Although the spine is resiliently crafted to withstand great stress while retaining flexibility, sometimes it fails. Around 700,000 vertebral compression fractures (VCFs) occur each year in America, mostly in people whose spines have already been weakened by osteoporosis. A VCF is a painful condition which can be remedied through either of two procedures: Vertebroplasty or Kyphoplasty. Both utilize bone cement products and offer instantaneous relief to patients at a very high success rate, ~90% (Cronin-Fine, et. al, 2008). Between 2002 and 2004, physicians testing products for the medical device company Synthes treated 31 VCFs with Norian XR, a bone cement (USA Eastern District Court, 2011). The problem? It was only approved by the FDA for use in the arm, and three people died as a consequence of its misuse.
Generally speaking, off- label usage has proven beneficial when pursued with the right intentions. For instance, Avastatin, a drug proven to treat colon cancer, was investigated for effectiveness in treating Age-related Macular Degeneration (AMD), a disease which leads to blindness and affects 1.6 million Americans. Avastatin was found to be equally effective in treating the disease as Lucentis, the established AMD drug. This was a significant finding for researchers, especially considering Lucentis costs thirty-nine times as much as Avastatin. Not only does this respect the patient’s pocketbook, but Medicare could also save three billion dollars per year (The CATT Research Group, 2011). There is nothing wrong with testing a product in a new manner, especially with the benefit of others in mind.
However, the FDA has strict regulations that corporations must follow if they want to engage in off-label testing. Unless all of the following six conditions are satisfied, the investigational use of marketed drugs, biologics, and medical devices needs FDA consent via approval of an Investigational Device Exemption (IDE):
1) It is not intended to support a significant change in use or labeling.
2) It is not intended to support a significant change in the advertising for the product.
3) It does not involve a route of administration or dosage level, use in a subject population, or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product.
4) It is conducted in compliance with the requirements for IRB review and informed consent.
5) It is conducted in compliance with the requirements concerning the promotion and sale of drugs—21 CFR 312.7 (products cannot be touted as safe or effective)
6) It does not intend to invoke 21 CFR 50.24 (informed consent is not necessary when other treatments are unsatisfactory or unavailable, or when subjects are incapable of making decisions due to their medical conditions).
(U.S. Food and Drug Administration, n.d.).
Originally, Synthes was granted FDA approval for the use of Norian XR in the arm (Dale, 2011). The company then set out to see if it was suitable for use in the spine, despite preliminary studies which found the cement had the potential to react with blood and form clots (The United States of America Eastern District Court, 2010). Of the conditions stipulated by the FDA, several were not met: (1) In changing the treatment area to the spine, a significant change in labeling would need to occur, considering that the original label warns strictly against usage there. (3) Use in the spine poses significantly more risk than use in the arm, considering it proximity to major arteries in addition to the aforementioned label warning. (4) The subjects in this unauthorized study were never told that the product used on their vertebrae was not made for spinal fractures. No informed consent was given concerning the off-label usage. (5) Misbranded shipments of Norian XR were sent to Texas, Maryland, California, Indiana, New York, Pennsylvania, Alabama, and Florida. These shipments lacked some of the product information, including the labeling prohibiting use for VCFs (The United States of America Eastern District Court, 2010).
As a result of the product testing, three subjects died. No blame was placed until four top executives from the company were tried in 2010. In a letter read in court, former Synthes spine division president Thomas Higgins stated, “I didn’t think at the time that we were doing anything illegal,” even though preliminary studies showed that not only could blood clots form if the cement was used in the spine, but that they could travel to the lungs and cause death within 30 seconds (Dale, 2011). In late 2011, Higgins was sentenced to nine months in jail along with former Synthes North America President Michael Huggins. Former Director of Clinical and Regulatory Affairs, John Walsh, was given a five month sentence, while former VP of Synthes, Richard Bohner, had his sentencing postponed. All four were fined $100,000 (U.S. Department of Justice, 2011). The presiding federal judge thought that the hunger for profit caused executives to disregard “the sanctity of human life” (Dale, 2011). This case outcome proved that those at the helm of corporations could be held responsible and truly penalized for wrongdoing.
Was justice fully realized? Greed can be a powerful source of motivation. Opening up the market for VCF treatment would have undoubtedly provided excellent financial returns for Synthes. The vital question is this: does the blame rest solely on the manufacturer, or does it extend to the physicians using the product as well? In 2011, results from a study financed by the National Institutes of Health were released, entitled: “Financial payments by orthopedic device makers to orthopedic surgeons.” In 2007, 939 orthopedic surgeons were paid more than $198,000,000 (over $210,000 per physician). A year later, 526 orthopedic surgeons were paid more than $228,000,000 (over $430,000 per physician) (Hockenberry, et. al, 2011). Endorsing products provides excellent financial returns for physicians. While payment to push medical products is not currently considered unethical, is it good practice?
Physicians are traditionally expected to investigate treatment options and give unbiased opinions regarding which medication or device to use, if any. Economic influence from corporations negates that expectation. Parties involved (save the physician) stand to possibly incur more expenses, and patients stand to potentially take unneeded medication or undergo unnecessary procedures (Sahm, 2011).
