The FDA’s Tuskegee Experiment in Lung Cancer Patients?
The Tuskegee Experiment was one of the lowest points in US Research history. This 40 year experiment, first conducted in 1932, was meant to record the natural history of syphilis in hopes of justifying treatment programs for blacks. This study was called the “Tuskegee Study of Untreated Syphilis in the Negro Male.”
In 1972, the associated press broke the news of the total lack of ethics of this study. The information below is from the CDC website:
- The study initially involved 600 black men — 399 with syphilis, 201 who did not have the disease
- The study was conducted without the benefit of patients’ informed consent.
- Researchers told the men they were being treated for “bad blood,” a local term used to describe several ailments, including syphilis, anemia, and fatigue.
- In truth, they did not receive the proper treatment needed to cure their illness.
- In exchange for taking part in the study, the men received free medical exams, free meals, and burial insurance.
Ethical Lessons from the Tuskegee Experiment
Below are key takeways from this socialworker.com article:
- Deception was used to recruit subjects. Patients were never explained the science. They were told that they had “bad blood” not syphillis
- Withholding Treatment for Research Purposes: Penicillin was withheld from patients despite data establishing the effectiveness in treating the disease
- Accurate Records were not Kept:The number of patients who died from Syphillis was never known
- Medical Professional beliefs about African Americans Clouded the study
- No Comprehensive Report was ever published
- There was no protest from anyone in the Medical Community
From the CDC Website:
The men were never given adequate treatment for their disease. Even when penicillin became the drug of choice for syphilis in 1947, researchers did not offer it to the subjects. The advisory panel found nothing to show that subjects were ever given the choice of quitting the study, even when this new, highly effective treatment became widely used.
The Tuskegee experiment caused so much damage that a recent NY Times article suggests that it may have caused a lasting mistrust of doctors among blacks
Sadly, We may have a New Tuskegee Experiment in Cancer Care
The FDA just announced the results of a Trial Known as IUNO in Lung Cancer. The ethical concerns for this trial are on par with the Tuskegee Experiment.
This Trial was conducted in patients with Non-Small Cell Lung Cancer, whose tumor does not possess a mutation known as EGFRmut. These patients are known as wild-type, and make up about 85% of lung cancer cases. Similar to the Tuskegee experiment, the trial was not conducted to determine the best therapy for the patients. Below is a quote from the European Medicines Agency regarding the Trial Design:
The study BO25460 (IUNO) was to compare erlotinib as first-line maintenance therapy with erlotinib at progression (second-line treatment)
This study was a post-marketing commitment by the FDA of the drug manufacturer OSI in partnership with Genentech(parent company Roche). The FDA required this comittment because it had approved the drug Tarceva (Erlotinib) based on questionable data for Maintenance Lung Cancer. The data was so questionable that the Doctors that Advise the FDA, Known as ODAC, voted 12–1 Against approving Tarceva.
So the FDA required another trial to see if the drug really actually worked. Guess What — -it didn’t. In fact nothing worked for patients on this trial. Patients were either given placebo which didn’t work, or Tarceva for EGFR-wild type Lung Cancer, which the doctors on ODAC voted 12–1 against.
- There were a similar number of participants in the IUNO Trial and the Tuskegee Experiment. The IUNO trial enrolled 319 Placebo patients and 322 Tarceva (Erlotinib) patients
- The study had a blinded phase where some patients received inactive therapy. Also, patients may not have been informed of the importance of EGFRmut for the effectiveness of the drug Erlotinib. No patients enrolled in this study had an EGFRmut due to ethical concerns. Yet, there were no ethical concerns for the Wild-Type patients receiving placebo or Tarceva
Patients with EGFR activating mutations were excluded as it was considered unethical to have such patients potentially being randomized to placebo in the first-line maintenance setting.-Europeaan Medicines Agency
3. By the start of the Trial in 2011, Alimta was well accepted as a standard of care for Maintenance therapy. In IUNO, these patients were offered either Placebo or Tarceva. Alimta had offered a 6 month survival benefit in this setting based on the FDA’s 2009 approval. In IUNO, none of the arms benefited from treatment.
