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?

What Would Michael Jackson Say?

2007-01-18T15:39:00.000-08:00

Back in August, FDA proposed withdrawing the tentative final monograph for hydroquinone, a skin-bleaching drug product. Hydroquinone has been marketed OTC for many years, but FDA feels that new data showing “'some evidence' of carcinogenicity in male and female rats and in female mice” necessitates a change in policy. The agency also reasons that the level of risk to safety is not justified because the benefits of the drug are limited, i.e., “the sole intended benefit would be to improve the user’s appearance by bleaching the skin.” Dermatologists and patients are pushing back, however. They say the use of hydroquinone for pigmentary disorders improves emotional well-being, social life and sexual relationships. A lot of comments are being submitted on this. Sounds like a reasonable argument to me. Gloved One, if you're reading this (okay, that's unlikely), what do you think?

p.s. The docket number is 1978N-0065

2007-01-17T14:26:00.000-08:00

FDA has placed a clinical hold on an IND for an adult stem cell therapy developed by ReNeuron. The agency’s concerns have not been disclosed publicly, although the company did say “the additional pre-clinical studies it is currently undertaking may answer the main points.” Anybody want to guess what additional data might FDA wish to see? I don’t know, but cancer is a potential problem with stem cell therapies. How do you know the implanted stem cells won’t divide uncontrollably? Maybe that’s what FDA wants addressed. Other thoughts?

FDA Recommendations Re PDUFA IV

2007-01-11T15:23:00.000-08:00

With PDUFA III scheduled to sunset in October 2007, the FDA’s proposed recommendations to Congress for PDUFA IV have been made available for review by interested parties. A public meeting to discuss the proposed recommendations will be held on February 16, 2007. If you can’t attend, you can submit written comments by February 23, 2007.

So, what are the FDA’s ideas for modifying PDUFA? They include:

Discontinue the continuous marketing application pilot programs – benefits not justified by costs
Discontinue the option for companies to request that FDA engage the use of independent consultants to help review clinical trial protocols for certain biotech products – option has not been used by industry
Initiate the discussion of labeling issues and postmarketing commitments earlier in the review process – this tends to occur very late in the review cycle, should happen earlier
Use user fees to fund the development of guidance documents re: 1) clinical hepatotoxicity; 2) non-inferiority trials; 3) adaptive trial design; 4) End of Phase 2(a) Meetings; 5) multiple endpoints in clinical trials; 6) enriched trial designs; 7) imaging standards for use as an endpoint in clinical trials
Free up more time for FDA reviewers to participate in industry workshops that may lead to guidances re: 1) predictive toxicology; 2) biomarker qualification; 3) missing data; 4) benefit/risk assessment
Implement technology enabling sponsors “to send in their electronic applications with automated cross-links to previously submitted data and information, so that they only have to submit things once” and FDA reviewers “to retrieve all relevant submissions and related data electronically from their work stations and…have efficient tools for searching and analyzing data to support their reviews”
Allow FDA to spend user fees to study post-market safety data beyond the current limited timeframe of two or three years after approval
“Enhance and improve communication and coordination between pre-and postmarket review staff”
Improve pharmacovigilance systems
Develop a guidance re epidemiology best practices and obtain access to additional epidemiologic databases – Relatively less reliance on adverse event data, more reliance on epidemiologic data
Develop a guidance re brand drug names, initiate a pilot program to explore a new way for FDA to review proposed brand drug names, and commit to review proposed brand drug names within 180 days
Develop a separate system, outside of PDUFA, to “assess, collect, and use fees for the advisory review of prescription drug television advertisements”

Nothing in there about user fees for generic drugs.

GLP Violations In Animal Study of Smallpox Vaccine

2007-01-10T17:11:00.000-08:00

INCELL Corporation, a small company working on a new and improved smallpox vaccine, has been warned by FDA for GLP violations. I suspect there will be no human trials of this product, thus these animal studies are especially important.

Naturally occurring smallpox was eradicated in the 1970s, but bioterrorism experts are concerned about the possibility of a smallpox attack. Smallpox weapons were developed by the former Soviet Union and their stockpiles have never been fully accounted for. The current whereabouts and occupations of many of the scientists who developed these smallpox weapons also is something of a mystery. For these and other reasons, the threat of a smallpox attack is real. Furthermore, the existing smallpox vaccine has some significant safety disadvantages. Specifically, the existing vaccine “was drained from the lymph of calves. The calves were infected with a virus vaccine strain that can replicate in humans and is unsafe for individuals who have skin conditions, are pregnant, or are immuno-compromised for any reason." This quote comes from INCELL's website, but it's consistent with what I happen to know about this subject because I took a course on bioterrorism recently. Approval of a safer version would be a very welcome development.

INCELL is attempting to develop a safer smallpox vaccine, but their efforts may have been set back somewhat by the FDA’s findings, which included:

1) No quality assurance unit
2) Incomplete study protocols
3) Inadequate study reports
4) Inadequate SOPs
5) Inadequate characterization of test and control articles
6) Inadequate maintenance and calibration of equipment
7) Inadequate record retention

From a public health and bioterrorism preparedness standpoint, I hope INCELL is able to overcome these problems and successfully develop their product.

Change Ahead for Post-Approval Changes

2007-01-04T16:21:00.000-08:00

FDA wants to revise the post-approval change regulations (21 CFR 314.70) “to allow for more manufacturing changes to be made without prior FDA approval using a firm's internal change control system.” Sounds good, right? Or no? What do you think?

The agency will hold a public meeting on February 7, at which the following questions will be discussed:

1. Is it valuable for the agency to move toward a more risk-based and quality systems oriented strategy for regulating postapproval CMC changes outside of the formal application review process? What are the advantages and/ or disadvantages?

2. Would revising § 314.70 as described in this notice provide the same level of protection to the public as the current regulatory scheme with respect to ensuring the safety and efficacy of human drugs? What inspectional approaches might the agency consider to evaluate manufacturing changes while ensuring public safety?

3. Would revising § 314.70 as described in this notice change the regulatory burden on the pharmaceutical industry? If so, how would the burden change?

4. Would reducing the prescriptiveness of § 314.70 provide manufacturers with greater regulatory flexibility? Would it encourage manufacturers to adopt CMC-related risk management strategies? Would there be disadvantages?

This is part of the whole cGMP Initiative and the FDA’s effort to promote Process Analytical Technology (PAT).

