Join Boston Biotech Clinical Research in Houston, April 15, at the premier professional development and networking event for the clinical research profession, the ACRP 2012 Global Conference & Exhibition.
SPEAKER: Candida Fratazzi, MD, President, BBCR, LLC
SESSION #S023: The Rising Interest in the Rare Disease Model could have a critically important role into Biomarker's implementation for Stratified Medicine.
ABOUT: Innovation in drug development has driven the rising interest in a niche market that strictly connects to stratified medicine. Biomarkers are key in identifying patients who are more likely to benefit in response to a given therapy, and are anticipated to affect significantly both the development of new drugs and diagnostics and clinical practice. More than 25 years of orphan drug regulations have proven the strength of the rare diseases model, and the possibility of providing a critically important window into drug development that can be of benefit across the full range of biomarkers’ implementation in stratified medicine. Tools that can help new biomarkers’ identification are available and need to be discussed.
“I’m a big proponent of starting all over and doing it right,” … how many individuals, experts, thought leaders, visionaries, policymakers, strategy designers, have explicitly or implicitly made this statement? In how many disciplines? We live in an era of chaos, in which many realms of existence are manifesting fundamental paradigm shifts. Clinical Trails is one of them. The continuation of the opening sentence above is {“[…]” Woosley says. “Randomized controlled trials are out of date, and it’s time to use the tools of the future.”}. The founder of The Critical Path Institute founder’s, Dr. Ray Woosley, clear statements capture the current status of the clinical trial process in a beautifully written article by Malorye Allison in last month’s issue of Nature Biotechnology. (1)
2012 will bring substantial changes to the conduct of clinical studies. And a critical component of such revolution is what I like to conceptualize as a “reveal-ution”, a process by which everything is revealed. In her Nature Biotechnology piece Ms. Allison offers a frame for naming what has not been working and calls for change, as well as novel approaches that are gaining traction.
Many key voices in the field are already discussing and implementing new paradigms: modeling and simulation methodologies, adaptive designs, seamless designs, sample size re-estimation methods, electronic data capture, precompetitive data sharing, virtual trials, regulatory evolution, market-access-minded clinical development … infinite possibilities start to be revealed. However, are we ready, do we know how to integrate them in a coherent and efficient manner? A revealing piece of data is that of 108 failed phase 2 trials in 2008 to 2010, almost 30% were related to strategy, or as the author refers to they were “strategy bombs”. (2)
In a series of upcoming blog posts, we intend to offer a forum for discussion of “must-have” strategies for an efficient revolution in clinical trials. We hope you choose to participate.
(1) Allison, M. Reinventing clinical trials. Nat. Biotech. 30 (1): 41-49 (2012).
(2) Arrowsmith, J. Phase II failures: 2008–2010. Nat. Rev. Drug Discov. 10: 328–329 (2011).
The creation of the concept for a Strategic Clinical Innovation Organization (SCIO) has been evolving over the past 10 years as the market has become aware of the risk from the lack of “upfront” clinical strategy and development plan. This process has been given added momentum with the advent of discovery drugs with potential multiple indications and the new class of device/drug combination therapeutics.
For more than 20 years, data-monitoring has been supporting biotechnology companies during the fundraising as well as licensing stages. In recent years, venture capital funds have become much more hesitant to invest in the biotechnology sector so it is crucial to make as strong a business case as possible to ensure that you secure the available funding as opposed to other opportunities. One of the key issues is making sure venture capital funds do not undervalue your product/technology proposition to potential investors. To enhance your position, it becomes crucial to demonstrate that your product/technology is the "safe" option for investment and a stand out opportunity by including a clinical roadmap and development strategy of your product/technology. This roadmap illuminates clearly for the investment team what the target indications will be and the paths to achieving a first cycle success.
