Skip to Content

Clinical Trials

The FDA’s Latest Actions and Problems

It’s been clear for many years now that some drug companies are abusing the “restricted distribution” idea to keep generic competitors from being able to enter their markets. That, in fact, was a basic part of Martin Shkreli’s entire business plan, but guess what? He was not the first person to think of doing that, and the practice continues in ways that don’t make the gaudy headlines that he did. The idea is that a generic company must show that their product is equivalent to the marketed (off-patent) drug in order to receive FDA approval. But what if they just absolutely can’t get any of it to run the trial? This is where companies set up a “closed distribution” system, which was designed to deal with potentially hazardous compounds that (for example) must be kept away from pregnant female patients (the FDA’s Risk Evaluation and Mitigation Strategy, REMS). But in this case, it’s used to keep the drug away from generic competitors, who basically have no recourse at that point.

I’ve been yelling about this for some time, as have plenty of other people, and I’m very happy to see that Scott Gottlieb of the FDA is taking the problem seriously and trying to take action. The agency has started by publicly identifying the companies that are gaming the system in this way described above. And now they’re addressing another REMS problem – when a generic competitor does manage to try to enter a market for a compound that’s under this system, the FDA wants both of the drugs (naturally enough) to be under the same REMS. But that requires negotiation between the original manufacturer and the generic firm, which gives another opportunity for foot-dragging. The agency is both clarifying the shared-REMS situation and now allowing for waivers when necessary in order to get generics to market in a more timely fashion. And good for them. As the agency says: “Our safety programs shouldn’t be leveraged as a way to forestall generic entry after lawful IP has lapsed on a brand drug. Our market-based system for rewarding innovation is dependent on this kind of legal competition.”

But while we’re talking regulatory affairs and the FDA, there’s another item that needs to be mentioned. The “right-to-try” legislation I wrote about the other day has indeed been signed into law. And I will again publicly predict that it will do virtually nothing for critically ill patients, while opening the door even wider to abusing them for profit (now under the cover of law). But what I wanted to note was an incident yesterday.

The FDA itself issued a press release on the signing of the bill, saying that “Our implementation of the Right to Try Act will build on our long-standing efforts to help patients and families who are facing life-threatening diseases or conditions, in a way that seeks to protect their autonomy, their safety, and the safety of others following in their paths.” Gottlieb himself has mentioned that new policies might have to be written to deal with the law as written. But Sen. Ron Johnson of Wisconsin (an author of the bill) detects a hidden agenda in that sort of language. He has sent an open letter to Scott Gottlieb and the agency, making his intent as clear as possible:

“This law intends to diminish the FDA’s power over people’s lives, not increase it. It is designed to work within existing FDA regulations, definitions, and approval processes.  It is not meant to grant FDA more power or enable the FDA to write new guidance, rules, or regulations that would limit the ability of an individual facing a life-threatening disease from accessing treatments.”

Just in case you were wondering. He’s also asking to meet personally with Gottlieb as soon as possible so he can hammer these points home a bit more, which sounds like fun. But I find Senator Johnson’s faith in our drug-discovery abilities touching and a bit embarrassing. He really does seem to believe that there are all sorts of cures that are just being stifled by masses of regulation, and that he’s really connecting desperately ill people with the medicines that they just haven’t been able to get until now. That isn’t true, but it’s pretty to think so, isn’t it? At the signing ceremony, the President made his own views quite clear:

“Thousands of terminally ill Americans will finally have hope, and the fighting chance, and I think it’s going to better than a chance, that they will be cured, they will be helped. . .”

Of all the concepts and facts I would like to see the President grasp, I will admit that those relating to drug discovery and development are rather far down the list. But still. What are people going to do when this law has been on the books for a while with no real effects? Or no real effects but bad ones? Does Scott Gottlieb (or his successor) get hauled in to explain why? Or (a more likely outcome), does no one ever bother to go back and check on anything after having taken their victory laps?

Update: changed to put Senator Johnson from the correct W-state.

30 comments on “The FDA’s Latest Actions and Problems”

  1. R M says:

    Senator Johnson is from Wisconsin

  2. Bagger Vance says:

    If the question is offering people something instead of nothing, or a placebo in place of ‘sorry our hands are tied’, do you really think there won’t be some positive return, even if it’s not statistically sound enough to prescribe generally? Isn’t that sort of typical of bio: there’s some response even if your ANOVA pooh-poohs it, and the family of some death sentence survivor probably won’t.

    “No real effects but bad ones” is something you’ve probably used to describe any number of clinical trials that ended.

    1. Hap says:

      Except you can’t tell if the drug saves people overall but not enough to be significant, if it doesn’t do anything, or if it harms more than it helps. “Can’t tell statistically” likely means that you can’t tell, and the expected effect will be zero (you can’t tell that it has an effect) which will mean that if people don’t die who should have, some will die who shouldn’t have as well.

    2. Shalon Wood says:

      “Some positive response”?

