Drug Pricing & Reimbursement

PUBLISHED BY: Editor: BioPharm Physicians

May 30,2015 | Leave a comment

On May 14, 2015, 60 senior physician executives from the Boston area biotech and pharmaceutical industry gathered at Alnylam Pharmaceuticals in Cambridge to hear Julia Gaebler, Ph.D., Vice President, Health Advances and Troyen Brennan, M.D., M.P.H. EVP & CMO, CVS Caremark, discuss Drug Pricing & Reimbursement. The event was moderated by Akshay Vaishnaw, EVP R&D & CMO of Alnylam.

Julia Aledort Gaebler, Ph.D. Vice President, Health Advances

Dr. Gaebler began by emphasizing three key messages for the audience:
1. Global Health Technology Assessment (HTA) is proliferating and payers are gaining influence
2. Payer evidence requirements have created a new ‘4th hurdle’ for manufacturers
3. Biopharma and Global Medical Affairs (GMA) must respond to the new payer landscape

Market access issues are now the leading risk to the biopharma business model and companies should be reassessing their level of investment to influence payer audiences.

Comparative effectiveness in a real world setting is increasingly required. Dr. Gaebler noted that Germany not only assesses cost-effectiveness relative to comparators, but also plays a large role in determining what the comparator(s) will be. She cited an example where the reimbursement price of a new drug was based on the comparative benefit of a non-drug course of physical therapy.

Reimbursement agencies also seek to reduce the potential patient population to a subset of the patients studied in randomized clinical trials. In Europe, after EMA approval, each country has its own process of evaluating and determining the price of a new product; the more direct evidence of clinical benefit (versus the Standard of Care) that a company can put forth, the better the chance of a higher price. The United States is alone in using free market pricing among first world countries. In the U.S., payers control their budget via utilization restrictions, including formulary restrictions, prior authorizations, step therapy and differential co-pays.

Today, failure to match price with value proposition and supporting evidence at launch will irreversibly restrict a product’s commercial and medical opportunity. The changing market access and reimbursement environment requires biopharma companies to make a number of operating changes:

• Companies need to invest “boots on the ground” to reach regional payers in Europe and the numerous third party payers in the U.S.
• Manufacturers need to engage payers earlier in the development process, optimally prior to Phase III.
• Health Economics Outcomes Research (HEOR) teams need to be integrated into the Clinical Development Plan at a much earlier date to ensure that payer-relevant data are collected, e.g., Quality-of-Life measures, impact on health care system resource allocation, cost-effectiveness data and patient-centred outcomes.

Link to Dr. Gaebler’s Slides: Julia Aledort Gaebler, Ph.D. – Drug Pricing & Reimbursement

Troyen Brennan, M.D., M.P.H. EVP & CMO, CVS Caremark

Dr. Brennan began by describing the impact of specialty drugs on overall spending for pharmaceuticals. Specialty drugs are defined as expensive drugs that often require special handling or distribution. In many cases, these drugs are administered by injection.

While specialty drugs comprise only 1% of prescriptions, they account for 32.5% of total drug spending. Dr. Brennan projects that the cost of these drugs will grow by 17% per year and comprise 50% of drug spending by 2018.

Dr. Brennan believes that some of the rapid growth in price increases for these drugs as well as the launch of new drugs at very high prices, is a result of selected aspects of the Affordable Care Act.

• Insurers are no longer allowed to deny coverage for pre-existing conditions.
• The Affordable Care Act prohibits health plans from putting annual or lifetime dollar limits on most benefits, including prescription drugs.
• The maximum out-of-pocket cost limit for any individual Marketplace plan for 2015 can be no more than $6,600 for an individual plan and $13,200 for a family plan.

As a result, the launch prices of new drugs continue to increase and drug companies have become very aggressive in price increases on specialty drugs and specific brands. CVS Health is using evidence-based approaches to control drug costs. In addition to encouraging the use of generics, CVS uses step therapy, prior authorization and formulary restrictions to reduce utilization of expensive brands and specialty drugs. He and his team primarily rely on the published literature to set utilization policies.

Dr. Brennan described the case history of Sovaldi for Hepatitis C as an example of the increasing cost of new specialty drugs. The cost of 12 weeks of therapy with Sovaldi, including ribavirin and interferon, is ~$130,000. He anticipates a continuing crisis in the cost of Hepatitis C treatment in the U.S. as more patients are diagnosed and treated. Dr. Brennan expressed concern that we have already arrived at two-tier medicine as he contrasted the Sovaldi Medicare reimbursement guidelines with those for Medicaid in the state of Illinois.

Link to Dr. Brennan’s Slides: Troyen Brennan, M.D., M.P.H. – Drug Pricing & Reimbursement

During a lively Q&A Session, Dr. Gaebler and Dr. Brennan provided some additional perspectives:

• Orphan Drug designation is important for manufacturers in terms of exclusivity, but does not have a big influence on how U.S. payers view a new drug. Some European countries, such as Germany, use orphan drug designation as a means of controlling overall spending on a drug.
• New therapies that improve patient compliance are not considered to be more cost-effective than existing therapies unless the manufacturer proves that improved compliance leads to better outcomes.
• While Dr. Gaebler encourages early outreach to payers, Dr. Brennan prefers to rely on published literature that is unbiased and peer-reviewed vs interactions with drug companies.
• Manufacturers are allowed to communicate health care economic information to formulary committees as part of FDAMA Sec. 114. However, this legislation was passed in 1997 and FDA has never issued guidelines interpreting it, particularly regarding the definition of “competent and reliable scientific evidence”

About the Boston CMO Network

The Boston CMO Network includes senior physician executives in the greater Boston area who are active in the biotech and pharmaceutical industry. The Network sponsors events for Boston-area physician executives to meet, interact and learn from each other.

A Steering Committee of physicians plans the group’s events:
Akshay Vaishnaw, M.D., Ph.D. (Chair) EVP & CMO, Alnylam Pharmaceuticals
Julie Krop, M.D. VP, Clinical Development, Vertex
Alfred Sandrock, Jr., M.D., Ph.D. SVP, Development Sciences & CMO, Biogen Idec
Matt Sherman, M.D. CMO, Acceleron Pharma
Nancy Simonian, M.D. CEO, Syros Pharmaceuticals
Gloria Vigliani, M.D. Principal at Vigliani Consulting
Chris Wright, M.D., Ph.D. CMO, Pronutria
Steven Rauscher (Organization) BioPharm Physicians



Collaborating with Patient Advocacy Organizations in Drug Development

PUBLISHED BY: Editor: BioPharm Physicians

Dec 23,2014 | Comments Off

A panel of Patient Advocacy Organization leaders spoke to an audience of 65 senior physician executives from the Boston CMO Network on Dec 2, 2014. The event was moderated by Matt Sherman, MD, CMO of Acceleron and hosted by Biogen Idec in Cambridge, MA.