Perhaps the agency should allow companies to earn the privilege of a reduced filing burden. If you have a good compliance history and a robust quality system, maybe you shouldn’t have to report changes that lesser companies have to report (or you should be able to use a lower reporting category).

Another approach would be to adopt a European-style model for Type I and Type II variations, with re-registration every 5 years. Hey, harmonization is not a bad thing, is it?

Public Hearing on eSubmissions

2006-12-22T15:49:00.000-08:00

On Monday, FDA held a public hearing on electronic submissions. One of the presenters was Nancy Smerkanich, Vice President of Regulatory Affairs for Octagon Research Solutions, Inc. Octagon provides e-submission software and services to FDA-regulated industry. Smerkanich presented the results of an informal survey on the challenges and benefits involved in implementing e-submissions. Most of the respondents were small pharmas, and there was nearly a 50/50 split between small pharmas that have and haven't implemented e-submissions already. Of those small pharmas that haven't, 48% cited time, costs, expertise, and resources as the reason why they haven't. Only 3%, meanwhile, said it was because FDA does not yet mandate e-submissions.

Fine, but if FDA does mandate e-submissions in the future, these small pharmas will implement e-submissions because they have to, not because time and cost issues suddenly disappeared.

When drafting a proposed or final rule, FDA is required by the Regulatory Flexibility Act to consider the economic impacts on small businesses. I wonder whether they'll mandate e-submissions but exempt small businesses? Would they do that? What say you? Interact with me and your peers.

p.s. I'm on vacation next week. See you in 2007.

Scott Gottlieb's Replacement Named

2006-12-21T16:20:00.000-08:00

Randy Lutter will be replacing Scott Gottlieb Acting Deputy Commissioner for Policy. Gottlieb is leaving FDA in January. Gottlieb was a figure of some controversy, and Lutter also has been a figure of some controversy. The juicy details are dished in a The Nation article re The Gutting of the Civil Service. Here’s an excerpt:

“One of the last things Hubbard did as a career FDA'er was to hire Randall Lutter from the conservative American Enterprise Institute to replace Lester Breslow, who was retiring as chief economist, a civil service slot in Hubbard's policy and planning shop. "I was in the process of recruiting the person behind Breslow, when [former Commissioner Mark] McClellan called me one day and said, 'I'd like to play on filling that economist's job,'" Hubbard remembered. "So I said, 'Well, how do you want to play it?' He said, 'This guy I know, a guy named Randy Lutter.' I said, 'I know him.' And so we brought him in and talked to him and all. But it was pretty much a done deal."

Not long afterward, Hubbard left and Lutter took over his old job as assistant commissioner so that in effect, Hubbard had hired a political replacement for himself.”

Any D.C. political insiders care to enlighten the rest of us? What’s going on? Use the Comments link below. Stir the pot!

Cost of Non-Compliance

2006-12-20T17:04:00.000-08:00

I wrote several months ago about MDS Pharma, a Canadian CRO, receiving a Warning Letter related to its conduct of bioequivalence studies.

The company recently reported fourth-quarter earnings. According to DrugResearcher.com, “Fourth-quarter revenues for the Canadian firm's bio-analytical services fell by 20 per cent after customer reaction to a letter from the FDA stating that submissions containing data from their Montreal facility would not be processed until the completion of a review of operations. The Pharma Services division focused significant resources on completing the FDA review, incurring C$10m.”

So, revenues fell by 20 percent and they’ve spent about $8.7 million (in U.S. dollars) so far to remediate the problem.

Ouch. Other examples of the cost of non-compliance? Don’t be shy, share with the group.

Conditional Approval of New Drugs?

2006-12-20T17:03:00.000-08:00

GAO issued a report recently on Science, Business, Regulatory, and Intellectual Property Issues Cited as Hampering Drug Development Efforts. R&D spending has been increasing, but the number of NDAs (especially for new molecular entities) submitted to FDA has not kept pace. GAO studied why this is and provided various recommendations on how to improve the situation, including this one:

"Identify diseases in great need of treatment, and implement an expedited regulatory process using conditional approval to decrease the time needed to develop drugs to treat these diseases. According to experts, a new expedited process would require less detailed study and information and allow for more limited clinical trials. Therefore, experts said that an expedited process would help lower the cost of creating drugs for these diseases, and serve as an incentive to increase drug development for such diseases. To help ensure safety, the drugs would have conditional approval—they would initially be distributed to certain populations whose usage of the drug can be studied and carefully monitored before wider distribution would be allowed."

Dear readers, how do you feel about conditional approval? Would be a pretty drastic departure from the status quo, no? Who would prevent physicians from prescribing conditionally-approved drugs outside of "certain populations"? Is FDA going to regulate the practice of medicine now? Finally, in your opinion, will this recommendation have legs???

Use the Comments link below. Really, go ahead, use it.

Acetaminophen Package Limitations?

2006-12-19T16:26:00.000-08:00

FDA is proposing new labeling requirements, i.e., warnings, for OTC drugs containing acetaminophen and/or NSAIDs.

There’s a lot of issues here. What shouldn’t get lost is the FDA’s request for comments “on package size or package configuration limitations on the sale of acetaminophen.” Apparently, the UK mandates such limitations. The maximum is 16 tablets of acetaminophen per package if sold in a supermarket, and 32 tabs per pack if sold in a pharmacy, plus an overall restriction that a maximum of 100 tabs can be purchased at one time. I’m not aware of any such package size or package configuration limitations in the U.S. To my knowledge, this would be precedent-setting. Somebody, please correct me if I’m wrong.

Stability Reports

2006-12-18T17:06:00.000-08:00

Here’s a question for CMC folks: How do you format the stability reports you submit to FDA? Do you condense all of the stability data into a one-page or two-page table? Or do your reports consist of several pages of text, with tables and graphs interspersed? Does it differ, depending on whether the stability report is intended to establish shelf, support a post-approval change, annual report, etc.?

Thanks

2006-12-14T20:18:00.000-08:00

I've been negligent the past few days. Making up for lost time...

1) Scott Gottlieb is leaving FDA. What’s the inside scoop? Are career FDA employees overjoyed? I want to know! I also want to know whether Gottlieb plans to revive his blog (fdainsider.com), which has been shut down since he joined FDA. He used to rail against FDA for slowing down drug development, and then all of a sudden he was appointed to be Deputy Commissioner. Maybe I should start railing against FDA.

