INSY: What the Advisory Committee Will Think & How the FDA Will Regulate

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SUMMARY

  • Advisory committee historical voting records don’t favor INSY’s buprenorphine sublingual spray (Buvaya).
  • The safety trial could be too short and confusing for the AdCom or FDA to make practical sense of.
  • Buvaya may have the potential for abuse: the FDA might not care but the AdCom probably will.
  • The AdCom might punish INSY for its “sins”.
  • A statistical re-analysis may negate some efficacy data.
  • A critical update is pending.

BACKGROUND

On May 22nd, an advisory committee (AdCom) will convene to discuss whether Insys Therapeutics’ (ticker: INSY) drug candidate, a buprenorphine sublingual spray (Buvaya), should be approved.

Buvaya is an immediate release opioid intended for the management of “moderate-to-severe acute pain where the use of an opioid analgesic is appropriate”.

Buvaya has an expected PDUFA action date of July 28th, 2018.

While this article focuses on the upcoming AdCom, most of its points are highly relevant to the FDA’s thinking and potential action on the NDA as well.

This is important because while the FDA commonly acts in accordance with an AdCom’s recommendations, it doesn’t do so roughly 13% of the time.

That’s because the AdCom’s judgements aren’t always based upon the same line of thinking as the FDA’s. This article will examine their similarities and differences.

ADCOM: HISTORICAL TRENDS

VOTING RECORDS

Historically, AdComs have voted to approve a drug 78% of the time between 2001-2010, 74% of the time between 2008-2012, and 73% of the time in the years 2013-2015.

The methodologies between the three papers linked-to above differed; so a conservative estimate of at least a 70% approval rate may be reasonable.

Noted in the aforementioned papers was the fact that different AdComs had different approval rates.

Healthonym decided to take a look at AdCom data from January 2009-May 2018 for more relevant statistics.

During this time-period, the Anesthetic and Analgesic Drug Products Advisory Committee (or a joint meeting including the latter) convened over a dozen times. In 12 of these instances, the AdCom had to decide whether an opioid, indicated for the management of acute and/or chronic pain, should be approved.

In 6 of these 12 meetings, the AdCom rejected the opioid. Of these 6 rejections, only once did the FDA disregard the AdCom’s decision outright and approved the drug during the same review cycle (Zohydro ER).

In another instance, the drug was rejected by the FDA as well but it was ultimately approved upon re-submission of the NDA given labeling changes the FDA and AdCom were concerned about (Apadaz).

In 4 of the 12 meetings the AdCom had to vote on an immediate-release opioid specifically indicated for the management of acute pain. In all four instances, the AdCom and FDA rejected the opioid.

Historically, opioids that met as many of the following characteristics were the most likely ones to be approved by an AdCom:

  • Extended/controlled-release formulations
  • Indicated for the management of chronic pain
  • With abuse-deterrent properties

Lastly, when an AdCom voted to approve or reject an opioid, the vote was only close in one instance (Troxyca); a vote of 9-6 in favor of approval. In all other instances the vote was overwhelmingly or entirely one sided.

REASONS FOR REJECTION

When an AdCom rejected an opioid indicated for pain, the reasons for non-approval revolved around at least one of the following:

  • The sponsor did not convince the AdCom that their Risk Evaluation and Mitigation Strategies (REMS) were strong enough or that they were committed to them.
  • Various risks outweighed the benefits of the drug. This included adverse events (e.g. cardiopulmonary dysfunction), abuse potential, and even interactions with food among others.
  • The study’s design or outcome to actual clinical practice was not relevant; or a primary endpoint was not met in at least one study.
  • Dose and dosing inflexibility; having only one approvable dose and a fixed dosing schedule, respectively.
  • Misuse as a result of potential labeling issues.
  • Failure to adhere to FDA Guidance.
  • Improper statistical analysis of data.
  • The use of questionable excipients.
  • Personal/subjective reasons.

