Drug discovery research is one of the most high-risk ventures of 21st century, millions can be spent on materials, employees, and clinical design. Potentially risking an entire business venture on a single drug, it’s a path not traveled by many business owners or CEOs. In my blog post series, I will highlight key considerations for the essential role of knowledge management in mitigating risk early and throughout the phases of drug discovery and making successive gains toward obtaining approval of IND applications.
Background
IND applications are the first steps taken by researchers and sponsors to gain the legal status to proceed with human clinical trials.[3] The future outcomes or the financial success of biopharmaceutical companies or startups depend directly the success of IND applications. Begging the question by many CEOs, CSOs, or CTOs, “Why do Investigational New Drug Applications fail?” Exploring this question in more depth and reflecting carefully on the key areas for improvement in your IND application can reveal the insight necessary to overcome the approval process.
From the beginning of 2020 to end of 2021, a total of 7,569 Investigational New Drug (IND) applications were submitted to the FDA for clinical trials approval, sourced from FDA-TRACK., the FDA’s agency-wide performance management system. [1] The FDA’s response was strong with total of 8,888 actions taken, either providing recommendations for changes or denying IND applications. Many failed to meet approval.
The pharmaceutical industry and numerous consulting companies spend a large amount of time, focus, and research on the clinical trials, $1.3 billion are spent on average to obtain a new drug approval.[2] An entire business ecosystem of companies with a plethora of products exists for clinical trials, NDA (New Drug Application), and BLA (Biological License applications). However, the IND phase and preclinical trials are only serviced by a few niche companies, who actively explore that question Criterion edge, Nuventra, or Veristat.
Lack of Public Information about the IND Application Process
However, there is a distinct lack of or a minimal amount of scientific literature on IND application process which pales in comparison to clinical trial success rates of New Drug Applications (NDAs) or Biological License applications (BLAs). Only a few publications, have provided a statistical answer to the question, such as “Scientific and Regulatory Reasons for Delay and Denial of FDA Approval of Initial Applications for New Drugs, 2000-2012”.[4]
Figure 1. Screen shot of “Scientific and Regulatory Reasons for Delay and Denial of FDA Approval of Initial Applications for New Drugs, 2000-2012”. [4]
The paper identifies the potential factors for the denial of IND applications. This study still does not cover all drug applications including branded, generics, supplementary drug applications, or biological applications. Only showing “therapeutics for new molecular entities (NMEs) submitted to the FDA”. Describing (NMEs) as tablets, suspensions, or injectables. The study utilized statistical text-analysis on FDA action letters to come to its findings.[4] Action letters are a direct explanation, as to why the study failed. The paper defines these as categorial reasons for failure or denial.
1) Efficacy (pharmacokinetic, pharmacodynamic)
2) Safety (Toxicological Studies)
3) Chemistry, Manufacturing and Controls (CMC)
4) Product Labels (Unable to determine suitable dose for drug labeling)
The following table outlines other major reasons that are defined in the study.
Figure 2. filtered table of “Scientific and Regulatory Reasons for Delay and Denial of FDA Approval of Initial Applications for New Drugs, 2000-2012”.[4]
Less Relevant Data and Fewer Analyses Is Currently a Reality
Performing experiments is very costly and time-consuming in drug discovery, so companies may have to rely less preclinical data and fewer analyses to back their claims for IND applications. Beyond having potentially limited data, the quality and format of the data may not be in a ready state to support and manage their data from the earlier through to the later phases of drug discovery before applying for regulatory clearance. A strategy is required, involving knowledge management, through all phases of drug discovery and pre-clinical development in readiness for the IND application process to ensure data integrity and allow you to back/solidify your claims.
IND applications require collaboration by a drug discovery team with diverse areas of expertise to develop a target product profile (TPP) or development strategy for a drug article with a clinical plan for dose and dose regimen. Generally, the types of data and information fall into the following categories:
- Pharmacodynamics, Pharmacokinetics, and Toxicology Studies
Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans. - Manufacturing Information about the Chemistry, Manufacturing, and Controls used for manufacturing the drug substance and the drug product. This information is assessed as to ensure the company can adequately produce batch consistency in the supply of the drug.
