What evidence FDA requires for drugs and biologics

An NDA is approved when FDA determines that the drug meets the statutory standards for safety and effectiveness, for manufacturing and controls, and for labeling. Effectiveness rests on substantial evidence consisting of adequate and well-controlled investigations as defined in § 314.126, and safety rests on adequate tests by all methods reasonably applicable to the labeled conditions of use.¹ A biologics license application is approved on data derived from nonclinical laboratory and clinical studies demonstrating that the manufactured product meets the prescribed requirements of safety, purity and potency.² The quantity and kind of evidence differ by route, and the routes described below each carry their own evidentiary test.

The evidence standard for an NDA

An NDA contains reports of all investigations of the drug product sponsored by the applicant. It also contains all other information about the drug pertinent to an evaluation of the NDA that the applicant receives or obtains from any source.¹ FDA exercises scientific judgment to determine the kind and quantity of data an applicant must provide for a particular drug to meet the statutory standards, because the range of drugs and uses subject to those standards demands flexibility.¹

Section 314.125(b) lists the grounds on which FDA may refuse to approve an NDA. They include the following.¹

• inadequate manufacturing methods, facilities or controls
• investigations that omit adequate tests to show safety
• test results that fail to show safety
• insufficient information to determine safety
• a lack of substantial evidence consisting of adequate and well-controlled investigations

Other grounds include labeling that is false or misleading, an untrue statement of material fact, the absence of bioavailability or bioequivalence data required under part 320, manufacture in an unregistered establishment, and refusal of an adequate opportunity to inspect.¹

FDA determines within 60 days of receipt whether an NDA may be filed. Filing is a threshold determination that the application is sufficiently complete to permit a substantive review. The date of filing is the date 60 days after FDA received the NDA, and that date starts the 180-day filing clock under section 505(c) of the act.¹

What makes a study adequate and well-controlled

The purpose of a clinical investigation under § 314.126(a) is to distinguish the effect of the drug from other influences such as spontaneous change in the course of the disease, placebo effect or biased observation. Reports of adequate and well-controlled investigations provide the primary basis for determining whether substantial evidence supports the effectiveness claims.¹

Section 314.126(b) sets out the characteristics of such a study. The protocol and the study report must state the objectives clearly and summarise the methods of analysis. The design must permit a valid comparison with a control to give a quantitative assessment of drug effect. The types of control recognised include placebo concurrent control, dose-comparison concurrent control and no treatment concurrent control.¹

An applicant may ask FDA to waive under § 314.126(c) any criterion of an adequate and well-controlled study described in § 314.126(b). A waiver request is submitted with supporting documentation in the NDA or in an amendment or supplement. It must explain why compliance is unnecessary or cannot be achieved, describe an alternative submission that satisfies the purpose of the requirement, or give other information justifying a waiver. A requirement waived under § 314.90 does not constitute a basis for refusal to approve under § 314.125.¹

The 505(b)(2) route

A 505(b)(2) application is an NDA in which at least some of the investigations relied upon for approval were not conducted by or for the applicant, and for which the applicant has no right of reference or use.¹ The route is available to a person seeking approval of a drug product that represents a modification of a listed drug, such as a new indication or new dosage form, where investigations other than bioavailability or bioequivalence studies are essential to approval of the change.¹

The application need contain only the information needed to support the modification. It must include the following.¹

• the items required under § 314.50(a), (b) and (c)
• the items required under paragraphs (d)(1), (d)(3), (e) and (g) of the same section
• the items under § 314.50(d)(2), (d)(5), (d)(6) and (f) as needed to support safety and effectiveness, and those under (d)(4) for an anti-infective drug

The applicant must identify each listed drug for which FDA has made a finding of safety and effectiveness and on which the applicant relies. At least one listed drug identified must be pharmaceutically equivalent to the proposed product and must have been approved before the original 505(b)(2) application was submitted.¹

The ANDA route

An abbreviated application is suitable for a drug product that is the same as a listed drug. The same means identical in active ingredient, dosage form, strength, route of administration and conditions of use. Conditions of use that cannot be approved because of exclusivity or an existing patent may be omitted.¹ Approval rests on the finding of safety and effectiveness already made for the reference listed drug, together with the applicant’s showing of sameness and bioequivalence. FDA approves an ANDA after determining that the drug meets the statutory standards for manufacturing and controls and for labeling. Where applicable the drug must also meet the standard for bioequivalence.¹

