Looking beyond bio-similarity – Importance of patient safety

Somdutt Prasad MS FRCSEd FRCOphth FACS

AMRI Medical Centre & Fortis Medical CentreKolkata, India

somprasad@gmail.com 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 somprasad@gmail.com www.somduttprasad.com