Warm Bits for a Cold Month

Doc Gumshoe on opioids, FDA approvals, and, yes the Wuhan Coronavirus

By Michael Jorrin, "Doc Gumshoe", January 30, 2020

Please indulge Doc Gumshoe while he presents his musings on what’s going on in general in the health-care arena, and in particular, which new drugs are getting the FDA blessing and why, as well as which ones are getting the short straw.   My impressions and conclusions are in some cases only loosely based on specific data. Some of these are notions that have taken up residency in my noggin after a year (or several years) of looking over the happenings and developments in medicine and pharmacology.   With no further ado, I will plunge in.

Are we doing better or worse than a few years ago, say 2010?   For those of us who are somewhat well-educated and well-off, my answer is that we are unquestionably doing better.   As I have pointed out repeatedly in my rants, the death rate from heart disease is significantly lower and keeps going lower, and the cancer death rate, although the improvement is not huge, is also dropping.   The reason that the cancer death rate is not dropping as fast is that a certain percentage of the heart disease survivors die of cancer instead. Recent years have seen quite a number of cancers – cancers that were previously nearly impossible to treat – succumb to treatment.  Or to put it in more positive terms, cancer patients who previously had few chances of survival now have treatment options that improve their odds considerably.

However, the improvement that many of us are experiencing has evaded a fairly large sector of the population.   The less well-off and less educated are disproportionately walloped by opioid addiction and by a high suicide rate.   The blame for this is spread around fairly widely – and indiscriminately, I might add – ranging from drug pushing by the pharmaceutical companies, to MDs who have been in essence bribed by the pharmaceutical companies to dispense those addictive opioids inappropriately, to a shortage of health-care providers in rural areas, to income inequality that leaves people without hope, and perhaps also to a general culture of pill-swallowing as a means of combating all evils.

The consequence of this inequality is that life expectancy in the United States has declined for the past three years.   This is the first time in our history that life expectancy has taken a U-turn, and it should be a matter of the gravest concern, not just in the health-care profession, but to all of us, including our highest leaders.

This is despite the cheerful little statistic that smoking rates in the US are at an all-time low.   Just 14% of the US population are smokers. The Surgeon General wags a finger, however – it seems that about half of our MDs do not take the trouble to advise their smoking patients to quit, despite the statistic that smoking is the top-ranked cause of preventable disease, death, and disability. 

The unequal benefits of our health-care system are at least in part due to a shortage of medical professionals, especially in primary care.   As older providers retire, there doesn’t seem to be an equal number of younger ones entering the field. It’s more than a bit surprising, since health-care providers are generally decently rewarded and well-respected.   But medical practice at all levels has become increasingly stressful, as the demands of electronic medical records and the bureaucratic procedures required by patient’s medical insurance gobble up the provider’s time and attention, diverting it away from the patient.   As a result, we hear increasingly of physician burn-out, which occurs in many cases in mid-career.            

Having mentioned electronic medical records (EMRs), these certainly have their benefits, but they are also saddled with cumbersome baggage that unnecessarily consumes the time and attention of providers.   The obvious benefit is that when a patient is ambulanced to the hospital with a TIA (a transient ischemic event, or “mini-stroke”), the hospital is immediately able to communicate with that patient’s primary physician, obtain the patient’s medical records, and keep the patient’s primary provider current on the patient’s status.   In other words, all the patient’s medical records are immediately available to whoever needs them.

But the EMRs have an inevitable downside, which is that the provider is required to answer a great number of questions that often have nothing whatever to do with the patient’s current medical needs.   For that reason, in some practices the physician works with a “scribe,” so that the physician can pay attention to the patient and not to the computer screen. The algorithms that drive the EMR appear to be focused on getting all the information into the record and not so much on meeting the patient’s needs in the moment.

What’s happening over at the FDA? 

