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2015 – A Record Year for Antibody Product Approvals, But Not For Biopharmaceuticals Overall

Monday Jan 25, 2016

By: Dawn M. Ecker  (deckeratbptcdotcom)  

Recombinant biopharmaceutical products have been a growing sector in the pharmaceutical landscape for over 10 years and antibody related products[i] are undoubtedly the cornerstone of the biopharmaceutical market. Based on a query of BPTC’s bioTRAK® database at the close of 2015, there were 194 recombinant therapeutic biopharmaceuticals approved on the US/EU market. Antibody related products represented nearly a third (1/3) of these products (57 of 194) and generated over half ($85B) of the $152B in sales of biopharmaceuticals for 2014.[ii]

Since recombinant products entered the market in 1982, 215 therapeutic products consisting of 69 antibody related therapeutics and 146 non-antibody therapeutics have been approved over the last 33 years.[iii] Although the FDA’s total approvals reached its highest levels since 1996 with 45 new active ingredient approvals and the EMA followed close behind with 39 new active substance approvals, 2015’s approvals for biopharmaceuticals were less than 2014 (see Figure 1 below, 13 vs. 21).

If we take a closer look of the total number of recombinant products approved every year since the approval of Humulin in 1982, in 2015 only three recombinant products were approved compared to 14 in 2014. The three 2015 approved products were all recombinant blood proteins – Ixinity, Vonvendi, and Adynovate.

With the approval of the first therapeutic monoclonal antibody Orthoclone OKT3 in 1986, 2015 saw a record number of antibody related approvals (10), surpassing 2014’s record of seven antibody product approvals. Of the 2015 approved products, eight are full length monoclonal antibodies: Cosentyx, Darzalex, Empliciti, Nucala, Portrazza, Praluent, Repatha, and Unituxin. The remaining two products consist of an Fc-fusion protein, Strensiq and an antibody fragment, Praxbind.

As we begin 2016, it is possible that the coming year’s approvals may surpass previous records for biopharmaceutical approvals in 2014 as well as antibody product approvals 2015. BPTC’s bioTRAK® database currently lists 22 products under FDA or EMA review, which could be approved in 2016 (see Table 1 below).

If we look even further back into the pipeline, it is clear from our bioTRAK® database that the interest in the development of biopharmaceuticals is strong, with over 450 recombinant products in Phase 2 or Phase 3 development. Over 70% of these clinical products are antibody related products. Although many of these products are still in active clinical trials, it is possible that some of these products may possibly file for review and be approved before the end of 2016.

As full pipelines and strong interest in biopharmaceuticals continues into the latter part of this decade, it is very likely that biopharmaceutical approvals will continue increasing their impact on the pharmaceutical landscape, with antibodies remaining the cornerstone of the biopharmaceutical market for the foreseeable future.






















[i] We consider antibody products to include full length monoclonal antibodies, antibody fragments (Fab fragments), Fc-fusion proteins, antibody-drug conjugates, and other conjugated antibody products for therapeutic use in humans.

[ii] Sales data for biopharmaceuticals sold in 2015 have not yet been released. Please check back for a new blog revealing 2015 sales.

[iii] Eleven therapeutic antibody products and 10 non-antibody recombinant therapeutics have been since withdrawn from the market.


WCBP 2016

Tuesday Jan 19, 2016

Joseph Siemiatkoski, Consultant, will be co-chairing a workshop entitled, “Product Quality Attributes, Risk Assessment and Control Strategies”, and facilitating a Round-table Discussion entitled, “Raw Material Testing, enough is enough! Or is it?” during the WCBP 2016 conference and CMC Strategy Forum to be held at the Mayflower Hotel in Washington, D.C. from January 25-28, 2016. If you’re interested in setting up a meeting to learn more about BPTC’s CMC and analytical consulting services while at the conference, please send me an email  (jsiemiatkoskiatbptcdotcom)  .


Breakthrough Therapy Designation-Not Necessarily a Slam Dunk

Wednesday Jan 6, 2016

Accelerating your CMC Timeline

By: Patti Seymour  (pseymouratbptcdotcom)  

Breakthrough therapy (BT) designations have been receiving much attention since the Advancing Breakthrough Therapies for Patients Act was approved in 2012. A drug candidate may receive BT designation if it treats a serious or life-threatening disease, and preliminary clinical data suggests that the drug provides a substantial improvement over existing therapies.

