- KTOV is facing a lawsuit and securities investigation into alleged data fabrication.
- Even if the NDA is perfect, the FDA may issue a CRL for KIT-302 as a result.
- The primary efficacy outcome, while successful, has a potential statistical issue.
- The pivotal trial’s results are also partially contradicted by several independent studies.
- The NDA might be missing an important substudy.
- KTOV’s chronic delays may have decreased its chances of approval by a factor of ~2.
- A lack of a PDUFA extension could be a bad sign.
KIT-302 (Consensi) is an oral combination product that contains an NSAID, celecoxib, and a calcium channel blocker, amlodipine. It’s being developed by Kitov Pharmaceuticals (ticker: KTOV), an Israeli company.
KTOV’s NDA for KIT-302 has an expected PDUFA action date of May 31st, 2018.
KIT-302’s main indication will be for the treatment of hypertension in patients who need to take an NSAID to relieve the signs and symptoms of their osteoarthritis as well.
During its clinical studies, KIT-302 wasn’t tested in its final commercial (fixed combination) form. Instead its two active ingredients were given simultaneously, but separately, to mimic the final formulation.
For brevity’s sake, we’ll refer to the test/mimic combination as “KIT-302” when discussing the pivotal trial below.
THE LEGAL PROBLEMS
Before any discussion about the scientific, statistical, and regulatory merits behind KTOV’s NDA can begin, we have to put everything into the context of an existing legal problem.
Based on everything we know at this point, it seems there were multiple whistleblowers who might have come forward with information that someone party to the pivotal trial deliberately misled the Data Monitoring Committee (DMC).
By extension, this means investors were misled when KTOV issued numerous positive statements about the trial.
The main accusation is that someone falsified the data to trick the DMC into thinking statistical significance for the co-primary (efficacy) endpoint was reached.
The data that was apparently falsified was the experimental arm’s; where the changes in blood pressure for those treated with “KIT-302” were modified to look better.
KTOV denies any and all such accusations. But what are the possibilities?
1. Nothing actually happened.
2. The clinical research organization (CRO) independently falsified the results. This is extremely unlikely but not impossible.
3. Someone pressured the CRO into falsifying the data.
4. The sponsor had access to, or complete control of, the data set. It’s possible then, that the sponsor falsified the data prior to its submission to the DMC. This appears to be the implication in the legal opinion/order.
Of course, lawsuits seeking compensation as a result of a sponsor’s “misleading information” are filed left and right; and are dismissed just as often.
Yet in KTOV’s case this doesn’t appear to be a frivolous lawsuit since it avoided outright dismissal.
That might be because it met a heightened pleading standard; based in part on the numerous whistleblowers who apparently stepped forward.
Above and beyond that, it’s hard to believe that the equivalent of the Israeli SEC would launch, and then continue to investigate for over a year now, something that is completely meritless.
WHAT THE FDA MIGHT DO
With that in mind, a question of data integrity is a relatively common basis for a CRL.
However, a small mistake in the data isn’t going to harm the NDA. This is because the FDA places an error into context and actually discusses its importance and the likelihood it was intentional vs. accidental.
This means the FDA must have reason to believe the error is substantial and/or was intentionally created in order to issue a CRL.
In KTOV’s case, the FDA will be aware of the current securities investigation and lawsuit at hand.
Thus, we can envision a scenario where the FDA moves to approve the drug but the investigation and/or lawsuit eventually concludes the data was, indeed, falsified. The headlines, from the FDA’s approval of a drug based on adulterated data, will be quite negative.
So what could the FDA do when faced with such a sensitive scenario? It might issue a “frivolous” CRL to buy itself some time; in this case, time to let the Israeli investigation and U.S. lawsuit run its course and come to a definite conclusion.
THE PIVOTAL TRIAL
There are also some scientific, statistical, and regulatory issues we have to go over in light of all of the aforementioned.
Let’s begin with the pivotal phase III trial.
The first thing to keep in mind is that the pivotal trial should’ve enrolled a minimum of 30 or 40 patients in each of the four arms. We don’t know if it’s 30 or 40 because the sponsor’s information on this point has been a bit inconsistent.
Regardless, we’ll be conservative and say it was 30 patients. Even in this case, one of the trial arms (placebo/placebo) had less than 30 patients. On the one hand, this may not be such a big deal as the main primary efficacy endpoint had nothing to do with this control arm.
But the FDA may still find fault with respect to non-adherence to the trial’s special protocol assessment (SPA), especially in light of a data-integrity concern; putting the trial results at risk.
The good news is that the trial’s primary efficacy endpoint was reached with a p-value of 0.001.
Moreover, using a conservative 2 x 2 table analysis we can show that “KIT-302” reduces the relative risk of adverse events by 11.44% when compared to the standard of care (SOC); with an absolute risk reduction of 7.12%.
