By Dr. Geoffrey Modest
A couple of articles came out in the press showing that drug companies seem to have grovelled to a new low.
- A STAT News investigation looked into required study reporting by major academic centers, finding pretty dramatic deficiencies http://www.statnews.com/2015/12/13/clinical-trials-investigation/ .
Details:
- In 2004 the New York attorney general filed a lawsuit against GlaxoSmithKline for concealing data finding that Paxil (paroxetine) was associated with increased suicidal thoughts in teens, which led to federal legislation to ensure that studies from drug and medical device makers report results through the NIH website ClinicalTrials.gov, or face a fine. The context here was that negative trials, or those finding significant adverse effects, might not be published, leading to clinicians using useless and perhaps harmful drugs or devices. These disclosures were to be reported on the website within one year of study completion or termination, or be subject to a fine of $10,000 per day per trial
- But, it turns out that compliance with these federal requirements is remarkably poor, especially in big academic centers: 4 of the top 10 recipients of medical research from the NIH filed reports late or not at all in >95% of the time, including Stanford, University of Pennsylvania, University of Pittsburgh, and University of California San Diego. (This was actually much worse than for drug companies…)
- No one has ever paid a fine for late or non-reporting, which translates to a potential collection of $25 billion from drug companies alone in the past 7 years (as a perspective, the total 2014 NIH budget was $30 billion, which was 14% less than the 2006 budget when adjusted for inflation)
- An example: in 2009 Hoosier Cancer Research Network terminated a study of Avastin early, with 18 patients being treated for metastatic breast cancer. The drug did not work, but there was serious harm, including hypertension, GI toxicity, sensory problems and pain. This was never reported, and debate of its efficacy continued nationwide. Finally in 2011 the FDA revoked its approval of Avastin for breast cancer.
- STAT identified 9000 trials in ClinicalTrials.gov that were subject to the disclosure law, focusing on 98 universities, nonprofits and corporations between 2008-2010. They found that academic institutions either were late or did not file 90% of the time and industry did not file 74% of the time (for us in Boston, it was notable that Beth Israel did not file or was late 91% of the time, Dana-Farber 85%, Mass General 84% and the Brigham was best at 81%)
- The defense by the academic institutions included the time it takes to download the data (which it turns out is not really a lot), that they did not have enough funding, they were waiting for journals to publish their results, or “some experts voiced concerns that the researchers might also face pressure from corporate sponsors to delay reports — whether negative or positive — for commercial reasons”.
- By the way, ClinicalTrials.gov is a pretty useful website, which gives anyone, including patients, free access. Just type in the drug in question and it pulls up studies, some done, some recruiting, and even a few with the results logged in….
Also, a recent article in BMJ open (see doi.org/ 10.1136/bmjopen-2015- 009758) assessed all clinical trials submitted to the FDA for approval in 2012, finding that the FDA approved 15 drugs sponsored by 10 large companies, there were 318 relevant trials with 99,599 subjects, a median of 57% of the trials were registered, and 20% reported results on ClinicalTrials.gov. Per drug, a median of 67% were compliant with FDA reporting rules and 51% of subjects were enrolled in non-compliant trials, with wide variation by company.
A prior blog https://stg-blogs.bmj.com/bmjebmspotlight/2015/08/31/primary-care-corner-with-geoffrey-modest-md-regulation-of-medical-devices/ looked at the poor DFA oversight of medical devices. And another in 2013 looked at the large number of trials with unpublished results and not reported in ClinicalTrials.gov. See https://stg-blogs.bmj.com/bmjebmspotlight/2013/11/26/primary-care-corner-with-dr-geoffrey-modest-more-drug-co-shenanigans/
So, bottom line: this regulatory consumer protection has been largely ignored by drug companies and academic centers, raising the very real possibilities that providers continue to prescribe drugs that are ineffective (except for the bottom line of the drug companies) and potentially harmful. And, for whatever reasons, the NIH is missing out on $25 billion from fines, which one can only assume could be used by the NIH to partially compensate for their underfunding… (see http://www.statnews.com/pharmalot/2015/12/16/pharmalot-nih-drug-trials/ highlighting that over the past decade there has been a 24% decrease in the number of studies funded by the NIH and a 43% increase in those funded by industry).
- The NY Times had yet another article on the unbounded greed of drug companies, centering again on Turing pharmaceuticals (see http://www.nytimes.com/2015/12/12/business/martin-shkrelis-latest-plan-to-sharply-raise-drug-price-prompts-outcry.html?emc=edit_th_20151212&nl=todaysheadlines&nlid=67866768&_r=0 ). This is the company highlighted in a prior NY Times article, where Turing acquired the rights for the anti-toxoplasmosis drug pyrimethamine and immediately raised the price from $13.50 a pill to $750 a pill (see https://stg-blogs.bmj.com/bmjebmspotlight/2015/09/30/primary-care-corner-with-geoffrey-modest-md-and-the-drug-company-shenanigans-continue/ )
The current outlandish act was focused on an old drug used for Chagas disease, where the head of Turing wants to take advantage of the federal program encouraging companies to develop drugs for neglected diseases. This case involves the drug benznidazole, a treatment used in South and Central America (where Chagas disease is very common) since the 1970s, but was never approved in the US (though the FDA does give it out for free by the CDC “on an experimental basis”). In Latin America, the drug costs $50-$100 for a 2 month course of treatment. Turing’s CEO Martin Shkreli said that if he got FDA approval for the drug, he would have exclusive rights to sell it and “the price would be similar to that of hepatitis C drugs, which cost $60,000 to nearly $100,000 for a course of treatment”. And, to boot, Shkreli also felt that it was unlikely they would need to do clinical trials to get FDA approval, “just some smaller, quicker studies” and approval should happen within a year. One comment in the NY Times article that I find quite perplexing is that Congress created a program whereby drugs approved for qualifying tropical diseases can get a voucher for an expedited review by the FDA of another drug (???), and that these vouchers (which decrease the review time by 4 months) can then be sold to another drug company, perhaps allowing them to market a blockbuster drug for a common condition such as diabetes or arthritis, and then have an extra 4 months on the market before the patent expires. And these vouchers have been sold for up to $350 million. Another pharmaceutical did this: Knight Therapeutics won FDA approval for the old drug miltefosine to treat leishmaniasis in 2014, never offered the drug for sale in the US, but sold the voucher to Gilead for $125 million.
So….. pretty awful. And, of all things, using the name “Turing” for such shenanigans. I suspect that Alan Turing would cringe and roll over in his premature grave. And, as another aside (and not so surprising) Martin Shkreli was arrested today (12/17) for securities fraud (see http://www.statnews.com/pharmalot/2015/12/17/why-martin-shkreli-arrested/ )