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Let’s Go to the Moon!

Fifty years ago, tomorrow, astronauts walked on the moon for the first time. Apollo 11’s success—just 66 years after the Wright brothers’ first flight—showcased humankind’s moxie and ingenuity. Now the moon is in our sights again, for a generation that will test where science meets profit.

In the 1960s our moon was still very much a mystery. To learn the most from the Apollo visits, NASA selected landing sites in a variety of lunar terrains, including the dark, flat plains sculpted by vanished lava oceans and highlands formed by meteor impacts.

From 1969 to 1972, U.S. astronauts landed at six sites, each chosen for different scientific objectives. All of them were on the moon’s mottled near side, where the terrain had been studied extensively by lunar orbiters and Mission Control could remain in direct contact with the astronauts.

Space agencies have sent probes, with no people on them and thus no need to worry about human safety, to visit far-flung places in the solar system. Spacecraft have explored 60 other moons and even set down on one, Saturn’s Titan. On our own moon, robotic rovers have left tracks at four sites.

Concepts like “the right stuff,” “moon shot,” and “light-years” figure into everyday conversation. Your first day back after vacation might be filled with “reentry” problems. Your craft-brewed IPA might taste like “rocket fuel” or even use those words as its name. And, on discovering a distressing situation, you might calmly say, “Houston, we have a problem.” All these words have moved into our current lexicon.

T MINUS

Today, in an intensely competitive environment, emerging biotech companies from small to large are continuously seeking creative ways of accelerating their development process. Timelines to commence clinical trials are becoming shorter as companies seek definitive results that would prove or disprove their product’s potential. With venture capitalists and other investors looking to put money into an industry that is continuously seeking innovative new products and where small to mid-sized pharmaceutical companies compete for their share of the financial pie, the race to show positive clinical results is intense.

Given that clinical trials make up a substantial portion of the overall drug development costs, it is little wonder that companies are intensely focused on ensuring that the trial is designed and developed to as near perfection as possible. Oftentimes, the other half of the project — the development of the actual product, the Chemistry and Manufacturing Controls (CMC) section of Investigational New Drug applications (INDs) and New Drug Applications (NDAs) — is not given the same level of attention.

In order to gain a competitive clinical edge, these companies may look to do the most minimal CMC work required while still maintaining an acceptable level of control, as required by the industry. However, the question that arises is whether such decisions truly accelerate the overall development project.

When embarking on the transition from preclinical to clinical trials (and beyond), it is important that the company truly understand its risk tolerance. Stated alternatively, how willing is a company to accept the catastrophes of decisions that they make regarding their CMC plan as they navigate through their product development process?

Regardless of therapeutic indication, every project requires a balance between three key, interconnected factors: time, regulatory compliance and budget. Compromises made in one or more key areas will depend on what the company would like to achieve at that particular moment in time versus the future; decisions based on how to continue forward in each may have significant immediate and long-term effects, both positive and negative, on the CMC plan and, ultimately, the clinical trial itself, and the state of the program.

Houston, we have a Problem

The reason why? Regulatory Agencies in the U.S. and Europe require in the CMC section of applications and submissions detailed information regarding the active pharmaceutical ingredient (API) and the dosage format in which the API will be administered. For the submission to be accepted, the Regulatory Agency must have a degree of confidence in the level of information surrounding the chemistries and production of the API and drug product; with increasing substantiation as the development project progresses.

Regardless of the clinical phase, critical time is defined by the start date or “first patient in.” Typically, these dates are predetermined by the company and may have even been promised to stakeholders. Often, actual supply of drug product is an afterthought, since the team planning the clinical trial is rarely involved in the actual product development. This does not mean that the two groups should be working independently of one another. In contrast, the CMC team need to be able to supply to the clinical group product(s) that will be used to evaluate the endpoints of the clinical trial in the most appropriate way. To be able to achieve this goal, the development team needs to understand what the clinical team is trying to achieve. In return, the clinical team needs to ensure that their clinical design can be readily translated into a supply of appropriate formulations and packaging configurations by the development team.

Given the amount of work that generally needs to be completed from a CMC perspective, the development plan of the drug product should be, at minimum, nine months to a full year ahead of the finalization of the clinical program.