What has become more important, and is somewhat new to the process, is the higher hurdles being erected by Regulators on the clinical study design and expected endpoint evaluation. This shift is clearly an effort to rebalance the process by focusing the clinical development component on science. This means we move from doing trials and taking the end data to make our case for release, to one of setting up each trial in a concrete but scientifically transparent manner and letting the data fall as it may. The latter requires a different method of reducing the “gap” between the discovery phase and the protocol implementation. Thereby reducing the risk inherent in the traditional method. It is essential to have a scientific and thorough clinical development plan that encompasses all the strategies and decision nodes needed for execution. SCIO’s, recognizing the missed segment of the chain, fill the gap by providing customized thinking and clinical planning that reduce the risk while accelerating the scientific underpinning of the program.
Investors want to know how much their ROI will be and by showing them that you have also put together an equally strong business proposition alongside SCIO scientific roadmap and strategic clinical plan will go a long way in differentiating yourself from the competitors seeking the same funding.
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Written by, Candida Fratazzi MD
Clinical Strategy and Trial Design Specialist
Boston Biotech Clinical Research
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Biomarkers in Drug Development has been "highly commended" at the British Medical Association Medical Book Awards. Boston Biotech Clinical Research is enthusiastic about this nomination due to our contribution to the book with the chapter titled: "Biomarkers for Lysosomal Storage Disorders" by A. Zimran, C. Fratazzi and D. Elstein.
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Written by, Candida Fratazzi MD
Clinical Strategy and Trial Design Specialist
Boston Biotech Clinical Research
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Diabetes mellitus affects millions of people in the United States and worldwide. It has become clear over the past decade that the chronic complications of diabetes result from lack of proper blood glucose concentration regulation, and particularly the toxic effects of chronic hyperglycemia on organs and tissues.
Causes and Defects
Type I diabetes mellitus (T1DM) results from T cell–mediated autoimmune destruction of pancreatic insulin-producing β cells. In the non-obese diabetic (NOD) mouse model of T1DM, multiple defects have been reported. The most striking of these defects is a polymorphism in the β chain of the MHC class II complex. Indeed, β chains from “at-risk” alleles have at least 1 amino acid substitution, which leads to improper interactions with the α chain and aberrant peptide presentation. Such conformational changes in the MHC/peptide complex may result in altered thymic selection. Another defect in the NOD thymus affecting T cell is apoptosis. The auto-reactive T cells that escape the checkpoint of central tolerance need to be controlled in the periphery, which may contribute to the autoimmune phenomenon. In human patients, several similar defects have also been reported. Human T1DM is also associated with the maintenance of tolerance is affected at both the central and the peripheral levels.
Treatment and Research
For more than eighty years, insulin injection has been the only treatment option for all type I and many type II diabetic individuals. Whole pancreas transplantation has been a successful approach for some patients, but is a difficult and complex operation. Recently, it was demonstrated that a glucocorticoid-free immunosuppressive regimen led to remarkably successful islet transplantation. However, both pancreas and islet cell transplantation are limited by the tremendous shortage of cadaveric pancreases that are available for transplantation. Therefore, a major goal of diabetes research is to generate an unlimited source of cells exhibiting glucose-responsive insulin secretion that can be used for transplantation, ideally without the need for systemic immunosuppression.
Transgenic non-obese diabetic mice were created in which insulin expression was targeted to proopiomelanocortin-expressing pituitary cells. Proopiomelanocortin-expressing intermediate lobe pituitary cells efficiently secrete fully processed, mature insulin via a regulated secretory pathway, similar to islet beta cells. However, in contrast to the insulin-producing islet beta cells, the insulin-producing intermediate lobe pituitaries are not targeted or destroyed by cells of the immune system. Transplantation of the transgenic intermediate lobe tissues into diabetic nonobese diabetic mice resulted in the restoration of near-normoglycemia and the reversal of diabetic symptoms. The absence of autoimmunity in intermediate lobe pituitary cells engineered to secrete bona fide insulin raises the potential of these cell types for beta-cell replacement therapy for the treatment of insulin-dependent diabetes mellitus.
Drs. Creusot and Fathman in J Clin Invest. 2004; 114(7) discussed the opportunity of inflammation-targeted therapies.
