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

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

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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

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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?

Regulatory Authorities’ Decision

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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

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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

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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)

Marketing Authorization

Generally based on one or two pivotal phase 3 trials

Number of Patents: Several hundreds to several thousands

Length of Study: 1 to 4 years

Study Objective: Efficacy, Safety, Dosage

Endpoints: 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

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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

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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

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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)

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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

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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

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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

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Bevacizumab EU US Swiss Canada Japan

Lung Cancer √ √ √ √ √

Colorectal cancer √ √ √ √ √

Breast cancer √ Accelerated

approval, then

withdrawn

√ Conditional

authorization,

then withdrawn

√

Glioblastoma √ (Accelerated

approval)

√ √ (Conditional

authorization)

kidney cancer √ √

Ovarian cancer √

Different Decisions based on Same Data

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

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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

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Common Reasons for Submission Rejection

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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

Conclusions

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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

Thank you

Merci

谢谢

Gracias

Cпасибо

감사합니다

jian.wang@hc-sc.gc.ca

613-957-0833