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Using research to identify the barriers to regulatory approval



Article ID:
20131011
Published:
October 2013, page 68
Author:
Andrew Meadow

Article Abstract

The author explains a method for identifying and mitigating the development risks associated with a regulated health care product’s life cycle.

Getting ahead of the game

Editor's note: Andrew Meadow is a biopharmaceutical and medical technology product strategy executive.

The debate is being waged both within the halls of market research and strategic advisory firms – not to mention biopharmaceutical and medical technology entities – over the need to conduct primary strategic research early in the new product development process and define what strategic conclusions will actually be confirmed.

In a decade in which biopharmaceutical and medical technology companies are being forced to do more with less, research firms must redefine the traditional primary research methodologies used to gather information during this process, the type of data that is ultimately obtained and the source(s) from which this insight is emerging. The data obtained needs to be both actionable and tangential for a compelling clinical trial protocol to be designed, one that takes into account the needs of clinical and regulatory executives, chief medical/scientific officers, as well as the commercial operations and reimbursement teams.

The mind-set of “data for the sake of data” needs to be replaced by an understanding of what information is necessary to achieve specific decision points and outcomes and how best to segregate the data into viable strategic initiatives that help executives make go or no-go decisions. Therapeutic-specific insight that is measurable and leads to tangible outcomes is vital if one is to effectively analyze and validate the assumptions related to the clinical development process while highlighting the unknown outcomes and adverse events associated with the regulatory approval process.

The desire to embark upon an adaptable clinical planning and evaluation initiative early in a regulatory product’s evolution is high. With no silver-bullet solution currently available, companies looking to launch FDA-approved products have had very few options to mitigate risk and improve outcomes.

In this article, I’d like to explore a method for using primary market research to analyze the merits and shortcomings of a clinical development process, be it a biologic compound or a device. The methodology is called channeled clinical trial deliberations (CCTD) and it evolved from a conversation with a client a number of months ago.

We were discussing a strategy issue that was limiting her company’s ability to achieve FDA approval for a novel therapeutic compound and I asked her which aspect of this development process most troubled her team. Without hesitation, she cited the need to ascertain the clinical and commercial viability of her development-stage portfolio early enough in each product’s life cycle to avoid making ongoing investments that will likely not be approved.

Her challenge was not the determination of whether this treatment modality was going to become a blockbuster product; rather, the first critical issue is whether the therapeutic compound would survive the various stages of the regulatory review process. Additionally, it’s important to know what type of investments – financial as well as time – are required to significantly reduce failure rates; improve the quality of the interaction with the FDA; and successfully prove safety, tolerability and efficacy.

Three critical questions

The three critical questions that we began to focus upon were: Will the product be approved? Will it be a viable commercial treatment modality? And what are the requisite resources and timing necessary to get the product into a patient’s medicine cabinet?

In addition, the systematic approach designed to answer these and other questions must be flexible and replicable so that the same type of evaluation can create a hierarchy that triages each opportunity, in rank order, by those compounds possessing the highest probability of clinical success. If the financial or operational requirements necessary to achieve this are not within a company’s means, what alternative development pathways and strategies can be employed to ensure that the company achieves commercial and economic relevancy for the product?

A tangible consensus

CCTD is a qualitative primary research methodology that examines how regulatory, clinical trial design and new product planning teams reach a tangible consensus on one or more development pathways for a product. CCTD is similar in many respects to the deliberations of a jury at the conclusion of a trial, as management reviews all of the material and information obtained prior to and during the clinical trials. The “jury” is then asked to reach a “verdict.”

With a sample population of 10 to 12 participants, CCTD engages tenured individuals with very specific professional profiles, such as former regulatory affairs executives, clinical development officers, pharmacologists, practicing physicians who specialize in a specific therapeutic category, former chief medical/scientific officers and clinical research advisors – none of whom have ever been employed by the company.

The group is given technical data pertaining to the product’s composition of matter and mechanism of action, as well as any clinical trial protocols and results, should any exist. The first deliberation during the first session with all the study’s participants is a review of the trial’s proposed end points, protocol, dosing regimen and design and implementation. The moderator will start with a defined set of objectives and questions that must be analyzed and a consensus reached before Part I of CCTD can be completed.

As the deliberation effort progresses toward a conclusion on each topic, the moderator will infuse new variables and clinical factors that must be incorporated into the overall analysis. Depending upon the size, scope and complexity of the clinical trial, this phase of the CCTD deliberation process can last two or three days.

