What would Bruce Lee do? Artist, Philosopher, and Regulatory Strategist?

WHAT WOULD BRUCE LEE DO?

BRUCE LEE = ARTIST + PHILOSOPHER + REGULATORY CMC STRATEGIST?

Lee Jun-fan (Chinese: 李振藩; November 27, 1940 – July 20, 1973), known professionally as Bruce Lee, was a Hong Kong-American actor, director, martial artist, martial arts instructor, and philosopher. He was the founder of Jeet Kune Do, a hybrid martial arts philosophy drawing from different combat disciplines credited with paving the way for modern mixed martial arts.

What if Bruce Lee was part of the Regulatory Chemistry, Manufacturing and Controls (CMC) team at an emerging biotech organization today, having to encounter the constant pressure of raising funds, building a creative and effective team, and keeping ahead of the competition while focusing on ensuring a viable and effective clinical development strategy to keep the product moving forward when the odds of clinical success were against him.

How would Bruce Lee develop and implement a viable and practical Regulatory CMC strategy? An effective strategy is critical to ensure that neither the manufacturing process nor the control testing of the product imposes any potential unacceptable human safety risk.

1. DEMONSTRATE IMPRESSIVELY

"The key to immortality is first living a life worth remembering."?– Bruce Lee

No feat of martial arts is more impressive than Bruce Lee's famous strike, the one-inch punch. Lee was able to land an explosive blow that could knock opponents from just a single inch away. So, when you demonstrate your skills, make sure to impress others, and no one will forget you!

Today emerging biotech sponsors are responsible for more than signing off on a checklist or having the staff generate a standard operating procedure on quality systems. The organization must demonstrate solid and visible support for the CMC regulatory systems and process and ensure its implementation throughout the organization.

To carry this out effectively, the organization must first understand the relevant CMC regulatory compliance issues and evolving expectations and then ensure that an effective quality risk management plan is appropriately and proportionately applied (especially in Phase 1).

2. EXPRESS YOURSELF

"Always be yourself, express yourself, have faith in yourself, do not go out and look for a successful personality and duplicate it."?– Bruce Lee

Do not go out and try to duplicate successful people. You can learn from them, but always be yourself. People will see through you if you try to fake it, so focus on being you, and you will be able to connect with people on a deeper level.

Probably nothing is more embarrassing (or more damaging to a company's financial valuation) than being placed on clinical hold in development due to a CMC safety risk when trying to initiate or during a clinical study.

It is recognized that modifications to the method of preparation of the new drug substance and dosage form, and even changes in the dosage form itself, are likely as development progresses. Therefore, the emphasis in an initial submission should generally be placed on providing information that will allow evaluation of the safety of subjects in the proposed study. Identifying a safety concern or insufficient data to evaluate safety is the only basis for a clinical hold based on the CMC section.

The pathway for CMC regulatory strategy is relatively well defined at Phase 1. Still, the organization needs to understand that the FDA's comments on GMPs at Phase 1 may not apply if the CMC strategy uses the Phase 1 investigational drug product batches in Phase 2 or Phase 3 clinical trials.

By applying quality risk management (risk assessment and control) and following available published guidance, an organization can ensure an effective CMC regulatory compliance strategy exists, even at Phase 1. The organization has the ultimate responsibility to protect the process to protect the product to protect the patients.

3. HAVE FAITH IN YOURSELF

"The doubters said, "Man cannot fly," The doers said, "Maybe, but we'll try," And finally soared in the morning glow while non-believers watched from below." – Bruce Lee

Don't let doubts take over your life, and have faith in your abilities because you can! You must believe in yourself when no one else does!

From the guidance, Quality by Design (QbD) is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based upon sound science and quality risk management. The emerging biotech organization is well advised to invest in process science and characterization and know the manufacturing process and its outcome.

But this investment should be made wisely, of course. Understanding science does not come cheap. Facing today's tight financial environment and the reality that only about 50% of drug products that transition from Phase 2 into Phase 3 make it into the marketplace, the organization must be selective in how limited time, resources, and money are invested.

The goal is to increase manufacturing process knowledge and understanding, not just to generate volumes of scientific data. Beware of the alternative. Famously known as Quality by Chance (QbC), it is a precarious option!

