The discovery, development and commercialization of a novel drug entity is not a quick or easy endeavor. Many compounds fail during safety and/or clinical testing for a variety of reasons. In addition, the compound may demonstrate chemical or physical characteristics that make it too difficult or expensive to manufacture as a viable dosage form at the commercial scale.

Further, one of the primary reasons why an NDA or MAA may not be approved is due to chemistry, manufacturing and control (CMC) issues; not the lack of safety and/or efficacy data.

Paraphrasing an often quoted saying, repeating the same things over and over again, and expecting a different result can be considered insanity. So, what are the lessons that can be learned from past development experiences?

Keep it simple; don’t over think. Let the data ‘talk.’ All data is ‘good data,’ even if it does not fit the desired story. Plan your regulatory submissions for success, not just to meet deadlines. Admit what you do not know. As needed, seek experts to help. Health Authorities, e.g., US FDA, etc., are not the ‘enemy’ of your submission. Seek their advice on complex issues. And finally, timelines can be adjusted.

A knowingly incomplete submission does not gain a Sponsor favorable considerations with Health Authority Reviewers. There is no advantage to an approach with states “we will fix it later if the problem or issues is noted… let’s negotiate.” FDA review timelines for an NDA generally do not allow for the submission of new data during the review process. Thus, lack of sufficient information or data in the original submission generally results in a non-approval/complete response letter.

For many small and intermediate pharma companies, development, document preparation and submission activities are performed by contracted organizations. Thus, if you have a concern on how their development work, activities, etc., are be done, voice it.

Contract Research Organizations (CROs), Contract Development and Manufacturing Organizations (CDMOs), test labs are your contract ‘employees’. They get paid regardless of the success or failure of your drug. Selecting which contract organizations are best suited for your particular development efforts may be a key factor in your success or failure.

Rarely, if ever, will a CRO, CDMO, etc., admit mistakes in judgements or decisions. A CRO, CMO will try and ‘shoehorn’ your drug into their technical platform if there is any potential for applicability. A vendor, CRO, CMO, etc. should not be given responsibility for technical, strategic, or regulatory decisions for your drug. They should not have a leading role in meetings with Health Authorities. A vendor, CRO, or CMO will not be issued a clinical hold or non-approval/complete response letter; although some of their activities may contribute to the issuance of these type of regulatory documentation. A vendor, CRO, CMO, etc. is not the expert in the development of you drug.

You are the expert on your drug. Delegation of this responsibility generally never results in a positive outcome. Admit, take responsibility for, and learn from your mistakes. Shortcuts generally do not result in success. Understand and implement recommendations from Health Authority interactions. Read, understand, and follow regulatory guidance documents.

Areas that should be addressed as part of lessons learned exercises are:

• • GMP status and readiness of manufacturing sites
  • Starting Materials including characterization, impurities, residual solvents. In the US, custom materials may be acceptable if there are sufficient synthetic steps in the synthesis. In the EU, custom materials are generally problematic.
  • Drug Substance fate and purge studies
  • Drug Substance & Drug Product Control Strategy
  • Drug Substance & Drug Product Impurities – genotoxic, degradation products versus process impurities, elemental impurities
  • Residual Solvents
  • Analytical Methods and their validation
  • Drug Substance and Drug Product Specifications
  • Formulation and Manufacturing Process Understanding – Adequacy of in-process manufacturing controls; variability of excipients, manufacturing process
  • Dissolution Method – Discrimination for formulation and process variables, variability in release rate, stability failures
  • Stability Data – Physical changes or instability, other tests which may be for, stability indicators such as PXRD, specific rotation, etc.

In summary, the success of your submissions is dependent upon how well you understand your product, are willing to make the necessary adjustments during development and learn from past positive and negative experiences.