2) FDA is soliciting comments re the international scheduling of dronabinol. Dronabinol is the active ingredient in Marinol, a synthetic marijuana pill used to treat nausea and vomiting associated with cancer chemotherapy and anorexia associated with weight loss in patients with AIDS. The United Nations Commission on Narcotic Drugs (CND) currently has dronabinol in Schedule II. WHO has recommended that it be transferred to Schedule III. The matter will be debated at a CND meeting in Vienna, Austria, March 12 to 16, 2007. FDA is soliciting comments re what the U.S. position should be. I imagine our position will be, Do whatever the heck you want, we’re not going to conform with your international scheduling, anyhow. In the U.S., dronabinol remains a Schedule I controlled substance, even though it is Schedule II elsewhere. All part of our whole War on Drugs thing, I believe.

3) The agency’s crackdown on “marketed unapproved drugs” continues. The newest target: quinine, a malaria drug sometimes used off-label to treat leg cramps. There’s going to be an FDA-sponsored meeting on “marketed unapproved drugs” issue in January. It’s drawing a lot of interest. FDA had to move it to a larger venue to accommodate the number of registration requests, and still it’s “sold out.”

New Rules Proposed for "Convenience-Size" OTC Drug Labels

2006-12-11T18:49:00.000-08:00

Ever run to the convenience store to buy a single pill of loratadine? I have. Such one-pill or two-pill packages are referred to as "convenience-size" OTC drugs. Because they typically come in small packages, it’s difficult to fit all of the Drug Facts Box information. Prompted by a petition from Lil' Drug Store Products, Inc., a company that specializes in "convenience-size" OTC drugs, FDA is proposing a rule to exempt these types of products from some of the Drug Facts Box requirements.

The agency is reasonable and flexible, don’t you think? C’mon, somebody must have an opinion about that.

p.s. Tomorrow I hope to comment on the departure of Scott Gottlieb from FDA. I need a little time to organize my thoughts.

Other Ways to Improve Drug Safety

2006-12-06T16:42:00.000-08:00

Ensuring physicians and pharmacists give patients proper info about their meds would improve drug safety, in combination with whatever steps are taken to reform FDA. Here’s some data re the percentage of patients who receive oral and written information at the doctor’s office and the pharmacy. The numbers have risen since 1992, but the target of 95% by 2010 has not yet been reached.

CDER Warns Clinical Investigators

2006-12-05T16:29:00.000-08:00

Earlier this month, CDER issued Warning Letters to two separate clinical investigators involved in unrelated studies.

One was issued to Philip B. Schworer of Florence, KY for allegedly failing to maintain records for the required records retention period. The investigational drug appears to have been a new antibiotic for the treatment of patients with acute exacerbation of chronic bronchitis

The other was issued to E. Clinton Lawrence of Atlanta, GA for allegedly committing myriad violations of GCP. A study monitor identified at least some of these violations, according to the Warning Letter, and yet they continued. The investigational drug appears to have been a pulmonary arterial hypertension treatment.

For a while there, CDRH was issuing these types of CI Warning Letters at a record-setting pace, but now CDER seems to be picking up its BIMO activity.

Torceptrapib/Atorvastatin and Data Safety

2006-12-04T17:04:00.000-08:00

The big news today (again, I prefer to comment on small news, but…) is Pfizer halting a large Phase 3 study due to an increased rate of mortality, which was identified by a data safety monitoring board (DSMB).

My angle will be to look at the role of DSMBs, also known as DMCs (for data monitoring committees). Earlier this year, FDA finalized its guidance on Establishment and Operation of Clinical Trial Data Monitoring Committees. The guidance explains that a DMC “is a group of individuals with pertinent expertise that reviews on a regular basis accumulating data from one or more ongoing clinical trials. The DMC advises the sponsor regarding the continuing safety of trial subjects and those yet to be recruited to the trial, as well as the continuing validity and scientific merit of the trial.” In this case, the DMC apparently advised Pfizer that continuing the study would be unethical in light of the newly obtained data, and Pfizer acted swiftly to end the study. The system appears to have worked as intended.

Importantly, however, DMCs are not mandatory (except in extraordinary circumstances), and until recently were rarely used in studies sponsored by drug companies. So, what if Pfizer had not established a DMC to oversee this study?

With all the Congressional interest in drug safety, I wonder whether this case will lead to laws and/or regulations requiring the use of DMCs.

I tried to track down the composition of the DMC overseeing this study but couldn’t find it. Anybody have it?

FDA Fighting to Protect Company’s Confidential Data

2006-12-01T18:50:00.000-08:00

It’s been all over the news already. I prefer to blog about lower-profile regulatory issues. But there’s not much else going on, and this is interesting.

Republican Senator Grassley wants FDA to give Congress more information related to the FDA’s review of Ketek, an antibiotic, the safety of which is in question. Grassley says the legislative branch needs this info to perform proper oversight of the executive branch. Congress and the Bush Administration have had a long-running feud over this sort of thing.

FDA says they’ve tried to give Grassley “access to as much data and as many agency personnel as possible, while remaining responsible stewards of the extraordinarily sensitive information we handle.”

NDAs are filled with loads of confidential information that companies wouldn’t want aired in public. Not necessarily because they’re trying to hide stuff from consumers, but because they definitely want to hide stuff from competitors.

I suspect industry is hoping acting FDA commish von Eschenbach won’t fold on this one. But he may have to, if he wants to be confirmed.

Defective Containers

2006-11-29T16:49:00.000-08:00

What are the most common causes of drug recalls? Packaging and labeling issues must be up near the top. Here's two from this week's FDA Enforcement Report.

______________________________
PRODUCT
Doxepin Hydrochloride Capsules, USP, 25 mg, Rx only, 1000 count bottles, NDC 0591-5630-10, Recall # D-407-7
CODE
Lot: L6G0879, Exp. 8/31/08
RECALLING FIRM/MANUFACTURER
Recalling Firm: Watson Laboratories, Inc., Corona, CA, by letters dated November 8, 2006.
Manufacturer: Watson Laboratories, Inc., Carmel, NY. Firm initiated recall is ongoing.
REASON
Defective containers (loose caps)
VOLUME OF PRODUCT IN COMMERCE
167/1000 count bottles
DISTRIBUTION
Nationwide

______________________________
PRODUCT
Neaclear Liquid Oxygen Scar Advantage, Hydrocortisone 0.5%, 1.0 oz (30 ml) bottles, Recall # D-402-7
CODE
Lots: 6994 and 8050
RECALLING FIRM/MANUFACTURER
Diversified Manufacturing Corp, Newport, MN, by telephone on July 27, 2007. Firm initiated recall is ongoing.
REASON
Defective container
VOLUME OF PRODUCT IN COMMERCE
20,000 bottles estimated
DISTRIBUTION
IL

2006-11-28T17:54:00.000-08:00

The FDA has finalized an important guidance for the gene therapy field, which in the past has been beset by serious adverse events in clinical trials. It's called Gene Therapy Clinical Trials - Observing Subjects for Delayed Adverse Events. A draft version was issued in August 2005. Changes include:

(1) Clarification on topics not included in the guidance;
(2) Revised recommendations for preclinical study design to assess vector biodistribution and persistence; and
(3) Revised recommendations for data collection and data reporting in trials involving integrated vectors (e.g., retroviral vectors).

