The US Food and Drug Administration’s authorisation of Purdue’s controlled-release methylphenidate for adult ADHD: comments on the regulatory practice

Pivotal trials of unprecedented short durations

The drug was approved for use in adults based on two trials. One was a four-week, parallel group randomised clinical trial ⁵ with four methylphenidate arms (25, 45, 70 and 100 mg) and a placebo arm. The primary outcome was investigator-rated ADHD symptoms measured on the DSM-V rating scale. The other was a cross-over trial ⁶ consisting of a two- to seven-week unblinded ‘dose-optimisation’ phase followed by 2 one-week periods with drug and placebo (FDA Clinical Review, p. 23). ⁷ At the end of each cross-over phase, the participants were tested in a ‘work environment setting’ and the primary outcome was a math test, the Permanent Product Measure of Performance test.

Two of three approved doses failed against placebo

According to FDA’s Drug Approval Package Review of Adhansia, ¹ in the four-week parallel group trial two of the four controlled-release methylphenidate arms (25 mg and 70 mg) were not better than placebo and two groups (45 mg and 100 mg) showed a statistically significant improvement measured on the trial’s primary outcome, investigator-rated ADHD symptoms (FDA Statistical Review, p. 9). ⁸ FDA approved the three lowest doses (25 mg, 45 mg and 70 mg) of controlled-release methylphenidate but not the 100 mg dose due to a ‘disproportionate’ increase in adverse events (FDA Clinical Review, p. 7). ⁷ Therefore, only one of the three approved controlled-release methylphenidate doses, the 45 mg dose, showed a statistically significant improvement compared to placebo. A meta-analysis combining all four groups versus placebo (Figure 1) shows a mean difference to placebo of 4.7 points (95% CI: 2.8--6.6) on the DSM-V rating scale (range 0–54 points), and 3.7 points (95% CI: 1.5--5.8) for the three approved doses, excluding the 100 mg group. It is uncertain if these differences are clinically relevant. OPEN IN VIEWER

Absence of patient-centred outcomes

Patient-centred outcomes, e.g. self-rated ADHD symptoms and functional capacity outcomes, e.g. absence from work, were not described in the regulatory documents. According to Health Canada’s Product Monograph of controlled-release methylphenidate, ² a quality of life outcome was measured in the pivotal four-week parallel group trial, but these results were not reported in the available regulatory documents from FDA ¹ or Health Canada ² or in the trial registry on ClinicalTrials.gov. ⁵ According to the trial registry entry, ⁵ 12 participants (4%) on methylphenidate experienced 16 serious adverse events in the four-week clinical trial and eight of these were psychiatric events, such as ‘psychotic disorder’, anxiety and feeling jittery, and two participants (3%) experienced serious adverse events on placebo (Table 1). Health Canada (Product Monograph, p. 11) ² reported only one serious adverse event (uterine cancer) of those available through clinicaltrials.gov, ⁵ and FDA reported the number of participants with a serious adverse event, but not the number or type of all events (FDA Clinical Review, p. 34). ⁷

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Table 1.

Serious adverse events reported in the randomised trial.

	Placebo	Methylphenidate 25 mg	Methylphenidate 45 mg	Methylphenidate 70 mg	Methylphenidate 100 mg
N group/ n affected	78 /2	77 / 4	73 / 2	73 / 2	74 / 4
Type of events/ (n events)	Headache (2)	Cellulitis (1), muscle strain (1), headache (1), nephrolithiasis (1)	Osteoarthritis (1), uterine cancer (1)	Feeling jittery (1), calculus urinary (1)	Diarrhoea (1), anxiety (1), emotional disorder (1), insomnia (3), mood altered (1), psychotic disorder (1)

The drug regulator’s role: provider or gatekeeper?

FDA concluded in their clinical review, ‘From the regulatory perspective, there is no reason to not approve PRC-063. Results of Phase 3 trials demonstrated reasonable safety and effectiveness when PRC-063 is dosed so that the benefits outweigh the risks (adverse events)’ (FDA Clinical Review, p. 7). ⁷

This drug approval raises questions about the drug regulators’ role when they decide on marketing authorisation for new drugs. The drug was approved on the basis of one parallel group trial with an unprecedented short duration of four weeks and one cross-over trial of work related tasks with a one-week treatment phase only; there were no patient-centered outcomes reported in the regulatory documents, e.g. patient-rated symptom improvement or quality of life; and there was no statistically significant improvement on the pivotal trial’s primary outcome for two of the three approved doses.

The bar set for drug approval by our drug regulators seems to be defined by political priorities rather than scientific needs. ⁹ If the role of our drug regulators is to act as drug providers, i.e. by approving drugs based on any signal of effect with minimal, or no considerations on the clinical relevance and leaving such considerations to guideline and policy makers, clinicians, and insurance companies or bodies responsible for reimbursement, then the approval of controlled-release methylphenidate for adult ADHD was arguably a failure. The drug failed to demonstrate a statistically significant effect compared to placebo in two of the three approved doses for the primary outcome.

If the role of our drug regulators is to act more restrictively as gatekeepers, ¹⁰ i.e. by approving drugs only when it is demonstrated that clinically relevant effects outweigh harmful effects, then the approval of controlled-release methylphenidate was clearly a failure. There was questionable evidence of clinically relevant effects presented in the regulatory documents, whereas there were concerns of the harmful effects, especially psychiatric serious adverse events.

Ensuring that new drugs improve clinical practice

One could argue that methylphenidate is a well-known drug with many available extended-release formulations (e.g. Concerta, Focalin, and Ritalin LA) already on the market and approved for use in adult ADHD. One could therefore conclude that the benefits and harms are already established and the required evidence to ensure approval should be less rigorous than for a new drug. However, there is one important counterargument to such position given what was submitted to the regulators; if methylphenidate has already been approved and is considered beneficial for the indication in question, it does not seem ethically justifiable to conduct more placebo-controlled trials because there is no clinical equipoise. ¹¹ New drugs should arguably always be tested against active comparators in indications where effective treatments already exist. For indications where the treatment effect of available drugs is questionable, it seems reasonable also to test new drugs against placebo.

Interestingly, FDA’s Guidance Document on designing pivotal trials for ADHD drug approvals ¹² recommends the design of placebo-controlled ADHD medication trials without explicitly requiring an active comparator. Conversely, the European Medicines Agency’s Clinical Efficacy and Safety guideline on how to conduct pivotal trials for ADHD drugs ¹³ recommends the use of a three-arm clinical trial design comparing the new drug of interest with placebo and an active comparator. In the case of stimulants for adult ADHD, the three-arm study might be the most feasible study design, considering that the benefits of already approved ADHD medications over placebo in adults with ADHD are questionable.^14–16

Regardless of the regulatory reasoning behind accepting such evidence base for this approval, we wish to highlight that Purdue’s controlled-release methylphenidate was approved despite a lack of demonstrated beneficial effects over placebo for two of three approved doses in the pivotal parallel-group clinical trial.

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