2018/2019 Oncology Drug FDA Approvals Notifications
Implications for Early Phase Clinical Trials
Dr. Wael Harb & Wes Chapman
August 18, 2019
Illustration of an immune system T cell killing a cancer cell
“The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured. Also called complete remission.” NCI
I read it, re-read it, then went to look up the meaning of complete response rate – and my memory had not deceived me.
I was reading about the Tisagenlecleucel Phase II trial (KYMRIAH, Novartis Pharmaceuticals Corp) back in August of 2017, with a reported complete response rate of 82.5%. This was a 63 patient trial with relapsed or refractory pediatric precursor B-cell ALL, including 35 patients who had a prior hematopoietic stem-cell transplantation. Patients received a single dose of Tisagenlecleucel intravenously within 2 to 14 days following the completion of lymphodepleting chemotherapy. This trial introduced a particularly promising class of therapy know as CAR T-cell technology.
Translation into layman terms – these were very sick kids with a very bad leukemia and little hope, 82.5% of whom were rendered disease free with one dose. That’s right – an 82.5% complete response rate – with a single dose. The treatment was not without risk – these kids were generally made very sick by the treatment, with serious (grade 3&4) adverse events caused by a systemic inflammatory release syndrome related problem called cytokine release syndrome.
But they were alive, in complete remission, headed home from the hospital, and all of this from a Phase II clinical trial. I had been involved with clinical trials for oncology for the last 15 years, and had generally regarded Phase II trials as a form of scientific purgatory – trapped between the first in man Phase I “dosing trials” , and the huge (thousands of patients) Phase III trials, designed for FDA approval.
I suspected that two things were changing simultaneously – it appeared that the drugs were much more efficacious and broadly applicable than in the past, and that early phase (I & II) trials were becoming the new launch pad for FDA approval. I had heard discussions about this with physician researchers regarding the new class of drug based on immune therapies – drugs called check point inhibitors – but really hadn’t investigated how these new drugs were impacting the fabric of oncology clinical trials. A corollary avenue of analysis was to analyze if the efforts made by the FDA to accommodate more rapid utilization of data to safely accelerate the approval of particularly efficacious drugs.
Shortly after the Kymriah announcement, Dr. Harb and I formed Verdi Oncology with the financial support of Pharos Capital, and we had an active and rapidly growing presence in early phase clinical trials through Horizon Oncology Research, based in Lafayette Indiana. Horizon had long participated in early phase clinical trials, participating in dozens of early phase trials, nine of which resulted in FDA drug approvals.
My experience in oncology clinical trials began with my last company, Medical Media Systems, in the early part of the last decade, largely doing secondary reads of radiographic images, to help determine surrogate endpoints related to the timing and duration of tumor response for phase 3 oncology trials. Required reading to understand what we were doing as part of these trials included a terrific paper, End Points and United States Food and Drug Administration Approval of Oncology Drugs, John R. Johnson, Grant Williams, and Richard Pazdur, Journal of Clinical Oncology, Vol 21, No 7 (April 1), 2003: pp 1404-1411.
This paper is a comprehensive review over a 13-year period (January 1, 1990 through November 2002) of all oncology drug approvals in the period – 71 during the period (about 5.5 per year on average). The 71 approvals included 14 drugs approved by the accelerated approval (AA) method allowed by regulations promulgated by the FDA in 1992. The paper really looked at the performance of surrogate endpoints, and therefore the AA process relative to regular approval used in the past.
Since the publication of the paper, there has been a general acceptance of expedited approval methods as effective means of getting new and promising drugs into use, while providing a reliable mechanism to ensure proper testing for safety and efficacy in subsequent larger confirmatory trials.
Targeted cancer therapy was initiated in the 1970’s with the introduction of tamoxifen, a drug that interferes with estrogen’s ability to stimulate cancer growth in ER-positive breast cancer. The approval of imatinib mesylate (Gleevec) in May of 2001 is noted as the first approval of a rationally designed, molecularly targeted therapy. Gleevec, a very successful therapy used on Philadelphia chromosome-positive CML and GIST cancers, was approved using AA and a single phase one trial of 83 patients, paired with three roughly simultaneous phase 2 trials totaling 1027 patients. The FDA approved ipilimumab (Yervoy) in March of 2011, the first checkpoint antibody (immunotherapy), for the treatment of melanoma. The approval was based on a phase 3 trial with 1783 participants.
The increasing number and efficacy of the new targeted therapies and immunotherapies has contributed to changes in the regulatory approval process by the FDA, and is leading to a sea change in how clinical trials are conducted in oncology.
The FDA recognized the critical need for patients to have access to effective therapies at the earliest possible opportunity, and created a number of mechanisms for patients to get access to drugs sooner than the traditional approval process allowed. The tools available to get more rapid patient access include:
- Accelerated approval, created in 1992, regulations that allow drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint.