Grounds for refusal under § 314.127 are correspondingly narrow. They include insufficient information to show that each proposed condition of use was previously approved for the listed drug, insufficient information to show that the active ingredient or ingredients are the same, insufficient information on route of administration, dosage form or strength, and insufficient information to show bioequivalence.¹

A product that differs from a listed drug in route of administration, dosage form or strength, or that substitutes one active ingredient in a combination, requires prior permission through a petition under § 314.93. The petitioner must show that the active ingredients are of the same pharmacological or therapeutic class and that the product can be expected to have the same therapeutic effect. FDA approves or disapproves the petition no later than 90 days after it is submitted.¹ An ANDA referring to a listed drug withdrawn from sale must be accompanied by a petition seeking a determination whether the withdrawal was for safety or effectiveness reasons.¹

Evidence for a biologics license

The manufacturer submits the application to the Director of CBER or the Director of CDER with data from nonclinical laboratory and clinical studies demonstrating safety, purity and potency. Each nonclinical study carries either a statement of compliance with part 58 or a brief statement of the reason for noncompliance. Each clinical investigation carries statements on institutional review under part 56 and informed consent under part 50.² The application also contains the following.²

• a full description of manufacturing methods
• stability data through the dating period
• representative samples
• summaries of lot test results
• label specimens
• the address of each manufacturing location

Approval follows examination of the product and a determination that it complies with the standards in the application and with the regulations, including the good manufacturing practice requirements in parts 210, 211, 600, 606 and 820. A license is issued only after inspection of each establishment listed in the application. One license covers all locations meeting the establishment standards identified in the approved application.²

An expectation carried over from NDA practice can mislead here. A biologics license application may not incorporate by reference drug substance, drug substance intermediate or drug product information contained in a master file, subject to the exceptions in § 601.2(g)(2) and (g)(3) for deemed licenses and for non-biological constituent parts of combination products.²

Accelerated approval

Subpart H of part 314 and subpart E of part 601 apply to products studied for safety and effectiveness in treating serious or life-threatening illnesses that provide meaningful therapeutic benefit over existing treatments.¹² FDA may approve on the basis of adequate and well-controlled clinical trials establishing an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit. The basis for that likelihood may be epidemiologic, therapeutic, pathophysiologic or other evidence. Approval may also rest on an effect on a clinical endpoint other than survival or irreversible morbidity.¹²

Approval carries a requirement that the applicant study the product further to verify and describe its clinical benefit. Those postmarketing studies must themselves be adequate and well-controlled, and the applicant must carry them out with due diligence.¹² FDA may require postmarketing distribution restrictions where a product shown to be effective can be used safely only under such conditions.¹² The requirements ordinarily cease to apply when FDA determines that the required postmarketing study verifies and describes the clinical benefit.¹

Approval on animal evidence

Subpart I of part 314 and subpart H of part 601 apply to products studied for safety and efficacy in ameliorating or preventing serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic biological, chemical, radiological or nuclear substances. The subparts apply only where definitive human efficacy studies would be unethical and field trials after accidental or hostile exposure have not been feasible.¹²

FDA relies on animal evidence for substantial evidence of effectiveness only when four conditions are met. There must be a reasonably well-understood pathophysiological mechanism of the toxicity and of its prevention or substantial reduction by the product. The effect must be demonstrated in more than one animal species expected to react with a response predictive for humans, or in a single sufficiently well-characterised model. The animal study endpoint must be clearly related to the desired human benefit, generally enhancement of survival or prevention of major morbidity. Kinetic and pharmacodynamic data must allow selection of an effective human dose.¹² Safety must be established independently, since these subparts do not address the safety evaluation.¹²

Approval carries three requirements: postmarketing studies to verify and describe clinical benefit when feasible and ethical, restrictions to ensure safe use where needed, and patient labeling explaining that approval was based on efficacy studies in animals alone.²

Diagnostic radiopharmaceuticals

Subpart D of part 601 applies to radiopharmaceuticals intended for in vivo diagnostic and monitoring use.² Effectiveness is assessed by evaluating the ability of the product to provide useful clinical information related to its proposed indications. A claim of disease or pathology detection is established by demonstrating sufficient accuracy in a defined clinical setting. A claim of diagnostic or therapeutic patient management is established by demonstrating usefulness in such management in a defined clinical setting. Accuracy is determined by comparison with a reliable assessment of actual clinical status, which may come from a diagnostic standard of demonstrated accuracy or from another means such as patient followup.²