While some of the above is irrelevant in terms of how the FDA interprets an NDA, the AdCom’s decision will nonetheless play an important role in the drug approval process.

FDA: REQUIREMENTS

MINIMAL STANDARDS FOR OPIOIDS

In theory, the FDA has made it very clear that opioids must be approved so long as there are no concerns with CMC, labeling, REMS, and their benefits outweigh their risks; that is, for reformulations: they are at least as safe and effective as marketed drugs in their class.

Bioequivalence testing is often more than enough to achieve this end; and even a lack of abuse deterrence mechanisms, on its own, is not grounds for rejection as numerous statements by the FDA and AdComs in the recent past have made clear.

But in practice, both the AdComs and the FDA can and do require greater proof of safety and efficacy beyond bioequivalence for novel opioid reformulations. Novel in terms of combinations, dosage forms, indications, etc.

This is where Buvaya squarely falls. This is why it needed an efficacy trial and conducted a safety trial.

In these cases, the bar for approval rises considerably and, in general, the AdCom and FDA have not been kind, with one notable exception.

A GOLD STANDARD FOR APPROVAL?

Since 2009, the FDA has approved only one non-abuse-deterrent opioid with immediate-release properties indicated for the management of acute pain that also required additional efficacy/safety data for its NDA.

That opioid was Xartemis XR (03/2014), which has both immediate and extended release attributes:

“Although the formulation has extended-release characteristics, the amount of oxycodone in each tablet is 7.5 mg, the same as available in immediate-release combination oxycodone and acetaminophen products. As a result, even if individuals were to mistakenly or intentionally attempt to defeat the extended-release characteristics of Xartemis, the amount of oxycodone would not exceed the amount available in an immediate-release product.

Furthermore, the total daily dose of oxycodone from Xartemis XR has the same limitations as immediate-release combination oxycodone and acetaminophen products in order to avoid exceeding the safe daily limit of acetaminophen. The overall risks associated with Xartemis XR are comparable to immediate-release combination oxycodone and acetaminophen products than to the products included in the ER/LA opioid REMS.”

The FDA, and/or a respective AdCom, rejected the only other two opioids that fell under the same criteria and study requirements as Buvaya and Xartemis.

They were: MoxDuo (04/2014) and Hydexor (02/2018-pending FDA action).

All four drugs used similar studies with respect to assessing pain in post-bunionectomy patients and other forms of moderate to severe acute pain. Despite one AdCom’s intimations to the contrary, such studies are proper pain assessment models.

Among the many major differences between the four drugs was the duration and follow-up of their pivotal trials.

While all four used an efficacy study with a duration of 48h, only Xartemis had a relatively lengthy 14 day follow-up in the efficacy trial.

All four NDAs had some form of novel safety information as well (other than reliance upon a scientific bridge for a reference listed drug).

The difference was that MoxDuo’s safety data was 48h long, Buvaya’s was 1 week long, Hydexor’s was 2 weeks long, and Xartemis’ was an impressive 35 days long.

Hydexor’s studies further differed from the other three as, part of the time, the drug was given as needed (PRN).

Coincidentally or not, prior to Hydexor’s trials, the MoxDuo’s AdCom noted the potential need for this in order to mimic real-world scenarios.

Perhaps this is why Hydexor’s sponsor designed its trial with PRN dosing in mind. Given the currently available data, it appears INSY did not follow suit.

WHAT DOES FDA GUIDANCE HAVE TO SAY?

Of course, other issues played a role in the approval/rejection of those four drugs.

Nevertheless the probable importance of, and need for, a Xartemis-like trial duration and follow-up period is further supported by numerous facets of a relevant FDA Draft Guidance.

