17 March, 2016 Dr. Candida Fratazzi, M.D., Founder/CEOBBCR Consulting, (Boston Biotech Clinical Research)
|For the past 20 years, the cost of new drug
development has risen at a rate that was 7.4%
higher than inflation, and clinical trials bear
responsibility for most of that increase.
Don’t Make Common Mistakes in Clinical Strategy
The average cost of developing a new drug is notoriously high. In a study conducted through the Tufts Center for the Study of Drug Development in 2014, Dr. Henry G. Grabowski and Dr. Ronald W. Hansen concluded, “The estimated average pre-tax industry cost per new prescription drug approval (inclusive of failures and capital costs) is 2,558 billion.” The story does not end here. For the past 20 years, the cost of new drug development has risen at a rate that was 7.4% higher than inflation, and clinical trials bear responsibility for most of that increase. However, the increasing cost of biomedical research is not reflected in an increase in the success rate of clinical development. Instead, it presents a major hindrance to innovation in the biotech industry, while the public must bear the brunt of the problems, absorbing the steep rise in the prices of drugs and medical devices. In order to boost the efficiency of the biotechnology industry, remove the burden of expensive drugs, and create life science products in line with the future of healthcare, we should be asking how best to modify the development process to make it cost-effective.
What is the “Common Sense?”
Biotech companies, after discovering a new product candidate, develop it through a pre-clinical research process. After completing validation of the product candidate, testing safety and efficacy in vitro and animal model, they move it into clinical trials, which progresses from phases I, II, and III, to commercialization of the regulatory agency-approved product. The whole industry has been following the same clinical research path for decades.
It is important to take a closer look at how an Investigational New Drug or Device Exemption (IND/IDE) application is planned, as it will be the key to answering the question in this article.
After completing lab studies, a biotech/pharmaceutical company moves its product forward with the submission of an IND/IDE application. Only those medical devices which show a level of complexity or risks of invasiveness for patients have to go through the IDE application.
This article is related to the White Paper:
FDA Inspections of Clinical Investigators: Are You Ready?
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For the IND application, the Food and Drugs Administration (FDA) requires the company to submit forms 1571, 1572, and 3674; CMC information; toxicology information; and information from previous studies related to in vitro and in animal model experience. In addition, the company also needs to provide clinical information that includes: (1) an investigational plan, (2) the investigator’s brochure, and (3) clinical protocol.
For an IDE, pre-clinical information that is being produced during the early research studies is required; this includes prior investigation, risk analysis, device description, manufacturing, labeling, monitoring procedure, and environment impact assessment. However, as soon as the company decides to go forward with an IDE application, the FDA will request (1) an investigational plan, (2) clinical investigators, (3) IRB information, and (4) the clinical protocol.
The process described above has been executed for decades. What, then, is wrong with this “common sense?” How does this serve to make clinical trials unsustainably expensive? Moreover, what is the solution for optimizing clinical trials, so that:
1. From the perspective of drug or device biotech company, we can:
- avoid making mistakes that kill our product
- reduce development cost and time
- optimize trials for patient safety
2. From the perspective of customers, we can:
- pay less for better treatments
- have access to the right treatment
3. From the perspective of the community, we can:
- provide the best treatment to individual patients
- improve healthcare sustainability
- boost innovation, adding value to the society
As indicated in the guidelines, both IND and IDE submissions should include an investigational plan, the investigator brochure, and the clinical protocol. The biotech company in question should present the rationale for the product in development— mainly in the clinical plan, but also in each of these documents. The IND and IDE should also include a description of a clinical development strategy and questions for the regulators.
Below, we present some of the common mistakes driving inefficiency in clinical research, as manifested by high costs and low success rates.
What Are The “Common Mistakes?”
What is one common mistake that myriad biotech companies have made, causing ineffective cost management of clinical trials? Underestimating the value of a clinical strategy that drives decision-making based on milestones prevents the identification of developmental objectives and gaps.
Most the drug and medical devices companies believe that their plan is sufficient to carry them through a clinical trial; in most cases, however, the IND/IDE application is limited to a phase I study protocol. This approach narrows the product’s opportunity to be successfully reviewed by the regulators and limits the capacity of the biotech sponsor to fully analyze alternative—and perhaps favorable—development avenues in clinical research. Similarly, cooperation of multiple competencies rather than single-function participation in any step of clinical development is crucial. Very often, we see situations where, for example, the preparation and submission of regulatory documents is delegated exclusively to people with regulatory knowledge; or the development of a study protocol is uniquely assigned to clinical operations experts, and developmental decisions are made without a proper understanding of the relevant medical needs. Sponsor companies often simply go into IND/IDE application without a strategy, believing that the phase I protocol is sufficient for their IND/IDE. A simple example is this: Most biotech companies start to think about biomarkers for endpoints or product differentiation only in phase II. Instead, these considerations should be included in their “strategic clinical planning” earlier in the developmental path, so to allow biotech companies to generate the needed data at the right time.
