August 1, 2009 (Vol. 29, No. 14)

Bruce F. Mackler Ph.D., J.D.

Regulatory Reflections on the Agency’s Expectations and Guidance for These Products

With Congressional actions on biosimilar/follow-on biologics approaching, FDA has issued a Guidance regarding the use of pens, jets, and other related injectors. (See Draft Guidance for Industry and FDA Staff: Technical Considerations for Pen, Jet and Related Injectors Intended for Use with Drugs and Biological Products, April 2009.) The Guidance recognizes that these are innovative approaches to deliver drugs or biologics products that may enhance accuracy and patient compliance.

One major significant issue of this Guidance lies in its application to biosimilars, facilitating their conversion into higher-value follow-on branded products. As an example, Novo Nordisk is now introducing its next-generation FlexPen, a prefilled insulin delivery device that the company reports has a 25–41% lower force than the existing SoloStar and KwikPen devices; diabetic patients prefer lower-force insulin injections since they are less painful.  

After obtaining FDA approval to market in the U.S., a first-generation biologic may have little commercial value as a commodity product and have a BX rating (not substitutable), since most biopharma companies have developed a second- or third-generation biologic with an innovative delivery system—a specialty product. It is anticipated that specialty products will command prices near or only 10–20% less than that of the originator product, even though they will not have a BX rating. In this scenario, the initial approval of the first-generation biosimilar is really a strategy to rapidly enter the marketplace, then quickly evolve into a higher-value specialty, often called a follow-on branded product.

The Guidance specifically outlines the regulatory data contents for marketing applications and makes the transition from a commodity biosimilar to a higher-value specialty follow-on branded product. It should not be lost on those utilizing this development vehicle that the limiting step in market penetration will be the lack of an AB substitutability rating, thus follow-on high-value branded specialty products will either require sales forces or significantly lower prices to make them attractive.

One can anticipate that in their lifecycle management strategies, biopharma companies of originator products will now develop patent strategies to anticipate this competitive follow-on branded approach.  Companies developing new delivery technologies that improve safety and/or efficacy of biologics will be attractive investments in the future for both originator and biosimilar manufacturers. 

It is interesting that Johnson & Johnson recently announced that it would consider selling branded generics abroad, perhaps in partnership with another company. Pfizer, Novartis, and other major pharma companies are pursuing similar strategies. One wonders if follow-on branded biologics will be far behind these marketing activities.


Glycosylation Perspective

An argument against approval of glycosylated biosimilars has been the significant carbohydrate differences caused by different expression systems and manufacturing processes in terms of quality, efficacy, potency, and safety of the product. Biological & Pharmaceutical Bulletin recently published an analysis of the glycosylation patterns of four epoetin products (α and β) available in Japan that found tangible differences in acetylation of sialic acids and significant differences in the nonfucosylated oligosaccharides.

One can anticipate the regulatory need for safety data to demonstrate that any  glycosylation differences do not adversely impact the biosimilar. While non-U.S. manufacturers can collect patient safety data from their early entry into local markets, U.S.-based biosimilar companies will need to consider having stronger preclinical and clinical databases to address this concern. This potential negative regulatory safety presumption should also be viewed from the safety profile of goat antithrombin alfa approved by EMEA in 2006, which has the same protein structure but different glycosylation patterns than the originator product.

While presenting a regulatory challenge, glycosylation also presents companies that developed the originator and the biosimilar/follow-on branded biologic opportunities to defend their product franchises and also to create safer and/or more therapeutic second- and third-generation products.


Government Actions

Promoting Innovation and Access to Life-Saving Medicine Act (H.R.1427, a bill from the first session of the 111th Congress) and the FTC’s report titled Emerging Health Care Issues: Follow-on Biologic Drug Competition are intended to provide the rationale for moving access to biosimilars/follow-on biologics and driving the legislative compromise. Of particular interest is the FTC’s projection of what cost savings (10–30%) will actually be achieved, and that the originator biologic manufacturer may likely retain 90% of its market.

When a new human growth hormone (hGH) product tried to compete with  Genentech’s hGH, physicians hesitated to move patients on to it, so its market was just new patients. If there is only a 10–30% price differential for biosimilar/follow-on biologics and they lack an AB substitutability rating, one would anticipate the same reluctance to switch patients. 


Other FDA Issues

To anticipate where FDA investigators will now focus their inspectional efforts and whether one’s own compliance has potential weaknesses, one should look at the listing of 483 Observations. Thusfar in 2009, the three major cGMP problem areas are: the failure investigation, equipment and facilities, and validation. Quality assurance should increase the thoroughness of internal audits in these areas, especially in vendor facilities.

In the medical device and diagnostic areas, industry is concerned that FDA may start conducting inspections of manufacturing facilities before clearing 510(k)s, leaving a 483 to be dealt with before 510(k) clearance can be obtained.

Traditionally, such inspections are not part of the 510(k) process; however, a review of the issued FDA Warning Letters indicates that many companies, especially first-time companies, fail to have complete device-history records—indicating the experimental basis for their performance specifications—and to be in compliance with cGMPs. The common situation is to rush to get the product cleared by 510(k), then attend to finishing cGMPs and Quality Systems documentation.


Meetings and Guidance Revisions

FDA recently published revisions to show how it conducts formal meetings with sponsors. These have several procedural subtleties that companies need to be sensitive to, but the underlying definitions have not changed.

Of particular interest are the FDA’s reasons for rescheduling or canceling a meeting. FDA now encourages a sponsor to reschedule if it is likely to experience “a minor delay” in submitting the meeting package; therefore, it is more incumbent upon sponsors seeking their first pre-IND type B meetings to prepare the meeting package before sending the formal meeting request letter. This approach is intended to better focus questions and also to determine whether there is sufficient information to frame each question.

FDA reserves the right to cancel the meeting if the meeting package is either too voluminous or inadequate. In terms of size, limit the package to 50–60 pages and provide all information in detailed summaries. Do not include lengthy preclinical or clinical protocols—two- to three-page summaries are sufficient. Do not reduce the margin size or the font size in order to fit more information; the text must be easily readable.

FDA reviewers will usually read the summaries and assume consistency with the original data that they will eventually see in the IND. Use good figures that integrate and summarize mechanisms of actions along with definitions; do not assume they understand your abbreviations or terms.

In regard to pre-IND meetings, a face-to-face can be requested, but today they are rarely granted—usually a teleconference will be offered. Frequently, two to five days before the meeting date, a company receives premeeting answers to its questions by fax. At this time, FDA will indicate that the meeting is cancelled unless the sponsor can provide a convincing rationale why the teleconference should still be held.

A company can agree to the cancellation with the proviso that if clarification of the answers is needed, FDA will be amenable to such. Given the finality of FDA answers, the quality and nature of the questions one asks FDA in its meeting request or in the premeeting package are critical, in terms of having adequate information/data to frame each question. 



























Bruce F. Mackler, Ph.D., J.D., a senior advisor in FDA matters, is lead contributor to GEN’s “Spotlight on the FDA” column. Web: www.brucemackler.net. This FDA column is intended to alert readers to rapidly evolving FDA issues and is not intended to be all inclusive of what is contained in the documents cited. Readers should carefully review the documents and consult the references discussed.

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