Trends in FDA Approvals for Sarcoma

Where are we going?

Obligatory—this is not medical advice

Previously, I have reviewed many of the subtypes of conditions which exist within bone and soft tissue sarcomas. Altogether, this accounts for approximately 20,000 patients annually, but these patients are divided into an excess of 100 separate diagnoses which can behave entirely differently. While there have been some major strides forward within the field, and I will enumerate many of them later in this article, nonetheless, a lack of focus in application of novel agents has ultimately led to inconclusive results in many instances. A consequence of this is that many trials will not meet their primary endpoints. Trials which have led to Food and Drug Administration (FDA) approval have been more selective in the histologies that they enroll. We need more of these trials.

What is FDA approval?

Information regarding the FDA drug approval process is available online. That is not to say that it is all readily interpretable, or easily digested. Rather, it is present. One of the better infographics that I have found, which strikes the correct balance between comprehensiveness and legibility is here.

https://www.fda.gov/drugs/information-consumers-and-patients-drugs/fda-drug-approval-process-infographic-vertical. Accessed 7/8/2023

In essence, approval requires a sequence of steps, and these are not necessarily exact, but must stand to scrutiny of the agency along the way.

1. A drug compound is developed

   1. This can be a protracted and scientifically intensive process, but is getting easier all the time, and will presumably advance further with the creation of novel computational techniques.¹

2. It undergoes preliminary in vivo testing

3. Applications proceed for creation of clinical trials

4. Clinical trials accrue/mature

5. Results are reviewed

6. Further applications are submitted and analyzed and final operational steps are taken

The culmination of all of the aforementioned is marketing approval within the United States. The implications of marketing approval are that the medication may be sold, after prescription, to patients and, given the vagaries of the United States, in fact directly marketed to those individuals.

Many, but not all, of these medications go on to be highly profitable. What I have left out, but is common knowledge, is that only a small handful of those medications which enter the aforementioned pipeline are able to scurry through the whole maze—that is ultimately garner approval. Some have shown that, despite this, given the statistical hurdles to clear, the pharmaceutical industry remains uniquely lucrative.²

What is FDA approved for Sarcoma?

Below, I have listed each individual FDA approved medication within sarcoma. This is not to say that non-approved medications (especially those that might have been studied in differing settings, or in the early days of oncology) would not be appropriate therapy. Many non-FDA approved treatments have actually been well studied in clinical trials.³ In fact, in many instances non-FDA approved treatments are preferred.⁴

Evaluating this list, there are some treatments, clearly, that are much more effective than others. Many of the trials that ultimately led to approval were of varying quality. Nonetheless, the trend that I notice is that those medications which ultimately received FDA approval tend to be in more focused populations. GIST and AIDS-related Kaposi sarcoma are standouts here. There are multiple arguments for why that might be, but that would be beyond the scope of this post. Most importantly, investigators studying those conditions ably accrued a critical mass of patients with rare conditions and robustly overcame an established endpoint. See more about GIST in this article.

For this reason, and many others, it is my expectation that if our desire as a field is to continue to build and fundamentally improve the treatment for our patients, we need to continue to work to narrow our studies. Many will remark on how ‘hard’ this might be ostensibly. I certainly here that, and as someone in the field, I know it to be true. Nonetheless, scattered studies without clear endpoints or populations has not led to FDA approvals, nor tremendous leaps in the care for our patients.

A principle example of what I expect to be a tremendous leap forward for patients with desmoids was the DeFI trial, which I have also reviewed here. It clearly answered numerous questions regarding the efficacy of therapy for a population of patients who required treatment. One may certainly debate about the results, but they do advance our understanding.

Final Thoughts

The treatment of patients with sarcoma is built on the history of well-defined clinical trials. The future, I presume, will likewise require well crafted and exacting studies. Given the incidence of each individual sarcoma diagnosis, these trials will require either novel mechanisms for recruitment/enrollment or more time to assess their endpoints. As clinicians and investigators, we should expect this. The result will be better outcomes and knowledge for our patients.

1. https://www.nature.com/articles/s41586-021-03819-2

2. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2653012

3. https://pubmed.ncbi.nlm.nih.gov/28882536/

4. https://www.nccn.org/home