looking beyond biosimilarity - importance of patient safety: presentation of dr somdutt prasad at...
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Looking beyond bio-similarity – Importance of patient safety
Somdutt Prasad MS FRCSEd FRCOphth FACS
AMRI Medical Centre & Fortis Medical CentreKolkata, India
[email protected] www.somduttprasad.com +91 7044 06 7754
Outline
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Overview of biosimilars
Extrapolation of one indication to others
Immunogenicity
Interchangeability Pat
ient
Saf
ety
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History of NamingSelected Terms Used to Describe “Generic” Biologics
• Post patent biologicals• Biogenerics • Subsequent entry protein pharmaceuticals• Second-generation biologicals• Follow-on biologicals • Follow-on protein products • Bio-betters• Biosimilars
Development
Pharmaceutical R&DFormulation
Clinical Investigator& patient
Clinical PharmacologyClinical Research
Statistics & EpidemiologyData CoordinationResearch Information SystemsInformation Services
Regulatory AffairsProject Planning & ManagementMarketing
Process R&DChem Eng. R&DManufacturing
Bio Process R&D
Safety AssessmentToxicology
Drug Metabolism(ADME)
Pharmacology
Pre-Clinical
Clinical
Clinical Trials
Product Profile Marketing SOI
Information Learned1. Absorption and metabolism2. Effects on organs and tissue3. Side effects as dosage is increased
Information Learned1. Effectiveness in treating disease2. Short-term side effects in health -impaired patients3. Dose range
Information Learned
1. Benefit/risk relationship of drug2. Less common and longer term side effects3. Labeling information
Compassionate Use
Phase IISeveral hundred health-impaired patients
Treatment Group Control Group
Phase IIIHundreds or thousands of health-impaired patients
InvestigationalNew Drug
Application
Phase I20 - 100 healthy volunteers take drug for about one month
Remote data entry
APPROVALPROCESS
(Ex. FDA)
Reviews,comments, and
discussions
Drug Co./Regulatoryliaison activities
APPROVAL
Submit toRegulatory Agencies
AdvisoryCommittee
RegulatoryReview Team
New DrugApplication
(NDA)
Worldwide Marketing Authorization (WMA) in other countries
Clinical Trials CONT...
Biologics vs. Small Molecule Drugs
Mellstedt H. EJC Supplements 2013;11:1-11.
FDA Approval Pathways
†FDCA = Federal Food Drug and Cosmetic Act ¥PHSA = Public Health Service Act
Drugs• Small-molecules• Approved via FDCA
Biologics• Approved via PHSA¥
New Drug Application
(NDA)505(b)(1)
Safety and Efficacy must be
demonstrated
Abbreviated New Drug
Application(ANDA)
505(b)(2)
Bioequivalence must be
demonstrated
Biologics License Application
(BLA)351(a)
Safety and Efficacy must be
demonstrated
Biosimilar Biologics License
Application351(k)
Must demonstrate that it is highly similar to 351(a)
reference
Interchangeable biosimilars
require more data
Guideline on Similar Biological Medicinal Products (Oct 05)
Guideline on Similar Biological Medicinal ProductsContaining Biotechnology-Derived Proteins as Active
Substance: Quality Issues (June 06)
Overarching
Quality
Annexes EpoetinJuly 2006
G-CSFJune 2006
InsulinJune 2006
HGHJune 2006
GeneralApplicableto allBiosimilars
Specific:Product data requirements
Guideline on Similar Biological Medicinal ProductsContaining Biotechnology-Derived Proteins as Active
Substance: Nonclinical & Clinical Issues (June 06)
Nonclinical& Clinical
Heparin LMWH & Others Draft
EMA Model : Biosimilars Regulations
EMA=European Medicines Agency
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Overview of biosimilars
Extrapolation of one indication to others
Immunogenicity
Interchangeability
In case the reference medicinal product has more than one therapeutic indication, the efficacy and safety of the biosimilar has to be demonstrated separately for each of the claimed indications.
If the safety profile of the product differs between the therapeutic indications, additional data may be needed to justify the extrapolation of safety and efficacy from the indication studied in the pivotal clinical trial.11
Extrapolation of efficacy and safety from one therapeutic indication to another
Study on biosimilar
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Parameter Bio-similar Study
Ideal Standard
Duration of the Study
Just 3 months To compare safety , a minimum of 1 year follow up is necessary and ideally landmark studies like CATT & IVAN have taken the 2 year follow up to compare the safety between bevacizumab and ranibizumab.
