Drug development can be an incredibly rewarding journey, which is what has attracted most of us to this industry. Whenever we attend industry events, we find ourselves surrounded by relentless optimists. However, the process can be extraordinarily costly and lengthy, always carrying elements of risk. Every stage of drug development is about finding the right balance of taking more risks with an increased probability of failure or carefully planning and taking more time to minimize risks. Biotechs face this reality and must be well-informed about the consequences associated with each of their decisions.
90% of clinical trials fail. While some of these failures are inevitable and related to the safety and efficacy of the active pharmaceutical ingredient (API), others are due to the design and execution of clinical protocols, as well as the use of clinical supplies (such as medications, packaging, and labeling) that are poorly suited to the clinical protocol and/or patients. In this blog, I will explore the solutions that a CDMO can offer to a biotech to make drug development less risky, faster, less expensive, and ultimately increase the probability of bringing their drugs to market and make them more attractive for acquisition by a large pharmaceutical company.
Key Points to Monitor to Minimize Failures, Delays, and Increased Costs
1. Not Adhering to ICH Standards
Compliance with regulations is a significant challenge for our industry. Regulations are complex, vary from country to country, continuously evolve, and the margin for error is very slim. However, some of the most common issues a biotech might encounter during drug development, and how a competent CDMO can mitigate these during the clinical studies leading to drug market entry, are outlined below.
At Corealis, we adhere to the guidelines established by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), a joint initiative involving regulatory authorities and pharmaceutical industry representatives from Europe, Japan, and the United States. ICH guidelines are not legally binding. However, they are widely adopted by the regulatory authorities of member countries, thus compliance facilitates global drug development and helps biotechs avoid unnecessary setbacks and delays.
Surprisingly, some biotechs choose to outsource formulation development to a CDMO operating in a less regulated country primarily to save money. However, the products they receive as a result of this practice may not be applicable elsewhere in the world due to unacceptable levels of impurities or to manufacturing processes unfamiliar to regulatory authorities.
2. Clinical Trials: Inadequate Clinical Supplies and Insufficient Documentation
Any anomaly in a clinical protocol, inadequate clinical supplies, or insufficient documentation can potentially raise concerns about the integrity of the study and the safety of participants (healthy volunteers and patients). At a minimum, the project will be delayed. Unfortunately, the complexity of clinical trial protocols is sometimes poorly understood by CDMOs, some consultants, and biotech executives, which can lead to the development of drugs and placebos that are poorly suited to the protocol and the patients.
Some excipients cannot be used safely above a defined daily limit. Obviously, we would never create an oral solid dosage (OSD) form containing an excipient that is harmful to patients. Instead, we would recommend alternative formulations that achieve similar plasma profiles while adhering to a safer acceptable daily dose for patients. We would, in collaboration with the client, thoroughly understand the design of their clinical protocol to ensure that the total daily dose (which may involve multiple units, multiple times a day) of the proposed excipient given to a study participant is acceptable and safe.
If a client insists on using an excipient that is not a standard pharmaceutical excipient (i.e., an excipient not documented in a recognized pharmacopoeia such as USP, EP, or JP), regulatory authorities will certainly require additional characterization of the excipient. This may include preclinical and clinical studies on the excipient, which will significantly increase costs and extend the drug development timeline by several years, not to mention the risk of rejection by regulatory authorities for the use of the excipient in the drug product.
Therefore, it is always advisable to use standard pharmaceutical excipients easily available from multiple suppliers, with no associated royalty requirements, and manufactured under Good Manufacturing Practice (GMP) conditions in full compliance with ICH guidelines. We can design the formulation with these excipients to meet the target drug product profile.
3. Failure To Adhere to Good Manufacturing Practices (cGMP) or Quality Issues
A lack of a robust and verifiable quality assurance system, compliant with current Good Manufacturing Practices (GMP), can at the very least compromise and derail a drug development timeline. While our industry is global and exceptionally diverse, it is also, in many respects, quite restrictive. A failure during a client audit can result in significant financial repercussions for the biotech, damage the reputation of biotech executives, and, in some cases, lead to legal consequences.
As a manufacturer of clinical batches only, we are not subject to regulatory authority inspections; however, we must still strictly adhere to Good Manufacturing Practices (GMP) in all our operations related to the production of clinical supplies. Our quality systems are regularly reviewed by our clients and our qualified quality auditor (QP). These reviews by our QP help our clients reduce risks throughout our partnership and often allow them to save time and money by significantly reducing the need for repeated audits during clinical material manufacturing campaigns for studies conducted in Europe.
4. Patient Non-Compliance in Clinical Trials
It is common for clinical trial results not to meet expectations due to issues with safety, efficacy, or poor performance related to the protocol and its execution. Unfortunately, 30% of drug development projects are ultimately abandoned due to unmanageable toxicity. But 40-50% of drug development failures are due to poor clinical trial design or poorly formulated drugs.
If significant problems occur with patients not following the clinical protocol, it can compromise the integrity and reliability of the study data. In such cases, regulatory authorities may require additional analyses to properly assess the drug's efficacy and safety, leading to delays in drug development and additional costs.
Protocol deviations by patients are often associated with complex medication dosing regiments (e.g., multiple units several times a day) as well as medications and/or their packaging that are inappropriate for the study protocol and/or for the patients. For example, if a medication is not suited to the patients' condition (such as large tablets for young children or patients with swallowing difficulties), is difficult to take (e.g., multiple daily doses and/or different medications), or unpleasant to take (e.g., bad taste), patients may deviate from the clinical study protocol, cause delays, or abandon the study. Additionally, patients taking a placebo may sometimes stop taking it if they suspect that the medication they are taking does not contain the active pharmaceutical ingredients (API). This highlights the importance of developing a drug that is suitable for the target population, easy and pleasant to take, and placebos that mimic the appearance, taste, texture, and side effects associated with the API.
Developing an appropriate drug product candidate demands substantial time and significant financial investment. Surprisingly, some biotechs choose to cut corners by focusing solely on saving time and reducing costs. The cost of failing a drug development program due to a lack of initial investment in formulation development can amount to hundreds of millions of dollars. At Corealis, our expertise in solid oral dosage formulations leads to efficient strategies to identify the appropriate formulations and address key targets for the drug product and clinical study.
In conclusion, a simple mistake can be devastating for regulatory compliance at many stages of the drug development process. However, this does not mean that a small biotech should simply accept an untenable level of financial risk.
Solid scientific expertise greatly contributes to minimizing delays and potential setbacks. Some savvy biotechs, as well as most pharmaceutical organizations, outsource part or all of the drug development process to a qualified CDMO. This partner understands how to mitigate risks, work with regulatory authorities, execute seamless technology transfers, and give a promising drug its best chance of commercial success.
At Corealis, our specialty is oral solid dosage formulations. We add the most value by partnering with our clients from the very beginning of the process, that is, from the selection of the API. This allows us to evaluate the "druggability" of the API, define a drug development plan based on the intended therapeutic application, support potential clinical studies, and minimize potential regulatory issues before they compromise or delay regulatory approval or a deal with a large pharmaceutical company.
Our facilities in Laval are just a five or six hour drive from Boston and New York, respectively, and we believe there is no better way to assess a potential partner than to meet in person. Take the time to discuss it with me and plan a visit!
