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Regulatory Affairs

You Wouldn’t Be Lying About That, Would You?

Biocentury has a really good interview with John Jenkins, who’s departing the FDA this week after 15 years as director of the Office of New Drugs at the agency’s CDER (Center for Drug Evaluation and Research). Any drug that’s been through the regulatory process during that time has gone across his desk, so he’s seen a lot, and he has some interesting things to say.

One remark that’s gotten a lot of attention refers to the way that (some) companies treat disclosure of FDA communications, such as CRLs (Complete Response Letters) when a drug is turned down. These are not made public; it’s up to the companies themselves to issue what information they well. And you know what? Some of them lie about it. That’s the only conclusion one can draw from this:

How often have you encountered situations where the statements companies made about their interactions with FDA weren’t accurate?

JJ: It’s pretty frequent. And as you know I’ve been an advocate for many years for greater transparency of sharing the communications and the interactions we have with companies, making those publicly available, because our communications are often not as clearly communicated by what companies say to the public as I think they should be or could be.

BC: I realize you can’t talk about specifics, but can you talk about the kinds of things companies say that are inaccurate?

JJ: Let’s say we have an end-of-Phase II meeting when we are giving advice on a Phase III program. Maybe the communication that the company gives to the public is much rosier than the actual advice or feedback we gave on their development program. Then later if the perception is that things didn’t work out for them as well [as they’d hoped] then the perception is why did the FDA give you such rosy advice in the past.

Another example would be downplaying the deficiencies in a [complete response] letter about what the agency said and what additional work they need to do. Sometimes companies claim when they get a CR letter that they were caught by surprise, that the agency had never raised these issues before, and that’s not true. I’ve heard companies make statements that they were blindsided by the agency raising an issue and it’s often not true.

Investors should keep this sort of thing in mind – you’d think that it wouldn’t be legal or wise for a company to just come right out and misrepresent what the FDA has told them, but under the current system that’s just what can happen, and often seems to happen without penalty. Experienced drug developers look at these situations and can guess that someone’s not being truthful, but smaller investors and the patient community  won’t realize what’s happening.

It’s easier for a company to blame Evil Regulatory Obstruction, but a big problem with that strategy is that people get a distorted view of the world. Many people (and many politicians among them) seem to imagine that there’s this big logjam of wonder drugs that’s having to work its way slowly through a thin hallway full of persnickity bureaucrats – if only we could open those floodgates! But this isn’t actually the case. If you look carefully at the number of New Drug Applications, it’s hard to make the case for a giant backlog. Now, another possibility is that if the drug approval process were faster and easier, that more investment would flow into the sector and more new drugs might eventually be the result. That’s not a crazy thought, but it’s not a complete picture of reality, either.

One big question that has to be asked in this case is how one makes the process faster and easier, while still having some expectation that said new drugs do anything for patients while not doing them actual harm. You’d think (if you haven’t done this stuff) that these questions could be answered a lot faster than they are now, but actually doing that a lot faster is really difficult. Designing clinical trials, recruiting patients, running the trials on a scale and in a way that can provide meaningful answers, and working up the data: all these things take more time than anyone who hasn’t done them can believe. “Come on! Does this drug work or not?” is the usual question, but the frustrating usual answer is “Well, we’re still trying to figure that out”.

Keep in mind that most drugs aren’t amazing slam dunks in the clinic, unfortunately, even the ones that were supposed to be. That brings up another key point: FDA approval is not the rate-limiting step for producing a truly new drug. The rate-limiting step for breakthroughs is the science, the flippin’ science. Having an idea about a new therapy, getting something that’s even remotely worth taking to the clinic in the first place – those are the long and hard steps, because they’re completely undefined and wide open. The paths through the clinic and through the FDA are much better laid out, but there is no path through the early-stage research. You have to make one.

65 comments on “You Wouldn’t Be Lying About That, Would You?”

  1. anonymous says:

    The company says we all need to maintain the privacy to protect the shareholders or else its stock get tanked!

