This article is more than 5 years old. Information may no longer be current.
Promise of biosimilars tempered by complexity, caution
Follow-on biologics could have a multibillion dollar effect on medicine in the United States, but the FDA has yet to craft guidelines for approval and surveillance.
Click Here to Manage Email Alerts
In the same way that the manufacture of brand-name chemical drugs leads to the development of less expensive generics, there is great hope in the medical world that biopharmaceuticals, such as bevacizumab, will lead to the development of less expensive biosimilars.
However, unlike generic drugs that are identical copies of the original product, biosimilars — as the name implies — are similar but not identical to the pioneer biologic therapy. That slight difference can have huge implications for efficacy and patient safety.
The European Medicines Agency has already established guidelines regulating the development and approval of biosimilars, also known as follow-on biologics, but the FDA is still considering how to proceed. The experts who spoke to HemOnc Today have high hopes for the future of biosimilars, but they caution that there are issues that must be addressed as the use of biosimilars become more prevalent.
“[The use of biosimilars] is an opportunity for us to use cutting-edge technology to solve health problems, guide clinical processes and guide an exciting sector,” said Graham B. Jones, MD, chair of chemistry and chemical biology and co-director of the Barnett Institute of Chemical and Biological Analysis at Northeastern University in Boston. “We’ve all waited for this. This is the post-genomic era. Having these biological drugs is exciting for us.”
|
Photo courtesy of G. Jones, MD |
Teva Pharmaceuticals is already working on a biosimilar for rituximab (Rituxan, Genentech/Biogen Idec). Patents for that monoclonal antibody effective against the protein CD20 are set to expire between 2015 and 2018.
From cell to market
One of the reasons it is so difficult to recreate biopharmaceuticals is that unlike relatively simple small-molecule synthetic drugs, biopharmaceuticals are significantly larger and more complex — as much as 1,000 times larger, according to one estimate published in International Urology and Nephrology in 2007. The large size and complexity mean that manufacturing is equally complex, and quality-control processes are vital because the “expression of the same genetic construct in different host cell expression systems has a great impact on the final structure of the protein,” according to the report.
“Unlike synthetic chemical drugs, biopharmaceutical products require the use of living biological host cells for their production. This includes the use of recombinant genetic engineering techniques for cloning of the appropriate genetic sequence into an expression vector, followed by the generation of a host cell expression system and scaling it up for large-scale protein production,” researchers wrote. “The desired protein must then be isolated and purified from the cell culture medium, using purification techniques that maintain the protein’s structural and functional integrity. The purified product must then be correctly formulated to ensure that it retains its biological activity up to patient delivery.”
The Biologics Price Competition and Innovations Act of 2009 tasked the FDA with finding a way to expedite approval of biosimilars. An FDA panel heard testimony from various stakeholders during a 2-day hearing in November.
The agency declined to comment for this story, but panel chair Rachel Behrman, MD, MPH, associate director for medical policy at the FDA’s Center for Drug Evaluation and Research, said during the hearing that the agency wanted input on the “scientific and technical factors related to a determination of biosimilarity or interchangeability; the type of information that may be used to support a determination of biosimilarity or interchangeability; development of a framework for optimal pharmacovigilance for biosimilar and interchangeable biological products; scope of the revised definition of a biological product; priorities for guidance development; scientific and technical factors related to reference product exclusivity; scientific and technical factors that may inform the agency’s interpretation of a product class as it relates to available regulatory pathways for certain protein products during the 10-year transition period following enactment of the [Biologics Price Competition and Innovations] Act; and the establishment of a user-fee program for biosimilar and interchangeable biological products.”
How similar is similar enough?
According to the Patient Protection and Affordable Care Act, a product can be declared a biosimilar if it is “highly similar to the reference product, notwithstanding minor differences in clinically inactive components” and if “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity and potency of the product.”
A biosimilar meets the higher criteria of “interchangeable” if: 1) it meets the criteria for being biosimilar to the reference product, 2) can be expected to produce the same clinical result as the reference product and 3) the risk in terms of safety or diminished efficacy in alternating or switching between use of the biological and reference product is not greater than the risk of using the reference product without the alteration.
There is controversy over how much testing a biosimilar must undergo before it can be declared safe and effective enough for use in clinical practice. Some argue that a biosimilar, because it is slightly different from an innovator biopharmaceutical, should undergo a full range of clinical trials before gaining FDA approval. I. Craig Henderson, MD, adjunct professor of hematology and oncology at the University of California at San Francisco, former president of Keryx Biopharmaceuticals and a former chairman of the FDA’s Oncologic Drugs Advisory Committee, told HemOnc Today that full human trials for biosimilars are unnecessary, but that testing for safety and efficacy was crucial.
