Module 2: The Role of the Food and Drug Administration and Key Regulations of New Prescribed Medications for Practitioners

http://www.fda.gov/oc/history/historyoffda/section5.html

Module 2 – Objectives

To increase prescribers’ To increase prescribers’ understanding of the understanding of the role and responsibilities role and responsibilities of the FDA in various of the FDA in various stages of U.S. drug stages of U.S. drug development and the development and the extent of governmental extent of governmental oversight with respect to oversight with respect to drug safety.drug safety.

Scenario BackgroundAt a recent meeting of your

medical society, a presenter provided information about a new Cox-2 NSAID, Novacoxib, that has just been released to the U.S. market.

Remembering your experience with the rofecoxib (Vioxx) withdrawal, you have some concerns about this new drug.

Question 1You first want to know whether Novacoxib is better at

controlling pain (i.e. its efficacy) than any of the other existing products.

For drug classes like NSAIDs where there are already proven therapies, the FDA standard minimally required to approve a new NSAID is that a manufacturer must show that it is:

More efficacious compared to nothing (placebo) (i.e. no requirement for a head to head study)A. At least as efficacious as an existing NSAID (i.e. non-

inferior to an active comparator).B. At least as efficacious and safe as an existing NSAID.C. At least as efficacious and safe, as well as cost-

effective, compared to non-generic NSAIDs.

Answer for Question 1

Answer: A

There is no requirement that the control arm of a trial has to contain an active compound.

For this reason, even for established for drug classes, it is usually cheaper and easier to compare a new compound only to placebo.

A new drug must be ‘safe enough for use’, but no explicit determination is made whether benefit outweighs harms, especially for particular subgroups of patients.

NEJM 2005; 353:969-72

Question 2In his presentation, you learn that Novacoxib has been

studied in ‘several’ phase III studies and has been shown to be both effective and safe.

You know that from the FDA perspective, the development of a new drug includes: preclinical research and development, phase I-III clinical research and development culminating in a new drug application (NDA), FDA review and approval, and postmarketing surveillance.

You know that the pivotal phase III studies required for FDA drug approval are generally powered to study efficacy and enroll approximately how many people?50-100100-500500-3,0003,000-10,000

Answer to Question 2Answer: CThe pivotal phase III trials required to approve a new drug

generally enroll 500 – 3,000 patients, and approximately only 25%-30% of drugs will pass phase III.

For this reason, many side effects that are rare or carry only small increased risks go undetected until they are studied in much larger patient populations.

Additionally, patients enrolled in clinical trials are often healthier and at less risk for side effects than those receiving the drug in the general population.

Studies of some arthritis medications estimate that only about 20-33% of patients treated in routine clinical practice would be eligible for large phase III RCTs.

You know that after phase III, the manufacturer can submit an NDA (new drug application) to the FDA for approval to market the drug. Approximately 20% of drugs that entered phase I are approved.

A&R 2006

Question 3Your are aware of at least one NSAID, bromfenac (Duract),

that was withdrawn from the U.S. market in 1998 because of severe hepatitis and liver failure among patients taking the drug for more than 10 days.

No cases of liver failure or hepatitis were seen in the Novacoxib study you review that enrolled 2,000 patients (1,000 in each treatment arm).

Based upon the absence of any cases of a particular side effect in a study with N treated patients, the true risk of that side effect is still up to 3 / N (make this bullet a mouse-over pop up).

Based on this information, the true incidence of this complication ranges from 0% to:Up to 3 people per 10,000 treated patients (0.03%)Up to 3 people per 1,000 treated patients (0.3%)Up to 3 people per 2,000 treated patients (0.15%)Up to 3 people per 100 treated patients (3%)

Answer to question 3

Answer: B

Based upon the absence of any cases of a particular side effect in a study with N treated patients, the true risk of that side effect is still up to 3 / N.

In a study with 1,000 treated patients, the true risk is up to 3 / 1000 = 0.3%.

JAMA 249:13: 1743-5.

Question 4You are surprised that the drug is so quickly available,

given that the pivotal phase III study ended just 7 months ago.