    1. Dr CNS says:

      Doesn’t senior leadership have a fiduciary responsibility to maximize profits to shareholders? Is that so even if they are using truthful hyperbole?

      Is there a conflict of interests here between benefits to society and to shareholders?

      Have integrity and drug discovery become incompatible?

      1. KN says:

        Dodge v. Ford Motor Company, 170 NW 668 (Mich 1919) is a case in which the Michigan Supreme Court held that Henry Ford had to operate the Ford Motor Company in the interests of its shareholders, rather than in a charitable manner for the benefit of his employees or customers. It is often cited as affirming the principle of “shareholder primacy” in corporate America.

        1. Crocodile Chuck says:

          Bullshit. The ‘maximise shareholder value’ principle arose in the early 1980’s, originally championed by Jack Welch [who subsequently decried the notion in 2009]. Not in 1919.

          Its a ridiculous idea. Legally, shareholders’ equity is a residual claim, inferior to all other obligations. Boards and management are required to satisfy all of the company’s commitments, which include payments to vendors & employees, honouring product warranties, paying various creditors, paying taxes, and meeting various regulatory requirements (including occupational health and product safety rules and environmental regulations).

          Profit is what falls out @ the bottom.

          That’s a different way of looking at it, isn’t it?

          1. johnnyboy says:

            I’m with Chuck. This idea that the Executive’s only priority should be to maximize shareholder value took is a recent development that took hold in the “Greed is good” eighties, and is now used as dogma (note the use of serious-sounding terms like “Fiduciary Responsibility”) to justify the worst corporate behaviors. When applied to pharma, this is the exact viewpoint that leads to the Valeants and Tur***gs of this world.

          2. Marilyn Mann says:

            I agree. There is no corporate law doctrine that says management has to maximize shareholder value, except in the very specific situation where the company has been put up for sale.
            People who say such things have never studied corporate law.

          3. Rich Rostrom says:

            I didn’t notice “social benefits” or “paying high wages” in the list of obligations that precede shareholder value.

      2. anon says:

        Do you really think that there is place for integrity in capitalism?

        1. Anon says:

          Depends on which type of capitalism (how you make money) – social or sociopathic: creating value and sharing it, or taking value from others while destroying it.

        2. skeptic says:

          To be fair, there is a dearth of integrity in many systems, because there is always an opportunity for those with authority or influence to put their fingers on the scales. All of us can think of plenty of examples in other countries.

          Not that it makes me feel any better about the situation here.

      3. anonymous says:

        WTF? In my long observation the legal mumbo-jumbo words like “fiduciary responsibility” is a ^&$*@% bogus claim! Call it a fig leaf to indulge in corruption.

      4. skeptic says:

        Presumably senior leadership shouldn’t be able to assume that shareholders are exclusively short-term speculators, but rather some might be long-term investors who actually care about the performance of the company and the prospects for its products. In which case the leadership has a fiduciary duty to tell shareholders the truth about the company.

  2. schinderhannes says:

    Simple lesson to learn for investors:
    Insist on getting the original CRL to read before continuing any investment.
    FDA cannot publish it but the startup can show it to you.
    If the refuse and say “read our press release its all we can disclose”.
    Then run!

    1. biotechtoreador says:

      “Insist on getting the original CRL to read before continuing any investment.
      FDA cannot publish it but the startup can show it to you.”

      A nice idea to be sure but, as far as I know it rarely happens. I can think of 1 example in the past decade in which a company disclosed a CRL (LJPC for riquent). Really a pity more companies don’t do so, but investors let these scummy companies get away with this behaviour, so why wouldn’t they?

    2. Fred the Fourth says:

      The very first thing I tell startup founders about talking to investors (of my ilk) is: “Rule 1: Don’t be secretive.”
      If I sense hesitation to disclose, I walk away immediately.

      1. Ann O says:

        And then there’s Theranos, the epitome of secrecy…and gullible fools who did not take this advice. Look how well that turned out.

