BIOSIMILARS data ,” noted Robert M . Rifkin , MD , medical director of biosimilars for McKesson Specialty Health- U . S . Oncology Network . The approval process for biosimilars , on the other hand , relies more on analytics and biosimilarity exercises outlined by the FDA . “ Basically , this means starting by reverseengineering a biosimilar to the originator ,” he said , adding that some submissions include as many as 40 analytics to show that a biosimilar is highly similar to its reference product .
Data are evaluated at each step of analysis to influence subsequent steps , and they are used to provide extensive , head-to-head comparisons of the biosimilar and reference product at many levels , including : 5
• structure and function ( the foundation of biosimilarity )
• pharmacokinetics and pharmacodynamics
• safety and efficacy
• immunogenicity
The biosimilars license application requires supporting clinical material , but the results of structural and analytic testing are better able to detect differences in agents ’ pharmacokinetics , potency , and purity than traditional phased clinical trials . Taken together , these data form the “ totality of evidence ” that the FDA examines when considering approval of a biosimilar .
Once the FDA is satisfied that the evidence is both substantial and sensitive enough to detect potential differences and to address residual uncertainty that may exist , the agency can approve the biosimilar .
Interchangeability and Extrapolation
In the survey referenced earlier , nearly 60 percent of respondents correctly understood the requirements a biosimilar must meet to be approved as “ interchangeable ” ( i . e ., must be shown to be safe and effective for back-and-forth switching with no negative impacts to safety or efficacy ), fewer people correctly understood what the term “ interchangeable ” meant in the context of biosimilars .
Some believe that this term refers to the ability to do a therapeutic exchange with the originator biologic product , as would be decided by a Pharmacy and Therapeutics Committee , Dr . Rifkin explained . However , interchangeability is a regulatory term that allows for pharmacy-level substitution without the intervention of the physician who originally prescribed the reference product .
To be granted interchangeability , biosimilars must go through a separate , more rigorous approval process . And , to date , no biosimilars have been granted such status .
“ Extrapolation ” is another fundamental premise of biosimilars about which many are unfamiliar . 1 Extrapolation is the process by which a biosimilar may be approved for one or more indications for which its reference biologic product is licensed , but for which there was no head-to-head clinical comparison . This process relies on the totality of evidence obtained in the initial stages of FDA review , and every indication for which extrapolation is sought must be scientifically justified .
For example , when filgrastim-sndz was the first biosimilar to be approved in the U . S . in March
2015 , it was indicated to reduce the risk of febrile neutropenia in patients receiving myelosuppressive chemotherapy . 6 After earning approval for that indication , it was later granted approval for all other indications for which its reference product was approved – without submission of separate clinical data for the other indications .
“ Extrapolation is an issue that has and probably will continue to concern hematologists ,” Dr . Lyman said . However , he added , “ if we required the same amount of both preclinical and clinical data for the biosimilar that we require for the reference product , we [ would ] undercut one of the motivations for developing biosimilars : reducing development costs and increasing competition in the marketplace .”
“ Although the FDA indication may be broad , I am not as confident that you can extrapolate all indications , especially if the dose changes , because there may not be a linear dose relationship ,” Dr . Shank reasoned . Rather than awarding extra indications without extra clinical evaluations , he would prefer to review the patient population included in the study that used a biologic , then evaluate the biosimilar in that same patient population before slowly advancing it out to other patients .
The concerns over extrapolation expose other concerns about the safety of biosimilar products , particularly because biosimilars do differ slightly from their reference products . There is also a lack of clinical data in the U . S . to show the safety and efficacy of biosimilars in various patient populations and over time .
Prescribing Biosimilars
Biosimilar approval has focused primarily on the supportive care aspects of oncology , such as the approval of myeloid growth factors like filgrastim-sndz . However , efforts have recently expanded to cancer treatment . On September 14 , 2017 , the FDA approved bevacizumab-awwb for the treatment of certain colorectal , lung , brain , kidney , and cervical cancers . 7
The FDA is also expected to issue its decision on the approval of MYL-1401O , a biosimilar of trastuzumab , which is used to treat breast and gastric cancers , by the end of the year . 8
As biosimilar approvals for cancer treatment become more prevalent , Dr . Shank said , so does the need for oncologists to educate themselves about what a biosimilar is and how it can be used in everyday practice . For instance , dosing and administration of a biosimilar may differ from its reference product .