Number of Patients in the study
The study with Bio-similar has only 100 patients. Lumina arm - 75 and Ranibizumab (Innovator) – 25
A minimum of 30 patients is required in any arm of a trial for statistical significance and the ranibizumab (Innovator) arm is under –represented.Head to Head studies done globally in wet AMD between 2 drugs such as CATT , IVAN , GEFAL , MANTA , LUCAS , VIEW have had equal number of patients in each arm . Sample sizes for most H2H studies of Anti-VEGF have been at least 300 patients
Ranibizumab and its biosimilar have been studied in one single trial and that too in patients of AMD only.
http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=7625&EncHid=&userName=ranibizumab. Accessed on 19/02/2016
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Overview of biosimilars
Extrapolation of one indication to others
Immunogenicity
Interchangeability
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Antibody Formation : “Immunogenicity”
Potential increases with amino acid sequence changes
Immune responses have different consequences• Neutralize the molecule, making it therapeutically ineffective• Hypersensitivity reactions• No clinical effect• Rare but serious autoimmune responses can be life-threatening
- Pure red cell aplasia (PRCA) with anti-epoetin antibody
Immunogenicity of biologic drugs is unpredictable, unforeseable• Scientific tools for detecting immunogenicity exist, but in some
cases they are undeveloped
Kessler M et al. Nephrol Dial Transplant. 2006; 21:v9-v12.
Chirmule N, et al. AAPS J. 2012;14(2):296-302
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Factors Affecting the Immunogenicity of Proteins
Chirmule N, et al. AAPS J. 2012;14(2):296-302
Disease Factors– Immune dysregulation– Inflammatory responses
Patient Factors– Major histocompatibility complex background
Product Factors– AA sequence, structure, etc.– Impurities– Formulation– Route of administration– Dose
What happens if Immunogenicity is overlooked ??
Recently, a biosimilar of Ranibizumab had to curtail the distribution, barely two months of launch following stray incidents of adverse reactions like inflammation in eyes.......
ET Bureau, Aug 21, 2015, 04.00AM IST
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Overview of biosimilars
Extrapolation of one indication to others
Immunogenicity
Interchangeability
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Interchangeability
Definition– “Biosimilar to the U.S.-licensed reference biological product … expected to
produce the same clinical result as the reference product in any given patient.”
– “For a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product will not be greater than the risk of using the reference product without such alternation or switch”
(biosimilar drug should neither increase AEs nor decrease efficacy when switched from the reference drug)
Note : The interchangeable product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411418.htm. Accessed 19 th Feb 2016
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• Biological products approved by FDA• Lists if a biosimilar is interchangeable• Defines exclusivity period• Gets periodically updated
FDA “Purple Book”
Updated – 12/02/2016
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411418.htm. Accessed 19 th Feb 2016
Possible study designs to investigate interchangeability of biosimilars
21 Interchangeability. An insurmountable fifth hurdle? APRIL 2014 DOI: 10.5639/gabij.2014.0302.022
A study with either of the following designs should be conducted to establish
interchangeability
How many biosimilars have been approved by FDA till date?
a) 1
b) 5
c) 9
Out of these how many are approved as interchangeable?
a) 0
b) 1
c) 3
22http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411418.htm. Accessed 19 th Feb 2016
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FDA’s strict standards continue
FDA rejects Hospira’s epoetin alfa application
Epoetin alfa is a more complex biologic product than Sandoz’s biosimilar.
Hospira filed an abbreviated Biologics License Application (aBLA) for its proposed biosimilar of Amgen’s epoetin alfa in December 2014.
FDA accepted Hospira’s application for review in February 2015.
FDA denied approval in October 2015.
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Hospira(now Pfizer) intends to resubmit its application to FDA in the first half of 2016
Conclusion
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Biosimilars are different than generics and are extremely difficult to replicate due to the complex manufacturing process involved
Can’t be readily extrapolated to different indications
Immunogenicity remains a threat even after demonstrating molecular similarity
Demonstration of interchangeability is a must to validate a biosimilar
Cost shouldn’t be a factor to compromise patient safety
Thank You
28 Thank YouSomdutt Prasad [email protected] www.somduttprasad.com