“For biosimilars … a proper randomized trial will be required. However, the trial might have as its primary endpoint progression-free or disease-free survival rather than overall survival as long as overall survival data are presented at a later time,” he said. “The FDA might be willing to accept a single trial, rather than the two trials that are usually required, as long as the trial is sufficiently large. In general, biosimilars are safer than the original drug since they must have some improvement to get physicians to prescribe them.”
The key question that must be answered, said Joseph P. Miletich, MD, PhD, senior vice president of research and development for Amgen, is just how similar a biosimilar has to be. Miletich, who spent 24 years at Washington University in St. Louis as a professor of internal medicine and pathology, said a given biosimilar must undergo clinical trial before physicians can be certain it can be safely prescribed to patients.
“It’s extremely difficult for me to see a situation, knowing what we know right now, whereby I would be comfortable saying without clinical trials that I would know the safety and efficacy of a biosimilar would be equivalent,” he said.
|
|
Miletich, who said Amgen supports the development of biosimilar products, said requiring clinical trials for biosimilars does not mean that a follow-on biologic needs the full testing or the expense required for an innovative product. According to Miletich, innovation is expensive largely because of the ideas that fail. The great economic advantage of biosimilars is that a manufacturer only needs to recreate an idea that has already been shown to work.
“It’s expensive and difficult to innovate,” he said. “Built into the cost companies have to cover is the expense of all the failed ideas.
“If you’re trying to make a therapeutic that will change the practice of medicine, confirmation that the molecular interaction that’s the basis of your hypothesis for benefit acutally works in people is the single hardest and costliest piece of information to get,” Miletich said. “If you’re making a biosimilar, you already have that. You don’t have to pay for it.”
In addition, class-specific guidelines would help biosimilar manufacturers know how much testing would be necessary before their product could be used in clinical practice, he said.
From similar to interchangeable
Under current legislation, the FDA must decide whether a biosimilar is interchangeable, meaning that it may be substituted for the reference biopharmaceutical without involving the prescribing physician. Additionally, biosimilars are deemed to contain a new active ingredient, whereas interchangeable products are not.
During his testimony before the FDA panel, Miletich said the agency had to take a leadership role on the issue of interchangeability or risk having the issue settled without agency input.
“Interchangeability will be very difficult,” he told HemOnc Today. “It’s hard for me to imagine how it would actually be possible until something was approved as a biosimilar first and had a track record on the market.”
Companies that manufacture innovative bioproducts are not required to divulge their manufacturing process. The manufacturing of biopharmaceuticals is extremely complex and bioproducts are highly sensitive to environmental factors, not only obvious factors such as heat and light. Amgen has found that changes in altitude can affect bioproducts that are shipped by air, Miletich said.
Because manufacturing is so intricate and consistency is so difficult from batch to batch, let alone between manufacturing facilities, Jones said the FDA will have to allow some variability in the products it deems biosimilar and interchangeable.
Questions about biosimilarity lead directly to the issue of immunogenicity, an unwanted immune response trigged by the biosimilar product. In its “Guideline On Immunogenicity Assessment Of Biotechnology-Derived Therapeutic Proteins,” the European Medicines Agency said “consequences of an immune reaction to a therapeutic protein range from transient appearance of antibodies without any clinical significance to severe life-threatening conditions. Potential clinical consequences of an unwanted immune response are a loss of efficacy of the therapeutic protein, serious general immune effects such as anaphylaxis, and, for therapeutic proteins used for substitution, a potential cross-reactivity with the endogenous counterpart in case it is still produced.”
Johnson & Johnson’s experience with epoetin alfa (Eprex) is an oft-cited cautionary tale about the dangers of both immunogenicity and small changes in the manufacturing of a biosimilar. Patients with anemia secondary to chronic disease were assigned to Eprex, but a small change in the formulation, switching from human serum albumin to polysorbate 80, caused some patients to develop neutralizing antibodies to both Eprex and native erythropoietin. Those who developed the antibodies experienced pure red cell aplasia, sudden-onset anemia that leads to a near-complete shutdown in the production of red blood cells.
A subsequent FDA study found that the risk for death among those assigned to Eprex was 78% higher than for patients assigned to placebo, 16% vs. 9%.
The problem of immunogenicity must be addressed before a biosimilar product can be introduced into the market, Miletich said. The story of Eprex, however, also contains the key to patient safety going forward.
Pharmacovigilance
Tracking patient outcomes after administration of a biosimilar product will be the best way of discovering potential problems such as those observed with Eprex. Jones said it was years of pharmacovigilance that allowed physicians to determine that the problem with Eprex occurred possibly because the switch to polysorbate 80 caused the drug to react to the rubber stopper used in vials.