    3. Fred the Fourth says:

      The very first thing I tell startup founders about talking to investors (of my ilk) is: “Rule 1: Don’t be secretive.”
      If I sense hesitation to disclose, I walk away immediately.
      However, there are plenty of investors with other rules…

  3. johnnyboy says:

    Well, you can certainly argue that companies hiding the substance of CRLs is a problem. But for investors in small biotech, this point is moot – if a CRL is issued that generally means your investment is toast, whatever the letter’s content. The real problem I have had as an investor stems from companies not fully disclosing the results of Ph3 trials prior to FDA review – ie. just releasing the good parts, and omitting those pesky safety signals, for instance. Aveo, and more recently Cempra, come to mind (painfully).

    1. cw says:

      Good point, johnnyboy, and I would add based on my experience in several venture-funded startups that there are a variety of reasons why they aren’t always “fully disclosing the results of Ph3 trials prior to FDA review”. I have seen one up-close example of leadership having “bad” Ph3 data but not sharing it with investors. The logic they were using was that the company had multiple indications in different stages of development and they downplayed results in the Ph3 indication while emphasizing the positive results from another indication at Ph1/2. Since the investors were bought into the platform-technology concept, leadership convinced themselves it was an ok approach. The more common reason I’ve seen leadership not give investors an accurate Ph3 story is that they simple don’t ask the right questions themselves and, in particular, don’t have the right stat plan. If I were ever to be in a position to be an investor, I would want the right to review every draft and revision of the stat plan. If you know the stat plan inside and out it will be much easier to ask later about the status of data from specific analyses.

    2. Michael says:

      Cempra did disclose everything except the one patient in the COPD trial. But that’s completely irrelevant.

      Repeat after me: non-damaging transient ALT elevation is not the same as a 1/123,000+ possibility of rare side-effects. Unfortunately, the FDA didn’t understand either, even though they did.

      The FDA did many things that don’t make sense. One of them is showing only peak ALT levels instead of the difference between baseline and peak. In the NASH trial, all patients had a lowered ALT after treatment, but FDA slides show that one out of the six had elevated ALT over 3x ULN at the end of the trial. Reprehensible.

      The safety signal that the FDA discusses which was higher than that of telithromycin is only about ALT, and nothing else. Solithromycin had reduced nausea levels even despite the fact that telithromycin was treated on mild patients, and solithromycin is less diarrhea-inducing than moxifloxacin. No c. difficile infections.

      Again, the main problem is that FDA (and adcom, and so-called sell-side “analysts”) conflated the temporary, asymptomatic raised ALT with the potential rare events of telithromycin. The incidence rate of that was 42 out of 5.2 million. The FDA and Cempra agreed that it’s actually closer to 5.5/100,000. To test and eliminate the probability that this rare event does not happen with solithromycin, you’d need to do an impractical 54,545 patient trial.. not 9,000.

      The FDA failed, miserably, in their duty here. But, it’s so easy to blame it on the company, isn’t it?

      1. Bobi B. says:

        Absolutely agree with you. However, it is a mistery for me why during
        adcom no one from the company referred to publications (and studies) authored by the company’s research scientists, including CEO, about effects of soli on patients with liver impaired function !? Perhaps you may know the answer?

        1. Michael says:

          It’s there on pages 7-8.

          “Based on the dedicated PK study in subjects with normal or reduced hepatic function, the results from the phase 3 trials (lower exposure not associated with efficacy decrease), and the E-R relationship between exposure and ALT elevation, we concur with the applicant’s proposal that no dose adjustment is needed for CABP patients with mild, moderate, or severe hepatic impairment.”

          Hepatic impairment is not a problem.

          Michael Green and Vincent Lo Re disagreed.

