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FDA Grants Ibrutinib Accelerated Approval for Marginal Zone Lymphoma
The U . S . Food and Drug Administration ( FDA ) granted accelerated approval to ibrutinib for marginal zone lymphoma ( MZL ) following at least one prior anti- CD20-based therapy .
The decision was based on the results of the pivotal , open-label PCYC- 1121 study presented at the 2016 ASH Annual Meeting that found that ibrutinib resulted in an objective response rate of 46 percent , including a complete response rate of 3.2 percent .
A total of 63 patients ( median age = 66 years ; range = 30-92 years ) with relapsed / refractory MZL ( including splenic [ n = 14 ], nodal [ n = 17 ], and extranodal [ n = 32 ]) received ibrutinib 560 mg orally once daily . Previous therapies included :
• splenectomy ( 6 %)
• radiotherapy ( 14 %)
• rituximab monotherapy ( 27 %)
• CD20 antibody-containing chemoimmunotherapy ( 64 %)
After a median follow-up of 19.4 months , the median duration of response and median overall survival were not reached . The median time to initial response was 4.5 months ( range = 2.3- 16.4 months ), and the median progression-free survival was 14.2 months
( range = 8.3 months to not reached ).
The most common adverse events ( AEs ) included thrombocytopenia ( 49 %), fatigue ( 44 %), anemia ( 43 %), diarrhea ( 43 %), bruising ( 41 %), musculoskeletal pain ( 40 %), hemorrhage ( 30 %), rash ( 29 %), nausea ( 25 %), peripheral edema ( 24 %), arthralgia ( 24 %), neutropenia ( 22 %), cough ( 22 %), dyspnea ( 21 %), and upper respiratory tract infection ( 21 %). The most common grade 3 / 4 AEs were increased hemoglobin ( 13 %), decreased neutrophils ( 13 %), and pneumonia ( 10 %). Serious AEs occurred in 28 patients ( 44 %), with grade 3 / 4 pneumonia being the most common ( n = 5 ; 8 %).
Three treatment-related AEs resulted in death , and 38 patients ( 60 %) discontinued treatment because of progressive disease ( 30 %), AEs ( 19 %), patient decision ( 5 %), or physician decision ( 6 %). The most common AE leading to treatment discontinuation was diarrhea ( n = 2 ; 3 %).
The FDA had previously approved ibrutinib for the treatment of mantle cell lymphoma , chronic lymphocytic leukemia , small lymphocytic lymphoma , and Waldenström macroglobulinemia .
Sources : AbbVie news release , January 19 , 2017 ; Noy A , de Vos S , Thieblemont C , et al . Single-agent ibrutinib demonstrates efficacy and safety in patients with relapsed / refractory marginal zone lymphoma : a multicenter , open-label , phase 2 study . Abstract # 1213 . Presented at the 2016 ASH Annual Meeting , December 5 , 2016 ; San Diego , California .
FDA Emphasizes Need for Phase III Clinical Trials
A report issued by the FDA noted discrepancies between phase II and phase III drug trials , emphasizing the need for appropriate – and sometimes lengthy – review of drugs and mature clinical trial data . The FDA ’ s report also cautioned against assumptions about the accuracy of phase II studies , which can be “ misleading ” and potentially harmful to the public .
There has been growing interest in exploring alternatives to requiring phase III testing prior to product approval . However , in the FDA ’ s research , based on 22 case studies of drugs , vaccines , and medical devices since 1999 , promising phase II clinical trial results were not confirmed in phase III clinical testing . Fourteen of these cases did not confirm efficacy , one did not confirm safety , and seven confirmed neither . In addition , two cases showed in phase III trials that the product increased the frequency of the problem it was intended to prevent .
According to the report , “ These unexpected results could occur even when the phase II study was relatively large and … assessed clinical outcomes . Phase II results can inaccurately predict safety and / or effectiveness for medical products in a wide range of diseases and patient populations . … These cases also help illustrate the potential public health implications of undue reliance on phase II studies and the benefits of conducting phase III studies .”
To read the FDA report , visit fda . gov / downloads / AboutFDA / ReportsManuals- Forms / Reports / UCM535780 . pdf .
Source : U . S . Food and Drug Administration report , “ 22 Case Studies Where Phase 2 and Phase 3 Trials Had Divergent Results ,” January 2017 .
HHS Issues Final Rule on Protecting Human Subjects in Research
The U . S . Department of Health and Human Services ( HHS ) and 15 other federal agencies issued a final rule to update regulations regarding the use of human subjects in research ( known as the Common Rule ) in an effort to strengthen protections for people who volunteer to participate in research , while ensuring the oversight system does not add administrative burdens .
“ We are very hopeful that these changes and all the others that reduce unnecessary
“ We are very hopeful that these changes will be beneficial to both researchers and research participants .”
— JERRY MENIKOFF , MD
administrative burdens will be beneficial to both researchers and research participants ,” said Jerry Menikoff , MD , director of the Office for Human Research Protections at HHS . The new ruling reflects changes that have occurred in the two decades since the Common Rule ’ s implementation , including evolving technologies , larger-scale studies , and an even more diverse population of study participants . Some highlights of the final rule include :
• Consent forms must provide potential research participants with an upfront and better understanding of a project ’ s scope , including the purpose of the research , risks and benefits , and appropriate alternative treatments , so they can make a more fully informed decision about participation .
• A single institutional review board ( IRB ) is required for multi-institutional research studies ( in most cases ).
• For studies on stored identifiable data or identifiable biospecimens , researchers can rely on broad consent obtained for future research as an alternative to seeking IRB approval to waive the consent requirement .
• New exempt categories of research based on the level of risk the research poses to participants were established .
• The requirement to conduct continuing review of ongoing research studies has been removed in certain instances where such review does little to protect participants .
• Consent forms for certain federallyfunded clinical trials must be posted on a public website .
Most of these provisions go into effect in 2018 .
In September 2015 , HHS published a Notice of Proposed Rulemaking ( NPRM ) and received 2,100 comments ; in response , the final rule contains significant changes from the proposed rule , including :
• The final rule does not require that research involving non-identified biospecimens be subject to the Common Rule , and it does not require that consent be obtained to conduct such research .
• To the extent that some of the NPRM proposals relied on tools or standards that had not yet been proposed , the final rule either does not adopt those proposals or includes revisions to eliminate such reliance ( e . g ., a template to be used for broad consent forms and a decision tool to be used for making exemption determinations ).
• The final rule does not expand the policy to cover clinical trials that are not federally funded .
• The final rule does not adopt the NPRM ’ s proposed concept of “ excluded ” activities . Generally , activities proposed to be excluded are now described as not satisfying the definition of what constitutes research under the regulations or are classified as exempt .
• The final rule does not include the proposed standardized privacy safeguards for identifiable private information and identifiable biospecimens .
To read the final rule , visit federalregister . gov / documents / 2017 / 01 / 19 / 2017-01058 / federal-policy-for-the-protection-of-humansubjects . ●
Source : U . S . Department of Health and Human Services press release , January 18 , 2017 .
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