Neuromuscular disease specialist and biotechnology company employee Timothy Miller says it can be a significant risk and financial hardship for a small company to supply a drug that has not been through the full approval process
Timothy Miller has been a university-associated neurologist specializing in neuromuscular disorders who has recently moved to the biotechnology industry. He has been the director of the MDA-supported pediatric neuromuscular disorders clinic at Children's Clinics for Rehabilitative Services in Tucson, Ariz.; an assistant professor of neurology, pathology and pediatrics at the University of Arizona in Tucson; and medical director for U.S. medical programs at the Cambridge, Mass., biotechnology company Genzyme. He is now senior director and head of medical affairs at Cytokinetics, a biopharmaceutical company in South San Francisco, Calif.
Q: The U.S. Food and Drug Administration has mechanisms like expanded access and accelerated approval that allow patients access to drugs that have not been approved (expanded access) or have been temporarily approved pending further studies (accelerated approval). What is it that people are least likely to understand about these FDA mechanisms? Let's take expanded access first.
A: The FDA has a process called expanded access that allows patients to receive investigational agents that are not proven to be safe or efficacious to the degree that the FDA would approve them. The FDA calls this expanded access. Patients want to call it compassionate use. I like to call it pre-approval access.
There are more companies interested in making a difference than in the past, but many are very small — some with as few as 20 people, while large pharmaceutical companies may have more than 100,000 employees. There are more companies at the table now, but they are smaller and more fragile than in the past.
At the same time, we now have lightning-fast communications, making it possible for families to make public their case for access to an unapproved drug before a company has a chance to figure out how it might provide that access.
One problem is that if a family is media-savvy, well off and educated, they can make their case much better than a family that doesn't have these assets. So access to unapproved drugs is not equitable.
A company that fulfills a request for expanded access or compassionate use has to make the drug, supply it, and track its effects. The company has to spend money to do that and has to hire staff and develop infrastructure. A small company, with limited resources, may be able to do that for a small number of patients. But if it can provide the drug to 20 patients, what about patient number 21?
There is no secret stash of an experimental drug. Money for manufacturing a new drug is dependent on investment and timelines, with the goal of bringing a treatment to market for all patients, not just some. A company that is coerced into supplying a drug that it can't afford to supply may have to close down, which doesn't help anyone.
In addition, the safety data that the FDA requires a company to gather through an expanded access program is likely to be taken from the sickest patients or from patients who do not have the precise disorder for which the drug is being developed. If there is a death or serious adverse event, that could negatively influence the future of the drug.
That's the industry side, but then there's the risk to patients associated with access to an unapproved drug. Every day, I put my industry hat on top of my doctor hat. I want what I work on to help patients, not harm them. We want to have data in hand saying a treatment is safe. I'm not an early adopter of new drugs, because many times, further experience tells you that you were wrong about a drug.
Things don't always work out the way you hope. One example is that of the drug minocycline, which, when tested in patients with amyotrophic lateral sclerosis, was found to hasten rather than slow functional decline.
Q: What are the challenges associated with accelerated approval?
A: There are two types of approval that the FDA can give — full approval and accelerated approval. Accelerated approval is no panacea. It means that the FDA approves the drug based on a "surrogate" marker [a biological indicator, such as dystrophin protein levels, that is believed to likely predict clinical benefit, such as longer survival or functional improvement, which are considered by the FDA to be "true" markers].
The FDA says to the company developing a new drug that if the company does the work it requires — conducting a confirmatory trial and following all patients taking the drug — it will consider an eventual full approval. If the company does the work and the predicted safety and efficacy isn't demonstrated, then full approval won't be granted. Likewise, if the company doesn't get the follow-up work done, there will be no approval, and the drug will be off the market. So accelerated approval has a lot of strings attached.
Genzyme used the accelerated approval mechanism for its drug Fabrazyme, developed to treat Fabry disease [ a genetic disorder that results from the buildup of a fatty material in cells, involving potentially life-threatening complications such as kidney damage, heart attack and stroke]. Fabrazyme received accelerated approval based on its ability to clear substance called GL3 from the kidneys. An accumulation of GL3 causes kidney damage. It's now incumbent on Genzyme to prove that this surrogate marker — clearing GL3 from the kidneys — actually predicts clinical benefit. They have to prove this before the drug can receive full approval from the FDA.
Genzyme can support this type of program and take the chance on not getting an approval, but a smaller company may not be able to. As much as they may not want to say so, they live hand to mouth. They may not have anything that is making money; everything is based on potential. What happens to patients if a company folds? If you don't have a business, you can't bring a product to market or keep it on the market.
In addition, as with the expanded access situation, I'm charged as a doctor to do no harm. There's a reason why a drug is not fully approved. It's because we don't have all the data. We don't know its safety, and we don't know if there is a real benefit. We need to prove that we can safely give it and that there is a benefit.
I've cared for many patients with amyotrophic lateral sclerosis, and I think I've been helpful in alleviating some of their symptoms, improving their saliva control, breathing, weight maintenance and muscle spasms and improving their life a tiny bit.
But a family dealing with ALS may be willing, out of desperation, to try anything. Patients in my clinic would say, "I'm going to Mexico or China to get intravenous immunoglobulins, or have part of my brain removed, or sit in a copper wire bath." But nothing has ever worked, and there are examples of significant side effects. Some people think their situation can't get any worse, but they're wrong: It can.
Many patients are asking for drugs that are not approved. I want patients to get a drug that is safe and effective as fast as possible, but we need to prove that as fast as possible.
Q: Do you see any way to improve things?
A: I don't have an answer. Conversation is part of the answer. I'm not terribly critical of the FDA. They're charged with a significant mission that is not easy. I have no ax to grind with the FDA; they're a mandatory part of the process. To get drugs approved on solid data, they have to be part of the solution. And companies have to be part of the solution.
I think we can do a better job than having a Twitter explosion that moves a company to do something. I'm a doctor. I want patients to have drugs that are safe and work.
Four Perspectives on Expanded Access
This article is part of a Web-exclusive series titled Four Perspectives on Expanded Access, which includes the following articles: