# Professionalism/Market Influences on Clinical Trials
## Introduction

Clinical trials are experimental periods of clinical research performed on humans. Clinical trials are a fundamental step in testing new treatments for introduction to the public; however, market influences that impact the nature of these trials lead us to further analyze the balance between science and business in this process.

## Overview of Clinical Trials
### Goals

The goal of a clinical trial is to learn the effectiveness and safety of a medical intervention. Manufacturers also use them to engage and familiarize clinicians and key opinion leaders with said medical interventions.They also generate commercially useful data, publicity, interest, and prestige for their product and organization. Medical professionals agree that trials should inherently be designed in such a way that they yield as much useful and unbiased information as possible from as few participants and clinical events as is necessary.

### Nature of the Business

Most medical manufacturers are not in any way altruistic entities: they are largely private companies and must be efficient and profitable while still producing safe and effective products. From a business mindset, clinical trials are necessary and expensive investments. In turn, not meeting goals or objectives in terms of time or results of a trial can cost companies millions of dollars a day. Organizations have expectations based on their research and evaluation of market influences: profitability can be directly correlated with how they market trials according to these influences.
Because of this, manufacturers act as any business would and leverage market influences to increase their output: in clinical trials output can be measured in terms of patient recruitment and retention. Regardless of science or opinions of professionals versed on the product or how clinical trials should be run, there is upper management in these organizations that are trained to cut costs and increase profits. This also leads manufacturers to turn to product seeding: this occurs when trials are used to get clinicians into the habit of prescribing a drug to increase sales after the trial. Manufacturers also hide their influence through attributional spin. Attributional spin occurs when, for marketing credibility, a company plays down its own involvement in a trial, but plays up the role of the academics they have enlisted into the project.
Although profits may increase, attempting to leverage market influence as a manufacturer leads to increased risk when it compromises the main objectives of the trial. People who are harmed in clinical trials can pursue compensation for their injuries, illnesses, and other expenses. Legal action is warranted against the manufacturer if the risks were not properly explained, proper guidance or clarification was not provided on paperwork and consent forms, you were coerced into participating in the trial, or your health significantly worsened as a result of partaking in the trial.

### Danger of Marketing in Clinical Trials

There is concern surrounding the idea of "marketing trials", which are clinical trials which have been designed or performed with market influences in mind. There is no black and white definition of a marketing trial: a marketing trial can be defined as a spectrum of commercial influence in any clinical trial, and this whole spectrum should be of concern to the medical community. The concern is due to the fact that marketing trials are less scientific because of bias that arise in the funding, design, conduct, analysis, and reporting stages.

## Participant Involvement in Clinical Trials
### Drug Manufacturers

Drug manufacturers have the goal of producing something in a way that is efficient, profitable, and effective in carrying out the goals of the manufacturer. These goals may, however, vary greatly depending on the context and organization: some manufacturers will focus on delivering the most effective product where others will focus on creating the best margins.

### Trial Patients

Research shows that, in terms of motivators for any patient to participate in a clinical trial, safety topped the list of priorities; however, because a significant portion of individuals who participate in clinical trials are from traditionally underserved groups, most are inherently disadvantaged in reading and comprehending the metrics of safety in a clinical trial. Patients also value the legitimate health benefits associated with the trial’s product: they hope the trial provides them with the advertised benefits that potentially could extend or improve their quality of life. Finally, patients stress the importance of being valued as a partner in the trial. A patient being a partner in a trial involves them being fully informed and valued as an equal in the entirety of the clinical trial process. However, allowing market influences to impact the nature of a trial and not fully disclosing that to participants strips them of any form of legitimate partnership.

### Outside Medical Professionals

Most outside medical professionals agree that trials should be conducted in a way that is as scientific as possible: they want to see transparency. Many medical professionals are also weary of how marketing and other characteristics of a clinical trial may impact the reliability of results. In turn, they believe that marketing undermines the purpose of clinical trials. Dr. Alastair Matheson, supporter of innovative pharmaceutical research, does a good job of putting the relationship between the two into words: “Science is about objectivity, openness and truth. Marketing is about rhetoric, half-truths and sales. When marketing creeps into clinical trials, science is the loser – and with it, good medicine and patient care.”