Walter Capone, President & CEO of the Multiple Myeloma Research Foundation (MMRF)

Walter Capone discussed MMRF’s history and mission and its impact on new drug development. Founded in 1998, the MMRF is the largest private funder of multiple myeloma research. MMRF functions as a virtual drug development entity, providing funding and fostering collaborations from discovery research through target identification, clinical development and registration. MMRF builds extensive networks of partnerships across academic research institutions, pharmaceutical companies and government entities.

Examples of MMRF programs include:

  • • The Multiple Myeloma Research Consortium (MMRC). Integrating 21 leading centers and facilitating tissue banking, the MMRC speeds Phase I/II clinical trials
  • • MMRF Research Cores – a collaboration with leading academic research institutions to accelerate pre-clinical R&D into the clinic
  • • Partnerships with industry across a pipeline of 50 products addressing multiple pathways
  • • Establishment of business processes across institutions and companies to speed clinical trial initiation and enrolment
  • • CoMMpass Study – a landmark, 8 year study to collect clinical and molecular profiling data on 1,000 newly diagnosed patients at over 90 sites globally. These data are provided via a Research Gateway to MMRF industry partners
  • • MMRF recently brought together NCI, FNIH and FDA along with academic and industry partners to initiate the development of a MM Master Protocol to allow patients to participate in clinical trials evaluating several investigational therapies at once.
  • • Patient Support Programs ranging from a myeloma/oncology trained nurse call-center, to on-line Community Gateway of >3,000 ‘connected’ patients, to continuing medical and patient education programming


Link to Slides: Walter Capone – MMRF Overview

Gina Cioffi, Esq., National Executive Director of the Cooley’s Anemia Foundation (CAF)

Gina Cioffi described the CAF’s mission and some of its initiatives to accelerate medical research in thalassemia:
• Fellowships to launch the careers of young scientists
• Funding to support academic researchers
• Grants to support trials of gene therapy

CAF support of medical research has led to advances in the treatment and understanding of thalassemia by exploring the role of hepcidin as a regulator of iron metabolism, evaluating the efficacy of iron chelator combination therapy as well as gene therapy and gene editing research. CAF is working with thalassemia experts to develop evidence-based guidelines for treatment.

Registries are central to research in rare diseases. CAF has also developed a registry of patients in the U.S. of ~1,000 patients and is expanding that registry via a collaborative agreement with CDC. Registries allow researchers to assess feasibility of clinical trials and trial planning.

A major initiative of CAF is to help patients understand clinical trials. CAF is conducting nationwide focus groups to explore patient attitudes toward clinical trials, as well as barriers and facilitators to adherence.

The goals are to:

• Better understand demographics, epidemiology, population size and access to care.
• Provide information on modifiable patient behaviors
• Evaluate co-morbid conditions
• Enhance and refine health messaging to the thalassemia community.

Link to Slides: Gina Cioffi – Clinical Trials in Thalassemia Insights from the Patient Community

Christine McSherry, RN, Executive Director of Jett Foundation, Co-Founder of Duchenne Alliance

Christine McSherry discussed her personal story as the mother of a child with Duchenne’s Muscular Dystrophy (DMD), the founder of a patient advocacy organization and the co-founder of an alliance of patient organizations.

The Duchenne Alliance is a group of independent non-profit organizations dedicated to defeating DMD. Christine co-founded the Duchenne Alliance to bring together many grassroots organizations to achieve a common goal.

Working together gives the members of the Duchenne Alliance a stronger voice. Each member seeks to achieve its own mission while collectively serving the entire Duchenne community.

Some of the initiatives of the Duchenne Alliance include:

  • • Communicating with sponsors and regulatory agencies to gather information and provide access to that information to families and patients
  • • Collaborating to co-identify, co-review, and co-fund the most promising biomedical research
  • • Establishing the Duchenne Alliance Research Fund to receive monetary donations and direct these resources to advancing the top biomedical research and clinical trials


The Jett Foundation and the Duchenne Alliance collaborate with pharmaceutical companies. Christine noted that the Duchenne Alliance and the companies have the same mission and the same purpose; to discover and develop a safe and effective drug for DMD. Christine stressed the importance of learning about sponsor limitations and how patient organizations can have the most impact.

Christine discussed a case history on the impact of the Duchenne Alliance. She became aware of a medication in a small clinical trial that was showing efficacy. She and her colleagues realized that there was an unmet need to include patient involvement in the regulatory process and became very active in interactions with FDA. They were able to educate the agency on the daily life of a child and family with DMD and provide input on permissible risk in clinical trials. As a result of these efforts, the FDA has allowed expanded access to this medication in a clinical trial for older children with more advanced disease.

Link to Slides: Christine McSherry – Case Study, From Advocacy to Action

Glenn Pierce, MD, PhD – Former SVP, Hematology, Cell and Gene Therapies, Biogen-Idec
Past President of the National Hemophilia Foundation

Glenn Pierce shared his unique experience from both sides of the Advocacy-Biotech axis. Glenn has been a volunteer for hemophilia organizations since age 14, having lived with hemophilia until his liver transplant in 2008. He is also an accomplished biotech executive and worked in hemophilia R&D since 2002. He led the teams at Biogen Idec that developed Alprolix (rFIXFc) and Eloctate (rFVIIIFc).

Glenn reviewed the history of hemophilia and the evolution of its treatment. He noted that hemophilia has strong advocacy groups, in part as a result of the past history of viral transmission, (HIV, HCV, HBV), prior to the development of recombinant clotting factor replacements.

