Stacking the Deck with Clinical Trials

© photosebia | stockfresh.com

© photosebia | stockfresh.com

In September of 2007 the “Food and Drug Administration Amendments Act of 2007” became law. This law requires that findings from human testing of drugs and medical devices be made publically available on the NIH website, ClinicalTrials.gov. But it seems that both drug companies and most research institutions—including leading universities and hospitals—routinely violate the law. An investigation by STAT News found that at least 95 percent of all disclosed research results were posted late or not at all.

Drug companies have long been castigated by lawmakers and advocacy groups for a lack of openness on research, and the investigation shows just how far individual firms have gone to skirt the disclosure law. But while the industry generally performed poorly, major medical schools, teaching hospitals, and nonprofit groups did worse overall — many of them far worse.

Four of the top ten recipients of federal medical research funding from the NIH were among the worst offenders. These four were: Stanford, the University of California, San Diego, the University of Pennsylvania, and the University of Pittsburgh. Researchers, university administrators and hospital executives interviewed by STAT News said they were not intentionally breaking the law. They were just too busy and lacked administrative funding to complete the required data entry on ClinicalTrials.gov. NIH estimated it takes, on average, around 40 hours to submit trials results.

Six organizations — Memorial Sloan Kettering, the University of Kansas, JDRF (formerly the Juvenile Diabetes Research Foundation), the University of Pittsburgh, the University of Cincinnati, and New York University — broke the law on 100 percent of their studies — reporting results late or not at all.

The Director of NIH, Francis Collins, said the findings were “very troubling.” He said pointing to the time demands on posting data to ClinicalTrials.gov was not an acceptable excuse for noncompliance. Beginning in the spring of 2016, after further refinement of the ClinicalTrials.gov rules, Collins said NIH and FDA will have “a firmer basis for taking enforcement actions.” The FDA is empowered to levy fines of up to $10,000 a day per trial for late reporting to ClinicalTrials.gov.

In theory, it could have collected $25 billion from drug companies since 2008 — enough to underwrite the agency’s annual budget five times over. But neither FDA nor NIH, the biggest single source of medical research funds in the United States, has ever penalized an institution or researcher for failing to post data.

When the “Food and Drug Administration Amendments Act of 2007” became law, Senator Charles Grassley said: “Mandatory posting of clinical trial information would help prevent companies from withholding clinically important information about their products. . . . To do less would deny the American people safer drugs when they reach into their medicine cabinets.” But the failure of drug companies and others to post clinical trial results, coupled with the failure of the FDA to hold them accountable via fines when they don’t, means the American people are being denied the ability to see for themselves if the drugs they take are safe and effective. Kathy Hudson, a deputy director for NIH, said:  “If no one ever knows about the knowledge gained from a study, then we have not been true to our word.”

The scarcity of clinical trial results posted to ClinicalTrails.gov is not the only issue with clinical trials and the NIH website. Drug companies and research facilities are also not prospectively registering clinical trials as they should. Scott, Rucklidge and Mulder found that “less than 15% of psychiatry trials were prospectively registered with no changes in POMs [primary outcome measures].” You can see Julia Rucklidge’s discussion of the study here. Also see “Clinical Trial Sleight-of-Hand” on this website.

Writing for Health Care Renewal, Bernard Carroll said there was a disconnection between the FDA’s drug approval process and what gets published in the medical journals. “Pharmaceutical corporations exploit this gap through adulterated, self-serving analyses, and the FDA sits on its hands.” He suggested that independent analyses of clinical trials be instituted, “because we cannot trust the corporate analyses.”

When corporations are involved, there is no point in prolonging the myth of noble and dispassionate clinical scientists searching for truth in clinical trials. It’s over. We would do better to stop pretending that corporate articles in medical journals are anything but marketing messages disguised with the fig leafs of co-opted academic authors and of so-called peer review.

Carroll proposed that Congress mandate the FDA to analyze all clinical trials data strictly according to the registered protocols and analysis plans. This should apply to new drugs as well as approved drugs being tested for new indications. And it should be applied to publications reporting new trials of approved drugs. “Corporations and investigators should be prohibited from publishing their own in-house statistical analyses unless verified by FDA oversight.” (emphasis in the original) Carroll quoted Eric Topol in a recent BMJ editorial as saying: “The disparity between what appears in peer reviewed journals and what has been filed with regulatory agencies is long standing and unacceptable.”

