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FDA’s DAARP is now DAAP, DPAP is now DPARP

Published March 10th, 2010 in News Commentary. 0 Comments

Effective March 15th, the FDA’s Division of Anesthesia, Analgesia, and Rheumatology Products is being reorganized. This reorganization is part of some other reassignments announced yesterday (3/09/2010) by the FDA.

The “R” part – Rheumatology, will move to the Division of Pulmonary and Allergy Products, which will be renamed the Division of Pulmonary, Allergy, and Rheumatology Products. The reviewers will move as will the applications under review. The FDA has provided a list of the IND’s and NDA’s that are affected for this DAARP to DPARP move.

The FDA announced the moves as needed to balance workload. Camargo’s experience with DAARP - we had 13 pre-IND meetings with them last year alone, indicated they did well meeting their PDUFA dates while under extreme pressure. One of the major initiatives at FDA, REMS is focused at many of the products reviewed by this Division. The burden of finding ways to deal with the abuse of opioids and the numerous sponsor views has also added to its workload. Presumably, the reassignment of rheumatology products will help.

Exalgo Approved

Published March 3rd, 2010 in Uncategorized. 0 Comments

Exalgo, hydromorphone extended release tablet was approved March 1, 2010. I waited a couple of days to see if it was approved under 505(b)(1) or 505(b)(2). At this writing, we don’t know.

We have previously detailed in this blog the regulatory approval saga for this drug. When we last heard, FDA had told CombinatoRx/Covidien/Alza (clinical developer/commercialization/manufacturer & IP holder, respectively) that the NDA was deficient under 505(b)(1) but perhaps the sponsors should consider 505(b)(2). As we have stated before, hydromorphone has been on the market for decades, so a 505(b)(1) filing was puzzling. We’ll continue to follow this until we get a verdict.

Do Not Neglect Your Third-Party Drug Substance Manufacturer

Published March 2nd, 2010 in Uncategorized. 0 Comments

Another example of the importance CMC was reported in January. Warner Chilcott plc received a complete response letter from the FDA. The “low dose” oral contraceptive NDA was the file in question. The FDA inspection of the third-party drug substance manufacturing facility and control testing laboratory used to support the application reported outstanding deficiencies which require satisfactory resolution before approval can be allowed.

Everyone down the supply chain is affected when a new drug product launch is held up. These problems can often be avoided with a proactive approach to working with third-party suppliers. The owner of the drug product in question must be present periodically and to inspect the sites providing critical components for their product. Prepare a contract with the third-party that requires communication and draft a quality agreement that meets your internal standards. Confirm that it is being followed.

Adventrx Pharmaceuticals received a refuse to file letter, March 1, 2010. The reason stated was that the data included in the initial submission from the intended commercial manufacturer was insufficient to support a commercially viable expiration dating period. Adventrx believed that they had supported the submission with sufficient stability data: “Site-specific stability data from lots manufactured at the intended commercial manufacturing site also were submitted in the NDA.” Apparently there was not sufficient data on the product manufactured at the intended commercial site. Commercial site data is pivotal, R&D data is supportive.

Neglecting these third-party sites can result in lost revenue every day the new drug product is not on the market.

 

Proposed FDA rule would make Sponsors more responsible for data integrity - way more responsible

Published March 2nd, 2010 in Uncategorized. 0 Comments

On February 19th, 2010, FDA published a proposed rule in the Federal Register to revise 21 CFR §§ 16, 58, 71, 101, 171, 190, 312, 511, 571 and 812 to require Sponsors of the various impacted regulatory applications to file a report with FDA providing specific information when someone “has or may have (emphasis added) engaged in the falsification of data. More specifically, “FDA is seeking information on falsification of data by any person involved in studies conducted by or on behalf of a sponsor or relied on by a sponsor.” Thus, under the regulation, you wouldn’t need to have anything at all to do with a study to incur the responsibility other than relying on it, as you do for a 505(b)(2). Further, under the proposed regulation, the Sponsor doesn’t have a lot of options: “This reporting obligation would exist regardless of the amount of evidence, if any; (emphasis added) the sponsor has with regard to the intent of the person who has, or may have, falsified data.”