First, the FDA recognizes that opioids for acute pain may be used for more than 1 week:

“For the purpose of this guidance, acute pain is defined as pain that is self-limited and generally requires treatment for no more than up to a few weeks…”

The Guidance goes on to say:

“As efficacy trials for acute indications are sometimes limited in duration by the clinical setting under study, efforts should be made to ensure an adequate collection of safety data over a duration of use that can be reasonably expected in the intended patient population…Consideration should be given to obtaining safety data from additional trials if it is likely that the drug can be used for days to weeks.”

But what is “reasonably expected” and “likely that the drug can be used for days to weeks”?

The need for longer-term safety data for acute pain opioids was supported by the Avridi AdCom, where it was made clear that acute pain opioids are frequently used on a chronic basis.

By implication, commensurate long-term safety data as per Xartemis should be considered by a sponsor even for an acute paid opioid.

The FDA Guidance independently notes this need:

“Analgesics considered appropriate for the management of acute pain are often used on a chronic, intermittent basis. To understand the durability of efficacy in this setting, and perhaps more importantly, the safety of this type of use, we recommend studying such drugs under these conditions of use.”

Consequently, the AdCom or FDA may also question INSY’s efficacy trial. The prior quote goes on to say:

“Analgesics considered appropriate for the management of acute pain are often used on a chronic, intermittent basis…An important question to consider is whether efficacy is sustained with chronic, intermittent use, particularly when around-the-clock dosing is no longer necessary. One approach to this evaluation is to permit subjects to use the analgesic on an as-needed basis following a multiple-dose, around-the-clock trial period. An additional efficacy analysis can then be performed to determine whether the drug continues to provide a reduction in pain.”

This specific aspect of trial design wasn’t used by Xartemis, as it was submitted for review prior to the Guidance and MoxDuo AdCom.

Hydexor, however, was subject to the guidance and, in addition to PRN dosing, conducted two efficacy trials:

“For proposed products that include a new route of administration, a new indication, or a new population, sponsors should conduct two adequate and well-controlled trials to support a finding of efficacy, but consideration may be given to alternate proposals with adequate justification.”

Buvaya, a novel buprenorphine dosage form, had neither two complete efficacy trials nor another efficacy/safety trial design aspect that accounted for its potential chronic use (e.g. longer duration, longer follow-up, or PRN dosing).

INSY did conduct a 1 week safety study. This is probably because the FDA required it, as it does so when novel dosage forms or combination products may pose a unique safety problem.

In the case of Buvaya, that safety issue likely includes mucositis.

Yet the FDA didn’t have to bring Buvaya to an AdCom had all of the requirements of the NDA been clearly approvable and/or no new safety signals arose.

Ergo, it’s reasonable to conclude that a safety signal or an unacceptable abuse potential, not fully elucidated given INSY’s trial designs, might have come up during NDA review of the sponsor’s currently available data:

“A safety database larger than recommended in these guidances may be warranted for a number of reasons (many of which are discussed in these guidances), including safety signals emerging as more clinical data become available”.

All in all the prior discussion points to the need for sponsors to provide greater safety data, above and beyond that of the FDA’s minimal requirements, if they want to have the best chance of approval.

INSY: THE SAFETY TRIAL

Other than what was mentioned before, we don’t have much other pertinent data about INSY’s safety study.

There are a couple of new points to cover nonetheless.

Buvaya is the only opioid brought before and AdCom in the last decade whose safety study’s control arm did not include the same drug as the one in the experimental arm (buprenorphine in this case).

Instead, INSY compared Buvaya to a combination of morphine IV followed by oxycodone PO (by mouth).

Buprenorphine (schedule III) has a lower abuse potential than this study’s “standard of care (SOC)” comparators. Morphine is a schedule II drug, as is oxycodone.

Yet buprenorphine is considered to be a more potent opioid. And although it appears to have a lower abuse potential than other opioids, it might pose a potentially greater risk to an individual given a relative lack of response to naloxone (an opioid antidote) in some cases of overdose.

*We ignore the potential bioavailability of buprenorphine solutions and how that affects things for brevity’s sake.