Glenn discussed a number of best practices for Biotech companies with advocacy groups:

  • • Partner with an advocacy relations team and/or encourage corporate support to develop an advocacy relations function
  • o Understand the advocacy organization’s values and partnership parameters
  • o Seek to develop innovative partnerships that are win/win
  • • Identify corporate internal needs that can benefit from partnering with advocacy (e.g., direct sales support, clinical trial recruitment)
  • • Engage with, listen to and learn from the advocacy organizations in your space:
  • o Crucial for all functions to be involved; demonstrate caring and commitment
  • o Understand the advocacy organization’s priorities and unmet needs
  • o Real commitment and transparent communications foster trust and long-term relationships
  • • Identify a natural intersection that also enables the advocacy organizations to maintain independence


Some common areas of collaboration can include:
• Clinical trial education and awareness
• Unbranded or disease-state educational programming
• HCP/Patient educational programs
• Advisory Board/focus group recruitment
• Government advocacy & payer relations

Glenn described how Biogen Idec reached out to the National Hemophilia Foundation, including early, frequent communication with CBER and physician organizations. Biogen Idec was able to enrol Phase 3 studies in ~2 years as a result.

Patient Advocacy and Drug Development – Accessing The Patient Voice

Glenn noted that health reforms worldwide are altering relationships between providers of goods and health systems, bringing increased importance to the patient voice in determining value. Increasing patient engagement early presents opportunities to improve understanding of real world clinical effectiveness and the ultimate value of drugs to patients.

Patients often won’t know to comment or engage unless formally invited or asked. Biotech companies should recognize this and reach out to patient advocacy organizations. Biotech companies should ensure that patients are not just observers of the process.

Link to Slides: Glenn Pierce – Advocacy and Drug Development

About the Boston CMO Network

The Boston CMO Network includes senior physician executives in the greater Boston area who are active in the biotech and pharmaceutical industry. The Network sponsors events for Boston-area physician executives to meet, interact and learn from each other.

A Steering Committee of physicians plans the group’s events:

Akshay Vaishnaw, M.D., Ph.D. (Chair) EVP & CMO, Alnylam Pharmaceuticals
Julie Krop, M.D. VP, Clinical Development, Vertex
Alfred Sandrock, Jr., M.D., Ph.D. SVP, Development Sciences & CMO, Biogen Idec
Matt Sherman, M.D. CMO, Acceleron Pharma
Nancy Simonian, M.D. CEO, Syros Pharmaceuticals
Gloria Vigliani, M.D. Principal at Vigliani Consulting
Chris Wright, M.D., Ph.D. Former SVP, Global Medicines Development, Vertex
Steven Rauscher (Organization) BioPharm Physicians



FDA Perspective on Rare Diseases

PUBLISHED BY: Editor: BioPharm Physicians

Apr 22,2014 | Comments Off

Rich Moscicki, M.D., Deputy Center Director for Science Operations, FDA spoke to an audience of 75 senior physician executives from the Boston CMO Network on April 7, 2014.  The event was hosted by Sarepta Therapeutics at the company’s new headquarters in Cambridge, MA.

Dr. Moscicki focused his prepared remarks on  current CDER priorities, with particular emphasis on:

  • Rare Diseases
  • Paths for expedited review
  • Drug Shortages & Pharmaceutical Quality
  • Patient focused drug development

  • Rare Diseases

    Rare Diseases continue to be a major focus for FDA.  More than one-third of novel drugs approved in 2013 were for rare diseases. This continues a trend in recent years.  From 2008-2013, one-third of NMEs and original biologics product approvals have been for rare diseases.   This trend is expected to increase.

    A therapy is considered a targeted therapy if the inclusion/exclusion criteria in pivotal trials or the label indications are based on a genetic test, biomarker or susceptibility test.  An increasing percentage of new approvals are for targeted therapies, particularly with rare diseases.  In 2013, 80% of rare disease approvals were for targeted therapies.

    The growth in targeted therapies is creating orphan subsets within more common diseases, such as BRAF V600 mutation subsets of melanoma.  Drugs developed for these smaller subsets of populations will have smaller clinical development programs and are expected to have improved risk-benefit profiles.  They create a need for flexibility, novel trial designs, translational science development.

    Dr. Moscicki noted that every FDA reviewer goes through rare disease training and senior leadership meets frequently to share views. The Rare Disease Program in CDER is a small group that provides education, training, input and advice to divisions and reviewers.  This group tends to be more involved with smaller companies, helping them do the right thing.

    Paths for Expedited Review

    FDA has a number of paths for expedited programs including priority review, Fast Track, Breakthrough designation and Accelerated Approval. Rare Disease drugs are the majority in each category.  Of the 14 Accelerated Approvals in 2013, 13 were for rare diseases.

    Breakthrough Therapy is a new designation, established by FDASIA for expediting development and review for serious and life threatening diseases.  Breakthrough Therapies receive more attention, with senior leadership updated and involved on a regular basis.

    The industry has responded enthusiastically to this new program:

  • 138 requests for breakthrough designation have been received
  • 40 have been granted
  • 3 have already been approved, 2 of which were for rare diseases

  • Dr. Moscicki outlined some of the lessons that have been learned to date:

  • Some drugs have been late in development.  However, the intent and focus of the program is for drugs that are early in development
  • Manufacturing development & scale-up, not clinical development, is often the rate-limiting step for these drugs
  • It is a very resource intensive program at FDA. The number of requests and designations exceeded expectations
  • When breakthrough therapy designation is denied, the most common reasons have been:

  • Lack of clinical data or evidence is too preliminary to be reliable
  • Failure to demonstrate substantial improvement over available therapy
  • Reliance on a biomarker or surrogate endpoint without sufficient evidence of patient benefit
  • Post-hoc analyses of failed studies that identify a subset that may benefit, “the triumph of hope over evidence”

  • Drug Shortages

    FDA has been devoting a lot of effort to improving drug shortages.  Dr. Moscicki noted that 66% of drug shortages were due to quality issues.  FDA’s plan has focused extensively on early notification as the key to resolving drug shortages.  The agency is conducting risk-based analyses to determine ways of addressing shortages, including:

  • Determining if other manufacturers can increase production
  • Expediting inspections and reviews of submissions
  • Exercise of temporary enforcement discretion for new sources of medically necessary drugs
  • Working with manufacture to investigate root causes of shortages
  • Reviewing possible risk mitigation measures for remaining inventory.
  • These measures are beginning to prevent and reduce the number of shortages.  However, the industry needs to devote more effort and focus to improving manufacturing quality.  There is a proposal to initiate a new Office of Pharmaceutical Quality with the following principles:

  • Put patients first by balancing risk and availability.
  • Have one quality voice by integrating review and inspection across product lifecycle.
  • Safeguard clinical performance by establishing scientifically-sound and clinically relevant quality standards.
  • Maximize focus and efficiency by applying risk-based approaches.
  • Encourage innovation by advancing new technology and manufacturing science.
  • Put Quality over Compliance
  • Attention on how well drugs are manufactured
  • Metrics, ie lot failure
  • Create an ability to examine Quality across the industry

  • Patient-Focused Drug Development

    Patient-focused drug development is part of FDA commitments under PDUFA V.  The agency is particularly interested in hearing from patients to help understand severity of condition, degree of unmet need and risk tolerance.