The two major setbacks in gene therapy have involved:

Death of a patient apparently due to immune response to the adenoviral vector used in the study. This is addressed in #2 above.
Side effect of leukemia reported in several patients. Retroviral vectors were used in this study. Retroviral vectors potentially may be inserted in the middle of a gene responsible for regulation of cell division. If this happens, cancer may develop. This is addressed in #3 above.

Labeling of Parenterals

2006-11-27T16:56:00.000-08:00

The FDA will hold a public meeting “to explore how labels on intravenous (IV) drug products could be designed to minimize medication errors.” Issues include:

the placement, style and type of information on the label
the need for standard expression of strength – I suspect this will focus on implementing the I suspect this will focus on implementing the ISMP’s recommendations re abbreviations
the quantity of information on the label – can some information be eliminated “to make room for more important information such as barcodes, larger font size for drug names, new standard ways to express drug concentration, and product warnings?”
the use of color on the label – FDA generally prefers different colors for different strengths of the same product. But for parenterals, “can different colors be used on intravenous bags? If not, what are the barriers and possible ways to address them?”

The public meeting will be held on January 11, 2007 at the Lister Hill Center Auditorium, NIH campus. No registration is required to attend the meeting . Seating will be on a first-come, first-served basis .

Electronic Submissions

2006-11-21T16:52:00.000-08:00

There’s going to be a public hearing on e-submissions. To me, the key part of the announcement is as follows:

“As we work towards establishing a modern, paperless submission environment, we have also become aware of the potential benefits of a common electronic platform that could be administered by a third party entity or entities (e.g. private or nonprofit entities not otherwise engaged in clinical research activities) with relevant expertise and organizational leadership to facilitate, coordinate and manage the functions necessary for electronic submissions. For example, a third party entity might perform the following tasks:

Build an electronic platform,
Maintain data warehouses,
Transition existing electronic data and information repositories to the electronic platform,
Produce other necessary components to facilitate electronic access and management of information,
Manage and support these functions.”

Sounds like the FDA doesn’t have the in-house IT expertise necessary to support the e-submission system it envisions. I guess IT isn’t one of the FDA’s core competencies, and they want to pay somebody else to do it?

The company I work for still does paper submissions. People have asked me, “Is the FDA going to start requiring electronic submissions soon?” In the past, my opinion has been no. Should this announcement and public hearing change my opinion?

Exception from Informed Consent Requirements

2006-11-20T18:40:00.000-08:00

Well, I’m back. I confess, my vacation ended some time ago. I haven’t been posting for a couple of reasons, which I don’t want to go into. But the other day a kind reader emailed me and encouraged me to keep at it, and I missed it, so I’ll try again.

The period for comments on the agency’s Draft Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors; Exception from Informed Consent Requirements for Emergency Research ended on October 30. Many of the comments that were received by FDA are available in the Dailies section of the FDA’s Dockets web site. I reviewed some of them and thought Novo Nordisk raised an interesting point:

“The exception from informed consent only applies to patients with a life-threatening medical condition. FDA, from an ethical standpoint, has determined that the average person would agree to participate in a clinical study if it could save their life. Thus the patient needs to be in a life-threatening situation in which they are unable to give consent. This ties in with the prospect of direct benefit to the subject, implying that the benefit will either be to save the patient’s life (decrease mortality) or improve their functional outcome (reduce morbidity). FDA has not assumed that patients would agree to have their decision rights denied for lesser potential outcomes.”

Any professional or armchair bio-ethicists out there? What if a patient is unconscious and not in danger of a life-threatening medical condition, but an experimental drug might possibly prevent a less serious condition, and a company wants to study the experiment drug for this purpose? Would the patient object? Or would the patient want the treatment? Since the patient is unconscious, should somebody else (a physician? a relative?) be allowed to make the decision for him/her?

Employees Suspended for Withholding Data from FDA

2006-10-16T18:30:00.000-07:00

According to Bayer's general counsel, "Bayer has acknowledged and regrets the error it made in not sharing with the FDA information regarding [an observational study on Trasylol®] prior to the September 21st Advisory Committee Meeting on Trasylol®. Bayer immediately initiated a full investigation into the matter and based on our investigation so far, we believe this was a serious error in judgment by two individuals. These individuals have been suspended with immediate effect."

Anybody know whether these two employees were regulatory affairs professionals?

FDA Debars Clinical Study Coordinator

2006-10-16T18:25:00.000-07:00

Ex-clinical study coordinator Anne Butkovitz, 48, who last year pled guilty to falsifying case report forms, has been debarred permanently by FDA. The study was a multi-site pediatric study of a rotavirus vaccine and was sponsored by an unidentified pharmaceutical company (anybody know who it might be? I know Merck was working on a rotavirus vaccine, but I'm not sure if this was their study. Regardless, the drug company apparently did nothing wrong.). According to the study protocol, the clinical study coordinator at each site was supposed to contact subjects’ parents at specified intervals to determine whether any serious adverse events had occurred. At one of the sites, however, Butkovitz failed to contact parents but stated on case report forms that she had contacted them and that no serious adverse events had occurred. The pharmaceutical company sponsor reportedly disregarded data from her site.

National Lampoon's Vacation

2006-10-11T09:42:00.000-07:00

I'm on vacation. Be back next week...

Syntho/Intermax Consent Decree

2006-10-05T17:16:00.000-07:00

The FDA continued its recent efforts to remove “grandfathered” drugs from the market, announcing a consent decree with Syntho/Intermax. The company will be barred from marketing:

Coldec Tablets;
Coldec D Tablets;
Coldec TR Tablets;
Dyphylline & Guaifenesin Tablets, USP;
Guaidex PD Tablets;
Guaidex D Tablets;
Crantex LA Tablets;
Migrazone Capsules;
Usept Tablets

For years, FDA turned a blind eye to these types of products, but no longer.

