Regulatory Affairs of the Heart

As you may have noticed, this blog is on hiatus until the end of the Spring 2007 semester (mid-May). Between work and school, I haven't been able to find the time. This is my last semester, however, and then Regulatory Affairs of the Heart will return better than before.

Thanks,
Anonymous, RAC

The headline says it all. I’ll forge on, nonetheless.

Offender: Takeda Pharmaceuticals

Product: Rozerem (ramelteon) Tablets

Violation: DTC reminder ad included oral and visual suggestions that Rozerem is safe and effective for pediatric use…but the drug is not indicated for pediatric use

What Else Did They Allegedly Do Wrong: Failed to submit Form 2253

Here’s the Warning Letter. Here’s a PDF version of the television ad, which apparently aired on MSNBC. Notice the children with backpacks going to school?

The FDA’s Manufacturing Subcommittee of the Advisory Committee for Pharmaceutical Science and Clinical Pharmacology will meet to discuss, among other things, “issues pertaining to the stability of tablets split for patient use.” A little background:

1. Pharmaceuticals (not to mention health care in general) are expensive
2. Patients (coached by their physicians, in some cases) sometimes split tablets in half to cut costs
3. When you split a tablet in half, the active ingredient is exposed to air and moisture and may decompose rapidly

Her's some more information.

So there you go. Between a rock and a hard place. Try and save a buck or two, and your meds may lose potency and/or gain toxicity. It’s a trade-off.

What, if anything, should the FDA do about this? The meeting will be held on April 30 in beautiful Rockville, MD.

According to a handout stating that Provigil is effective for fatigue…when in fact Provigil is not indicated for fatigue! The nerve of Cephalon. DDMAC found other faults, as well, such as omitting risk information from the handout, not including a copy of the PI with the handout and not submitting a Form FDA 2253 for the handout.

I’m not a promotion and advertising expert. Somebody, please take a look at the handout and tell me, does FDA normally consider such handouts to be “promotional pieces”? To me, it looks more like a – well, like a handout.

FDA yesterday announced two more recalls of levothyroxine sodium tablets, which (and as I've written before) I believe to be the most oft-recalled drug.

What is it about this drug? Why is it recalled so often? I notice these two recalls are both due to subpotency. Is it difficult to formulate? Or is it because levothyroxine sodium is manufactured mostly by tiny generic drug manufacturers who do not have the resources to invest in robust quality systems? Just asking...

FDA is issuing a draft guidance on the briefing packages given to advisory committee (AC) members before AC meetings. These briefing packages include information developed by FDA and the sponsor of the product to be discussed at the meeting, and they generally are posted on the FDA’s website two days prior to the meeting, although FOIA-protected information is redacted. The following types of information typically ARE NOT redacted:

• Summaries of clinical safety and effectiveness data;
• Summaries of non-clinical safety and effectiveness data;
• Summaries of adverse drug reaction data;
• Written discussion or analysis of safety or effectiveness data relevant to the topic of the meeting;
• A general description (such as that which would typically be included in product labeling) of product functions, mechanics, and/or engineering;
• A general description of physical characteristics and performance parameters;
• Clinical or preclinical protocols or summaries of protocols;
• Statistical protocols and analyses;
• Information that is proposed to be included in product labeling, such as indications and usage, dosage and administration, and safety information such as warnings and precautions;
• Literature references;
• Any other information that has been previously publicly disclosed by the sponsor;
• Copies of the sponsor’s slides to be presented at the advisory committee meeting, if included in the briefing materials; and
• Guidance documents.
  

Why does this matter? Often, the information in the briefing package is reported in the Wall Street Journal and other publications read by investors. So, whatever FDA tells the AC members about the product becomes a story, as investors try to glean whether FDA is likely to approve the product or not, and stock prices may rise and fall based upon the information in the briefing package.

The following types of information typically ARE redacted:

• Information about product functions, mechanics, engineering, and schematic drawings not in the proposed labeling and not within the scope of the agenda for the meeting;
• Proprietary physical characteristics and performance parameters not in the proposed labeling and not within the scope of the agenda for the meeting;
• Manufacturing process information;
• Manufacturing quality control information;
• Clinical raw data;
• Non-clinical raw data;
• Supplier names, customer lists, production costs, inventory information, failure rates of products, production quality control information;
• Information for which the release would constitute an unwarranted invasion of personal privacy; and
• Product formulation information not in the labeling.

Actavis Totowa has received a cGMP Warning Letter. This comes after the company was warned last year re postmarketing ADE reporting. I wonder whether they’re regretting purchasing Alpharma’s generics business?

Anyhow, below are selected excerpts:

• "our investigators uncovered out-of-specification test results in laboratory raw data that were not documented in laboratory notebooks, and found that products were released based on retesting without any justification for discarding the initial out-of-specification test results"
• "manufacturing process deviations occurred and in-process specifications were not met, yet there is no indication that action was taken promptly to investigate or to correct the deviations and the products were approved for release and distribution by your quality control unit"
• "analysts do not always document the preparation and testing of samples in their notebooks at the time they are done"
• "The chromatographic test data reflecting the out-of-specification test results were not recorded in laboratory notebooks. Instead, a new sample preparation was injected within the same chromatographic run without supervisory approval"
• "electronic data files were not routinely checked for accuracy and, as mentioned in the above observations, our investigators found numerous discrepancies between the electronic data files and documentation in laboratory notebooks"
• "your firm's quality control unit either ignored or failed to recognize that some tablets that did not meet in-process specifications."
• "Although your firm's procedures require the collection of in-process blend uniformity samples of three times the weight of finished product tablets or capsules, master production records do not require, and batch records do not contain, documentation that the samples are being collected accordingly"

There's more, read the whole thing if you've got time on your hands (and who doesn't). The letter goes on to recommend: "We feel that to provide such assurance, your firm should promptly initiate an audit program by a third-party."

Which lucky consultant(s) has been hired as the third-party auditor? Anybody know?

There's an wrote recently about a joint agreement by the FDA and the VA to study this issue.

A lot depends on how the product is stored by the consumer, whether the known degradants are toxic and other considerations. Companies don’t have much economic incentive to push for longer expiration dating periods, and FDA is inclined to be conservative from a safety standpoint and not worry about cost.

It is a shame to throw away safe and effective meds, especially when the cost of pharmaceuticals is such an issue. But I don’t see how to solve this issue…although one thing FDA could do is mount a PR campaign emphasizing to consumers how important it is to store your medicines properly. Other ideas?