Although the physicians trained for the Norian XR trials were given altered documents which hid certain properties of the product, they still should be held partially accountable. They have a responsibility to be thoroughly knowledgeable about the products they use and to test them without bias towards a specific outcome. Those employed in another Synthes study (ProDisc™) in 2006 were not in a position to be objective. The Attorney General of New Jersey, Anne Milgram, wrote that, “The investigation revealed that a majority of the physicians who participated in these clinical trials had significant investments in the products — investments that would have been worthless had the product failed to obtain regulatory approval from the FDA” (2009). Financial conflicts of interest cloud physicians’ minds, whether they accept money to favor a product or find it safe for market use.
For that reason, safety and efficacy must be tested impartially. Monetary incentives and close proximity to the corporation create subjectivity, and can even lead to dishonesty. Several doctors who worked for Synthes, including Dr. Barton Sachs, trained other doctors to use Norian XR. “On January 10 and 11, 2004, defendants Synthes and Norian held the first surgeon forum, which was approved by defendants Huggins, Higgins and others, at which approximately 30 surgeons were trained to use XR to treat VCFs, and at which the companies delegated to Dr. Sachs the task of explaining the warning on XR’s label, ‘not intended for treatment of’ [VCFs]. The evidence shows that Dr. Sachs re-worded the warning” (The United States of America Eastern District Court, 2010). In doing so, he played an active role in the alleged deceit of practitioners, patients, and the FDA. Additionally, Sachs was involved in the previously mentioned ProDisc™ study. He published several papers validating usage of that product (Sachs, 2010), and likely had certain “significant investments” referred to by the Attorney General.
Had the physician researchers in the Norian XR trials been more objective and thorough, they would have requested preliminary study information. They would have inquired as to why an Investigational Device Exemption was not needed. They would have noted that the substance was too liquid and prone to leaking. After each fatality, they should have questioned if it was the product which was deadly and not the happenstance of surgery. Ultimately, they should have refused to endorse a flawed product by continuing trials and jeopardizing human life.
In practice, physicians are welcome to employ off-label usage. The FDA only states that, “If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product’s use and effects” (U.S. Food and Drug Administration, n.d.). Synthes failed as a corporation when they commenced unlawful clinical trials with a product they knew was unfit for use in the spine. The physicians failed when they let monetary incentives impair their ability to recognize a faulty product.
The responsible corporate officer doctrine was enacted in this case and dealt sufficient justice to one guilty party. It sets a precedent for future cases and serves as a warning to corporations who are employing the same unethical practices. Still, it is not enough. The government’s next step should be to create legislation that would make physicians like Dr. Sachs who knowingly participate in unlawful trials and perpetuate harm more accountable for their actions. Further laws to regulate physician payouts (both cash and stock) by pharmaceutical and device companies, to increase the transparency of these transactions, and to require the investigation of both new and established products by truly independent sources could help deter financial conflicts of interest. More research is needed to document how widespread these questionable ethics are.
Clearly, at present, some biomedical device companies are willing to sacrifice positive patient outcomes in the pursuit of profits. If a physician cannot separate their clinical decision making processes from this industry, then not only are the companies spineless, but the physician is as well.
The CATT Research Group, (2011). Ranibizumab and bevacizumab for neovascular age-related macular degeneration. The New England Journal of Medicine, 364, 1897-1908.
Cronin-Fine, L., Miranda, D., Morabito, K., Rainbow, M., & Sharp, W. (2008, Apr. 24). Kyphoplasty:a treatment for vertebral compression fractures. Retrieved from http://biomed.brown.edu/Courses/BI108/BI108_2008_Groups/group01/BIOL1080_2008 -Kyphoplasty_Group_Webpage_Project/Home.html
Dale, M. (2011, Nov. 11). 3 synthes execs get jail time for fatal bone cement trials. The Daily Local
Hockenberry, J., Weigel, P., Auerbach, A., & Cram, P. (2011). Financial payments by orthopedic device makers to orthopedic surgeons. Archives of Internal Medicine, 171(19), 1759-65.
Milgram, A. New Jersey Department of Law and Public Safety, Office of the Attorney General. (2009). Retrieved from website: http://www.nj.gov/oag/newsreleases09/050509-FDA- letter.pdf
Sachs, B. (2010). Curriculum vitae . (Medical University of South Carolina) Retrieved from http://www.muschealth.com/cvs/FY11/SachsB_bls21_CV2010_scrubbed.pdf
Sahm, S. (2011). Of mugs, meals and more: the intricate relations between physicians and the medical industry. (15 ed.). Netherlands: Springer.
U.S. Food and Drug Administration. (n.d.). “Off-label” and investigational use of marketed drugs, biologics, and medical devices – information sheet. Retrieved from FDA website: http://www.fda.gov/RegulatoryInformation/Guidances/ucm126486.htm
U.S. Department of Justice, Eastern District of Pennsylvania. (2011). Former Executives of International Medical Device Maker Sentenced To Prison in Unlawful Clinical Trials Case. Retrieved from http://www.justice.gov/usao/pae/News/2011/Nov/synthesexecs_release.pdf
The United States of America Eastern District Court. (2010). The United States Of America v. Michael D. Huggins, Thomas B. Higgins, Richard E. Bohner, John J. Walsh (Case 2:09- cr-00403-LDD Document 94). Retrieved from http://www.circare.org/lex/synthes/09cr00403_9420100330.pdf
The United States of America Eastern District Court. (2010). The United States Of America v. Norian Corporation Synthes, Inc. (Case 2:09-cr-00403-LDD). Retrieved from http://www.justice.gov/usao/pae/Pharma-Device/synthessupersedinginformation.pdf