Quality Systems Guidance

2006-09-29T15:32:00.000-07:00

FDA is publishing a final guidance on Quality Systems Approach to Pharmaceutical CGMP Regulations.

The guidance previously was issued in draft form in 2004. According to the pre-publication announcement, “No substantive changes were made to the final guidance, although a number of clarifying edits were made throughout the guidance based on the comments received. In addition, the reference list and the graphic depicting a quality management systems approach were updated.”

FDA: Help Wanted

2006-09-29T15:30:00.000-07:00

Know somebody who is knowledgeable in pediatric research, pediatric subspecialties, statistics, and/or biomedical ethics? Or somebody who is knowledgeable in the fields of arthritis, rheumatology, orthopedics, epidemiology or statistics, analgesics, and related specialties? If yes, why not nominate he or she to be a Voting Consumer Representative on the FDA’s Pediatric Advisory Committee or Arthritis Advisory Committee?

Nominees must meet the following criteria:
(1) Demonstrate ties to consumer and community-based organizations
(2) be able to analyze technical data
(3) understand research design
(4) discuss benefits and risks
(5) evaluate the safety and efficacy of products under review

See this announcement for more info.

New Guidance Related to Viral Vaccine Production

2006-09-28T16:36:00.000-07:00

FDA is issuing a new guidance containing “recommendations for the characterization and qualification of cell substrates and viral seeds used for the production of viral vaccines for human use.”

Current vaccines use only a limited number of different cell substrates, thus vaccine manufacturers are very familiar with them. However, novel vaccines to protect against bird flu, SARS, agents of bioterrorism, etc., may require the use of a wider range of cell substrates, some of which may be less familiar or unfamiliar. This guidance tells manufacturers what tests they should do to demonstrate that cell substrates are appropriate for use and will not negatively influence the safety or purity of the finished product.

E-Submission Guidances to Be Withdrawn

2006-09-28T16:34:00.000-07:00

CDER is withdrawing the following guidances:

Providing Submissions in Electronic Format-NDAs
Providing Regulatory Submissions in Electronic Format-ANDAs
Providing Regulatory Submissions in Electronic Format : Annual Reports for NDAs and ANDAs

Ever since the publication of the newer eCTD guidance, industry has had the option of following either the old guidances or the newer eCTD guidance. But this has resulted in confusion for both drug companies and CDER reviewers, thus the old guidances are being put out to pasture. So long, we hardly knew ye.

Note that CBER is not withdrawing "Providing Regulatory Submissions to the Center for Biologics Evaluation and Research (CBER) in Electronic Format -Biologics Marketing Applications [Biologics License Application (BLA), Product License Application (PLA) / Establishment License Application (ELA) and New Drug Application (NDA)]”.

I guess biotech companies and CBER reviewers are not as susceptible to confusion?

Combination Products

2006-09-27T17:13:00.000-07:00

The Medical Device User Fee and Modernization Act (MDUFMA) required FDA to review its policies re the assignment of combination products to CDER, CBER or CDRH. That internal review is complete. FDA concluded:

The intercenter agreement (ICA) between CDER and CDRH should stay in effect as is
The ICA between CBER and CDRH should stay in effect as is
However, the ICA between CDER and CBER is obsolete due to the transfer of many therapeutic biological products from CBER to CDER and therefore should be withdrawn.

FDA also notes that it has taken many actions to increase the transparency of its jurisdictional decision-making. For example, a final rule defining ‘‘primary mode of action’’ has been issued, and assignment decisions now are published on the Office of Combination Products website.

In short, “the agency has preliminarily determined that its practices are consistent with the requirement contained in [MDUFMA] that it promptly assign combination products to an agency center based on the product’s PMOA.”

Do you agree? Disagree? Post a comment here or, better yet, submit your comments to FDA by November 27.

PQRI Workshop on Excipient Testing and Control Strategies…

2006-09-26T16:36:00.000-07:00

…will be held October 10 and 11 in North Bethesda, MD. Issues to be discussed include:

commonly used ways to control and communicate the quality attributes of excipients manufactured using a continuous flow process

best practices for the use of "skip lot" testing based on scientific rationale and risk analysis

ways to improve pharmaceutical product quality by characterization and control of physical and chemical properties of critical excipients

third party audits of excipient manufacturers

increasing danger of excipient manufacturers not producing pharmaceutical grade excipients that meet USP-NF criteria

Remove the “F” from “FDA”?

2006-09-26T16:33:00.000-07:00

Democrats in the House and Senate are pushing legislation to create a federal agency devoted solely to food safety oversight. Currently, food safety is managed by a patchwork of various federal agencies, including the USDA, FDA and others, who would cede authority to the new agency.
Given that the legislation is being pushed by Democrats and Congress currently is controlled by Republicans, expect nothing to happen – unless Democrats regain control of the House and/or Senate on Election Day, a distinct possibility.

MRSA Antiobiotic Resistance

2006-09-21T16:47:00.000-07:00

Vancomycin for decades has been the leading treatment for methicillin-resistant Staphylococcus aureus (MRSA), but in response to the emergence of vancomycin resistance in MRSA and a rise in the incidence of MRSA, the Clinical and Laboratory Standards Institute (CLSI) has petitioned the FDA to “amend the package insert of the antibiotic vancomycin to include newly revised susceptibility interpretive criteria that recognize emerging resistance to this agent in the important bacterial pathogen Staphylococcus aureus.”

CLSI is a well-established organization with a long history in setting antimicrobial susceptibility testing breakpoints. Usually, its standards are identical to FDA-approved drug labels. However, CLSI more actively reviews post-marketing literature and updates its standards accordingly, thus occasional discrepancies exist. This is one of those situations.

I look forward to FDA’s response. So far, the only commenter has been – who else but the ever prolific Dave Lowe. The totality of his comment is as follows: “I oppose the petition, safety and efficacy should be established outside the Federal Register. Executive Order 13258/12866 applies as well.”

Post-Approval Labeling Changes

2006-09-19T06:30:00.000-07:00

FDA is issuing a new draft guidance related to labeling changes submitted in a Changes Being Effected (CBE) supplement. The draft guidance informs industry that FDA will publish such revised labeling on its website and the DailyMed website as soon as it is received, not necessarily after FDA has reviewed and approved the changes.

The goal is to ensure the public has access to the currently in use labeling. Companies often implement revised labeling at the time they submit it to FDA, which is allowed under the CBE regulations. If FDA were to hold off from publishing the revised labeling until after completing its review, then there would be a gap of time during which the currently in use labeling would not be accessible to the public.

