Opinion requested: Should new drugs always be compared not just with placebos but with old drugs for the same conditions?

While I agree this would make determining drugs more effective for treating patients, this process will likely never happen. As it stands now, most clinical trials for investigational drugs are not designed to evaluate if the new drug is going to be more effective or safer than a previous drug, but only to prove that the agent being tested will work for the disease/condition the company is applying for. It’s real purpose is making sure any adverse effects or reactions are not severe enough that it would overstep the risk vs benefit comparison. We have to keep in mind that the FDA drug approval process is really nothing more than the government stepping in to say, “Hey, does this drug do what it says? But above all, can it harm or kill people?” The FDA is essentially a reactionary regulating body. Prior to the establishment of the Food Drug and Cosmetics Act (FDCA), which gave the FDA the power it has now, they had little to no regulatory power. The passage of the FDCA itself was largely due to the sulfanilomide disaster during that time.

Also, let’s look at who is actually paying for these clinical trials. There are grants and foundations here and there that help with mitigating some costs, but largely they are funded by the pharmaceutical companies. Costs for running clinical trials generally range from millions to tens of millions, and since the companies have a vested stake in the result of their product being successful, the data they want has to be as convincing as possible that their agent works. That’s the reason that most of the studies are going to compare to placebo, and not an API. There are definitely some trials that do compare active ingredients, called active-treatment concurrent control studies, but if you think about it from a financial standpoint, a pharma company will generally avoid those sorts of trials unless pre-clinical or Phase I testing has shown great promise. To be asking those companies to compare a potential pipeline agent is like asking a trader to only invest in high risk stocks.

This current system isn’t exactly efficient, nor does it really benefit the general population. The industry landscape is changing however, since we are moving into the direction of outcomes based medicine. With the fall of the patent cliff and fewer drugs in the pipelines, pharmaceutical companies are hard pressed to recover that lost profit. One way we can combat the rising power of third-party payer is to prove that their current brands or pipeline drugs are more effective than existing therapies. If we can replace the existing “gold standard” with a a newer agent, then everyone wins. However, for a pharmaceutical company to shift focus from their existing drug development phase to this new method requires substantial risk. In my opinion, if an industry giant were to take this leap of faith, and others follow, we may be able to both improve the quality of care for patients, while also create a potential new revenue stream. There are two ways to deal with the rising power of third-party payers: fight them and delay the inevitable, or find a way to use that changing landscape towards your benefit by changing your existing structure to work with the new dynamic.

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Opinion requested: Should new drugs always be compared not just with placebos but with old drugs for the same conditions?

4 thoughts on “Opinion requested: Should new drugs always be compared not just with placebos but with old drugs for the same conditions?

  1. David Zhou says:

    Hey Wayne, I have a question regarding what you said in the above article. You said “…a pharma company will generally avoid those sorts of trials unless pre-clinical or Phase I testing has shown great promise.” From my understanding Phase 1 tests for the safety of the IND on healthy candidates. Phase 2 and 3 is testing for efficacy of the drug on patients. So how would pharma companies feel more comfortable comparing their IND with an existing API from Phase 1 testing results, even if it is showing great promise? I would expect pharma companies to feel more comfortable comparing their IND with existing API from promising Phase 2 and 3 results.
    I recently learned about the different phases of tests so I am trying to apply that knowledge here. Maybe I am missing the bigger picture. Thanks!

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    1. Great question David. You are correct in your statement that promising Phase II and III results will generate more confidence for the pharma company in their IND. I believe that in between each clinical trial phase, the drug companies will collect their data and re-evaluate their focus whether it be more efficacy and/or reduced side effects. You certainly see there are Phase III clinical trials where you see IND drugs being compared to existing APIs. However, what I meant was that sometimes, before the IND even gets to Phase II and Phase III, the company will already have an idea of how well that drug will perform. Either from data modeling or existing data sets. I’ll give you a classic example, Nexium (esomeprazole) vs. Prilosec (omeprazole).

      A bit of history on these drugs, Prilosec first came out on the market in 1989 as the first drug of it’s class (proton-pump inhibitors) used to treat gastroesophagel reflux disease (GERD) and duodenal ulcers. Over the course of it’s product life, the drug has brought owner AstraZeneca billions of dollars. However, in the early 2000’s, the patent was expiring, and AstraZeneca needed to solve this problem. They either had two options, find a new indication for Prilosec, thereby extending it’s patent life for another few years, or create a replacement drug. AstraZeneca chose to do the latter, and released Nexium in 2001.

      Now the chemical name for Nexium is esomeprazole. Prilosec’s chemical name is omeprazole. Doesn’t that sound a little too similar? Fact is, esomeprazole is a stereoisomer of omeprazole. For those of you that forgot chemistry, stereo-isomer literally means mirror image. I’ve shown the chemical configurations below: Prilosec on the left, and Nexium on the right.

      Prilosec (omeprazole)Nexium (esomeprazole)
      “sources: wikipedia.org”

      See how they are almost carbon copies of each other?

      The point I’m trying to make is that AstraZeneca played around with omeprazole before it went off patent, created a more efficient version of it, and then subsequently patented the compound and began the IND process. So during the initial R&D phases and pre-clinical trials, they had already gathered the data that made them confident they had a superior molecule. Now in the case of AstraZeneca, I don’t think a pharmaceutical company would run Phase clinical trials comparing their own drugs, because they can still get some life out of their precursor molecule, but a company creating a superior molecule to a rival company would almost certainly compare their IND to the API.

      To summarize, yes, you are right that a lot of drug companies probably get data in Phase II and Phase III that they would subsequently use for further clinical trials to make their IND look better, but sometimes, they know from the get go they have a superior product. And yes, while the main purpose of Phase I trials are testing for safety, they’re still getting efficacy data as well. I’ve included the drug R&D process below.

      R&D Process
      “source: http://www.phrma.org/innovation/clinical-trials

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  2. David Zhou says:

    Thanks Wayne for that explanation. Loved that R&D timeline as well. So a follow up question is that do you think FDA should regulate stereo-isomer, to make sure that drug manufacturers attempt to create the “most efficient” version of a drug the very first time around, rather than doing it the way AstraZeneca did it. Obviously, industry will be opposed to it.
    In a way I can answer my own question since I know FDA’s mandate is pretty narrow: 1) protect the public from harmful drug/food 2) provide the public with a variety of effective treatments for diseases. I guess “most efficient” doesn’t really matter as long as those two objectives are achieved.

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  3. David Zhou says:

    And plus, it might just drag the review process out too long and put too much pressure on FDA reviewers to identify the “most efficient” form of a drug (I don’t even think it is technically possible just by reading the IND application). Consumers already complain it takes too long for FDA to approve drugs.

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