Conducting An Independent Analysis Of Drug Development Practices

By Chris Plaford, Founder and CEO, Claravant

Industry research shows that about 90% of all drugs in clinical development will be rejected by the FDA or will fail to reach the final stages of regulatory review for other reasons. Given the FDA’s stringent rules and standards for review of drugs, this failure rate is not completely surprising. But while we tend to associate a development program’s failure with dangerous adverse events or underwhelming efficacy data, analysis of the true risks associated with clinical research yields some surprising conclusions.    

For example, only half of the drugs rejected by the FDA fail due to lack of efficacy.[1] In many cases failures are caused by more mundane technical issues that have nothing to do with a drug’s quality, formulation, mechanism of action or efficacy. These technicalities can include a failure to adhere to established regulatory protocols or a failure to maintain adequate levels of correspondence with the FDA. There have been many cases in which these errors have resulted in the delay or complete derailment of a drug development program. Though these factors are often foreseeable and avoidable, many drug developers miss them – leading to delays or rejections that can cost millions of dollars. Understanding the nature and scope of these risks is essential to avoid errors that could lead to costly infractions or the outright rejection of a drug in the long run. To identify them, drug developers must be able to carefully assess all aspects of a development program with both a high degree of expertise and an unbiased perspective.

Analysis of drug development programs also reveals that different risks are associated with each phase of development. While pre-clinical requirements are focused on toxicological, pharmacological and CMC (drug substance) concerns, later stage research is more often plagued by clinical design or execution errors, CMC (drug product) delays or communication failures with regulatory agencies. Frequently, sponsors fail to effectively communicate with the FDA or accurately interpret FDA correspondence. Effectively communicating with the FDA seems obvious, however in reality it is significantly more complicated than those without expertise in this area often expect, and can end up dramatically reducing a drug’s chances at approval.

While there are risks at every stage of development, the costs and delays incurred by carelessness and oversight grow exponentially as a drug proceeds through the development process. It can also be particularly difficult to correct problems in late-stage trials; in many cases the only option is to cancel the program or repeat a trial. While cancellation of a clinical research program may seem like an option of only last resort for most companies, a study of 842 molecules and 637 development program failures found that companies that proactively cancel a project once an issue is identified have a much higher likelihood of correcting course and ultimately getting their drugs to market.[2] Obviously drug developers would want to have available a careful analysis of options before making this decision.

Identifying potential problems early in the drug development process is key to avoiding costly delays and improving a drug’s chances of approval. During the development process, however, it can be difficult for companies to maintain an objective eye when assessing risk and progress.  As a result, many companies are considering the use of outside, third-party reviewers to help identify risks before they threaten a program with increased costs or delays.

The benefits of a preemptive, third-party review in drug development are readily apparent. By hiring reviewers with relevant clinical and regulatory experience in a particular therapeutic area, results are more likely to be comprehensive, pertinent and insightful. A proper independent review that mimics the FDA’s own standards and system of review can inform companies about the same issues the Agency will focus on when a new drug application is submitted for review. An early impartial analysis can help drug developers identify both strengths and weaknesses in a development program, and position companies to address many issues proactively to keep a development program on track.

Recently, Canadian pharmaceutical company Cynapsus underwent a third-party review for the development program for their lead product candidate APL-130227, an adjunctive therapy in development for the treatment of “off” episodes caused by Parkinson’s disease. Symptoms of Parkinson’s disease can be difficult to predict and control with medication, and they can return without warning. This sudden resurgence of symptoms after a patient has taken their standard medication is called an “off” episode. Cynapsus’ APL-130227 is an investigational sublingually administered therapy in development to reduce the duration of these episodes.

While the development program for APL-130227 was progressing as anticipated, Cynapsus opted to engage a research team from Claravant to conduct a review of the program prior to beginning two pivotal Phase 3 studies. The team investigated a wide range of factors that are crucial to advance a development program to NDA filing, including completion and thoroughness of manufacturing protocols, the amount and quality of pharmacology and toxicology data, and the statistical approach used to monitoring clinical safety and efficacy. The review, conducted by a team of experts in CNS drug development, reconfirmed that the program was sound and well executed, and that any remaining risk factors were surmountable with no major delays expected.[3]  The reviewers provided Cynapsus with a full report of their findings, assigning their development pipeline an “A” rating with a score of 95 out of 100. The report also confirmed Cynapsus’ proposed “Efficacy Path” that outlined the major events and milestones that are scheduled to be completed before an anticipated U.S. NDA submission in 2016.[4] 

“We found the results of the review very insightful and an important validation of our hard work in advancing the program for APL-130227 for our team and our investors,” said Cynapsus CEO Anthony Giovinazzo. “After reviewing the report with our senior team and board members, we were able to identify the areas that needed the most focus as we planned for our Phase 3 trials.”

To help improve a drug’s chances of regulatory approval, drug developers must be able to identify problems and address them as early as possible. An impartial, third-party review that follows the FDA’s own procedures and guidelines can provide companies with an objective look at a development program, as well as important new insights that can be used to reduce risk and keep a program’s costs and timelines on track.