By John Avellanet, Managing Director, Cerulean Associates LLC

If you lack FDA guidance on a newly discovered biomarker, should you use the biomarker in an upcoming clinical trial?

Many Regulatory Affairs professionals would argue “no” and yet, if the biomarker is later proved scientifically valid by the agency, the FDA may very well require you to conduct another costly, time-consuming clinical trial with the biomarker before granting marketplace approval.

Advances in science and technology are increasingly exponentially. Drug, biologic and device development executives are increasingly forced to factor in rapidly changing levels of genetic implications, technologic complexities and adjacent industry innovations or risk continuing costly development of a product that will be near obsolesce by the time market approval occurs 7, 10, even 13 years later.

Rapid advances and changes in knowledge demand faster, smarter decision-making under complex, almost chaotic conditions. Can a Quality by Design philosophy help? And if so, at what point should we incorporate Quality by Design? And how?

Impact of Rapid Knowledge Growth

Today’s rapid pace of knowledge and technological change are rewriting the rules Quality Systems, Regulatory Affairs and other life science executives have long labored under. So much of our work has been based on what has gone before — predicate rules, personal experiences, company history. The way in which we encapsulate processes into detailed standard operating procedures speak of a conservative, risk averse mentality focused on uniformity and standardization. Indeed, even the proliferation of “me too” drugs and devices hints at our comfort with what has come before.

As we edge toward an era of personalized medicines, our decisions increasingly rely on the experiences and wisdom gained under a one-sized-fits-all, standardized, “the customer can have any color he wants as long as it’s black” framework of product development, quality systems and regulatory compliance.

The Greek philosopher Heraclitus wrote, “You cannot step twice into the same river; by the second step the river’s water has already changed.” More than two thousand years later, his message is painful: all of our carefully crafted controls and processes are transient.

Today’s rapid rate of knowledge growth, scientific discovery and technology advances results in processes and controls that go out of date at a faster pace.

Years ago, it was not unusual to find companies working off standard operating procedures (SOPs) approved three, four or even five years beforehand. Now, the US Food and Drug Administration (FDA) and the global harmonization groups, the International Conference on Harmonization (ICH) and the Global Harmonization Task Force (GHTF), expect active reviews (and appropriate revisions) of your procedures and controls at least every 1-2 years (see my recorded seminar, Best Practices for Quality System Management Reviews, for advice and checklists to help you manage this; http://www.ceruleanllc.com/Seminars/eSeminar726576.htm).

To deal with transient conditions, we need the latest information, we need to rapidly breakdown that knowledge and then we need the organizational and compliance flexibility to quickly adapt and adopt that knowledge.

In other words, just because a new biomarker has not yet been qualified by the FDA, does not make the biomarker any less valid. So do you or do you not collect data with that biomarker in an upcoming trial?

Taking Advantage of Knowledge Change

Nowhere is knowledge more available than in universities. The question becomes, how to take advantage of this knowledge to lower the costs and reduce the risks of developing new medicines? And can we use this expertise to increase our chances for regulatory approval?

Incumbent in leveraging universities is being able to use any results in submissions to the FDA, a challenge made all the harder given that most university labs do not operate in compliance with Good Laboratory Practices (GLP), and therefore are apt to produce results that the agency has historically looked upon with a significant degree of skepticism.

Tackling this requires a three pronged approach. First, a philosophy of Quality by Design; second, innovative ways to mine the knowledge in universities; and then third, understanding how to make sure university work can be used — either directly or in support of — any regulatory submission.

This article will focus on innovative, Quality by Design based tactics to collaborate with universities. As we will see, the sooner you adopt Quality by Design in your development pipeline, the more the return on your investment in a university collaboration — and the greater your chance of regulatory approval.

The simplest way to address identifying what universities can offer in a product development, knowledge-sharing collaboration is to classify your options based on two stages of product development: preclinical work and clinical trials. Six collaborative knowledge-sharing opportunities universities can provide are:

• Literature surveys
• Compound optimization
• Formulation sampling
• Pharmacometrics modeling
• Preliminary adaptive clinical trial design
• Phase 0 clinical trials

Preclinical

When we discuss the preclinical stage, we are talking about medicines at least 7-10 years away from any approval to market. These are perfect pipeline candidates to be able to get the most out of university collaborations, so you will want to make sure to put in place appropriate FDA Quality by Design frameworks as soon as possible.

