatively” confident of a drug’s safety and effectiveness. “They don’t want to harm patients, of course, but they also do not want to threaten the drug’s eventual regulatory approval with an adverse event in [a] very sick patient population.”

Melissa Hogan, who consults on clinical trials for rare diseases and is an , attributes the lack of access to the high cost of therapies and the tightknit nature of the rare disease community, where patients and their families often set up social media groups and exchange ideas and treatment plans. Companies “know that if one patient gains access, other patients will know” and ask for access, said Hogan, who has a son with mucopolysaccharidosis type II. That could overwhelm small drugmakers with little manufacturing capacity.

These concerns cause “many companies [to] just throw up their hands and take a hard line of no [expanded access] until they reach approval stage,” said Hogan.

The 2018 offers another option for some patients. Unlike expanded access, the law applies only to requests for medicines — not medical devices — and does not require approval from the FDA or an , a committee that reviews and monitors people participating in research for their protection. The legislation, however, doesn’t oblige companies to grant a request.

For Cali Orsulak, expanded access may be her husband’s only option. He was diagnosed with ALS in 2019 at age 43.

“We did our best with the skill level we had to search clinical trials all over Canada and the U.S., and then covid hit and it became increasingly difficult,” said Orsulak, explaining that they live in Canada but seek medical care in the United States. “Now that my husband has progressed, it’s even harder to get into clinical trials.”

ºÚÁϳԹÏÍø News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about .

USE OUR CONTENT

This story can be republished for free (details).

“I didn’t really want to do it,” recalled Tran, who had just turned 21 and was living in New York City, “but she kept on emailing me about it and was really adamant that I do it.”

Tran knew she had an elevated risk of developing breast cancer because of her family history — her mother died of the disease and a maternal aunt was diagnosed and survived. Given this, she planned to follow the to begin breast cancer screenings at an early age.

But she feared that if the testing her doctor was suggesting revealed a genetic variation known to cause breast cancer, she would have to decide whether to have her breasts surgically removed. That was a decision she was not ready to make.

Doctors are increasingly testing people’s genes for signs of hereditary risks for cancer, said , a medical oncologist and the director of the Women’s Clinical Cancer Genetics Program at Stanford University. If the tests find a genetic variation known to cause cancer, treatments or preventive measures may be recommended to prevent the disease, she said.

But the trend can unsettle patients like Tran, sometimes unnecessarily, because many genetic findings are ambiguous, leaving doctors uncertain about whether a particular variant is truly dangerous.

Multiple-gene panel tests emerged in 2012 and the number of genes covered in these panels has since ballooned, with commonly available.

However, the chances of finding an inconclusive result — which can be troubling for patients and confusing for doctors to interpret — rises as more genes are tested. A showed that multiple-gene screening was 10 times more likely to find inconclusive results than a test that examines only two genes, , long associated with a higher risk of breast and ovarian cancer.

An inconclusive result is known within the medical community as a variant of uncertain significance, or VUS. It may be a harmless variation in a gene — or one linked to cancer.

Detecting such variations is common. showed the percentage of patients who learn they have a VUS after multiple-gene panel testing varied in studies from 20% to 40%.

“The larger the panel someone orders, the more likely we are to find one or even multiple variants of uncertain significance,” said genetic counselor Meagan Farmer, director of genetic clinical operations at My Gene Counsel, a Connecticut company that provides online genetic counseling tools.

Farmer has seen patients change their minds when she informs them of this reality. “That patient that thought they wanted everything [tested] might then kind of scale back what they were looking for.”

Kurian said patients can be tested for all the cancer genes available as long as they understand that the analysis of many genes will likely not be informative. Several years later, if more evidence accumulates for a particular gene, those results may inform medical decisions.

“It’s not wrong” to conduct the tests, said Kurian. “But it needs to be appropriately handled by all parties.”

In fall 2018, having never heard of a VUS, Tran settled on the most comprehensive screening: a gene panel that at the time evaluated 67 genes for various cancer types.

People who belong to racial minority groups have of harboring a VUS because most genes were sequenced first in white people, who also tend to have better access to testing, according to a study by Stanford researchers including Kurian. It showed that, among a racially diverse group of people who had multiple-gene panel testing, more than one-third who were not white had a VUS result, whereas one-quarter who were white did.

Testing revealed that Tran, who is Vietnamese, had a VUS in a gene associated with , a hereditary condition that increases the risk of developing colon cancer, uterine cancer and other cancers. The genetic counselor explained the VUS was inconclusive and should not be used to inform medical decisions.

Although Tran does not dwell on the VUS, the testing process itself caused emotional turmoil. “I really did the test mostly for my doctor and not for myself,” Tran said. “If I could have chosen, I would not have done it.”

But other patients are more unnerved by uncertain results. “The VUS is scary because it’s a crapshoot,” said Logan Marcus, of Beverly Hills, California. She has a rare variation in BRCA1 that one genetic testing company said is “likely pathogenic” and another said is a “VUS.”

A genetic variant found in testing can be classified — in decreasing severity — as “pathogenic,” “likely pathogenic,” “VUS,” “likely benign” or “benign,” and that commercial laboratories and companies sometimes disagree on how to classify a variant.

The consensus among experts is not to make medical decisions, such as whether to have surgery, based on a VUS because as more research is done and more people are tested.

Yet, doctors who do not have training in genetics often don’t follow that advice.

“I’ve actually seen this a number of times, and it’s a very real concern,” said , a clinical cancer geneticist and the director of the Center for Cancer Prevention and Wellness at the Icahn School of Medicine at Mount Sinai in New York City.

Researchers recently found that doctors may be inappropriately recommending surgery based on a VUS. The results were presented virtually at the 2020 American Society of Clinical Oncology annual meeting and have not yet been published in a peer-reviewed journal.

More than 7,000 women were surveyed about their experience with multiple-gene panel testing, and among those with a VUS in a gene associated with ovarian cancer, 15% had their ovaries and fallopian tubes removed. Surgery was not warranted for these women because experts say a VUS should not be used to make medical decisions. Furthermore, many of these women did not have a family history of ovarian cancer and had not reached menopause, yet 80% reported that their doctor recommended surgery or discussed it as an option.

It is not just the procedure that causes problems, explained the researcher who led the study, , a medical oncologist and executive director of the Basser Center for BRCA at Penn Medicine’s Abramson Cancer Center. Women who have their ovaries taken out before menopause start menopause early, which raises their risk of developing health problems such as osteoporosis and heart disease.

The study also showed that doctors often recommended surgery even for women who had alterations in genes not associated with ovarian cancer — more evidence, Domchek said, that doctors who lack training in genetics often misinterpret these results.

In another , Farmer and her colleagues described instances when health care providers ordered the wrong genetic test or misinterpreted the results. that nearly half of 100 surveyed doctors were unable to correctly define a VUS.

Experts say patients who learn they have a VUS or receive conflicting results should see a provider with expertise in genetics, such as a genetic counselor or clinical cancer geneticist, especially if surgery is being recommended.

Having had multiple relatives with cancer and after seeking advice from a genetic counselor, Marcus plans to have a double mastectomy to prevent breast cancer and give her peace of mind, but she’s unsure whether she’ll have her ovaries removed to prevent ovarian cancer. At age 39, she has not had children yet.

“This has been a two-plus-year struggle for me,” said Marcus. “I felt very alone, and nobody could give me any answers.”

ºÚÁϳԹÏÍø News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about .

USE OUR CONTENT

This story can be republished for free (details).