      On average? No. No, I don’t, or far, _far_ more drug trials would succeed. In fact, I feel rather confident in the assertion that this will _kill_ more patients than it helps — not cures, helps at all. To clarify, I think that the number of people who die who would have lived because of ‘right to try’ will outnumber the people who had even the smallest increase in quality of life as a result of ‘right to try’.

      And look; I lost my wife to cancer last year, at 44. If _anyone_ should be grasping at straws and blaming ‘Big Pharma’, it should be me. So if _I’m_ skeptical, well, I’m not saying Congress is full of idiots who don’t know their left from their right. I’m just saying I wish I had the concession on printing ‘R’ and ‘L’ on their shoes.

    3. loupgarous says:

      I worked on contract to one of the largest multinational drug firms during the NDA process for a new dosage form of its recombinant insulin analog, which was being pushed on the theory that reversing two amino acids in the middle of the original human insulin molecule would result in a faster-acting insulin which would also be less apt tot trigger insulin resistance (a big actor in type 2 diabetes). The new stuff did work fast, but diabetics need a “lente” version of their insulin which works slowly, so the remaining theory of reduced insulin resistance was the only selling point for the “lente” version of the insulin analog.

      Only statistical study allowed the customer to establish whether or not the new analog reduced insulin resistance in the study population, and it was such a close thing that FDA’s advisory committee deferred approval until more studies could be done.

      “No real effects but bad ones” has been a problem with pharmaceuticals going back to when Paracelsus invented modern pharmacology with his maxim “the dose makes the poison”. Since then, pharmacovigilance is, or ought to be, job one in the drug development process, watching for adverse effects of new drugs.

      Derek’s recent blog on reasons for the fluoroquinolones not being as safe as we’d thought shows exactly why we ought to be vigilant for drugs which have “No real effects but bad ones”.

      “Right to Try” can involve drugs which have only gone through healthy volunteer safety studies, and might bypass the later stage of clinical trial in which we look at safety in people who are ill with the condition the drug’s supposed to treat. If Merck’s osteoporsis drug odanacatib had been available under “Right to Try”, the unforeseen increased risk for stroke in patients caught in the third phase clinical trial might never have been seen, and odanacatib could have been given to elderly women without patients or prescribers knowing about the increased stroke risk.

      Since most of the new generation of drugs target disease mechanisms which aren’t fully understood at the “whole organism” level, unforeseen toxicities such as odanacatib’s are a real worry for patients who are given drugs which may not have been studied as exhaustively as odanacatib was.

      For this reason alone, I hope Gottlieb stands firm on developing policy to protect patients who are getting drugs under “Right to Try”. The only thing worse than withholding hope from patients wish a bad prognosis is giving them worse health problems than they had to begin with.

  3. R/S says:

    Does anyone know, at what point does a compound become eligible for right-to-try? Does it (for instance) have to be in an active phase-3 trial, or what?

    1. b says:

      It has to have passed Phase I. That’s a pretty low barrier.

      1. b says:

        My apologies. It has to have “completed a Phase I trial”. Even lower.

        1. biotechtoreador says:

          I may be mistaken, but I thought under old regs a patient could get a drug under compassionate use with just an active IND.

  4. A Nonny Mouse says:

    I was told by the owner of an Indian generics company that this was happening with mefloquine which was being sold into the US military at $50/tablet rather than 50c (they are the biggest client). A different formulation was being sold for public use (a very small market).

    He could obtain comparison material via a “contact” but could not use the data as he would have to explain where the material had come from and so the military has to pay this inflated price.

  5. mallam says:

    What’s the problem in getting the original patented drug for the trial? Just have a doctor on staff write some scripts, and buy it for full price. That’s what we did many years ago.

    1. John Wayne says:

      That used to be the standard practice. There are two current issues (1) doctors don’t want to do this because it not really ethical, and (2) that script will end up on the fulfilling person’s medical records (providing a permanent record of the first issue.)

      This is a fairly amusing side effect of having much better medical records.

      1. Shalon Wood says:

        How many buildings have to convieniently burn down to fix this problem?

        Asking for a friend.

    2. An Old Chemist says:

      The generic drug makers typically need up to 5,000 doses of a brand drug in order to run bioequivalence and bioavailability studies to prove the generic medicine is the same as its brand drug.
      https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm609365.htm
      (FDA Statement
      Statement from FDA Commissioner Scott Gottlieb, M.D., on new policies to reduce the ability of brand drug makers to use REMS programs as a way to block timely generic drug entry, helping promote competition and access)

    3. aairfccha says:

      Why does a pharmaceutical company need a prescription in the first place? They are not an individual end user.

  6. johnnyboy says:

    ” What are people going to do when this law has been on the books for a while with no real effects?”

    Well that’s the problem – no one will be able to tell that there are no real effects. All we’ll have are media stories about the occasional patient that got better (whether from the drug, from placebo effect, from natural disease variability), no stories about the ones that didn’t, and no way to figure it all out. But try putting that Genie back in the bottle and you’ll have thousands of patient advocates (and their congressmen) trying to tear your face off.