Practically, this means it may be difficult to properly prove that the experimental arm and SOC arm were truly equivalent or adequately comparable in terms of abuse-related risks, general safety, and potency. Ergo, some bias in study design might have been introduced into the trial.

On the point of potency alone, the Zohydro AdCom discussed the inability to reach a reliable morphine equivalency comparison between different opioids out on the market; which led to a lot of confusion and undoubtedly contributed to the AdCom’s rejection of the drug.

And so, these jumbled concerns might force the AdCom to legitimately question the design of this trial, the potency comparisons between treatment arms and what they mean for clinical practice, and the abuse-related risks of, what could be, a readily extractable and injectable drug.

Given a special protocol assessment or a meeting, the FDA might have approved the core of this trial’s design but the AdCom is under no pressure to give that aspect of things much consideration.

ABUSE POTENTIAL: THOUGHTS FROM SUBSYS

The latter concern is based off of Buvaya’s sister drug, Subsys (fentanyl sublingual spray), which was approved by the FDA despite some initial debate between FDA reviewers regarding its potential for ease of extraction and abuse.

We don’t know how closely the Buvaya device mimics the Subsys one. Therefore, we can’t be sure about Buvaya’s true potential for extraction and subsequent abuse. Yet given the fact that INSY designed both, they’re probably similar.

At least for Subsys, the FDA ultimately decided that the risk of abuse was no greater than similar opioids already out on the market and that labeling and REMS would take care of the issue. Hence, Subsys was approved.

Of course, not long after approval, INSY began to undermine numerous aspects of its REMS. This led to several independent investigations and lawsuits over the past several years.

But remember, Subsys did not face an AdCom and AdComs are historically less tolerant of a drug candidate’s high risk of extraction and abuse, as may be the case with Buvaya.

Furthermore, AdComs have questioned a sponsor’s true commitment to, and strength of, its REMS in the past. This AdCom will likely be aware of INSY’s past transgressions on the point.

While the FDA, as a representative has stated, cannot reject a drug candidate for past “sins”, at least one AdCom certainly has done something pretty similar in the past.

INSY: THE EFFICACY TRIAL

So far, our discussion has mainly focused on safety-related issues.

The available efficacy data doesn’t appear to have nearly as many possible concerns.

The first efficacy trial was terminated based on a “business decision”. It’s hard to speculate exactly what that means.

The limited posted results from that trial suggest that INSY may have quickly determined that Buvaya did not demonstrate an adequate risk/benefit or efficacy profile given some of the dosages involved.

So another, slightly modified, efficacy trial was conducted.

While the efficacy data appears robust the sponsor did not, as claimed, conduct an intention to treat (ITT) analysis (analyze as randomized analysis). A discussion of why is beyond this article’s scope but a great reference can be found here.

The same exact thing happened for INSY’s Subsys NDA, where the FDA then went on to conduct an actual ITT analysis and impute some of the missing data. Something INSY didn’t do for Subsys or Buvaya.

It’s unclear how, this time around, the FDA’s ITT analysis will impact the efficacy values. The best guess here is, not by much.

Unless, of course, the FDA chooses to adjust for multiplicity given the trial’s multiple doses/arms and secondary outcomes potentially seeking labeling claims. In this scenario, serious questions about the efficacy of the two lower doses of the trial could arise; especially if the alpha value was held to 0.01 since INSY only had one adequately designed efficacy trial.

All of this might leave the 0.5 mg dose as the only approvable one, which some AdCom members might not like.

Again, none of this seems very likely but is worth mentioning for completeness’ sake.

CONSIDERATIONS UNIQUE TO BUVAYA

CLUES FROM SUBUTEX & ZOLPIMIST

Last, we move on to some unique considerations. None of these are highly probable but they have all arisen either in past AdComs or NDAs.

Subutex was an FDA approved medication that closely resembled Buvaya. It was a sublingual buprenorphine tablet (albeit indicated for opioid dependence).