Finite and defined

The methodology’s objective is to evaluate a product development process in which the possible outcomes are finite and defined; the execution is flexible enough to incorporate new factors and decisions to account for possible new or evolving scenarios in the clinical trial process; and the clinical study could be replicated as the treatment modality progresses through the clinical development process.

An advantage of the CCTD methodology to corporate officers is that an independent group of tenured clinical, scientific and regulatory professionals are rendering a definitive opinion regarding the existing clinical study design and implementation efforts in addition to creating a series of alternative steps and modifications, if not redesigning the protocol itself, that will mitigate the risk associated with the ensuing clinical trial.

An empirical study

To evaluate the design, approach and implementation of CCTD, we undertook an empirical study of the method. We conducted individual interviews with five executives within the clinical, product development, payor/provider access and regulatory affairs disciplines, as well as five chief medical officers. Seventeen of the 25 participants came from the biotechnology and pharmaceutical industry and eight from the medical device market, with all participants working in the United States.

Each respondent received a series of questions that we covered in the interview five days before the conversation. The questions focused on evaluating a series of pre-commercialized product development approaches that each of the 25 respondents had employed historically to identify any practical or strategic similarities with respect to defining end points; protocol design; the steps taken to create a trial that achieved both the predetermined end points and the protocol itself; implementation; and the actual outcomes.

With each respondent, we defined the number of products, irrespective of therapeutic classification, that began in any given early stage trial and the clinical process that ultimately weeded out the vast majority. For the sake of comparison of like products only, we removed all orphan drug candidates from the analysis. What we found is that each of these executives were very committed to creating and bringing to market clinically-approved products that redefined the way doctors approached and treated debilitating diseases. What’s more, the clinical trial design, approach and step-by-step process that each of the biotechnology, pharmaceutical and medical technology executives embarked upon in the areas of clinical, regulatory and reimbursement planning were very similar.

As part of this effort, we also evaluated the type and frequency of correspondences that each received from the FDA, along with the time that elapsed between when a correspondence from the agency was received and a corporate response was submitted. In addition, we analyzed the total number of products that received first-cycle approval for the new drugs and biologics, as well as those that underwent a multi-cycle review process, and compared these figures to the company’s total number of products that began the clinical study process at a given point in time. This helped identify the actual value-add that a customized and targeted strategic approach would contribute to a regulated product’s clinical development pathway.

Myriad of vantage points

Equally important, another benefit that emerged when implementing this methodology is the various scenario analyses that defined successful critical assessments. Oddly enough, when the client was asked what a success or failure looks like and how is each measured, alternative milestones such as strategic partnerships and co-development alliances were not mentioned. The CCTD methodology allows key opinion leaders to evaluate the product in question from a myriad of vantage points to ascertain the clinical and commercial viability and help define the requisite steps necessary to achieve these varying levels of success.

As greater insight into the potential shortcomings of the clinical trial design, protocol submission and implementation is received, management can utilize CCTD to review and deliberate this material with the benefit of knowing that each aspect of the study is being evaluated by a vertically-integrated group of key opinion leaders within each aspect of the clinical trial design and regulatory review processes.

This research methodology is not designed to take the place of a regulatory or scientific advisory board. Rather, it is part of a comprehensive review process that utilizes a different set of information variables and qualitative research insights to determine whether to continue with the clinical trial process and, if yes, how these efforts should be structured and implemented. The flexibility of the design and implementation of this solution lets the deliberation process be modified and customized as needed throughout the product’s life cycle.

The finite outcomes

What differentiates the CCTD methodology from traditional primary research techniques are the finite outcomes and go or no-go decision points that emerge at an appropriate time, including:

  • whether the defined clinical trial end point is compelling, achievable and validates the product’s safety and tolerability profile;
  • if achieving these predetermined objectives has the potential to satisfy a regulatory body’s detailed review and assessment;
  • the potential exposure and risk that might result from the implementation of a clinical trial’s protocol, what assumptions are to be considered, as well as the alternative strategies to be implemented that can alter the scenario and ensuing outcome; 
  • the appropriateness of alternative trial plans so that if the initial protocol is not approved, modifications to the existing plan have been considered and evaluated early and thus delays are minimal; and 
  • the potential exposure inherent to any new product’s evolution, especially those that are subject to the scrutiny of a regulatory review process, irrespective of industry segment and focus.