One of the factors in quicker U.S. drug approval is the Prescription Drug User Fee Act (1992, 2002 and 2007), under which FDA was allowed to charge manufacturers a fee for reviewing a new drug application (NDA) Although the majority of the money is used to speed up drug approval times, the proportion of this fee that went to fund studies that examine the safety of medications after product launch (i.e. post-marketing surveillance) was:

0%3%10%20%

PDUFA Fact Sheet. http://www.fda.gov/cder/pdufa/default.htm; http://www.fda.gov/cder/pdufa/default.htm

Answer to Question 4Answer: A

Although the FDA has dramatically shortened drug approval times (median of 14.9 months in 1993 vs. 6.7 months in 2003), none of these additional monies were allowed to be used to improve post-marketing safety surveillance. So additional fees were provided only to shorten drug approval times, not to monitor safety.

IOM Recommendations on Drug Safety. 355:1753-5

FDA Responsibilities for Approving & Monitoring Drugs

To summarize, the FDA’s responsibilities include:– Determination of safety and efficacy of a drug before

its approval, and– Monitoring its use after approval to ensure that the

drug is safe and that the drug labeling appropriately reflects its potential risks.

This results in a perceived conflict of interest since the agency responsible for new drug approval is also responsible of monitoring for adverse effects.

The perception is that an agency that certified that the drug was safe enough to approve may be loathe to reverse its position and issue new safety warnings based on post-marketing data collected after approval.

FOOD AND DRUG ADMINISTRATION MODERNIZATION ACT OF 1997. http://www.fda.gov/cder/guidance/105-115.htm#SEC.%20406

Question 5At the end of the medical meeting, the expert tells you that

the FDA has mandated that the pharmaceutical company conducts a 2 year safety study (phase IV postmarketing commitment study) examining the long term cardiovascular side effects of Novacoxib. You are hesitant to prescribe the drug without these results available.

Given the above-described FDA required, you expect the results of the safety study will be available:

A. In ~3 years; without such a study being conducted, the FDA would likely require the drug be withdrawn

B. In ~ 3 years; although the FDA will not sanction the drug manufacturer if it took longer

C. In 5 years or longer; there is no formal requirement as to how soon the study must begin or how long it can take to conduct

D. Unclear if the study will ever be done; the FDA usually has no power to compel pharmaceutical manufacturers to perform these types of follow-up studies. JAMA, 1983;249:1743-1745

Answer Question 5Answer: D

Phase IV post-marketing commitments are studies required of, or agreed to, by the sponsor at the time of new drug approval.

The FDA has authority to require these studies only in select cases.

The FDA does not have authority to fine companies if the post-marketing commitment studies are not done after a drug has been brought to market [ref1].

The FDA has authority only to take the drug off the market, a drastic step that is not often used.

In fact, the Federal Register reported in 2006 that of approximately 1,300 “required” follow-up studies, 65% were never even initiated [ref2], and only 14% are actually completed.

FDA Consum 2002; 36(1):11-7. Fed Regist 2004; 69(50):12162-4. Fed Regist 2005; 70:8379-81. DHHS, OIG, 2006. FDA’s Monitoring of Postmarketing Study Commitments (OEI-01-04-00390). Ganslaw LS. Drug Safety. New Legal/Regulatory Approaches, 2005:7-10.

Patient Scenario

Mrs. J, a 68 year old woman with knee and hand osteoarthritis (OA) comes to you for management. She has no additional comorbidities.

She has tried acetaminophen, without much benefit. She is currently taking ibuprofen 2 pills twice daily (400mg bid), although she says it doesn’t help much.

You consider whether to prescribe Novacoxib to her, or perhaps an older NSAID.

Question 6She mentions that she saw an advertisement on

television for Novacoxib and wonders if it might be appropriate for her.

Based on your knowledge of the FDA restrictions on direct-to-consumer advertising, you know that the advertisement for the drug:A. May attempt to persuade a consumer to use the

drug, B. Must promote public health by providing information

regarding the disease that the drug is indicated for,C. Must include a balanced disclosure of risks and

benefits.D. A and CE. All of the above NEJM 2005; 325:325-8

Answer to Question 6Answer: DDrug-specific advertisements must include a

‘balanced’ discussion of risks and benefits, although this balance is subjectively determined.