4. The trial had a significant rate of Diarrhea and Rash in patients taking Tarceva.
5. It was well known in Europe that EGFR TKIs, the class of drug of Tarceva, had efficacy tied to the presence of EGFR mutation. In fact, this trial was a post marketing committment for a trial known as SATURN which demonstrated exceptional activity in EGFRmut patients. Were patients informed of this data? The trial sponsor Roche had just received an approval in Europe for patients with this genetically distinct disorder during the 1st month of the IUNO trial, September 2011.
The DEATH CURVE in the IUNO TRIAL
The below chart demonstrates the Survival Curve which is basically overlapping for Placebo and Tarceva — -Demonstrating similar Surivival — or lack of Survival in this Horrible Study
The Progression Free Survival (PFS) Curve is just as Sad
In the chart below, there is once again no separation of the lines. In fact, that sharp drop represents about 60% of the patients either dying or progressing with Cancer within the 15 weeks of entering the trial.
For Comparison sake, this is what a PFS curve looks like when the drug works. In this case, this is the 2008 Chart of Tarceva in the SATURN Trial. The PFS of Tarceva with patients with EGFRmut is shown in Light Blue. Once again for comparison sake, notice the difference in the curves when a drug adds benefit to patients. EGFRmut patients were not allowed in the IUNO Trial.
Adverse Events and Death During the Blinded Phase
During the Blinded Phase of this study, there were 36 deaths, and twice as many deaths in the Patients that took Tarceva versus the Placebo Group.
Below is a summary of the cause of death for the treatments taken above
Interestingly, the investigators did not attribute any of the deaths above to Tarceva(Erlotinib). They simply attributed the deaths to progression of Lung Cancer or other comorbities.
Many Patients Experienced Rash and Diarrhea
It is difficult to determine which patients in this study were harmed more by the trial. The placebo patients received no active agent despite the data that Alimta provided a 6 month survival benefit. For the patients that received Tarceva, they also derived no survival benefit from the drug, and also had a very high rate of toxic side effects. 24% of patients on the Tarceva arm experienced Diarrhea, nearly 6x the rate of the placebo population. 39% of patients experienced a rash, nearly 4x the rate of the placebo population.
As a reference, these links provide examples of EGFR TKI therapy related rash in patients. These are not photos from the IUNO trial
Modern Day Tuskegee Experiment in Lung Cancer Patients?
Similarities to the Tuskegee Experiment
- Both Trials had about the same number of patients in each arm of the trial, about 300 in each arm
- Both Trials utilized Blinding even though there were active therapies available for the disease
- Patients may not have been informed of the importance of the new science at the time of their diseases. In Tuskegee, Penicillin was a new treatment with exceptional benefit for syphillis. With IUNO, Europe had recenlty approved Tarceva for EGFRmut patients, IUNO’s predecessor, SATURN, had demonstrated significant survival for patients with EGFRmut. Also, Alimta had demonstrated significant efficacy in the FDA label in 2009 for Lung Cancer Patients.
- Both Trials resulted in harm for patients suffering from miserable diseases
- The Data for the IUNO trial has never been published in a medical journal nor presented in a major Medical Meeting. Since the IUNO trial was first reported via the European Medicines Agency, there have been two major Medical Oncology Meetings: ASCO 2016, and ESMO 2016. IUNO was not presented at either meeting.
- There has been no outcry from the Medical Community regarding the IUNO Trial with the exception of the Tweet Below from a Thoracic Oncologist from London, England.
The 8 Year Timeline of IUNO- Also Known as This Miserable Trial of Certain Death, Rash and Diarrhea?
November 7, 2008 — OSI Reports the SATURN TRIAL
OSI’s Leung said it was “too early to comment on specifics” from the SATURN trial and added that it was “difficult and treacherous” to try to compare the SATURN study of Tarceva to the Alimta trial.
