It depends on the drug. They are going to already know what delivery will likely work without further modification. For example, oral delivery is going to need to survive the stomach and get absorbed. Timing of release and half-life in the blood stream also factor into delivery method. They take these into account when deciding the best way to deliver the drug. Target organ also matters.

Let's say target organ is the liver. Couldn't that be handled numerous ways (injested, injected, orally, rectally, vaginally?) I'm thinking of all the ways that people can administer alcohol into their systems.

Do pharma companies evaluate all those methods when testing a drug intended to target the liver?

The answer is no, they don’t. Those modalities are tested and approved by the FDA individually.

They would love to deliver it the way that is most likely to be done correctly and most welcomed by the patients and doctors. That’s oral pills. They’ve come up with clever ways to do slow release that is protected from the stomach but absorbed in the intestines, for some drugs. Then it has to be protected from degrading enzymes so it stays in the blood or liver at the right level the longest before another pill is needed. Then the degradation products have to be harmless.

When a drug can’t be designed for this, you end up with things like multiple pills per day, or injections, or liquids, or patches, or nasal sprays, or rectal suppositories. Sometimes a patch is best because it can be slow release.

Also depends on the nature of the chemical and the desired results, and how anxious the developers want to bring it to market. For example, certain compounds are easy to inject, but developing an oral formulation (which are generally more desirable) would take longer. But if the drug is the first drug in a new class, the first to market status could trump oral availability.

Also, sometimes drugs are for specific applications - there is no point in testing a topical agent orally. Or the rectal absorption of a drug intended for join injections.

But sometimes it happens that a smart person thinks "hey, this drug I've been injecting could work on hemorrhoids." So then that might be studied.

Hey, my field here (still in pharm school, but I'll specialize in delivery).

1. Getting an approval is a long, hard and expensive process, all things that you want to avoid. On top of that, a patent expires after a while, so other companies who didn't spend money on the research process can manifacture the med and sell it (the so-called generic drugs), BUT you can extend the patent if you re-patent it in a different-enough formulation.

2. Each route has its advantages and disadvantages, and the main ones are actually different enough to just choose in advance depending on the effect you need (instant vs slow release, for instance). However, there are A LOT of finer delivery methods which can be used, that can modulate the release (targeting something like a tumor or releasing through a precise pattern like concerta / ritalin XR, not to mention advanced methods that involves heat or other external stimuli).

Now, given 1) and 2), you can understand how the first try for at least a general method, the ones that fits the reason why it's being developed, patent and get the AIC (Italian for Autorizzazione all'Immissione in Commercio, don't know the English term, basically authorization to sell it) as soon as possible, after refining the chosen one.

After it's on sale, they'll find a way to repurpose or formulate it differently, maybe trying for an XR version, and testing for different delivery methods, which will be patented right before the other one expires. They calculate it to day precision.

I'm by far not an expert. Someone else can probably weigh in more, but in veterinary drug books, they often list the drug and all routes of administrations and efficacy/ effects species, etc. It can get interesting in different species. Not all animals will take a pill.

Your question seems to assume that the drug is submitted to regulatory authorities for approval with no thought to how the patient will take the drug. A drug is submitted for approval for a specific mode of delivery to the patient. If the drug is developed for oral delivery using a pill, the submission is for oral delivery using a pill.

I didn't assume that at all? I was asking about how the approval process was tied to methods of delivery during the R&D

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In that case, I think that pharmokinetic and pharmodynamic information is used to determine how the drug interacts with the body. As I understand, the pharmokinetics looks at how the drug gets into and around the body, which involves dissolution of pills in the digestive system or movement within the body after injection. The pharmodynamics looks at how the drug interacts in the body with the target of the drug, such as binding to receptors of interest that affect the disease of interest. So the mode of drug delivery that is developed is determined to maximize the effective drug delivery to where it is needed in the body.

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No. If at all possible the oral route is preferable. Patients prefer this, easier to sell more etc. But the drug itself will determine the delivery route other wise. If the drug cannot be absorbed through the gut it may require injection. If this is not a life saving drug, say it is an antihistamine for example people are not going to be willing to take the time and expense for an injectable drug like that unless for some specific reason someone really needed it.

Every method? No, that just wastes money.

Standard practice is to have a "target product profile" which guides development. The mode of delivery is typically established in advance. Since clinical studies are very expensive, it is normal to initially focus on one method of delivery. After initial market introduction, additional methods could be added to expand the market.

To answer your question in the simplest way, every difference in dosage form is a separate New Drug Application (NDA) in the USA. The process is usually called a license application or Marketing Authorization elsewhere, but the processes are broadly similar. In one NDA, you could say, “we are going to offer this in 5, 10 and 20 mg capsules…” and you’d need to justify why those are the sizes.

You can reference information from one application in another. If the same impurities were in a capsule and oral liquid for a drug, and both hit the bloodstream the same way, you don’t have to repeat the tox study on the impurities.

I should point out that in the days when everything sent to an agency was on paper, forests trembled at the size of these filings. Now they are electronic and are even bigger.

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Not necessarily, but government regulation forces them to test for every method for which they will be authorized for use and often asks for additional information which could include the effects from different delivery methods.

Before it can be legally sold in most countries, the company will have to prove to the government regulator that the drug is safe and effective when used in the manner prescribed. If the drug company wants to sell the prescription as a pill, they will have to prove that the drug is safe and effective when ingested. Then the government regulator allows the company to sell that new drug in that specific form, for that specific method of delivery.