Literature Surveys

All of us are familiar with the scientific literature survey as a tool to provide broad understanding upon which we then conduct development, determine which toxicology tests to pursue, identify potential molecular characteristics to investigate and so on.

Under the Quality by Design rubric, the literature survey is also used to help determine which tests need to be conducted and which do not (see “Quality by Design: Defining Your Preclinical Package,” European Biopharmaceutical Review, Autumn 2007; a copy can be downloaded from my website’s article resource library). File the results of the literature survey with the new medicine’s development history records. These records then help guide (and support) safety and efficacy decisions.

Our ideal survey sketches in all the components of our development program in such a manner that any actual work undertaken is simply confirmatory in nature. An ideal literature survey should identify your preliminary critical quality attributes (CQAs); analyses of general production processes may also give you one or two preliminary critical process parameters (CPPs). While our efforts in the real world may not be so straightforward, with luck, our testing can end up validating our survey results, development plan, CQAs and CPPs, and our safety and efficacy decisions.

This “end result” validation is one way to overcome any non-GLP compliance of individual components. It is a subtle point, but one well worth noting both here — and in any pre-submission meeting with agency officials. If validation is about overall systemic integrity rather than just piecemeal projects, then we want to make sure to draw any FDA reviewer’s attention to success in this arena.

For instance, if our literature survey finds and documents multiple clinical tests and laboratory assays previously undertaken that are similar to our proposed development activity, how much more informed would our decision-making become? Would we even need to conduct such testing? Alternatively, could we simply limit our testing to confirming the survey results?

This type of literature survey will take significant time — paying your staff to undertake this will be a significant outlay of monies; paying university grant money will be substantially less expensive.

Compound Optimization

Work can also begin in university labs for compound optimization. Admittedly, much of this will go hand-in-hand with other activities (such as formulation development and sampling), but you can get much of the base optimization work underway as soon as possible, particularly in graduate student-level laboratories.

Again, let us set aside our worry about conducting this optimization under GLPs. Once the university labs have identified the most promising optimizations, your GLP-compliant laboratories can conduct confirmatory studies (make sure to include upper and lower-limit boundary testing).

As development progresses, you will want to continue this collaborative effort to identify, optimize and confirm (e.g., validate) critical quality attributes (CQAs) and critical process parameters (CPPs) as part of your Quality by Design efforts. Success here will also help ease your adoption of process analytical technologies (PAT) for real-time quality control in clinical pilot production.

Formulation Sampling

At a benchtop level, universities can develop and test various formulations alongside their attempts to optimize your compound.

Focus first on formulations that support findings in the literature survey. For instance, you may have found that a certain subsection of patients in need of your new drug or biologic are also on heartburn medication. While your compound itself does not react adversely to the various heartburn medicines, the literature survey reveals that formulation scientists need to be cautious about several chemicals typically utilized in your formulations. Workarounds will need to be found, something that is costly and time-consuming (and again, a perfect candidate for a university to tackle even in a non-GLP manner).

The more we learn about the role of genetics in medicines, the greater the potential for hundreds of time-consuming miscibility challenges; where will your monies be better spent — sleuthing and solving with graduate students and post-docs or with your employees?

Pharmacometrics Modeling

To make the most of your development dollars (Euros, Yen, etc.), take advantage of the rapidly evolving field of pharmacometrics. Assuming you have not already invested the large sums of money and time required to set up an internal pharmacometrics program, this is one university service to seek out aggressively.

Pharmacometrics quantifies drug, disease and trial information to aid drug development and regulatory agency reviews. Subcomponents of pharmacometrics includes pharmacokinetics, pharmacodynamics, biomarkers and medicinal efficacy relationships, trial design, genetics and other aspects that seek to provide quantitative analyses and predictive models.

The ICH is at the final review stage (Step 4) of its E15 guidance, Terminology in Pharmacogenomics, which will help guide further adoption of pharmacometrics. A copy of the guidance draft is available on the ICH website: http://www.ich.org/LOB/media/MEDIA3383.pdf.

The FDA’s Center for Drug Evaluation and Research has also posted a specific section on its website for pharmacometrics that is worth reviewing — as well as sharing with your university collaborators. The site contains a mix of internal FDA goals and strategic objectives for the industry to achieve by 2020, including incorporation of a pharmacometrics section on new drug applications and the leveraging of cumulative knowledge to design clinical trials for pediatrics. Agency officials, in both public and private conversations, expect many, if not most, new drug and biologic products on the market by 2020 to make significant use of pharmacometrics in their development. For more details on FDA expectations, see http://www.fda.gov/cder/regulatory/pharmacometrics/default.htm.