The Code of Federal Regulations require that print advertisements must disclose every risk listed in the FDA-approved label as part of a brief summary, but broadcast advertisements may either contain a brief summary of side effects and contraindications or make adequate provision including a toll-free telephone number or Web site.

Communications that discuss only a disease or advocate screening and are not drug specific are not subject to regulation by the FDA.

Section 502 (n) of the FD&C Act, and Title 21 Code of Federal Regulations, section 202.1

Question 7

Based on the restrictions relevant for direct to-consumer advertising, the FDA must review these advertisements at what point?

A. Before they are televised or printedB. There is no requirement for FDA reviewC. Within 3 months of them being televised

or printedD. Within 12 months of them being televised

or printed

Answer to Question 7Answer: B

FDA does not have the authority to approve drug advertisements or require that advertising materials be reviewed prior to their use.

FDA can enforce corrective actions (e.g. untitled letters, warning letters, injunctions and consent decrees, referrals for criminal investigation or prosecution) only after the drug advertisement has been broadcast.

Question 8One of the drugs that you consider

prescribing instead of Novacoxib is meloxicam (Mobic), which has lost patent protection in 2006 and has become available in a generic formulation at a much reduced cost.

The duration of patent protection for a new drug is typically:

A. 7 yearsB. 10 yearsC. 15 yearsD. 20 years

Answers to Question 8

Answer: D (20 years)

The duration of patent protection afforded to new drugs is 20 years, although much of the patent life may be used up by the time the drug is actually brought to market, resulting in a much shorter ‘effective patent life’.

http://www.bos.frb.org/economic/nerr/rr2003/q1/toomuch.htm#sidebar. http://www.ucpress.edu/books/pages/10083/10083.ch08.html

Question 9

Compared to the patent life of a first-in-class drug, the duration of patent protection of a similar drug in the same medication class is:

A. Much shorter (1/2 the duration, rounded to the nearest whole year)

B. Slightly shorter (2 years less)

C. The same

D. Slightly longer (2 years longer)

Answers to Question 9Answer: C (the same duration)In contrast to the substantial resource investment

required for new drug development, producing a drug very similar (but not identical) to one already available requires much less money and time (often as little as 1 year).

This results in promoting development of ‘me-too’ drugs rather than encouraging new drug development.

Once a patent actually expires, generic makers no longer have to repeat safety and efficacy tests; they only need to demonstrate to the FDA that their product is equivalent to the trade-name counterpart.

http://www.bos.frb.org/economic/nerr/rr2003/q1/toomuch.htm#sidebar. http://www.ucpress.edu/books/pages/10083/10083.ch08.html

“Me-Too” DrugsThese are known as “me-too” drugs because they are

relatively equivalent to one or more drugs already on the market in a similar class.

The dearth of an explicit requirement for head-to-head comparisons for “me-too” drugs results in a lack of data about whether new products offer any efficacy or safety advantage over existing products.

Many more patients (i.e. as many as 4 time more) are needed to show that a new drug is at least as good (or better) than an existing compound. Therefore, there is a strong financial incentive not to perform head-to-head comparative effectiveness studies.

FDA allows the development of these drugs because some or many patients are not receiving adequate treatment with current therapy, develop tolerance, or experience unintended adverse effects that may be drug-specific.

NEJM 2005; 353:969-72

Question 10Your patient also brings in a new over-the-counter nutritional

supplement which (on the bottle) claims that it promotes joint health. She asks you whether she should keep taking it for her OA and whether it’s likely to be helpful.

You reply that:A. The product would not be allowed to be sold without being

demonstrated to be efficacious.B. The product may or may not be effective but has been at least

demonstrated to be safe in order to be sold on the U.S. market.C. The FDA Dietary Supplement Health and Education Act requires that

new nutritional supplements actually contain the stated ingredients on the packaging. However, manufacturers do not need to demonstrate efficacy or safety.