“Many products have shown some efficacy in blocking the function of pathogenic T cells in autoimmune diseases. To avoid affecting the whole immune system, it is important to confine the activity of cell-specific therapy to the inflamed lesions. Adoptive cellular gene therapy uses different cell types with specific migratory capabilities (that have also been expanded and transduced ex vivo) as vehicles to express immune-regulatory products locally, at sites of inflammation. On the one hand, antigen-specific T cells have proven useful vehicles in the mouse model of rheumatoid arthritis but their isolation from human patients is limiting. On the other hand, DCs are easier to isolate from the blood as precursors, and they can then be differentiated and transduced ex vivo. In the immature stage, they can migrate to sites of inflammation, and this migration pattern may be enhanced or prolonged by transgenic expression of specific chemokine receptors. If suitably conditioned ex vivo, they may even retain their immature phenotype and be tolerogenic… In conclusion, emerging approaches are proving that it may be possible one day to block an undesirable immune response in an antigen-specific or a site-specific manner.”
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Written by, Candida Fratazzi MD
Clinical Strategy and Trial Design Specialist
Boston Biotech Clinical Research
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There’s encouraging news for rare diseases experts and patients. Today, pharmaceutical companies are devoting more resources to developing treatments for less-common disorders and diseases that affect mostly minority populations. The trend, which is slowly gaining momentum, is being driven by several factors, including the emergence of “personalized medicines” (based on an individual’s genetic makeup), and the success of companies that already specialize in making drugs to treat rare diseases.
Many legislators, pharmaceutical executives, patient advocates, and patients are working together to draw attention to rare diseases. Evidence that awareness for rare diseases has risen was also illustrated by third year that the state of Massachusetts has officially drawn attention to the issue, with Governor Deval Patrick signing a proclamation declaring Feb. 28 as Rare Disease Day.
People with rare diseases often face challenges that those with more common diseases do not, such as delays in diagnoses or missed diagnoses, fewer treatments, and expensive treatment options that often are not covered by insurance. People who work in the rare-disease fields are aware of the struggles facing the afflicted, but the general public has little knowledge of what patients and parents go through to find treatments. The more people are aware, the more support they can get.
In less-common diseases, drug development is difficult all around. There is often very little understanding of the disease, its natural history and how to treat it, and little scan data on managing or treating patients. That makes it very hard for companies to know what information the FDA will need to decide that a surrogate endpoint meets its standard of being “reasonably likely” to predict a benefit in a patient.
Standard clinical trials are not feasible for rare diseases drug development. Patients exhibit a wide range of heterogeneous symptoms often needing personalized regimens. The use of placebo controlled trials is usually not ethically possible and standardized treatments are not available for comparison. Working with key opinion leaders and rare diseases clinical development experts is instrumental to design tailored clinical program and study design.
Also, having very few patients for each disease and having them scattered all over the world, makes it is virtually impossible to work the logistics of a clinical trial. Working with treating physicians, patients associations and patients’ families is essential to bring the patients together in one trial.
The 1992 initiative by the FDA to accelerate the approval process in HIV/AIDS could be a model to follow. Under this initiative, promoted by the wake of advocacy by HIV/AIDS patients angry at the slow pace of drug development, drug companies could ask FDA to approve a new therapy using so-called surrogate endpoints — blood tests, urine tests, or other biomarkers that likely predict a patient will benefit from a drug. If the drug is approved, the company has to agree to keep testing to make sure that the results hold up.
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Written by, Candida Fratazzi MD
Clinical Strategy and Trial Design Specialist
Boston Biotech Clinical Research
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In the last three decades, biopharmaceutical companies have made great progress in the fight against rare, or “orphan,” diseases (each of which affect fewer than 200,000 people in the United States) and scientists are working each day to make the coming decades as bright as the last.
Since 1983, when the Orphan Drug Act was passed, more than 350 medicines for rare diseases have been approved.
And the outlook has continued to improve in recent years: According to the Tufts Center for the Study of Drug Development, the number of medicines in development designated as “orphan products” more than doubled from 208 in 2000 through 2002 to 425 in 2006 through 2008. A recent report from the Pharmaceutical Research and Manufacturers of America (PhRMA) echoes the trend, finding that the number of drugs in development for rare diseases increased from 303 in 2007 to 460 in 2011. Each of these medicines offers hope and relief to patients with diseases that often have no other treatment options.