    The agency is convening at least 20 meetings on specific disease areas to gain patient perspectives.  The 2013 meetings included narcolepsy and muscular dystrophy.

    The agencies focus for meetings in FY 2014-2015 will be:

  • Alpha-1 antitrypsin deficiency
  • Breast cancer
  • Chronic Chagas disease
  • Female sexual dysfunction
  • Fibromyalgia
  • Hemophilia A, Hemophilia B, von Willebrand disease, and other heritable bleeding disorders
  • Idiopathic pulmonary fibrosis
  • Irritable bowel syndrome, gastroparesis, and gastroesophageal reflux disease with persistent regurgitation symptoms on proton-pump inhibitors
  • Neurological manifestations of inborn errors of metabolism
  • Parkinson’s disease and Huntington’s disease
  • Pulmonary arterial hypertension
  • Sickle cell disease

  • Summary Q&A Session

    Dr. Moscicki summarized his prepared remarks noting that CDER initiatives in drug shortages, pharmaceutical quality, expedited reviews, pediatric rare disease vouchers, and patient informed decision making should have a significant impact on rare disease drug development.  Rare Diseases have always been a leader in innovation and will continue to do so.

    During a lively Q&A session, Dr. Moscicki touched on some additional topics:

  • Sponsors developing drugs for rare diseases sometimes encounter difficulties with the reviewing division. Dr. Moscicki suggested that it is a good idea to get the Rare Disease Program involved, along with the review division.  You can also request senior management attendance at meetings.
  • The Sentinel Initiative – This new program will be looking at safety signals via claims databases for over 150 million lives.  The results will be made public.
  • Unlike pilot programs in Europe, Dr. Moscicki does not expect FDA to collaborate on decision making with payers unless mandated by Congress.


  • About the Boston CMO Network

    The Boston CMO Network includes senior physician executives in the greater Boston area who are active in the biotech and pharmaceutical industry. The Network sponsors events for Boston-area physician executives to meet, interact and learn from each other.



    Hot Topics in Drug Development: The EMA perspective

    PUBLISHED BY: Editor: BioPharm Physicians

    Oct 6,2013 | Comments Off

    Dr. Hans-Georg Eichler spoke to an audience of 55 senior physician executives from the Boston CMO Network on Sep 17, 2013. The event was hosted by Genyme Corporation in Cambridge, MA.


    Dr. Eichler discussed four topics in his prepared remarks:

  • Flexible Pathways to Market Authorization
  • The Regulatory – Health Technology Assessment interface
  • Clinical trial data transparency
  • Global harmonization of evidence standards
  • Flexible Pathways to Market Authorization

    Dr. Eichler described the current model of approval which relies on a “magic moment”, where sufficient knowledge about a product has been gained to grant a license to market.  Unfortunately, in the current scenario, while the treatment population grows rapidly, that treatment experience does not contribute a great deal of evidence generation.  He asked the question: “Can we replace the current model with something else, such as Adaptive Licensing ?”

    He suggests the answer is yes, under certain conditions:

  • the unmet medical need is significant enough to make regulatory authorities willing to accept uncertainty
  • the post-licensing treatment exposure is via a measured roll-out with surveillance.
  • the growth of the product is managed to allow gradual access to larger populations.

  • He noted that the concept of Adaptive Licensing goes beyond Accelerated Approval, which is limited to life-threatening diseases.  He mentioned that it would be important for Adaptive Licensing to have a mechanism to capture real-world observational data.

    Regulatory – Health Technology Assessment Interface

    A challenge we all face is how to avoid conflicts between regulators and payers on the path to market access.  A concept that EMA has been exploring is to convene a meeting with sponsors, regulators and payers together during which both the regulators and payers discuss their evidence requirements.  The process is voluntary and private and 20 drugs have used it.  Payers and Regulators have also exchanged guidelines as part of these activities.

    Dr. Eichler believes that there is no question but that post-licensing research requirements will continue to grow.  Regulators will move toward adaptive licensing and payers will move toward allowing coverage, but with requirements for additional evidence development.

    Clinical Trial Data Transparency

    Dr. Eichler believes that clinical trial data transparency will, in the long run, provide benefits to the industry that will outweigh the risks.  Transparency should allow companies to learn from the mistakes of others.  Nonetheless, he acknowledged some of the risks, including the challenge of a level playing field for industry and the use of clinical trial data by academicians for meta-analyses.

    However, despite the risks, clinical trial data transparency is here to stay. This is not something that EMA can resist.

    Global Harmonization of Evidence Standards

    Much progress has been made via ICH on non-clinical and CMC issues, but this process won’t work for harmonizing clinical standards.  Currently, the agencies exchange guidelines and confer of a frequent basis, but some differences of opinion will continue to exist.  Dr. Eichler noted that sponsors can seek to get parallel scientific advice from FDA & EMA, but that this has been infrequent.  Most sponsors continue to approach FDA & EMA separately.

    Dr Eichler’s prepared remarks were followed by a lively Q&A session.

    About the Boston CMO Network

    The Boston CMO Network includes senior physician executives in the greater Boston area who are active in the biotech and pharmaceutical industry. The Network sponsors events for Boston-area physician executives to meet, interact and learn from each other.

    A Steering Committee of physician executives plans the group’s events, which are hosted at local biotech companies.



    Three New FDA Initiatives that Matter

    PUBLISHED BY: Editor: BioPharm Physicians

    May 28,2013 | Comments Off

    Dr. Janet Woodcock spoke to an audience of 75 senior physician executives from the Boston CMO Network on May 6, 2013. The event was hosted by Alnylam Pharmaceuticals in Cambridge, MA.

    Dr. Woodcock focused her prepared remarks on three topics.