One of the concerns the FDA noted during its review revolved around the administration and use of Subutex. The issue focused on a scenario where a doctor or patient decided to use two doses in concert.

In such a scenario, should the doses be given simultaneously or sequentially? What would happen in either case?

It’s unclear if INSY conducted a pharmacokinetic study examining the FDA’s historical thinking on the matter. It’s been 16 years since Subutex was approved so we can’t be sure if anyone in the FDA or AdCom would even consider this point.

Nevertheless, such a consideration is a possibility given the fact that the AdCom might be concerned about someone accidentally or intentionally spraying multiple doses of the opioid into the oral cavity at once.

Abuse of the drug aside, this could even happen accidentally.

How so? Well, Zolpimist’s 2008 NDA provides a clue. The FDA discussed the possibility that someone might not feel or taste the spray. This could lead someone to think the device never discharged, resulting in a double dose.

It will be interesting to see if INSY accounted for this or if it’s even brought up during the AdCom.

OTHER POSSIBLE ROADBLOCKS

Aside from this, the FDA and/or AdCom might consider:

1. How/if temperature, pH, or even other orally administered medications affect Buvaya.

2. If a drug’s Cmax (maximum concentration) is delayed or its half-life is longer as compared to the reference listed drug, a longer safety study may be necessary. It will be interesting to see how INSY’s PK/BE trials fared.

3. If INSY accounted for Buvaya’s effects on cardiac rhythm and oxygen saturation.

4. If the efficacy trial’s placebo was adequately similar in design and taste to Buvaya.

5. Subsys was approved for a very narrow indication and population. Buvaya is indicated for a much broader population and, in these instances, the AdCom may be even more worried about its potential for abuse.

THE SILVER LINING

While all of the information presented thus far may seem to be making the case for a pending disaster, it’s important to point out some silver linings to all of this.

On the note of abuse: most abuse-related concerns can be taken care of with proper labeling/REMS. The AdCom might not think so (some of the time) but the FDA can choose to ignore their decision so long as the abuse potential is not worse than marketed opioids.

Neither does this drug need to have abuse deterrent features as both the FDA and AdCom have realized they aren’t as effective as once hoped.

On the note of safety: if there are no novel safety signals, and the PK trials establish full bioequivalence, it’s unlikely the AdCom will demand more safety data.

Doing so would simply be unfair in light of the minimum requirements for approval. It would hold Buvaya to a higher minimal standard than mandated and that which other recently marketed drugs have been held to.

On the note of potentially conflicting efficacy trial data: the FDA can be lenient when it comes to endpoints on patient-important/subjective outcomes like pain. In these cases, positive trial results are more difficult to achieve and the FDA might give them more weight as a result.

Finally, this entire discussion was based on a small sample size of unique AdComs and NDAs (less than 20). Unfortunately, there’s little more relevant and recent historical data to work off of than that.

CRITICAL UPDATE

The FDA recently published numerous documents pertaining to Buvaya’s AdCom. To summarize, the FDA is concerned about Buvaya’s efficacy, safety, and abuse.

Historically, when so many potential problems on various fronts were discussed by an AdCom, the committee voted to reject the drug.

Nevertheless, we’ll outline this AdCom’s likely concerns in a bit more detail.

Please note: this discussion foregoes a highly scrutinous look at INSY’s briefing document. This is only because AdCom members are historically more likely to focus on the concerns pointed out by the FDA rather than the positive potentials cited by a sponsor.

This makes sense: safety (and thus caution) must take precedence when approving a new drug.

Therefore, the discussion that follows is a conservative, worst-case, scenario.

EFFICACY – PROBLEMS AND CONCLUSIONS

In this article, we noted that the FDA has minimal standards an opioid must meet in order to be approved.

To recap these standards: INSY must prove that Buvaya’s benefits outweigh its risks and, by extension in this case, that it’s at least as safe and effective as similar drugs out on the market.

INSY’s trial data showed us that Buvaya was statistically effective.