          Michael Green:
          “Then, I would consider in their package insert, recommending against the use in people with pre-existing liver conditions, because I think it was a contra-indication to enter the study, and therefore we have no idea how this drug will work in that setting”

          Vincent Lo Re:
          “We really weren’t presented with data on ALT elevations after initiation of solithromycin among persons who previously used macrolides or other structurally-related drugs or patients with chronic liver disease, and I felt that this was important to characterize the hepatotoxicity profile.”

  4. loupgarous says:

    We’ll soon have a guy in the White House who got there by promising to eighty-six all that evil Federal regulation. Perhaps it’d be a good idea to get the facts out about why FDA says “no” so often, and why it arguably ought to do it even more often (or at least tell Big Pharma to go back to the drawing board more often).

    Trump might not listen at first, but if his critics do, word gets out in a press which mysteriously won’t cover for him the way it did for the guy in office now, and there’s no real way for him to finesse the issue – we’ve seen in the campaign that Trump’s mind can be changed.

  5. Anonymous says:

    It’s not only a problem for investors but for employees. At one startup we were told repeatedly that we had FDA go ahead. We even hired additional research staff based based upon that rosy assurance. Later it came out there was an FDA letter saying no way.

  6. loupgarous says:

    Good article, and it’s impossible to make your point “most drugs aren’t amazing slam dunks in the clinic, unfortunately, even the ones that were supposed to be” too often. We’re only now learning that identifying the enzyme responsible for X Syndrome (the thing you see on the evening news, generally ending with “and researchers hope that this will lead to new treatments for Syndrome X”) is sort of like taking the field glasses out in the backyard at night and locating Mars. Fine. Now get there.

    For Big Pharma in general, the goal posts keep moving. Bacterial disease was considered a solved problem until MRSA showed it wasn’t. Now we have to find new anti-microbials which will do what the old ones won’t a few years down the road. The former deputy director of Biopreparat, Ken Alibek, says the issue is better immune systems, not better vaccines and better drugs. While he’s got a point, that’s like finding Venus. Now get there.

    The whole class of problems Big Pharma’s tackling – the dementias, cancers and metabolic diseases of affluence and aging (diabetes mellitus, osteoporosis, impotence, heart disease, i>et cetera) and the extension of the human life span into hitherto unexplored numbers – are new problems.

    We have new tools, such as genetic engineering, molecular biology, continually improving computers among them, but unforeseen issues abound. Off-target effects of medication have been with us since alkaloids and other folk medication, but the occasional dramatic breakthroughs feed the expectation that every disease will eventually have a cure that is equally dramatic, available with a low co-pay, and has few untoward side-effects (I keep praying for a cancer chemotherapy agent that cures impotence instead of causing it).

    Startups in high-tech medicine need money to deliver new stuff. They’ve got to convinced people to give them the money in exchange for (hopefully) a chance to share in the profits down the road. Why people expect medicine to be exempt from the general rule that investment carries irreducible risk is beyond me.

    Complete response letters ought, by law, to be public. At the very least, the Securities and Exchange Commission ought to punish lies about why a drug didn’t go to market. Perhaps SEC ought to have access to CRLs to determine when a company’s obeying the law and being honest with investors, and when it’s lying to keep investors investing in junk.

    It’s a draconian cure, but one that will raise the bar for start-ups to the point where they only seek funding to do what can reasonably can be done and give investors a degree of risk they can live with.

  7. Barry says:

    part of this problem is implicit in Phase III Clinicals run by the interested companies. It would be better for the companies to take the drug through Phase II (maybe multiple Phase IIs ’til they get it right) and then hand it (and the needed funding) over to a trusted 3rd party to run the Phase III.

    1. Ted says:

      Phase III clinical trials are risky and enormously expensive investments. No rational organization would turn their future over to a third party. No rational independent third party would take on the legal risk that would be associated with any failure.