This doesn’t apply to labeling changes submitted in a Prior Approval Supplement.

One Small Step for FDA, One Giant Leap for Industry?

2006-09-18T08:47:00.000-07:00

At an FDA-industry jointly sponsored workshop last year, FDA’s Janet Woodcock posed the question, “How do we get to genomic tests that are usable for regulatory decisions in drug development and interpretable and valuable in the clinic?”

A step toward this goal has been taken with FDA’s publication of a Table of Valid Genomic Biomarkers in the Context of Approved Drug Labels. The table provides a list of genomic biomarkers associated with FDA-approved drug labels as well as links to pharmacogenomic data.

The promotion of pharmacogenomics is part of FDA’s Critical Path Initiative.

505(b)(2) NDA vs. ANDA

2006-09-15T08:05:00.000-07:00

Mayne Pharma today received final approval of cancer drug Epirubicin Hydrochloride for Injection, 50 mg vial, 200 mg vial. The product had been tentatively approved on August 17. Final approval was granted today, because today the brand version’s orphan drug exclusivity period expired.

Of interest to me is that the application was filed as a 505(b)(2) NDA, not an ANDA. Epirubicin Hydrochloride for Injection 2 mg/ml is marketed by Pfizer under the brand name Ellence. So, it looks like Mayne Pharma changed the dosage strength. Couldn’t they have filed an ANDA suitability petition and gone that route?

Somebody enlighten me, please.

Who Is Dave Lowe?

2006-09-14T06:11:00.000-07:00

If you've been checking out the FDA's Dockets Managements website, particularly the "Dailies" section which includes links to comments submitted re proposed rules, proposed guidances, petitions, etc., then you must have noticed that somebody named Dave Lowe is a profilic commenter, at least recently. I would guess he submits more comments related to more dockets than any other person, company or trade association. Most of his comments have a similar theme. Here's a typical example of his thinking. He appears to have a very libertarian worldview and wants FDA to cede much of its authority to individual states. Perhaps, though, I'm mis-stating his positions. Mr. Lowe, if you're out there, please feel free to correct me if necessary!

Two Lots of Cocaine Recalled

2006-09-14T05:58:00.000-07:00

Boehringer Ingelheim has recalled two lots of Cocaine Hydrochloride 4% topical solution because "the folding carton for the Cocaine Hydrochloride 4% topical solution lists the incorrect milligram strength for the product."

I wasn't aware that cocaine has an approved medicinal use. Acording to Wikipedia, it's an anaesthetic used during eye, nasal and lacrimal duct surgery, but apparently it is not used much anymore, having "been largely replaced in Western medicine by synthetic local anaesthetics such as benzocaine, proparacaine, and tetracaine."

p.s. You may have noticed I post a lot about recalls. I don't know why this is, except I'm interested in recalls and look forward to the FDA's Weekly Enforcement Report. The reasons for recalls are telling indicators of what issues companies are struggling with and potential areas of growing concern for FDA.

MDS Pharma Warned Re BE Studies

2006-09-12T07:01:00.000-07:00

MDS Pharma, a Canadian CRO, has received a Warning Letter related to its conduct of bioequivalence studies. Allegedly, after FDA noted deficiencies related to several BE studies, the company promised it would conduct a thorough review of all BE studies for the past five years, but then failed to follow through on this promise to FDA's satisfaction. Read all about it.

Take-home lesson? Be clear in your communications with FDA, and if you make a commitment, expect FDA to hold you to it.

Good Review Practices

2006-09-12T06:44:00.000-07:00

FDA has published a new MAPP on the publication and use of good review practices (GRPs) within CDER.

This is part of CDER's effort to improve and standarize practices across different divisions - a worthy effort, certainly. If one division comes up with a way to make NDA reviews more efficient, for example, it is a good idea to document this "GRP" and disseminate it to other divisions.

FDA Urges WHO Not to Change INN Policy

2006-09-12T06:21:00.000-07:00

A little background:

WHO designates the International Non-proprietary Name (INN) for drug substances
The emergence of biosimilars has caused a dilemma with regard to INNs. Specificially, two large molecules may have the same INN yet not be therapeutically interchangeable.
Some countries base interchangeability decisions on the INN, i.e., if two large molecules have the same INN, they can be freely substituted for each other even though they may not be therapeutically interchangeable. To address this situation, some countries want WHO to change its INN assignment policies to avoid the assignment of the same INN for non-interchangeable molecules.

What's new on this front? FDA has come out with a statement urging WHO not to to change its INN designation policies. FDA feels, rather, that instead individual countries should change their prescribing policies, if necessary. In the U.S., for example, therapeutic interchangeability is determined not by the INN, but by the Orange Book and other measures.

For those interested in generic biologics, it's worth a look.

Actavis Warned Re Alleged ADE Violations

2006-09-12T06:05:00.000-07:00

FDA issued a Warning Letter to Actavis, which recently bought Alpharma's generic business, for alleged violations of postmarketing Adverse Drug Experience (ADE)
requirements. The alleged violations include:

Failure to report 6 potentially serious and unexpected ADEs
Failure to investigate serious and unexpected ADEs
Failure to submit periodic safety reports
Failure to establish SOPs related to ADEs

Consistent with the FDA's compliance policy guide on marketed unapproved drugs, the Warning Letter also notes Actavis manufactures 6 prescription products that are not the subject of approved applications (i.e., grandfathered or DESI drugs) and asks Actavis to submit "a statement describing the basis on which you claim for the drug an exemption from the drug approval requirements."

Drug Interactions

2006-09-11T06:18:00.000-07:00

FDA is releasing a new draft guidance on Drug Interaction Studies – Study Design, Data Analysis, and Implications for Dosing and Labeling, which “reflects the current view that the metabolism and transport of a new drug should be- defined during drug development and that its interactions with other drugs should be explored as part of an adequate assessment of the safety and effectiveness of the drug.”

When finalized, it will replace two previously issued guidances: 1) "Drug Metabolism/Drug Interaction Studies in the Drug Development Process: Studies in Vitro" and 2) "In Vivo Drug Metabolism/Drug Interaction Studies-Study Design, Data Analysis, and Recommendations for Dosing and Labeling."

Harmonization in Latin America

2006-09-07T06:02:00.000-07:00

IMS Health released their monthly top-line pharmaceutical sales data yesterday.