Yet the FDA’s briefing data elucidated the fact that that its effectiveness is clinically questionable in a large proportion of patients for the two lower doses (0.25 mg; 0.125 mg).

Questionable in that:

1. The percentage of patients needing rescue medication was roughly the same for the placebo, 0.25 mg, and 0.125 mg arms.

2. As time went on, the pain intensity scores for the 0.25 mg dose were, at some points, surprisingly worse than the 0.125 mg dose (and not much better than placebo for either). These are exactly the kinds of paradoxical results committee members often try to clear up.

3. As defined by the sponsor’s methodology, about 55% of the patients taking the lower doses did not experience adequate analgesia prior to needing a second dose or rescue medication.

4. The placebo’s “therapeutic effect” may begin far sooner than any of the two lower doses’.

In the end, despite an evident statistical difference over placebo, the two lower doses have highly questionable efficacy as it pertains to clinical practice.

With an AdCom’s tendency to focus on practical as opposed to purely statistical/regulatory interests, as well as the misuse discussion that’s forthcoming, this might be a serious problem for INSY.

As for the higher dose (0.5 mg), it’s technically more effective than a placebo as well. Yet 35% of patients taking this dose did not experience adequate pain-relief prior to needing rescue medication or a second dose.

Furthermore, the median time to onset of meaningful pain relief was 92 minutes for the higher dose. This is quite a long period of time for a drug indicated for acute (severe and/or sudden in onset) pain.

To summarize the efficacy discussion:

  • At the very least, it’s hard to see the AdCom concluding that the lower two doses are clinically, meaningfully, effective when compared to placebo.
  • Unless INSY can show that all of the statistics mentioned above are normal for other marketed opioids (which might be somewhat possible for the 0.5 mg dose given the available data), the AdCom may conclude that Buvaya is not as effective as other opioids for any given dose.

Even if INSY can show that the 0.5 mg dose is as effective as other approved opioids, this dose faces serious questions on the safety front.

SAFETY – GI

This is because Buvaya clearly demonstrated a concerning dose-dependent increase in adverse events that could not be reasonably attributed to causes other than the drug.

The lower doses are reasonably safe. There’s not much more to add to that.

However, the 0.5 mg dose is characterized by a comparatively poor safety profile. For instance, the rates of discontinuation due to nausea and vomiting were far higher than even INSY’s own “standard of care” (SOC) arm of morphine and oxycodone, as well as other approved opioids with comparable trial methodologies.

At least for nausea and vomiting, INSY could argue such adverse events are expected in opioid-naïve patients, especially at the outset of treatment, and that anti-emetics can be given as necessary.

However, AdComs don’t really like these arguments.

They don’t like the idea of having to give yet another drug (the anti-emetic), with its own side effects, to counter the adverse effects of a drug that’s effective but not as safe as reasonable alternatives.

In essence, if this was an orphan-status drug following an expedited pathway, such arguments could definitely work based on a clear need. But in the case of what is just a novel dosage form, for an indication with numerous potentially safer alternatives, these arguments don’t carry as much weight.

SAFETY – HYPOXIA

More problematic than gastrointestinal issues, Buvaya’s overall risk of hypoxia was nearly five times greater than INSY’s SOC. When discussed, concerns revolving around hypoxia were very difficult to overcome in AdCom meetings.

So what might INSY do in this case? Based on their briefing document, INSY will probably argue that buprenorphine has a quasi-protective ceiling effect for respiratory depression. This is a fair argument, albeit one that the FDA hasn’t fully bought according to its own briefing document for numerous reasons.

Additionally, the AdCom may bring up the fact that the “protective” ceiling effect was studied in relatively healthy individuals.

What happens when this drug is given to those already prone to hypoxia/respiratory depression, especially in light of Buvaya’s increased risk over SOC? For example: the obese, smokers, and those with sleep apnea.

Will this protective ceiling hold then or will this drug be indicated only for those free of such morbidities?