D. There is no guarantee that the product is safe, effective, or even contains the stated ingredients since it is sold as a nutritional supplement.

Answer to Question 10Answer: D

The Dietary Supplement Health and Education Act severely limits the ability of the FDA to regulate nutritional supplements and they are not required to be shown to be efficacious, safe, or to contain the stated ingredients.

For example, a supplement claiming that it contains a certain amount of glucosamine is not actually required to contain this amount. In fact, it does not have to contain any glucosamine at all.

For this reason, results of randomized clinical trials of dietary supplements may not be generalizable to even similar-sounding products that patients purchase, since formulations may differ substantially from those studied.

Question 11

After the patient leaves, you run into your colleague in the hall, who tells you about an article in which Novacoxib reduced the incidence of colon polyps that may lead to colon cancer. Novacoxib does not have an FDA indication for this condition.

The next time you see the drug representative that helps market Novacoxib, you ask about this study’s findings. Because there is no FDA-indication for reduction in colon polyps, you are told:

A. She cannot personally provide you with any information about this and would need to refer you to the company’s scientific liaison to answer further questions.

B. She can provide you with a reprint of this study but would need to refer you to the company’s scientific liaison to answer further questions.

C. She can provide you with a reprint of this study and can answer verbal questions but is not allowed to distribute other printed materials about this topic.

D. She can provide you with a reprint of the study and can answer verbal questions as long as she does not specifically ask you to prescribe the drug for this indication.

Answer for Question 11Answer: A

The FDA must approve the indications and labeling for all drugs.

Moreover, pharmaceutical representatives are prevented from detailing physicians in any form regarding off-label uses of drugs.

A pharmaceutical company could disseminate peer-reviewed journal articles about an off-label indication of its product, only if it commits itself to file, within a specified time frame, a supplemental application based on appropriate research to establish the safety and effectiveness of the unapproved use.

The FDA Modernization Act of 1997. http://www.fda.gov/opacom/backgrounders/modact.htm

Question 12You would like to give your patient something to

read regarding the potential risks associated with NSAIDs. Additionally, you realize that your copies of the Physicians Desk Reference (PDR) are many years out of date.

Where can you and your patients find the latest information regarding drug labeling?

A. The medication’s package insert.B. The National Institute of Health’s electronic

resource: DailyMed.C. The FDA NSAID Medication Guide. D. The FDA drug website.E. Medline Plus.F. All of the above.

http://dailymed.nlm.nih.gov/dailymed/about.cfm. http://www.fda.gov/cder/drug/infopage/COX2/NSAIDmedguide.htm. http://www.fda.gov/cder/drug/DrugSafety/DrugIndex.htm. http://www.nlm.nih.gov/medlineplus/medicines.html

Answer to Question 12

Answer: F

All of these resources can be useful for both healthcare professionals and consumers to obtain updated, relevant drug prescribing information.

Question 13

In the event that your patient experiences a serious adverse event that you suspect is associated with an FDA-regulated drug or a dietary supplement, you should:

A. Notify the pharmacy that sold the product to the patient.

B. Ask your patient to contact the pharmacy that sold the product to the patient.

C. Submit an FDA Medwatch report.D. Contact the manufacturer by phone, with a

follow-up letter to provide written documentation.

Answer to Question 13

Answer C

The FDA collects information (via Form 3500) from healthcare professionals and consumers for voluntary reporting of adverse events noted spontaneously in the course of clinical care.

This process is not applicable to events that occur during clinical trials, where another reporting mechanism is used.

Although the Medwatch program is extremely valuable in detecting safety signals associated with drugs and devices, it does have some limitations.

http://www.fda.gov/medwatch/report/hcp.htm

Answer to Question 13

For example, based on Medwatch spontaneous reports, it may know that 86 persons had a heart attack while taking drug X (i.e. the numerator of a rate), but it does not know how many people overall were taking drug X (i.e. the denominator) to know if this represents a large or small risk.

Additionally, because reporting is voluntary, the number of adverse events that occur is likely significantly under-reported.

More information about the FDA Medwatch program is available here: http://www.fda.gov/medwatch/report/hcp.htm