Drug Approval Process Flashcards by Barrett Thompson

How does the approval of cancer drugs differ from other types of drugs?

They can be approved on the basis of Surrogate end products (made up goals)
They don’t have to cure cancer they just have to stop it

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Why might data for the side effects of drugs be incomplete?

Average amount of time used to determine drug side effects is 6 months so you don’t get an idea of the long term side effects of taking a drug

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What kind of patients are used in phase I clinical trials?

Phase I trials

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T or F: many trials don’t compare the drug to a gold standard and just use a placebo instead

True, they don’t want you to know that the new drug is worse than the old drug

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What is an orphan drug?

Drug that would be used by so few patients that is would never be made if it weren’t for FDA help (incentive)

**Any drug for a target of less than 200,000 ppl

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T or F: OTCs reduce cost, but the cost then shifts from the HMO to the consumer.

True

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What Milestones in drug regulation were met in:

1906
1938
1962

1906:
- Drugs were no longer allowed to be mislabed or adulterated (PURITY was the goal)

1938:
- Required SAFETY in addition to Purity

1962:
- Drugs need to be EFFECTIVE, SAFE, and PURE

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What group of drugs is approved solely on the basis of animal testing?

Anti-Bioterrism Drugs

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Why should you be very cautious about prescribing a new drug?

1/5 of approved drugs will be pulled from the market due to toxicity issues

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What are the 4 general phases of making a drug?

In vitro studies (0-2 years):
- A library of similar compounds is made and tested

Animal Testing (2-4 years): 
- Efficacy Selectivity we just want to see if it works in animals

Clinical Testing (4-8 years): 
- Clinical Testing (phase 0 - phase 3)

Marketing:
- Phase 4 “trials”

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After what phase can drugs fill out their new drug application?

After clinical Testing - this takes 8-9 years to get to this point meaning it only has 11-12 years left before generics can compete.

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What happens during phase 0 of the clinical trials?

Drugs in this day and age have a defined target and we want to see how well it hits that target

**Measure relationship between dose and target

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How many chemical entries are submitted to get 1 drug candidate?
- what are the variations exist among these entries?

5,000 to 10,000 entries to get one drug

Change pks, metabolism, solubility, route of delivery etc.

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Before moving to human trials what is the goal?

Keep it simple and cheap
Use less animals
Keep the amount of drug that needs to be synthesized down to a minimum

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What is the difference for 1st in class drugs and Follower drugs as far as targeting to specific receptors goes?

First in Class drugs:
- we look more at outcome - is the patient getting corrected to the right phenotype

Follower Drugs:
- We start looking at How well the Drug is binding to the RECEPTOR

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How have drug companies changed their minds about potency and efficacy?
- what do they now do to ensure drugs work?

Old Way:
- Make a compound with the highest potency and wait until off on animal trials to look at pharacokinetics

New Way:
- Use RAPID ADME-TOX assays to assess solubility, Absoption (artificial membranes), and Metabolism (Hepatocytes or Microsomes)

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How can we look at how much a molecule will interfere with CYPs without using an animal?

Put 3-5 compounds on an HPLC column loaded with CYP proteins to see what drugs interact most strongly

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What are Herg Channels?

- how do we test for interactions here?

Herg Channels are the K+ channels of the Heart

Terfenadine was a drug put on the market before this testing was done and had to be pulled back off (Costed the company tons of money)

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What is the general trend if you’re trying to determine any sort of toxicity or carcinogenicity in the drug you’re trying to get approved?
- Time needed for tests?

You need to Test it in 2 different species

Acute Toxicity - (2 diff. routes)
Sub-Acute Toxicity - (1-3 months of dosing)
Chronic Toxicity - (more than 6 months of dosing)
Carcinogenicity - (2 years)

Mutagenicity - done with an Ames test in a rat (so I guess only one species needed)

How long does the FDA have to review paperwork for a drug once its sent in?

30 days

aka IRB application approval

When is the only time you’ll see sick patients in a Phase I clinical trial?

If its a cancer drug

*Cancer patients who have failed other treatments may are allowed to enter these trials

Phase I clinical Trial:

Purpose?
People used?
Size?

Purpose:
- Find the Minimum Toxic Dose

People Used:
- Healthy adult volunteers

Size:
- Small 10-15 adults (or 20-100 according to his chart)

Phase II clinical Trials:

Purpose?
Dosing?
People used?
Size?

Purpose:
- See if it fixes the illness in humans, Try to figure out dosing and pharacokinetics in humans

Dosing:
- START at the Minimum Toxic Dose from the First trial

People Used:
- People affected by the disease of interest

Size:
100-200 patients

**Note if it doesn’t work in the first 14 pts. Statistics say that there is more than a 95% chance that the drug won’t work

Phase III clinical Trials:

Purpose?
Dosing?
People Used?
Size?