## Vioxx Case
### Background

In late 1998, the pharmaceutical company Merck & Co. filed an application with the Food and Drug Administration for U.S. approval of the drug rofecoxib, also known as Vioxx. Vioxx was approved in 1999 as a prescription medicine to treat symptoms of arthritis, acute pain in adults, and painful menstrual cycles.After data from new clinical trials revealed that extended use of Vioxx substantially increased the risk of cardiovascular events in patients, Merck voluntarily withdrew Vioxx from the market in 2004. Over 2 million patients were taking Vioxx at the time of the withdrawal.

### VIGOR trial

Shortly before receiving FDA approval, Merck began its largest clinical trial of Vioxx. The Vioxx Gastrointestinal Outcomes Research (VIGOR) study was intended to show that Vioxx would have fewer gastrointestinal side effects than its competitor, naproxen. If the trials produced data showing that Vioxx had fewer gastrointestinal side effects than naproxen, Vioxx would be viewed as a safer product and likely lead to a boost in sales for Merck.
In the summer of 2000, Merck reported its final data and conclusions from the VIGOR study. The data showed Vioxx had less gastrointestinal side effects than naproxen but patients taking Vioxx in the study had cardiac events such as heart attacks at a rate 4 times greater than those taking naproxen. Selective reporting in the published results of the VIGOR study concealed the cardiac risks of Vioxx. The report included one more month of gastrointestinal events than cardiac events. The missing month of cardiac events understated the true cardiac risk to patients as it was later revealed that three cardiac events had occurred in patients that were left out of the report. The report also included a misleading hypothesis that Vioxx was not increasing the risk for cardiac events but that naproxen was decreasing the risk for it, despite no supporting evidence.
In 2001, the FDA reviewed the VIGOR report and decided to change the labeling on VIOXX to include a warning about cardiac side effects. A congressional hearing found that there was deliberate marketing done by Merck to downplay the severity of cardiac risks including “The Cardiovascular Card”, a pamphlet created by Merck which stated that Vioxx was associated with 1/8th the mortality rate from cardiovascular problems than other ant-inflammatory drugs.

### APPROVe trial and voluntary withdrawal

In 2004, an additional clinical trial, called the APPROVe trial, was being conducted to test other uses for Vioxx. Initial data from APPROVe found that patients taking Vioxx had an increased risk of cardiovascular events compared to a placebo group. The trial was cut short and Merck voluntarily removed Vioxx from the market in September 2004. According to FDA investigators, at the time of market removal Vioxx was estimated to have caused 140,000 heart attacks and 60,000 deaths.

### Court proceedings

Immediately after recalling Vioxx, multiple personal lawsuits were filed against Merck for damages caused by taking Vioxx. Merck successfully litigated as many as 10 cases as it was hard for plaintiffs to prove Vioxx was the cause of their health problems. In 2013, Merck settled a class action lawsuit for $4.25 billion class action lawsuit filed by patients who had taken Vioxx for 30 days or more.

## TGN1412 Case
### Background

In 2006, TeGenero, a German drug manufacturer, was working on developing a novel drug, TGN1412, intended to treat B-cell chronic lymphoma or rheumatoid arthritis. After seemingly successful preclinical trials in monkeys and rats, TGN1412 entered the first-in-man phase 1 clinical trial, which was run by Parexel, an American clinical research organization, at Northwick Park Hospital in London. On March 13, 2006, the drug was administered to six healthy male volunteers and within minutes, all were suffering from adverse reactions. The subjects experienced cytokine release syndrome, which is a systemic inflammatory response that can be triggered by certain drugs, as well as with multi-organ failure.

### Issues with TGN1412 Phase 1 Trial Procedures

An official investigation and report was conducted by the Expert Scientific Group (ESG) to determine ways in which the trial directly put the 6 healthy volunteers at risk.

