Merck Vioxx

In the late 90’s a leading pharmaceutical manufacturer Merck had been working on a treatment for osteoarthritis, rheumatoid arthritis and other conditions associated with pain (Prakash S, Velentine V. 2007). Merck’s solution to this health issue came in the form of Vioxx, showing promising therapeutic effects with minimal and reduced side effects associated with competitors (Union of Concerned Scientists, 2017). 1998 saw the submission by Merck for approval by the FDA for vioxx after being tested on 5400 subjects in 8 separate studies (Prakash S, Velentine V. 2007). Come 1999 another study was conducted in order to compare the drug to a popular competitor known as naproxen in which, 8000 participants were observed (Prakash S, Velentine V. 2007). Half of the participants took vioxx and the other naproxen (Prakash S, Velentine V. 2007). By the end of the year the results of the study were compiled among the Vioxx Gastrointestinal Outcomes Research study AKA Vigor where vioxx showed far fewer ulcers and intestinal bleeding than those taking naproxen (Prakash S, Velentine V. 2007). A second meeting however was focused on heart problems where 79 patients of the 4000 taking vioxx were found to have a serious event compare too 41 of 4000 taking naproxen (Prakash S, Velentine V. 2007). These figures were deemed as comparatively small and to be re-evaluated in 30 days (Prakash S, Velentine V. 2007). VIGOR re convened and were notified that vioxx patients were twice as likely to have serious heart problems and or death than those of naproxen (Prakash S, Velentine V. 2007). A vote was successfully held to continue the study under the defense of not knowing if vioxx caused the heart problems or if the patients taking naproxen was acting as a low dose aspririn and protecting patients from them (Prakash S, Velentine V. 2007).

Many pharmaceutical studies are conducted using a placebo in their control group whereas here Merck decided to use naproxen. The reason placebos are commonplace is so to have an understanding of what the effects a drug can have on an individual that isn’t taking the drug at all in order to deem its safety and effectiveness (National Institute on Aging. 2020). The comparative nature of the study was seen as a means of skewing data to push the drug through FDA approval (Union of Concerned Scientists, 2017). Scientists were seen as highlighting the benefits of naproxen making it appear as though Vioxx was safer than the results suggested (Union of Concerned Scientists, 2017). Weinblatt, a safety chair as part of the advisory committee had initially pushed for information in 2000 on cardiovascular risks but ultimately succumbed to waiting on the results to be combined with all other studies (Union of Concerned Scientists, 2017). Another form of data manipulations was found when the first draft of 16 out 20 reports listed an employee as the author but upon final draft the author had changed to an external academic drawing questions of a ghost writer (Union of Concerned Scientists, 2017). Furthermore evidence of three heart attacks were removed from records of patients taking vioxx, thousands of deaths and 100,000 heart attacks due to its approval in 1999 to its recall in 2004 (Union of Concerned Scientists, 2017). Patients who have stopped taking vioxx are still facing complications related it its use (Union of Concerned Scientists, 2017)

An estimated 20 million Americans are thought to have taken the drug and the company began facing 13000 lawsuits on behalf of 23,000 plaintiffs (Union of Concerned Scientists, 2017). Trials persisted for years to which Merck defends the study and withholding information on grounds of certain instance reporting falling outside the timeline required by the studies reporting guidelines(Union of Concerned Scientists, 2017). Of the 7 trials held Merck won 3 and came to a settlement in 2007 noted as the largest drug settlement of its time  seeing Merck pay $4.85 Billion into a settlement account and allowing them to avoid personal injury lawsuits of approximately 47,000 plaintiffs and 265 class action lawsuits (Union of Concerned Scientists, 2017).

1. How much fault would you place on the scientists conducting the study vs the company itself and do you think they should bare any of the repercussions?
2. Do you think including a placebo in this study either as a replacement to naproxen or in addition to it would have prevented this from happening?
3. Weinblatt the safety chair, agreed to wait for all results to be compiled before reviewing the cardiovascular study specifically. A few months later filled out a financial disclosure statement stating he and his wife had purchase $72,985 of Merck stock. Do you think this is indicative of anything fishy?

References:

Merck Manipulated the Science about the Drug Vioxx. 2017 Oct 12. Union of Concerned Scientists. 

Prakash S, Valentine V. 2007 Nov 10. Timeline: The Rise and Fall of Vioxx. NPRorg. 

National Institute on Aging. 2020. Placebos in Clinical Trials. National Institute on Aging. 

 

 

After reading answer briefly answer the 3 questions. 