Moreover, with total Phase I to Phase III clinical trial costs per product escalating to over $800 million, CCTD can help mitigate the uncertainty normally associated with a clinical trial’s design, implementation process and regulatory review outcome. CCTD does this by:

  • identifying the tangible strategic conclusions that must arise from the protocol’s design and implementation;
  • highlighting the likely and required outcomes that regulatory authorities expect to see in the final trial results;
  • determining if the clinical trial plan will meet the intended end points (i.e., How do these end points compare with approved and marketed products and those that are undergoing clinical trials?);
  • defining the potential clinical trial’s focus to address any unmet treatment needs (i.e., How does this compare to commercialized and approved products within the same therapeutic category?);
  • evaluating the variance between the clinical trial protocols and projected outcomes vs. actual outcomes of currently-available treatment modalities;
  • uncovering potential modifications that may need to be employed to the clinical trials based upon preliminary results from earlier studies;
  • scenario-planning of potential outcomes given modifications to a predefined clinical trial’s designs; and
  • defining the relevant and requisite data necessary to achieve regulatory approval.

Not a silver bullet

CCTD is not a silver bullet. To be effective, such initiatives should be conducted prior to and in lockstep with each phase of the clinical trial and product development process so that management can take advantage of the insight, learnings and scientific research conclusions that emerge from the two parallel paths. This way, corporate executives can compare and contrast in real time the learns along with the outcomes surfacing from each of the two studies.

The analysis must produce cross-functional insights into the potential problems that may adversely affect a product’s development well before these issues surface. The CCTD methodology is more than scenario-planning and trial simulation. It begins with this question: How is the product’s success and failure measured?

Given that the approval rate of new therapeutic compounds that successfully complete the full regulatory review process is arguably less than 2 percent, it’s statistically likely a new compound will fail to satisfy a regulatory body’s safety, tolerability and efficacy thresholds. But if we augment the type of data that product development, medical, clinical and regulatory executives have at their disposal when designing and implementing a clinical trial’s protocol, decisions regarding the viability of a product can be defined well before any documentation is submitted to a regulatory body for approval and certainly well before significant capital is invested in research and development. The timing and availability of the insight and information emerging from the CCTD review is mission-critical so that contingency plans can be designed and implemented to avert a significant setback.

Its root cause

If a problem does arise during the evaluation process, what can companies do to ascertain its root cause? Why do clinical trials fail? There is no shortage of smart, tenured clinical research professionals who are supported by seasoned clinical research organizations. Yet even with great minds, significant cash resources and months or even years of planning, the vast majority of treatment modalities do not make it past Phase II.

For the moment, let’s assume that more than 75 percent of the clinical-stage products that enter Phase I lack the clinical relevancy, scientific merit or requisite medicinal safety profiles necessary to be approved for Phase II. For the remaining products, an even greater development challenge awaits: designing a Phase II clinical trial that proves safety, tolerability and efficacy. For many clinicians though, Phase II planning should begin earlier – even before Phase I.

The focus of the clinical effort needs to change from “How do we not fail?” to “How do we succeed?” The statistical hypothesis is that a clinical-stage product will be denied commercial relevancy in its current form. This is not to argue that innovation, along with research and development, should stop. Rather a new approach needs to be created to improve clinical outcomes. To achieve this, we need to first explore why drugs fail in clinical trials. Also, a drug can achieve all predetermined and requisite clinical outcomes, earn FDA approval and still “fail” once the treatment alternative reaches the market. Hence, at the beginning of any trial, the first, most-important questions are: What does success look like for this compound? How is success defined? What is required to achieve this defined level of success?

A much higher standard

A medical product’s success is measured by a much higher standard than those used with consumer products. While CPG brand executives focus on unit sales, market share, brand recognition and dollar sales, in health care the desired outcome is gauged by how many lives were improved through the use of this product. Further, through the use of this product, did someone live who otherwise would not have? Also looming is a commitment to the Hippocratic oath to “do no harm” when serving as a treatment alternative to a patient.

Commercial success and failure transcends pure economic gains when it comes to regulated medical products. And with differing mechanisms to action and chemical compositions, what has worked in the past for one product may not work again.

Equally troubling, the one area of the development process that seems to be absent from the market research conversation is regulatory affairs. What type of market research methodologies and study designs are available to address the unknown associated with bringing a therapeutic or medical device through the regulatory approval process? If market research’s mission is to provide answers to questions that cannot be addressed through off-the-shelf materials and assist clients in redefining the way they compete in the market, addressing the unknown is critical.

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