BTT status can significantly shorten product and process development as well as launch timelines. However, the FDA has stressed that BT designation does not mean sponsors can do less development; rather they need to start sooner with certain activities. This may necessitate committing development resources while the overall program is still considered high-risk. For example, process development and scale-up may need to start before definitive proof-of-concept (POC) data is available and risk analysis is complete. Postponing risk analysis activities until after POC is achieved will require allocation of additional resources in order to generate the necessary regulatory filing data for an accelerated approval. The bottom line is that BT designation does not change the fundamental FDA expectations. However, the designation will likely change the timing of when certain activities must be completed. FDA has been open to discussions with companies about how best to plan for the completion of certain activities.

At BPTC, we recommend that companies conduct an early risk-benefit assessment to determine what activities to start earlier and identify where there will be a need to deploy more resources later. The tradeoff is between the risk of having less robust quality and CMC information available at the time of license application versus patient benefit by getting the product on the market faster. The associated accelerated clinical timelines will necessitate new approaches to product and process development, commercial readiness, launch and regulatory filings. This can be accomplished by focusing on reliable product supply of appropriate quality at launch, and not worrying as much about process optimization.

When short pivotal trials (< 2 years) are involved, process characterization and validation activities will be on the critical path for inclusion in a license application. The decision to accelerate these activities can require a significant increase in resources. For example,

  • front-loading process characterization studies by using a Quality by Design development strategy before seeking BT designation, or
  • front-loading analytical studies to offset the limited process understanding and to support future comparability analysis, or
  • testing qualification lots before assay validation is completed.

Each of the above options has its own unique associated risks that need to be carefully evaluated as part of the overall risk-benefit assessment.

These risk trade-offs shift the focus on the reliability of the Phase 1 cell line, process and formulation. If a front-loading strategy is followed, only critical CMC issues are likely to be addressed before filing and many post-approval process changes may be needed. This approach may be acceptable for well-characterized products such as monoclonal antibodies, but can lead to significant risk for complex products such as cell therapy products.

Additional acceleration approaches to consider can include leveraging supportive platform process data where applicable rather than generating de novo data. Stability data from representative pilot scale lots with the same formulation can be used as lead-in supportive data if a shorter timeframe, such as 6 or 12 months, of real time stability of commercial lots is submitted. A commitment to provide real time confirmatory data during review and post approval is expected. The sponsor should request flexibility to modify the control strategy, specifications, or Critical Process Parameters post-launch with additional manufacturing experience if they file with more tests initially and provide justification to eliminate some test post-launch.

It is important to understand what CMC/cGMP requirements can be deferred post-approval without compromising patient safety. The sponsor should identify potential patient safety related activities and classify them into three categories:

  • must comply fully to address patient safety
  • may be delayed post filing but completed prior to launch
  • can be deferred until post-approval

Submitting a Post-Approval Lifecycle Management Plan with the license application to support completion of deferred activities post-launch will communicate to the FDA the commitment to follow-through on certain activities. The options described above need to be negotiated with the FDA prior to an application submission. However, once you have successfully negotiated a filing and approval strategy with the FDA, that strategy is very likely to be further complicated by expectations for simultaneous submissions in other markets (EU, Japan, Emerging Markets).

Since its inception, FDA has received approximately 283 requests for BT designations, but fewer than half (103) of the requests have been granted. As of the end of September 2015 (most recent data available), 27 BT commercial approvals have been granted. The actual number of products approved as BTs is lower since this number includes approvals of multiple supplements for the same product. The ratio of requests to grants of BT designation has been relatively steady at approximately 60-65%, but the rate of commercial approvals has declined between 2014 to 2105 (14 versus 10, respectively) This drop may reflect the need to devote significant additional resources to the rapid development of a product with this designation. The BT designation is an extremely useful designation to accelerate your product through the clinic, but may not necessarily accelerate your product approval.


Creating Meaningful Protocols: Key Recommendations from FDA and EMA

Friday Nov 20, 2015

By: Mike Glacken  (mglackenatbptcdotcom)  , Senior Consultant

Early in my career I had a Sr. VP tell me, quite seriously, after I presented CMC timelines for a given project that “the problem with timelines, Mike, is that people expect you to keep them”. I had reason to recall this Captain Obvious moment recently when discussing with colleagues how to set acceptance criteria for a Process Performance Qualification (PPQ) protocol. Protocol authors seem to be afraid to set meaningful acceptance criteria in their protocols for exactly the same reason. Not that I can blame them. Failing acceptance criteria in a PPQ protocol will generate headaches.