Furthermore, over a treatment period of two weeks, one adverse event will be prevented for every 14 patients treated with “KIT-302” as opposed to the SOC.
So on the face of things, “KIT-302” appears to be not only as effective but also at least as safe as the SOC.
Of course, the trial’s SPA didn’t specify that amlodipine must be the SOC comparator. This could raise the argument that a weak comparator was used to make “KIT-302” look better.
AN INCORRECT USAGE OF ITT ANALYSIS?
This is where many of the positive notes on the trial appear to end.
Based on the description of the primary outcome’s statistical analysis, it seems that the study’s authors/statisticians calculated everything using the intention to treat (ITT) principle (aka analyze-as-randomized).
ITT minimizes systematic error (bias) in superiority trials.
But when it comes to non-inferiority trials, ITT is largely inappropriate and can be very misleading (the FDA is well-aware of this). A discussion of why this is so is beyond this article’s scope but you can read a superb explanation of all of this here.
Thus, it’s unlikely that the FDA actually told the sponsor to conduct an ITT analysis (and nothing else) unless we presume it was the FDA who made the error.
Other than that, there are a limited number of more plausible explanations as to why this happened:
1. KTOV simply disregarded the SPA; they have every right to do so but at some risk.
2. The SPA never specified how things should’ve been analyzed.
3. Some sponsors erroneously use the term ITT when they actually conduct anything but such an analysis in its truest form.
4. KTOV found that the correct analysis didn’t reach statistical significance but ITT did; so they put a positive statistical spin on negative results. This seems unlikely but other sponsors have tried similar things in the past.
5. KTOV conducted both sets of analyses yet reported only the less appropriate one to the public.
We don’t know for sure what happened here. A clue to a potential explanation can be found buried in an SEC form.
During the pre-NDA meeting, the FDA apparently asked KTOV to re-analyze the primary efficacy endpoint using another “mathematical technique”; which maintained statistical significance.
Unfortunately, this vague wording doesn’t permit us to be sure of what really happened.
Optimistically, we can hope that the FDA saw the need for one of several alternative analyses and pointed that out to the sponsor. Of course this doesn’t explain why, 1.5 years later, KTOV reported the incorrect ITT analysis to the public after presumably being told to perform the correct one.
INCONSISTENCIES WITH HISTORICAL TRIALS
Furthermore, the results of the primary outcome are not entirely consistent with the results from a much larger, moderate quality, trial. This larger trial evaluated the concomitant use of celecoxib and calcium channel blockers with respect to changes in blood pressure.
The larger trial’s results suggests that non-inferiority, especially in the long run, shouldn’t have been reached in KTOV’s case. Perhaps a long-term efficacy/safety study is in order for KTOV?
Moreover, two low quality but independent trials (here and here) with similar patient selection criteria to KTOV’s analyzed the antihypertensive effects of amlodipine (both at half the dose of KTOV’s).
The results from these trials posit that we should’ve expected a much greater decrease in the SOC arm’s systolic blood pressure at week 2 than we saw in KTOV’s trial (especially at the latter’s higher dose). Their overall results are not inconsistent with numerous other higher quality trial data, suggesting their 2 week data was relevant despite a low quality design.
Thus, we have to reasonably ask why the SOC arm in KTOV’s trial performed unexpectedly poorly and the “KIT-302” arm performed unexpectedly well compared to historical data.
This is not to imply any falsification of data on KTOV’s part. Not at all. We simply don’t have enough information from any of the studies in order to distinguish between several important confounding factors that could’ve played a role in these discrepancies.
But all of this raises pertinent questions and avenues of investigation nonetheless.
Things are also interesting with respect to the secondary outcomes/endpoints.
Quite possibly the SPA required a much smaller alpha value (e.g. 0.01), as has happened in similar situations in the past. We can’t be sure either way as the sponsor hasn’t been clear on this point.
But, for argument’s sake, we’ll assume that the FDA required a very liberal (and very unlikely) alpha value of 0.05.
MULTIPLICITY AND CONTRADICTORY RESULTS
Even so, the problem is that the trial used numerous endpoints and many tests for each endpoint.
This presents us with an issue of multiplicity. Meaning, even this liberal alpha value must ultimately be adjusted to a much smaller value than 0.05 to accurately judge any statistically significant result–namely for the secondary endpoints.
We don’t know which multiplicity correction was used for the alpha value in this case, and the discussions of each possible one are beyond this article’s scope.
But when using a conservative correction, it’s quite clear that every secondary endpoint comparing every blood pressure value between “KIT-302” and the SOC failed to demonstrate superiority.
The failure of these relevant secondary endpoints on its own isn’t grounds for a CRL. It may simply draw the FDA’s attention to these quasi-contradictory results; and what they do with that in light of the legal problems is anyone’s guess.
And there’s one last critical thing we have to go over with respect to the pivotal trial.
