Drug makers and the FDA don't want you to find out about adverse trials

Byoliveridley

if you have not been following the Avandia story, an article published in the New England Journal of Medicine revealed that Avandia, a popular drug used in diabetes control significantly increased the threat of heart attacks and heart failure. A couple of things to note here, firstly, this fact was known to the FDA in 2002 per this memo obtained by Public Citizen. So, why the FDA (and GSK) thought that no one would notice, is beyond me. Secondly, when the drug was introduced in Europe, it was contra-indicated for people with heart disease. This fact must have been known to the FDA and GSK as well. It is one thing for GSk to not want to run long term epidemiological and safety studies on their drugs, but other people did the work, and the FDA just stood by and watched until the work was published in the US. The European Drug agency had acted on this information quite a while back.

So, when I come across this article in the NY Times about a “downside” to full disclosure, I don’t really know what to say. I don’t care whether there is a downside to GSK or not. If I work as a waiter in a restaurant, there is a “downside” to reporting my tip income to the IRS (yes, higher taxes!). This does not mean I should not pay my taxes! This is a matter of life and death for people. Diabetes and heart disease go together in thousands of people, they needed to know if the drug they were taking to control one disease would kill them off with the other disease.

For Drug Makers, a Downside to Full Disclosure – New York Times

This week, GlaxoSmithKline learned what that greater disclosure could mean.

A cardiologist at the Cleveland Clinic, Dr. Steven Nissen, stumbled onto the Glaxo Web site while researching Avandia last April. He and a colleague quickly analyzed the data, and on Monday, The New England Journal of Medicine released its finding that Avandia posed a heightened cardiac risk.

“It was a treasure trove,” Dr. Nissen said about the Web site.

GlaxoSmithKline has disputed the journal’s interpretation. Officials with the Food and Drug Administration said they were reviewing whether to take any action on Avandia.

Also, note this “concern” from the FDA, no less:

“I would be very concerned about wholesale posting of thousands of clinical trials leading to mass confusion,” said Dr. Steven Galson, the director for the Center for Drug Evaluation and Research at the F.D.A.

Yes, respond to results in a very prestigious peer reviewed journal by pretending that some dude with a computer in his basement (yes, all computers reside in basements) randomly picked up a couple of clinical trials and created “mass confusion”. The FDA should at least pretend to care…

The risks and benefits involved with taking a drug to control a chronic condition are completely different from those you would take for an acute, immediately life threatening condition. If you are treating cancer, you expect side effects, and deal with them because the alternative is certain death. When you’re dealing with diabetes, you have alternatives that will not kill you. In addition, millions of people have diabetes and use Avandia. So, a small percentage increase in a side-effect can affect thousands. And, they need to know because there are alternatives that would work for them.

GSK is not going to tell them because there is an obvious conflict of interest. They need to sell their new and expensive drug even if other alternatives work. This is why we have the FDA, and full disclosure of all clinical trials, not just the ones that worked for you.

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  • Biologic Generics Closer to Market

    Byoliveridley

    Congress Seeks Compromise on Generic Drugs – New York Times

    Biotech drugs, also known as biologic products, are typically proteins made by modifying the DNA of bacteria, yeast or mammal cells, and they are often given by injection or infusion. Supporters of the legislation received an unexpected boost when the chief medical officer of the Food and Drug Administration, Dr. Janet Woodcock, told Congress last month that the agency had the expertise and experience to decide what types of human and laboratory tests were needed to ensure that copies of a biotechnology drug worked as well as the original. Brand-name drug manufacturers have urged Congress to require human trials before allowing the sale of any products billed as comparable or equivalent to biotechnology medicines already on the market.

    It is a complex issue, and clearly, proteins and large molecules that would not be synthesized, but “grown” are subject to larger batch by batch variation, especially when the generic company does not have access to the top-secret proprietary information that genentech, or J&J used to grow their molecule. So, some level of judgment is going to be required on the part of the FDA, which has the information from both the original, and the generic manufacturers. It looks like the FDA needs to, and is prepared to deal with each generic on a case by case basis, which is how it should be.

    Protein characterization and analysis have come a long way in the last 10 years, with your fancy mass spectrometers and proteomics. It is a lot easier now to compare proteins with each other, to look for changes and differences. Mass spectrometric technology, improved electronics and huge increases in data processing and computing power make protein characterization increasingly routine. It would be up to the FDA to decide at what level of change would a protein behave so differently that its effect on humans could change significantly from the original drug, but they seem to be ready to do it.

    “Some level of clinical testing should be required in all cases,” said Dr. Susan D. Desmond-Hellmann, president for product development at Genentech. Dr. Jay P. Siegel, a senior scientist at Johnson & Johnson, said: “I would never take a biologic that had not been tested in humans. The risks are too high.”