4. EXPLOIT OPPORTUNITY

"A good martial artist does not become tense but ready. I was not thinking, yet not dreaming. Ready for whatever may come. When the opponent expands, I contract. When he contracts, I expand. And when there is an opportunity, I do not hit, and it hits all by itself."?– Bruce Lee

We need to become yes – people (almost). Say yes when you perceive these prompts. Say yes to new life. Say yes to experience. Do not say yes to everything, however. Saying yes to every opportunity will burn you out completely. Trust your gut, and it will take you down the path that is right for you.

The transition from Phase 2 clinical trials (studies to evaluate the drug's effectiveness for a particular indication in clinical subjects) to Phase 3 clinical trials is a significant milestone for an emerging biotech company. An effective regulatory strategy is critical at this stage to ensure that all CMC activities necessary for eventual market approval are being planned for, and any identified CMC impediment is under discussion with the regulatory agency.

Want to avoid CMC regulatory delays? Seek out regulatory agency advice. It sounds easy, but for some in the organization, it also sounds threatening. What if the regulatory authority wants much more to be done than is currently scheduled? What impact would that have on the corporate-determined marketing submission date?

An organization must understand that it is not about a company believing that it knows more about its process and product than the regulatory agency; it involves the regulatory authority as a team member. Since the regulatory agencies ultimately control the drug product's fate, it can only be advantageous for a company to ensure that the reviewer profoundly understands the science behind the manufacturing process and outcome.

The responsible team in the organization needs a reality check for their CMC regulatory strategy at this transition from Phase 2 to Phase 3, and the regulatory agency can provide it. See the value of CMC-focused End-of-Phase 2 (EOP2) meetings and consider these meetings a "critical opportunity."

5. BE CONFIDENT

"All of the time, people come and say, 'Hey Bruce, are you that good?' I say, 'Well, if I tell you I'm good, probably you will say I'm boasting. But if I tell you I'm no good, you know I'm lying.'" – Bruce Lee

Confidence is the key to success in every area of life. If you are not confident, others will not believe in you. And if you are not convinced right now, do not worry; confidence can be learned. It comes with practice – the more you practice in an area, the more confident you become!

Completing Phase 3 clinical trials brings confidence, meeting the definition of the manufacturing process and product, and is a significant milestone for any emerging biotech company. Activities now focus on preparing the appropriate marketing application (the New Drug Application (NDA) for small molecules and the Biologics License Application (BLA) for all other biotech products).

The goal of this submission from a CMC perspective is to provide enough information to permit the respective regulatory agencies to determine whether the methods used in manufacturing the drug and the controls used to maintain its quality are appropriate and adequate to ensure the drug's identity, strength, quality, purity, and safety.

By the end of Phase 2 studies, the company has devoted considerable time, expertise, and expense to understanding the science of how the drug product works in humans and how to clinically administer the drug product to maximize its medical benefit and minimize its medical risks.

Have similar resources been expended to understand the science of how the drug product can be manufactured consistently to yield the desired quality with confidence?

6. BE LIKE WATER

"Empty your mind, be formless, shapeless – like water. Now you put water into a cup, and it becomes the cup, you put water into a bottle, it becomes the bottle, you put it in a teapot, it becomes the teapot. Now water can flow, or it can crash. Be water, my friend." – Bruce Lee

It is the complete and unconditional acceptance of the self where it melts and becomes formless, fluid, and flexible. When you attain that state, you are water!

Manufacturing process changes are inevitable and even desired, during clinical development, whether for scale-up to increase capacity, to improve process consistency, quality, or safety, or to reduce the cost of goods. However, demonstrating product comparability following such manufacturing process changes can become challenging.

The desire to improve everything at this late stage (make the process more robust and commercial) quickly is often the result of discovering holes in the scientific understanding of the manufacturing process itself during the preparation of the Common Technical Document (CTD) – marketing application. Process improvements may be desired at this late stage, but they must be entered carefully.

7. CREATE YOUR ART

"Though Jeet Kune Do is not thousands or even hundreds of years old, it started in around 1965 by a dedicated and intensified man called Bruce Lee. And my martial Art is something that no serious martial artist can ignore."?– Bruce Lee

The Art of continual improvement. An example is a commercial manufacturing process is the refinement of product specifications as additional manufactured batches provide more excellent knowledge. At the time of submission of the marketing application, all too frequently, there are limited manufactured batches available to set specification limits. Some emerging biotech companies are now filing their proposal based upon experience with ten or fewer affected batches.