This is a fairly onerous proposal, with potentially devastating consequences for a large number of people. FDA must be providing some pretty clear guidance on what would trigger a report, right? Unfortunately, the answer is ‘no’.

“We (FDA) purposely are not proposing to specify in the regulations any particular information threshold that must be met before the reporting requirements are triggered, such as the exact form, quantity, or reliability of information about possible falsification that would require a sponsor to report to FDA. We do not believe it is possible to codify all forms of information on possible qualification (some examples provided)…or specify a quantity of information that would constitute a minimum threshold for sponsor reporting, and we do not inadvertently exclude information that, upon further investigation by the Agency, could help uncover falsification.”

The justification for giving no standard is the Agency’s apparent lack of confidence in its ability to provide a perfect standard.

In this regard, there is at least a possibility for improvement: “…we invite comment on whether the regulation should specify some form of evidentiary standard or minimum threshold, such as what form(s) or quantity of information is needed to create a requirement to report and, if so, what the standard should be.”

Camargo recommends comments - lots of comments, because there are potential consequences under the proposed rule for failure to report confirmed or possible falsification.

“Failure to report possible falsification of data might constitute a violation of Section 301(e) of the Federal Food, Drug and Cosmetic Act (the act) (21 U.S.C. 331(e)) (concerning failure to make a required report) or 18 U.S.C. 1001 (concerning the submission of a false statement to the Federal government).”

Thus, worst case, Sponsors (employees?) could be looking at fines or even imprisonment for failing to report something which may or may not have taken place under a regulation without a set standard for reporting it. This one needs a lot of work. The potential for both abuse and unintended consequences under the regulation as written is extremely high. 21 CFR §1301.91, regarding employee responsibility to report (controlled) drug diversion might be a good place to start.

Spending on DTC Ads

Published February 23rd, 2010 in News Commentary and Uncategorized. 0 Comments

At GPhA last week, one of the CEO’s on an industry panel said that big pharma spent more on DTC (direct-to-consumer) advertising than on R&D.  Clearly, generic companies don’t like this promotional activity, but I was skeptical of the facts.  A quick Google of DTC costs brought an article in the New England Journal of Medicine with the following table:

 dtc-spending

N Engl J Med. 2007 Aug 16;357(7):673-81. A decade of direct-to-consumer advertising of prescription drugs. Donohue JM, Cevasco M, Rosenthal MB. Department of Health Policy and Management, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA.

Okay, we’re sure it has gone up since 2005, but you’ll notice that spending on DTC advertising  is a small fraction (14.2% in 2005) of the total cost of promotion. 

Turning to R&D expenditures, I went to the PhRMA site and found this report, showing a total of $50.3 billion was spent in 2008 on R&D.

Thus, the CEO misstated her facts.  But I clearly hear the sentiment - that DTC hurts adoption of generics.  Maybe that fact should be checked too?

Generic Approvals Taking Longer

Published February 20th, 2010 in ANDA's and Events. 0 Comments

I attended the Annual GPhA meeting this past week.  This event is attended by the CEO’s and other top brass of most of the major generic pharmaceutical companies. This year was highlighted by a presentation from the FDA Commissioner, Dr. Margaret Hamburg.  In her remarks, Dr. Hamburg admitted to a need for FDA to step up in food and drugs, to be less reactive and more proactive.  In the area of generic drugs she admitted to the poor record of approvals (see below) and said that only better science and more resources would help.  She didn’t elaborate on what ‘better science’ is needed, but she specifically pointed out that the President’s 2011 budget included additional money for the Office of Generic Drugs - all from proposed user fees.  Dr. Hamburg pledged to work with GPhA to enact user fees this fiscal year.  She offered no details on what this would look like.