#### Failing to Establish Safe Dosing Procedures for Humans

The preclinical trials met regulatory requirements but failed to predict a safe dose for human use. In the preclinical studies, monkeys were given doses as high as 50mg/kg over the course of 4 weeks without any adverse reactions. Due to the lack of testing done in the preclinical trials, the investigators arbitrarily chose a dose to administer to the volunteers that they assumed would be safe. The volunteers were given doses of 0.1mg/kg, a significantly smaller dose than the preclinical tests, but at a much faster rate of 10 minute dosing intervals. The choice to do this without any statistically significant data to support it likely played a role in the horrible reactions suffered by the subjects.

#### Overlooking Previous Studies

Investigators in the TGN1412 study stated in their brochure given to the volunteers that the preclinical trials reported low levels of cytokine release. However, studies done on two other monoclonal antibodies, anti-CD3 mAb OKT3 and Visilizumab, concluded that non-human primates do not predict cytokine release in humans and it was not safe to assume 100% homology between the primates and humans. This oversight by TeGenero and Parexel directly impacted the lives of the 6 volunteers in ways that could have been avoided had the investigators kept up with current research.

### Aftermath
#### TeGenero

Immediately following the trial, TeGenero's chief scientific officer, Thomas Hanke, apologized to the patients and their families. Four months after the disastrous clinical trial, TeGenero went filed for bankruptcy, leaving those affected fearing that they may not received proper compensation.

#### Changes to Regulatory Guidelines

The report written by the ESG contained 22 recommendations as to how phase 1 clinical trials could be more safely carried out in the future. This included updated methods for calculating a safe starting dose for humans, sequential rather than simultaneous testing to monitor effects, and consideration of the appropriate route and rate of drug administration. The Medicines and Healthcare Regulatory Agency (MHRA), which regulates clinical trials in the UK, took the ESG's recommendations into account and they established additional guidelines for certain categories of drugs that had never been used in humans before in order to avoid repeating the disasters seen in the TGN1412 trial.