Today, the number of new drugs in development for rare diseases continues to rise as America’s biopharmaceutical research companies are intensifying research into rare diseases, which often are among the most devastating to patients and complex for researchers. A record 460 medicines for rare diseases are in late stages of the pipeline, either in clinical trials or awaiting Food and Drug Administration (FDA) review, according to a new report by the Pharmaceutical Research and Manufacturers of America (PhRMA).
Special challenges are faced by those who fight against rare diseases. For example, it can be difficult to find enough patients for clinical trials and enough medical experts to both conduct clinical trials and sit on review boards. Balancing access to a medicine against safety issues can also be particularly difficult when a rare disease, left untreated, has devastating or fatal consequences. For example, a medicine that can help control infantile spasms, in which young victims can suffer hundreds of seizures a day, also carries the risk of damaging peripheral vision.
A major area of research involves rare cancers. Solid tumors of the liver and thyroid, cancer of the blood and melanoma, or skin cancer, account for more than one-third of all rare disease drugs under development. Other major areas of research include: genetic disorders, such as cystic fibrosis, with 67 medicines in development; neurologic disorders, such as multiple sclerosis and muscular dystrophy, with 37 medicines in development; infectious diseases, such as anthrax and West Nile virus, with 31 medicines in development.
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Written by, Candida Fratazzi MD
Clinical Strategy and Trial Design Specialist
Boston Biotech Clinical Research
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As many Pharma companies scramble to partner with large CRO’s, is there still room in the industry for the small niche provider?
Over 70 comments from Pharma professionals with both client and vendor experience contributed:
While many Pharma groups are seduced by the size of larger CRO’s that offer a “one stop shop” and reduced costs, many believe that smaller niche providers are better positioned to provide local knowledge and understanding the client’s exact requirements, while building closer and more involved relationships that deliver quicker project turnaround and high quality flexible services. Of course, this is only the case provided that the niche provider can differentiate itself by offering specialist knowledge and experience.
Digging further into the opinions reveals that the question is a multifaceted one. But given the array of client demands that need to be met and the complexity of relationships between sponsors, clients and CRO’s – both large and small – the overriding view appears to be that there continues to be a place for smaller players in the Pharma industry.
Opinions within the industry appear to suggest that small niche service can provide:
1. specialist knowledge and experience
2. be local to where the sponsor wants them to be located
3. compete on cost and reliability of service
4. build a strong relationship with the sponsor
5. offer flexibility of service and involvement
6. quality - response time - and decreased turnover
7. very much become an extension of the client's in-house team
Have your say!!
What are your views on the role of niche providers in the current evolution of the Pharma industry?
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Written by, Candida Fratazzi MD
Clinical Strategy and Trial Design Specialist
Boston Biotech Clinical Research
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Personalized medicine is a medical model emphasizing the customization of healthcare, with all decisions and practices being tailored to individual patients in whatever ways possible. Personalized medicine seeks to provide an objective basis for consideration of individual differences.
It is a young but rapidly advancing medical model that is informed by each person's unique clinical, genetic, genomic, and environmental information. Because these factors are different for every person, the nature of diseases—including their onset, their course, and how they might respond to drugs or other interventions—is as individual as the people who have them. Essentially, personalized medicine is about making the treatment as individualized as the disease.
A key attribute of personalized medicine is the development of companion diagnostics, whereby molecular assays that measure levels of proteins, genes or specific mutations are used to provide a specific therapy for an individual's condition by stratifying disease status, selecting the proper medication and tailoring dosages to that patient's specific needs. Additionally, such methods can be used to assess a patient's risk factor for a number of conditions and tailor individual preventative treatments.
In order for personalized medicine to be used effectively by healthcare providers and their patients, these findings must be translated into precise diagnostic tests and targeted therapies. This has begun to happen in certain areas, such as testing patients genetically to determine their likelihood of having a serious adverse reaction to various cancer drugs.
