Regulatory Affairs of the Heart

Hiatus

2007-03-24T09:23:00.000-07:00

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

DDMAC Wrist-Slaps Takeda for Inappropriate Reminder Ad

2007-03-09T15:22:00.000-08:00

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?

Splitting Tablets

2007-03-05T16:33:00.000-08:00

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.

Handout, Promo Piece or Both?

2007-03-03T06:04:00.000-08:00

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.

Why Is Levothyroxine Sodium Recalled So Often?

2007-03-01T17:10:00.000-08:00

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...

Advisory Committee Briefing Packages

2007-02-28T17:03:00.000-08:00

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 Warned Again

2007-02-27T17:08:00.000-08:00

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?

Drug Product Shelf Life

2007-02-27T17:05:00.000-08:00

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?

Sorry

2007-02-26T18:04:00.000-08:00

I've been extra busy the past few days. Posting will resume tomorrow, I hope.

Digitally Signed FDA Submission

2007-02-21T16:04:00.000-08:00

“SAFE-BioPharma Association and Arcot Systems today announced that AstraZeneca, a major international healthcare business, has become the first company to send digitally-signed submissions to the FDA.” See this press release for more information.

No mention of what type of submission it was. Pretty cool, though. I’m jealous. I wish my company was using digital signatures. We’re still in the paper world, so I’d settle for an e-submission with a traditional handwritten signature.

Potent and Hazardous Compounds

2007-02-20T15:49:00.000-08:00

A story caught my eye this morning:

“Northern Ireland-based Almac Services has recently been awarded a potent compound safety certification by SafeBridge, confirming that Almac is capable of handling potent compounds safely and is able to limit exposure using closed laboratory systems.”

It caught my eye because I met SafeBridge’s President & CEO, John Farris, at a Potent and Hazardous Compounds conference a couple of years ago. SafeBridge provides safety, health and environmental services to the life sciences industries.

Then, this afternoon, I read that Bell-More Laboratories received a warning letter for alleged cGMP violations, including “your firm lacked an adequate assessment of the cross-contamination risks posed by the manufacture of several potent compounds (e.g. cytotoxic and hormone products, as well as other products of high pharmacologic activity) at your facility.”

They should give John Farris a call. (Unfortunately, I have no financial or other connection to SafeBridge and would be surprised if John Farris even remembers me.)

...only stupid questions

2007-02-19T15:36:00.000-08:00

Over the past week or so, it has been reported that federal agents raided Ranbaxy’s U.S. offices and manufacturing facility.

I’ve been following the story, but not many details have surfaced yet. What were they looking for? What did they find? Nobody who knows is talking.

But some are speculating the U.S. government is hassling Ranbaxy at the behest of big pharma. Ranbaxy, of course, is one of the biggest of the Indian generic manufacturers, and its CEO has a habit of tweaking big pharma. For example, a recent article in The Economist stated: “Ranbaxy's boss, Malvinder Singh, scoffs that Big Pharma ‘is struggling to come up with true innovation.’”

So, the motive for big pharma is established. But do they have the means? In other words, are these companies so powerful and politically connected that they can pull a few strings and all of sudden federal agents are breathing down Ranbaxy’s neck?

If you believe such speculation, are you paranoid? If you don't, are you naive?

There are no stupid answers...

Failure Investigations

2007-02-16T16:24:00.000-08:00

FDA issued a warning letter dated December 18, 2006 to Abraxis Pharmaceutical Products for alleged cGMP violations, including “failure to conduct adequate investigations, and notably, to properly extend failure investigations to all associated batches or product.” This seems to be a relatively common failure and something that FDA field investigators are watching out for closely.

The relevant regulation is 21 CFR 211.192, which I shall quote in full:

“All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy (emphasis added). A written record of the investigation shall be made and shall include the conclusions and followup.”

Clear enough, no? Yet too often an investigation focuses only on the specific batch(s) in which the problem was found. This approach won’t cut it in the modern era of quality systems and quality risk management.