    Yes, I would absolutely trust the word of the people who had the most to lose in this case, no conflict of interest here! To be fair, Dr. Siegel is understandably cautious. We have enough problems even with small molecules (think Vioxx!). But as I mentioned previously, it should be possible to come up with good enough metrics to decide when/where human re-testing is appropriate, instead of doing it always.

    But Dr. Woodcock (of the FDA – inserted for context) said: “Where trials are not needed, it is of questionable ethics to repeat them. The use of human subjects for trials that are not needed is not desirable.”

    People tend to forget that we’re experimenting on humans here, thanks Dr. Woodcock! Note that this is an issue where the established biologicals companies can use the safety card with impunity to protect their enormous profits. But they are not the ones who get to decide, it’s the FDA, and ultimately, Congress.

    The chief lobby for makers of biotech drugs, the Biotechnology Industry Organization, strongly opposes the bill, saying it would endanger patients and kill incentives for research and innovation.

    Oh really, how many times has this argument been raised, and proven to be false (see plutocracy-protectionary principle!). To believe this argument, we would have to believe that the 1984 generics law completely killed the small molecule industry. Not really, Glaxo, Pfizer, etc are still bigger and badder than ever.

    Assuming a multiple sclerosis treatment costs $20,000 a year (from the article). If generics come in and there’s a 10% (low end) decline in price for the treatment, the amount saved is $2000 per patient. MS is estimated to have a prevalence rate of 0.1% in North America. So, that makes 0.3 million in the US. If half of them are on this treatment (random fudge factor), you (or your insurer) will save $300 million on one disease treatment option per year (and the biologics manufacturers will lose some portion of that). This is pretty big money, no wonder they’re throwing up roadblocks!

  • |

    FDA Issues Dietary Supplements Final Rule

    Byoliveridley

    The FDA issues rules that will finally make dietary supplement manufacturers conform to some rules in the manufacturing of the products.

    Which ones?

    1. Accurate potency and labeling – 30 mg glucosamine will now contain something close to 30mg
    2. Impurities Testing – All the raw materials will now be tested for impurities/contaminants. They will probably follow USP guidelines.
    3. Adverse event reporting – Manufacturers/sellers will need to report adverse events. This is after the fact safety testing, wholly inadequate, but better than what we had previously.

    See something missing? Efficacy!! You do not have to prove that your product actually works! Basic safety? What is the overdose level? Interactions with other medicines/supplements? Is your dosing form actually bioavailable? Meaning, if you swallow a pill, will it actually get into your bloodstream and reach the intended target?

    Who knows, but standardizing, cataloging and auditing manufacturing processes is a start, I guess. 1.5 cheers for the FDA!

    I would be curious to find out how these companies are going to get audited by the FDA to prove that they’re following the quality control measures they’re supposed to implement. Guess I have to read the 815 pg bundle of joy that is the actual rule to find out more. A cursory word search on audits suggests that the manufacturers do audits on their suppliers, that the quality control unit of manufacturer perform audits on their manufacturing process, but nothing about the FDA conducting audits. Of course, calling yourself a GMP (good manufacturing processes) manufacturer is usually enough to trigger an FDA audit if you’re in pharma. I wonder how the FDA will deal with this one.

    FDA Issues Dietary Supplements Final Rule

    The U.S. Food and Drug Administration today announced a final rule establishing regulations to require current good manufacturing practices (cGMP) for dietary supplements. The rule ensures that dietary supplements are produced in a quality manner, do not contain contaminants or impurities, and are accurately labeled.

    “This rule helps to ensure the quality of dietary supplements so that consumers can be confident that the products they purchase contain what is on the label,” said Commissioner of Food and Drugs Andrew C. von Eschenbach, M.D. “In addition, as a result of recent amendments to the Federal Food, Drug, and Cosmetic Act, by the end of the year, industry will be required to report all serious dietary supplement related adverse events to FDA.”

    The regulations establish the cGMP needed to ensure quality throughout the manufacturing, packaging, labeling, and storing of dietary supplements. The final rule includes requirements for establishing quality control procedures, designing and constructing manufacturing plants, and testing ingredients and the finished product. It also includes requirements for recordkeeping and handling consumer product complaints.

    “The final rule will help ensure that dietary supplements are manufactured with controls that result in a consistent product free of contamination, with accurate labeling,” said Robert E. Brackett, Ph.D., director of FDA’s Center for Food Safety and Applied Nutrition.

    Under the final rule, manufacturers are required to evaluate the identity, purity, strength, and composition of their dietary supplements. If dietary supplements contain contaminants or do not contain the dietary ingredient they are represented to contain, FDA would consider those products to be adulterated or misbranded.

