Researchers and regulators did not miss a single step in the fast-tracked federal process of developing successful COVID-19 vaccines. And the same goes for fast-tracking gene therapies for rare disease treatments, Dr. Wiley A. Chambers II of the U.S. Food and Drug Administration said during a recent webinar hosted by Sofia Sees Hope.

As the Supervisory Physician in the FDA’s Division of Ophthalmology, Dr. Chambers discussed vaccines and processes necessary for drugs to be approved for human use in our February 16 webinar episode: “Let’s Chat About…What it takes to receive approval for a new treatment for rare disease.” Sofia Sees Hope Director of Marketing and Communications Elissa Bass moderates the free monthly webinar series. You can watch the webinar here.

Dr. Chambers joined the FDA in 1987 as a primary reviewer for ophthalmic drug products and in 1990 became a Supervisory Medical Officer for Ophthalmologic Drug Products. He has supervisory responsibility for the clinical review of ophthalmologic drug products and ophthalmic therapeutic biologic products submitted to the Center for Drug Evaluation and Research.
He has clinically reviewed more than 100 ophthalmology drugs that have received FDA approval, including the first gene therapy, LUXTURNA®, approved in December 2017. The drug – administered through subretinal injection – is a human-engineered virus containing a healthy version of the RPE65 gene that causes blindness in patients with a form of Leber congenital amaurosis (LCA) called LCA2 (RPE65).

Vaccines: “We’ve Got That Down”

Talking about the recently authorized COVID-19 vaccines, Dr. Chambers said it wasn’t a matter of starting from scratch.
“We know how to make vaccines. We’ve been making vaccines for over a hundred years. We make new vaccines every year. The flu shots that come out are a change in the vaccine every year and we put a vaccine out every year that’s specific to different strains of the flu. Every year. So, we’ve got that down.”

The process did differ in two aspects because of the urgency to quell the pandemic.

“What happened with COVID is the federal government said, ‘You companies go make the vaccines. We’re still going to go through the normal process of testing it, having the FDA go and review it, but don’t wait to see if the product works or not before you make up all those doses. Make them now. And we’re going to pay you for them whether it works or not.’

“So, the companies went and did that. We didn’t skip any steps. We know how to make vaccines. We did what we typically know. We made a series of vaccines and at the same time the companies were mass-producing, as everybody would suggest now, not enough, but made a number of doses out so that when the products got approved, they already had doses made. They didn’t have to start manufacturing doses.”

The second distinction is COVID-19 – which has killed more than 550,000 Americans and more than 2.6 million people worldwide – created a public health emergency requiring urgent mitigation.

Rather than getting FDA approval or clearance, COVID-19 vaccines received Emergency Use Authorization (EUA), one of several tools the FDA is using to help make certain medical products available quickly during the pandemic. Under an EUA, the FDA makes a product available to the public based on the best available evidence, without waiting for all the evidence that would be needed for FDA approval or clearance.

EUAs are effective until the emergency declaration ends, and they also can be revised or revoked by the FDA as it continues evaluating available data and patient needs during the public health emergency.

Developing gene therapies to improve vision also meets fast-tracking requirements because vision loss is considered serious. Fast-tracking gene therapy in ophthalmology means extra meetings and FDA communication.
“But you’re not skipping any steps at all,” Dr. Chambers said.

Improving Visual Acuity

The FDA is a gatekeeper requiring that a product be safe and efficacious for its intended population before it can be marketed for human use. Dr. Chambers regularly talks with patients and solicits comments from groups about what is important to them in the search for potential treatments or cures. The information then can be modified into endpoints, or outcomes, measured scientifically through clinical trials.

“We strive to approve products that are going to benefit patients. That’s who’s going to take them. That’s who they’re for, that’s what we’re trying to go and match.”

Dr. Chambers said his personal preference is cures.

“I like diseases to go away. My endpoint, if given the choice, would be to have something go away. But I’ve got to have a product that’s capable of doing that too, so there’s a reality that sets in that I may not get a product that cures, that does everything I would like it to go and do, but we strive for as many of those things as possible and to then try to include them in the trials.”

As an example, he cited visual acuity (clarity of vision) and the ability to drive.

“For better or worse, in the United States, if you want to be independently mobile, as far as living alone in many parts of the country, you have to be able to drive…and every state in the United States has a visual acuity value that if you’re not at the visual acuity or better, you can’t get a driver’s license…

“We think visual acuity is an important thing to be able to improve for patients. Not because they say they want it but because we know if they don’t achieve that level, they’re not going to be able to drive and they’re not going to have the mobility that we know people want.”

Whether someone can see better in some aspect is an important endpoint, even if it means vision is not completely restored.
“I frequently make the comment that my head is going to hurt just as much if I get hit by a ball that I saw or that I didn’t see. If I have a blind spot and I can now not see a ball coming to me and I get hit with that ball, it’s going to hurt. It would have been nice if I had had the full field of vision so that I could see the ball coming and avoid it. So, if I improve my field of vision, even if it’s not dead center, even if it’s not visual acuity, it’s still a benefit to me.

