Image courtesy of the Biotechnology Industry Organziation.
The second day of BIO 2014 International Convention, Tuesday June 24th, presented at least two opportunities to learn about biosimilars, which haven’t only been gaining momentum from research and development over the last several years, but also from receiving attention by the US Food and Drug Administration (FDA) as biosimilars get closer to being marketed in the US. I basically thought that the sessions, to a lesser or greater degree would essentially review and or summarize recent documents published by the FDA to help guide the biopharmaceutical industry develop and gain approval of a biosimilar product. However, I realized after attending the second session that I had come away with seeing the biosimilars approval landscape from two perspectives. The first perspective was that from the eyes of the patient and healthcare professionals and the second perspective was from that of the drug manufacturer complying with FDA requirements. My first thought was that I could report on the two sessions in a point counterpoint format, but I chose to instead present them as two perspectives for the reader since the two parties were not speakers in the same session participating on a moderated panel discussion that potentially would be a point counterpoint opportunity.
The first session was titled Ensuring the Safety and Commercial Success of Biosimilars in the United States, which was monitored by Brian Rye (Senior Health Care Analyst for Bloomberg Government) and included speakers Dr. Robert Yapundich (board certified neurologist), Phillip Schneider (Associate Dean and Professor at the University of Arizona College of Pharmacy), and Marcia Horn (President and CEO of the International Cancer Advocacy Network). Dr. Yapundich cares for post-stroke and multiple sclerosis patients and mentioned his use of botulinum toxin. He presented a slide depicting the structures of aspirin and botulinum toxin. He noted that aspirin is prepared by synthesis in the lab whereas botulinum toxin is made biologically by a living organism and involves recombinant DNA technology. Aspirin is a much smaller molecule than botulinum toxin and is far less complex with respect to structure. Yapundich noted his concerns over proper storage and stability of the biologic with respect to its safety and efficacy and discussed other similar aspects such as preparation of the drug for administration involving dissolution in water for injection which requires proper technique in order to prevent inactivation by denaturation or unfolding of its higher order structure by excessive vigorous shaking. Yapundich also emphasized the importance of communication between a healthcare team for a patient which could involve a family or primary care physician, a specialist physician, and a pharmacist, all of whom should be kept informed about their patients prescriptions. One apparent point of contention had to do with the physician and patient being informed about a pharmacist dispensing a substitution for a prescribed drug because there should be no mistake that a substitution by a generic drug is not in the same league as a substitution involving a biologic with respect to efficacy and safety.
Another topic discussed by Yapundich had to do with the naming of biosimilars such that naming should specifically be linked to the manufacturer and the lot number because of the complexity of a biologic and for post-marketing surveillance. Professor Schneider emphasized the establishment of standards for measurement and performance of medical use systems with respect to biosimilars to identify gaps in efficacy, monitor adverse events and address and prevent conflict arising from innovation and affordability of biosimilars. A medication use system for a drug and its use for treatment or prevention involves the five steps of prescribe, prepare, dispense, administer, and monitor. Schneider offered that advances and improvement in the medical use system for biosimilars involved collaboration between the pharmacist and physician, expansion or modification of the rules for formulary access, a clear distinction between interchangeability and substitution of drugs, and evidence-based clinical practice. Horn also touched on some of the things mentioned by Yapundich and Schneider such as continuous communication between the patient’s health care team. She also presented BIO’s five principles on biologic substitution which are 1) substitution should occur only when the FDA has designated a biologic product as interchangeable, 2) the prescribing physician should be able to prevent substitution, 3) the prescribing physician should be notified of the substitution, 4) the patient should be notified of the substitution, and 5) the pharmacist and physician should keep records of the substitution.