Safety assessment considers the radiation dose, the pharmacology and toxicology of the radiopharmaceutical, the risks of an incorrect diagnostic determination and the adverse reaction profile. FDA may require pharmacology data, toxicology data, clinical adverse event data and a radiation safety assessment. The radiation safety assessment must establish the radiation dose by dosimetry evaluations in humans and appropriate animal models. The maximum tolerated dose need not be established.²

Pediatric data and foreign data

Each application for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration must contain data adequate to assess safety and effectiveness in all relevant pediatric subpopulations. Where the course of the disease and the effects of the product are sufficiently similar in adults and children, FDA may conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled studies in adults supplemented with other pediatric information such as pharmacokinetic studies.¹² FDA may defer submission until after approval in adults, and may grant a full or partial waiver on the grounds set out in § 314.55(c) and § 601.27(c).¹² Section 601.27 does not apply to a product for an indication for which orphan designation has been granted under part 316, subpart C.²

An application based solely on foreign clinical data may be approved if the data are applicable to the US population and US medical practice, the studies were performed by clinical investigators of recognised competence, and the data may be considered valid without an on-site inspection or FDA is able to validate them by inspection or other appropriate means. Failure on any of the three criteria makes the application unapprovable on the foreign data alone. Applicants are encouraged to meet with agency officials in a presubmission meeting when approval on foreign data alone will be sought.¹

Questions people also ask

What counts as substantial evidence of effectiveness? Substantial evidence consists of adequate and well-controlled investigations as defined in § 314.126. Such a study states its objectives clearly, summarises its methods of analysis in the protocol and the report, and uses a design permitting a valid comparison with a control to give a quantitative assessment of drug effect. A lack of substantial evidence is a ground for refusal to approve an NDA under § 314.125(b)(5).¹

How many studies does FDA require? The regulation does not fix a number. FDA exercises scientific judgment to determine the kind and quantity of data an applicant must provide for a particular drug to meet the statutory standards.¹ An applicant may ask FDA to waive any criterion of an adequate and well-controlled study under § 314.126(c), with supporting documentation submitted in the NDA or an amendment or supplement.¹

Does an ANDA require clinical trials? Approval of an ANDA rests on the safety and effectiveness finding already made for the reference listed drug. The applicant shows that the product is the same as the listed drug in active ingredient, dosage form, strength, route of administration and conditions of use, and shows bioequivalence. Insufficient information on bioequivalence is a ground for refusal under § 314.127(a)(6).¹

What is the difference between accelerated approval and the animal rule? Accelerated approval under § 314.510 and § 601.41 rests on adequate and well-controlled clinical trials showing an effect on a surrogate endpoint reasonably likely to predict clinical benefit, or on a clinical endpoint other than survival or irreversible morbidity.¹² The animal rule under § 314.610 and § 601.91 rests on adequate and well-controlled animal studies where human efficacy studies would be unethical and field trials have not been feasible. The animal rule subparts do not apply to products that can be approved on efficacy standards described elsewhere in FDA’s regulations.¹²

Can a biologics license application reference a drug master file? A biologics license application under section 351 of the Public Health Service Act may not incorporate by reference drug substance, drug substance intermediate or drug product information contained in a master file. Two exceptions apply: applications deemed to be licenses under section 7002(e)(4) of the Biologics Price Competition and Innovation Act of 2009 that already incorporated such a file, and non-biological constituent parts of combination products. Information in a master file that is not drug substance, drug substance intermediate or drug product information may still be incorporated.²

Footnotes

1. 21 CFR Part 314, Applications for FDA Approval to Market a New Drug. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-314 ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹ ↩¹² ↩¹³ ↩¹⁴ ↩¹⁵ ↩¹⁶ ↩¹⁷ ↩¹⁸ ↩¹⁹ ↩²⁰ ↩²¹ ↩²² ↩²³ ↩²⁴ ↩²⁵ ↩²⁶ ↩²⁷ ↩²⁸ ↩²⁹ ↩³⁰ ↩³¹ ↩³² ↩³³ ↩³⁴ ↩³⁵

2. 21 CFR Part 601, Licensing. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-F/part-601 ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹ ↩¹² ↩¹³ ↩¹⁴ ↩¹⁵ ↩¹⁶ ↩¹⁷ ↩¹⁸ ↩¹⁹ ↩²⁰ ↩²¹ ↩²²