“The end goal is to make sure that we have a healthy system, and that patient safety is of the highest order. We don’t want anyone to lose confidence in the promise of delivering biologics to improve health care,” Miletich said. “If we don’t have a robust ability to track individual products once they are marketed, it will be virtually impossible to get at the root cause of any problems that arise.”
In a 2007 review published in Annals of Oncology, researchers wrote that pharmacovigilance programs may be useful for early detection of emerging safety issues and for assessing the safety of products in specific patient populations.
“Pharmacovigilance plans developed and implemented by manufacturers are frequently part of the post-approval commitments to regulatory agencies to provide follow-up safety assessments,” they wrote. “These programs provide a means of quantifying the frequency of adverse events and a way of expediting the reporting of serious or previously unknown adverse events. These programs may include patient registries and retrospective or prospective observational and pharmacoepidemiologic studies.” – by Jason Harris
For more information:
- Covic A. Int Urol Nephrol. 2010;doi:10.1007/s11255-006-9167-5.
- European Medicines Agency. Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins. Available at: www.tga.gov.au/docs/pdf/euguide/bmwp/1432706en.pdf. Accessed Dec. 20, 2010.
- Locatelli F. Nephrol Dial Transplant. 2006;Suppl 5:v13-6.
- Mackler B. Biosimilars and follow-on branded biologics. Genetic Engineering & Biotechnology News. Aug. 1, 2009. Available at: www.genengnews.com/gen-articles/biosimilars-and-follow-on-branded-biologics/2981/. Accessed Dec. 9, 2010.
- Mellstedt H. Ann Oncol. 2008;19:411-419.
- Mellstedt H. Future Oncol. 2010;6:1065-1067.
- Nowicki M. Kidney Blood Press Res. 2007;30:267-272.
- Roger SD. J Pharm Pharm Sci. 2007;10:405-410.
- Schellekens H. Clin J Am Soc Nephrol. 2008;3:174-178.
- Schellekens H. NDT Plus. 2009;2(Suppl_1):i27-i36.
- Shea TJ. New U.S. law establishes long-awaited abbreviated approval pathway for biosimilars. Nat Law Review. Available at: www.natlawreview.com/article/new-us-law-establishes-long-awaited-abbreviated-approval-pathway-biosimilars. Accessed Dec. 20, 2010.
- Wiecek A. Nephrol Dial Transplant. 2006;21 Suppl 5:v17-20.
Disclosures: Dr. Behrman reports no relevant financial disclosures. Dr. Henderson is a consultant with Neotope Biosciences, a division of Elan Pharmaceuticals, and owns stock in Keryx Biopharmaceuticals and Johnson & Johnson. Dr. Jones reports no relevant financial disclosures. Dr. Miletich is employed as a senior executive with Amgen.
Will biosimilars lower the cost of medical care?
Yes, if enough biosimilars come to market to create competition.
|
|
If we only have one biosimilar approved for a given innovator product, just like when there is only one generic approved for a brand-name drug, the cost will not go down very much. It’s when multiple generics or biosimilars are introduced to the market that we’ll see a price decrease.
In addition, brand manufacturers sometimes will negotiate contracts with hospitals or health care systems to offer a lower price for the brand-name drug than for the generic.
This process could take years, if not decades. It’s hard to say what the pharmaceutical manufacturers will do. The only biosimilar we have seen come to market was generic enoxaparin and we have not seen a great uptake of that because the brand name company decided to be financially competitive with a generic biosimilar.
Even if a biosimilar is approved by the FDA, we’re not going to see a dramatic cost savings overnight. It will happen over time.
Mandy Leonard, PharmD, is assistant director of drug information services and formulary management at Cleveland Clinic. She reports no relevant financial disclosures.
Cost is of less concern than efficacy.
|
|
In cancer, a drug has to improve response compared with the already-approved drug, or at least have less toxicity. So, in oncology, there are fewer biosimilars. Different countries deal with cost in different ways. Nations like Canada won’t allow some of these expensive drugs to be used because, although they extend survival for a few months, officials do not feel like there is cost-effectiveness in their system. In England, for some drugs, like bortezimib (Velcade, Millennium) officials will approve the drug if it has an effect for the patient. If it does not have an effect, they will not approve it.
The real issue now is that several drugs have been approved with time-to-progression of a few months or survival of a few months over the standard treatment. It’s worth it to the patient, of course, but is it draining our financial system?
Joseph R. Bertino, MD, is the director of the Cancer Institute of New Jersey and associate medical editor for HemOnc Today.