Biosimilars: Harmonizing the Approval Guidelines
2. Regulatory Background
2.1. The US Scene
2.2. The EMA Scene
2.3. The WHO Scene
- The WHO states that “the clinical data should be generated using the biosimilar product derived from the final manufacturing process, reflecting the product for which authorization is being sought. Any deviation from this recommendation must be justified, and additional data may be required. For changes in the manufacturing process, relevant guidelines like the ICHQ5E should be followed”. However, the ICH comparability guideline applies only to the changes in the manufacturing of a biotechnology product that has already been approved and thus requires testing the product before and after the change, not with the reference product. To avoid confusion, the FDA has made a strong point by labeling these studies as “analytical assessments,” not even analytical comparisons.
- In its earlier guidelines, the WHO had indicated no need for any statistical modeling of the critical quality attribute comparisons. The recent draft suggests using statistical modeling but warns about the risks of employing statistical tests on limited samples (false-positive and false-negative conclusions). This reluctance of the WHO to propose solid statistical modeling has resulted in many agencies requiring only 3–4 lots  for testing. It is well understood that a larger number of lots are required before the statistical modeling can be initiated. The WHO also states that the most frequently applied overall similarity criteria require that a certain percentage of the biosimilar batches (usually between 90% and 100%) fall within the similarity range. Given that in an equivalence range, 90% of biosimilar lots must fall within three standard deviations for the reference product. This means that only one lot out of ten can fall outside the range, but if there are less than ten lots tested, the analysis becomes moot.
- For efficacy studies, the WHO allows using a non-inferiority model discouraged by the FDA and EMA as inappropriate to consider higher efficacy leading to higher safety issues.
- The WHO suggests that the chosen reference product must have been marketed for a “suitable period” with proven quality, safety, and efficacy to serve the reference product. No suitable period is defined, and the advice has led to distrust in the safety of biological drugs approved under stringent regulatory compliance. While there is a 12-year restriction in the US and ten years in the EU, the WHO member agencies do not have to comply with this restriction. The WHO statement has caused great damage to the adoption of biosimilars in developing countries, and it must be removed.
- The WHO suggests that a biosimilar developer may use one source of reference product for analytical testing and another for clinical testing. This argument is illogical; all testing should be performed using the same reference product derived from the same manufacturing source and bearing the same approval designation.
- The WHO maintains its position, despite many criticisms, that regional agencies can decide the labeling and prescribing information. This is not only improper, but it is also unethical, giving the regulatory agencies to modify the safety and efficacy disclosures. The FDA has provided details of how the prescribing information should be developed; this should be followed by the WHO.
- According to the WHO, if a comparison reveals differences in product-related substances and impurities between the biosimilar and the reference product, the impact of the differences on the clinical performance of the drug product (including its biological activity) should be evaluated. This is the most misguiding advice. A reference product had been thoroughly tested with its impurity profile for safety and efficacy. Unmatched impurities cannot be validated by any means, including animal testing or clinical efficacy testing. The quantity of matched impurities can vary, within certain limits, as they can only bring a change in efficacy that is not likely to be significant. This argument extends to process-related impurities as well. The process-related impurities can be adjusted; thus, there is little rationale for qualifying an impurity not present in the reference product. If a biosimilar product production can remove these uncertainties, it should, regardless of their assumed risk.
- In the past, the WHO had given little importance to accelerated or stress condition testing; this is now changed to follow the rationale that these testing are meant to be part of the analytical assessment.
- The WHO statement, “It is up to the manufacturer to justify the relevance of the established similarity ranges and criteria”, is inappropriate. These determinations should be based on scientific principles, not individual agency preferences. This advice from the WHO has resulted in the NRAs adopting irrational test limits without justification.
- The WHO statement, “Nevertheless, any quality attributes not fulfilling the established similarity criteria should be considered a potential signal for non-similarity and assessed for possible impact on clinical safety and efficacy”, invites developers to seek waivers based on animal or clinical testing. Here, the WHO goes back to the assumption that differences in analytical similarity can be justified through any non-clinical or clinical study.