He gave three reasons for prohibiting in-house corporate analyses of clinical trials data. First, the inherent conflict of interest is too great to be ignored. Carroll described Forest Laboratories and citalopram as an example in his article to illustrate this point. Second, when corporate statisticians are encouraged to play around with the statistical analysis of the trial data (i.e., p-hacking), “they are no longer testing the defined study question with fidelity to the methods specified in the IND protocol.” Third, the FDA should monitor the publication of clinical trial reports in medical journals. The FDA inspects production facilities for evidence of physical adulteration, why not verify that what gets published in journals matches what they presented to the FDA for drug approval? “The harms of adulterated analyses can be just as serious as the harms of adulterated products.”

Pharmaceutical corporations are betting on huge profits with drug development. And allowing them to play fast and loose with clinical trial registration and the analysis of the trial data is akin to stacking the deck in their favor. It’s time to require pharmaceutical companies to stop trying to rig the clinical trial process in their favor.


Russian Roulette with Heroin?

Some of the most intriguing research into addiction treatment being done today is with vaccines. The idea is rather simple. Drugs of abuse pass through the blood-brain barrier because they are too small, too simple to be targeted by the immune system. So researchers have designed vaccines that take key fragments of the drug molecules and attach them to larger, more immune-provoking carriers (such as a cholera toxin or a tetanus toxin). The antibodies produced by this work-around will attack the drug and prevent it from passing through the blood-brain barrier and reaching the reward pathway in the brain. In other words, you can ingest the drug BUT WON’T GET HIGH!

Vaccines are being developed for drugs of abuse like alcohol, marijuana, heroin, methamphetamine, nicotine, and cocaine. A previous blog post, “Raising the Stakes in the War on Cocaine Addiction,” looked at the attempts to develop a cocaine vaccine by Thomas Kosten. His research has developed to the stage of clinical trials with humans, but a concern was discovered. Some of the human participants used tem times as much cocaine while attempting to override the blocking action of the cocaine vaccine. That trick could kill an individual who tried it with heroin.

Heroin has been a moving target for vaccine research because it quickly degrades into 6-acetylmorphine (6AM) and morphine. Kim Janda and his team of researchers associated with The Scripps Research Institute have developed a “dynamic vaccine” that creates antibodies against heroin and its psychoactive metabolites. You can read the academic journal article on their work found in the Proceedings of the National Academy of Sciences here or a summary of their research on The Scripps Research Institute website here or here.

There are positives and negatives to Janda’s dynamic heroin vaccine. First, while it will attach to heroin and its metabolites, it won’t work with oxycodone (OxyContin) or hydrocodone (Vicodin, Zohydro); or any other opioid. This is a trade-off because of the above-mentioned rapid degradation of heroin into its psychoactive metabolites. Second, this means the dynamic vaccine also won’t work with methadone or buprenorphine (Suboxone, Subutex), which are both opioids. So it can be used in conjunction with opioid maintenance therapy.

Although Janda’s research suggested that his vaccine helped limit heroin seeking behavior and halted the progression of compulsive heroin taking with rats, there are easy work-arounds for human beings. A human addict could ingest oxycodone or hydrocodone while taking the heroin vaccine to get high. They could even take a benzodiazepine along with their methadone or Suboxone for a nice, heroin-like buzz while taking the Janda vaccine. These limitations were acknowledged by Janda’s research team: “Although the dynamic heroin vaccine is not targeted to treat the ‘addicted’ brain, it represents a robust tool in the continuous blockade of all heroin activity.” In the concluding paragraph of the journal article, the research team said:

The prospect of heroin vaccine use in the treatment of addiction presents a high-payoff, low-risk opportunity. Drug vaccination requires minimal medical monitoring and compliance to maintain opiate resistance, allowing for greater potential worldwide accessibility. Furthermore … drug vaccines represent a low risk for long-term side effects. . . . Although it may not be a “magic bullet” against all aspects of drug addiction, the dynamic nature of our heroin vaccine represents a promising and innovative adjunct therapy in the treatment of heroin addiction.

But Janda’s research is stalled because it ran out of funding. In an interview with The Fix, he said: “We are not anywhere near human trials because nobody wants to pay for them.” Earlier funding was obtained by the Scripps Research Institute, the Pearson Center for Alcoholism and Addiction Research and the National Institute of Health (NIH). Janda and others have approached the NIH for additional funding, but so far have been unsuccessful.

Pharmaceutical companies aren’t interested either. Janda commented: “I have talked to many different companies and not one has shown any interest whatsoever. They don’t feel there is value for their company.” He doesn’t understand this from the standpoint of the greater good of society, but will attempt the route of applying for more research grants from the government. “I think we’ll probably just have to keep going it alone.”