May 31, 2009-SATURN Trial data is presented At ASCO
Indeed, the study showed a significant 41% improvement in PFS in patients on Tarceva maintenance therapy compared to patients on placebo. Interestingly, Tarceva showed greater benefit in the EGFR mutated patient sub-population. In this patient population, maintenance treatment with Tarceva improved survival by 90%.
July 6, 2009-FDA Approves Alimta for Maintenance Therapy for Lung Cancer
June 25, 2009 — OSI Submits Application for Approval of Tarceva for Maintenance Therapy
We are pleased with the FDA’s decision to review the data to evaluate Tarceva as a first-line maintenance therapy,” stated Colin Goddard, Ph.D., Chief Executive Officer of OSI Pharmaceuticals. “This decision puts us one step closer toward accomplishing our goal of making Tarceva available earlier in the course of lung cancer treatment, offering a non-chemotherapy choice for all NSCLC patients in the maintenance setting.”
The subgroup analysis of patients whose tumors possessed an activating EGFR mutation and were eligible for analysis (n=49) demonstrated a statistically significant ten-fold increase in the time patients live without their disease worsening (as measured by PFS) for patients treated with Tarceva compared with placebo
December 17, 2009-FDA Advisory Committee Votes 12–1 Against Tarceva Maintenance
Ronald Richardson, MD, of the division of medical oncology at the Mayo Clinic in Rochester, Minn., was one of the panelists who voted against the therapy. “We were presented with a single study that has some design flaws showing some very modest or even minimal benefit,” he said during the meeting.
“My other concern is [that] this committee should be careful about setting precedence, particularly with the approval of drugs through single studies in which the design is an issue and benefits are marginal. We should maintain the integrity of the data at which we look,” Richardson said
December 17, 2009 — Lung Cancer Alliance Fights for Tarceva Approval
“We hope that FDA leadership will not follow the recommendations of ODAC and will approve Tarceva(R) in the maintenance setting so that lung cancer patients have another option that will help them live longer and enjoy a heightened quality of life,” concluded Fenton Ambrose.
April 16, 2010 FDA Approves Tarceva for Maintenance Therapy
“We hope this approval will help more people fight the leading cause of cancer death in the United States,” said Hal Barron, executive vice president, Global Development and chief medical officer. “Tarceva is the first oral maintenance option for people with advanced NSCLC who want to continue treating their cancer before it grows or spreads again.”
April 23, 2010 — FDA Explains their ODD Decision
One issue was regulatory precedent, he said. The agency had approved bevacizumab (Avastin) in a regimen for nonsquamous non-small cell lung cancer (NSCLC) based on a 20% reduction in the risk of death, compared with chemotherapy alone. It had also accepted pemetrexed (Alimta) as a maintenance treatment for nonsquamous NSCLC “based on a 30% reduction in the risk of death compared to no maintenance therapy and a 21% reduction in the risk of death in patients with all types of NSCLC,” noted Dr. Justice.
“The reduction in the risk of death with erlotinib maintenance treatment compared to no maintenance therapy was similar at 19%,” he said.
The double-blind, international SATURN (Sequential Tarceva in Unresectable NSCLC) trial that formed the basis of the erlotinib application had randomized almost 900 patients with locally advanced or metastatic NSCLC that did not progress during first-line, platinum-based chemotherapy.
Median progression-free survival was 2.8 months in patients who were given erlotinib as maintenance therapy vs. 2.6 months in a placebo arm — a statistically significant difference that represented a 29% reduction in risk of progression. Overall survival, a secondary end point, reached a median of 12 months with erlotinib and 11 months with placebo — again, a statistically significant difference.
A second issue was trial design, Dr. Justice said. He cited general agreement “that the optimal trial design would have been erlotinib maintenance vs. erlotinib at progression of disease.” Although OSI has agreed to do such a study as part of its postmarketing commitment, he suggested that “this may not reflect what will actually happen in practice.”