From an API perspective, for a Phase I clinical trial, information about the characterization and proof of structure, small-scale synthesis process, preliminary testing methodologies and stability should be included in the application or submission package. Furthermore, given that at this stage available quantities of API may be small, there needs to be enough lead time made available to the API manufacturer to supply enough quantities to be used in actual formulation and product manufacture.

Similarly, for the drug product, investigative formulations need to be determined by the development team and manufactured for Phase I clinical trials. Preliminary testing methodologies and stability need to be assessed and included. For many sponsors, such activities may be contracted out to a Contract Manufacturing Organization (CMO). Companies utilizing such contractors must realize that unless a CMO is selected and managed with care, the CMC work being performed could be on the critical path of the clinical start date.

Sponsors should ask for references or speak with colleagues in the industry to gain insight regarding the width of gaps between what a CMO promises and what was delivered. A company should not enlist the services of a CMO without performing its own due diligence.

Independent of choice, a sponsor should place a high priority on managing its interaction with the CMO. With competing timelines and resources between itself and other clients in the queues, it is not uncommon — and, yet, understandable — that timelines within a CMO can and do slide. Without proper upstream preparation in the CMC strategy and attentive oversight during execution of CMC-related tasks by the company, such delays at the CMO in the development process will severely impact the timely supply of clinical materials.

Another example of a timing risk stems from designing formulations quickly and delaying any further product development until a later date, without correspondingly moving out the clinical start dates. Depending on the development program, the downside to such an approach lies in the risk of proceeding further along the development program without fully understanding the product.

For example, a company looking at a combination product for a 505(b)2 submission performs a clinical trial using the two active materials in their current, separate dosage formats. Anticipating favorable results, the company decides that within a year from receiving the results, it would proceed with a next-staged trial with a single dosage format that contains both APIs. However, being risk averse, the decision to commence formulation and development activities is delayed until definitive positive results are obtained. This leaves the company less than a year to complete the CMC requirements for the drug product.

In a perfect world where all tools and personnel are completely at one’s disposal, experimentation can be performed in numerous parallel fashions and results are perfect and errors never occur, such a project could be accomplished. Yet reality relates a different story. Sponsors begin to push their CMOs. Sturdily forged relationships between the two begin to suffer, experiments do not always work exactly as planned and mistakes happen. In a rush to supply product, concessions begin to be made. A “Last Minute” attitude may begin to creep into the scenario, and experiments that worked once are used as the basis for proceeding ahead full force. Think Apollo 13.

Regulatory Compliance

It is a common misconception that following current Good Manufacturing Practice (cGMP) will cause unnecessary delays in the supply of clinical materials. Increased paperwork and adherence to stricter guidelines during manufacturing, packaging and testing are sometimes seen as obstacles in accelerating the delivery of product for a clinical trial, particularly for Phase I clinical materials.

These CMC activities, performed in a cGMP environment, do not in and of themselves ensure that the product will pass for use in a human trial. What such environments do provide, however, are assurances that each element executed has an internal system of checks and balances which would prevent failing product to be released and used in a clinical trial.

The extent and integrity of a CMO’s quality system should be determined through an audit performed by a company or its representative. Weak systems can significantly delay getting finished product to the clinic on time. For example, a product manufactured in equipment that has not been properly maintained which could impact the results obtained during laboratory testing. If a product is formed in an improperly installed blender that has not been maintained properly and, upon testing, aberrant blend uniformity (BU) results are obtained, is there confidence that the failing BU results are due to the manufacturing process, the formulation, the equipment, or all of these? In such a case, it may be difficult to assess; time would also be lost in waiting for the blender to be re-installed and re-qualified, and for experiments to be repeated so that the impact of that variable could be determined.

Increased documentation also allows for an easier compilation of a development history that can be traced and understood. Having strongly documented, cGMP-compliant, supportive CMC documentation only leads to greater assurances of control, something that is viewed favorably by a Regulatory Agency. Knowing up front where the strengths and weaknesses of a CMO’s quality system lie will assist in selecting the best contractor for the company.

Funding the Budget

Investors or potential partners of today are more sophisticated than ever before. With the increasing number of issues surrounding breakthrough products over the past decade, deeper levels of confidence in both the CMC and the clinical trial results are required. Activities delayed due to cost, and therefore not available for scrutiny by investors, may delay a potential investment or partnership.

