Everything a company files before a drug is tested in people

A contents list, written into law

Most people picture drug approval as a verdict at the end. The far more revealing document sits at the beginning.

Before a company may give a new compound to a person, it files an application, and one regulation states exactly what goes in it. The wording is unusual for a rule: it requires the material in the following order.

Reading that order is the cheapest way to see what a claim about a regulated compound is standing on, and what a claim about an unregulated one is standing on instead.

Item one: a cover sheet carrying five promises

The first item is a cover sheet on a numbered agency form. It carries the sponsor name, address and telephone number, the date, and the name of the investigational drug.

It also has to identify the phase or phases of the clinical investigation to be conducted, so the filing states its own scope up front.

Then come the commitments. A commitment not to begin clinical investigations until an application covering them is in effect. A commitment that a review board complying with the relevant part will be responsible for the initial and continuing review and approval of each study.

A commitment that the investigator will report proposed changes in the research activity to that board. And a commitment to conduct the investigation in accordance with all other applicable regulatory requirements.

Two roles must be named personally. One is the person responsible for monitoring the conduct and progress of the investigations. The other is the person or people responsible for review and evaluation of information relevant to the safety of the drug.

The two answers hidden on that cover sheet

The cover sheet also settles who else is involved and who signs.

Where a sponsor has transferred obligations to a contract research organization, the sheet must name and locate that organization, identify the study, and list the obligations transferred. A general statement is allowed only where all obligations went across.

Then a signature from the sponsor or an authorized representative. If the person signing does not reside or have a place of business in the United States, the application must name and be countersigned by an attorney, agent or other authorized official who does.

That countersignature rule is the quiet answer to a question this market raises constantly. A foreign company can sponsor an American study, but it cannot do so without a named domestic signatory.

Items two and four

Item two is a table of contents. It is in the rule because a reviewer has to navigate the filing, not because anyone was being fussy.

Item four is reserved, meaning the slot exists and holds nothing. It is a leftover of amendment history, and it is why the list runs to eleven with only ten items of substance.

Item three: what the drug is, and the plan for the year

The introductory statement is short and dense. It gives the name of the drug and all active ingredients, the pharmacological class, and the structural formula if known. It also gives the formulation of the dosage forms, the route of administration, and the broad objectives and planned duration of the investigations.

It then requires a summary of previous human experience with the drug, referencing other applications where pertinent, and investigational or marketing experience in other countries relevant to safety.

One sentence in this item is worth reading twice. Where the drug has been withdrawn from investigation or marketing in any country for any reason related to safety or effectiveness, the filing must identify those countries and give the reasons.

The item closes with a plan for the coming year. It gives the rationale for the drug or the research, the indications to be studied, and the general approach to evaluating it. It also gives the kinds of trials planned in the first year and the estimated number of patients.

And a final element that is easy to miss. The plan must state any risks of particular severity or seriousness anticipated on the basis of the animal toxicology or prior human work.

Item five: the document the trial doctors get

Where the rules require one, a copy of the investigator brochure goes in the filing, and this section specifies what is in it.

Five things. A description of the drug substance and formulation. A summary of pharmacological and toxicological effects in animals and, to the extent known, in humans. A summary of pharmacokinetics and biological disposition. A summary of safety and effectiveness information from prior clinical studies. And a description of possible risks and side effects.

That last element also has to describe precautions or special monitoring to be done as part of the investigational use.

Item six: a protocol for every planned study

Each planned study gets a protocol, and the rule scales the detail to the phase.

First-phase protocols may be less detailed and more flexible. They are meant to outline the investigation and to specify in detail only the elements critical to safety, such as necessary monitoring of vital signs and blood chemistries.

Second and third phase protocols are the opposite. Detailed protocols describing all aspects of the study are expected, designed so that anticipated deviations have alternatives or contingencies built in at the outset.

Whatever the phase, seven things must appear. The objectives and purpose. The name, address and qualifications of each investigator, the names of subinvestigators, the research facilities, and each reviewing review board.

Then the criteria for patient selection and exclusion, with an estimate of numbers. The design, including any control group and the methods used to minimize bias. The method for determining doses and the planned maximum. The observations and measurements to be made, and the procedures and tests used to monitor effects and minimize risk.

