Health Canada's Clinical Evaluation Division chief Jian Wang presented on clinical data requirements and key issues for market authorization of biotherapeutics. Wang discussed Health Canada's international collaborations and highlighted regulatory authorities' decision-making based on efficacy and safety. He outlined submission data requirements including quality, non-clinical, clinical, and risk management data. Wang also reviewed key clinical trial design considerations and common efficacy and safety issues with biologics. He emphasized that benefit-risk assessments are context-specific and can lead different regulatory decisions in different jurisdictions based on the same data.

1. Clinical Data Requirements and Key Issues for
Market Authorization of Biotherapeutics
Jian Wang, MD PhD
Chief, Clinical Evaluation Division
Biologics and Genetic Therapies Directorate
Health Canada
Latin America Conference on Biotherapeutic Medicines
Lima, Peru, Nov 19-20, 2013

2. Health Canada’s International Collaboration
• WHO:

Expert Committee on Biological Standardization of WHO
(ECBS)

WHO Blood Regulators Network (BRN)

WHO International Conference on Drug Regulatory Authorities
(ICDRA)

WHOCC for Biological Standardization and Evaluation of
Biologics
• Pan-American Network for Drug Regulatory Harmonization
(PANDRH):

Biotech Working Group (NAFTA: Drs. Jian Wang and Agnes
V. Klein, Canada)

Vaccines Working Group
2

3. Highlights
• Regulatory authorities’ decision and ICH and WHO regulatory
guidelines for biologics
• Submission data requirement and clinical assessment
• Key issues associated with the evaluation of late phase clinical
trials
• Key issues associated risk/benefit assessment
• Key issues associated with risk mitigation and marketing
authorization
3

4. Regulatory Authorities’ Decision
Regulatory authorities’ decision whether to authorize a new drug
(including biologics) for marketing is fundamentally based on two
questions:
• Whether the results of well-designed studies provide substantial
evidence of efficacy/effectiveness?
• Whether the results show the product is safe under the
conditions of use in the proposed labeling?
4

5. Regulatory Guidelines
Regulatory Authorities follow Quality, Safety and Efficacy guidelines
Guidelines prepared by individual regulatory authorities, such FDA, EMA,
Health Canada and others
Guidelines prepared by the International Conference on Harmonization
(ICH) and abided by regulatory agencies in many developed countries
(Website: www.ich.org), for example:
– S6 (R1) (Preclinical Safety Evaluation of Biotechnology-Derived
Pharmaceuticals)
– E3 (Structure and Content of Clinical Study Reports)
– E5 (Ethnic Factors in the Acceptability of Foreign Clinical Data)
for particularly useful documents
– E6 (Good Clinical Practice)
– E9 (Statistical Principles for Clinical Trials)
– E10 (Choice of Control Group and Related Issues in Clinical
Trials
5

6. Regulatory Guidelines (con’t)
These guidelines are general guidelines prepared for pharmaceuticals
except ICH S6 (R1), although the principle of these guidelines are still
applicable to biotherapeutic products
WHO has taken the initiative in updating the WHO Guidelines on the
Quality, Safety and Efficacy of Biotherapeutic Products Prepared by
Recombinant DNA Technology to meet the needs of developing countries
(http://www.who.int/biologicals/publications/en/)
This revised WHO guideline now includes comprehensive non-clinical,
PK/PD, clinical and statistical sections
The revise guideline is prepared just for the biotherapeutic products based
on the principle of ICH Guidelines and has a focus on issues specific to
biotherapeutic products
This guideline is a good example for developing guidance documents based
on the existing guidelines, which may lead to the regulatory convergence
6

7. Submission Data Requirements
Sufficient data and information required to enable regulatory authorities
to assess quality, safety and efficacy of biologics
 Comprehensive summary (Module 2 in eCTD)
 Quality data (Module 3: physicochemical parameters, biological activity, purity and
impurity profiles)
 Non-clinical data (Module 4: in vitro and in vivo studies according to ICH S6[R1])
 Clinical PK/PD data (Module 5)
 Clinical efficacy/safety/immunogenicity data (Module 5: for each claimed indication)
 Proper product labelling (variable by jurisdictions)
 Risk Management Plan (WHO rDNA guidance, ICH E2E)
 (Post-market safety/efficacy data if already marketed in other jurisdictions)
7

8. Marketing Authorization
Generally based on one or two pivotal phase 3 trials
Number of Patents:
Several hundreds to several thousands
Length of Study:
Study Objective:
Endpoints:
1 to 4 years
Efficacy, Safety, Dosage
Primary, Secondary, Tertiary, Safety
Pivotal Trials: The principle of GCP should be generally applied
•
•
•
Trials should be well-planned, designed and controlled
Data are properly collected and recorded, and analysed by using appropriate
statistical tests
Trials are conducted by qualified investigators
8

9. Clinical Trial Design
•
•
•
The overall design should be appropriate to support the claimed
indications in the targeted population(s)
Randomization and blinding are essential in phase 3 clinical trials
The study design selected should be clearly described in the
protocol, including the choice of control group (placebo or
standard of care)
•
•
•
•
•
superiority design (placebo, active control)
non-inferiority design (active control)
equivalence design (PK/PD study, biosimilars)
Clinical trial should address questions of safety, efficacy and
PK/PD related to the product
Unique properties of biological products must be considered on a
product-specific basis, e. g., immunogenicity
9

10. Analysis of Study Outcomes
The study endpoint/outcome variable that is being used and how
it’s evaluated is also critical
• An objective endpoint (e.g., confirmed disease by laboratory
measures) is preferable
• Survival is always objective, but may have too few events during
the study period
• A surrogate endpoint should be clinically validated
• If a subjective endpoint is used, then measures to minimize bias
and improve the accuracy of the data collected should be put in
place at the design stage
10