In the phase III trial, KTOV did not use the final KIT-302 formulation. Instead, KTOV used two separate pills to mimic the final commercial product.
This is actually ok so long as bioequivalence is established between the commercial product and the drugs used during the study. Bioequivalence that KTOV successfully demonstrated.
But there has been no mention that KTOV conducted a separate trial or a phase III substudy that demonstrated that the over-encapsulated tablets/capsules used during the trial were bioequivalent to the same, non-over-encapsulated, drugs out on the market.
This is not an irrational concern as drugs that use over-encapsulation during a trial are likely going to need to demonstrate bioequivalence to their non-over-encapsulated versions via a separate study or, perhaps, via a phase III substudy. As well, KTOV is probably referencing the latter as listed drugs in its 505(b)(2).
It even appears that the FDA has asked KTOV for this kind of information. Yet as of March of this year it looked like KTOV was still gathering the requested data.
In KTOV’s case, it doesn’t seem that a completely separate trial for this was required.
But given the FDA’s historical requests on the matter, we need to wonder if a phase III substudy on this point was ever conducted. Even more so: why was this type of data, when it’s clear the FDA would require it, never submitted in the NDA right from the start?
This could very well be another reason for a CRL.
THE ADDITIONAL PHASE III STUDY
In addition to the pivotal trial, KTOV conducted a phase III/IV study to further strengthen its claim of efficacy and better elucidate some novel renal benefits. Based on the available data, it appears this study definitely strengthens the efficacy and safety findings of the pivotal trial.
In their latest annual form 20-F, KTOV mentioned that data from this trial would be submitted in 6-8 weeks.
That is to say, as with the over-encapsulation data, it will be submitted near the PDUFA action date.
Submitting an entire phase III trial within the last three months of review is almost certainly grounds for an extension.
Nevertheless, the FDA will not issue an extension if it believes that no amount of additional data is going to help prevent a CRL. Issuing an extension under such circumstances would needlessly waste the FDA’s and sponsor’s time.
SILENCE MAY BE A BAD SIGN
And so, investors bullish on KTOV should hope that the FDA grants a 3 month extension for either data set; it will be a good sign despite a likely over-reaction by the market to it.
But if we don’t hear about an extension soon, this may be a case where the silence will be deafening for it might be a clear-cut sign that either the sponsor failed to submit the data or the FDA thought the data wouldn’t help KTOV’s cause.
What’s interesting is that the additional phase III/IV trial met a primary outcome that was similar to the original phase III trial but the patient selection criteria weren’t exactly the same so an accurate comparison is not possible.
Even so, it seems highly unreasonable to say that even this trial’s data was falsified. That’s because the trial was concluded after the ISA launched the securities investigation and if KTOV proceeded to falsify even this data thereafter, then that would be preposterous.
This means that if KTOV falsified the data for the pivotal trial, it was a premature mistake given the (likely honestly) successful phase III/IV trial.
DELAYS & DISCREPANCIES
We’ll end this discussion with one last thing. We know that the drug development process is anything but easy. Accordingly, we should expect that a company has the necessary resources (money and quality personnel) to tackle such a mountainous task and maximize the chances of FDA approval.
It seems that KTOV has struggled in this regard:
- Their SPA requirements were originally approved in 2011-2012 but morphed from there from one thing to another along the way. It’s unclear why this happened.
Perhaps KTOV wasn’t methodical in describing the detailed requirements to investors or the SPA was properly modified along the way (the latter appears likely).
In the dangerous-case scenario, KTOV simply ignored the SPA. While this is reason for the recession of an SPA, it isn’t automatic grounds for a CRL so long as the trial data is adequate enough for approval anyways.
2. KTOV was going to submit their NDA in 2015, this got pushed to 2016, then 2017 for one reason or another. This happens, of course, but it wasn’t always entirely clear what the delays were always about—especially since the SPA was approved long ago and the pivotal trial concluded years ago as well.
3. They were supposed to submit the phase III/IV data in January 2018 but this got pushed back to the spring of 2018 (and may still be pending as of this article’s publication) because of technical irregularities.
4. Their pre-NDA meeting was held long before the NDA was submitted.
The last point is actually the most crucial one.
The time-frame between the important pre-NDA meeting and NDA submission was well over a year. This leaves an incredible amount of time for requirements to change, mistakes to happen, or things to go wrong.
In fact, NDAs submitted within 6 months of the pre-NDA meeting are historically about 1.8 times more likely to be approved during the first review cycle compared to those submitted after 6 months have passed precisely because of that.
This should make investors wonder if, given their limited resources and historical struggles and delays, KTOV and its contracted partners managed to pull-off all of the voluminous, detailed, and complex steps they needed to in order to gain FDA approval.
Last Updated: 5/13/2018 for elements of style.
No one associated with this article has any financial stake in, or ties to, KTOV.