Fig A: Provided by Synthropy’s research
Figure A shows how the implementation of a poor or neglectful strategy early in clinical development is responsible at least for 29% of phase II clinical study failures.
In this scenario, people mix up the concept of “process” with the concept of “strategy.” To put this idea into perspective, simply enacting a “process” is similar to a climbing a mountain with a map but no clues about the best route to take, obstacles, time frame, safety, et cetera. On the other hand, “strategy” might involve developing a timeline for your hike, equipping yourself with the proper gear, evaluating all of the possible problems/dangers that you could encounter, and coming up with the solutions for the worst-case scenarios.
A clear clinical regulatory roadmap would allow companies to proactively select the most appropriate financial and scientific approach, with full confidence about timely resource planning, and, most importantly, identifying the best path for achieving clinical trial success.
Fig B: Elements of a Clinical/regulatory strategy and its impact on clinical phases
Figure B summarizes some of the key elements that are required to formulate a clinical regulatory strategy as part of an IND/IDE application. Furthermore, we can see that a proper inclusive clinical/regulatory strategy, customized for a given product, influences any stage of clinical development from phase I / II and beyond.
What is a “Clinical Plan?”
A clinical plan is much more than a mere description of a sequence of events. It is actually the result of a comprehensive analysis, generating a “clinical regulatory development strategy.” Personally, I call it “strategic clinical innovation” (SCI), which includes not only the phase I study but also the proof-of-concept study. It involves the rationale for the research studies, selection of the patient population, a trial design that will be conducted following the IND/IDE submission, and anticipates development risks on the basis of toxicology data in animals, or prior studies in humans with the same product or products within the same class.
The value proposition of the SCIO (Strategic Clinical Innovation Organization) concept is streamlining the clinical research approach, and launching strategy into trial model to achieve cost–effectiveness. Starting from the assumption that strategy is the key to innovation, we can innovate the overall clinical research process by renovating the drug development process at the time of IND or IDE and inserting a customized clinical/regulatory strategy before the beginning of clinical trials. The SCIO concept essentially expands the transitional area between pre-clinical and IND or IDE submission/first in human study. Adoption of the SCIO concept constitutes an innovative solution that helps companies evaluate pre-clinical data to satisfy unmet medical and market needs, ongoing regulatory innovation, and healthcare demands. The SCIO concept involves scientific and medical knowledge combined with regulatory experience, and a good understanding of what is to be the health care of the future. Conducting clinical research and designing clinical studies today is a complex endeavor, which must be guided by a comprehensive strategy, as opposed to the more commonly used step-by-step approach. The SCIO concept involves the development of a unified, integrated strategy in which relevant factors play a role both in product development and clinical trial optimization. Ultimately, it deploys the development of a clinical regulatory road map, plans design-centric trials, streamlines study design, and assigns unique objective to each study in the context of a clinical plan. This eliminates the need for costly and time-consuming duplications due to incomplete data sets.
This is extremely important because if you overlook this step and proceed with your IND/IDE application submission without including a proper clinical regulatory strategy and roadmap, you will miss the opportunity to get helpful feedback and advice from the regulatory agency that will be very important for your product development. Investors truly appreciate regulatory agency feedback and approval on your product’s development plan as well. Furthermore, the development of a clinical regulatory strategy and roadmap will allow for maximum capital efficiency in clinical trials, the most expensive step for the development of any life science product.
Optimizing life science product development by developing a clinical regulatory strategy prior to the start of first-in-man clinical trials will significantly improve cost-efficiency, potentially reducing up to 30% of cost and time expended on clinical research. Some of the benefits that can be realized are the reduction of study patient number, the selection of achievable endpoints, the identification of PoC indication, and so on. We believe that a second opinion on any clinical development plan and trial design is worthwhile given the cost, time, and risk associated with conducting clinical trials.
A clinical regulatory roadmap and strategy are absolutely required for conducting cost-effective clinical trials. Biotech companies need to recognize that strategy and roadmap are keys for solving the problems of high cost and high risk that are associated with clinical research today. It is a common mistake that can be avoided by recognizing that adding strategy to the clinical development and IND/IDE preparation is not an extra step, but a vital consideration that simplifies clinical development and provides enormous advantages.
Dr. Fratazzi will be presenting this concept in a webinar on Thursday, April 14. For registration information, call 1 (617) 401-2327 or visit http://bbcrconsulting-1.eventbrite.com.
With over 25 years’ experience in biomedical research, Dr. Candida Fratazzi devised the SCIO concept. She founded BBCR Consulting (www.BBCRConsulting.com) in 2009, with the objective of actively contributing to the ongoing innovation in clinical development. Dr. Candida Fratazzi holds a higher degree in Immunology and is an Orphan disease expert. She worked in Cystic Fibrosis, Fabry disease, Gaucher’s disease, Multiple Sclerosis and more. Dr. Fratazzi consults to biotech, pharmaceutical, and medical device companies, advising her clients on clinical/regulatory development road maps and cost-efficient trial designs. Dr. Fratazzi may be reached at http://bbcrconsulting-1.eventbrite.com.