Three New FDA Initiatives that Matter

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 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.

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