Refusal to File for Advancis

2007-02-15T16:35:00.000-08:00

FDA has refused to file an Advancis Pharmaceutical NDA for Amoxicillin Pulsys, a strep throat treatment, due to insufficient information re how the company plans to scale up its manufacturing process to produce commercial-scale batches.

A company spokesperson says Advancis is seeking clarification from FDA. "Do you want us to actually have produced commercial-size batches, or can we just provide you with more information on how we're producing the new product?"

Usually the latter is sufficient, isn’t it?

Developing Products for Weight Management

2007-02-14T16:03:00.000-08:00

FDA is issuing a draft guidance on ‘‘Developing Products for Weight Management.’’ Obesity is a large and growing market (not funny?), and this should provide clarity to drug developers re:

the development of products for weight management in pediatric patients and in patients with medication-induced weight gain
the development of combinations of weight-management products (remember fen-phen?)

These topics were not addressed in a September 1996 draft guidance entitled ‘‘Guidance for the Clinical Evaluation of Weight-Control Drugs,” which will become obsolete once the new draft guidance is finalized.

I’ve been waiting with bated breath for this to come out.

Regulatory Risks

2007-02-09T16:38:00.000-08:00

From the world of medical devices, a world that is interesting but generally outside the scope of this blog, because there have to be limits...

Nonetheless, this caught my eye: “A class-action shareholders' suit has been filed against U.S. device maker Cyberonics, the law firm Goldman Scarlato & Karon said Thursday…The complaint alleges that Cyberonics failed to disclose and misrepresented material information known to the company regarding review and approval by the Food and Drug Administration of a new use for the company's Vagus Nerve Stimulation device to treat depression.”

I love to read the Management Discussion and Analysis section of pharma company annual reports, because therein the company acknowledges risks that investors should be aware of, including regulatory risks. Go to Pfizer’s or Merck’s or Genentech’s or any publicly-traded pharma or biotech’s website, find the Investors section (there will be one), and download the Annual Report (or 10K or 10Q). As a regulatory affairs professional, it’s satisfying to see in print that what you’re doing is important to the company’s bottom line.

Anyhow, back to Cyberonics. According to the suit, they didn’t disclose their regulatory risks properly. It’s not clear (to me, anyhow) whether the alleged lack of disclosure occurred in an annual report, a press release, or some other type of communication. Doesn’t matter, for my purposes. I just wanted to take the opportunity to encourage regulatory affairs professionals to read the MDA sections of pharma annual reports.

Rx at High Dose, OTC at Low Dose

2007-02-08T16:52:00.000-08:00

FDA yesterday approved the diet drug orlistat for OTC use. As the agency's press release noted, "orlistat was initially approved in 1999 as a prescription drug to treat obesity, and remains a prescription drug for obesity at a higher dose than the OTC version. " How often is a drug available Rx at one dose and OTC at a lower dose? I can think of one other example. Ibuprofen 400 mg is Rx, while ibuprofen 200 mg is OTC. Your thoughts?

Formal Dispute Resolution

2007-02-06T16:11:00.000-08:00

Genta “today announced that the Company will appeal the non-approvable notice from the Food and Drug Administration's (FDA) Office of Oncology Drug Products of its New Drug Application (NDA) for the use of Genasense® (oblimersen sodium) Injection plus chemotherapy in patients with chronic lymphocytic leukemia (CLL). The appeal will be filed pursuant to the Formal Dispute Resolution process that exists within FDA's Center for Drug Evaluation and Research (CDER). The Company filed notice reserving its rights to appeal in December 2006 and expects to complete the filing of this appeal during the current calendar quarter.”

The formal dispute resolution process is outlined in CDER’s guidance on Formal Dispute Resolution: Appeals Above the Division Level. A couple of notable items include:

The formal dispute resolution request should not include any new information that was not a part of the original review
The agency’s response may be a decision one way or the other, or it may be that an advisory committee meeting will be scheduled

The relevant reg to look at is 21 CFR 10.75.

In my limited years of experience, I haven’t heard of formal dispute resolution being used very much. I assume this is because companies generally figure it will be a waste of time. Genta apparently believes otherwise.

