Jul 14 2011

Recap of the DIA Annual Meeting 2011

DIA 2011 Annual MeetingThe 47th Annual DIA Meeting was held on 19-23 June 2011 in Chicago and was a great success with thousands of attendees from the health care industry and regulators from around the world including representatives from the FDA, the EMA, and many other global agencies.

This year’s keynote speaker was the renowned AIDS researcher and Time Magazine’s Man of the Year in 1996, Dr. David Ho, who spoke to the exciting history and future outlook of AIDS research and treatment efforts since the disease was first presented in the US in the early 1980s.  While there is no commercially available AIDS vaccine at this point, several highly effective treatments to control HIV have been developed over the past 30 years.

As a regulatory affairs professional at Cato Research, I was particularly interested in the latest developments of some regulatory topics.  For those of you who couldn’t attend, here are snapshots on biosimilar policies, EU Scientific Advice, and US- EU agency collaborations.

Biosimilar Policies in the US and Abroad

The excellent biosimilar sessions focused on the recent US biosimilar legislation presented by officials from FDA’s Center for Drug Evaluation and Research (CDER) and comparisons of biosimilar regulations in different regions.  The path for biosimilars in the US was paved by the Biologics Price Competition and Innovation Act (BPCI Act) and signed into law by President Barack Obama on March 23, 2010.  This Act creates an abbreviated licensure pathway for biological products shown to be biosimilar to or interchangeable with an FDA-licensed reference product.  This new licensure pathway under section 351(k) permits a biosimilar to be licensed based on less than a full complement of product-specific nonclinical and clinical data.  The requirements for a 351(k) application for biosimilars were explained by FDA’s Janice Weiner (Regulatory Counsel, CDER) and must demonstrate that the biological product is:

  • Biosimilar to a reference product
  • Utilizes the same mechanism of action to the extent known for the reference product
  • Conditions of use in the label have been previously approved for the reference product
  • Has the same route of administration, dosage form, and strength as the reference product
  • Is manufactured, processed, packed, or held in a facility that meets standards designed to assure that the biological product continues to be safe, pure, and potent

The bar for an interchangeable product is higher in that it not only needs to be biosimilar to the reference product but it must also produce the same clinical results as the reference product in any given patient, and, for products administered more than once, the safety and reduced efficacy risks of alternating or switching are not greater than with repeated use of the reference product without alternating or switching.   In contrast to a biosimilar product, an interchangeable product may be substituted for the reference product without the authorization of the health care prescriber.  Examples of issues still open for further debate on biosimilars include the following:

Definition of a biological product?

The BPCI revises the definition of “biological product” as “a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product …” the FDA is evaluating public comments regarding this definition.

Use of non-US reference product acceptable?

The reference product for a 351(k) application is defined as a single biological product licensed under section 351(a) in the US.  The question is whether nonclinical or clinical data with non-US-licensed products can be used to support biosimilarity to a US-licensed reference product.

What constitutes interchangeability?

Clear standards still need to be established for data that allows FDA to determine that a biological product meets the statutory requirements for interchangeability and for factors to evaluate the potential risk associated with alternating or switching between the reference product and the proposed product.

Standard for naming?

At this point no policy relating to the naming of biosimilars, interchangeables, and biological products that are not biosimilars, have been established in the US.

These and other unresolved issues may be further defined in a draft guidance on biosimilar products that FDA is currently working on and expected to be published later this year.  To date, 21 pre-IND meeting requests for proposed biosimilar products to 9 reference products were received and 15 pre-IND sponsor meetings held.  Review challenges identified by FDA’s Leah Christl (Associate Director for Biosimilars, CDER) include requests to use data previously generated to support ex-US approvals and requests to follow EMA guidance that may or may not be suitable to demonstrating biosimilarity according to the US statute.  To help ensure consistency in FDA’s regulatory approach regarding biosimilar reviews, three committees were established:

  • CDER/CBER Biosimilar Implementation Committee
  • CDER Biosimilar Review Committee
  • CBER Biosimilar Review Committee

The global perspective on biosimilar legislation was provided by Joseph Scheeren (Head Global Regulatory Affairs, Bayer Healthcare Pharmaceuticals) and officials from the European and Japanese regulatory agencies.  The first region to facilitate biosimilar approval is the EU (first approval: April 2006), followed by Japan (first approval: June 2009), the US and then the emerging markets.  To date, 14 marketing approvals for biosimilars have been granted in the EU and 4 applications were withdrawn or rejected.  The market share of biosimilars in Europe, however, is still very small with approximately 5-10% of the innovator products.  This small percentage is due to the fact that the marketing of biosimilars is not the same as the marketing of generics, the interchangeability question mentioned above is a hurdle for prescribers, and, if biosimilars cannot be prescribed by their international nonproprietary name, the pharmacist cannot substitute the product – the latter issue touches on the unresolved naming problem.  Similar to the US legislation which requires the use of an US-licensed reference product, the EU, Japan, Korea, and Canada require the use of a reference product licensed by their own regulatory authorities, which is an interesting challenge in the quest for harmonization of the biosimilar regulations amongst the different regions.  However, the different regions share their opinion on the overall requirements for the content of the biosimilar dossier and definition of a biosimilar product.