“ Health-care professionals will need to learn the differences in administration , preparation , and procedures ,” he said . “ If there are 10 biosimilars for one product and each insurance company requires a separate , specific biosimilar , it will be quite complex for a provider to adhere to or for a pharmacy to manage .”
Regulations stipulate that biosimilars can be used for newly diagnosed patients or those who have already received the reference product . Physicians must write the specific name of the biosimilar on the prescription order when prescribing such medications . Pharmacists can only dispense the specified biologic , unless they receive approval from the prescribing physician to make a substitution .
Interchangeable biosimilars are the sole exception to this rule , but the concept doesn ’ t sit well with some physicians . Dr . Lyman noted that 35 states have drafted legislation that would require a pharmacist to alert a physician about any change .
International Reputation
Biosimilars are now starting to enter U . S . clinical practices , but many physicians are reluctant to prescribe them . For a glimpse into the future of biosimilars , clinicians can look to Spain , Canada , Australia , Japan , and other countries where biosimilars have taken hold .
“ In the beginning , there was a lot of lack of education , and people confused biosimilars with generics , which have very poor press ,” said Pere Gascón , MD , PhD , senior consultant and chairman of the oncology program at the Hospital Clinic of Barcelona , of the initial reception in Europe . “ It was difficult to convince physicians to switch to biosimilars because of the bad reputation of generics .”
However , after a decade of educational efforts , Dr . Gascón has seen physicians ’ comfort levels grow substantially . “ It was a progression ,” he said . “ Right now , I would say biosimilars are widely accepted in Europe .”
The uptake could also be attributed to Europe ’ s more extensive biosimilar approval processes , which may help allay health-care providers ’ concerns about safety and efficacy . “ There is no accelerated approval pathway for biosimilars through the European Medicines Agency ,” Dr . Gascón explained . “ The process takes basically the same amount of time as the originator product .”
In the U . S ., insurance companies are likely to drive the acceptance and use of biosimilars , Dr . Lyman noted . “ Clinicians may be concerned that their control or ability to choose among these products – or to choose the brand name that they have grown comfortable with over the years – will be usurped by health systems and insurers , who will require that they use the new biosimilar if it ’ s less expensive ,” Dr . Lyman said .
Regardless of physician attitudes toward biosimilars , one thing is certain : “ Biosimilars are coming ,” Dr . Rifkin promised , “ and physicians need to be familiar with them .”— By Jill Sederstrom ●
REFERENCES
1 . Cohen H , Beydoun D , Chien D , et al . Awareness , knowledge , and perceptions of biosimilars among specialty physicians . Adv Ther . 2017 ; 33:2160-72 .
2 . U . S . Food and Drug Administration . Information on biosimilars . Accessed October 3 , 2017 , from www . fda . gov / drugs / developmentapprovalprocess / howdrugsaredevelopedandapproved / approvalapplications / therapeuticbiologicapplications / biosimilars /.
3 . U . S . Food and Drug Administration . Information for healthcare professionals ( biosimilars ). Accessed October 3 , 2017 , from www . fda . gov / drugs / developmentapprovalprocess / howdrugsaredevelopedandapproved / approvalapplications / therapeuticbiologicapplications / biosimilars / ucm241719 . htm .
4 . U . S . Food and Drug Administration . Implementation of the Biologics Price Competition and Innovation Act of 2009 . Accessed October 3 , 2017 , from www . fda . gov / drugs / guidancecomplianceregulatoryinformation / ucm215089 . htm .
5 . Biosimilars Forum . Biosimilars FAQs . Accessed October 3 , 2017 , from www . biosimilarsforum . org / biosimilars-insights / biosimilars-faqs # biologic .
6 . U . S . Food and Drug Administration . FDA approves first biosimilar product Zarxio . Accessed October 3 , 2017 , from www . fda . gov / newsevents / newsroom / pressannouncements / ucm436648 . htm .
7 . U . S . Food and Drug Administration . FDA approves first biosimilar for the treatment of cancer . Accessed October 3 , 2017 , from www . fda . gov / NewsEvents / Newsroom / PressAnnouncements / ucm576112 . htm .
8 . Mylan press release , July 13 , 2017 . Accessed October 3 , 2017 , from http :// newsroom . mylan . com / 2017-07-13-FDA-Oncologic-Drugs-Advisory-Committee-Unanimously- Recommends-Approval-of-Mylan-and-Biocons-Proposed-Biosimilar-Trastuzumab .
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