However, validation philosophy has evolved greatly over the last decade or so. There have certainly been new guidance documents issued on the subject, from the FDA in 2011, to the EMA in 2014 and the PDA in 2013. A thoughtful reading of these documents provides some insight into how to generate more meaningful, yet generally achievable, acceptance criteria.

The FDA guidance document states that the PPQ protocol should contain:

  1. “criteria and process performance indicators that allow for a science- and risk-based decision about the ability of the process to consistently produce quality products” and there should be
  2. “a higher level of sampling, additional testing, and greater scrutiny of process performance than would be typical …”.

The EMA guidance document advises that controls during PPQ:

  1. “are expected to go beyond the routine control system as described in S.2.2 and S.2.4”,
  2. validation of the upstream process should “focus on the confirmation of consistency of performance indicators and quality attributes” while,
  3. validation of the downstream process should “confirm the clearance capability”, and
  4. demonstrate that the process is “able to consistently generate the targeted quality of process intermediates and active substance”.

This language certainly suggests that much more is expected than simply following the batch record and meeting batch drug substance (BDS) specifications.

In my role at BPTC, I recently reviewed a PPQ protocol with acceptance criteria that stated “All batch record ranges and IPCs must be met” and “The BDS from all conformance lots must meet specifications”, but little else. I wondered whether implementation of this protocol would be a valueless exercise. I had to ask “Don’t all commercial lots need to follow the batch record and produce BDS that meets specifications?” “Of course”, was the answer. I followed up with “Then what’s the purpose of the PPQ protocol?” The response was “That’s the way we have always written the acceptance criteria”. Unfortunately, almost all the PPQ protocols I’ve seen over the years were written the same way.

Given the above observation, how then should we set the acceptance criteria? While we want to make the criteria meaningful, we certainly do not want to fail. That’s something that Sr. VP apparently did not understand: I crafted those CMC timelines with the expectation that they would be met. The same must hold true for the acceptance criteria in PPQ protocols. This is a topic for another blog. I’d be interested in your opinion about how to improve PPQ protocols.


Top 3 COGS Drivers for Peptide Therapeutics

Wednesday Nov 11, 2015

By Terence Davidovits  (tdavidovitsatbptcdotcom)  

In the last few years, there has been a renewed interest in peptide therapeutics directed toward a wide range of indications, including diabetes, cardiovascular disease, HIV and cancer. Peptides, compared to other small molecule drugs, offer increased specificity while potentially offering greater metabolic stability and oral availability than protein biologics. These peptide therapies can be manufactured using either recombinant methods or chemical synthesis alone or in combination. Recently, innovative synthesis methods have been described for generating long peptides that can be classified as proteins. For example, Provence Technologies recently synthesized IL-10, consisting of 160 amino acids. The FDA classifies any peptide produced synthetically containing over 100 amino acids as a protein. This blog outlines the three elements that affect costs of producing a peptide therapeutic.

First, a critical factor in the cost of peptides made by chemical synthesis is the product yield per amino acid addition step. A high number of sequential synthesis steps to grow a peptide can prove detrimental to process economics. For example, even a 95% step yield repeated over 20 reactions gives a total product yield of around 36%. In addition, a similar yield challenge exists as the number of peptides to be linked together to form the final product increases. Therefore, gaining the highest possible overall yield is critical to achieving cost-effective processes for longer peptides. One option for longer peptides is to perform a hybrid synthesis where peptide fragments are produced using solid phase synthesis first, then joined using solution phase synthesis to generate the product. Two other significant variables to quantify when considering costs are the coupling reaction time needed per step and the raw materials required. In the case of chemical synthesis, costs are also dependent of whether the process utilizes solution or solid phase synthesis.

Second, costs for recombinant fermentation-based production depend on how much product is produced per batch and fermentor turnaround time. These two factors determine the length of time these batches will keep a manufacturing facility busy. The amount of product produced will depend on the size and number of fermentors used. Recombinant process costs also include downstream separation steps that differ depending on whether the peptide is held within the cells or excreted into the growth medium. Recombinant processes tend to require more up-front investment, but have better economies of scale.

Third, the scale of the manufacturing operation and market demand are key factors. Each of these parameters affects the major cost categories in COGS calculations as outlined in a previous BPTC blog written by my colleague Rick Stock. In many cases, it would be a worthwhile tradeoff to assess quantitatively which method is likely to be the most efficient before making a final manufacturing process selection. Early process development work could both inform the analysis and show how much development work remains for each case. Such an analysis is used to generate the metrics associated with a specific COGS target, and indicate which strategy would likely yield the lowest COGS.