With that said, clinical trials comprise a substantial cost of the overall drug development program, from hundreds of thousands of dollars for Phase I studies through tens of millions of dollars for later-phase trials. Companies, for the most part, have an acute understanding and a willingness to spend. However, when it comes to the execution of CMC-related activities, many sponsors begin to select activities that they feel will give them the bare minimum of information required for a clinical trial application. Such decisions are often made with the desire to defer any work that has substantial costs associated with it to a time when a partnership can be formed, or additional funds can be procured from investors (generally after a successful clinical trial).

As with the factors of “time” and “regulatory compliance,” money-based decisions have a direct bearing on what can be achieved. Prudent financial officers and will try to balance their budgets, although they may not fully comprehend the ramifications of certain activities.

Furthermore, finance departments may be hesitant to release funds for work that could arguably be postponed until later, again impacting the CMC activities that need to be accomplished.

Given the direct impact that CMC has on the overall clinical trial, it is imperative that companies begin to develop and integrate their CMC strategies as early in the development process as possible. To develop the best and most acceptable path is to gain an understanding and appreciation within the organization as to what it is willing to accept. The implications of such decisions, as seen through the interaction of time, quality and budget can mitigate any risk a company needs to manage during a clinical project.

If ‘quality’ is the uncompromising factor for a company, there needs to be an understanding that the time to execute CMC tasks may take longer and that performing such activities in a cGMP environment may cost more. If ‘time’ is key, then the company itself may need to be willing to accept, certain quality responsibilities and their consequences from the CMO. The company may also need to pay additional funds to the CMO to accelerate their development process for additional staffing requirements and overtime. Finally, if ‘budget’ is the primary driver, then the organization may need to accept that CMC information for its applications and submissions may take longer to obtain. A CMO that is providing their services at a reduced cost may not have the integrity in its quality systems that would allow for confidence in Regulatory compliance.

Small Steps, Giant Leaps

In the era of Breakthrough Therapy and Fast Track drug designations, CMC submissions can cause delays to bring a drug to market.

Sponsors need to provide enough information to satisfy the regulatory requirements while recognizing that providing too much information early will result in the need to make changes later. The Reality is that there are different approaches to both obtaining and then preparing required CMC data to the agencies during the early clinical phase of drug development through ultimate approval.

The initial Investigational New Drug (IND) submission must be focused on safety and contain information such as drug dose form, investigation population parameters and dosage quantity. Phase 1 reports are still mainly safety-focused, with inclusions of methods of manufacture, toxicology studies and impurity profiles.

As drug trials progress beyond Phase 1, the agency expects reports to contain preliminary efficacy data, and as manufacture is scaled up companies need to report if new stability or impurity issues occur. Any shorter clinical timeline means less CMC time, creating the need to prioritize tasks and focus on important trial aspects such as risk assessment.

By locking down active pharmaceutical ingredient (API) production, formulation and packaging methods early, companies can address these methods in early CMC versions without needing to revise later. Using cGMP qualified ingredients from the earliest clinical trial phases and qualifying secondary contract manufacturing organizations (CMOs) before clinical trials begin are additional ways to prevent unwanted delays. To avoid delays, stability studies need to be locked down early, while other areas such as specifications can be tightened later.

There are different styles of CMC submissions used within the pharmaceutical industry, some most appropriate for certain situations. Sponsors using a “minimal style” of CMC preparation include very little information when summarizing early trial phases. The advantage of this methodology is that early-phase write-ups move quickly, and there is less need to resubmit information that has changed as the trial has progressed.  One of the big disadvantages to this method is that there is still a lot of work left to do close to the submission deadline.

Another approach, the “NDA-ready” style is where a company assembles everything as each trial phase is performed as though the FDA will be receiving those summaries as a finished product. This method allows the team to use the CMC as a project management tool and spreads regulatory work out evenly across all trial phases.  The disadvantage is that any major changes in the project will result in wasted effort as early CMC work needs to be redone.

Sponsors can consider a “transition-style” CMC submission, where the document begins as a “bare-bones” outline which is fleshed out as the trials progress.  This method provides reviewers with a good baseline, but still requires a great effort immediately preceding the submission deadline. The bottom line, who dares call anything impossible today? Not when scientists have created rockets and missiles that bring the moon itself within our reach. The Eagle has Landed!