- Fast track; created in 1997, a process designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need.
- Priority Review; created in 2007, designation means FDA’s goal is to act on an application within 6 months.
- Breakthrough therapy; created in 2012, a process designed to expedite the development and review of drugs which may demonstrate substantial improvement over available therapy.
- The real time oncology review pilot (RTOR) begun in 2019 to facilitate much earlier review of trial data for high potential drugs in straightforward studies using easily interpreted endpoints.
Finally, as oncology drug development has increasingly focused on specific genetic disorders, more of these drugs are focused on a small number of patients. Accordingly, these drugs are also frequently accorded Orphan Drug Status by the FDA, which provides certain tax credits for their clinical development and other commercial advantages.
The FDA has adopted a practical and balanced view regarding the design and implementation of clinical trials to be responsive to:
- Patient needs for new, safe and efficacious therapies
- The need for open and vigorous debate over evolving trial design and scientific criteria
- The need for safety and efficacy of those therapies validated by ongoing rigorous scientific analysis, and
- A scientific approach to the development and validation of surrogate endpoints in clinical trials.
In commenting on this ongoing effort, Dr. Scott Gottlieb, Commissioner of the FDA commented,” Applying the most efficient clinical trial designs and using meaningful endpoints that measure benefits important to patients is key to our efforts to modernize clinical trial development programs.”
Johnson’s paper begged a lot of questions about changes since 2002, and answers weren’t readily apparent about present conditions, so we decided to look at all oncology drugs approved since 2016, and see if there was an increase in:
- Total approvals – if drug discovery was accelerating this should be the most basic measure increasing over time
- Novel compounds being discovered
- The increase use of Phase I and II trials in oncology drug approvals
- The growth and absolute number of drugs being approved in accelerated and other expedited programs
- The success and growth of combination drug trials
- The type of drug/trial being approved, broken down into immune therapy, targeted biological, combination trial, immune/combination trials, hematological drugs, chemotherapeutic drugs, and CAR T based therapies, and
- The addition of metrics of noteworthy clinical effectiveness from a physician/patient perspective rather than simply the statistical requirements for approval. Did these drugs have the potential materially improve patient care? These measures are based on practical experience of Dr. Harb and his team and are outlined below.
|Progression Free Survival Advantage Months (PFS)||>6 months|
|Complete Remission + Incomplete Remission Advantage %||>15% advantage|
|Reduction of risk of disease progression||>25%|
|Overall Survival Advantage (months)||>2 months|
|Objective Response Rate||>50%|
|Disease free survival advantage%||>25%|
|Overall Response Rate||>50%|
|Complete response rate||>1%|
|Recurrence Free Survival Advantage (RFS)||>10%|
|Overall Response Rate Advantage %||>25%|
We based our research on the annual lists of oncology & hematology approvals from the FDA since 2016 through the first half of 2019, reduced slightly by the elimination of selected hematology only drugs and drugs designed for symptom relief. Many drugs had multiple approvals over the period, and all approvals are included herein:
|Time Period||2019 (Q1+Q2)||2018||2017||2016|
|Total Oncology Drug Approvals||22||52
|Novel Oncology Compounds||4||15||14||1|
|Secondary Approvals of Previously Approved Drugs||18||35||32||19|
|Other Related Approvals (Bio sims)||0||2||2||0|
|Phase 1&2 Approvals||5||20||22||7|
|Other Expedited Approvals||19||40||39||15|
|Combination Drug Trials||7||17||9||5|
Total oncology drug approval clearly increased every year over the period considered, reflecting an increased pace of both new compound approval and increased multiple approvals for previously approved compounds over the 3.5 years considered. Specifically, total oncology drug approvals increased on average by 809% from the 5.5 per year average during the period from 1990 to 2002, compared to the last two complete years – 2017 and 2018. A longer view confirms this apparent trend:
|Total Oncology Drug Approvals||32||19||17||19||15||10|
Change in trial design, dramatic increases in the number and efficacy of targeted biological drugs and the very broad applicability of many immune therapy drugs has resulted in a dramatic increase in the number of approvals of certain drugs in the periods examined. Two of the most commercially successful immune based drugs, OPDIVO (Bristol-Myers Squibb) and Keytruda (Merck & Co.) account for 10 and 14 approvals respectively in the period – almost half of the 49 total multiple approvals.