Generic Drug User Fee

2007-02-05T17:06:00.000-08:00

The White House released its budget proposal for FY 2008. Among the FDA-related highlights are a proposed Generic Drug User Fee. How much would generic drug companies have to pay to get an ANDA reviewed? That detail is not included in the budget proposal. However, it is estimated that the user fee will generate $15.7 million in funding for FDA. The money would go toward hiring staff and “establishing criteria for determining the bioequivalence of complex drugs and drugs with non-traditional dosage forms.”

I doubt this proposal will be enacted. Not this year, anyhow. Too expensive for generic drug companies. GPhA will fight it and probably win.

Failure to Disclose the Full Indication

2007-02-01T14:57:00.000-08:00

DDMAC warned MGI Pharma for a relatively rare type of violation of the FDA’s drug ad regulations. According to the agency, the journal ad in question “is misleading because it includes efficacy and safety data for patients implanted with Gliadel Wafer during initial craniotomy, but fails to present the corresponding approved indication for Gliadel (i.e., Gliadel Wafer is indicated in newly-diagnosed high-grade malignant glioma patients as an adjunct to surgery and radiation). See 21 CFR 202.1(e)(3)(ii).”

We did see 21 CFR 202.1(e)(3)(ii), and here’s what we saw: “The information relating to effectiveness shall include specific indications for use of the drug for purposes claimed in the advertisement; for example, when an advertisement contains a broad claim that a drug is an antibacterial agent, the advertisement shall name a type or types of infections and microorganisms for which the drug is effective clinically as specifically as required, approved, or permitted in the drug package labeling.”

In other words, if you’re going to claim that your drug is effective, include the approved indication. MGI Pharma apparently didn’t do that, and thus the warning. I haven’t seen too many companies get in trouble for this type of violation. Anybody beg to differ?

The warning letter also alleges unsubstantiated claims were made in the journal ad, but that type of violation is so common it doesn’t merit attention here at Regulatory Affairs of the Heart.

What’s on the Back of Your Dry Erase Board?

2007-01-30T16:30:00.000-08:00

We all know that if promotional materials for a drug present effectiveness claims, they also must communicate risk information associated with its use. Right?

Daiichi Sankyo apparently distributed wall calendars and dry erase boards for Evoxac Capsules, a dry mouth treatment. These promotional materials communicated risk information…but on the backs of the calendar and board. Now, when you hang up a dry erase board or a calendar, can you see what’s printed on the back? No, of course not. FDA accordingly sent the company a Warning Letter and requested “that Daiichi immediately cease the dissemination of violative promotional materials.”

Clarification re eSubmissions

2007-01-30T16:29:00.000-08:00

I received an email asking: “Someone told me that FDA is mandating eSubs for NDAs etc by 2008 - is that true does anyone know? I can't find any verification of it and actually it seem FDA is far from ready for eCTDs.”

Not exactly. Companies still may choose whether to submit NDAs in paper or electronic form. However, back in September the FDA published a notice stating that:

They have withdrawn the guidance documents on ‘‘Providing Submissions in Electronic Format—NDAs,’’ ‘‘Providing Regulatory Submissions in Electronic Format—ANDAs,’’ and ‘‘Providing Regulatory Submissions in Electronic Format: Annual Reports for NDAs and ANDAs.’’

References to these guidances will be removed from the electronic submissions docket on December 31, 2007.

They are recommending that companies use the guidance on ‘‘Providing Regulatory Submissions in Electronic Format— Human Pharmaceutical Product Applications and Related Submissions Using the e-CTD Specifications’’ instead of the withdrawn guidances

In the past, if you decided to submit an NDA or ANDA electronically, you could use one of the withdrawn guidances or the newer eCTD guidance. The former option will expire at the end of the year. From then on, e-submissions of NDAs/ANDAs should follow the eCTD guidance.

But FDA is not mandating eSubs for NDAs, as you can still do a paper submission if you want. That may change eventually, but it has not changed yet.

Industry to FDA: Your Silence Is Deafening

2007-01-26T16:44:00.000-08:00

“Such a conclusion cannot be based on 3 of 4 or 5 of 6 passing results, but possibly 7 of 8.”