- WHO states, “Based on the totality of quality and nonclinical in vitro data available and the extent to which there is residual uncertainty about the similarity of a biosimilar and its reference product, it is at the discretion of the involved NRA to waive or not to waive a requirement for additional nonclinical in vivo animal studies”. This statement is misleading as it has caused many agencies to develop extensive animal testing, such as the Indian CDSCO , which suggests using several times the human dose to establish safety. The WHO further states, “To address the residual uncertainties, the use of conventional animal species and specific animal models (for example, transgenic animals or transplant models) may be considered”. This is not sound scientific advice, leaving an impression that it may be possible to resolve differences in analytical similarity using tests without relevance.
- WHO suggests that local tolerance studies are not required unless excipients are introduced for which there is little or no experience with the intended clinical route of application. Biosimilars can have formulations different from the reference product, and a tolerance study is required to evaluate the formulation. If a formulation includes ingredients that have not been used before, this creates significant risk and cannot be resolved.
- According to the WHO, “Clinical studies should be designed to demonstrate confirmative evidence of the similar clinical performance of the biosimilar and the reference product, and therefore need to use testing strategies that are sufficiently sensitive to detect any clinically relevant differences between the products”. The testing strategies are always the same, either a response on a clinical marker. Both are the least sensitive to tell the difference compared to analytical assessment and clinical pharmacology testing.
- Using reference products remains unclear with issues such as using a foreign reference product instead of a domestic product if a suitable reference product is not licensed locally. In this case, the NRA may accept a reference product that has been licensed in another jurisdiction.
- If required by the legislation in place, the comparability of the local and foreign-sourced versions of the product should be demonstrated by analytical “bridging” studies and, where needed, complemented by additional PK/PD data. Here the WHO allows precedence of any local regulations to overcome scientific arguments.
- The WHO statement, “It may also be prudent not to waive the efficacy and safety study when the reference product has common or unpredictable serious adverse effects that cannot be merely explained by exaggerated pharmacological action”, is based on the wrong assumption that efficacy study can overcome any unusual effects.
- The WHO also allows the NRAs to develop their prescribing information, which leads to abuse of biosimilar products. There must be a unified approach to creating the label.
2.4. The MHRA Scene
2.5. The ROW Scene
3.2. Reference Product
3.3. Materials and Standards
4. Expression System
6. Release Specification
7. Analytical Assessment
- Visual display. This is most suitable where spectra are produced; most important is the peak locations. This is one of the most important tests as it applies to the critical comparison of primary, secondary, and tertiary structures.
- MinMax: A MinMax range is defined by a sample’s lowest and highest values. The MinMax test is accepted if the MinMax range of the test sample is within the MinMax range of the reference sample (minTest > minRef and maxTest < maxRef). The MinMax is a conservative approach with a low false acceptance rate but a high false rejection rate.
- 3Sigma: the 3Sigma range is calculated for the reference sample as (μref-3σref, μref + 3σref). The 3Sigma test is accepted if the MinMax range of the test sample is within the 3Sigma range. The 3Sigma approach provides a more practical compromise of error rates, further improving with a larger sample size.
- Tolerance interval (TI): The tolerance interval is calculated for the reference sample as (μ − k*σref, μ + k*σref). The k-factor is calculated two-sided with a confidence level of 0.9 and a proportion of the population covered by the tolerance interval of p = 0.99. The tolerance interval test is accepted if the MinMax range of the test sample is within the tolerance interval calculated for the reference sample. Tolerance interval testing is only usable if the sample size is sufficiently large.
- Equivalence testing of means (EQT): A two one-sided t-tests’ (TOST) procedure is used to test for equivalency of the means of the reference product and the test product. The equivalence margin is δ = 1.5 SDref (standard deviation of the reference product sample). The Type I error probability is controlled at level α = 0.05 for a conclusion of equivalence. The test is accepted if the (1 − 2α)100% = 90% confidence interval for the difference in the means is within (−δ, +δ). Equivalence testing has a high false rejection rate and, with increasing sample size, a considerable false acceptance rate.
8. Non-Clinical Testing
- Presence of potentially relevant quality attributes that have not been detected in the reference product (e.g., new post-translational modification structures).
- Presence of potentially relevant quantitative differences in quality attributes between the biosimilar and the reference product.
- Relevant differences in formulation, e.g., excipients not widely used for biotechnology-derived proteins.