- Drug Labeling Investigational new drugs require labeling with “Caution: New Drug – Limited by Federal Law to investigational use.” by CFR Part 312. No misleading statements nor indications of the drug being safe or effective. Since it hasn’t passed clinical approval.
- Clinical Protocols and Investigator Information and Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks. Also, information on the qualifications of clinical investigators at clinical study sites, who oversee the administration of the experimental compound to assess whether they are qualified to fulfill their clinical trial responsibilities.
Inconsistent results for endpoints or misrepresentations of endpoints can cause the FDA to respond unfavorably with actions and significantly affect your relationship with the FDA. Knowledge management is key to maintaining and preventing inconsistent results from separate study sites. Consolidating the dataset, protocols, and models into one repository or unifying your intellectual property or your knowledge asset. Early pharmaceutical companies can leverage knowledge into their advantage in negotiations.
However, since the amount of public information on the approval process of IND applications is very limited. I want to provide some resources so you can obtain more public information about IND applications on your own for research or data mining purposes.
The ability to explore how other IND applications failed to gain approval can provide valuable insight about tracing the failure back to its root cause within the drug discovery and development process. Being better prepared in advance with insights into the approval process along with cultivating a knowledge management strategy for your research and experimental data will position you and your company for a much higher probability of success.
Understanding the FDA’s Markers for IND Applications
To successfully pass the approval IND process for IND applications, we need it’s necessary to understand what’s called the FDA’s current thinking. The FDA’s perspective is when a sponsor of a drug, does a submission of an IND application it requires that the selected molecule be screened for pharmacological activity and acute toxicity in animal models to quantify the diagnostic or therapeutic potential in humans, and report on adverse effects. From the FDA’s current thinking the term “use of intend” is when you successfully change your drug’s legal status under regulatory law. The drug’s legal status becomes subject to specific controls, including Standard Operating Procedures, of the drug regulatory system, i.e.e.g., specification of dose, dose regime, and factual advertising of its beneficial/ or adverse effects.
In the last 30 years, the FDA has leaned towards a more public and transparent engagement with applicant companies by the release of internal working of committees and regulations since the protest of FDA for “obstructionist drug approval process” by ACTUP movement which advocated for HIV/AIDs patients.[5] Now some of the most insightful online resources are in-depth video lectures by individual FDA regulators from the FDA’s YouTube channel.
Researching Publicly Available Information about Failed IND applications
Hopefully, researchers will be willing to generate retrospective studies on failed IND applications and interviews of FDA regulators as to why INDs fail to gain drug approval. Researchers will be required, however, to contact drug sponsors to gain access to failed INDs. Access to INDs applications can be accessed via the Freedom of Information Act, with the exception of requiring approval by that drug sponsor to release that information. IND applications content and whether they met approval are only known to the drug sponsor and investigators. Only a few researchers and journals have acquired failed or past IND applications. Such as the American Chemical Society, Pharmacology & Translational Science Journal, and published research by Noel T. South for “Freedom of Information Act Access to an Investigational Drug Application”.
I reached out to Noel via email, for advice on gaining access to IND applications, however the FOIA process can only be used in a limited circumstance to access one IND. Still Noel’s research has shown the public and many companies can request past or failed Investigational New Drug (IND) applications via the Freedom of Information Act (FOIA). Potentially gaining insight into the reason “Why do IND applications fail?”.
To convince a drug sponsor to disclose their IND, it helps to pick a drug that has failed IND application phase and has lost patent protection or does not have the commercial interest of its sponsor. Currently, you can only access information, such as safety and effectiveness data, because manufacturing methods are protected by an exemption of FOIA for trade secrets and commercial information.
Finally, I reached out to the FDA FOI CDER division and was directed to a section in the code of federal regulations, 21 CFR 314.430 bullet point D Sub (1). Titled § 314.430 Availability for public disclosure of data and information in an application or abbreviated application. FDA applications including IND applications cannot be disclosed to the public unless disclosure was made by the Sponsor or the Commissioner of Food and Drugs at their discretion. Currently, Dr. Janet Woodcock is acting Commissioner. The drug sponsor will have to authorize the public disclosure to enable us to see the FDA’s response to why INDs applications failed to gain approval.