      1. milkshaken says:

        A biotech company that I worked for has put its first drug through phase III in colorectal cancer even though there were indications the drug may not be effective due to poor systemic absorption from gut – it was after the second drug has fizzled out in clinic (lack of efficacy due to very high plasma protein binding – they never bothered to actually measure it with human plasma proteins, they only did it with BSA…) and their third candidate (which eventually did become a drug) was still in preclinical stage – so it was more important to go ahead to expensive phase III with a flimsy candidate, so as to please the investors and keep the merger/acquisition negotiations on track

    2. David Cockburn says:

      In reality large parts of a PhIII project will be run by trusted third parties. The labwork will be done by a contract lab. The sites will be enrolled and managed by a CRO. The protocol writing will certainly be reviewed by ethics committees. It could not be otherwise as no company could have the global reach to run a modern PhIII.
      As Derek says, the really hard part of drug development is the pre-clinical phase and yet the proportion of drugs failing in the clinic is still 1000/1 and much of what the FDA demands serves to cause delay without adding much to certainty.

  8. Isidore says:

    Out of curiosity, does anyone know what the rationale behind CRLs not being made public by the FDA is? Is it a concern about divulging proprietary information? FDA Warning Letters are made public, with sensitive parts redacted.

    1. tnr says:

      Yes, I think that is the issue. It helps a competitor to read the FDA’s letters. Once a drug is approved, FDA correspondence becomes public information after a certain time period with certain things redacted. At my previous company, that was required reading for clinical folks looking to get something approved for the same indication. It would have been even more helpful to read the correspondence for things that never got approval.

      1. tangent says:

        Is there a particular reason for non-approved drugs not to do similar delayed/redacted publication? Considered to have higher commercial value because there’s not the approved drug taking up some opportunity? Not sure about that.

        1. Me says:

          Don’t know the reason, if there is one, but it makes sense that marketed drugs get stuff made public, because they are prescribed to the public and concern the public. For development products, the only concerned parties are the patients in the trial and the investors paying for the trial.

          1. Mark says:

            Well, that’s not strictly true: the patients who took part in a risky clinical trial also should have a say! Given that any time you run a trial on humans you are (even if to a tiny degree) risking a human life, I think there is a strong ethical argument to require all clinical trial data to be public (possibly after a short delay for commercial reasons, say a max of 2 years).

        2. tnr says:

          I don’t know the rationale behind this difference between approved compounds and those not approved. If I had to guess, it was put in place to encourage companies to submit drugs for approval, especially for a brand new indication. Oftentimes, it is not clear cut from your clinical data that you will get an approval. The FDA would still prefer to review that data as opposed to not seeing.

  9. milkshaken says:

    when you have huge bonus/stock options incentives to fool the investors, and little or no penalty for getting caught misrepresenting the facts, then I guess lying it is going to be normal state of affairs. Few extra millions USD in cash-ins to the top management does things to business and science integrity.

    1. Michael says:

      There *is* a penalty for issuing material misstatements as management of a public company. The FBI can put you in jail for decades and the SEC can fine you every dime you ever made.

      1. Anonymous says:

        Are there any recent examples of jail time or fines, particularly in biotech / Big Pharma? I am waiting to see what happens to Elizabeth Holmes. (I predict nothing other than a huge offer to CEO some other new startup.)

        (I think that Jeff Skilling was the only conspirator to go to prison for the Enron frauds. Others were acquitted or had their convictions vacated. Finance is much different from biotech/Pharma and those players (Madoff, Rajaratnam, Boesky, Milken, et al.) were in a whole different fraud game.)

        1. Michael says:

          I don’t know.

          Assuming that you believe the USA justice system works:

          If someone is clearly frauding in biotech, and there is a lawyer who is willing to devote time and effort into prosecuting the fraud, they will go to jail. It’s as simple as that.

  10. Greg says:

    The obfuscation and distortions designed to please Wall St. and attract investors; the alarming price increases for Rx drugs (even many generics) far above the rate of inflation for decades now; the crass advertising and legal maneuvers that now exceed spending on R&D; the record spending on lobbying that puts Congress in their back pocket, restricting price negotiations to secure much higher prices in the US than elsewhere; the buy-offs and buy-outs that conspire to keep cheaper generics off the market. I could go on.

