Health Policy

The FDA’s Culture: Should Safety Dominate All Practices?

By STEVEN ZECOLA

An organization’s culture is an internal set of shared values, attitudes and practices. The cohesiveness of the organizational culture will affect whether the entity will meet its vision, purpose, and goals.

One type of organizational culture is hierarchical in nature.   Unlike a risk-taking culture, this structure features policy, process and precision. It is best suited for mature and stable organizations.

The disadvantage of a hierarchal culture is that its stability and control can turn into rigidity. In many cases, the organization develops a negative attitude towards ideas supplied by third parties. It paints itself as having the perfect answer for every issue, no matter how large or small.

My interactions with the FDA suggest that its cultural practices are focused on safety, seemingly to the exclusion of all other issues.  This practice may be appropriate in the regulation of food, but not for drug research where flexibility and creativity are required to cure complex diseases.

Over the past decade, I have witnessed an excessive adherence to its existing practices in the context of BRCA1-related breast cancer, metastatic cancer, precision medicines, “Big Data” and Parkinson’s disease. While the rulings were directed at me, the FDA’s position on these issues has impacted millions of people for the worse.

My first interaction with the FDA came when my fiancée was diagnosed with breast cancer and received the news that she had a BCRA1 mutation.  As is the case for most BCRA1 carriers, she was also diagnosed as Triple-Negative, implying a more aggressive form of cancer with fewer approved pathways for treatment.

She reluctantly accepted the recommendation to undergo a double mastectomy and a chemotherapy regime consisting of Adriamycin, Cytoxan and Taxol (ACT).

ACT is a powerful concoction that has a deleterious effect on many parts of the body, including one’s hair. Patients wonder out loud if it is worth the bother.

Hearing that feedback, I began looking into the research to see if there were any alternatives in the pipeline. At the time, there was some encouraging news coming out of the early trials with PARP inhibitors and platinum-based drugs for BRCA1 victims.

Additionally, I realized that only one trial had been designed to show the effect of ACT on BRCA1 cancer victims as opposed to the broader class of Triple-Negative victims.  Looking at raw data, BRCA1 victims were worse off than non-BRCA1 victims when receiving ACT.

I then Petitioned the FDA to change its approach.  My fiancée was up to her third bout of metastatic cancer and it seemed that ACT was the culprit, and even if not, it was causing much pain without much benefit.

Luckily, she managed to get into a trial featuring Olaparib. Within months, the tumors completely disappeared.   However, the potency of Olaparib wears off after a couple of years and the bouts of metastatic cancer returned. She died at the age of 57 from her eighth bout of cancer that had metastasized to the brain.  It was the same age that her mother had died of the same cause.

Meanwhile, the FDA was busy defending its approach. It produced a 12-page letter rejecting my petition. It contained several non sequiturs and outright falsehoods to support its position, including:

“But the prognostic significance of having a BRCA mutation is not clear” and “it is not completely understood how similar BRC1-related breast cancers are to non-BRCA1 breast cancers”. FDA Letter, page 6.

“There are side effects with all chemotherapeutic agents (not just ACT).  In addition, you have not presented any evidence suggesting that side effects are more deleterious in BRCA1 patients being treated with ACT drugs than in other patients”.  FDA Letter, page 7.

“Given that adjuvant treatment was not assigned, it is not statistically valid to compare the survival rates of the 24 BRCA-1 patients who received chemotherapy and the 17 patients who did not receive chemotherapy”. FDA Letter, page 7.

“There is no evidence, however, that the deleterious effect of ACT on DNA in BRCA1 mutations is greater than the deleterious effect caused by other agents (e.g., platinum-based chemotherapy agents).”  FDA Letter, page 8.

“We do not agree with your claim that the results of any clinical trial of TNBC cannot be applied with statistical validity to the BRCA1 subcategory of TNBC unless that subcategory is specifically separated out and monitored.” FDA Letter, page 9.

I believe that all of these statements have been proven to be false.  Certainly, the author’s understanding of multivariable statistics is lacking. More importantly, the drug Lynparza® (Olaparib) has since been approved by the FDA for patients with metastatic breast cancer who have inherited mutations in the BRCA1 gene.

In reality, there was enough information for the FDA to be flexible and responsive to BRCA1 cancer victims before Lynparza was approved.   Over 500,000 women would have lived longer and with less pain if the FDA did not rigidly apply its cultural norms to the situation.

My second encounter with the FDA unsurprisingly involved metastatic cancer.  I noticed that only 8% of government spending on cancer research was directed to metastatic cancer but that 90% of the deaths from cancer were from metastatic cancer.  I suggested that the FDA champion an increase to 15% of the funding and to establish a separate center to raise the visibility and focus on this very efficient killer. I also suggested a modification of the standard FDA approval process for metastatic cancer.

The FDA responded with a seven-page letter denying my request.

The FDA wrote that their regulations “do not prescribe any particular type of trial design” and “nothing…requires that drugs undergo testing in distinct phases”.  

The FDA said: “in addition to flexibility in designing clinical trials, FDA has various other programs to expedite development and review of new drugs including…metastatic cancer”.