    1. Shazbot says:

      Yeah, the ones who are now dead not being able to talk is a very good way to avoid the negative aspects of this. Since the lucky ones live longer, naturally there will be more of them around.. those who weren’t so lucky aren’t available for comment.

  7. Anonymous says:

    But this is open to interpretation: “… Our market-based system for rewarding innovation is dependent on this kind of legal competition.” First of all, I am in favor of the legal competition and I’m against gaming the system (Allergan, Restatis, Mohawk Indian Tribe) to prevent the timely approval of generics.

    IN GENERAL, generics companies are NOT the innovators, they are the copy-cats. (Sometimes, they do innovate. Apotex developed a better process to manufacture Prozac (I think) and Lilly even licensed the Apotex process patent. When the Prozac utility patent expired, Lilly’s own (unused) process patent remained in force. Apotex tried to compete as a generic and Lilly sued claiming that the Apotex process patent infringed their own process patent. Apotex argued, “Why have you been paying us to use our process all these years if it’s the same as yours?” and won the case.)

    It is the Big Pharma, biotechs and other risk takers that are the innovators and do need to have their LEGITIMATE patent rights protected. (The patent system has some modifications to allow for the long approval times of drugs, but maybe it could use some further tweaks so that companies can recoup some of their investments.)

    Once again, my issue is not about generic competition (I’m for it!), it is about who the innovators actually are.

    1. DCRogers says:

      What does a company gaming the system to keep an OFF PATENT medicine from facing generic competition have to do with protecting LEGITIMATE patent rights?

      1. Anonymous says:

        I guess I introduced an unnecessary distraction with that comment. What I meant was, as patents approach the end of their lifetime and become targets for generic competition, companies do have some legal options to extend their monopolies a bit longer. … Congress has the power to extend patent life by specific legislation. (Columbia U lost their effort to extend the Axel cotransformation patents that way.) But companies have also gamed the system by making illegal deals with (payments to) generics companies to keep the competition off the shelf – not legitimate. And so on.

    2. AVS-600 says:

      This seems like a non-sequitur when taken in context. The REMS program that Gottlieb references in his press release has nothing to do with intellectual property rights. Thiola, daraprim, and the like aren’t having their prices hiked because of their cost of development. They’ve been off-patent for a long time, and indeed the companies selling them never held any IP rights to them in the first place.

    3. x says:

      It would help to keep in mind that so-called “intellectual property” was never intended to be permanent. Rather, art and invention was (and is) considered the property of the public, and creators were granted a LIMITED license as a kind of incentive.

      Obviously, if creators are allowed to use legal shenanigans to withhold their creations from the public after their limited license has expired, the system is indeed broken and the owners’ rights to their property is being violated. It’s just that the actual owners who are being harmed aren’t who you seem to think they are.

  8. Emjeff says:

    Derek, you can of course be against right-to-try, and there are probably sound reasons for that. However, I have to call you out on your criticism of the Senator’s actions. It is perfectly within the purview of Congress to direct the FDA, not the other way around.

    You say the president and others have too much faith in our ability to create new drugs, and I agree with you. However, you have too much faith in the FDA. Being a medicinal chemist, you are shielded from interactions with the agency, but I am not, and I can tell you that FDA reviewers get dumber every year. CDER needs an overhaul badly.

    1. john says:

      FDA recruitment is not by merit but by connections and nepotism. One of my acquaintances works in FDA. His wife wanted job in FDA. She had degree in physics. There was job opening requiring microbiologist. Guess who got the job? Of course B.S. physics over PhD microbiologists. If you look at USAjobs website, most jobs are only open for internal folks and not to public.

  9. b says:

    Still waiting to hear some suggestion/guidance on who pays for these treatments. And what happens if the company says the price is $1,000,000? And as several folks on the supply side have mentioned, what batch does the treatment come from? I guess since the goal is to undermine and bypass the FDA here, we don’t even need a GMP batch?

    1. biotechtoreador says:

      Under prior rules companies could recoup costs associated with providing the drug. No doubt there’s some crafty accounting that can go into making that a big number.

  10. Philip says:

    I have said many times that congress needs to use Martin Shkreli and Valeant Pharmaceuticals, sorry I mean Bausch Health, as a road map to what needs to be changed. Add Celgene to the list.

    I know this congress will not change anything, but I am hoping that the next one will.

    1. Chrispy says:

      What did Celgene do?

  11. Spell says:

    Maybe a little buddy is the answer. Hey, it worked for some of the profs in the field. Once you have a little buddy all is golden, and you will have billions$$$$$$$##$#$$#$$$$#$$$$##$#$#########@#$$$%%%$##@!/^^^^^###$#. What are u waiting for. Have yourself a lil’ buddy grad student.

Leave a Reply

Your email address will not be published. Required fields are marked *

Time limit is exhausted. Please reload CAPTCHA.