New Rivers Pharmaceuticals (NRP) was the original sponsor of the lisdexamfetamine NDA. During the 2/23/2007 approval, FDA determined that the API was a new molecular entity (NME) and granted the product 5-year exclusivity, thus preventing the filing of an ANDA until 2/23/2012. [5-year exclusivity bars filing an ANDA until the exclusivity expires.] Actavis Elizabeth filed suit against FDA in February 2009, claiming that FDA erred in its determination that lisdexamfetamine is an NME and that FDA should accept its ANDA filing immediately.

This post examines why FDA decided that lisdexamfetamine was an NME and then why the NDA was a 505(b)(1) rather than a 505(b)(2).

First, what is a prodrug? It is not defined in FDA regulations. A working definition states that prodrugs are:

• pharmacological substances administered in an inactive (or significantly less active) form.
• metabolized in the body into active drugs (i.e., metabolites).

So, the question boiled down to what constitutes a new molecular entity.  This was the FDA’s statement to the Court:

“Lisdexamfetamine consists of dextroamphetamine bonded covalently to lysine through an amide bond. Lisdexamfetamine is a prodrug that is metabolically converted to produce dextroamphetamine, which is responsible for the drug’s activity. Under FDA’s regulation at 21 CFR § 314.108, a non-ester covalently bonded molecule is considered the active moiety of a drug and, if not previously approved, it will be considered a new chemical entity entitled to 5 years of exclusivity. A non-ester that requires metabolic conversion to produce a previously approved active moiety is considered a new chemical entity. Because lisdexamfetamine is a non-ester covalently bonded molecule, and because it requires metabolic conversion to produce dextroamphetamine, lisdexamfetamine is a new chemical entity and is thus entitled to 5 years of exclusivity.”

The Court agreed that FDA was within its rights to make this judgement.  So let’s turn to the question of (b)(1) or (b)(2).

NRP established that lisdexamfetamine is transformed by hydrolysis into amphetamine, an active that has already been approved in the U.S. (Figure 1).

Figure 1. Metabolic pathway of lisdexamfetamine:

A major driver behind what makes the NDA a (b)(1) or a (b)(2) is where and to what extent the prodrug converts into the active moiety. In this case, where does lisdexamfetamine transform into d-amphetamine?  The following table shows possible classifications of prodrugs:

In this table, prodrug of class I are most likely (b)(1)’s - the prodrug itself provides all (Type IA) or most (Type IB) of the efficacy and safety of the drug product.  To determine which class and type of a prodrug, pharmacokinetic studies are generally employed.

NRP conducted a pharmacokinetic study to examine the extent of hydrolysis (Figure 2). The results show that there are measurable amounts of lisdexamfetamine (denoted as lysine-amphetamine in the legend) in systemic circulation several hours after oral administration. Because the conversion is not rapid in the GI tract and occurs over time in the systemic circulation, the NDA is a  505(b)(1); both the prodrug and metabolite are involved in the drug activity.

Figure 2. Lisdexamfetamine PK

Those seeking further support that the pharmacokinetics of lisdexamfetamine are very different than d-amphetamine are encouraged to review the Clinical Pharmacology and Biopharmaceutics reviews. Specifically, you will see that the pharmacokinetics of lisdexamfetamine are not linear, as contrasted with the linearity of d-amphetamine.

Yet, the FDA approval documents contain numerous reviewer comments that d-amphetamine was a reference product.  Adderall and Dexidrine were used as pharmacokinetic comparators:

NRP seemed to believe that it could use literature for tox data.  But, based on the pk study in Figure 2, which showed appreciable circulating lisdexafetamine the FDA asked for tox in juvenile rats and dogs.   In the end, most of the safety and efficacy information for Vyvanse came from Sponsor studies, making this a 505(b)(1).

[Given my last name, I have interest in knowing why is  dexamphetamine spelled with 'ph' and  lisdexamfetamine spelled with an 'f' - anyone know? Ken Felps just doesn't look right]

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.

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.

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.

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.

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?

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.

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

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.