How do clinical trials work at ADOA?
Right now, several companies are about to start clinical trials (PYC, Stoke, etc.). These are necessary to demonstrate that their treatment actually works. But what steps must be taken before a drug can be prescribed by your doctor?
Before a pharmaceutical company can begin clinical trials in humans, researchers must first submit their laboratory data obtained from tissue and animal studies to a regulatory agency. In the US, pharmaceutical companies submit their data as part of an Investigational New Drug (IND) application to the Food and Drug Administration (FDA). In Europe this is an Investigational Medicinal Product Dossier (IMPD) and is submitted to the European Medicines Agency (EMA). After a successful application, a clinical trial can begin.
Figure 1. Clinical studies https://www.centerforcognitivehealth.com/clinical-trial-myths-vs-facts/
Trials usually consist of three phases: first-in-human or phase 1 studies, phase 2 safety and efficacy studies, and phase 3 efficacy studies. The first phase determines whether a new drug or treatment is safe. If the drug or treatment is considered unsafe, or if it has very unwanted side effects, the study will fail and will not proceed to additional testing. Because side effects often depend on the medication dose, the optimal dosage is also determined during this phase. If a drug successfully passes this phase, it can move on to the next phase, Phase 2, to test its efficacy. When studying a rare disease such as ADOA, it is often difficult to recruit patients to participate, so these studies are sometimes conducted together as a combined phase 1/phase 2 study. Because the natural progression of ADOA is slow, it takes time to assess the effect of a drug or treatment, so a study may last four years with multiple assessments during that period. If there is any effect, the magnitude of the effect will be evaluated in a phase 3 clinical trial. In this final phase, patients are divided into two groups, where the toss of a coin determines whether a patient receives a treatment or a fake treatment (a treatment that cannot be distinguished from the real thing, but has no active substance). This allows researchers to 1) take into account the fact that patients often experience improvement from the sham treatment and 2) compare the two groups to assess improvement, or in the case of ADOA, the visual function of those taking the treatment have received versus those who think they have received it.
Because there are currently no treatment options for ADOA, the first company with an effective treatment does not necessarily have to complete all 3 phases before applying for market approval. If there are early signs of improvement during an efficacy trial, and especially if the improvement is large, the pharmaceutical company may attempt to apply for early market approval. So for example, if a study lasts four years, but after two years there is data showing the product's efficacy, a company may be able to apply for early market approval while the study is still ongoing.
Although standard tests usually involve looking at changes in a person's visual functioning, there are other measures to assess the effectiveness of a drug or treatment. As we know, the ADOA disease process begins with reduced OPA-1 protein, which in turn leads to reduced mitochondria, which leads to damage to cells, which leads to changes within the optic nerve and ultimately to vision loss. Before vision loss occurs, multiple physiological changes take place, so it is possible to look for early markers, such as a person's mitochondria or the presence of damaged retinal ganglion cells. The ability to look at these markers would be especially useful for early detection of the disease, especially in those with known OPA-1 mutations who do not yet have visual symptoms. This information could potentially help guide treatment decisions and determine whether a therapy would be appropriate to begin with.
Once a drug is considered safe for adults, a company can conduct additional testing to determine safety in children. This process would start with children aged 12-18, followed by a younger population, and so on. But none of this can happen until adult safety testing is completed, and sometimes even more data is needed according to regulators before moving on to testing in children.
It is important to note that market access is not the end of the story. Gene therapy can be extremely expensive, with some treatments costing hundreds of thousands or millions of euros/dollars. Although doctors can prescribe such treatments, only a select few can afford them, which is why it is important that health systems and insurance companies cover the treatments. Health systems have additional requirements for reimbursement, they may want additional studies or analysis from the pharmaceutical companies.