  • Breakthrough Therapy designation,
  • Special or Limited Medical Use designation, and
  • Structured Approach to Benefit-Risk Assessment
  • Breakthrough Therapies

    The designation of Breakthrough Therapies was one of the provisions in the FDA Innovation and Safety Act (FDASIA), signed into law in July, 2012.  Dr. Woodcock noted that the agency was seeking to develop a new approach as a result of the remarkable efficacy that was being seen in early stages of clinical development for a number of therapies.  In most cases, the results were being observed with targeted therapies and replacement therapies in previously intractable diseases.

    The agency wanted to accelerate the development of these new therapies.  The Breakthrough Therapy designation is designed to mobilize efforts and attitudes similar to what had occurred with HIV.  The objective is to create an “all hands on deck” approach within the agency to work closely with the sponsor to identify the most effective way to substantiate the early clinical findings and further understand safety risks.  Additionally, the agency wants to work with sponsors to expedite effort on manufacturing issues, which can sometimes be a rate-limiting challenge at the end of the review process.

    When an application for Breakthrough Therapy designation is received, it is quickly reviewed by the Medical Policy Council, comprised of senior FDA leaders across all areas at FDA. To date, the agency has had more than 30 applications, of which 13 have been designated as Breakthrough Drugs.  Not all of these have been made public, as the agency leaves the disclosure decision to the sponsor.

    The next steps in this program are to issue guidance, which Dr. Woodcock expects in the near future.  The agency is then going to work on the evidentiary standards for accelerated approval.

    Dr. Woodcock mentioned that the FDA is clearly seeing a better quality of drug candidates coming forward.  In many cases, these candidates are based on a deeper understanding of the biology at the molecular level.  In some cases, these drugs have a companion diagnostic.  She sees this as foreshadowing a new era of therapeutics for the treatment of serious diseases.  The agency is very supportive of working with sponsors to bring these new drugs to the patients who need them.

    Fact Sheet: Break Through Therapies

    Frequently Asked Questions: Breakthrough Therapies

    Special or Limited Medical Use designation

    This concept is similar to Staged Approval or Progressive Approval.  The idea is to study a drug in a limited sub-population of patients providing a pathway to approval for that limited subgroup of patients.  As a sponsor continued to study the drug in additional populations, its approved uses would be expanded as appropriate.

    Dr. Woodcock emphasized that FDA would not have the resources to police how a drug that is approved for a special limited medical use would be used by health care providers.  The agency could monitor a product’s use, but the onus should be on the health care provider to use the drug responsibly.

    She noted that BIO currently supports this concept, but that PhRMA has not yet supported its adoption.

    FDA Mulls Fastest Track for ‘Limited-Use’ Drugs

    Structured Approach to Benefit-Risk Assessment in Drug Regulatory Decision-Making

    FDA published a Draft PDUFA V Implementation Plan on Benefit-Risk Assessment in February, 2013. In the draft, FDA describes this initiative as follows:

    “In 2009, FDA initiated an effort to explore more systematic approaches to benefit-risk assessment and communication as part of the human drug review process. This effort was driven first by the Center for Drug Evaluation and Research (CDER) leadership’s desire to be clearer and more consistent in communicating the reasoning behind drug regulatory decisions, including which benefits and risks are considered, how the evidence is interpreted and what the implications of the evidence are for the benefit-risk assessment. Secondly, CDER also identified a need to ensure that reviewers’ detailed assessments could be readily placed in the larger patient care and public health context.”

    Dr. Woodcock began her remarks by describing what a structured assessment of the risk/benefit for a new therapy would include:

  • A description of the disease burden
  • An evaluation of the existing therapies and their respective risks and benefits
  • The proposed new therapy’s risks and benefits
  • A discussion on how to mitigate the new therapy’s risks
  • A significant challenge is how to describe risk/benefit in a semi-quantifiable way.  We need to develop new tools to do this. The benefits, in particular, need to be meaningful to patients.

    The agency is working to develop new pathways to market for drugs.  As part of this effort, FDA wants to understand risks and benefits that are meaningful to patients. Dr. Woodcock describes this as patient-focused drug development.  She mentioned that our language in discussing drugs would be better served by talking about risks and benefits vs safety and efficacy.

    This concept is described in paragraph 10 of the Draft PDUFA V Implementation Plan:

    “FDA recognizes that patients have a unique and valuable perspective on these considerations and believes that drug development and FDA’s review process could benefit from a more systematic and expansive approach to obtaining the patient perspective….In PDUFA V, FDA committed to a new initiative known as Patient-Focused Drug Development with the objective of obtaining the patient perspective on the condition and the currently available therapies for a set of disease areas during FY 2013-2017. For each disease area, FDA will conduct a public meeting and will invite participation from FDA review divisions, the relevant patient advocacy community, and other interested stakeholders.”

    FDA will hold over 20 public Patient-Focused Drug Development Meetings to discuss disease burden and understand how much risk and side effects patients are willing to accept for potential benefits.  The objective in these meetings is to find meaningful ways to describe efficacy, emphasizing issues that are important to patients.  The meetings planned for FY 2013-2015 can be found here.

    Dr. Woodcock cited the example of MS as a disease that can benefit from patient-focused language.  The efficacy language for drugs in MS frequently discusses reductions in the time to exacerbations. However, patients are more interested in other issues, such as cognition, level of disability, ambulation and activities of daily living.  In obesity, patients want more than just cardiovascular benefits. “We need to work together to develop new endpoints that are meaningful to patients.”

    Dr. Woodcock noted that one of the ills of our health care delivery system is that physicians often don’t discuss risk/benefit tradeoffs with patients.  FDA is trying to step in and help overcome this weakness.

    Q&A Session

    During a lively and wide-ranging Q&A session, Dr. Woodcock covered a number of topics.  Some of the highlights included:

    Breakthrough Therapy Applications

    Some applications have been very compelling, while others have show some “irrational exuberance”.  Dr. Woodcock emphasized the following:

    • Sponsors need clinical data. Animal and pharmacokinetic data are not sufficient. The clinical data, which could include biomarker data, need to be compelling, indicating that the new therapy is likely to be MUCH better than existing therapy in some patients.

    Mainstream Diseases vs Orphan Diseases

    The disease mechanism for orphan diseases is often tied to a single gene or protein.  Because far more patients would be exposed and the disease mechanisms are more complex, the bar is understandably higher.