    We now have a heroin (often laced with fentanyl or carfentanyl) addiction problem in this country that is killing tens of thousands every year, thanks to an over prescribing of Oxycontin and other related products that later send many to seek cheaper street drugs to satisfy the dragon. The response to date has primarily been to market a new drug for the constipation opiates bring. I’m not suggesting any conspiracy here, just the usual shortsighted business models designed to worship the quarterly bottom line and make bank, no matter what it may cost others.

    Small science (biotech startups, academia) may be a part of the solution, because Big Pharma’s blockbuster model has gone bust and their response has been to bust people’s pocketbooks to keep that gravy train on track. These issues will not subside until single payer (i.e. Medicare for all) and stricter regulations against price gouging are finally the law of the land, but I wouldn’t count on it anytime soon with this incoming bunch in DC, where everything has a free market solution. Yeah, the healthcare free market: your money AND your life.

    1. Dalis VanderYacht says:

      Your statement, ” an over prescribing of Oxycontin and other related products that later send many to seek cheaper street drugs to satisfy the dragon.” has been proven mostly false. It’s not the Rx drugs, as most people who get opiates via a legit source, take them responsibly.
      It’s the easy accessibility to street drugs that causes addiction, not a ‘previous exposure’ to strong Rx opiates.
      Unfortunately, I cannot attribute the exact source of this info, but IIRC, it’s fairly new information, and therefore not well known.
      “Hell is other people” – Sartre

      1. tangent says:

        Your statement “most people who get opiates via a legit source, take them responsibly” is actually consistent with a statement “most people who end up addicted started with legit Rx”, you realize? Or with a statement “legit Rx increases the risk for addiction by a large factor.”

        The data I’ve seen is that a majority of opioid addicts say they were addicted to pharmaceuticals p.o. first — some prescribed to them, some diverted (those usually given by friends rather than bought). Numbers vary by population, but here’s an example:
        “(41%) felt that their addiction began with “legitimate prescriptions,” 24 (32%) with diverted prescription medications, and 20 (27%) with “street drugs” from illicit sources”

        Or just consider the numbers that there are several times more pharmaceutical-opioid addicts than heroin addicts in the U.S. Most addicts started on pharmas and stayed on pharmas. Whether they were Rxed to them or not, the current Rx pattern supplies the availability.

        What’s your data?

        1. Design Monkey says:

          Stuff, of course, varies between different countries, but around here (not USA) : 1. prescription of opiates is rather draconically controlled, they are rather underprescribed than overprescribed 2. there still is quite a lot of opiate addicts 3. they tend to be correlated with certain social and ethnic groups, and not at all with anything of official medicine.

        2. Scott says:

          Too small a study, total number of participants is only 75. You need a significantly larger study (roughly 1000 participants) to get +-4%.

  11. steve says:

    None of this will matter now that the US in its infinite stupidity has elected Trump, who in turn is nominating a number of outstanding imbeciles to run the country:

    “The possibility that President-elect Donald Trump could nominate Jim O’Neill, a Silicon Valley investor with no medical background and controversial views, as head of the Food and Drug Administration (FDA) is setting off alarm bells among some healthcare experts.

    Bloomberg News reported Wednesday that O’Neill, a libertarian and associate of billionaire Peter Thiel, who is close to the Trump team, is under consideration for the FDA position. The agency oversees the approval of new drugs and is responsible for ensuring their safety.

    O’Neill lacks a medical background, traditionally a prerequisite for the job, and has raised eyebrows with his past comments about overhauling the agency.

    On a more basic level, experts expressed concern that O’Neill has no medical background. He was a Principal Associate Deputy Secretary of the Department of Health and Human Services under President George W. Bush.

    “He is stunningly unqualified in terms of his understanding of medicine,” Carome said.

    1. fajensen says:

      I think it is good that Trump got elected – for several reasons.