The poor record of approvals that Dr. Hamburg addresssed  was discussed in an earlier closed session by OGD Director Gary Buehler.  He indicated that the median approval time had increased to 26 months.

During a panel session with the presidents of Mylan, Actavis, Watson, Par and Teva, it was pointed out that the 2010 budget for OGD, $55 million, is the same as the left side of the field for the NY Yankees.  Given the  billions of dollars saved by the government when generics are used, the increase of US government funds would be warranted.  A generic user fee could tilt the generic business to larger producers and reduce the number of generics in the small volume markets favored by small generic producers.

Can and Should ANDA Labeling Differ from the RLD?

Published February 11th, 2010 in ANDA's and News Commentary. 0 Comments

In the past two months, two appellate courts, the Fifth Circuit and the Eighth Circuit have handed down decisions which essentially state that generic pharmaceutical companies can be sued in state courts for failure-to-warn regarding serious side effects, where the generic companies had conformed their labeling to that of the current Reference Listed Drug.

For a long time, the working model was that the generic companies’ labeling had to be virtually identical to that of the RLD when an ANDA was filed, and to continue to conform to it, i.e., to make any substantive changes in lockstep with the RLD. Originally FDA would send all ANDA holders a letter requesting a CBE (changes becoming effective) supplement following the approval of a substantive label change to the RLD labeling. A number of years ago, FDA shifted the responsibility for monitoring the RLD labeling to the ANDA holders themselves. Everyone at least behaved as if the generic labeling could not deviate from that of the RLD - ever.

Now, the Fifth and Eighth Circuits have said that (and this is a bit of an oversimplification) while they agree that the ANDA labeling must be virtually identical at the time the application is filed, they see nothing in any statute or regulation strictly prohibiting ANDA holders from filing, say, a CBE labeling amendment proposing a labeling change based on their taking note of safety or efficacy issues in their ADE reporting or in, e.g., medical and scientific literature. The courts refused defendant’s argument that 21 CFR 3141.50 will not allow/prevent generic firms from making such changes, or that doing so might prompt FDA to withdraw approval of the ANDA involved.

Needless to say, most generic firms do not devote a great deal of time or resources to monitoring medical and scientific literature or performing detailed analysis of post-marketing Pharmacovigilance data. ADEs are reported and labeling is kept in conformance with the RLD.

What are the implications? Short term, there are probably a LOT of plaintiff’s attorneys looking for folks who have had a serious ADE with a generic drug. The Fifth Circuit decision noted that other federal courts have decided the other way, so those same attorneys are likely doing some serious forum selection. Also, a conflict of decisions in various federal courts usually is a set up for an eventual appeal to the Supreme Court. That is the same Supreme Court which last year in Wyeth v. Levine held that the federal regulatory scheme did not preempt state law failure-to-warn claims against the innovator company. Overall, it might be best for generic companies to at least do some planning as to how to deal with potential suits and a change in legal (but not regulatory) requirements. And perhaps there might be an enterprising company out there who will look over the available safety information for a product and go ahead and file a CBE changing their labeling absent a change to the RLD, and see how OGD responds. And one more question: if FDA accepts the change, and everybody jumps in, what are the implications for substitutability if all the labels are similar but not quite the same?

 

William (Bill) Stoltman, J.D., Camargo’s Director of Regulatory Compliance contributed this post. He can be contacted at bstoltman@camargopharma.com

Roche’s Actemra Approved For RA After Year’s Delay

Published February 11th, 2010 in 505(b)(2) Issues and News Commentary. 0 Comments

John Jenkins, Office of New Drugs Director, remarked on the low rate (30 percent) of firstcycle approvals for standard review applications (‘The Pink Sheet,’ Dec. 7, 2008). He attributed the low approval rate in part to the submission of applications that require amendments, often because the original submissions were incomplete or incorrect. A recent example of this problem is Roche’s Actemra.