One of the oldest medications still used often in clinical practice is heparin. It was founded in 1916 before the Food and Drug Administration was created. Generated nearly solely from pigs' mucosal tissues. (Hedlund, 2013) The market for heparin depends on China because of its sizable swine herds. The drug's supply chain starts at slaughterhouses, then moves on to tiny workshops that collect heparin crude by removing the mucous membranes from pig intestines. Then, after being further refined into an active pharmaceutical component, the crude heparin is sold to other facilities, often via consolidators (API). In order to generate a completed heparin product, such as an injectable pharmaceutical vial, this API is then mixed with inactive components (typically a sterile solution). (Heparin: A Wake-Up Call on Risks to the U.S. Drug Supply, 2012)

The drug heparin was recalled on a global scale in 2008. Numerous fatalities and adverse events were found to be caused by a contaminate identified as oversulfated chondroitin sulphate, according to researchers. (Hedlund, 2013) 81 individuals died as a result of it.  Eventually, it was discovered what triggered the undesirable effect that resulted in the fatalities and injuries. The contaminated chemical was an over-sulfated derivative of chondroitin sulfate, a similarly comparable compound derived from animal or fish cartilage and frequently used as an arthritis therapy. Since over-sulphated chondroitin is not a naturally occurring molecule, it is not as expensive as actual heparin starting material, and it matches the in-vitro characteristics of heparin, the fake was very definitely made intentionally rather than by mistake during production. The contamination was caused by a combination of a lack of appropriate pigs in China and cost-effectiveness, also it was discovered that the raw heparin batches had been reduced by 2 to 60% with the fake chemical. (Chinese Heparin Manufacturer Again Involved in Falsification and GMP Non-Compliance - ECA Academy, 2016)

Following the adulteration, investigations revealed that OSCS was present in both the finished heparin API produced by SPL-CZ and the raw material sent to the firm by Chinese contractors. The specific source or suppliers of the heparin adulteration are still unknown to Baxter and the FDA; however, evidence shows that OSCS was most certainly introduced by organizations upstream of the Chinese API production facility, Scientific Protein Laboratories-Changzhou (SPL-CZ). Starting in 1996, Chinese raw materials have been used to make Baxter's heparin API; SPL-CZ joined the company's heparin production process in 2004. (Heparin: A Wake-Up Call on Risks to the U.S. Drug Supply, 2012)

The U.S. Centers for Disease Control and Prevention (CDC) started looking into an epidemic of unanticipated allergic-type responses in dialysis patients in early 2008, which started in 2007. The majority of them had received heparin intravenously from Baxter Healthcare. Additional analysis found that oversulfated chondroitin sulphate (OSCS), an artificial adulterant with hazardous effects, had been added during the production of heparin in China. Given its close resemblance to the original medication, routine testing was unable to identify OSCS, which is produced for roughly a hundred times less than heparin. (Heparin: A Wake-Up Call on Risks to the U.S. Drug Supply, 2012)A number of Americans experienced negative effects, including fatalities. At least 11 medication items and 72 healthcare products containing heparin were recalled by 14 additional American companies, including Baxter Healthcare, the main heparin producer in the United States. Heparin items were already suspended in Australia, Switzerland, Sweden, Denmark, Germany, France, and Italy as per regional health organisations and press sources. (Heparin: A Wake-Up Call on Risks to the U.S. Drug Supply, 2012)

The heparin scandal exposed a variety of supervision and supply chain management mistakes. Despite not doing a pre-approval examination, the FDA accepted SPL-CZ as a source for Baxter, in part because it mistook SPL-CZ for another website in its database. Investigators from Baxter were not allowed entry to upstream factories and aggregators in 2008 when they attempted to retroactively review their supply chain. (Heparin: A Wake-Up Call on Risks to the U.S. Drug Supply, 2012) Two heparin upstream consolidators were likewise off-limits to the FDA. Baxter started receiving heparin API produced by SPL-CZ in 2004, but somehow it didn't verify the facility until 2007; instead, it relied on an earlier evaluation by a separate business. A variety of production quality concerns were discovered during the investigation of SPL-CZ after the FDA discovered that it had been adulterated, including inadequate quality control procedures for incoming raw materials. SPL-CZ was not licensed by the Chinese State Food and Drug Administration since it was considered a chemical facility in China. It therefore probably received no supervision from the Chinese government. (Heparin: A Wake-Up Call on Risks to the U.S. Drug Supply, 2012)

Questions:

1. To avoid another situation like heparin adulteration in the future what steps should be taken by the government to protect people?
2. What could have been the major reason behind heparin adulteration? 
3. Do you think heparin contamination was intentional? Why or why not?

sources: 

1. Chinese Heparin Manufacturer again involved in Falsification and GMP Non-Compliance. (2016, march 2). Retrieved from gmp compilance:  [Accessed on: 2023 February 5]

After reading answer briefly answer the 3 questions. 