I have mixed feelings about this vaccine, not because of the research, but because of what I know about how some addicts think. The research from the cocaine vaccine clinical trails discussed above noted how some addicts tried to test the vaccine with ten times as much cocaine as they usually ingested to get high. If heroin addicts test Janda’s heroin vaccine in a similar way, they will be risking their lives. It will be like playing Russian roulette with heroin.

There is also an “addiction” to the ritual of getting high (tying off, cooking the heroin, etc) for some addicts that the vaccine will not touch. I’ve known heroin addicts under the influence of this kind of obsession who compulsively “shoot up” water attempting to satisfy this urge. As Janda himself said, while it will blockade all heroin activity, it is not targeted to treat the “addicted brain.”



Raising the Stakes in the War on Cocaine Addiction

War on Drugs

image courtesy of iStock

A 28 year old Viennese neurologist named Sigmund Freud read about the benefits of cocaine on Bavarian soldiers. He decided to use it to treat his own problems with depression and chronic fatigue and acquired some from Merck. On April 30th 1884, Freud used cocaine for the first time. He thought it was “a magic drug.”

Cocaine turned his bad mood into cheerfulness; it even helped his indigestion.  He wrote to Martha, his fiancée: “In short, it is only now that I feel I am a doctor, since I have helped one patient and hope to help more.” Freud encouraged Martha to try cocaine, “to make her strong and give her cheeks a red color.” He warned her that when he came for a visit, she should expect “a big wild man who has cocaine in his body.”

He gave cocaine to his sisters and also to medical colleagues—both for themselves and for their patients. By July of 1884 he had written and published his first essay praising the therapeutic uses for cocaine. His hope was that he would become a pioneer in the medical uses of cocaine. But there would not be a happy ending to the story of Freud and cocaine.

These days the ongoing saga of medicine and cocaine is the quest to find a vaccine to cure those who become addicted to it.

I’ve been following the attempts to develop a vaccine for cocaine and other illicit drugs since 2009, when the National Institute of Health (NIH) reported on the work of Thomas Kosten with TA-CD. Nora Volkow, the Director of the National Institute on Drug Abuse (NIDA), said: “The results of this study represent a promising step toward an effective medical treatment for cocaine addiction.”

But some of the participants in Phase 1 of the clinical trials reported using TEN TIMES as much cocaine when trying to override the blocking action of the cocaine vaccine. The Washington Post, reported on the Kosten’s research in January of 2010, saying: “Some of the addicts reported to researchers that they had gone broke buying cocaine from multiple dealers, hoping to find a variety that would get them high.”

A 2011 article in the New York Times highlighted the work of Kim Janda who was working on a cocaine vaccine. His laboratory, the Scripps Research Institute, has also worked on vaccines for nicotine and heroin. In June of 2011 Janda published positive results with what he called an “anti-heroin vaccine.”

New York Magazine reported in September of 2013 that Ronald Crystal, the head of genetic medicine at Weill Cornell, had success with the third version of Janda’s original cocaine vaccine. He hopes to begin human trials by the middle of 2014. A side bar indicated that vaccines were in development for alcohol, nicotine, marijuana, heroin, methamphetamine and rohypnol (the date rape drug).

But as Clint Rainy commented in his New York Magazine article, the problem with addiction is it’s not just a physical problem, it’s also psychological. “Even if you can cancel the effects of drugs, can you make us not want to take them?” Crystal thinks that shouldn’t be a problem for his compound, as it was with TA-CD, because they tweaked their compound (dAd5GNE) to have a “more robust” immune response. Crystal’s response seems to miss an important limitation to a purely physiological attempt to cure addictive “disease.” The vaccine can only inhibit the physiological response to the drug; not the psychological one.

While Kosten’s work with TA-CD has begun clinical trials with humans, the work of Janda with heroin and Crystal with cocaine has yet to be tried on humans. But it’s coming soon. One person who responded to the New York Magazine article about Crystal’s cocaine vaccine said: “This would be a dream come true for me and save my life.” He believed that with the vaccine, he wouldn’t get high. After a few months, he imagined he wouldn’t be thinking about it anymore, but would “just keep getting vaccinated to be safe.”

But it seems that developing a cocaine vaccine as an attempt to end cocaine addiction merely raises the stakes for some addicted individuals by requiring larger amounts of the drug to overcome the vaccine. A vaccine doesn’t address the psychic desire for the drug. If a vaccine is successfully developed for heroin and other opioids, their current potential for deadly use could also increase tenfold.

Do you think that drug vaccines would be a helpful or a dangerous addition to the available treatments for addiction?