**** SALES THROUGH RETAIL PHARMACIES **** (Twelve months to June 2006*)

NORTH AMERICA $202.0 billion, up 5%
United States $189.1billion, up 5%
Canada $12.9billion, up 7%

EUROPE (leading 5) $91.8billion, up 4%
Germany $26.9billion, up 6%
France $24.4billion, up 5%
United Kingdom $14.9billion, down 1%
Italy $14.6billion, up 5%
Spain $10.4billion, up 5%

JAPAN (including hospitals) $57.7billion, up 3%

LATIN AMERICA (leading 3) $18.1billion, up 12%
Mexico $7.8billion, up 9%
Brazil $8.1billion, up 14%
Argentina $2.1billion, up 16%

AUSTRALIA/NEW ZEALAND $5.7billion, up 3%

As usual, the fastest-growing market is Latin America. Regulatory authorities in this region are attempting to harmonize requirements (a la ICH, except for Latin America). The organization is called Pan American Network for Drug Regulatory Harmonization (PANDRH). They have working groups devoted to GMP, GCP, bioequivalence, pharmacopoeia, drug registration, etc. It’s worth checking out, if you do business in this area of the world.

Levothyroxine Sodium

2006-09-06T06:03:00.000-07:00

Every week, seemingly, another recall of levothyroxine sodium tablets is announced. This week is no exception. Six lots are being recalled because one of the lots was sub-potent at the 9-month stability test interval.

My wife takes these pills. There are many different manufacturers, and I’m not sure which manufacturer makes the pills she takes. Does it change each time her scrip is re-filled? Anyhow, it always worries me a little bit.

Is there some reason why levothyroxine sodium tablets are difficult to manufacture?

Open Source Software

2006-09-01T06:15:00.000-07:00

FDA posted on its website a recent PowerPoint presentation discussing FDA’s views on open source software. Some highlights:

21 CFR Part 11 doesn’t prohibit the use of open source software but does require validation and other controls
The guidance document on Computerized Systems Used in Clinical Trials is currently in the process of being updated (will it mention open source software?)
Many FDA statisticians already have used open source software back in their graduate school days and are comfortable with it
Critical Path initiative is encouraging use of open source software
FDA is working with DIA to enable use of open source software

All of this indicates the use of open source software for drug development activities may increase in the future.

On the other hand, the presentation also noted that FDA’s internal IT policies make it cumbersome for FDA statisticians to install and use open source software on their desktops. They’ll have to fix that somehow, if they want to go in this direction.

Is This FDA's Idea of a Teaser?

2006-08-31T11:40:00.000-07:00

It’s that time of year again. No, not Christmas. FDA is publishing its annual guidance document agenda.

The list is twelve pages long. Some of the guidance documents I’m anticipating most eagerly include:

Potency Measurements for Cell and Gene Therapy Products
Clinical Study Design for Early Phase Studies of Cellular and Gene Therapies
Preparation of Investigational Device Exemptions and Investigational New Drugs Do for
Tissue Engineered and Regenerative Medicine Products
Facilities and Controls for Cellular and Gene Therapy Product Manufacturing Do Operations Guidance
Presentation of Risk Information in Prescription Drug and Medical Device (is there more to this title?)
Patient Specific Drug Products
Quality by Design
Obesity and Weight Loss
Process Validation . General Principles and Practices
Importation of Active Pharmaceutical Ingredients
Good Naming, Labeling and Packaging (GNLP) Practices
Selecting and Submitting Proprietary Names for Evaluation
Drug Names and Dosage Forms
Target Product Profile-A Strategic Development Process Tool
Application Integrity Policy

What about you? Any leave you drooling?

Note: not every guidance document on the list will be published within the next year – or ever.

OTC-to-Rx Switch?

2006-08-31T05:58:00.000-07:00

FDA has changed its mind regarding hydroquinone, a dermatology product used to lighten dark areas of the skin due to conditions including injury, rashes, acne, and sun damage. Back in 1982, the agency proposed that hydroquinone be Generally Recognized as Safe and Effective (GRASE) and therefore eligible for marketing under the OTC monograph system. Approximately 200 hydroquinone products currently are on the market.

Since 1982, however, new data have shown that hydroquinone may present a carcinogenic risk and "has been shown to cause disfiguring effects." FDA now proposes that hydroquinone not be GRASE. Instead, they would have to be marketed under an NDA/ANDA.

Comments on the proposed rule are due December 7.

Study: Phenylephrine Is No Pseudoephedrine

2006-08-30T14:56:00.000-07:00

Given the well-publicized issues with pseudoephedrine -- namely, drug addicts and dealers can convert it to methamphetamine and therefore all sorts of restrictions are being placed on its sale (e.g., moving it from over the counter to behind the counter) -- many drug manufacturers are looking to substitute phenylephrine for pseudoephedrine. Like pseudoephedrine, phenylephrine is an OTC monograph ingredient for nasal decongestant products. The problem? Phenylephrine doesn't work, according to a study by pharmacists at the University of Florida.

The whole situation isn't fair to non-drug addicts and dealers with stuffy noses. But who will stand up for them?

2006-08-29T11:15:00.000-07:00

Over at Eye on FDA, a blog you should check out if you haven't already, there is a post today in response to the National Research Center for Women & Families, "who sponsored a report implying advisory committees are biased in favor of drug approvals." Eye on FDA makes several good points, particularly that advisory committees only review drugs that are very close to approval. In other words, they're not reviewing preclinical candidates or Phase I molecules. If an advisory committee is looking at a a drug, that means the drug already has generated promising Phase III data. To a large degree, this explains why many drugs that are reviewed by advisory committees go on to be approved.

I would add that advisory committees often do more than simply vote thumbs up or thumbs down. Their role is more nuanced than that. In many cases, they recommend whether to include a black box warning on the label, how a risk management program should be designed, etc. These issues can have tremendous implications.

Informed Consent and Emergency Research

2006-08-28T07:09:00.000-07:00

Informed consent is one of the bedrock principles of human subject protection and Good Clinical Practice. Under certain circumstances, however, informed consent is not possible or practical. For example, if you are developing a therapy administered to unconscious patients, how are you going to inform them of the risks and benefits and obtain their consent? And yet such therapies need to be studied.

FDA regulations allow for exceptions to informed consent requirements for emergency research. The agency is releasing a draft guidance intended to clarify how these types of situations should be managed by IRBs, CIs and sponsors.

A public meeting on the issue has been scheduled for October 11.