One of the oldest medications still used often in clinical practice is heparin. It was founded in 1916 before the Food and Drug Administration was created. Generated nearly solely from pigs' mucosal tissues. (Hedlund, 2013) The market for heparin depends on China because of its sizable swine herds. The drug's supply chain starts at slaughterhouses, then moves on to tiny workshops that collect heparin crude by removing the mucous membranes from pig intestines. Then, after being further refined into an active pharmaceutical component, the crude heparin is sold to other facilities, often via consolidators (API). In order to generate a completed heparin product, such as an injectable pharmaceutical vial, this API is then mixed with inactive components (typically a sterile solution). (Heparin: A Wake-Up Call on Risks to the U.S. Drug Supply, 2012)

The drug heparin was recalled on a global scale in 2008. Numerous fatalities and adverse events were found to be caused by a contaminate identified as oversulfated chondroitin sulphate, according to researchers. (Hedlund, 2013) 81 individuals died as a result of it.  Eventually, it was discovered what triggered the undesirable effect that resulted in the fatalities and injuries. The contaminated chemical was an over-sulfated derivative of chondroitin sulfate, a similarly comparable compound derived from animal or fish cartilage and frequently used as an arthritis therapy. Since over-sulphated chondroitin is not a naturally occurring molecule, it is not as expensive as actual heparin starting material, and it matches the in-vitro characteristics of heparin, the fake was very definitely made intentionally rather than by mistake during production. The contamination was caused by a combination of a lack of appropriate pigs in China and cost-effectiveness, also it was discovered that the raw heparin batches had been reduced by 2 to 60% with the fake chemical. (Chinese Heparin Manufacturer Again Involved in Falsification and GMP Non-Compliance - ECA Academy, 2016)

Following the adulteration, investigations revealed that OSCS was present in both the finished heparin API produced by SPL-CZ and the raw material sent to the firm by Chinese contractors. The specific source or suppliers of the heparin adulteration are still unknown to Baxter and the FDA; however, evidence shows that OSCS was most certainly introduced by organizations upstream of the Chinese API production facility, Scientific Protein Laboratories-Changzhou (SPL-CZ). Starting in 1996, Chinese raw materials have been used to make Baxter's heparin API; SPL-CZ joined the company's heparin production process in 2004. (Heparin: A Wake-Up Call on Risks to the U.S. Drug Supply, 2012)

The U.S. Centers for Disease Control and Prevention (CDC) started looking into an epidemic of unanticipated allergic-type responses in dialysis patients in early 2008, which started in 2007. The majority of them had received heparin intravenously from Baxter Healthcare. Additional analysis found that oversulfated chondroitin sulphate (OSCS), an artificial adulterant with hazardous effects, had been added during the production of heparin in China. Given its close resemblance to the original medication, routine testing was unable to identify OSCS, which is produced for roughly a hundred times less than heparin. (Heparin: A Wake-Up Call on Risks to the U.S. Drug Supply, 2012)A number of Americans experienced negative effects, including fatalities. At least 11 medication items and 72 healthcare products containing heparin were recalled by 14 additional American companies, including Baxter Healthcare, the main heparin producer in the United States. Heparin items were already suspended in Australia, Switzerland, Sweden, Denmark, Germany, France, and Italy as per regional health organisations and press sources. (Heparin: A Wake-Up Call on Risks to the U.S. Drug Supply, 2012)

The heparin scandal exposed a variety of supervision and supply chain management mistakes. Despite not doing a pre-approval examination, the FDA accepted SPL-CZ as a source for Baxter, in part because it mistook SPL-CZ for another website in its database. Investigators from Baxter were not allowed entry to upstream factories and aggregators in 2008 when they attempted to retroactively review their supply chain. (Heparin: A Wake-Up Call on Risks to the U.S. Drug Supply, 2012) Two heparin upstream consolidators were likewise off-limits to the FDA. Baxter started receiving heparin API produced by SPL-CZ in 2004, but somehow it didn't verify the facility until 2007; instead, it relied on an earlier evaluation by a separate business. A variety of production quality concerns were discovered during the investigation of SPL-CZ after the FDA discovered that it had been adulterated, including inadequate quality control procedures for incoming raw materials. SPL-CZ was not licensed by the Chinese State Food and Drug Administration since it was considered a chemical facility in China. It therefore probably received no supervision from the Chinese government. (Heparin: A Wake-Up Call on Risks to the U.S. Drug Supply, 2012)

Questions:

1. To avoid another situation like heparin adulteration in the future what steps should be taken by the government to protect people?
2. What could have been the major reason behind heparin adulteration? 
3. Do you think heparin contamination was intentional? Why or why not?

sources: 

1. Chinese Heparin Manufacturer again involved in Falsification and GMP Non-Compliance. (2016, march 2). Retrieved from gmp compilance:  [Accessed on: 2023 February 5]