      First one is that while Obama and Hillary seemed to be able to bomb, spy, assassinate and regime change with almost total impunity and blind support from “the international community”, Trump, roundly vilified as he is, will have a much harder sell ahead of him.

      Second is that Trump now cloaking himself in the imperial powers of secret laws and black-budget intelligence services created by Bush and compounded by Obama will – perhaps – wake people up and make congress / the senate put some limits on what the presidents power *is*.

      Third is now, maybe, my government won’t kiss the ass of the US of A administration quite so much now said ass is attached to the non-orange end of Donald Trump.

      Fourth – maybe Tribalism (aka Identity Politics) will now be considered a Bad Idea by “The Good & The Great”? Especially if Trump indulges in it!?

      Fifth? Dunno. I just very much like to see “leading experts” betting on the wrong horse once in a while and experiencing their own “Minsky Moment”. Keeps skepticism and the idea of good process viable, which we need.

  12. DV Henkel-Wallace says:

    I see that last week the HUD told Fox News they should correct a major misstatement (about food stamps fraud). Seems like material misrepresentation of the FDA’s communication should be fodder for the SEC or CPSC. Or since the agency already has the power to approve your label text, marketing etc — don’t they have the authority to correct misstatements by companies (in regards to the content of FDA communication I mean).

    Also, can we say this a few more times: “FDA approval is not the rate-limiting step for producing a truly new drug. ” “FDA approval is not the rate-limiting step for producing a truly new drug. ” “FDA approval is not the rate-limiting step for producing a truly new drug. ” There. I feel a bit better.

    1. J Severs says:

      I expect there would be heavy 1st Amendment issues before the HUD (or SEC or CPSC) could order Fox to correct alleged misstatements.

    2. Michael says:

      It can be a rate-limiting step. Look at the number of approvals in 2016 vs. 2010. The number of NDAs fell, but slightly. Do you really think biotech management suddenly started lying all over the place, or maybe the FDA and Califf (or even this “John Jenkins”) had something to do with it?

  13. Anon says:

    Sadly, when some people encounter issues, they bury their head in the sand and fool themselves that the problem will go away while they keep it hidden from others. I think that is why some managers hide and/or gloss over issues raised in a CRL. It takes courage to accept issues as they are and communicate them fully to others.

  14. qvxb says:

    Nobel prize winner Bob Dylan explained it this way:

    “At times I think there are no words
    But these to tell what’s true
    And there are no truths outside the Gates of Eden”

  15. Jonas Udmark says:

    Well, as far as the stock market is concerned Keynes described that pretty well. It’s a beauty contest, alright.

    At the end (well, more often the very beginning) of the day, all the objective data (some) people count on to price a share can be overruled by a great big flashing sign of FREE MONEY HERE–“hey, everybody’s buying that, let me get in on it too”. And it can be hard not to be tempted taking part in that.
    It’s a rather intricate poker game.
    Unless you stay in the share for a looong time, then its performance should reflect real company value. But then you don’t care about those zany company announcements, right…:-P

  16. Emjeff says:

    “Many people (and many politicians among them) seem to imagine that there’s this big logjam of wonder drugs that’s having to work its way slowly through a thin hallway full of persnickity bureaucrats – if only we could open those floodgates! But this isn’t actually the case. If you look carefully at the number of New Drug Applications, it’s hard to make the case for a giant backlog.”

    Absolutely true, but the bigger problem is that the FDA seldom has the expertise in a given therapeutic area to give sound advice. I was involved in a pediatric anticoagulant trial where the FDA insisted that the patients transition to warfarin despite 1) every pediatric hematologist we talked told us they don’t use warfarin in kids, and 2) the FDA approved labeling states that warfarin is contra-indicated in those under 18. They did not let up until they hired a pediatric hemotologist

  17. Dr. Lloyd T J Evans says:

    The FDA is a government department, is it not? So a CRL or any other document they produce should be a public document. Unless for some reason the FOIA doesn’t apply to the FDA. If that reason is that CRLs contain commercially sensitive information, then why not just redact the sensitive parts and make the rest of it public? That way, companies wouldn’t be able to lie about it – or if they do, they could be easily found out. Though when a CRL is issued for a drug which is turned down, that surely means that said drug no longer has any commercial use or value. So how exactly can any information about a useless drug possibly be commercially sensitive? It’s not as if the structure of the drug is some sort of trade secret. Patents have to be taken out long before clinical trials start, which means any information of that nature is going to be in the public domain already.

