It’s been almost 20 years since the FDA approved a group of New Drug Applications (NDA) and Biologic License Applications (BLA) as large as the class of ’15. The 45 approved drugs represent a 10% increase over the prior year and an increase of 114% from the beginning of the decade. What accounts for this increase and how modeling and simulation has impacted the rise in approvals is the subject of this article.
New drugs approved in 2015, by the numbers
Aside from the size of the class, there were several notable trends and accomplishments:
- 14 drugs, representing 31% of the total, were approved for oncology. This compares with just 2 such drugs in 2010, pointing to the phenomenal scientific breakthroughs in combatting cancer that have been achieved in recent years.
- 21 drugs, representing almost half of all approved drugs in 2015, were for the treatment of orphan or rare diseases. Thanks to a combination of regulatory and commercial incentives, along with scientific development, this category of drugs has been steadily increasing over the decade. Additionally, about half of these drugs are for specific cancer indications, portending our movement away from the ‘one size fits all’ drug development of the past to today’s narrowing of segmentation (stratified populations), on our way to personalized medicine.
- 16 drugs were considered ‘first in class,’ which means that they have a mechanism of action that is different from existing therapies. An analysis of the origins of all 113 first-in-class drugs approved by the FDA from 1999 to 2013 showed that the majority were discovered through target-based approaches.
- 25 drugs, or 56% benefited from one or more of the agency’s programs used to expedite the approval of drugs and biologics for meeting unmet medical needs. Those programs are accelerated approval, fast track designation, priority review, and breakthrough therapy designation.
- 10 drugs were approved under FDA’s most recent program, the designation of breakthrough therapy. This program, which was authorized under 2012’s FDASIA, saw the first use of this mechanism in 2013 with Vertex’ cystic fibrosis drugs.
FDA Novel Drug Approvals for 2015. FDA website
Where did modeling and simulation fit in the class of 2015?
Modeling and simulation technology continues to have a profound impact on drug development, for informing key decisions and for labeling. As we have discussed, the key benefits of modeling and simulation are many, including
- Making data-driven decisions at all stages of drug development through a quantitative framework;
- Using innovative strategies like model-based meta-analysis (MBMA) to make better use of available data, resulting in increased knowledge and better decision making in clinical development;
- Designing safer, targeted, and more efficient trials;
- In some cases, eliminating the need for clinical trials;
- Selecting the right dose for the right patients, the first time;
- Simulating virtual patients in hard to recruit or test patient populations, such as pediatric, pregnant women, elderly and/or organ-impaired;
- Maximizing the probability of commercial success
Upon review of the 45 drugs in the class of ’15, 91% had clearly used population pharmacokinetics (PopPK) and/or physiologically-based pharmacokinetic (PBPK) modeling (as documented within the Office of Clinical Pharmacology reports) to inform that drug label. This trend certainly aligns with the guidance documents emerging from global regulators, starting with the 1999 FDA guidance on the use of population pharmacokinetic analysis.
Certara’s role in 2015
Certara has played a prominent role in supporting the approvals for the class of ’15. We are honored and humbled by these facts:
- Certara participated in the drug development programs for 40% of all approvals, through our Certara Strategic Consulting, Simcyp PBPK, or Synchrogenix Regulatory Writing units.
- Of those approvals, our work impacted 6 out of 14 in oncology; 9 out of 21 for rare diseases/orphan drugs, and 4 out of 10 breakthrough drugs. These data make sense when considering the clear benefits of modeling and simulation for these difficult to test populations, along with the agency’s openness to alternative drug development strategies.
- Of the 91% of drugs identified as using modeling and simulation (PopPK or PBPK specifically), almost all rely on Certara’s Phoenix WinNonlin software— for either toxicological, NCA or PopPK work— and several labels cited the use of that software for bioequivalence studies.
Leveraging modeling and simulation technology to facilitate obtaining approval for a targeted cancer treatment
We have selected one of the class of ’15 to expand upon. In this case study, Certara leveraged its modeling and simulation technology to facilitate obtaining regulatory approval for a targeted combination treatment for melanoma. This drug combination also received orphan status.
Cancer cells have a remarkable ability to become resistant to targeted therapies. Combining two or more therapies that target different parts of a cellular signaling pathway can help to address this challenge.
To gain approval for the drug combination, the sponsor needed to understand the pharmacokinetics and exposure-response relationship of the two drugs to develop an optimal dosing strategy. They also needed to determine whether patients with certain characteristics, such as organ impairment, might require dose adjustment. Another crucial step was to assess the potential for drug-drug interactions (DDIs).
Certara Strategic Consulting scientists worked with the sponsor by developing exposure-response, concentration-QT, and population PK models to inform the dosing strategy, define the exposure-response relationship of the combination therapy, determine if it could cause cardiotoxicity, and gain FDA approval. The Simcyp Simulator was leveraged for in silico DDI studies, with the agency accepting the PBPK model results in lieu of actual studies for 16 potential DDI scenarios.