How has the FDA been behaving in the past year or so?   The general sense is that they have become somewhat friendlier to the pharmaceutical industry.   According to the FDA’s count, they gave the imprimatur to 48 new molecular entities in 2019, which was down from the 59 approved in 2018, but a bit more than the 46 approved in 2017 and way more than the 22 that got the nod in 2016.   Part of what accounted for the growth in the number of new drugs approved in the past few years is that an increasing number have made use of special development and approval programs, which were instituted to speed the approval process for drugs which were considered urgently needed – the Orphan Drug Act, Fast Tracking, Priority Review, and Breakthrough Therapies. In the years just before the turn of the millennium (i.e., the 1990’s), about 48% of applicants for FDA approval qualified for one of those programs. By 2018, more than 80% of new drug applications qualified.

Those programs have made it quite a bit easier to gain FDA approval.   The clinical trials are smaller – about 100 versus about 300 participants.   Also they are more often not randomized – about 30% versus 80% for drugs not qualifying for those programs.   The drugs that were qualified to be in one of those programs got the FDA blessing in about half the time – 4 years compared to 8 years for most other drugs.   Half were approved based on Phase I or Phase II clinical trials, and nearly half of those on Phase I trials alone.

Also, and potentially of considerable importance, is that an increasing amount of the FDA’s budget came from the pharmaceutical industry’s users fees, which amounted to about $4 billion in the past few years, compared with about $300 million in the 1990s.   It was estimated that in 2018, users’ fees from the drug industry paid about 80% of the FDA reviewers’ salaries.       

Does that mean that the FDA is “friendly” to the pharmaceutical sector?   Or that, as some would claim, that the FDA is under the thumb of Big Pharma?   On the whole, I would say “yes” to the first question and “no” to the second. Permit me to tell you a story that may illuminate those questions.

Back in October 2017, I posted a Doc Gumshoe piece, entitled “Pain Management vs. Opioid Abuse: Glimmers of Light,” which included an optimistic prediction about a drug, then in development, from Nektar Therapeutics, called oxycodegol, but then just labeled NKTR-181.   Based on the information then available, I thought that the drug was likely to fill a much needed niche in pain management.   

My optimism was based on several of the drug’s basic characteristics.   First, that is was absorbed very slowly and took about eight hours to cross the blood-brain barrier, which would make it extremely unlikely that seekers of an opioid high would find it the least bit attractive.

Also, at higher than the recommended dosage, the Nektar drug produced highly disagreeable side effects – nausea, vomiting, constipation, headache, fatigue.   At high doses, these nasty side effects emerged before any signs of narcotic highs. 

Therefore, the Nektar drug looked like an excellent candidate for chronic pain relief, which is what the company was targeting.   Nektar therefore applied to the FDA for a fast track indication for their drug for the treatment of chronic pain in cancer patients, based on a single clinical trial.   It was a shock and surprise when, on January 15, 2020, the FDA Advisory Committee rejected the application by a vote of 27 to 0.    

This was based not so much on the data supplied to the Advisory Committee as on the fact that Nektar wanted approval based on just one clinical trial.   Nonetheless, Nektar has announced that it would do no further development work on oxycodegol, claiming that spending the additional $125 million that it would take to do a further clinical trial and submit it to the FDA would be wasted.

Another proposed pain medication, Aximris XR from Intellipharmaceutics also got a big thumbs down from the FDA Advisory Committee, which voted 24 to 2 to reject the application   Aximris XR is supposedly an abuse-deterrent controlled-release oral formulation of oxycodone hydrochloride developed for long-term 24-hour pain release.

Overall, despite the general sense that the FDA is somewhat more friendly to the pharmaceutical industry than formerly, they are evidently very cautious when it comes to potentially addictive pain-killing drugs.   As advisory committee member Steve Meisel, PharmD, of Fairview Health Services in Minneapolis, said at the oxycodegol review, “We can’t approve a drug in the midst of a public health crisis on the basis of speculation.”

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