11. Common Efficacy Issues with Biologics (Examples)
•
Lack of long term efficacy in some biologics (resistance:
Interferon treatment for hepatitis)
•
Lack of efficacy due to immunogenicity
•
Less effective when used alone
•
Small fraction of the treated population respond to treatment
(10 to 50%)
•
Requirement of appropriate biomarkers for prediction of
response (so far, EGFR, HER2 and KRAS)
11

12. Common Safety Issues with Biologics (Examples)
• Species specificity: lack of standard pre-clinical models for
safety testing
• Effects on immune system: infections, malignancies
• Mode of administration: infusion reactions, injection site
reactions, etc.
• Mode of action: immune-mediated effects
• Immunogenicity is an important safety consideration in the
development of biologics:
• Hypersensitivity & autoimmunity
• Altered PK/PD due to HADA
• Drug neutralization
• Abnormal biodistribution
• Enhanced clearance rate
12

13. Immunogenicity Issues

Most biologics induce human anti-drug antibodies

Biologics should be studies in a sufficient number of patients (>
100 patients) and a sufficiently long study duration (e.g., minimal
follow-up period for chronically administered agents should be
one year)

Current analytical methods cannot fully detect all changes and
predict biological properties

Immunogenicity of biologics may have serious clinical
consequences, which may not be predictable or foreseeable
during clinical trials

Post-marketing Risk Management Plan (RMP) is required
13

14. Benefit/Risk Assessment
Assessing in the (Canadian) context of the currently available
therapeutic options, the following factors should be considered, i.e.,
efficacy, disease, patients, risks and available therapies:
• Significant clinical benefits: a cure or a relief of symptom (permanent
or temporary)
• Nature and severity of the disease for which the drug is intended
• Target patient population
• Class of the drug
• Severity and frequency of adverse events
• Availability and risk of alternate treatments for the condition
• Risk related to the lack of benefit
• Risk related to the withholding of the drug
In every case, it must have a favourable Benefit/Risk profile.
However, the final decision could be different among regulatory
agencies
14

15. Different Decisions based on Same Data
Bevacizumab EU
US
Swiss
Canada
Japan
Lung Cancer
√
√
√
√
√
Colorectal cancer
√
√
√
√
√
Breast cancer
√
Accelerated
approval, then
withdrawn
√
Conditional
authorization,
then withdrawn
√
√ (Accelerated
√
√ (Conditional
Glioblastoma
approval)
kidney cancer
√
Ovarian cancer
authorization)
√
√
15

16. Risk Mitigation
Minimize the risk and maximize the benefit by modification of the dosage
(dose titration at initiation or termination of treatment, reduced dosage in
high risk patients, adjustment of dosage when used in combination with
other products, specification of maximal dose, etc)
Restrict the use of the drug
• contraindications or restricted use in certain high risk patients
• limitation of the duration of treatment
• screening measures prior to initiation of the treatment
Identify risks and adverse reactions in the product labelling
Need monitoring measures during treatment (ECG, blood tests, etc)
Issue a Deal Healthcare Professional Letter (DHPL in Canada) and require
educational materials
Set up a patient registry
16

17. Risk Mitigation: Example
NATRECOR® (nesiritide) is a human B-type natriuretic peptide
(hBNP).
Proposed Label as in other jurisdictions
NATRECOR® (nesiritide) is indicated for the treatment of patients with
acutely decompensated heart failure who have dyspnea at rest or with
minimal activity
Canadian Label
Conditional market authorization has been issued for NATRECOR® for the
treatment of hospitalized symptomatic Acute Decompensated Heart
Failure (ADHF) patients, presenting with moderate to severe dyspnea.
These are patients who present with signs and symptoms of persistent
heart failure despite 2 hours of treatment with intravenous loop diuretics
17

18. Common Reasons for Submission Rejection
Regulatory
•
•
•
Inability to address issues of non-authorized comparator
Incomplete or inadequate response to questions raised during the review
Specific claims based only on published literature and insufficient information to validate results
Study Design
•
•
Study endpoint, duration, sample size
Invalid endpoints, invalidated surrogate markers
Study Outcome
•
•
•
•
Unable to demonstrate bioequivalence
Lack of data to support a proposed dosing regimen or strength
Unfavourable study outcomes to establish a favourable benefit to risk ratio
Statistical measures not suitable for the type of outcomes evaluated
Safety Concerns
•
•
Safety issues with the product on the market while supplement under review has potential to
significantly alter the benefit to risk profile
Refusal to include requested safety information in the labelling
18

19. Conclusions
Biologics can be
marketed only if
the manufacturers
can demonstrate
their products are
safe and effective
and the regulatory
authorities are
satisfied.
Biologics are diverse, complex products for the treatment and
prevention of a broad range of common and rare diseases
Drug manufacturers need to carefully conduct clinical trials for
biologics according to appropriate local and international guidelines
to gain marketing authorization
Regulatory authorities pay close attention to factors that may
introduce bias and create equivocality in the interpretation of clinical
outcomes
Risk/benefit assessment is a complex process. Perceptions of risks
versus benefits are influenced to a great extent by the context in
which they occur
Based on the same clinical data and information, each regulatory
authority may render different regulatory recommendations for the
same product
No harm to patients is the bottom line for convergence
19

20. Thank you
Merci
谢谢
Gracias
Cпасибо
감사합니다
jian.wang@hc-sc.gc.ca
613-957-0833