In conclusion, the preclinical development process and IND applications are complex and well understood by a select few. However, for biopharmaceutical companies, startups, or investors that pour millions or billions of dollars into drug development and build their foundations as a company on a single point of interest (an ‘all your eggs in one basket’ bet in hope that the IND application will prove successful) failures in clinical trials could trace back their failures to the IND applications. INDs focus on the safety and risk/benefit to patients which is the foundation to be built upon. Dose and Dosage regime and scaling production foundations are built from studies of the IND applications. So, it would be beneficial to research to and investigate IND applications phases for emerging markets, investors, and Global Pharmaceutical companies.
If you have further questions, I recommend contacting CDER’s Freedom of Information Division. I would like to thank Guruprasad Udapi for answering my questions and pointing me to the correct parts of the regulation. [1] The knowledge and guidance by the FDA is invaluable and building a good relationship with the FDA is a core business objective of pharmaceutical companies.
Work Cited
[1] Number of Original Investigational New Drug (IND) applications received in the quarter. https://www.accessdata.fda.gov/scripts/fdatrack/view/track.cfm?program=cber&status=public&id=CBER-All-IND-and-IDEs-recieved-and-actions&fy=2021
[2] Wouters, O. J., McKee, M., & Luyten, J. (2020). Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018. JAMA, 323(9), 844–853. https://doi.org/10.1001/jama.2020.1166
[3] https://www.fda.gov/drugs/types-applications/investigational-new-drug-ind-application
[4] Sacks L.V., Shamsuddin H.H., Kaminskaya Y.I., Bouri K., Lanthier M.L., Sherman R.E. Scientific and regulatory reasons for delay and denial of FDA approval of initial applications for new drugs, 2000-2012. JAMA. 2014 Jan 22-29;311(4):378-84. Doi: 10.1001/jama.2013.282542. PMID: 24449316
https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-312
[1] https://www.fda.gov/regulatory-information/freedom-information/whom-contact-about-foia
[2] https://www.fda.gov/regulatory-information/freedom-information/foia-fees\
[3] https://www.linkedin.com/pulse/keys-success-inds-part-1-achieving-regulatory-your-first-trey-putnam/
[4] https://www.fda.gov/media/153971/download
[5] https://www.fda.gov/about-fda/fda-history-exhibits/history-fdas-role-preventing-spread-hivaids
List of videos worth watching – Watching for IND approval
https://www.youtube.com/watch?v=jPiPJMl8Lr4&ab_channel=RegisTechnologies%2CInc.
https://www.youtube.com/watch?v=_WNhHkbFxgg&t=1375s&ab_channel=U.S.FoodandDrugAdministration
https://www.youtube.com/watch?v=GFb0JZL7i9w&ab_channel=NIHNINDS
https://www.youtube.com/watch?v=n2xud4OxIO8&ab_channel=GlobalCompliancePanel
https://www.youtube.com/watch?v=9Dj9pw9LJgQ&ab_channel=GlobalCompliancePanel
https://www.youtube.com/watch?v=oG1_NYcgy3c&ab_channel=U.S.FoodandDrugAdministration
https://www.youtube.com/watch?v=8L7IrrSnShE&t=214s&ab_channel=U.S.FoodandDrugAdministration
https://www.youtube.com/watch?v=O2OtnrT4Ww4&ab_channel=U.S.FoodandDrugAdministration
https://www.youtube.com/watch?v=d0zMTtpe1X8&ab_channel=U.S.FoodandDrugAdministration
https://www.youtube.com/watch?v=GFb0JZL7i9w&ab_channel=NIHNINDS
https://www.youtube.com/watch?v=jPiPJMl8Lr4&ab_channel=RegisTechnologies%2CInc.
https://www.youtube.com/watch?v=GF2Y8LYK68U&ab_channel=UWCoMotion
https://www.youtube.com/watch?v=vEqBDO1di0g&ab_channel=U.S.FoodandDrugAdministration
21 CFR citation and more reading An different approach is why the NDA and BLA receive complete cycle defines sustain enough feedback.
21 CFR 312.130
21 CFR 601.50 IND
21 CFR 601.51 – Analogues Citation BLA