If the company then wanted to take that pill and sell it as, say, a patch, they would have to prove to the government regulator that a patch is safe and effective, which is treated as an Abbreviated New Drug Submission - so it requires less information, because you've already proven to the government that the drug works when you applied for permission to sell it as a pill, now you're just proving that it's also safe and effective in this new form.

This is the way it works for Health Canada, anyways, and I'd assume it's the same for other Western government regulators as well.

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Great- I would just add for additional nuance that the intended population is taken into account, as well. For example, if you’re developing a drug for a disorder in which many patients end up having feeding tubes, you may prefer to first test an oral solution even if you can make a tablet, because you can help more patients with that formulation.

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They used to be about a truckload of paper. That included a couple of copies for the reviewing agency’s convenience.

The ones I work with nowadays are around 100.000 to 1.000.000 pages as pdf.

To be honest, most of those pages are tables tabulating detailed test results (eg every single blood test taken in every study). Those are then summarized to more high level documents which are fortunately shorter.

I used to prep drug master files for the API. They’d be smaller of course, but still with three copies printing, etc was a chore. And yes, a lot of it was executed batch records and the environmental statement, which i guarantee no one ever read.

I once accidentally discovered a note in the middle of one I was compiling yelling at my group for monopolizing the printer. It could easily have gone to FDA. I would’ve loved to get that deficiency letter. “Please explain the copier/printer drama…”. Same guy who put in the note made a complaint about me to HR because I let the FDA ask him a question on a tour. (We were a small shop.). They had to explain the law to him. He was still pissed. “Hey, bud I answer their questions 8 hours a day, you can answer one about a lab balance.” Good times.

I appreciate that story!! I’m sure the FDA must have received lots of copier drama without even knowing it.

Made me remember someone who accidentally sent their yearly development plan to the authorities in a handful of countries. Not her best working day.

No, the FDA does not run these tests. They'd have to pay for them then, rather than get the company to do them and pay for them.

Generally no. They will usually go with whatever route is expected to be used for the final drug. That depends on things like oral bioavailability (if you swallow it, does it actually reach the bloodstream), and is it most likely to be used in a hospital setting or by patients themselves. Generally, oral is preferred where possible, because it has higher patient compliance levels, but if that’s not suitable (you need something shorter or longer lasting, say, or it breaks down in the gut to something useless), you’d probably do some in vitro and in vivo DMPK to figure out what route would be better. Early DMPK testing will give an idea on which route is to be used. Thereafter, the testing is done by that particular route, plus some IV injections here and there for Pharmacokinetic comparisons.

Companies need to test any delivery method they intent to get marketing approval for. If a drug is approved for oral ingestion (pill or liquid), they need to test it that way. If approved and brought to market, that’s how it should be used. If someone is silly (or stubborn) enough to use it any other way (lets say, snort a crushed pill), that is not the company’s responsibility (though they probably will get some flack for it….) For some medication where alternative intake is a concern, companies may alter the formulation, for instance add a substance to the pill that makes it impossible to crush fine enough to snort, or make a liquid for ingestion very viscous so it can’t be injected.

Most drugs have a delivery dependent on molecule type. Most „small molecules“ are delivered orally as they can pass through the intestinal walls and are not denatured whereas big molecules (for example antibodies) would be denatured in the gut and hence rendered useless which means they are generally injected. Another thing to consider is pharma cocinnetics but in the end you will never be able to use a big molecule drug in a pill to be swallowed

I meant tested (by the companies) and then approved (by the fda). I know lol.

>Pharmaceutical companies typically test multiple methods of drug delivery during the development process for a new prescription drug.

No, that would be unusual.

>some drugs may be more effective when delivered intravenously (through an injection) because they can be quickly absorbed into the bloodstream and distributed to the target tissue.

Speed is rarely a concern. Exposure (duration of effect) is the common issue. Here oral delivery can have an advantage, since a pill formulation can reside in the digestive system for hours, extending the time for absorption.

I got one or two of those. I felt honor bound to delete them. We were a smallish business but part of a pretty big company. Some of our customers were enormous. Once when discussing a newly identified but inconsequential impurity with an enormous pharma, they got into a big internal fight in front of us. Ok one time. But it was every week.

Same company berated us for missing a particle size spec we didn’t know existed. They had a senior VP on the call to yell at us. He realized they had added the spec without telling us and yelled at his people in front of us. Pharma can be nuts.

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Oral is the most effected for reaching the liver. All those other administration techniques skip first pass metabolism which means they’ll go everywhere in the body THEN then liver while oral admin will go mouth>stomach>intestines>liver> rest of body

Typically, it's an expensive proposition to study unnecessary delivery methods, especially when user error can become a problem, this complicates the path to market. Typically, there's not a lot of benefit to the extracted from just testing every type of delivery.

If oral delivery poses certain challenges, then other methods can be explored.

There's not typically a problem with the pharmacokinetics, where additional benefit can potentially be extracted from alternative delivery methods. If the oral route works, that's almost always the best way to go.

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I worked for a biotech company. The methods tested are designed to deliver the drug via a specific route for a specific population versus a negative (typical standard of care) control. Someone working with a glaucoma drug that involves eyedrops is not going to test the drug for intravenous or rectal administration.

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