April 29, 2010 — Tarceva Received Approval in the European Union for Maintenance Therapy
“We are pleased that the European health authorities recognize Tarceva as a valuable option for lung cancer patients and their physicians when used in the first-line maintenance setting,” said Colin Goddard, Ph.D., Chief Executive Officer of OSI Pharmaceuticals. “We look forward to working with our partner, Roche, to advance the robust Tarceva lifecycle program, which includes evaluating Tarceva in the adjuvant setting and as a first-line treatment for advanced NSCLC patients with an activating EGFR mutation as well as branching into other disease settings including liver cancer.”
September 1, 2011-Roche Receives European Approval for Tarceva in EGFRmut Lung Cancer
“The European approval for Tarceva is good news for patients with a genetically distinct form of lung cancer because these patients may derive greater benefit when the medicine is used as an initial treatment,” said Hal Barron M.D., Chief Medical Officer and Head, Global Product Development. “Advanced lung cancer is often diagnosed with little warning of symptoms and progresses aggressively so it is important to identify which patients may benefit from early treatment with Tarceva.”
September, 2011 — IUNO Trial Starts Accrual, Study Author has restrictions from Study Sponsor
December 17, 2015 — European Medicines Agency Changed Tarceva Indication Based on Reported IUNO Data
The efficacy of erlotinib in patients with advanced NSCLC with EGFR activating mutation has previously been demonstrated in clinical trials (e.g. EURTAC, EMA/657134/2011). However, the indication of “switch maintenance use of erlotinib in patients with locally advanced or metastatic NSCLC with stable disease after 4 cycles of standard platinum based first line chemotherapy” is no longer justified based on the findings in the IUNO study
January 21, 2016 — Canada Changed the Indication for Tarceva based on the IUNO Trial
The benefit-risk of TARCEVA as maintenance treatment in patients with advanced non-small cell lung cancer (NSCLC) whose tumours do not have an epidermal growth factor receptor (EGFR) activating mutation is not considered favourable.
TARCEVA is not effective for maintenance treatment in patients with locally advanced or metastatic NSCLC whose tumours do not have an EGFR activating mutation.
The Canadian prescribing and consumer information for TARCEVA will be updated to reflect the new data.
A recent study, IUNO (B025460), demonstrated that the benefit-risk of using TARCEVA for maintenance treatment after 4 cycles of standard platinum-based first line chemotherapy in patients with locally advanced or metastatic NSCLC whose tumours do not have an EGFR activating mutation is negative.
June 7, 2016 — DOJ Settlement Regarding Tarceva
“We believe our Tarceva promotional communications and practices were and are entirely proper and in compliance with the law,” said Andrew Villani, a Genentech spokesman.
The lawsuit claimed that from 2006 to 2011 Genentech and its marketing partner OSI Pharmaceuticals promoted Tarceva to treat all patients with non-small-cell lung cancer even though studies had shown that it worked for just those who had never smoked or had a certain gene mutation known as EGFR. Epidermal growth factor receptor is a type of protein found on the surface of cells in the body.
June 27, 2016 — Genentech and OSI sent IMPORTANT CORRECTION OF DRUG INFORMATION to Healthcare Professionals
The US prescribing information will be revised to limit non-small cell lung cancer (NSCLC) indications to patients with epidermal growth
factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitutions. This action is being taken as a result of the IUNO study which failed to demonstrate efficacy in patients with EGFR wild-type NSCLC in the maintenance setting.
October 18, 2016 — The FDA Changed the Tarceva Indication Based on the IUNO Trial
The trial’s primary endpoint was overall survival. Results demonstrated that survival following treatment with erlotinib was not better than placebo administered as maintenance in patients with metastatic NSCLC tumors not harboring EGFR-activating mutations. No difference in progression-free survival between the erlotinib arm and the placebo arm was observed.
October 18, 2016
Results revealed no significant improvement in OS or PFS among those assigned erlotinib compared with placebo.