## References

* ↑ London, A. J., Kimmelman, J., & Carlisle, B. (2012). Research ethics. Rethinking research ethics: the case of postmarketing trials. Science (New York, N.Y.), 336(6081), 544–545. https://doi.org/10.1126/science.1216086
* 1 2 3 Alastair Matheson, P. (2017, March 16). How marketing is undermining clinical trials. Retrieved May 1, 2021, from https://blogs.biomedcentral.com/on-medicine/2017/03/16/how-marketing-is-undermining-clinical-trials/
* 1 2 Clinical trial Branding: Cg Life: Life science and healthcare marketing agency. (n.d.). Retrieved May 3, 2021, from https://cglife.com/clinical-trial-branding/
* ↑ Can people harmed in clinical trials sue for medical malpractice? (2020, August 24). Retrieved May 9, 2021, from https://www.nphm.com/blog/medical-malpractice/can-people-harmed-in-clinical-trials-sue-for-medical-malpractice/
* ↑ Barbour, V., Burch, D., Godlee, F., Heneghan, C., Lehman, R., Perera, R., . . . Schroter, S. (2016). Characterisation of trials where marketing purposes have been influential in study design: A descriptive study. Trials, 17(1). doi:10.1186/s13063-015-1107-1
* ↑ Fred D. Ledley, M. (2020, March 03). Profitability of large pharmaceutical companies vs other large public companies. Retrieved May 6, 2021, from https://jamanetwork.com/journals/jama/fullarticle/2762308#:~:text=From%202000%20to%202018%2C%20the%20cumulative%20revenue%20of%20companies%20in,eTable%202%20in%20the%20Supplement).
* 1 2 The patient perspective on clinical trials. (n.d.). Retrieved May 6, 2021, from https://www.appliedclinicaltrialsonline.com/view/patient-perspective-clinical-trials
* ↑ False advertising by Smith & nephew can put patients at risk of PRESSURE Ulcers, mölnlycke LAWSUIT AllegesDeceptive marketing claims Misled Clinicians, Healthcare decision makers on KEY PREVENTION... (n.d.). Retrieved May 10, 2021, from https://markets.businessinsider.com/news/stocks/false-advertising-by-smith-nephew-can-put-patients-at-risk-of-pressure-ulcers-moelnlycke-lawsuit-allegesdeceptive-marketing-claims-misled-clinicians-healthcare-decision-makers-on-key-prevention-1004490854
* ↑ Reuters. (Aug. 19, 2005) A Time Line of Vioxx. New York Times. https://www.nytimes.com/2005/08/19/business/a-time-line-of-vioxx.html
* ↑ Food and Drug Administration (Sept. 30, 2004). Vioxx Questions and Answers. FDA. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/vioxx-rofecoxib-questions-and-answers
* 1 2 Compton, K. (2021). Vioxx. drugwatch. https://www.drugwatch.com/vioxx/
* 1 2 3 Krumholz, H. M., Ross, J. S., Presler, A. H., & Egilman, D. S. (2007). What have we learnt from Vioxx?. BMJ (Clinical research ed.), 334:758, https://doi.org/10.1136/bmj.39024.487720.68
* 1 2 Waxman, H. (June 23, 2005). The Lessons of Vioxx - Drug Safety and Sales. The New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/nejmp058136
* ↑ Sibbald B. (2004). Rofecoxib (Vioxx) voluntarily withdrawn from market. Canadian Medical Association journal 171:(9), https://doi.org/10.1503/cmaj.1041606
* ↑ Compton, K. (2021). Vioxx Lawsuits. drugwatch. https://www.drugwatch.com/vioxx/lawsuits/
* ↑ Wadman, M. (Nov. 13, 2007). Merck settles Vioxx lawsuits for $4.85 billion. nature. https://www.nature.com/news/2007/071113/full/450324b.html
* ↑ Attarwala, H. (2010). Tgn1412: From discovery to disaster. Journal of Young Pharmacists, 2(3), 332-336. doi:10.4103/0975-1483.66810 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964774/
* ↑ Shimabukuro-Vornhagen, A., Gödel, P., Subklewe, M., Stemmler, H. J., Schlößer, H. A., Schlaak, M., Kochanek, M., Böll, B., & von Bergwelt-Baildon, M. S. (2018). Cytokine release syndrome. Journal for immunotherapy of cancer, 6(1), 56. https://doi.org/10.1186/s40425-018-0343-9
* ↑ Expert Scientific Group (ESG) On Phase One Clinical Trials. Final Report. 2006:1‒107.
* ↑ Parexel. Clinical trial protocol: A phase-1, single-centre, double-blind, randomised, placebo-controlled, single escalating dose study, to assess the safety, pharmacokinetics, pharmacodynamics and immunogenicity of TGN1412 administered intravenously to healthy volunteers. 2000:1‒58.
* 1 2 Agyeman AA, Ofori-Asenso R. A decade after the TGN1412 disaster: what have we learnt about safety-predicting methods for new biological agents? Pharm Pharmacol Int J. 2016;4(7):499-500 DOI: 10.15406/ppij.2016.04.00103
* ↑ Horvath CJ, Milton MN. The TeGenero Incident and the Duff Report Conclusions: A Series of Unfortunate Events or an Avoidable Event? Toxicol Pathol. 2009;37(3):372‒383.
* ↑ Staff, D. (n.d.). German company apologizes to victims of DISASTROUS DRUG Test: DW: 17.03.2006. Retrieved May 11, 2021, from https://www.dw.com/en/german-company-apologizes-to-victims-of-disastrous-drug-test/a-1936590
* ↑ Welle Staff, D. (n.d.). German company Behind Disastrous clinical trial goes Bankrupt: DW: 05.07.2006. Retrieved May 11, 2021, from https://www.dw.com/en/german-company-behind-disastrous-clinical-trial-goes-bankrupt/a-2079701
* 1 2 Matthews, G., & Baker, C. (2016, April 14). Ten years after the 'Elephant MAN' drug trial. Retrieved May 11, 2021, from https://www.lexology.com/library/detail.aspx?g=c827f92c-2bb9-4276-a160-75a415788ddc