The issue of hypoxia is even more poignant in this case because Buvaya poses a unique safety concern this article mentioned before. Unlike other opioids, naloxone will not readily reverse the respiratory depression caused by a buprenorphine overdose. If a rescuer is unaware that a patient has overdosed on Buvaya, this could lead to grave consequences.

SAFETY – CONCLUSIONS

Although INSY laid out numerous comprehensive arguments for why buprenorphine is a relatively safe opioid, the FDA and AdCom aren’t discussing buprenorphine in general, but Buvaya specifically.

As we just went over, treatment with Buvaya more than doubled the relative risk of various adverse events over SOC. The same SOC that INSY implied had numerous issues that could be improved upon with a buprenorphine spray.

Consequently, even if INSY is able to prove the 0.5 mg dose is as effective as other opioids, it’s going to have a very tough time arguing it’s as safe as other marketed opioids, especially given that its own data appears to contradict this notion in many respects.

One avenue that INSY might take in this case is to argue that “the safety of Buprenorphine Sublingual Spray is consistent with the established safety of approved buprenorphine products.”

But consistent with respect to, or compared to, what? If it’s with respect to unique safety signals, then Buvaya is indeed consistent with what we’d expect with buprenorphine.

If it’s with respect to the rate or severity of various adverse events, the data is far murkier.

STANDARD OF CARE

On the note of standard of care. The FDA AdCom briefing document, as this article in more than one instance, put “standard of care” in quotes. That’s likely because we all have questions about what that even means in this particular instance.

Given past AdCom thoughts on very similar matters, we might expect the following questions for INSY:

1. What is even meant by standard of care? Meaning: did INSY use the term with respect to treating post-bunionectomy pain, any post-surgical pain, or any acute pain in general? This discussion might segue into questions about the intended population vs. INSY’s evidence for such a population.

2. What evidence is there to suggest morphine and oxycodone are standards of care in any of the settings mentioned in #1?

3. What are reasonable alternatives (e.g. perhaps the same NSAIDs or acetaminophen used as rescue medication)? Why weren’t they used as the standards of care or as part of another study arm?

4. How was morphine equivalency determined between arms? In other words: what was the risk of introducing systematic error into the study’s design as a result of this?

ABUSE

The abuse potential discussion is perhaps the easiest one. This isn’t to imply it’s the least important one.

However all of the data on this point is, at best, inconsistent and/or incomplete. We can cherry-pick numerous statements from INSY’s and the FDA’s briefing documents that will make it seem that Buvaya is reasonably prone to abuse (or not).

Yet the reality is that there is no clearly demonstrable evidence that Buvaya is going to be any more likely to be abused than other immediate release opioids out on the market.

Furthermore, Buvaya was never intended to have abuse-deterrent properties. Ergo, by the FDA’s own admission, Buvaya has to be approved (when looking at this point alone).

But the AdCom may take issue with something.

In INSY’s briefing document, INSY mentioned that while it’s not seeking abuse-deterrent claims, schedule III narcotics are less likely to be abused. By implication, Buvaya is “abuse-deterrent” to an extent by default.

INSY won’t be the first to make an oblique argument such as this. And every sponsor that did so failed to convince the AdCom that their opioid was safer by some sort of default measurement.

In other words, the AdCom could latch on to this potentially dangerous line of thinking and demand that Buvaya specifically prove its “abuse-deterrence” is consistent with buprenorphine in this regard.

After all, Buvaya’s safety profile wasn’t entirely consistent, so why should its abuse potential be given its novel dosage form?

Be that as it may, this article’s prior discussions have made one thing clear: AdComs vacillate on precisely the issue of abuse and its importance for any given drug for a wide variety of reasons. It’s the luck of the draw on what any committee member will think about this on any given day.