On 8 Jan, FDA approved Roche’s novel interleukin-6 inhibitor Actemra, a
second-line therapy for rheumatoid arthritis. This approval came after a delay of more than a year following FDA’s issuance of a “complete response” letter. Among other things, the FDA required a Risk Evaluation and Mitigation Strategy (REMS), along with additional information. Whether the need for a REMS should have been anticipated is unclear. For more about REMS, see here. However, much of the additional information requested could reasonably be expected to have been included in the submission. For example, one of the requests was for an extensive safety update with data from preclinical and clinical studies regardless of indication, dosage form or dose level. The M4E Guidance clearly states that all relevant safety information (eg, data for other indications) should be included. This update also was to include case report forms and narrative summaries for patients who died during a study or who dropped out because of an adverse event, as well as narrative summaries for all serious adverse events. This statement probably refers to the clinical studies ongoing or completed after the submission because, for the studies included in the submission, all of this information should have been included in the clinical study reports (see Guideline for Industry: Structure and Content of Clinical Study Reports).

In addition, the letter requested that Roche fix some inconsistencies and formatting errors in its proposed labeling and to submit essential paperwork, such as debarment certifications and financial disclosures. A more careful review and check for completeness against the comprehensive table of contents for the submission would have been expected to catch these issues.

While a large company like Roche may be able to absorb the financial impact of a year’s delay in approval, smaller companies may not. Thus, it is important to make sure that submissions meet FDA requirements from the beginning. Companies should stay current with legal and regulatory requirements or hire a company with expertise to ensure a smooth pathway to approval. It is important for drug companies to ensure that they adhere to all relevant guidances for regulatory documents and submissions.

Camargo Researcher Lisa McChesney contributed this post.

News on the Biosimilar Front

Published February 8th, 2010 in News Commentary and Uncategorized. 0 Comments

Tuesday, February 2nd, Teva Pharmaceuticals announced that the FDA will review its new biologic license application (BLA) to sell a biotechnology medicine, Neutroval, to boost white blood cells, which is “similar” to Amgen Inc’s Neupogen®(filgrastim). The new product is already marketed as TevaGrastim in Europe. There is a regulatory pathway for approving generic versions of biotech drugs in place in Europe. The US still does not have this option; therefore Teva treated this application like a new BLA.

The route to biosimilar approvals or generics for biologics is tied up in the U.S. Congress as part of the healthcare reform legislation, with no light at the end of the tunnel.

Pediatric Assessments in Drug Development: timing in Europe vs. US

Published February 5th, 2010 in 505(b)(2) Issues, How to: and Uncategorized. 0 Comments

As we have noted in this blog on several occasions, under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all new drug applications for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in all relevant pediatric subpopulations unless this requirement in waived, deferred, or inapplicable. This includes products approved via the 505(b)(2) pathway. Given that a drug developer may want to obtain approval for adults first, it is common to request that the requirement for pediatric studies be deferred until after approval of the new drug application.

The European Medicines Agency (EMEA) implemented a new “Pediatric Regulation” in January of 2007. This regulation requires an initial submission of a pediatric investigation plan (PIP) by pharmaceutical companies upon completion of adult PK studies. A PIP is required for acceptance of any marketing authorization application. Unless a waiver or deferral has been granted, all products that have not been authorized in the European Union before 16 January 2007 must include the results of pediatric studies conducted based on a PIP.

The difference in the US and European approaches has the potential to put discussions with EU regulatory agencies about pediatric clinical studies ahead of discussion with the US. For companies pursuing simultaneous drug development in the US and EU, the submission of a PIP is likely to occur before discussions would ordinarily be held with the FDA. The FDA is aware of this issue and recommends that Sponsors begin discussions about an acceptable pediatric program with the FDA when they begin discussions with the EMEA. Even if a deferral is being requested for US pediatric studies, it is wise to seek the FDA’s input before finalizing a PIP. Communication is the key to make certain that any pediatric studies meet both agencies’ requirements.

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