“You’ll see us potentially approve products on things less than fixing the whole thing, but fixing some portion, and again, we’re absolutely open to suggestions by people of things that they think benefit them that we could use as endpoints.”

Research Models

Mice and rats, cats and dogs, rabbits and monkeys – they all play important roles in developing new treatments and drugs. With inherited retinal disease, dogs take the cake.

Researchers use animal models that most resemble humans, and in the case of LCA, studies showed dogs gained improved vision, leading to the federal approval of the groundbreaking drug LUXTURNA®.

Lancelot, a Briard descended from an ancient breed of large herding dogs in France, carried the same RPE65 gene that caused his blindness.

By contrast, rats would not make for good study models in retinal research because they do not have a macula.
“Rats are more interested in going around in the dark. Their eyes are different,” Dr. Chamber said. “You want to pick an animal that has similar receptors in that species.”

Lancelot and his cousins paved the way for FDA approval of the first-ever gene therapy for inherited disease in humans.

Road to Approval through Clinical Trials

The goal of the FDA is to approve a product proven to be safe and efficacious. The product’s potential adverse events are weighed against its benefits in the balancing act of risk versus reward.

The agency regulates interstate commerce, acting as a gatekeeper for any product intended for human use. Because a biotechnology company probably wants to ship the investigational drug to clinical investigators in many states, it first must seek an exemption from that legal requirement. The exemption is granted after the company submits its research for review.
“If we say nothing, they’re allowed to proceed. If we have an objection, we tell them in 30 days.”

The company can move forward with trials after the FDA assigns an Investigational New Drug (IND) number.

Beware of phony trials, Dr. Chambers said. The website clinicaltrials.gov lists both trials that have been issued an IND number and those overseen by the FDA. It also lists trials not reviewed by the FDA.

“First thing: Ask what the IND number is,” he advised. Dr. Chambers noted that clinical trials, for better or for worse, are never conducted for the people in the trial. They are geared to inform what is going to happen in the future with the product.
Rare diseases – such as the more than 25 forms of LCA and other rare inherited retinal diseases (IRDs) – present bigger challenges in finding participants for clinical trials because the rare disease community inherently represents fewer people. The definition of a rare disease in the United States is one affecting fewer than 200,000 Americans.

If only 30 people are studied, you are likely to see adverse events that occur in 10 percent or more of individuals, he said. If you study 300, adverse events can be picked up at a rate of 1 percent or above.

“It’s all about the numbers, numbers, numbers, numbers…It’s a numbers game.”

The process wends its way through more protocols, comparisons, studies, and trials until a company submits a marketing application reviewed by experts at the agency.

The FDA may hold Advisory Committee meetings for public comment from external reviewers, special government employees, patients, consumers, and advocates. In the case of LUXTURNA®, Sofia Sees Hope Co-Founder and Board Chair Laura Manfre testified at an Advisory Committee meeting on behalf of Spark Therapeutic’s application.

FDA oversight does not end after it approves a drug and a biotechnology company begins marketing it for human use.

“We now start monitoring for adverse events that might occur with the product,” Dr. Chambers said.

The process of receiving federal approval of products for human use can be long and expensive: LUXTURNA® research, development, and approval took 12 years and $500 million. The rewards, though, can be priceless, in helping children and adults see the world in a new light.

Had he received a more definitive rare disease diagnosis in 2003, Alan Gunzburg said he might not have lost so much vision and still might be able to drive.

In 2016 – 13 years after his initial diagnosis – the Greenwich, Conn., man learned his vision and hearing loss was caused by Adult Refsum Disease (ARD), a genetic metabolic disorder with symptoms that perhaps he could have staved off years ago through dietary restrictions.

Doctors initially diagnosed Gunzburg with retinitis pigmentosa (RP) – a rare inherited retinal disease (IRD) causing progressive loss of peripheral and night vision. Those are also symptoms of Refsum disease, which, if undiagnosed, can be life-threatening.

The disorder results in a buildup in the nerves and liver of phytanic acid, a type of fat found in certain foods. Other symptoms are loss of smell and hearing, numbness, unsteadiness, itchy skin, and shortened fingers and toes.

Gunzburg joined more than two dozen speakers who shared their stories during a Feb. 26 virtual Connecticut Rare Disease Day celebration sponsored by the National Organization for Rare Disorders (NORD) and the Connecticut Rare Action Network (RAN).

Read Hope in Focus (formally Sofia Sees Hope) 2021 Rare Disease Day letter to our elected representatives

His story reflects the plight of many people living with a rare disease because the more than 7,000 rare diseases in the United States are just that – rare.

It’s difficult to correctly diagnose rare diseases when little information exists about them.