  18. Michael says:

    “That brings up another key point: FDA approval is not the rate-limiting step for producing a truly new drug.”

    This is pure nonsense.

    The number of approvals in 2016 is at the lowest level since 2010, while the number of applications is only slightly down. FDA approval is clearly the rate-limiting step for producing a truly new drug.

    1. Fenichel says:

      The approvals/applications ratio is uninformative as to where the rate-limiting step lies. If applications in 2016 were less meritorious than those of 2010, then the approval/applications ratio would have gone down even if FDA’s application-to-action time were zero.

      1. Michael says:

        Occam’s razor applies.

        The number of approvals has halved while the number of applications is barely down. You cannot explain this as pure chance, nor can you state that the industry has decided to markedly reduce the quality of their applications.

        1. Fenichel says:

          I did not make my point sufficiently clear. The unit of FDA throughput is the action, not the approval. Unless 1980s-style queues are accumulating at FDA, then actions are being taken at least as frequently as applications are arriving. Only a proper fraction of these actions are approvals. Before the use of Complete Response Letters, some applications cycled back and forth between sponsors and FDA many times, but that is now uncommon.
          If your baseball team had played about the same number of games in 2016 as in 2015, but has won fewer of them, you might say that the umpires were the rate-limiting step keeping your team out of the World Series, but my description would be different.

          1. Michael says:

            Ok, thanks for clarifying. Framing it that way, I tend to agree. The rate of accepting applications for review has stayed the same, but that is meaningless in the context of the modern responsibility of the FDA’s CDER, which is to approve safe and effective drugs for marketing in the United States. If you frame it that way, then the FDA is the rate-limiting step keeping medicine from reaching American consumers.

            2016 has been the year of rushed reviews by less-than-qualified bureaucrats likely enforcing an often-incomprehensible safety mandate set forth by the new Commissioner. I could cite multiple examples where it is not even a question of a company’s honesty versus the FDA’s honesty, but more of a question of FDA competence.

            For example (as a very simple example), in the recent Cempra CRL, the FDA used some basic statistics to state that they wanted 9,000 patients in a new safety trial to reduce the risk of severe DILI to less than 1/3000. However, there are already over 900 patients in the safety database as the FDA themselves admitted to. So you’d need 8100 patients, not 3000. I highly doubt the company would lie about such very simple matters, so I can only conclude FDA incompetence. (thanks, John Jenkins!)

            (P.S.: The applications do cycle back and forth, but just much more slowly and with an extra few layers of bureaucracy. A CRL provides a (usually expensive) path forward.)

          2. Michael says:

            Not 9000*, I meant. Mis-typed.

      2. Michael says:

        And another thing. If you don’t count the multiple NDAs slated for Jan/Feb 2017 which were rushed through to December to massage the numbers, it’s even worse.

  19. Janex says:

    There is also the issue that the regulatory authorities are indirectly rate limiting. While the time to read/approve the application may not be rate limiting, running larger more complex clinical trials is. It seems like we are doing more and more clinically (and even preclinically in some cases) and getting out less and less. The thing is the changes are slow but if you look at 1990 for example and compare the drug approval process then to the drug approval process now and ask the outcome question are these extra steps genuinely making approved drugs safer and more effective or not. In the case of biologics I would say that the answer is yes, the new process are producing drugs which are significantly safer (or at least we understand how to dose them more safely) than the early generation biologics approved in that era. In the case of small molecules, I’d say no that for the most part (there are always exceptions), drugs approved now are not any safer than drugs approved in 1990.

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