The second session was entitled Navigating the Biosimilars Landscape: Dispelling the Myths presented by Dr. Sarfaraz Niazi, Chairman and CEO of Therapeutic Proteins International (TPI), as part of the BioProcess Theatre in the convention exhibit hall. I also conducted a short interview the day after Niazi’s presentation with Celina Dopoulos, Director of Global Strategy and Business Development at TPI. The five most common misconceptions were discussed and disproved with the following facts, as outlined by Niazi in his presentation, were 1) approved biosimilars are not inferior to the reference product, 2) an approved biosimilar has no greater safety risk than the reference product, 3) there is more than one approval pathway for a follow-on biologic, 4) there are numerous ways to manufacturer the same biologic product, and 5) evolving thinking in approval process and novel technologies allow for impactful savings.
Niazi also depicted aspirin and a large protein molecule in his presentation to demonstrate the complexity in molecular structure of a biological compared to a small molecule synthesized in the lab. Yapundich expressed concern over decrease in efficacy or safety due to the fragility of the complexity of a biosimilar and its potential for becoming nonidentical to the reference product for example during prescription preparation for administration. Niazi pointed out in his presentation that not only will a biosimilar never be identical to the reference product, but that variability is intrinsic to biologics including the existence of batch to batch variability in the reference product. Dopoulos pointed out that the FDA approaches the 351(k) biosimilar approval process with the same rigor as the 351(a) traditional biologic approval process. The FDA is additionally involved with the biological drug sponsor at every stage of the stepwise process that makes up the 351(k) biosimilar approval pathway. The goal of the sponsor is the elimination of all residual uncertainty that there is any meaningful difference between a biosimilar and a reference product by leveraging analytical methods at each stage of the production process as well as any additional clinical studies the FDA may require based on the biosimilarity profile. An FDA approval means is the product is judged as safe and as efficacious as the reference product and by nature of the 351(k) pathway, may qualify for indication extrapolation with respect to intended use compared to the reference product. The first guidance document on the determination of biosimilarity was released by the FDA in 2012 and a second draft is nearly at the end of its open review period during which the public may submit constructive criticism.
As for safety, Niazi pointed out the history of withdrawals of new molecular entities, which includes drugs and biologics. A product is withdrawn completely from the market because of risks to the patient. Only 44 drugs have been withdrawn from the market since 1980 and zero have been therapeutic proteins or biosimilars. Niazi additionally referenced a pooled analysis of 5 post-approval studies of EU approved filgrastim biosimilar Zarzio, which has been on the market since 2009. No new safety signals or clinical concerns were determined from exposure to the EU biosimilar filgrastim market leader over the five years analyzed which translated to safety data over a period of 4.5 million patient days involving 1302 patients spanning 12 countries.
Schneider held some concerns over the designation of being an interchangeable biosimilar. The term interchangeable as described by the FDA refers to a biological product that can be expected to produce the same clinical result as the reference product in any given patient and, if the biological product is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch. This is essentially a nontopic since there does not yet exist a guidance document issued by the FDA on the protocol for conducting switching trials in order to be approved as an interchangeable biosimilar. Nonetheless, the FDA has the authority to designate a biosimilar as interchangeable under the Biologics Price Competition and Innovation Act of 2009 (BPCIA) with the provision that interchangeable products may be substituted for the reference product without the intervention of the prescribing healthcare provider. This portion of the BPCIA,which was signed into law by President Obama in 2010, has been controversial with industry stakeholders There continues to be enactment of legislation on a state by state basis pertaining to notification of the patient and physician by the pharmacist in the event of substitution by a biosimilar which contradicts the BPCIA as written which is evident by the most recent being MA Governor Patrick signing House Bill 3734.
In conclusion, it seems that in some cases, such as regarding the safety of biosimilars that a point/counterpoint would have been evident if all the speakers had been part of one session; whereas, in others, such as naming of biosimilars, that the debates are premature until the FDA issues a guidance document. Although there is a mechanism for filing a Citizen Petition with the FDA regarding policy, both existing and perceived as necessary, there is also a period for submitting comments to an issued draft FDA guidance as part of the process of its finalization.