    The aim of the final rule is to prevent inclusion of the wrong ingredients, too much or too little of a dietary ingredient, contamination by substances such as natural toxins, bacteria, pesticides, glass, lead and other heavy metals, as well as improper packaging and labeling.

  • |

    Snake Oil Comes a Full Circle

    Byoliveridley

    Ah, back to the good old days of snake oil..

    ScienceDaily: Snake Venom As Therapeutic Treatment Of Cancer?

    This certainly sounds unusual, but Dr. Son and colleagues report on the effectiveness of the snake venom toxin (SVT) Vipera lebetina turanica in the inhibition of androgen-independent prostate cancer (AICAP) in the journal Molecular Cancer Therapeutics.

    These novel findings suggest that SVT can inhibit the growth of AICAP through the induction of cell death.

    I am glad they put the question mark at the end, lest people extrapolate from a few cells in a petri dish (or a small animal study) to a cancer cure, as happened recently with dichloroacetate! Health reporting is very tricky because the average reader cannot understand much more than the headline. It almost seems like every health article should have the following things clearly labeled:

    1. Human, animal or cell?
    2. Clinically tested, or anecdotal?
    3. Double blinded, controlled, etc, or not?
    4. Any chance that this result applies to people?
    5. How far away are we from a real cure?
    6. DO NOT TRY THIS AT HOME!

    At least viper venom is hard to find! The Madras crocodile bank helped start a venom extraction cooperative run by the Irula Tribe, so I’ve seen viper venom being extracted, pretty cool. India is home to two vipers, the Russell’s and the Saw Scaled vipers.

    Russell's
    Russell’s viper

    saw scaled
    Saw scaled viper.

    The Russell’s is 3-5 feet long, and slow, but a big hisser! The saw scaled viper is tiny, a feet or two, but aggressive and very venomous. One of my favorite wild snake sightings was a saw scaled viper, looked very innocuous curled up in a parking lot in Pondicherry.

    Cool, snake oil and venom for all…

  • |

    Brazil bypasses patent on U.S. AIDS drug – Yahoo! News

    Byoliveridley

    As I mentioned previously, compulsory licensing is a perfectly legal option underlined by TRIPs (Agreement on Trade-Related Aspects of Intellectual Property Rights) in response to national emergencies for governments to authororize the bypassing of drug patents. Thailand threatened to do it recently, Brazil goes one better.

    Brazil bypasses patent on U.S. AIDS drug – Yahoo! News

    President Luiz Inacio Lula da Silva took steps Friday to let Brazil buy an inexpensive generic version of an AIDS drug made by Merck & Co. despite the U.S. drug company’s patent.

    Silva issued a “compulsory license” that would bypass Merck’s patent on the AIDS drug efavirenz, a day after the Brazilian government rejected Merck’s offer to sell the drug at a 30 percent discount, or $1.10 per pill, down from $1.57.

    The country was seeking to purchase the drug at 65 cents a pill, the same price Thailand pays.

    This story fits the script in every possible way. Here’s the drug company’s “disappointed” response:

    Amy Rose, a spokeswoman for Whitehouse Station, N.J.-based Merck, said earlier that the company would be “profoundly disappointed if Brazil goes ahead with a compulsory license.”

    “As the world’s 12th largest economy, Brazil has a greater capacity to pay for HIV medicines than countries that are poorer or harder hit by the disease,” Merck said in a statement after Silva’s announcement.

    Ah, the irony of a large pharma company appealing to Brazil’s sense of fairness!

    The usual US government/chamber of commerce type’s scold and threat to withold further foreign investment:

    But the U.S.-Brazil Business Council said the decision was a “major step backward” in intellectual property law and warned it could harm development.

    “Brazil is working to attract investment in innovative industries … and this move will likely cause investments to go elsewhere,” the council said in a statement.

    Who are the US-Brazil Business Council? It is an affiliate of the U.S Chamber of Commerce. Its website reveals it to be a lobbying and networking group of high powered U.S executives “fostering” U.S-Brazil trade relations. Hmm, I wonder who’s side they will take!

    But, we forget what this is about, the health of thousands of AIDs patients (and the money it costs to treat them).

    Brazil provides free AIDS drugs to anyone who needs them and manufactures generic versions of several drugs that were in production before Brazil enacted an intellectual property law in 1997 to join the WTO.

    But as newer drugs have emerged, costs ballooned and health officials warned that without deep discounts, they would be forced to issue compulsory licenses.

    Efavirenz is used by 75,000 of the 180,000 Brazilians who receive free AIDS drugs from the government. The drug currently costs about the government about $580 per patient per year.

    Brazil is doing absolutely the right thing by bargaining and playing hardball. it wants to pay the same prices Thailand pays, and should continue to bargain till it gets there. There’s no sense in being a sovereign powerful nation if you can’t shakedown a pharma company, is there!