MISUSE

Perhaps the more important part of this discussion has less to do with abuse and more to do with misuse. Based on this entire article, there is a very clear line of thought that can reasonably emerge in a committee member’s mind:

First, a patient is prescribed Buvaya for their acute pain. At what dose? Well if we prescribe it at the higher, more effective dose, we risk an unreasonably high chance of side-effects compared to alternative medications. So we choose the safer, lower, doses to start off with.

We know that Buvaya can be poorly effective in a relatively significant proportion of patients at such lower doses.

Consequently, a patient’s pain may not be relieved and s/he might double dose (misuse the drug) in order to get rid of the pain. Or, the patient might take another pain reliever (opioid, NSAID, or acetaminophen) that interacts poorly with Buvaya.

In the end, this increases the risk of side-effects and/or potential for abuse.

What will the AdCom think of this? On the one hand, we can argue that this scenario can be taken care of with clear labeling, 6th-grade-level medication guides, and proper risk mitigation strategies in general.

This is the FDA-way of looking at things.

But AdComs in the past were not always swayed by such arguments. For instance: what would happen when non-native English speakers (or people who can’t even speak English at all) are prescribed Buvaya?

By extension, we can further extrapolate this exact scenario on to people who have poor health literacy skills even if they are native English speakers. Or when an intelligent patient nods that they’ve understood a set of instructions yet have not actually done so; nor asked clarifying questions out of fear of appearing incompetent.

Combine any of the above with a potentially visceral desire to relieve an acute episode of pain at any cost—which clouds a person’s ability to recall or think clearly through a set of oral/written instructions—or other distractions, and one can see how Buvaya could be misused if it lacks an effect.

FINAL THOUGHTS

In its briefing documents, the sponsor makes the claim that there is a lack of an adequate pain reliever between schedule II and non-opioid analgesics. This is a reasonable assessment.

Still, as numerous prior committees made clear: when a sponsor proposes a drug that is quite novel in many respects (dosage form in Buvaya’s case) but doesn’t provide concrete evidence of safety/efficacy, then it’s a solution in search of a problem.

Perhaps we can summarize this entire update by looking at the actual question the AdCom will vote on:

“Overall, do the benefits of Buvaya outweigh the risks for the indication, “the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate,” supporting approval of Buvaya?”

At the risk of nitpicking, the most pertinent part of the question is: “AND for which alternative treatments are inadequate”.

So we must ask ourselves:

In what scenario would all of the alternative treatments be inadequate; such that Buvaya would be the best option despite its own, not insignificant, safety and efficacy drawbacks when compared to some of these same alternatives?

Perhaps one could claim that an individual who is intolerant of NSAIDs, extremely fearful of needles and hospitals, and has trouble swallowing might be given this spray. That’s quite the narrow patient set.

Moreover, it doesn’t appear that labeling or a risk mitigation strategy is going to preclude the use of this medication to extremely narrow instances; where no other alternatives even exist and thus, by default, Buvaya is the best “option”.

This means the AdCom and FDA will presume that Buvaya is indicated for a wide range of patients where alternatives are plenty. Or, we must reasonably presume, it will be used in an off-label manner as so many opioids have been.

Consequently, Buvaya will be prescribed where it isn’t the best option; where it poses a greater threat to patient safety compared to well-established alternatives.

So, in a case where the benefits may not outweigh the risks, where does Buvaya fit in within the scope of pain management?

Published: 5/12/2018

Updated 5/17/18 – the FDA finally posted the full Hydexor AdCom meeting transcript on 5/14/18. It came to light that a lot of the AdCom’s concerns with dose inflexibility had to do with specifics of Hydexor that are not entirely applicable to INSY’s Buvaya.

Updated 5/18/18– all instances of BSS (buprenorphine sublingual spray) were converted to the trade name, Buvaya, in the article’s text.

Updated on 5/20/2018 – “Critical Update” section was published.

Author: Artem Cheprasov

No one associated with this article has any financial stake in, or ties to, INSY.

2018-12-05T16:02:32+00:00