FDA Guidance and New Drug Approvals

During 2017, the Food and Drug Administration (FDA) approved 46 novel drugs.¹ This represents the highest total since 1996.² Does this represent a trend to more approvals or a unique year? The number of drugs approved in 2017 was similar to 2015 and just a little higher than 2012 and 2014. So, we likely saw an increase that was within the normal behavior of the FDA. The low number of approvals in 2016 was likely more notable than the high number in 2017. A review of approvals for the past 7 years shows a higher number of approvals than in 2016 (Figure 1).¹ During the past 7 years, 249 drugs were approved. During this time period, we saw the addition of significant advances with treatments such as oral antivirals to cure Hepatitis C, immunological modulators to treat many cancers, and a new class of oral drugs for type 2 diabetes with a mortality benefit.

Figure 1.

Total FDA unique drug approvals by year.

So, if there was a change in philosophy at the FDA on drugs reviews, then we would expect to see an increase in 2018. If we look at the number of approvals in the first 4 months of each year, back to 2011, it suggests this may be a year with a depressed number of approvals. The beginning of 2013 suggested a robust year for approvals but ended as the second lowest total. In 2012 and 2014, the year started off modestly but ended robustly. So, the pace of approvals could pick up in the remainder of the year, but the current volume suggests a total similar or slightly higher than 2016 (Figure 2).¹

Figure 2.

Year to year comparison of drug approvals in the first 4 months of each calendar year.

Ease of Requirements for Neurologic Drugs

FDA Commissioner Scott Gottlieb has been pushing changes to optimize the review of new drugs. As part of this effort, the FDA has begun updating guidance documents for drugs in development.³ In February, the FDA issued final and draft guidance for five neurological disease.⁴ Final guidance documents were released for two diseases. The FDA guidance on the development of drugs for Duchenne muscular dystrophy discussed the challenge of designing trials where patients lose function over time, so each trial needs to be individualized. This is similar to current practice. However, the FDA did offer biomarkers such as the level of dystrophin in muscles as a trial end point. Clinical benefit is still the primary goal for approval.⁵ Migraine trials were formerly required to address pain, nausea, and sensitivity to light and sound as individual end points. With the new FDA guidance, trials will need to address pain and the symptoms an individual patient finds most bothersome. So, researchers will need to identify the most bothersome symptoms for each patient. Efficacy is determined as relief of pain and the most bothersome symptoms within 2 hours and use of rescue drugs at 48 hours. Separate studies are required for safety and use in children.⁶

The FDA also issued draft guidance for three more neurological diseases. The FDA has proposed that if reliable biomarkers can be developed to diagnose Alzheimer disease before the onset of subtle cognitive or functional changes, these biomarkers could be used as surrogate end points for drug approval. As there are no accepted biomarkers for Alzheimer disease, the FDA has encouraged researchers to develop them.⁷ For amyotrophic lateral sclerosis (ALS), the FDA has proposed that efficacy would be measured by a drug’s ability to show a clinically meaningful decrease in the time to worsening of symptoms, decrease in functionality or death.⁸ In partial onset seizures trials, the FDA has suggested that an FDA analysis found a similar dose response for adult and pediatric patients. This made it acceptable to use data from adult trials for pediatric approval. Pediatric data are still needed to determine the appropriate dose, safety, and unique characteristics of a pediatric formulation.⁹

Some of these changes were clarifications, while others suggested a broadening of the end points to seek approval. Two therapeutic areas with the biggest changes are the guidance documents for Alzheimer disease and migraine.¹⁰ These two diseases provide examples of the impact of the revised guidance statements on the development of drugs.

Alzheimer Disease

It has been debated whether potential treatments would be more effective if used before development of symptoms in Alzheimer disease. Studies in early stages of the disease have not been successful, so the drugs may need to be tested in patients at risk of developing the disease. As noted, to address this issue, the FDA proposed reliable biomarkers be developed to diagnose Alzheimer’s disease before the onset and used for drug approval.⁷

Researchers for the National Institute on Aging (NIA) and the Alzheimer’s Association (AA) have proposed a new biomarker-based definition of Alzheimer’s disease for research purposes. NIA/AA have suggested that Alzheimer’s disease be defined by beta-amyloid deposition, pathologic tau, and neurodegeneration. This amyloid-tau-neurodegeneration (ATN) classification system would provide a way to stage the disease from preclinical to overt dementia. The classification system includes both a cerebrospinal fluid (CSF) and imaging biomarker in each group.¹¹ There is some concern over the expense and burden of using these biomarkers. CSF collection may be an impediment for some patients and PET imaging is not universally available at all hospitals. The ATN classification system is being recommended for research purposes only and is not felt to be suitable for clinical use.¹²

Migraine

The new guidance for the development of drugs to treat acute migraine suggests two efficacy end points, pain and a combined end point of the most bothersome symptoms. While the final guidance was issued in February, the draft guidance was issued in 2014. Since then, some trials have been designed to use the combined end point.⁴ The results from a rimegepant trial reported in February and a ubrogepant trial reported in March used the combined “most bothersome symptoms” end point recommended in the new guidance.^13,14 It is interesting to note that lasmiditan, an acute migraine treatment from a different drug class, reported clinical trial results in August 2017 and also used the combined end point.¹⁵

Direction of FDA Approvals

The FDA is working on ways to modernize its drug review process to reflect advances in science, FDA experience in assessing new drugs, and improving access for safe and effective drugs.³ While 2017 was a banner year for drug approvals, it appears that 2018 will not see as many approvals. So, the changes being made will be seen in future years.