FDA-EMA Agency Collaboration

The main presenters for this session were officials from the FDA (Murray Lumpkin, Deputy Commissioner, Internal Programs) and the EMA (Martin Harvey, Head of the Office of the Executive Director; Hilde Boon, Liaison Official at the FDA).

The framework for the FDA-EMA agency interactions is based on the confidentiality agreement first signed in 2003.  These agreements facilitate agency interactions in the areas of product development, product evaluation and surveillance, product manufacture and compliance and liaison activities.  Hence, both agencies are talking to each other about new and pending applications which means that e.g. oncology drug applications submitted in the US and the EU are likely compared and discussed between both agencies.  This confidential exchange between the agencies is important for the sponsor to keep in mind and has implications on the level of consistency between the US and EU dossiers.  The dialogue between FDA and the EMA continues to expand and resulted in “clusters”, which are topic-specific groups composed of personnel from both agencies.  To date, there are 9 clusters with the most recent cluster for biosimilars established this summer:

  • Advanced technology medicinal products
  • Orphan products
  • Blood
  • Pediatrics
  • Gastrointestinal
  • Veterinary
  • Oncology
  • GMP
  • Biosimilars
  • GCP
  • Pharmacogenomics
  • Pharmacogivilance

Examples for activities within the e.g. orphan cluster are a common annual report for designated orphans, monthly exchanges of all orphan designation applications and teleconferences focusing on “difficult” applications, including analysis of divergent opinions.  Additional mechanisms for information exchange include:

  • Exchange of assessment reports and review documents
  • Regular tele-/videoconferences on specific topics and product classes
  • Ad-hoc teleconferences between EU-US experts
  • Sharing of pharmacovigilance and inspections information
  • Joint GMP/GCP inspections
  • Participation in workshops, meetings, trainings
  • Agency Liaison placements
    • Janice Soreth (FDA) at EMA since June 2009
    • Hilde Boone (EMA) at FDA since Jan 2010
  • Ad-hoc Agency staff visits
  • ‘FDA Fellowships’ for EMA staff

EU Scientific Advice

Cecil Nick (Vice President, Technical, Parexel Consulting) started off the session on EU Scientific Advice by providing background on the procedure and considerations of why, when, who, and how to ask for advice.  A real-world example was given by Robert Miller (Chief Consultancy Physician, Aptiv Solutions) followed by Spiros Vamvakas (Head of Scientific Advice, EMA) who provided the EMA perspective.

Why ask for scientific advice?

The take-home message was that the potential positive impact of asking for scientific advice (i.e., resolve difficult issues upfront, improve probability of favorable outcome) outweighs the potential downside of investing time and money into this procedure.  An analysis of 188 marketing applications during 2004-2007 supports the view that compliance with scientific advice is associated with a positive outcome: only 72% of applications were authorized without receiving advice compared with 97% authorizations for applications that received and followed scientific advice.  At the same time, authorizations were down to 30% for those applications that received advice but did not follow it, suggesting that applicants must be committed to act on the advice in order to benefit from this procedure.  The scientific advice procedure first started in 2000 with 58 advice procedures and has steadily gained popularity reflected in an increase to 332 scientific advice procedures and 68 protocol assistance procedures (scientific advice for orphan drugs) in 2010.  Interestingly, all 14 biosimilars authorized in the EU, have received scientific advice.

When to ask for scientific advice?

Typically, scientific advice is sought at the nonclinical/clinical stage, but it can be given at any stage in development and any combination of quality, nonclinical and clinical questions can be asked.  Advice is most important when one is faced with the following scenarios:

  • Innovative trial design
  • Innovative indications
  • Innovative products such as biosimilars and advanced therapy products (e.g., cell-based products, gene therapy products)
  • No guideline available or when deviating from the guideline
  • Rare diseases
  • Critical clinical issues (e.g., primary endpoints, statistics, comparator studies, pediatric and geriatric studies)

Who to ask?

Scientific advice can be given by individual European member states (national advice) or the EMA (centralized advice), which is then applicable in all EU countries and a good way to obtain an EU consensus view.  National advice is typically a face-to-face meeting, faster, more informal, and cheaper (sometimes free) than advice from the EMA.  Neither advice is non-binding but national advice must be included in clinical trial applications and marketing authorization applications as well as the request for EMA advice.  The EMA often provides written advice with no opportunity for a meeting but this feedback is important when different member states are likely to have different opinions on key issues.  If advice is sought on a national and centralized level, national advice is typically requested before advice from the EMA.

How to ask?

The EMA provides a website with information on how to request EMA scientific advice as well as a guidance document on “European Medicines Agency Guidance for Companies requesting Scientific Advice and Protocol Assistance” (EMEA-H-4260-01-Rev.6).  Briefly, the sponsor provides questions and the company’s position and justification in writing with cross-references to the relevant parts of the annexes.

This is a post by Sybille Sauter, Ph.D., RAC (US & EU).  Sybille is the Associate Director, Regulatory Affairs and the Assistant Managing Director of our San Diego, CA office.