This profound and historic statement appeared as a footnote in U.S. vs. Barr Laboratories, and the investigation of out-of-specification (OOS) results has never been the same since.

I believe that to appreciate a footnote, one must read the passage to which it is linked:

“The USP contemplates retesting for quality control purposes, although it does not prescribe or recommend the number of individual tests that must be performed in order to reach a definitive conclusion about the quality of a product. Thus, the number of retests performed before a firm concludes that an unexplained out-of-specification result is invalid or that a product is unacceptable is a matter of scientific judgment. Yet the goal of retesting is clear; firms must do enough testing to isolate the out-of-specification result, in order to reach the point at which the additional testing overcomes the out-of-specification result.”

So, according to settled law, the magic number is 7 of 8.

Well, the FDA in October 2006 released a final guidance on OOS investigations, which included no mention of 7 of 8 or the Barr decision. With regard to retesting, the final guidance simply stated:

“FDA inspections have revealed that some firms use a strategy of repeated testing until a passing result is obtained, then disregarding the OOS results without scientific justification. This practice of “testing into compliance” is unscientific and objectionable under CGMPs. The maximum number of retests to be performed on a sample should be specified in advance in a written standard operating procedure (SOP). The number may vary depending upon the variability of the particular test method employed, but should be based on scientifically sound principles. The number of retests should not be adjusted depending on the results obtained. The firm’s predetermined retesting procedures should contain a point at which the additional testing ends and the batch is evaluated.”

No mention of 7 of 8 or the Barr decision? What’s that wise saying about ignoring the elephant in the room?

Arthur Fabian of SST Corporation noticed the omission and submitted the following comment to the agency:

“The section lacks any comment on how many retests would be acceptable to overturn an original OOS result. Understandably, the Agency wants the Firm to decide this. However, given the existence of the Barr Decision…there is already a very strong statement out there originating in the Courts. It would seem appropriate then for the Agency to at least acknowledge this and comment on it. Every company worth its salt knows that one cannot test into compliance and knows that the number of retests needs to be predetermined. This issue is how many retests overrule the OOS result and can the retests themselves contain a failure? This is what Industry is looking to the Agency for their thinking. Unfortunately, the silence is deafening on this point.”

I agree with you, Dr. Fabian.

Meta-Post

2007-01-23T18:46:00.000-08:00

There hasn't been any regulatory news I've wanted to comment on the past few days, but I thought I'd take this opportunity to talk about the site a little. I started Regulatory Affairs of the Heart in August, and I've been moderately encouraged by the response. I've had almost 700 visitors this month and might top 1000 by the end of the month if I close strong. That's not bad. Readers are coming from a lot of different pharma companies as well as some law firms, software companies, even FDA.

My only disappointment has been the paucity of comments. I'm hoping eventually this will become a community of voices, instead of just me spouting off. What can I do to encourage that? Is it easy or difficult to comment? Maybe there's some technological thing I can do to make commenting easier.

Okay, I'm going to go watch some of the State of the Union address.

FDA and VA to Collaborate on Shelf Life Extensions?

2007-01-19T15:51:00.000-08:00

Are many drugs safe and effective beyond their expiration date? If yes, wouldn’t it be a good idea to use them, not throw them away? Wouldn’t that lower the cost of health care (a little)?

The House this week passed H.R. 331, which would direct the Secretary of Veterans Affairs to conduct a study of the accuracy of expiration dates on certain prescription drugs that are bought by the VA. It is short and may be read quickly, if you’re interested. It basically says that drugs on the VA’s formulary should be reviewed to determine whether the expiration date can be extended, and if so for how long. It would require the FDA to assist the VA as necessary. Finally, it would require the potential cost savings to be estimated.

Sure, at some point in time degradation products may cause toxicity and/or loss of potency may result in the drug not working anymore. Maybe that doesn't always happen exactly at 24 months, however. If you have data justifying a longer shelf life, what's the argument against?

Is this bill a small step toward extending expiration dates (where justifiable) in general?