Currently, when firms take advantage of pharmacometrics, it is for three clinical design purposes:

• Identification of patients at risk for unexpected adverse drug reactions
• Dosing ranges by patient profile
• Patient therapeutic modeling

As I have noted in my SmarterCompliance newsletter, use this data — combined with anything relevant in the literature survey — to estimate effectiveness, including defining any expected therapeutic values to patients participating in clinical trials. This is crucial information to clarify to ensure clinical patients are eligible for reimbursement.

While you may decide to work with an outside reimbursement specialist as you get closer to marketplace launch, using students at pharmacy schools and other university programs for initial groundwork is smart planning. If you are a small company, you can also use this information to help drive funding requests or licensing arrangements.

Clinical

At the clinical stage, we are talking about medicines no more than 5-7 years away from any approval to market. Compliance and data integrity play a far more visible role, and so you will want to limit university collaborations planning and feasibility testing. In this way, you can ensure the information gathered can be used to directly support your submission (see my recorded seminar, How to Improve Data Quality and Record Integrity in your NDA, 510(k), or BLA; a copy can be obtained from my website at: http://www.ceruleanllc.com/Seminars/eSeminar920716_DataIntegrityNDA.htm).

Preliminary Adaptive Clinical Trial Design

All of this leads to university help with preliminary clinical trial design. Over the next ten years, I expect adaptive trials to be de rigueur in the industry. University biostatisticians can help you design and document the various checkpoints and efficacy levels for each adaptive trial.

Universities that have a relationship with the National Cancer Institute (NCI) may be of significant help in this arena. The NCI’s developmental therapeutics program (http://dtp.nci.nih.gov/index.html) can work as a “broker” to arrange for the conduct of clinical trials to test new cancer drugs. University faculty with ties to NCI may be able to help you streamline clinical trial selection (the NCI works with hundreds of medical trial sites), but more importantly, use their expertise to set up a very small Phase 0 human trial with two goals: validate your new drug hits its molecular target and verify specific biomarkers.

Phase O Clinical Trials

Phase 0 clinical trials are very small (10-12 patients or less), very brief (7 days or less) human trials designed simply to validate the viability of a technology or new molecular therapy as worthy of further development for humans.

The device and diagnostic field originally pioneered the concept of Phase 0 clinicals or “feasibility tests.” A Phase 0 trial is designed simply to ensure that the technology can work on the human (as opposed to animal) model. Efficacy and safety parameters are not part of such feasibility testing. 

In the context of Quality by Design, Phase 0 clinicals can help you further identify new potential CQAs, as well as validate your new medicine can hit them. If you have not yet determined your critical process parameters, production of the molecule for Phase 0 is the time to start. In 2006, the FDA published a guidance document Exploratory IND Studies on Phase 0 clinical trials for drug and biologic firms, adapting many of the standard practices and Quality by Design expectations from the device and diagnostic field to drugs.

Final Thoughts

Collaborations with a university require some level of supplier qualification. Taking a traditional Quality Systems qualification approach to the university will likely fail; university qualification as a supplier requires combining FDA quality systems experience with operational flexibility and a risk management mindset.

Fostering a creative, knowledge-based collaboration with a university allows you to take advantage of the rapid pace of knowledge growth and technological advance. Focusing on Quality by Design development goals — knowledge about your product and processes — the six collaborative tactics in this article give you the ability to turn a weakness (the non-GLP university environ) into a strength.

At the beginning of the article, I posed a question: should you use a new biomarker as yet unqualified by the FDA in a clinical trial? Perhaps the real question is How.

Are you ready?

About the Author

John Avellanet is the founder of the FDA regulatory intelligence and lean quality systems compliance advisory program for executives and business owners, SmarterCompliance. He is the author of more than 100 articles, the compliance columnist for both the Journal of Commercial Biotechnology and Pharmaceutical Processing magazine and a contributing author to the book Best Practices in Biotechnology Business Development (Logos Press). He serves on the advisory boards of several trade associations, is a frequent speaker at industry events, business schools, corporate workshops and meets often with regulatory officials. He can be directly reached through his independent advisory firm, Cerulean Associates LLC, on the web at www.ceruleanllc.com.