Item seven: what is in it and how it was made

This item is the chemistry, manufacturing and control section, and its opening principle is that the amount required varies with the phase and the scope of the investigation.

For the drug substance the filing describes physical, chemical or biological characteristics, names and locates the manufacturer, and gives the general method of preparation. It also states the acceptable limits and analytical methods used to assure identity, strength, quality and purity.

It must also carry information sufficient to support stability of the substance during the toxicology studies and the planned clinical studies.

For the finished product the requirement is broader in one striking way. The filing lists all components used in the manufacture, including both those intended to appear in the product and those which may not appear but which are used in the manufacturing process.

A placebo used in a controlled trial gets its own brief description of composition, manufacture and control. And labeling is item seven, not an afterthought: a copy of all labels and labeling to be provided to each investigator.

Item eight: the animal work, and who signed off on it

The pharmacology and toxicology item is the one most often quoted, because it is where the sponsor states a conclusion that human study is reasonably safe.

Two requirements inside it are quoted far less and matter as much.

The filing must identify the individuals who evaluated the results of those studies and reached that conclusion, and give their qualifications. A conclusion about human safety has named authors with stated credentials.

It must also state where the investigations were conducted and where the records are available for inspection. The underlying data has a physical address someone can visit.

And each nonclinical study covered by the good laboratory practice regulations needs a statement that it complied, or a brief statement of the reason for the noncompliance. Falling short is permitted; being silent about it is not.

Item nine: what has already happened to people

Previous human experience is its own item, and the standard for disclosure is generous rather than selective.

Where the drug has been investigated or marketed before, in the United States or elsewhere, the filing gives detailed information relevant to the safety of the proposed investigation or to its rationale.

Published material relevant to safety or to an assessment of effectiveness should be provided in full. Less directly relevant material may be supplied as a bibliography.

Combination products are handled component by component, with a carve-out where a component is already approved or otherwise lawfully marketed.

The item ends where item three began, and the repetition is deliberate. A list of countries where the drug has been marketed, and a list of countries where it has been withdrawn from marketing for reasons potentially related to safety or effectiveness.

Items ten and eleven: the special cases

Item ten collects topics that only apply to some drugs.

A psychotropic substance, or one that otherwise has abuse potential, requires a section on relevant clinical studies and experience and studies in test animals.

A radioactive drug requires enough animal or human data to allow a reasonable calculation of radiation dose to the whole body and critical organs.

Every filing carries plans for assessing pediatric safety and effectiveness, plus a brief statement of any other information that would aid evaluation.

Item eleven is a catch-all: any other relevant information needed for review, if the agency asks for it.

The six rules about the paperwork itself

After the contents list come rules about form, and they are more revealing than they look.

Information already submitted need not be resubmitted, but a reference has to identify the file by name, reference number, volume and page number. Referring to someone else's submission requires their signed written authorization.

Anything not in English needs an accurate and complete English translation, and a copy of each original literature publication must accompany it.

Submissions go in as an original and two copies, covering the initial filing and all amendments and reports.

Every submission relating to the application is numbered serially with a single three-digit number, and the initial filing is numbered 000. The file is therefore a sequence with no gaps, which is what makes a missing item visible.

And where a study involves an exception from informed consent, the sponsor must identify that prominently on the cover sheet.

What the list is worth outside a trial

A compound sold online produces none of this, and the useful part is knowing exactly what none of it means.

No named individual has stated, with their qualifications attached, that human use is reasonably safe. No address holds records available for inspection.

No document lists every component used in manufacturing, including the ones that are not supposed to end up in the vial.

No filing states the countries where the substance has been withdrawn for reasons related to safety or effectiveness, because no filing exists to state it.

That is not a claim that a given compound is unsafe. It is a description of the specific paperwork a reader is being asked to do without.

Sources

Each document below is named as it names itself, with the date printed on that document rather than the day it was read.

1. 21 CFR 312.23 — IND content and format — Office of the Federal Register, Electronic Code of Federal Regulations, August 2026
2. 21 CFR 312.55 — Informing investigators — Office of the Federal Register, Electronic Code of Federal Regulations, August 2026