    Payers and Pricing for New Therapies

    FDA stays out of pricing discussions.  This is a “third rail” topic.  However, Dr. Woodcock expressed the hope that payers would “hold their fire” to make it possible for firms to make real breakthroughs with new therapies.

    Biomarkers

    Biomarkers are exciting developments that present some challenges.  Evidentiary standards have not yet been published for biomarkers.  We need to make sure that biomarkers are both valid and reproducible.  She drew a distinction between biomarkers, which are used to identify appropriate patients and perhaps measure treatment response vs surrogate markers that are reasonably likely to predict clinical benefit.

    About the Boston CMO Network

    The Boston CMO Network includes senior physician executives in the greater Boston area who are active in the biotech and pharmaceutical industry. The Network sponsors events for Boston-area physician executives to meet, interact and learn from each other.

    A Steering Committee of physician executives plans the group’s events, which are hosted at local biotech companies.

    Creating Efficiencies in Clinical Trial Design – Dr. Robert Temple, FDA, CDER

    PUBLISHED BY: Editor: BioPharm Physicians

    Mar 23,2012 | Comments Off

    On March 1st, the Boston CMO Network sponsored its second event. Dr. Robert Temple, presented to a group of 80 physician executives from Boston area biotech and pharmaceutical companies on the topic of “Creating Efficiencies in Clinical Trial Design”. Dr. Chris Wright, SVP, Global Medicines Development and Affairs of Vertex Pharmaceuticals was host of the event, which was held at Vertex facilities in Cambridge, MA.

    Dr. Robert Temple is Deputy Center Director for Clinical Science of FDA’s Center for Drug Evaluation and Research and is also Acting Director of the Office of Drug Evaluation I. Dr. Temple received his medical degree from the New York University School of Medicine in 1967. In 1972 he joined CDER as a review Medical Officer in the Division of Metabolic and Endocrine Drug Products. He later moved into the position of Director of the Division of Cardio-Renal Drug Products. In his current position, Dr. Temple oversees ODE-1 which is responsible for the regulation of cardio-renal, neuropharmacologic, and psychopharmacologic drug products. Dr. Temple has a long-standing interest in the design and conduct of clinical trials and has written extensively on this subject, especially on choice of control group in clinical trials, evaluation of active control trials, trials to evaluate dose-response, and trials using “enrichment” designs.

    Enrichment Designs in Clinical Trials

    Dr. Temple discussed the many ways to show drug effect in smaller trials that are encompassed in the concept of enrichment, which is the subject of a future FDA guidance document.

    “Enrichment is prospective use of any patient characteristic – demographic, pathophysiologic, historical, genetic, and others – to select patients for study to obtain a study population in which detection of a drug effect is more likely. This occurs to a degree in virtually every trial, although enrichment may not be explicit, and is intended to increase study power by:


    • Decreasing heterogeneity; choosing an appropriate population
    • Finding a population with many outcome events, i.e., high risk patients or patients with relatively severe diseases – prognostic enrichment
    • Identifying a population capable of responding to the treatment – predictive enrichment”



    A clear benefit of selecting high-risk patients is the ability to have enough endpoints to demonstrate a possible drug effect, at least in one group of patients. Of course, there is always a question about the benefit/risk equation in patients with lower risk, which usually requires additional study.

    Randomized Withdrawal Studies

    Dr. Temple also discussed the use of Randomized Withdrawal studies to show long term effectiveness or determine how long patients should be treated. He cited the challenges of showing a benefit vs placebo in a cyclical disease, such as depression, when treating people for only a short period of time. Randomized withdrawal can be used to demonstrate the benefit in prevention of the next episode of depression in these patients.

    “Randomized WD trials are carried out in people who appear to have responded. They are regularly used:

    • To show long-term effectiveness when long-term placebo cannot be ethically used (hypertension),
    • To see how long you should give an adjuvant cancer treatment (tamoxifen) or a bisphosphonate, and
    • To demonstrate maintenance effects for anti-depressants and other psychotropic drugs
    • Recent discussion (NSF report) of how to handle dropouts (LOCF not liked) suggest another use: make studies short, then show durability with a randomized WD study.
    • Illustration of value with anti-depressants, famous for showing small (if any) effects in acute studies.”



    Dr. Temple’s presentation was followed by a Q&A session.

    About The Boston CMO Network

    The Boston CMO Network includes senior physician executives in the greater Boston area who are active in the biotech and pharmaceutical industry. The Network sponsors events for Boston-area physician executives to meet, interact and learn from each other.

    A Steering Committee of physician executives plans the group’s events, which are hosted at local biotech companies. The Boston CMO Network expects to hold its next event in June, 2012.

    Health Economics and Outcomes Research: Why a Wise Manufacturer Should Think of It Early and Often

    PUBLISHED BY: Marya Zilberberg, MD, MPH

    Mar 3,2012 | Comments Off

    A couple of years ago I went to a meeting in Washington, DC, to be a part of the conversation on the value of Health Economics and Outcomes Research (HEOR) within the biopharmaceutical and device industry. It was a great meeting, mostly attended by people who were intimately involved in HEOR in their every-day lives. It was also somewhat spooky. None of the presenters had shared thoughts prior to the meeting. Yet everyone’s message was oddly aligned: we need more quality HEOR studies earlier in technology development.

    There was broad consensus that most companies need a better understanding of the role, methodologies, and value of HEOR within their development programs. And while clinical trialists are a well appreciated asset in the industry, HEOR groups still tend to be the red-headed step children. They get little buy-in from other departments and minimal support from the leadership, and their output is viewed with suspicion. To be sure, there are companies who understand the role of HEOR, and these are the success stories. But many remain in the dark. The message at the meeting was clear, albeit a bit paradoxical: we must do a better job articulating our own value proposition!

    There are many compelling reasons why this needs to happen. The 21st century healthcare landscape is filled with tremendous challenges that are here to stay. While 20 years ago all of the emphasis in drug development was on the FDA approval, today, in our economically constrained healthcare system, no approved technology can succeed without articulating what value it brings to the table. Therefore, the industry cannot afford to lag behind the payor community in their understanding of economic arguments. For the manufacturer who is willing to accept them, these challenges create an opportunity to become a real partner in patient-centered, high quality, efficient healthcare delivery.