Today’s Not-So-Big Story

2006-08-24T11:05:00.000-07:00

The big news of the day is that FDA has approved Plan B. But you’ll find plenty of coverage on that elsewhere.

Less widely publicized is the FDA’s proposed rule on drug registration and listing. A couple of weeks, the HHS Inspector General recommended that FDA move to electronic submission of drug registration and listing information. FDA already was far long in the process of doing so, as now they have come out with this proposed rule. Some highlights include:

The aforementioned e-submission of drug registration and listing forms
NDC numbers must appear on drug labels
FDA will assign NDC numbers

Go to http://www.fda.gov/OHRMS/DOCKETS/98fr/oc94634.pdf

p.s. Sorry I've been posting less frequently. But is anybody reading?

FDA Shuts Down Tissue Manufacturer

2006-08-18T16:06:00.000-07:00

Good Tissue Practice (the newest member of the GxP family) claimed a victim today, as FDA ordered Donor Referral Services of Raleigh, NC to cease operations. The company allegedly violated donor screening and record keeping requirements.

Intriguingly, “FDA also found several instances where records provided by DRS to another [tissue] establishment were at variance with the official death certificates FDA had obtained from the state where the death occurred.”

FDA’s press release is available at http://www.fda.gov/bbs/topics/NEWS/2006/NEW01433.html.

The official Order of Cessation is available at www.fda.gov/cber/compl/drs081806.htm.

HHS to FDA: Enforce Drug Listing More Vigorously

2006-08-16T05:59:00.000-07:00

HHS is FDA’s parent department. The Office of the Inspector General (OIG) within FDA investigated whether the FDA’s National Drug Code Directory is complete and accurate – and discovered that no, it isn’t.

Approximately 9,187 drugs that should be listed aren’t, while approximately 34,257 drugs that shouldn’t be listed are.

OIG came up with seven recommendations for FDA:

1. Finalize guidance documents for submission of forms to list drug products,
2. Assume greater control over the assignment of National Drug Code (NDC) numbers,
3. Continue efforts to implement electronic submission of listing forms by drug firms,
4. Implement a mechanism to routinely identify omissions and inaccuracies in the Directory,
5. Resolve the status of drug product listings in the pending file,
6. Enhance communication with drug firms, and
7. Identify and take appropriate action against drug firms that consistently fail to list drug products and update information.

It’s that last one I seized upon for my headline, but #2 is interesting also. Currently, drug companies assign their own NDC numbers, but OIG feels FDA should assign NDC numbers.

FDA apparently agrees with all of the above recommendations. All children should be so obedient!

A link to the OIG’s report is here: http://oig.hhs.gov/oei/reports/oei-06-05-00060.pdf

FDA to Industry: Stop Marketing Unapproved Drugs

2006-08-15T07:17:00.000-07:00

For the past several years, FDA has been more aggressive in its efforts to remove so-called “grandfathered” and “DESI” drugs from the marketplace. Such drugs were marketed before safety requirements were established in 1938 or between 1938 and the introduction of efficacy requirements in 1962, and they remain on the market today even though they have not been approved via an NDA or ANDA.

The crackdown continues. In a warning letter posted today on FDA’s website, FDA warns Concord Laboratories not to continue marketing Colchicine Tablets, Hyoscyamine Sulfate Tablets and Nitroglycerin Sublingual Tablets because “there are no approved applications on file for the above products and their continued marketing violates section 505(a) [21 U.S.C. § 355(a)].” http://www.fda.gov/foi/warning_letters/g5973d.htm

This is a murky and interesting (to me, if not to many) area of FDA regulation. Last month, FDA issued a Compliance Policy Guide on the topic, which includes a BRIEF HISTORY OF FDA MARKETING APPROVAL REQUIREMENTS AND CATEGORIES OF DRUGS THAT LACK REQUIRED FDA APPROVAL. Excellent beach reading.

DailyMed

2006-08-14T11:52:00.000-07:00

After a slow start, the number of product labels that have been converted to SPL and posted on the DailyMed website has skyrocketed lately. (I'm given to hyperbole, you'll notice.) The count is up to about 833 now.

See for yourself at http://dailymed.nlm.nih.gov/dailymed/about.cfm

Help a Colleague in Need

2006-08-14T10:25:00.000-07:00

I can’t find any “news” to write about today, so instead here’s a question: When you submit an NDA or ANDA, do you submit draft labeling or final printed labeling?

21 CFR 314.50(e)(2)(ii) seems to indicate you can submit either: “4 copies of draft labeling or 12 copies of final printed labeling.”

What is normally done? I’d prefer to submit draft labeling in the NDA or ANDA, and submit final printed labeling only after the drug is approved. I think this is acceptable, but can anybody confirm?

Thanks…

Teach FDA About Nanotechnology

2006-08-11T06:00:00.000-07:00

FDA will hold a public meeting October 10, 2006, on nanotechnology. The agency wants to learn more about: 1. What types of nanotechnology-related products are under development2. Do these products present unique safety issues?
The scope of the meeting includes all FDA-regulated products, including foods, animal feeds, cosmetics, etc.

My interest is only in drugs and biologics. Here, nanotechnology holds great promise for drug delivery. For example, nanotechnology may facilitate the delivery of molecules across the blood-brain barrier, opening up many new possibilities.

Anybody else have other examples?

Info on how to register for the meeting is available at http://www.fda.gov/OHRMS/DOCKETS/98fr/06-6867.htm

Breakdown in Packaging Controls!

2006-08-10T06:28:00.000-07:00

Okay, my headline is overly alarmist. Nonetheless, this week’s FDA Enforcement Report includes three drug recalls, and the reason for each is related to packaging:

1. The outer packaging is labeled as Hydralazine Hydrochloride, 100 mg tablets, but the unit dose blister strips inside the outer packaging may contain and be labeled as Benztropine Mesylate, 0.5 mg tablets.
2. Lorazepam 1 mg tablets packaged and distributed as Lorazepam 2 mg tablets
3. Incorrect package insert (older version) was sent instead of revised current version

Details of these recalls are available here: http://www.fda.gov/bbs/topics/ENFORCE/2006/ENF00964.html

For a refresher on what FDA investigators look for when inspecting the Packaging and Labeling System, go to http://www.fda.gov/ora/cpgm/7356_002/7356-002FINAL.pdf and scroll down to Pages 18-19 of 30.

p.s. This is a new blog devoted to pharmaceutical and biotechnology regulatory affairs. I’ll try to post every day – except weekends. I hope readers will comment and we can get good discussions going. Thanks for visiting!