9. Clinical Evaluation
“As a scientific matter, FDA expects a sponsor to conduct comparative human PK and PD studies (if there is a relevant PD measure(s)) and a clinical immunogenicity assessment. In certain cases, the results of these studies may provide adequate clinical data to support the conclusion that there are no clinically meaningful differences between the proposed biosimilar product and the reference product. However, if residual uncertainty about biosimilarity remains after conducting these studies, an additional comparative clinical study or studies would be needed to evaluate whether there are clinically meaningful differences between the two products.”
10. Clinical Pharmacology
11. Clinical Safety and Efficacy Studies
13. Summary of Harmonized Guideline
- A uniform terminology. Products labeled as “biosimilar” are “approved” using “analytical assessment”. “Comparability” confuses the use of ICHQ5E; it is “comparative similarity”.
- The reference product should be the first approved as a new drug in the US, EU, UK, or Japan. The test samples must be secured from the source country, not from any other country where the same product is distributed unless the product is approved using the same dossier; no bridging study is required.
- The expression system type (e.g., mammalian, bacterial, yeast, etc.) used should preferably be the same as used by the reference product, notwithstanding differences in the type of expression species that may not be known. In addition, there should be no antibiotic contamination.
- Must demonstrate that process is controlled and reproducible. Use ICH guidelines.
- All excipients should be free of animal products, and no novel excipients should be added to the formulation.
- Pharmacopeia test methods can be used for validating test methods only, not for comparative testing. The specifications in pharmacopeia should not be used to establish biosimilar specifications.
- Product-specific monographs and the specifications suggested cannot be used to support the claim of biosimilarity.
- If legally possible, the formulation should be the same as the reference product; or one with fewer components.
- It should have the exact mode of action, same concentration, same dose, same route, and same indications.
- Release specifications should be based on testing of reference lots for only non-legacy attributes. Legacy attributes may use compendial specification. All test methods to establish specifications must be validated. Tolerance intervals may be preferred to establish specifications.
- Product-related attributes that are not included in the release specification should be compared using a suitable, not necessarily a valid, method. Compendial test methods can be used if available.
- Analytical assessment of data subject to statistical testing must be derived from at least 9–10 lots of the reference and biosimilar products. The data must be normally distributed. Where applicable, the 3Sigma approach is recommended. The visual comparison is applied wherever the output is a non-quantified graphic display.
- Forced stability testing should be part of the analytical assessment. It should include at least one lot at a commercial scale and manufactured under cGMP compliance that will be used as a clinical lot.
- No unmatched impurities unless a safety profile is established for the same impurity, not the same type. It is preferred to modify the downstream process to remove unmatched impurities.
- Process-related impurities must be fixed with process optimization.
- No animal testing.
- Pharmacokinetic/pharmacodynamic testing in healthy subjects or patients at two dose levels; one at the full dose and the other at half the dose. A parallel-group switching in the second cycle allows for immunogenicity evaluation and cross-reacting antibody evaluation. Use restricted inclusion criteria to reduce study size. A lower dose is likely to be more sensitive in establishing similarity .
- No changes in the product are allowed after the PK/PD study has been conducted. ICHQ5E does not apply to biosimilars until they are approved. The clinical lot must be GMP and at scale.
- The label must conform to the reference product label; use the FDA format available. Must include all indications and no new indications .
- Post-market safety reporting is required.
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
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|Biosimilars||WHO, Canada, China, Egypt, Ghana, Indonesia, Iran, Jordan, Malaysia, Korea, Singapore, Thailand, USA, and Zambia|
|Follow-on Biologics||Japan, Brazil|
|Similar Biologics||India, Peru|
|Similar Biologic Medicinal Product (SBMP)||EU, Ukraine|
|Multisource Known Biological Products||Cuba|
|Product||Reference Product (N)||Biosimilar Product (N)|
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Niazi, S.K. Biosimilars: Harmonizing the Approval Guidelines. Biologics 2022, 2, 171-195. https://doi.org/10.3390/biologics2030014
Niazi SK. Biosimilars: Harmonizing the Approval Guidelines. Biologics. 2022; 2(3):171-195. https://doi.org/10.3390/biologics2030014Chicago/Turabian Style
Niazi, Sarfaraz K. 2022. "Biosimilars: Harmonizing the Approval Guidelines" Biologics 2, no. 3: 171-195. https://doi.org/10.3390/biologics2030014