It is important to note that one of the Keytruda approvals, May 23, 2017, was the first example of a tissue-agnostic FDA approval of a treatment based on a patient’s tumor biomarker status, rather than on tumor histology. As discussed in the Journal for ImmunoTherapy of Cancer (2018;6:35), “ The discovery and validation of immune checkpoints (signal-transducing pathways that modulate immune system activity) as therapeutic targets has transformed cancer immunotherapy… This first FDA approval of a therapy based on tumor biomarker status aligns with the clinical vision of precision medicine—highly individualized, customizable health care that many believe is the future of cancer diagnosis and treatment. Oncologic precision medicine involves screening for, and selecting therapies based on, an individual’s tumor-specific biomarkers to enhance clinical outcomes and minimize adverse events.”
|Applicant Identifier||2019 YTD||2018||2017||2016||Total Approvals in Period|
|OPDIVO, Bristol-Myers Squibb||0||3||4||3||10|
|Cabometyx, Exelixis, Inc||1||2||3|
|Gazyva Injection, Genentech, Inc||0||0||1||1||2|
|KEYTRUDA, Merck & Co||4||3||5||2||14|
|BAVENCIO, EMD Serono||1||0||2||0||3|
|IBRANCE, Pfizer Inc||0||0||1||1||2|
|Revlimid, Celgene Corp||0||0||1||1||2|
|TECENTRIQ, Genentech Oncology||2||1||0||2||5|
|VENCLEXTA, AbbVie Inc. and Genentech Inc.||1||2||0||1||4|
|DARZALEX, Janssen Biotech, Inc||1||0||0||1||2|
|Erlotinib||TARCEVA, Astellas Pharm Global||0||0||0||2||2|
Phase 1 and 2 approvals have continued to grow during the period, with growth in novel compound approvals:
|Number of novel
Phase 1 and 2 approvals have continued to grow during the period, with growth in total drug approvals:
|Total number of
Perhaps most striking, is the growth and noteworthy effectiveness of immune therapies and targeted biological therapies, together with the nearly complete absence of cytotoxin based chemotherapies (only 2 of 143 approvals analyzed in the period) approved in the 3.5 year period.
Total approvals by Drug Type
|Drug Type||2019 Approvals (Q1&Q2)||2018||2017||2016||Total in Period|
Total approvals: Novel Drugs
|Drug Type||2019 Approvals (Q1&Q2)||2018||2017||2016||Total in Period|
Total approvals: Noteworthy Effectiveness
|Drug Type||2019 Approvals (Q1&Q2)||2018||2017||2016||Total in Period|
Note: Several trials had multiple noteworthy effectiveness metrics.
Oncology drug approvals over the last 3.5 years have grown by all relevant metrics:
- Total number of compounds approved
- Total number of novel compounds approved
- Increased use of expedited approval methods
- Increase in multiple approvals for individual compounds
- Increased use of combination trials
- Increased noteworthy effectiveness
- Growth in early phase trials – particularly Phase 1, and
- Tumor agnostic approvals based on molecular markers Keytruda and Opdivo: microsatellite instability-high (MSI-H) or mismatch repair deficient, VITRAKVI (larotrectinib) with a neurotrophic receptor tyrosine kinase (NTRK) gene fusion
Analysis and Conclusions
Clinical trials in medical oncology are responding to changes in drug therapy mechanisms of action, from the chemotherapy of the 60’s and 70’s, targeted therapies beginning with tamoxifen in the 70’s, rationally designed, molecularly targeted therapy (Gleevec) in 2001, immunotherapies known as checkpoint inhibitors (Yervoy in 2011, and finally CAR T-Cell therapy first approved in 2017.
The changes in drug mechanisms of action has increased the potential for new drug design and discovery, which is clearly reflected in the increase in rate of oncology drug approvals from the 90’s (around 5.5 per year) to an average of 50 drug approvals per year in the last two years. During the 13 year period of the study by Johnson et al, a total of 45 novel compounds were discovered over the 13 year period (around 3.5 per year), versus an average of around 15 for the last two years.
The FDA has worked with patient advocates, industry and scientific bodies to examine new and more efficacious ways to approve drugs. It is striking that over half of the novel compounds approved in the last two years have been in phase 1 or phase 2 trials. This methodology dramatically reduces the time to launch a drug into the general population, and reduces the cost to the manufacturer to bring the drug to market. The requirement in all of these approvals for trials to confirm safety and efficacy with larger subsequent trials ensures the integrity of the system.
The vast majority of drug approvals today are based on one or more forms of expedited approval, and the number of surrogate endpoints is expanding. Based on our criteria for noteworthy effectiveness, the majority of new drugs deliver benefits relevant to patients – particularly the targeted biologicals.
The world of oncology clinical trials is evolving to deliver increasing numbers of highly efficacious drugs to patients. The increased use of early phase trials for approvals is opening access to those drugs much sooner than was available before. The rate of discovery, as evidenced by the number of approvals and efficacy of the drugs clearly indicates accelerating rates of scientific discovery and drug therapy development.
And all of this is good news for patients.