Purpose:
- Compare the drug to a placebo and see if it works
- Eliminate any bias
(this stage is make or break, do benefits outweigh risks?)

Size:
1000-6000 pts.

Why might a Phase III trial be stopped?

1. Superior Efficacy of the Trial Agent - you don't want to screw people out of treatment 2. Increased risk to patients

What drugs have historically been susceptible to the placebo effect?

- Antihypertensives | - Psychiatric Drugs

T or F: 30-50% of pts. receiving placebo in a trial will improve

True, so drug must have an effect greater than the placebo - If the trial just looked at effect being greater than existing agent, there would be no way to determine how much of the effect that due to the placebo FDA therefore requires new vs. old. vs. placebo

What 4 documents are submitted to the FDA for review for drug approval?

- Drug Safety in Animals and humans - Evaluation of Carcinogenic Status - Evaluation of Teratogenic Status - Drug Stability

What are the 3 responses the FDA may give to a drug application?

Approve, Approvable, Disapprove Approvable - means gather more information

What is pharmacometrics? | - purpose?

- Simultaneous Qualitative Understanding of Drug dose or Exposure and Response (pharmacodynamics) ***Extrapolates info from clinical trials to more scenarios without need for additional phase III trials - Applied to lead/support the final approval and labeling related decisions

What is the use of data obtained from Pharmacometrics?

- Evidence of Effectivness - Dose Optimization - Improvement in future Trial design by gaining insight into causes of Clinical Trial Failure

What is needed to make a generic drug?

- Only need to show Bioequivlence

How do you demonstrate Bioequivalence for a generic?

- Measure AUC drug levels in 24-36 healthy volunteers | - Compare to brand name

When do brand name drugs have to do demonstrate bioequivlence on themselves?

When the drug is reformulated

What is involved in Phase IV of FDA review? | - how does the FDA collect info in this phase and what is done with this info?

Phase IV the drug is on the market and its monitored mainly by the FDA medwatch program so they can get info on adverse events *FDA can use this info. to pull the drug if necessary

What adverse affects would you expect to pick up in phase IV that were not picked up in any of the clinical trial phases of Drug approval?

Adverse effects that occur in Less Than 1 in 3,000 to 5,000 ppl. *b/c this is usually your sample size in a phase III trial

Differentiate the data the is collected by the FDA in: - 15-day Reports - Periodic Reports - Direct Reports

Company Submissions: 15-day Reports -adverse events that were serious and unexpected as well as adverse events form clinical trials that are serious and unexpected and are reasonably associated with the drug Periodic Reports - all of the other reports not in the Direct or 15-day category (presumably benign and expected side effects) Public Submissions Direct - drug reports to the FDA that come straight from PUBLIC

What is Active Surveillance? - aka? - Risks?

aka Sentinel Initiative - Compiling information on drug days by using automated healthcare databases (no reporting, just looking for trends etc.) Risks: - Information may be misinterpreted and False positive correlations may be made

For what event type is it easiest to establish a causal relationship; common or rare?

Rare events - causal relationships are easy to make because they don't happen for any other reason (flowers growing out of your head) Common events - having an MI when your 50-70 could be due to a number of factors. Its hard to just blame the drug

What rules were implimented by the Controlled substances Act of 1970?

- States can have MORE stringent controls on drugs but not less - All drugs containing a controlled substance must be labeled - You must be licensed to Distribute these

``` What is the highest class of drug that can be prescribed? - examples of drugs in this category. ```

Class II (Class I is just your standard illegal drugs) Class II examples: - Morphine - Meperidine - Amphetamine

T or F: the FDA rejects about 1/5 of the drug names it gets each year before marketing

False, it rejects about 1/3 of Drug name submissions

What is Pharmacogenomic Labeling? | - is this required by the FDA?

- Tells you the impact the drug will have on a given genotype or phenotype or it if it even matters at all Pharacogenomic Labeling is required by the FDA in some cases but it recommended in other cases

What is unique about Off-Label Prescription writing? | - why don't drug companies change this?

Physicians can prescribe drugs for things other than what they were manufactured to do * Drug companies cannot Advertise these positive aspects of the drug unless they run through the clincal trials and all of that - Cost outweighs the benefit for companies

In Product Claim Drug companies must include: - Drug Name (brand and generic) - at least one FDA-approved use for the drug - Most significant risks of the drug - Balanced description of benefits and risks

Reminder Advertisements - give name of drug but not uses - Drugs with Blackbox warnings must include those

Top 10 Reasons for Drug Recall - Lack of assurance of Sterility - Deviations from GMP - Sub-Potency - Microbial Contamination - Chemical Contamination - Penicillin cross-contamination - Drug Marketed w/o approval - Failure to Dissolve Properly - Exceeding limits for impurities or degradation