  • | |

    Indian firms push down global vaccine prices – Lessons for Canada

    Byoliveridley

    Cheaper vaccines from India are forcing global giants to slash prices. GSK announced its rotavirus vaccines at $2.50 per dose — or $5 to fully immunise a child — in response to a current tender administered by UNICEF.The offer is a 67% reduction in the current lowest available public price.

    Hindustan Times

    This is good news for many reasons. Preventable diseases kill over a million people every year, and one of the biggest factors in getting vaccinated is cost. India’s healthcare spending was estimated at US$ 40 billion in 2008, going up to 300+ billion in 2023. Forty billion is less than $40 per person, so saving 7-8 dollars on vaccinations alone for every one of the 26 million children born every year is a huge deal.

    Development costs of vaccines and drugs are high and success is often uncertain. Pharmaceutical companies have used this to justify government enforced monopolies and per dose prices that are sometimes a 1000 times higher than the incremental cost of production. While this makes for good profits, it means severe lack of access in India, many African countries, and many excess deaths that could have been prevented. For years, India had what was called a process patent, not a product patent, which meant that if you could make a drug with a slightly different process, it would not get patent protection any more. How did this help India?

    1. Affordable drugs – Indian companies could make and sell drugs at a fraction of the cost without paying for drug development.

    2. Pharmaceutical Industry – This enabled the industry to grow and mature.

    Of course, this also meant that India was considered an outlaw, and Indian pharmaceutical industry came under great pressure from the WTO to tighten patent laws, which it did. At the time, the concern (rightly) was that tightening patent restrictions would harm India’s pharmaceutical industry and reduce access to drugs. Has this come to pass? In some ways, yes. But the Indian pharmaceutical industry has also matured, and with government help, has been able to do its own development, clinical trials and production (which it was always good at). The focus on tropical diseases like rotavirus also means that US, European Companies, which have since moved away to treating chronic conditions like high cholesterol, erectile dysfunction, etc., have much more competition in the tropical diseases area and cannot charge premium prices to poor people any more.

    So dear Canada, while you are negotiating with Europe about “free trade”, and trying to give European companies much greater patent protection for their drugs, know that this will very surely raise costs in the short term. Two important questions:

    1. Will Canada’s drug companies benefit?

    2. Will Canada’s consumers benefit?

    Um, let’s take a look at Canada’s top 10 in 2009:

     

    Rank Leading Companies Country Market Share (%)
    1 Pfizer US 13.4
    2 Apotex Canada 7
    3 AstraZeneca UK 6.6
    9 Merck US 6
    4 Johnson & Johnson US 5.3
    6 Novopharm (Teva) Israel 4.2
    7 Novartis Switzerland 4
    5 GlaxoSmithKline UK 4
    8 Abbott US 3.9
    10 Roche Switzerland 3.1
    Source: IMS Health

    There is one Canadian company in the top 10, and four European companies. Our pharmaceutical industry is not well positioned to be independent, or work to reduce Canadian drug prices, especially if laws strengthening patent protections for European companies come into effect. This will serve to weaken Apotex, and Canada does not have a big independent pharmaceutical company network born out of years of “isolation” to take advantage of any competition, or competitive advantages. So, while patent “reform” seems to not have hurt Indian industry as much as feared, it sure will hurt Canadian consumers.

     

  • |

    India Rejects Obvious Patents

    Byoliveridley

    Would have been my headline. Apparently, the New York Times byline writer was more concerned about a multi billion dollar company losing a small amount of money than the fact that a different ruling in this case would have made life saving drugs unaffordable for millions of people. When did American newspapers become shills for the elite?

    Setback for Novartis in India Over Drug Patent – New York Times

    Indian companies will be free to continue making less expensive generic drugs, much of which flow to the developing world, after a court rejected a challenge to the patent law on Monday.

    Aid organizations declared the ruling a victory for the “rights of patients over patents,” but the Swiss drug company Novartis, which filed the case, warned that the ruling would discourage investments in innovation and would undermine drug companies’ efforts to improve their products.

    At issue is the degree of innovation required for a drug to be regarded as truly “new”, where there is a significant enough chance for failure that the company would never develop it unless afforded monopoly rights for 10 years. A very well known tactic by drug companies is to make a slightly different formulation of an existing drug, say an extended release form of a drug which takes a little longer to dissolve, and hence is available to the body at a different time. Under US patent law, this qualifies for full patent protection on the extended release form. By now, the science of making an extended release tablet is well known, it’s just a question of formulating the drug with a different set of inactive ingredients that take longer to dissolve, or sometimes, through a differently engineered tablet. The chemistry of this change is predictable, published and not really innovative. Why should these small changes have patent protection?

    Bonus Note: Madras is my home city, so I’m glad it was decided there!

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