FDA: Critical Path for Generic Drug Development

The FDA used to focus on the challenges faced by the development of innovative drugs, devices, and biologics, but the development of generic drugs also faces various scientific challenges

PART 0 1.

Bioequivalence means that the absorption rate and degree of absorption of the active ingredients of the generic drug at the site of action are equivalent to those of the reference drug

The above methods for evaluating pharmaceutical equivalence and bioequivalence are not applicable to complex generic drugs and topical generic drugs; scientific challenges have hindered the development of such generic drugs

PART 0 2.

Improvements in the above aspects will accelerate the listing of generic drugs

1.

Quality comes from design.

When using QbD to develop a generic drug that is bioequivalent to the reference drug, the applicant of the generic drug must understand the influence of the prescription process parameters of the drug containing the specific active ingredient on the bioavailability

1.

The current formulation development strategy is mainly based on trial and error, internal databases, and the experience of researchers

1.

The generic drug and the reference preparation can have different release mechanisms, provided that the generic drug and the reference preparation are pharmacologically equivalent and bioequivalent

ANDA applicants often do bioequivalence studies on 1/10 of the commercial batch

2.
Method of bioequivalence of generic drugs for systemic action

For systemic drugs, the key path goal is to accelerate the approval of safe and effective generic drugs by expanding bioequivalence exemptions, optimizing dissolution methods and bioequivalence methods
.

2.
1 Expanding the bioequivalence exemption based on the biopharmaceutical classification system

The Biopharmaceutical Classification System (BCS) is a drug development tool
.
Applicants can apply for a bioequivalence exemption for fast-release generic drugs that have both BCS class I (high solubility and hypertonicity) and rapid dissolution
.
BCS II (low solubility and hypertonicity) and BCS III (high solubility and hypotonicity) can also apply for a bioequivalence exemption
.

Bio-related dissolution methods: The development of bio-related dissolution methods will provide formulation researchers with reliable standards related to in vivo release, while allowing regulators to compare meaningful dissolution profiles through different products
.

2.
2 Postprandial bioequivalence study

Even if the label of the reference preparation clearly states that the food does not affect the absorption of the drug, the current FDA bioequivalence guidelines still recommend that generic drugs conduct pre- and post-prandial bioequivalence studies
.
The purpose of postprandial studies is to ensure that generic drugs are also free of food effects, but for fast-dissolving BCS class I drugs, postprandial bioequivalence studies can be exempted
.
The critical path includes:

Food and drug interactions: If the mechanism of interaction between drugs and food can be understood well, the other three BCS types of drugs may not need to undergo post-prandial experiments to prove that the generic drugs and reference preparations have biological effects after meals.
Effectiveness
.

2.
3 Bioequivalence of new drug delivery technologies

Different from traditional fast-release oral tablets and capsules, researchers continue to develop generic drugs for new drug delivery technologies
.
For new drug delivery technologies, additional research is needed to improve the assessment of bioequivalence
.
The critical path includes:

The pharmacokinetic curve contains multiple peak bioequivalence: a single dose of a new modified release formulation (such as a subcutaneous implant formulation) can produce multiple peaks in the drug-time curve
.
The FDA currently uses Cmax and AUC to assess bioequivalence
.
The development of new methods for evaluating bioequivalence has application value
.

Transdermal products: Develop new clinical trial designs and standards to investigate the consistency of generic drugs in skin irritation, potential sensitization and adhesion properties with reference preparations
.

2.
4 Bioequivalence of high-variability generic drugs

For drugs with high individual variability in Cmax and AUC, there are a series of challenges in conducting BE studies
.
For example, for a drug with 50% variability, even if the generic drug and the reference drug are exactly the same, it still requires 100 subjects to prove its bioequivalence
.
Unless highly variable drugs have a wide therapeutic index, such drugs are neither safe nor effective
.
According to current FDA guidelines, drugs with a wide therapeutic index are more valuable for research than those with a narrow therapeutic index
.
The critical path includes:

Bioequivalence study design: Develop bioequivalence clinical trials that require fewer subjects
.

references:

1.
FDA, Challenge and Opportunity on the Critical Path to New Medicinal Products (March 2004).

2.
FDA, Critical Path Opportunities Report (March 2006).

3.
FDA, Critical Path Opportunities List (March 2006).

4.
Center for Drug Evaluation and Research, Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book), 26th ed.
(2006).

5.
J.
Woodcock, Biomarkers: Physiological & laboratory markers of drug effect, FDA (2006).

6.
J.
Woodcock, The concept of pharmaceutical quality, American Pharmaceutical Review p.
106 (November/December 2004).

7.
Guidance for Industry:Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System (August 2000).

8.
Draft Guidance for Industry Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action (April 2003).