A Bio-specific Approach to Cancer Care 
The oncology community is increasingly embracing bio-specific medicine, an approach based on the discovery that some tumors have unique pathologic and molecular characteristics that may warrant different treatment strategies. By understanding specific differences in tumor biology, researchers are identifying biomarkers for many tumor types, which are helping them to develop treatments targeting these underlying disease pathways. With these targeted therapies, clinicians can develop a more specific treatment strategy that is potentially more effective based on the patient's tumor characteristics. At the same time, physicians can try to help their patients avoid side effects from treatments that may be less-than-optimal for their specific tumor. The ultimate goal is to deliver the right treatments to the right patients at the right time.
Because the 2003 sequencing of the human genome provided crucial insight into the biological workings behind countless medical conditions, scientists and physicians are advancing the field of personalized medicine at a fast pace. It is not yet an established part of clinical practice, but a number of top-tier medical institutions now have personalized medicine programs, and many are actively conducting both basic research and clinical studies in genomic medicine. Since about 2007 the term Stratified medicine has been used for the current approach.
Specific advantages that personalized medicine may offer patients and clinicians include,
- Ability to make more informed medical decisions
- Higher probability of desired outcomes thanks to better-targeted therapies
- Reduced probability of negative side effects
- Focus on prevention and prediction of disease rather than reaction to it
- Earlier disease intervention than has been possible in the past
- Reduced healthcare costs
To develop drugs that meet the personalized medicine standards require a strategic clinical plan and specialty clinical trial protocols.
Today drug development is very different from the blockbuster approach utilized in the past. Most important, the clinical development of drugs for personalized medicine must start with the phase 1/first in man studies.
Would you like to read more about personalized medicine?
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Written by, Candida Fratazzi MD
Clinical Strategy and Trial Design Specialist
Boston Biotech Clinical Research
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The last couple weeks have been busy but I am happy to say that all our work has paid off. The BIO International Convention in Washington DC was a great success. In the coming week, our entire slideshow will be available for viewing on website, but for now I’d like to share with you the highlights of our BBCR presentation.
To introduce you to our topic, I was the moderator for Biomarker Session #86 on Tuesday, June 28, titled Rare Diseases Experience as a Model to Critically Affect Innovation in Biomarker Strategy and Precision Medicine. Joining me were speakers:
Claudio Carini MD, PhD, FRCPath, Sr. Director, Translational Medicine, Pfizer Inc.;
Gloria Feuerstein MD, MSc, FAHA, President, Farmacon Consulting, LLC;
Mark Trusheim, President, Bioconsulting, LLC; and
Collin Williams PhD, Director, Thomson Reuters,
with Marc and Collin presenting on Rare Diseases as Stratified Medicine Economic Models and The Effective Use of Information Resources to Support Innovation, respectively. In one of the more insightful portions of our session, we asked the following questions in order to get the audience’s opinion on four major issues related to the topics covered.
- Can Precision Medicine impact Health Care by reducing treatment cost and increasing the quality of treatments, both on safety and efficacy?
- Can the clinical use of Diagnostic Markers drastically reduce drug related adverse events (AEs), and costly hospitalization?
- Can the use of Biomarkers drastically reduce drug development’s cost, time and failure rate?
- Can the Rare Diseases Model pave the way to innovation and acceleration of drug development of non-rare medical conditions?
This is what we found:
1. Can Precision Medicine impact Health Care by reducing treatment cost and increasing the quality of treatments, both on safety and efficacy?
2. Can the clinical use of Diagnostic Markers drastically reduce drug related adverse events (AEs), and costly hospitalization?
3. Can the use of Biomarkers drastically reduce drug development’s cost, time and failure rate?
4. Can the Rare Diseases Model pave the way to innovation and acceleration of drug development of non-rare medical conditions?
Almost everyone agreed that precision medicine could reduce treatment costs and improve quality, and the clinical use of diagnostic markers could drastically drug related AEs. But more than 30 percent disagreed that biomarkers could drastically reduce drug development costs and failure rates, or that the rare disease model could pave the way to innovation in drug development for non-rare conditions. Do you agree? Feel free to share your comments below. I am interested in knowing what your opinions are on these issues.
Thanks for visiting our blog and be sure to visit our site again soon when the full BIO Convention presentations will be available.