The emerging biotech organization negotiates with regulatory authority reviewers for a proposed interim specification based upon the available but limited manufactured batch experience during the submission review. Upon obtaining marketing approval, and after a specified number of commercial batches have been manufactured, the regulatory agency requires the company to re-evaluate the interim specifications.

If the manufacturing process is adequately controlled, this re-evaluation should lead to tightening the specifications, yielding better control over the consistency of the manufacturing process.

Each will require time and resources to correct if the regulatory agency believes the company's CMC regulatory strategy is not enough. Having the issues identified at an EOP2 meeting gives the company adequate time to respond to those concerns. Regulatory agencies expect thoughtful consideration and a scientifically justified response pointing towards data.

An investment in science rather than hand-waving will pay off in improved manufacturing process control for later clinical and commercial production. The organization needs to encourage communication and teamwork with the regulatory authorities. It is an Art!

Meetings between the company and the regulatory agencies can help assure the company that there will be no significant CMC strategic surprises that could significantly delay the approval and marketing of the product.

8. COMMIT FEARLESSLY

"I fear not the man who has practiced 10 000 kicks once, but I fear the man who has practiced one kick 10 000 times."?– Bruce Lee

Focus on getting better and improving every single day. Step by step, day by day – but it requires commitment, and if you do not commit, you won't reach your full potential! So, stay on track and grind every day.

Organization pressure keeps things moving forward at an emerging biotech company that must stay ahead of its competition but should not lead to rash decisions—avoiding the urge to fix everything late needs to be approached with caution.

A premature submission may meet a preset corporate target, but it can lead to longer review times in the end. The organization's goal should not be the application filing date but the marketing application approval date. Commit fearlessly but avoid rushing to file the marketing application.

9. DON'T THINK, FEEL

"Don't think. FEEL. It's like a finger pointing at the moon. Do not concentrate on the finger, or you will miss all of the heavenly glory."?– Bruce Lee

To think, you tend to examine. To feel, it is more instinct. To judge means to be aware. To believe means to assess. If you think you won't have any prejudices—your culture and everything that your "world" has taught you are not in practice. Sometimes common sense is wrong. If you feel the situation (infighting, for example), you might come to a different conclusion than if you were to think. It means to be sensitive. To unlearn what you have learned. That is why he said, "don't think, feel."

Corporate deadlines will be set and officially announced, and then the pressure is on for the CMC team to meet the timeline for submission of the marketing application. A premature marketing submission may meet a corporate target, but it can significantly longer review times.

The FDA approval system permits the agency to issue a "refusal to file" letter declining to review a submission if there are significant gaps in CMC information. Or worse, after months of review, an "approvable letter" informing the company that it has completed its review of the application and determined that there needs to be a resolution of minor deficiencies, which are identified in such letter, further delaying approval.?

One CMC senior reviewer offered this advice on knowing whether your company is ready to file: "If you have to ask, 'Can we submit the [fill in the blank] section of the application [fill in the length of time) after we apply?', you are not ready!"

10. TAKE ON THE BEST

"If you always put limits on everything you do, physical or anything else, it will spread into your work and your life. There are no limits. There are only plateaus, and you must not stay there, you must go beyond them."?– Bruce Lee

You are the only person that has control over your life, and you hold the keys to success. You are the one in charge, and you have the power to either make it or break it. You've probably heard countless times that you only have one life, one opportunity, and that life is relatively short. Thus, it would be best if you lived to your fullest, and while that is cliché, it's true. So, don't be afraid to dream big, and as Bruce Lee said, it is glorious even to fail in great attempts.

Emerging biotech organizations need to advocate for continual improvement at the company and any contract partners—somebody nurtures the relationship with the contract manufacturing partner(s). The people involved-their competency, training, and cooperation are vital to the success or failure of managing any novel or complex manufacturing process and product.

Nurture the relationship by communicating both good and bad performance; by being honest about the goals, both written and perceived; and not over-promising on any deadlines or the amount of product to be manufactured.

As the expanded body of manufacturing knowledge and data occurs with the contract partner, the organization should ensure that continual process improvement and control are evaluated and given an appropriate response. As an organization, you establish the corporate CMC regulatory culture.

What would Bruce Lee say?