    I have always argued that a manufacturer needs to be the biggest expert on the disease being pursued and its treatment; and this, I believe, is largely the case. Yet by necessity this expertise must extend to the value proposition for their technologies that goes well beyond the statistically significant improvements over placebo required by the FDA for approval. We must develop objective milestones by which to judge worthiness of technologies in development at every point in the development process. Those who do, will adapt to and succeed in this atmosphere of cost controls. Those who don’t, do so at their own peril. It is imperative to engage in this ongoing evaluation of our innovations with a critical eye to what value they will bring to the society.

    The Boston CMO Network

    PUBLISHED BY: Editor: BioPharm Physicians

    Nov 27,2011 | Comments Off

    “We are rapidly becoming the major biotech/pharma hub in the US.  As senior medical leaders, we should be meeting to discuss critical industry issues, network, and expand our horizons beyond the day-to-day activities in our respective organizations.  We can learn about progress, share our experiences & ideas and, of course, describe our challenges and success stories.” Akshay Vaishnaw, Chief Medical Officer, Alnylam Pharmaceuticals

    The idea for the Boston CMO Network grew out of discussions between Akshay Vaishnaw, Chief Medical Officer for Alnylam and other senior physician executives in the Boston biotech hub.  They all recognized a need for Boston-area biotech and pharma medical leaders to meet periodically to exchange ideas, network, and share interesting news and opinions. Steve Rauscher of BioPharm Physicians worked with the group to organize and plan activities.  Al Sandrock, SVP of Medical Research-Neurology at Biogen Idec graciously agreed to host the first event.

    Boston CMO Network Inaugural Event

    On November 10, 2011, the Boston CMO Network held its first networking event at the Biogenic Idec Cambridge campus.  Fifty senior physician executives from the Boston area biotech and pharmaceutical industry gathered to hear Christoph Westphal MD PhD, Founder and Partner of Longwood Fund, present “Ups and Downs for Drug Innovation — a Dozen Years in Boston Biotech”.  A lively Q&A session ensued, which continued during the reception that followed.


    Future Events

    Attendees were surveyed about upcoming events.  Most recommended that 3 or 4 events per year would be the ideal frequency.  Suggested ideas for future topics included the following:

  • Presentations by larger biotech firms on what their companies are seeking to bring in house
  • Recent changes in the biotech landscape in Cambridge
  • Effect of the economy on start-ups
  • Trends in therapeutic targets
  • Funding issues facing start ups:
  • Tips on VC road-shows and raising money
  • Big Pharma partnerships as a source of funding and resources
  • BD/in-licensing/partnering as a way to either grow your portfolio or sustain your company; potential benefits and pitfalls
  • Personalized medicine, new clinical trial design with POC moving to(wards) Phase I, targeted therapeutics with efficacy-predictive biomarkers
  • Best tools for keeping abreast of information
  • Managing talent:  how to acquire and keep the best
  • Issues on our future:
  • Nanotechnology – is it the future?
  • RNA based technology – is there a future?
  • Generics/Biosimilars – will they take away our future?
  • Companion diagnostic development
  • New trial designs and trends in outcomes research
  • Effects of evolving regulatory standards changes in payer philosophy and criteria for reimbursement

  • The next Boston CMO Network Event is planned for late February or early March, 2012

    Recent Posts from Blogs We Follow

    PUBLISHED BY: Editor: BioPharm Physicians

    Aug 21,2011 | Comments Off

    Pharma Strategy Blog

    One of our favorite blogs is the Pharma Strategy Blog authored by Sally Church, PhD.  Sally provides “Commentary and insights on Pharma & Biotech new product development with a focus on oncology and hematology.”  It is a must-read for anyone in the oncology and hematology space.

    One of Sally’s recent posts, “On T Cells and chronic lymphocytic leukemia” provides an excellent overview and a more measured interpretation of the results from a small pilot study done by University of Pennsylvania researchers David L. Porter, MD, Carl H. June, MD, and colleagues.  Much of the coverage in the general media over the results of this small study was clearly overblown.

    Applied Clinical Trials Online

    This is the blog for the online version of Applied Clinical Trials magazine, “the global, peer-reviewed journal whose coverage features the process of managing clinical trials at the intersection where pharmaceutical product developers meet the strictly regulated medical researchers who test their new drugs.”

    A recent post on this site, The Confusion Surrounding Comparative Effectiveness Research, was authored by Richard Gliklich, MD, the President of Outcome Sciences.  The post discusses some of the issues and confusion around comparative effectiveness or patient-centered outcome research.

    On Biostatistics and Clinical Trials

    This blog is authored by Chunqin (CQ) Deng, who describes himself as “A Medical Doctor turned into Biostatistician in Clinical Trial and Drug Development.”  In his blog, he discusses issues in biostatistics and clinical trials.  A recent post, Equipoise and Lack of Equipoise in Randomized Clinical Trials, discusses a clinical trial design approach that Dr. Deng and his colleagues used to overcome the lack of equipoise in a trial using IVIg, (intravenous 10% caprylate-chromatography purified immunoglobulin) for the treatment of CIDP, (chronic inflammatory demyelinating polyradiculoneuropathy).

    Crowd-Sourcing in Clinical Development

    PUBLISHED BY: Editor: BioPharm Physicians

    Jul 25,2011 | Comments Off

    Guest Post from Tomasz Sablinski, MD, PhD

    FDA’s Janet Woodcock recently testified to a subcommittee of the House of Representatives that drug approvals in 2011 may be headed for a 20 year high.  However, most of the news in the industry lately has been negative.

    As noted in Fierce Biotech:

    “A recent Thompson Reuters report found that the number of experimental drugs moving in to Phase III trials plunged 55 percent in 2010. The stats weren’t much better in earlier stages either: new Phase I studies dropped by 47 percent and while new Phase II trials fell over 50 percent. That high failure rate partially explains why only 21 new drugs got the green light in 2010–fewer than both 2009 and 2008, when 25 and 24 were approved, respectively.”

    A long-time drug developer in the industry, Tomasz Sablinski, MD, believes the industry needs new and novel approaches in drug development.  In addition to his role as Head of Development at Celtic Therapeutics he recently founded Transparency Life Sciences, and is inviting a diverse audience of patients, providers and scientists  “to help create the world’s first open-source, completely transparent drug development organization”.