Some families living with rare disease find they must create their own advocacy avenues to educate the public and the medical community about diseases they’ve never heard of.

Gunzburg created the Global DARE Foundation with the mission of Defeating Adult Refsum Everywhere. His website gets the word out about the disease and gives information on symptoms, treatments, and research.

Laura Manfre, co-founder and board president of Hope in Focus (formally Sofia Sees Hope), took that same route in 2014 after doctors genetically diagnosed her daughter with a form of Leber congenital amaurosis (LCA). As a global patient advocacy organization, Sofia Sees Hope helps transform the lives of those affected by blindness caused by LCA and IRDs by generating awareness, supporting affected families, and raising funds to advance research for diagnosis, treatments, and cures.

Creating Rare Disease Advisory Councils

The global phenomenon of Rare Disease Day exists to create awareness of rare disease, characterized in the United States as affecting fewer than 200,000 people. With more than 7,000 rare diseases, 25 million to 30 million Americans are affected by rare disease. That means one in 10 Americans suffer from rare diseases, and more than half of them are children. The European Organization for Rare Disorders (EURODIS) organizes the international campaign.

Nationally, Rare Disease Day brings together each state’s RAN ambassador – in Connecticut’s case, Volunteer State Ambassador Lesley Bennett – along with patients, caregivers, doctors, advocates, legislators, academics, and business and biotech leaders to generate awareness, increase patient and caregiver support, and drive research for treatment and cures.

This year’s event focused on creating Rare Disease Advisory Councils (RDACs) in all 50 states through NORD’s Project RDAC. Councils are made up of various stakeholders, including patients, caregivers, doctors, insurers, biotechnology companies, researchers, and state officials.

Project RDAC’s goals are to optimize existing councils and increase the number of groups nationally by opening collaborative opportunities among councils, creating educational resources to guide them, and helping more states pass legislation that establishes high-functioning councils.

More than a dozen states have RDACs, 12 are pursuing RDAC legislation, and another 23 states do not have an RDAC.

Connecticut is working toward creating a permanent RDAC task force, after a temporary group disbanded in 2019. Check out this map to see if your state has an RDAC or if NORD is working on legislation to create one. To start an effort in a state, click here.

Telling Rare Disease Stories

NORD’s Kristen Angell moderated the virtual celebration that featured more than two dozen people, sharing stories about the struggles and successes in the world of rare disease. A recording of the celebration will be available soon.

Suzanne Candela literally told an uplifting story as outreach and mission coordinator for Patient Airlift Services (PALS) with the motto: “Going Above and Beyond to Lift People Up.”

Volunteer pilots help eliminate logistical barriers to treatments by using their own aircraft, fuel, and time to fly patients to appointments. Over the course of 10 years, the company helped 2,900 families in 23,000 flights, covering more than 5.4 million miles. Candela told of a girl flown from northern Maine to Boston for repeated cancer treatments. The patient has flown on PALS flights about 60 times and counting.

The service could eliminate transportation barriers for participants in out-of-state clinical trials. The company also has flown 900 flights bringing combat-wounded veterans to appointments.

Connecticut State Sen. Cathy Osten described the story behind proposed legislation that she and State Rep. Christine Conley introduced this session to help a local family struggling to pay for special food for their two children diagnosed with phenylketonuria (PKU). The family’s share of the cost is about $36,000 per child per year. Osten said insurance companies hesitate to pay but the expense is well worth it when it comes to the quality of life for people with PKU.

David Leeds of Avon has the rare disease Hereditary Angioedema with normal C1 Inhibitor (HAE-nC1Inh), a new form of hereditary angioedema (recurring episodes of swelling) identified in 2000.

If he goes to the hospital in this time of the COVID pandemic and no one knows about his rare condition and no one can speak on his behalf, Leeds said, “We just have to hope that my rare disease doesn’t kill me before they send me home.

“I have to know everything about my disease because my doctors don’t.”

John Hopper, one of the emcees of the virtual celebration, heads the Greenwich-based Fibrolamellar Cancer Foundation that advocates for people living with fibrolamellar carcinoma, a rare liver cancer that usually occurs in adolescents and young adults with no history of liver disease.

Hopper, who also co-chairs NORD’s Rare Cancer Coalition, said his strategy is to be what he calls “the mouse that roared.”

“That means we know we’re small, but we know we have to be loud,” Hopper explains on his foundation’s website. “Most people don’t know about rare diseases. Unfortunately, a lot of people don’t care about them. Our strategy is to be that loud voice – that leader – to make sure that every stakeholder from government to academia to pharmaceutical pays attention to this cancer and understands that working on this small cancer may lead to bigger things too for the rest of them.”

Hopper encouraged all the participants in the virtual rare disease day event to be that mouse that roars.

Month: March 2021

“Let’s Chat About …” Webinar Provides Insight Into How the FDA Handles Rare Disease Treatments