It added: “The Agency reorganized its oncology review office in 2011….and does not believe that its current structure lacks ‘sufficient organizational structure’ on metastatic disease, is inefficient, or otherwise impedes the conduct of clinical trials for…. metastatic cancer”.

These statements reflect an Agency that is in denial of reality. The reality is that eight years after this letter was written, the goal posts for metastatic cancer have not moved appreciably. Virtually all drug candidates go through multiple phases before approval. It is a long and costly process.

The budgets for metastatic cancer remain underfunded in general and in relation to other cancer targets. Metastatic cancer continues to be bad news no matter how you slice it.  Whatever the FDA is doing for metastatic cancer, it is far from perfect and hardly enough.

My third encounter with the FDA relates to precision medicines. In his 2015 State of the Union address, President Obama announced the launch of the Precision Medicine initiative “to revolutionize how we improve health and treat disease”. The White House subsequently specified that the Initiative “will include reviewing the current regulatory landscape to determine whether changes are needed to support the development of this new research and care model”. White House Fact Sheet: January 30, 2015.

On September 17, 2015, under the leadership of the NIH Director, the Precision Medicine Initiative Working Group recommended the creation of a national research participant group (a cohort) that would lead to trials of precision therapies, among other things.

In February 2016, I filed a Petition for the FDA to initiate a rulemaking seeking, legal, economic, scientific input on how best to analyze and approve new Precision Medicine Initiatives.

In March 2020, I received a letter denying my Petition.  The FDA said that “between 2013 and 2018, 76 out of 240 novel new drugs approved (31.7%) would likely be considered precision medicines…Additionally, we note that FDA currently employs many vehicles and authorities to encourage drug development”.

The FDA relies upon a serious case of tunnel vision to miss the point. There are likely to be several breakthrough findings emanating from the data in the cohort, but the sponsors of the research findings will need to deal with the FDA’s existing regulatory process.   I don’t think that is what President Obama had in mind when he said the PMI would: “revolutionize how we improve health and treat disease”.  The ensuing applications will take years if not decades to gain FDA approval at a cost of over $1 billion per approved drug. 

My fourth entanglement with the FDA revolved around “Big Data”.  More specifically, researchers collaborating between China and Iowa had found a correlation between Terazosin and Parkinson’s disease.  This was not a trial.  It was what actually happened in the real world. Terazosin had been approved 30 years ago for prostate issues.  The researchers then tracked what effect Terazosin had on the incidence of Parkinson’s and the progression of the disease.  The results were noticeably beneficial on both scores.  This is exactly the type of breakthrough that “Big Data” had promised (presuming the results are not fraudulent).

Despite this fantastic news, I saw little activity around Terazosin so I filed a Freedom of Information Act request with the FDA to determine if the FDA was putting unwarranted burdens on Terazosin before it could be used in the filing of an IND.

I received a phone call denying my request.  The caller said my request would be rejected orally so that no processing fee would be applied.

As a point of reference, FDA’s website says that “if a request for records is denied, a letter of explanation will be sent to the requester, who has the right to appeal the denial”.  This language reflects the wording of federal law.  No such letter was sent.

My fifth and less formal interaction with the FDA transpired with a senior executive to whom I had suggested that not much progress had been made in finding a cure for Parkinson’s disease since I had been diagnosed with the disease over twenty years ago.

I was told that: “Parkinson’s disease research is a very vibrant scientific field. There are a number of different streams of research that are ongoing that we hope will lead to highly impactful therapies…We have frequent communications with all of the U.S. Parkinson’s disease organizations, the Parkinson’s Study Group, academic investigators, and we coordinate on a variety of projects. The NIH system of funding the most meritorious projects has substantially increased our knowledge of Parkinson’s. Our failures in bringing treatments to the goal line are due to remaining large gaps in knowledge of the underlying biology that causes and drives the disease. As we fill in these gaps, the chances of success will increase. Some of the gaps we know about, others we only find out about when the science opens another door”.

While these remarks are sincere, the reality is that there is no plan with tangible steps to find a cure for Parkinson’s disease by a reasonably attainable target date.  The agency appears to be tone deaf to the negative impact that it perpetuates upon the cost and delays of research.

Do these instances provide a basis for concluding the nature of the FDA’s culture?  I think not, but I believe that The House Committee on Oversight and Reform should investigate the FDA’s culture and its practices to determine if the behavior described herein is the exception or the rule.  If the Committee members get answers to their questions that suggest what the FDA is doing is perfect or near perfect, they will have the answer.  The end-result will be that the FDA will not listen to outside ideas or change its practices.  This is particularly harmful in the area of drug research.

My view is that the FDA ignores the “big picture” of the massive hurdles to research it has created by its practices. The rigidity surrounding the practice of safety has overwhelmed the flexibility and creativity needed to cure complex diseases. The cultural trait of believing it has the perfect approach produces results that are nowhere near perfect and its practices – if left unchecked — will continue to bog down progress in the healthcare industry.

Steven Zecola is the managing director of Competitive Strategies and has held executive positions in large companies and the federal government.

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