    Dr. Tomasz Sablinski is the Head of Clinical Development and a member of the Executive Committee of Celtic Therapeutics Development (CTD).  He is Founder of Transparency Life Sciences. Prior to joining CTD, Dr. Sablinski served as Vice President at Novartis in charge of US Clinical Development and Medical Affairs. Prior to this, Dr. Sablinski held several leadership positions at Novartis headquarters including Vice President of Clinical Research and Development and Head of Global-Japanese Coordination. He also held multiple leadership positions in Novartis’ Transplantation Business Unit. He participated in, and supervised numerous NDA and IND submissions in the US, Europe and Japan.

    Dr. Sablinski joined the Pharmaceutical Industry with Parexel in the mid-nineties as  Medical Director. Prior to joining the pharmaceutical industry he conducted basic research while appointed as Instructor of Surgery at Harvard Medical School, Massachusetts General Hospital, and Fellow at the Brigham and Women’s Hospital in Boston. His other clinical appointments include Lahey Clinic, Burlington, MA, and Central Clinical Hospital in Warsaw, Poland.

    Dr. Sablinski earned his MD and his Ph.D. in transplant immunology at Warsaw Medical School.

    Dr. Sablinski sat down with BioPharm Physicians to talk about innovation in drug development.

    BioPharm Physicians: Dr. Sablinski, you’re involved in two organizations, Celtic Therapeutics and Transparency Life Sciences. Both are using novel approaches to drug development.  Can you begin by telling us a little about Celtic?

    Dr. Sablinski: Celtic Therapeutics is a limited partnership private equity fund focused on drug development.  Unlike a classic venture capital or private equity partnership, we focus on acquiring and developing promising new therapeutics using a small team of experts and a virtual drug development model.  The goal of the partnership is not to build new companies.  Rather, the goal is to build value in new products through smart, cost-effective development and then sell or out-license those products to pharmaceutical companies for downstream commercialization.

    We are building and developing a diversified portfolio of products in quite diverse areas including ophthalmology, Amyloid A (AA) amyloidosis and variety of cancer indications.  Our approach is novel, since we avoid the costs and overhead associated with building individual companies.  We focus only on building value in individual products.

    BioPharm Physicians: What have been some of the biggest challenges in the virtual drug development model?

    Dr. Sablinski: Traditionally, many have viewed “virtual” development, as inferior to a “bricks and mortar” approach. Thus, the first challenge is to convince external audiences (development partners, investors) that the main reason to be virtual is not the shortage of money, but rather the superiority of the approach versus one that calls for using resources to build a stagnant “built to last” organization.

    The second challenge is to find the right people.  There is no room for free-riders in a super-dynamic, content–centered and transparent development environment. The engagement of contributors starts and ends with an enthusiasm for the content, and from applying one’s expertise to contribute to moving a project forward.  It is increasingly easier to identify people who share such a mindset, and knowledge networks such as LinkedIn and your community of physicians are great enablers.

    Another interesting challenge is to appropriately reward contributors who will often meet in the “cloud” only – different models exist and are successful in other industries.

    Drug development in our industry has not yet embraced and faced these challenges. It is not surprising, as in my estimate this industry is about a decade behind other industries in effective use of computers  and new information technologies.  Unfortunately, this decade-gap is widening rapidly, and I do not think it can be bridged without a radical re-engineering of the entire model.

    BioPharm Physicians: You’ve recently launched Transparency Life Sciences.  Can you describe for us what you hope this new initiative can accomplish?

    Dr. Sablinski: Transparency Life Sciences (TLS) is a web-enabled biopharmaceutical company whose mission is to develop medicines for significant unmet medical needs, using a fundamentally superior approach compared to current industry standards. Initially, TLS will focus on acquiring and re-directing the development of compounds that have demonstrated a signal of efficacy, and a clean safety profile, but are “on the shelf” as a result of poor alignment with the owner’s corporate strategy, unsuitable properties for the current indications of interest, or financial reasons.

    Transparency Life Sciences will develop products using a game-changing approach based on three pillars:

    1. Collaborative intelligence (cIQ), a.k.a crowd-sourcing, open source
    2. Transparency of data
    3. Convergence of modern health information technology with drug development know-how

    As a result we hope to develop much less expensive medications, much faster and with relevance and quality of data exceeding today’s standards.

    BioPharm Physicians: Can you discuss the importance of an open-sourced approach and the value of transparency in drug development?

    Dr. Sablinski: The value of this approach to product design has been well proven in software (Linux), and many other industries. It is increasingly recognized as a valuable method in basic research, and drug discovery (references available on request). However, no company has adopted cIQ as a way to design, execute, and analyze clinical studies – the crucial, most expensive and most time-consuming part of the development of new treatments.

    With open-sourced development, anyone anywhere will be able to contribute to the planning and design of TLS compound development strategies and tactics in real-time. By granting full data access to a broad expertise, the TLS open source approach will add substantial value to its pipeline of products, benefiting TLS stakeholders, partners, and product acquirers. Algorithms and filters to manage crowd input will be implemented to enable efficient processing of information. A reward system will provide incentives to users offering high quality, high impact contributions. Based on the open source approach, TLS can cover a wide range of therapeutic areas and diversify overall business risk.

    In contrast to the historical approach taken by Pharma companies in most aspects of their business, TLS believes that the benefits of working in a transparent environment far outweigh the risks. Pfizer, Merck, Lilly and others have recognized this value, and launched “open source” efforts in early research to supplement and improved the productivity of their internal discovery efforts. TLS however believes that transparency should facilitate every step of its business process, from evaluating and selecting compounds for acquisition; developing the clinical plan and study protocols; recruiting and executing studies; processing, analyzing and interpreting data; regulatory and reimbursement discussions; and ultimately making decisions related to potential asset sales.

    BioPharm Physicians: The industry faces tremendous challenges in improving its research productivity and reducing the cost of late stage failures in development.  What are your thoughts on some of the things that industry physicians need to consider to improve R&D productivity?

    Dr. Sablinski: I have a very clear and blunt message here:

    1. Do not waste time attempting to improve existing model(s) of clinical stages of drug development, as these are based on mid – twentieth century principles and completely ignore the fact that we live and operate in the world driven by technology. Consequently, these approaches are, in fact, trying to adjust the world around you to fit the glacial pace of change in the industry.  They will fail.

    2. Look for successful models in other industries, particularly in computer sciences and information technology.  Adopt and try them in drug development.

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